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Theses & Dissertations: Cancer Research

Theses/dissertations from 2024 2024.

Novel Spirocyclic Dimer (SpiD3) Displays Potent Preclinical Effects in Hematological Malignancies , Alexandria Eiken

Chemotherapy-Induced Modulation of Tumor Antigen Presentation , Alaina C. Larson

Understanding the role of MASTL in colon homeostasis and colitis-associated cancer development , Kristina Pravoverov

Dying Right: Supporting Anti-Cancer Therapy Through Immunogenic Cell Death , Elizabeth Schmitz

Therapeutic Effects of BET Protein Inhibition in B-cell Malignancies and Beyond , Audrey L. Smith

Targeting KSR1 to inhibit stemness and therapy resistance , Heidi M. Vieira

Identifying the Molecular Determinants of Lung Metastatic Adaptation in Prostate Cancer , Grace M. Waldron

Identification of Mitotic Phosphatases and Cyclin K as Novel Molecular Targets in Pancreatic Cancer , Yi Xiao

Theses/Dissertations from 2023 2023

Development of Combination Therapy Strategies to Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors , Nicholas Mullen

Overcoming Resistance Mechanisms to CDK4/6 Inhibitor Treatment Using CDK6-Selective PROTAC , Sarah Truong

Theses/Dissertations from 2022 2022

Omics Analysis in Cancer and Development , Emalie J. Clement

Investigating the Role of Splenic Macrophages in Pancreatic Cancer , Daisy V. Gonzalez

Polymeric Chloroquine in Metastatic Pancreatic Cancer Therapy , Rubayat Islam Khan

Evaluating Targets and Therapeutics for the Treatment of Pancreatic Cancer , Shelby M. Knoche

Characterization of 1,1-Diarylethylene FOXM1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells , Cassie Liu

Novel Mechanisms of Protein Kinase C α Regulation and Function , Xinyue Li

SOX2 Dosage Governs Tumor Cell Identity and Proliferation , Ethan P. Metz

Post-Transcriptional Control of the Epithelial-to-Mesenchymal Transition (EMT) in Ras-Driven Colorectal Cancers , Chaitra Rao

Use of Machine Learning Algorithms and Highly Multiplexed Immunohistochemistry to Perform In-Depth Characterization of Primary Pancreatic Tumors and Metastatic Sites , Krysten Vance

Characterization of Metastatic Cutaneous Squamous Cell Carcinoma in the Immunosuppressed Patient , Megan E. Wackel

Visceral adipose tissue remodeling in pancreatic ductal adenocarcinoma cachexia: the role of activin A signaling , Pauline Xu

Phos-Tag-Based Screens Identify Novel Therapeutic Targets in Ovarian Cancer and Pancreatic Cancer , Renya Zeng

Theses/Dissertations from 2021 2021

Functional Characterization of Cancer-Associated DNA Polymerase ε Variants , Stephanie R. Barbari

Pancreatic Cancer: Novel Therapy, Research Tools, and Educational Outreach , Ayrianne J. Crawford

Apixaban to Prevent Thrombosis in Adult Patients Treated With Asparaginase , Krishna Gundabolu

Molecular Investigation into the Biologic and Prognostic Elements of Peripheral T-cell Lymphoma with Regulators of Tumor Microenvironment Signaling Explored in Model Systems , Tyler Herek

Utilizing Proteolysis-Targeting Chimeras to Target the Transcriptional Cyclin-Dependent Kinases 9 and 12 , Hannah King

Insights into Cutaneous Squamous Cell Carcinoma Pathogenesis and Metastasis Using a Bedside-to-Bench Approach , Marissa Lobl

Development of a MUC16-Targeted Near-Infrared Antibody Probe for Fluorescence-Guided Surgery of Pancreatic Cancer , Madeline T. Olson

FGFR4 glycosylation and processing in cholangiocarcinoma promote cancer signaling , Andrew J. Phillips

Theses/Dissertations from 2020 2020

Cooperativity of CCNE1 and FOXM1 in High-Grade Serous Ovarian Cancer , Lucy Elge

Characterizing the critical role of metabolic and redox homeostasis in colorectal cancer , Danielle Frodyma

Genomic and Transcriptomic Alterations in Metabolic Regulators and Implications for Anti-tumoral Immune Response , Ryan J. King

Dimers of Isatin Derived Spirocyclic NF-κB Inhibitor Exhibit Potent Anticancer Activity by Inducing UPR Mediated Apoptosis , Smit Kour

From Development to Therapy: A Panoramic Approach to Further Our Understanding of Cancer , Brittany Poelaert

The Cellular Origin and Molecular Drivers of Claudin-Low Mammary Cancer , Patrick D. Raedler

Mitochondrial Metabolism as a Therapeutic Target for Pancreatic Cancer , Simon Shin

Development of Fluorescent Hyaluronic Acid Nanoparticles for Intraoperative Tumor Detection , Nicholas E. Wojtynek

Theses/Dissertations from 2019 2019

The role of E3 ubiquitin ligase FBXO9 in normal and malignant hematopoiesis , R. Willow Hynes-Smith

BRCA1 & CTDP1 BRCT Domainomics in the DNA Damage Response , Kimiko L. Krieger

Targeted Inhibition of Histone Deacetyltransferases for Pancreatic Cancer Therapy , Richard Laschanzky

Human Leukocyte Antigen (HLA) Class I Molecule Components and Amyloid Precursor-Like Protein 2 (APLP2): Roles in Pancreatic Cancer Cell Migration , Bailee Sliker

Theses/Dissertations from 2018 2018

FOXM1 Expression and Contribution to Genomic Instability and Chemoresistance in High-Grade Serous Ovarian Cancer , Carter J. Barger

Overcoming TCF4-Driven BCR Signaling in Diffuse Large B-Cell Lymphoma , Keenan Hartert

Functional Role of Protein Kinase C Alpha in Endometrial Carcinogenesis , Alice Hsu

Functional Signature Ontology-Based Identification and Validation of Novel Therapeutic Targets and Natural Products for the Treatment of Cancer , Beth Neilsen

Elucidating the Roles of Lunatic Fringe in Pancreatic Ductal Adenocarcinoma , Prathamesh Patil

Theses/Dissertations from 2017 2017

Metabolic Reprogramming of Pancreatic Ductal Adenocarcinoma Cells in Response to Chronic Low pH Stress , Jaime Abrego

Understanding the Relationship between TGF-Beta and IGF-1R Signaling in Colorectal Cancer , Katie L. Bailey

The Role of EHD2 in Triple-Negative Breast Cancer Tumorigenesis and Progression , Timothy A. Bielecki

Perturbing anti-apoptotic proteins to develop novel cancer therapies , Jacob Contreras

Role of Ezrin in Colorectal Cancer Cell Survival Regulation , Premila Leiphrakpam

Evaluation of Aminopyrazole Analogs as Cyclin-Dependent Kinase Inhibitors for Colorectal Cancer Therapy , Caroline Robb

Identifying the Role of Janus Kinase 1 in Mammary Gland Development and Breast Cancer , Barbara Swenson

DNMT3A Haploinsufficiency Provokes Hematologic Malignancy of B-Lymphoid, T-Lymphoid, and Myeloid Lineage in Mice , Garland Michael Upchurch

Theses/Dissertations from 2016 2016

EHD1 As a Positive Regulator of Macrophage Colony-Stimulating Factor-1 Receptor , Luke R. Cypher

Inflammation- and Cancer-Associated Neurolymphatic Remodeling and Cachexia in Pancreatic Ductal Adenocarcinoma , Darci M. Fink

Role of CBL-family Ubiquitin Ligases as Critical Negative Regulators of T Cell Activation and Functions , Benjamin Goetz

Exploration into the Functional Impact of MUC1 on the Formation and Regulation of Transcriptional Complexes Containing AP-1 and p53 , Ryan L. Hanson

DNA Polymerase Zeta-Dependent Mutagenesis: Molecular Specificity, Extent of Error-Prone Synthesis, and the Role of dNTP Pools , Olga V. Kochenova

Defining the Role of Phosphorylation and Dephosphorylation in the Regulation of Gap Junction Proteins , Hanjun Li

Molecular Mechanisms Regulating MYC and PGC1β Expression in Colon Cancer , Jamie L. McCall

Pancreatic Cancer Invasion of the Lymphatic Vasculature and Contributions of the Tumor Microenvironment: Roles for E-selectin and CXCR4 , Maria M. Steele

Altered Levels of SOX2, and Its Associated Protein Musashi2, Disrupt Critical Cell Functions in Cancer and Embryonic Stem Cells , Erin L. Wuebben

Theses/Dissertations from 2015 2015

Characterization and target identification of non-toxic IKKβ inhibitors for anticancer therapy , Elizabeth Blowers

Effectors of Ras and KSR1 dependent colon tumorigenesis , Binita Das

Characterization of cancer-associated DNA polymerase delta variants , Tony M. Mertz

A Role for EHD Family Endocytic Regulators in Endothelial Biology , Alexandra E. J. Moffitt

Biochemical pathways regulating mammary epithelial cell homeostasis and differentiation , Chandrani Mukhopadhyay

EPACs: epigenetic regulators that affect cell survival in cancer. , Catherine Murari

Role of the C-terminus of the Catalytic Subunit of Translesion Synthesis Polymerase ζ (Zeta) in UV-induced Mutagensis , Hollie M. Siebler

LGR5 Activates TGFbeta Signaling and Suppresses Metastasis in Colon Cancer , Xiaolin Zhou

LGR5 Activates TGFβ Signaling and Suppresses Metastasis in Colon Cancer , Xiaolin Zhou

Theses/Dissertations from 2014 2014

Genetic dissection of the role of CBL-family ubiquitin ligases and their associated adapters in epidermal growth factor receptor endocytosis , Gulzar Ahmad

Strategies for the identification of chemical probes to study signaling pathways , Jamie Leigh Arnst

Defining the mechanism of signaling through the C-terminus of MUC1 , Roger B. Brown

Targeting telomerase in human pancreatic cancer cells , Katrina Burchett

The identification of KSR1-like molecules in ras-addicted colorectal cancer cells , Drew Gehring

Mechanisms of regulation of AID APOBEC deaminases activity and protection of the genome from promiscuous deamination , Artem Georgievich Lada

Characterization of the DNA-biding properties of human telomeric proteins , Amanda Lakamp-Hawley

Studies on MUC1, p120-catenin, Kaiso: coordinate role of mucins, cell adhesion molecules and cell cycle players in pancreatic cancer , Xiang Liu

Epac interaction with the TGFbeta PKA pathway to regulate cell survival in colon cancer , Meghan Lynn Mendick

Theses/Dissertations from 2013 2013

Deconvolution of the phosphorylation patterns of replication protein A by the DNA damage response to breaks , Kerry D. Brader

Modeling malignant breast cancer occurrence and survival in black and white women , Michael Gleason

The role of dna methyltransferases in myc-induced lymphomagenesis , Ryan A. Hlady

Design and development of inhibitors of CBL (TKB)-protein interactions , Eric A. Kumar

Pancreatic cancer-associated miRNAs : expression, regulation and function , Ashley M. Mohr

Mechanistic studies of mitochondrial outer membrane permeabilization (MOMP) , Xiaming Pang

Novel roles for JAK2/STAT5 signaling in mammary gland development, cancer, and immune dysregulation , Jeffrey Wayne Schmidt

Optimization of therapeutics against lethal pancreatic cancer , Joshua J. Souchek

Theses/Dissertations from 2012 2012

Immune-based novel diagnostic mechanisms for pancreatic cancer , Michael J. Baine

Sox2 associated proteins are essential for cell fate , Jesse Lee Cox

KSR2 regulates cellular proliferation, transformation, and metabolism , Mario R. Fernandez

Discovery of a novel signaling cross-talk between TPX2 and the aurora kinases during mitosis , Jyoti Iyer

Regulation of metabolism by KSR proteins , Paula Jean Klutho

The role of ERK 1/2 signaling in the dna damage-induced G2 , Ryan Kolb

Regulation of the Bcl-2 family network during apoptosis induced by different stimuli , Hernando Lopez

Studies on the role of cullin3 in mitosis , Saili Moghe

Characteristics of amyloid precursor-like protein 2 (APLP2) in pancreatic cancer and Ewing's sarcoma , Haley Louise Capek Peters

Structural and biophysical analysis of a human inosine triphosphate pyrophosphatase polymorphism , Peter David Simone

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Breast Cancer—Epidemiology, Risk Factors, Classification, Prognostic Markers, and Current Treatment Strategies—An Updated Review

Sergiusz Łukasiewicz.

1 Department of Surgical Oncology, Center of Oncology of the Lublin Region St. Jana z Dukli, 20-091 Lublin, Poland; lp.lzoc@zciweisakulS (S.Ł.); [email protected] (A.S.)

Marcin Czeczelewski

2 Department of Forensic Medicine, Medical University of Lublin, 20-090 Lublin, Poland; [email protected] (M.C.); lp.teno@amrofa (A.F.)

Alicja Forma

3 Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland; [email protected]

Robert Sitarz

Andrzej stanisławek.

4 Department of Oncology, Chair of Oncology and Environmental Health, Medical University of Lublin, 20-081 Lublin, Poland

Simple Summary

Breast cancer is the most common cancer among women. It is estimated that 2.3 million new cases of BC are diagnosed globally each year. Based on mRNA gene expression levels, BC can be divided into molecular subtypes that provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. This review addresses the overview on the BC epidemiology, risk factors, classification with an emphasis on molecular types, prognostic biomarkers, as well as possible treatment modalities.

Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.

1. Introduction

Being characterized by six major hallmarks, carcinogenesis might occur in every cell, tissue, and organ, leading to the pathological alternations that result in a vast number of cancers. The major mechanisms that enable its progression include evasion of apoptosis, limitless capacity to divide, enhanced angiogenesis, resistance to anti-growth signals and induction of own growth signals, as well as the capacity to metastasize [ 1 ]. Carcinogenesis is a multifactorial process that is primarily stimulated by both—genetic predispositions and environmental causes. The number of cancer-related deaths is disturbingly increasing every year ranking them as one of the major causes of death worldwide. Even though a significant number of cancers do not always need to result in death, they significantly lower the quality of life and require larger costs in general.

Breast cancer is currently one of the most prevalently diagnosed cancers and the 5th cause of cancer-related deaths with an estimated number of 2.3 million new cases worldwide according to the GLOBOCAN 2020 data [ 2 ]. Deaths due to breast cancer are more prevalently reported (an incidence rate approximately 88% higher) in transitioning countries (Melanesia, Western Africa, Micronesia/Polynesia, and the Caribbean) compared to the transitioned ones (Australia/New Zealand, Western Europe, Northern America, and Northern Europe). Several procedures such as preventive behaviors in general as well as screening programs are crucial regarding a possible minimization of breast cancer incidence rate and the implementation of early treatment. Currently, it is the Breast Health Global Initiative (BHGI) that is responsible for the preparation of proper guidelines and the approaches to provide the most sufficient breast cancer control worldwide [ 3 ]. In this review article, we have focused on the female breast cancer specifically since as abovementioned, it currently constitutes the most prevalent cancer amongst females.

2. Breast Cancer Epidemiology

According to the WHO, malignant neoplasms are the greatest worldwide burden for women, estimated at 107.8 million Disability-Adjusted Life Years (DALYs), of which 19.6 million DALYs are due to breast cancer. [ 4 ]. Breast cancer is the most frequently diagnosed cancer in women worldwide with 2.26 million [95% UI, 2.24–2.79 million] new cases in 2020 [ 5 ]. In the United States, breast cancer alone is expected to account for 29% of all new cancers in women [ 6 ]. The 2018 GLOBOCAN data shows that age-standardized incidence rates (ASIR) of breast cancer are strongly and positively associated with the Human Development Index (HDI) [ 7 ]. According to 2020 data, the ASIR was the highest in very high HDI countries (75.6 per 100,000) while it was more than 200% lower in medium and low HDI countries (27.8 per 100,000 and 36.1 per 100,000 respectively) [ 5 ].

Besides being the most common, breast cancer is also the leading cause of cancer death in women worldwide. Globally, breast cancer was responsible for 684,996 deaths [95% UI, 675,493–694,633] at an age-adjusted rate of 13.6/100,000 [ 5 ]. Although incidence rates were the highest in developed regions, the countries in Asia and Africa shared 63% of total deaths in 2020 [ 5 ]. Most women who develop breast cancer in a high-income country will survive; the opposite is true for women in most low-income and many middle-income countries [ 8 ].

In 2020 breast cancer mortality-to-incidence ratio (MIR) as a representative indicator of 5-year survival rates [ 9 ] was 0.30 globally [ 5 ]. Taking into consideration the clinical extent of breast cancer, in locations with developed health care (Hong-Kong, Singapore, Turkey) the 5-year survival was 89.6% for localized and 75.4% for regional cancer. In less developed countries (Costa Rica, India, Philippines, Saudi Arabia, Thailand) the survival rates were 76.3% and 47.4% for localized and regional breast cancer respectively [ 10 ].

Breast cancer incidence and death rates have increased over the last three decades. Between 1990 and 2016 breast cancer incidence has more than doubled in 60/102 countries (e.g., Afghanistan, Philippines, Brazil, Argentina), whereas deaths have doubled in 43/102 countries (e.g., Yemen, Paraguay, Libya, Saudi Arabia) [ 11 ]. Current projections indicate that by 2030 the worldwide number of new cases diagnosed reach 2.7 million annually, while the number of deaths 0.87 million [ 12 ]. In low- and medium-income countries, the breast cancer incidence is expected to increase further due to the westernization of lifestyles (e.g., delayed pregnancies, reduced breastfeeding, low age at menarche, lack of physical activity, and poor diet), better cancer registration, and cancer detection [ 13 ].

3. Risk Factors of Breast Cancer

The number of risk factors of breast cancer is significant and includes both modifiable factors and non-modifiable factors ( Table 1 ).

Modifiable and non-modifiable risk factors of breast cancer.

3.1. Non-Modifiable Factors

3.1.1. female sex.

Female sex constitutes one of the major factors associated with an increased risk of breast cancer primarily because of the enhanced hormonal stimulation. Unlike men who present insignificant estrogen levels, women have breast cells which are very vulnerable to hormones (estrogen and progesterone in particular) as well as any disruptions in their balance. Circulating estrogens and androgens are positively associated with an increased risk of breast cancer [ 14 ]. The alternations within the physiological levels of the endogenous levels of sex hormones result in a higher risk of breast cancer in the case of premenopausal and postmenopausal women; these observations were also supported by the Endogenous Hormones and Breast Cancer Collaborative Group [ 15 , 16 , 17 ].

Less than 1% of all breast cancers occur in men. However, breast cancer in men is a rare disease that’s at the time of diagnosis tends to be more advanced than in women. The average age of men at the diagnosis is about 67. The important factors increase a man’s risk of breast cancer are: older age, BRCA2/BRCA1 mutations, increased estrogen levels, Klinefelter syndrome, family history of breast cancer, and radiation exposure [ 18 ].

3.1.2. Older Age

Currently, about 80% of patients with breast cancer are individuals aged >50 while at the same time more than 40% are those more than 65 years old [ 19 , 20 , 21 ]. The risk of developing breast cancer increases as follows—the 1.5% risk at age 40, 3% at age 50, and more than 4% at age 70 [ 22 ]. Interestingly, a relationship between a particular molecular subtype of cancer and a patient’s age was observed –aggressive resistant triple-negative breast cancer subtype is most commonly diagnosed in groups under 40 age, while in patients >70, it is luminal A subtype [ 21 ]. Generally, the occurrence of cancer in older age is not only limited to breast cancer; the accumulation of a vast number of cellular alternations and exposition to potential carcinogens results in an increase of carcinogenesis with time.

3.1.3. Family History

A family history of breast cancer constitutes a major factor significantly associated with an increased risk of breast cancer. Approximately 13–19% of patients diagnosed with breast cancer report a first-degree relative affected by the same condition [ 23 ]. Besides, the risk of breast cancer significantly increases with an increasing number of first-degree relatives affected; the risk might be even higher when the affected relatives are under 50 years old [ 24 , 25 , 26 ]. The incidence rate of breast cancer is significantly higher in all of the patients with a family history despite the age. This association is driven by epigenetic changes as well as environmental factors acting as potential triggers [ 27 ]. A family history of ovarian cancer—especially those characterized by BRCA1 and BRCA2 mutations—might also induce a greater risk of breast cancer [ 28 ].

3.1.4. Genetic Mutations

Several genetic mutations were reported to be highly associated with an increased risk of breast cancer. Two major genes characterized by a high penetrance are BRCA1 (located on chromosome 17) and BRCA2 (located on chromosome 13). They are primarily linked to the increased risk of breast carcinogenesis [ 29 ]. The mutations within the above-mentioned genes are mainly inherited in an autosomal dominant manner, however, sporadic mutations are also commonly reported. Other highly penetrant breast cancer genes include TP53 , CDH1 , PTEN , and STK11 [ 30 , 31 , 32 , 33 , 34 ]. Except for the increased risk of breast cancer, carriers of such mutations are more susceptible to ovarian cancer as well. A significant number of DNA repair genes that can interact with BRCA genes including ATM , PALB2 , BRIP1 , or CHEK2 , were reported to be involved in the induction of breast carcinogenesis; those are however characterized by a lower penetrance (moderate degree) compared to BRCA1 or BRCA2 ( Table 2 ) [ 29 , 35 , 36 , 37 , 38 ]. According to quite recent Polish research, mutations within the XRCC2 gene could also be potentially associated with an increased risk of breast cancer [ 39 ].

Major genes associated with an increased risk of breast cancer occurrence.

3.1.5. Race/Ethnicity

Disparities regarding race and ethnicity remain widely observed among individuals affected by breast cancer; the mechanisms associated with this phenomenon are not yet understood. Generally, the breast cancer incidence rate remains the highest among white non-Hispanic women [ 51 , 52 ]. Contrarily, the mortality rate due to this malignancy is significantly higher among black women; this group is also characterized by the lowest survival rates [ 53 ].

3.1.6. Reproductive History

Numerous studies confirmed a strict relationship between exposure to endogenous hormones—estrogen and progesterone in particular—and excessive risk of breast cancer in females. Therefore, the occurrence of specific events such as pregnancy, breastfeeding, first menstruation, and menopause along with their duration and the concomitant hormonal imbalance, are crucial in terms of a potential induction of the carcinogenic events in the breast microenvironment. The first full-term pregnancy at an early age (especially in the early twenties) along with a subsequently increasing number of births are associated with a reduced risk of breast cancer [ 54 , 55 ]. Besides, the pregnancy itself provides protective effects against potential cancer. However, protection was observed at approximately the 34th pregnancy week and was not confirmed for the pregnancies lasting for 33 weeks or less [ 56 ]. Women with a history of preeclampsia during pregnancy or children born to a preeclamptic pregnancy are at lower risk of developing breast cancer [ 57 ]. No association between the increased breast cancer risk and abortion was stated so far [ 58 ].

The dysregulated hormone levels during preeclampsia including increased progesterone and reduced estrogen levels along with insulin, cortisol, insulin-like growth factor-1, androgens, human chorionic gonadotropin, corticotropin-releasing factor, and IGF-1 binding protein deviating from the physiological ranges, show a protective effect preventing from breast carcinogenesis. The longer duration of the breastfeeding period also reduces the risk of both the ER/PR-positive and -negative cancers [ 59 ]. Early age at menarche is another risk factor of breast cancer; it is possibly also associated with a tumor grade and lymph node involvement [ 60 ]. Besides, the earlier age of the first menstruation could result in an overall poorer prognosis. Contrarily, early menopause despite whether natural or surgical, lowers the breast cancer risk [ 61 ].

3.1.7. Density of Breast Tissue

The density of breast tissue remains inconsistent throughout the lifetime; however, several categories including low-density, high-density, and fatty breasts have been established in clinical practice. Greater density of breasts is observed in females of younger age and lower BMI, who are pregnant or during the breastfeeding period, as well as during the intake of hormonal replacement therapy [ 62 ]. Generally, the greater breast tissue density correlates with the greater breast cancer risk; this trend is observed both in premenopausal and postmenopausal females [ 63 ]. It was proposed that screening of breast tissue density could be a promising, non-invasive, and quick method enabling rational surveillance of females at increased risk of cancer [ 64 ].

3.1.8. History of Breast Cancer and Benign Breast Diseases

Personal history of breast cancer is associated with a greater risk of a renewed cancerous lesions within the breasts [ 65 ]. Besides, a history of any other non-cancerous alternations in breasts such as atypical hyperplasia, carcinoma in situ, or many other proliferative or non-proliferative lesions, also increases the risk significantly [ 66 , 67 , 68 ]. The histologic classification of benign lesions and a family history of breast cancer are two factors that are strongly associated with breast cancer risk [ 66 ].

3.1.9. Previous Radiation Therapy

The risk of secondary malignancies after radiotherapy treatment remains an individual matter that depends on the patient’s characteristics, even though it is a quite frequent phenomenon that arises much clinical concern. Cancer induced by radiation therapy is strictly associated with an individual’s age; patients who receive radiation therapy before the age of 30, are at a greater risk of breast cancer [ 69 ]. The selection of proper radiotherapy technique is crucial in terms of secondary cancer risk—for instance, tangential field IMRT (2F-IMRT) is associated with a significantly lower risk compared to multiple-field IMRT (6F-IMRT) or double partial arcs (VMAT) [ 70 ]. Besides, the family history of breast cancer in patients who receive radiotherapy additionally enhances the risk of cancer occurrence [ 71 ]. However, Bartelink et al. showed that additional radiation (16 Gy) to the tumor bed combined with standard radiotherapy might decrease the risk of local recurrence [ 72 ].

3.2. Modifiable Factors

3.2.1. chosen drugs.

Data from some research indicates that the intake of diethylstilbestrol during pregnancy might be associated with a greater risk of breast cancer in children; this, however, remains inconsistent between studies and requires further evaluation [ 73 , 74 ]. The intake of diethylstilbestrol during pregnancy is associated with an increased risk of breast cancer not only in mothers but also in the offspring [ 75 ]. This relationship is observed despite the expression of neither estrogen nor progesterone receptors and might be associated with every breast cancer histological type. The risk increases with age; women at age of ≥40 years are nearly 1.9 times more susceptible compared to women under 40. Moreover, breast cancer risk increases with greater diethylstilbestrol doses [ 76 ]. Numerous researches indicate that females who use hormonal replacement therapy (HRT) especially longer than 5 or 7 years are also at increased risk of breast cancer [ 77 , 78 ]. Several studies indicated that the intake of chosen antidepressants, mainly paroxetine, tricyclic antidepressants, and selective serotonin reuptake inhibitors might be associated with a greater risk of breast cancer [ 79 , 80 ]. Lawlor et al. showed that similar risk might be achieved due to the prolonged intake of antibiotics; Friedman et al. observed that breast risk is mostly elevated while using tetracyclines [ 81 , 82 ]. Attempts were made to investigate a potential relationship between hypertensive medications, non-steroidal anti-inflammatory drugs, as well as statins, and an elevated risk of breast cancer, however, this data remains highly inconsistent [ 83 , 84 , 85 ].

3.2.2. Physical Activity

Even though the mechanism remains yet undeciphered, regular physical activity is considered to be a protective factor of breast cancer incidence [ 86 , 87 ]. Chen et al. observed that amongst females with a family history of breast cancer, physical activity was associated with a reduced risk of cancer but limited only to the postmenopausal period [ 88 ]. However, physical activity is beneficial not only in females with a family history of breast cancer but also in those without such a history. Contrarily to the above-mentioned study, Thune et al. pointed out more pronounced effects in premenopausal females [ 89 ]. There are several hypotheses aiming to explain the protective role of physical activity in terms of breast cancer incidence; physical activity might prevent cancer by reducing the exposure to the endogenous sex hormones, altering immune system responses or insulin-like growth factor-1 levels [ 88 , 90 , 91 ].

3.2.3. Body Mass Index

According to epidemiological evidence, obesity is associated with a greater probability of breast cancer. This association is mostly intensified in obese post-menopausal females who tend to develop estrogen-receptor-positive breast cancer. Yet, independently to menopausal status, obese women achieve poorer clinical outcomes [ 92 ]. Wang et al. showed that females above 50 years old with greater Body Mass Index (BMI) are at a greater risk of cancer compared to those with low BMI [ 93 ]. Besides, the researchers observed that greater BMI is associated with more aggressive biological features of tumor including a higher percentage of lymph node metastasis and greater size. Obesity might be a reason for greater mortality rates and a higher probability of cancer relapse, especially in premenopausal women [ 94 ]. Increased body fat might enhance the inflammatory state and affects the levels of circulating hormones facilitating pro-carcinogenic events [ 95 ]. Thus, poorer clinical outcomes are primarily observed in females with BMI ≥ 25 kg/m 2 [ 96 ]. Interestingly, postmenopausal women tend to present poorer clinical outcomes despite proper BMI values but namely due to excessive fat volume [ 97 ]. Greater breast cancer risk with regards to BMI also correlates with the concomitant family history of breast cancer [ 98 ].

3.2.4. Alcohol Intake

Numerous evidences confirm that excessive alcohol consumption is a factor that might enhance the risk of malignancies within the gastrointestinal tract; however, it was proved that it is also linked to the risk of breast cancer. Namely, it is not alcohol type but rather the content of alcoholic beverages that mostly affect the risk of cancer. The explanation for this association is the increased levels of estrogens induced by the alcohol intake and thus hormonal imbalance affecting the risk of carcinogenesis within the female organs [ 99 , 100 ]. Besides, alcohol intake often results in excessive fat gain with higher BMI levels, which additionally increases the risk. Other hypotheses include direct and indirect carcinogenic effects of alcohol metabolites and alcohol-related impaired nutrient intake [ 101 ]. Alcohol consumption was observed to increase the risk of estrogen-positive breast cancers in particular [ 102 ]. Consumed before the first pregnancy, it significantly contributes to the induction of morphological alterations of breast tissue, predisposing it to further carcinogenic events [ 103 ].

3.2.5. Smoking

Carcinogens found in tobacco are transported to the breast tissue increasing the plausibility of mutations within oncogenes and suppressor genes ( p53 in particular). Thus, not only active but also passive smoking significantly contributes to the induction of pro-carcinogenic events [ 104 ]. Besides, longer smoking history, as well as smoking before the first full-term pregnancy, are additional risk factors that are additionally pronounced in females with a family history of breast cancer [ 105 , 106 , 107 , 108 ].

3.2.6. Insufficient Vitamin Supplementation

Vitamins exert anticancer properties, which might potentially benefit in the prevention of several malignancies including breast cancer, however, the mechanism is not yet fully understood. Attempts are continually made to analyze the effects of vitamin intake (vitamin C, vitamin E, B-group vitamins, folic acid, multivitamin) on the risk of breast cancer, nevertheless, the data remains inconsistent and not sufficient to compare the results and draw credible data [ 108 ]. In terms of breast cancer, most studies are currently focused on vitamin D supplementation confirming its potentially protective effects [ 109 , 110 , 111 ]. High serum 25-hydroxyvitamin D levels are associated with a lower incidence rate of breast cancer in premenopausal and postmenopausal women [ 110 , 112 ]. Intensified expression of vitamin D receptors was shown to be associated with lower mortality rates due to breast cancer [ 113 ]. Even so, further evaluation is required since data remains inconsistent in this matter [ 108 , 114 ].

3.2.7. Exposure to Artificial Light

Artificial light at night (ALAN) has been recently linked to increased breast cancer risk. The probable causation might be a disrupted melatonin rhythm and subsequent epigenetic alterations [ 115 ]. According to the studies conducted so far, increased exposure to ALAN is associated with a significantly greater risk of breast cancer compared to individuals with lowered ALAN exposure [ 116 ]. Nonetheless, data regarding the excessive usage of LED electronic devices and increased risk of breast cancer is insufficient and requires further evaluation as some results are contradictory [ 116 ].

3.2.8. Intake of Processed Food/Diet

According to the World Health Organization (WHO), highly processed meat was classified as a Group 1 carcinogen that might increase the risk of not only gastrointestinal malignancies but also breast cancer. Similar observations were made in terms of an excessive intake of saturated fats [ 117 ]. Ultra-processed food is rich in sodium, fat, and sugar which subsequently predisposes to obesity recognized as another factor of breast cancer risk [ 118 ]. It was observed that a 10% increase of ultra-processed food in the diet is associated with an 11% greater risk of breast cancer [ 118 ]. Contrarily, a diet high in vegetables, fruits, legumes, whole grains, and lean protein is associated with a lowered risk of breast cancer [ 119 ]. Generally, a diet that includes food containing high amounts of n-3 PUFA, vitamin D, fiber, folate, and phytoestrogen might be beneficial as a prevention of breast cancer [ 120 ]. Besides, lower intake of n-6 PUFA and saturated fat is recommended. Several in vitro and in vivo studies also suggest that specific compounds found in green tea might present anti-cancer effects which has also been studied regarding breast cancer [ 121 ]. Similar properties were observed in case of turmeric-derived curcuminoids as well as sulforaphane (SFN) [ 122 , 123 ].

3.2.9. Exposure to Chemical

Chronic exposure to chemicals can promote breast carcinogenesis by affecting the tumor microenvironment subsequently inducing epigenetic alterations along with the induction of pro-carcinogenic events [ 124 ]. Females chronically exposed to chemicals present significantly greater plausibility of breast cancer which is further positively associated with the duration of the exposure [ 125 ]. The number of chemicals proposed to induce breast carcinogenesis is significant; so far, dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyl (PCB) are mostly investigated in terms of breast cancer since early exposure to those chemicals disrupts the development of mammary glands [ 126 , 127 ]. A potential relationship was also observed in the case of increased exposure to polycyclic aromatic hydrocarbons (PAH), synthetic fibers, organic solvents, oil mist, and insecticides [ 128 ].

3.2.10. Other Drugs

Other drugs that might constitute potential risk factors for breast cancer include antibiotics, antidepressants, statins, antihypertensive medications (e.g., calcium channel blockers, angiotensin II-converting enzyme inhibitors), as well as NSAIDs (including aspirin, ibuprofen) [ 129 , 130 , 131 , 132 , 133 ].

4. Breast Cancer Classification

4.1. histological classification.

Invasive breast cancers (IBC) comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. The World Health Organization (WHO) distinguish at least 18 different histological breast cancer types [ 134 ].

Invasive breast cancer of no special type (NST), formerly known as invasive ductal carcinoma is the most frequent subgroup (40–80%) [ 135 ]. This type is diagnosed by default as a tumor that fails to be classified into one of the histological special types [ 134 ]. About 25% of invasive breast cancers present distinctive growth patterns and cytological features, hence, they are recognized as specific subtypes (e.g., invasive lobular carcinoma, tubular, mucinous A, mucinous B, neuroendocrine) [ 136 ].

Molecular classification independently from histological subtypes, invasive breast cancer can be divided into molecular subtypes based on mRNA gene expression levels. In 2000, Perou et al. on a sample of 38 breast cancers identified 4 molecular subtypes from microarray gene expression data: Luminal, HER2-enriched, Basal-like, and Normal Breast-like [ 137 ]. Further studies allowed to divide the Luminal group into two subgroups (Luminal A and B) [ 138 , 139 ]. The normal breast-like subtype has subsequently been omitted, as it is thought to represent sample contamination by normal mammary glands. In the Cancer Genome Atlas Project (TCGA) over 300 primary tumors were thoroughly profiled (at DNA, RNA, and protein levels) and combined in biological homogenous groups of tumors. The consensus clustering confirmed the distinction of four main breast cancer intrinsic subtypes based on mRNA gene expression levels only (Luminal A, Luminal B, HER2-enriched, and basal-like) [ 140 ]. Additionally, the 5th intrinsic subtype—claudin-low breast cancer was discovered in 2007 in an integrated analysis of human and murine mammary tumors [ 141 ].

In 2009, Parker et al. developed a 50-gene signature for subtype assignment, known as PAM50, that could reliably classify particular breast cancer into the main intrinsic subtypes with 93% accuracy [ 142 ]. PAM50 is now clinically implemented worldwide using the NanoString nCounter ® , which is the basis for the Prosigna ® test. The Prosigna ® combines the PAM50 assay as well as clinical information to assess the risk of distant relapse estimation in postmenopausal women with hormone receptor-positive, node-negative, or node-positive early-stage breast cancer patients, and is a daily-used tool assessing the indication of adjuvant chemotherapy [ 143 , 144 , 145 ].

4.2. Luminal Breast Cancer

Luminal breast cancers are ER-positive tumors that comprise almost 70% of all cases of breast cancers in Western populations [ 146 ]. Most commonly Luminal-like cancers present as IBC of no special subtype, but they may infrequently differentiate into invasive lobular, tubular, invasive cribriform, mucinous, and invasive micropapillary carcinomas [ 147 , 148 ]. Two main biological processes: proliferation-related pathways and luminal-regulated pathways distinguish Luminal-like tumors into Luminal A and B subtypes with different clinical outcomes.

Luminal A tumors are characterized by presence of estrogen-receptor (ER) and/or progesterone-receptor (PR) and absence of HER2. In this subtype the ER transcription factors activate genes, the expression of which is characteristic for luminal epithelium lining the mammary ducts [ 149 , 150 ]. It also presents a low expression of genes related to cell proliferation [ 151 ]. Clinically they are low-grade, slow-growing, and tend to have the best prognosis.

In contrast to subtype A, Luminal B tumors are higher grade and has worse prognosis. They are ER positive and may be PR negative and/or HER2 positive. Additionally, it has high expression of proliferation-related genes (e.g., MKI67 and AURKA) [ 152 , 153 , 154 ]. This subtype has lower expression of genes or proteins typical for luminal epithelium such as the PR [ 150 , 155 ] and FOXA1 [ 146 , 156 ], but not the ER [ 157 ]. ER is similarly expressed in both A and B subtypes and is used to distinguish luminal from non-luminal disease.

4.3. HER2-Enriched Breast Cancer

The HER2-enriched group makes up 10–15% of breast cancers. It is characterized by the high expression of the HER2 with the absence of ER and PR. This subtype mainly expresses proliferation—related genes and proteins (e.g., ERBB2/HER2 and GRB7), rather than luminal and basal gene and protein clusters [ 154 , 156 , 157 ]. Additionally, in the HER2-enriched subtype there is evidence of mutagenesis mediated by APOBEC3B. APOBEC3B is a subclass of APOBEC cytidine deaminases, which induce cytosine mutation biases and is a source of mutation clusters [ 158 , 159 , 160 ].

HER2-enriched cancers grow faster than luminal cancers and used to have the worst prognosis of subtypes before the introduction of HER2-targeted therapies. Importantly, the HER2-enriched subtype is not synonymous with clinically HER2-positive breast cancer because many ER-positive/HER2-positive tumors qualify for the luminal B group. Moreover, about 30% of HER2-enriched tumors are classified as clinically HER2-negative based on immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) methods [ 161 ].

4.4. Basal-Like/Triple-Negative Breast Cancer

The Triple-Negative Breast Cancer (TNBC) is a heterogeneous collection of breast cancers characterized as ER-negative, PR-negative, and HER2-negative. They constitute about 20% of all breast cancers. TNBC is more common among women younger than 40 years of age and African-American women [ 161 ]. The majority (approximately 80%) of breast cancers arising in BRCA1 germline mutation are TNBC, while 11–16% of all TNBC harbor BRCA1 or BRCA2 germline mutations. TNBC tends to be biologically aggressive and is often associated with a worse prognosis [ 162 ]. The most common histology seen in TNBC is infiltrating ductal carcinoma, but it may also present as medullary-like cancers with a prominent lymphocytic infiltrate; metaplastic cancers, which may show squamous or spindle cell differentiation; and rare special type cancers like adenoid cystic carcinoma (AdCC) [ 163 , 164 , 165 ].

The terms basal-like and TNBC have been used interchangeably; however, not all TNBC are of the basal type. On gene expression profiling, TNBCs can be subdivided into six subtypes: basal-like (BL1 and BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR), as well as an unspecified group (UNS) [ 166 , 167 ]. However, the clinical relevance of the subtyping still unclear, and more research is needed to clarify its impact on TNBC treatment decisions [ 168 ].

4.5. Claudin-Low Breast Cancer

Claudin-low (CL) breast cancers are poor prognosis tumors being mostly ER-negative, PR-negative, and HER2-negative. CL tumors account for 7–14% of all invasive breast cancers [ 147 ]. No differences in survival rates were observed between claudin-low tumors and other poor-prognosis subtypes (Luminal B, HER2-enriched, and Basal-like). CL subtype is characterized by the low expression of genes involved in cell-cell adhesion, including claudins 3, 4, and 7, occludin, and E-cadherin. Besides, these tumors show high expression of epithelial-mesenchymal transition (EMT) genes and stem cell-like gene expression patterns [ 169 , 170 ]. Moreover, CL tumors have marked immune and stromal cell infiltration [ 171 ]. Due to their less differentiated state and a preventive effect of the EMT-related transcription factor, ZEB1 CL tumors are often genomically stable [ 172 , 173 ].

4.6. Surrogate Markers Classification

In clinical practice, the key question is the discrimination between patients who will or will not benefit from particular therapies. By using molecular assays, more patients can be spared adjuvant chemotherapy, but these tests are associated with significant costs. Therefore, surrogate subgroups based on pathological morphology and widely available immunohistochemical (IHC) markers are used as a tool for risk stratification and guidance of adjuvant therapy [ 174 ]. A combination of the routine pathological markers ER, PR, and HER2 is used to classify tumors into intrinsic subtypes [ 175 ]. Semiquantitative evaluation of Ki-67 and PR is helpful for further typing of the Luminal subtype [ 176 , 177 ]. Moreover, evaluation of cytokeratin 5/6 and epidermal growth factor receptor is utilized to identify the Basal-like breast cancer among the TNBC [ 178 ].

In St. Gallen’s 2013 guidelines the IHC-based surrogate subtype classification was recommended for clinical decision making [ 179 ]. However, these IHC-based markers are only a surrogate and cannot establish the intrinsic subtype of any given cancer, with discordance rates between IHC-based markers and gene-based assays as high as 30% [ 180 ].

4.7. American Joint Committee on Cancer Classification

The baseline tool to estimate the likely prognosis of patients with breast cancer is the AJCC staging system that includes grading, immunohistochemistry biomarkers, and anatomical advancement of the disease. Since its inception in 1977, the American Joint Committee on Cancer (AJCC) has published an internationally accepted staging system based on anatomic findings: tumor size (T), nodal status (N), and metastases (M). However, gene expression profiling has identified several molecular subtypes of breast cancer [ 181 ]. The eighth edition of the AJCC staging manual (2018), outlines a new prognostic staging system for breast cancer that, in addition to anatomical features, acknowledges biological factors [ 182 ]. These factors—ER, PR, HER2, grade, and multigene assays—are recommended in practice to define prognosis [ 183 , 184 ].

The most widely used histologic grading system of breast cancer is the Elston-Ellis modification [ 185 ] of Scarff-Bloom-Richardson grading system [ 186 ], also known as the Nottingham grading system. The grade of a tumor is determined by assessing morphologic features: (a) formation of tubules, (b) mitotic count, (c) variability, and the size and shape of cellular nuclei. A score between 1 (most favorable) and 3 (least favorable) is assigned for each feature. Grade 1 corresponds to combined scores between 3 and 5, grade 2 corresponds to a combined score of 6 or 7, and grade 3 corresponds to a combined score of 8 or 9.

In addition to grading and biomarkers, the commercially available multigene assays provide additional prognostic information suitable for incorporation in the AJCC 8th edition. The 21-gene assay Oncotype DX ® assessed by reverse transcription-polymerase chain reaction (RT-PCR) was the only assay sufficiently evaluated and included in the staging system. This assay is valuable in the staging of patients with hormone receptor-positive, HER2-negative, node-negative tumors that are <5 cm. Patients with results of the assay (Recurrence Score) less than 11 had excellent disease-free survival at 6.9 years of 98.6% with endocrine therapy alone [ 187 ]. Hence, adjuvant systemic chemotherapy can be safely omitted in patients with a low-risk multigene assay [ 188 ].

The AJCC staging manual includes a pathological and a clinical-stage group. The clinical prognostic stage group should be utilized in all patients on initial evaluation before any systemic therapy. Clinical staging uses the TNM anatomical information, grading, and expression of these three biomarkers. When patients undergo surgical resection of their primary tumor, the post-resection anatomic information coupled with the pretreatment biomarker findings results in the final Pathologic Prognostic Stage Group.

The recent update of breast cancer staging by the biologic markers improved the outcome prediction in comparison to prior staging based only on anatomical features of the disease. The validation studies involving the reassessment of the Surveillance, Epidemiology, and End Results (SEER) database ( n = 209,304, 2010–2014) and the University of Texas MD Anderson Cancer Center database ( n = 3327, years of treatment 2007–2013) according to 8th edition AJCC manual proved the more accurate prognostic information [ 189 , 190 ].

5. Prognostic Biomarkers

5.1. estrogen receptor.

Estrogen receptor (ER) is an important diagnostic determinant since approximately 70–75% of invasive breast carcinomas are characterized by significantly enhanced ER expression [ 191 , 192 ]. Current practice requires the measurement of ER expression on both—primary invasive tumors and recurrent lesions. This procedure is mandatory to provide the selection of those patients who will most benefit from the implementation of the endocrine therapy mainly selective estrogen receptor modulators, pure estrogen receptor downregulators, or third-generation aromatase inhibitors [ 193 ]. Even though the diagnosis of altered expression of ER is particularly relevant in terms of the proper therapy selection, ER expression might also constitute a predictive factor—patients with high ER expression usually present significantly better clinical outcomes [ 194 ]. A relationship was observed between ER expression and the family history of breast cancer which further facilitates the utility of ER expression as a diagnostic biomarker of breast cancer especially in cases of familial risk [ 195 ]. Besides, Konan et al. reported that ERα-36 expression could constitute one of the potential targets of PR-positive cancers and a prognostic marker at the same time [ 196 ].

5.2. Progesterone Receptor

PR is highly expressed (>50%) in patients with ER-positive while quite rarely in those with ER-negative breast cancer [ 197 ]. PR expression is regulated by ER therefore, physiological values of PR inform about the functional ER pathway [ 197 ]. However, both ER and PR are abundantly expressed in breast cancer cells and both are considered as diagnostic and prognostic biomarkers of breast cancer (especially ER-positive ones) [ 198 ]. Greater PR expression is positively associated with the overall survival, time to recurrence, and time to either treatment failure or progression while lowered PR levels are usually related to a more aggressive course of the disease as well as poorer recurrence and prognosis [ 199 ]. Thus, favorable management of breast cancer patients highly depends on the assessment of PR expression. Nevertheless, the predictive value of PR expression still remains controversial [ 200 ].

5.3. Human Epidermal Growth Factor Receptor 2

The expression of human epidermal growth factor receptor 2 (HER2) accounts for approximately 15–25% of breast cancers and its status is primarily relevant in the choice of proper management with breast cancer patients; HER2 overexpression is one of the earliest events during breast carcinogenesis [ 201 ]. Besides, HER2 increases the detection rate of metastatic or recurrent breast cancers from 50% to even more than 80% [ 202 ]. Serum HER2 levels are considered to be a promising real-time marker of tumor presence or recurrence [ 203 ]. HER2 amplification leads to further overactivation of the pro-oncogenic signaling pathways leading to uncontrolled growth of cancer cells which corresponds with poorer clinical outcomes in the case of HER2-positive cancers [ 204 ]. Overexpression of HER2 also correlates with a significantly shorter disease-free period [ 205 ] as well as histologic type, pathologic state of cancer, and a number of axillary nodes with metastatic cancerous cells [ 205 ].

5.4. Antigen Ki-67

The Ki-67 protein is a cellular marker of proliferation and the Ki-67 proliferation index is an excellent marker to provide information about the proliferation of cancerous cells particularly in the case of breast cancer. The proliferative activities determined by Ki-67 reflect the aggressiveness of cancer along with the response to treatment and recurrence time [ 206 ]. Thus, Ki-67 is crucial in terms of the choice of the proper treatment therapy and the potential follow-ups due to recurrence. Though, due to several limitations of the analytical validity of Ki-67 immunohistochemistry, Ki-67 expression levels should be considered benevolently in terms of definite treatment decisions. Ki-67 might be considered as a potential prognostic factor as well; according to a meta-analysis of 68 studies involving 12,155 patients, the overexpression of Ki-67 is associated with poorer clinical outcomes of patients [ 207 ]. High expression of Ki-67 also reflects poorer survival rates of breast cancer patients [ 208 ]. There are speculations whether Ki-67 could be considered as a potential predictive marker, however, such data is still limited and contradictory.

Mib1 (antibody against Ki-67) proliferation index remains a reliable diagnostic biomarker of breast cancer, similarly to Ki-67. A decrease in both Mib1 and Ki-67 expression levels is associated with a good response of breast cancer patients to preoperative treatment [ 209 ]. Mib1 levels are significantly greater in patients with concomitant p53 mutations [ 210 ]. Mib1 assessment might be especially useful in cases of biopsy specimens small in size, inappropriate for neither mitotic index nor S-phase fraction evaluation [ 211 ].

5.6. E-Cadherin

E-cadherin is a critical protein in the epithelial-mesenchymal transition (EMT); loss of its expression leads to the gradual transformation into mesenchymal phenotype which is further associated with increased risk of metastasis. The utility of E-cadherin as a breast biomarker is yet questionable, however, some research indicated that its expression is potentially associated with several breast cancer characteristics such as tumor size, TNM stage, or lymph node status [ 212 ]. Low or even total loss of E-cadherin expression might be potentially useful in the determination of histologic subtype of breast cancer [ 213 , 214 ]. E-cadherin levels do not seem to be promising in terms of patients’ survival rates assessment, however, there are some reports indicating that higher levels of E-cadherin were associated with shorter survival rates in patients with invasive breast carcinoma [ 213 , 215 ]. Lowered E-cadherin expression is positively associated with lymph node metastasis [ 216 ].

5.7. Circulating Circular RNA

Circulating circular RNAs (circRNAs) belong to the group of non-coding RNA and were quite recently shown to be crucial in terms of several hallmarks of breast carcinogenesis including apoptosis, enhanced proliferation, or increased metastatic potential [ 217 ]. One of the most comprehensively described circRNAs, mostly specific to breast cancer include circFBXW7—which was proposed as a potential diagnostic biomarker as well as therapeutic tool for patients with triple-negative breast cancer (TNBC), as well as hsa_circ_0072309 which is abundantly expressed in breast cancer patients and usually associated with poorer survival rates [ 218 ]. Has_circ_0001785 is considered to be promising as a diagnostic biomarker of breast cancer [ 219 ]. The number of circRNAs dysregulated during breast carcinogenesis is significant; their expression might be either upregulated (e.g., has_circ_103110, circDENND4C) or downregulated (e.g., has_circ_006054, circ-Foxo3) [ 220 ]. Besides, specific circRNAs have been reported in different types of breast cancer such as TNBC, HER2-positive, and ER-positive [ 221 ]. Recently it was showed that an interaction between circRNAs and micro-RNA—namely in the form of Cx43/has_circ_0077755/miR-182 post-transcriptional axis, might predict breast cancer initiation as well as further prognosis. Cx43 is transmembrane protein responsible for epithelial homeostasis that mediates junction intercellular communication and its loss dysregulates post-transcriptional axes in breast cancer initiation [ 222 ].

Loss-of-function mutations in the TP53 (P53) gene have been found in numerous cancer types including osteosarcomas, leukemia, brain tumors, adrenocortical carcinomas, and breast cancers [ 223 , 224 ]. P53 protein is essential for normal cellular homeostasis and genome maintenance by mediating cellular stress responses including cell cycle arrest, apoptosis, DNA repair, and cellular senescence [ 225 ]. The silencing mutation of the P53 gene is evident at an early stage of cancer progression. In breast cancer, the prevalence of TP53 mutations is present in approximately 80% of patients with the TNBC and 10% of patients with Luminal A disease [ 226 ].

There have been many studies showing the prognostic role of p53 loss-of-function mutation in breast cancer [ 227 , 228 ]. However, the missense mutations may alters p53 properties causing not only a loss of wild-type function, but also acquisition novel activities-gain of function [ 229 ]. The IHC status of p53 has been proposed as a specific prognostic factor in TNBC, and a feature that divides TNBC into 2 distinct subgroups: a p53-negative normal breast-like TN subgroup, and a p53-positive basal-like subgroup with worse overall survival [ 230 , 231 , 232 ]. However, there is not enough evidence to utilize p53 gene mutational status or immunohistochemically measured protein for determining standardized prognosis in patients with breast cancer [ 233 ].

5.9. MicroRNA

MicroRNAs (miRNA) are a major class of endogenous non-coding RNA molecules (19–25 nucleotides) that have regulatory roles in multiple pathways [ 234 ]. Some miRNAs are related to the development, progression, and response of the tumor to therapy [ 235 ]. Several studies have investigated abnormally expressed miRNAs as biomarkers in breast cancer tissue samples. According to meta-analysis by Adhami et al. two miRNAs (miRNA-21 and miRNA-210) were upregulated consistently and six miRNAs (miRNA-145, miRNA-139-5p, miRNA-195, miRNA-99a, miRNA-497, and miRNA-205) were downregulated consistently in at least three studies [ 236 ].

The miRNA-21 overexpression was observed in TNBC tissues and was associated with enhanced invasion and proliferation of TNBC cells as well as downregulation of the PTEN expression [ 237 ]. Similarly, the high expression of miRNA-210 is related to tumor proliferation, invasion, and poor survival rates in breast cancer patients [ 238 , 239 ].

The miRNA-145 is an anti-cancer agent having the property of inhibiting migration and proliferation of breast cancer cells via regulating the TGF-β1 expression [ 240 ]. However, the miRNA-145 is downregulated in both plasma and tumors of breast cancer patients [ 241 ]. Similarly, miRNA-139-5p and miRNA-195 have tumor suppressor activity in various cancers [ 242 , 243 ].

Nevertheless, further clinical researches focusing on these miRNAs are needed to utilize them as reproducible, disease-specific markers that have a high level of specificity and sensitivity.

5.10. Tumor-Associated Macrophages

Macrophages are known for their immunomodulatory effects and they can be divided according to their phenotypes into M1- or M2-like states [ 244 , 245 ]. M1 macrophages secrete IL-12 and tumor necrosis factor with antimicrobial and antitumor effects. M2 macrophages produce cytokines, including IL-10, IL-1 receptor antagonist type II, and IL-1 decoy receptor. Therefore, macrophages with M1-like phenotype have been linked to good disease course while M2-like phenotype has been associated with adverse outcome, potentially through immunosuppression and the promotion of angiogenesis and tumor cell proliferation and invasion [ 246 , 247 ]. In literature, tumor-associated macrophages (TAMs) are associated with M2 macrophages which promote tumor growth and metastasis.

For breast cancer, studies have shown that the density of TAMs is related to hormone receptor status, stage, histologic grade, lymph node metastasis, and vascular invasion [ 248 , 249 , 250 , 251 ]. According to meta-analysis conducted by Zhao et al. high density of TAMs was related to overall survival disease-free survival [ 252 ].

Conversely, M1 polarized macrophages are linked to favorable prognoses in various cancers [ 253 , 254 , 255 ]. In breast cancer, the high density of M1-like macrophages predicted improved survival in patients with HER2+ phenotype and may be a potential prognostic marker [ 256 ].

However, further studies are needed to clarify the influence of macrophages on breast cancer biology as well as investigate the role of their intratumoral distribution and surface marker selection.

5.11. Inflammation-Based Models

The host inflammatory and immune responses in the tumor and its microenvironment are critical components in cancer development and progression [ 257 ]. The tumor-induced systemic inflammatory response leads to alterations of peripheral blood white blood cells [ 258 ]. Therefore, the relationship between peripheral blood inflammatory cells may serve as an accessible and early method of predicting patient prognosis. Recent studies have reported the predictive role of the inflammatory cell ratios: neutrophil-to-lymphocyte ratio, the lymphocyte-to-monocyte ratio, and the platelet-to-lymphocyte ratio for prognosis in different cancers [ 258 , 259 , 260 , 261 ].

5.11.1. The Neutrophil-to-Lymphocyte Ratio (NLR)

In an extensive study on 27,031 cancer patients, Proctor et al. analyzed the prognostic value of NLR and found a significant relationship between NLR and survival in various cancers including breast cancer [ 262 ]. There are pieces of evidence of the role of lymphocytes in breast cancer immunosurveillance [ 263 , 264 ]. Opposingly neutrophils suppress the cytolytic activity of lymphocytes, leading to enhanced angiogenesis and tumor growth and progression [ 265 ].

Azab et al. first reported that NLR before chemotherapy was an independent factor for long-term mortality and related it to age and tumor size in breast cancer [ 266 ]. In a recent meta-analysis by Guo et al., performed on 17,079 individuals, the high NLR level was associated with both poor overall survival as well as disease-free survival for breast cancer patients. Moreover, it was reported that association between NLR and overall survival was stronger in TNBC patients than in HER2-positive ones [ 267 ].

5.11.2. Lymphocyte-to-Monocyte Ratio

The association of the lymphocyte-to-monocyte ratio (LMR) with patients’ prognosis has been reported for several cancers [ 268 , 269 ]. As lymphocytes have an antitumor activity by inducing cytotoxic cell death and inhibiting tumor proliferation [ 270 ], the monocytes are involved in tumorigenesis, including differentiation into TAMs [ 246 , 247 , 271 ]. In the tumor microenvironment, cytokines, and free radicals that are secreted by monocytes and macrophages are associated with angiogenesis, tumor cell invasion, and metastasis [ 271 ].

A meta-analysis investigating the prognostic effect of LMR showed that low LMR levels are associated with shorter overall survival outcomes in Asian populations, TNBC patients, and patients with non-metastatic and mixed stages [ 272 ]. Moreover, high LMR levels are associated with favorable disease-free survival of breast cancer patients under neoadjuvant chemotherapy [ 273 ].

5.11.3. Platelet-to-Lymphocyte Ratio (PLR)

A high platelet count has been associated with poor prognosis in several types of cancers [ 274 , 275 , 276 ]. Platelets contain both pro-inflammatory molecules and cytokines (P-selectin, CD40L, and interleukin (IL)-1, IL-3, and IL-6) and many anti-inflammatory cytokines. Tumor angiogenesis and growth may be stimulated by the secretion of platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-beta, and platelet factor 4 [ 277 , 278 , 279 ].

A meta-analysis study investigated the prognostic importance of PLR by analyzing 5542 breast cancer patients. High PLR level was associated with poor prognosis (overall survival and disease-free survival), yet, its prognostic value was not determined for molecular subtypes of breast cancer. Nevertheless, an association was found between PLR and clinicopathological features of the tumor, including stage, lymph node metastasis, and distant metastasis [ 280 ]. In the aforementioned meta-analysis, there was a difference in the incidence of high levels of PLR between HER2 statuses [ 280 ], while other studies found a difference between hormone ER or PR statuses [ 281 , 282 ].

6. Treatment Strategies

6.1. surgery.

There are two major types of surgical procedures enabling the removal of breast cancerous tissues and those include (1) breast-conserving surgery (BCS) and (2) mastectomy. BCS—also called partial/segmental mastectomy, lumpectomy, wide local excision, or quadrantectomy—enables the removal of the cancerous tissue with simultaneous preservation of intact breast tissue often combined with plastic surgery technics called oncoplasty. Mastectomy is a complete removal of the breast and is often associated with immediately breast reconstruction. The removal of affected lymph nodes involves sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND). Even though BCS seems to be highly more beneficial for patients, those who were treated with this technique often show a tendency for a further need for a complete mastectomy [ 283 ]. However, usage of BCS is mostly related to significantly better cosmetic outcomes, lowered psychological burden of a patient, as well as reduced number of postoperative complications [ 284 ]. Guidelines of the European Society for Medical Oncology (ESMO) for patients with early breast cancer make the choice of therapy dependent to tumor size, feasibility of surgery, clinical phenotype, and patient’s willingness to preserve the breast [ 285 ].

6.2. Chemotherapy

Chemotherapy is a systemic treatment of BC and might be either neoadjuvant or adjuvant. Choosing the most appropriate one is individualized according to the characteristics of the breast tumor; chemotherapy might also be used in the secondary breast cancer. Neoadjuvant chemotherapy is used for locally advanced BC, inflammatory breast cancers, for downstaging large tumors to allow BCS or in small tumors with worse prognostics molecular subtypes (HER2 or TNBC) which can help to identify prognostics and predictive factors of response and can be provided intravenously or orally. Currently, treatment includes a simultaneous application of schemes 2–3 of the following drugs—carboplatin, cyclophosphamide, 5-fluorouracil/capecitabine, taxanes (paclitaxel, docetaxel), and anthracyclines (doxorubicin, epirubicin). The choice of the proper drug is of major importance since different molecular breast cancer subtypes respond differently to preoperative chemotherapy [ 286 ]. Preoperative chemotherapy is comparably effective to postoperative chemotherapy [ 287 ].

Even though chemotherapy is considered to be effective, its usage very often leads to several side effects including hair loss, nausea/vomiting, diarrhea, mouth sores, fatigue, increased susceptibility to infections, bone marrow supression, combined with leucopenia, anaemia, easier bruising or bleeding; other less frequent side effects include cardiomyopathy, neuropathy, hand-foot syndrome, impaired mental functions. In younger women, disruptions of the menstrual cycle and fertility issues might also appear. Special form of chemotherapy is electrochemotherapy which can be used in patients with breast cancer that has spread to the skin, however, it is still quite uncommon and not available in most clinics.

6.3. Radiation Therapy

Radiotherapy is local treatment of BC, typically provided after surgery and/or chemotherapy. It is performed to ensure that all of the cancerous cells remain destroyed, minimizing the possibility of breast cancer recurrence. Further, radiation therapy is favorable in the case of metastatic or unresectable breast cancer [ 288 ]. Choice of the type of radiation therapy depends on previous type of surgery or specific clinical situation; most common techniques include breast radiotherapy (always applied after BC), chest-wall radiotherapy (usually after mastectomy), and ‘breast boost’ (a boost of high-dose radiotherapy to the place of tumor bed as a complement of breast radiotherapy after BCS). Regarding breast radiotherapy specifically, several types are distinguished including

• (1) intraoperative radiation therapy (IORT)
• (2) 3D-conformal radiotherapy (3D-CRT)
• (3) intensity-modulated radiotherapy (IMRT)
• (4) brachytherapy—which refers to internal radiation in contrast to other above-mentioned techniques.

Irritation and darkening of the skin exposed to radiation, fatigue, and lymphoedema are one of the most common side effects of radiation therapy applied in breast cancer patients. Nonetheless, radiation therapy is significantly associated with the improvement of the overall survival rates of patients and lowered risk of recurrence [ 289 ].

6.4. Endocrinal (Hormonal) Therapy

Endocrinal therapy might be used either as a neoadjuvant or adjuvant therapy in patients with Luminal–molecular subtype of BC; it is effective in cases of breast cancer recurrence or metastasis. Since the expression of ERs, a very frequent phenomenon in breast cancer patients, its blockage via hormonal therapy is commonly used as one of the potential treatment modalities. Endocrinal therapy aims to lower the estrogen levels or prevents breast cancer cells to be stimulated by estrogen. Drugs that block ERs include selective estrogen receptor modulators (SERMs) (tamoxifen, toremifene) and selective estrogen receptor degraders (SERDs) (fulvestrant) while treatments that aim to lower the estrogen levels include aromatase inhibitors (AIs) (letrozole, anastrazole, exemestane) [ 290 , 291 ]. In the case of pre-menopausal women, ovarian suppression induced by oophorectomy, luteinizing hormone-releasing hormone analogs, or several chemotherapy drugs, are also effective in lowering estrogen levels [ 292 ]. However, approximately 50% of hormonoreceptor-positive breast cancer become progressively resistant to hormonal therapy during such treatment [ 293 ]. Endocrinal therapy combined with chemotherapy is associated with the reduction of mortality rates amongst breast cancer patients [ 294 ].

6.5. Biological Therapy

Biological therapy (targeted therapy) can be provided at every stage of breast therapy– before surgery as neoadjuvant therapy or after surgery as adjuvant therapy. Biological therapy is quite common in HER2-positive breast cancer patients; major drugs include trastuzumab, pertuzumab, trastuzumab deruxtecan, lapatinib, and neratinib [ 295 , 296 , 297 , 298 , 299 ]. Further, the efficacy of angiogenesis inhibitors such as a recombinant humanized monoclonal anti-VEGF antibody (rhuMAb VEGF) or bevacizumab are continuously investigated [ 300 ].

In the case of Luminal, HER2-negative breast cancer, pre-menopausal women more often receive everolimus -TOR inhibitor with exemestane while postmenopausal women often receive CDK 4–6 inhibitor palbociclib or ribociclib simultaneously, combined with hormonal therapy [ 301 , 302 , 303 ]. Two penultimate drugs along with abemaciclib and everolimus can also be used in HER2-negative and estrogen-positive breast cancer [ 304 , 305 ]. Atezolizumab is approved in triple-negative breast cancer, while denosumab is approved in case of metastasis to the bones [ 306 , 307 , 308 ].

7. Conclusions

In this review, we aimed to summarize and update the current knowledge about breast cancer with an emphasis on its current epidemiology, risk factors, classification, prognostic biomarkers, and available treatment strategies. Since both the morbidity and mortality rates of breast cancer have significantly increased over the past decades, it is an urgent need to provide the most effective prevention taking into account that modifiable risk factors might be crucial in providing the reduction of breast cancer incidents. So far, mammography and sonography is the most common screening test enabling quite an early detection of breast cancer. The continuous search for prognostic biomarkers and targets for the potential biological therapies has significantly contributed to the improvement of management and clinical outcomes of breast cancer patients.

Author Contributions

Conceptualization, A.F., R.S. and A.S.; critical review of literature, S.Ł., M.C., A.F., J.B., R.S., A.S.; writing—original draft preparation, M.C., A.F.; writing—review and editing, S.Ł., M.C., A.F., J.B., R.S., A.S.; supervision, R.S. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

UKnowledge > College of Medicine > Toxicology and Cancer Biology > Theses & Dissertations

Theses and Dissertations--Toxicology and Cancer Biology

Theses/dissertations from 2024 2024.

UNDERSTANDING THE MECHANISM OF FERROPTOSIS SUSCEPTIBILITY VARIATION IN COLORECTAL CANCER , Aziza Alshahrani

Elucidation of Mismatch Repair Regulation by ABL1: Advantages/Disadvantages of Tyrosine Kinase Inhibitor Treatment , Hannah Daniels

RPS6KB1 IS A CRITICAL TARGET FOR OVERCOMING TUMOR LINEAGE PLASTICITY AND THERAPY RESISTANCE , Saptadwipa Ganguly

PORCUPINE’S ROLE IN THE ENHANCEMENT OF ENZALUTAMIDE EFFICACY IN DRUG RESISTANT PROSTATE CANCER , Katelyn Jones

ACQUIRED TREATMENT RESISTANCE IN PROSTATE CANCER VIA THE PRODUCTION OF RADIATION DERIVED EXTRACELLULAR VESICLES CONTAINING MITOCHONDRIAL PROTEINS , Caitlin Miller

Delineating Contributions of Genotype and Lineage to Lung Cancer Therapy Response , Kassandra Jo Naughton

THE CRITICAL ROLE OF NAC1 IN TRIPLE-NEGATIVE BREAST CANCER STEMNESS AND IMMUNOSUPPRESSION , chrispus ngule

THERAPEUTIC APPROACHES AND NOVEL MECHANSIMS IN CANCER PROGRESSION , Kendall Simpson

Theses/Dissertations from 2023 2023

ELUCIDATING THE FUNCTIONAL IMPORTANCE OF PEROXIREDOXIN IV IN PROSTATE CANCER AND ITS SECRETION MECHANISM , Na Ding

Targeting EZH2 to Improve Outcomes of Lung Squamous Cell Carcinoma , Tanner DuCote

UNDERSTANDING AND TARGETING THE TPH1-SEROTONIN-HTR3A AXIS IN SMALL CELL LUNG CANCER , Yanning Hao

CONSERVED NOVEL INTERACTIONS BETWEEN POST-REPLICATIVE REPAIR AND MISMATCH REPAIR PROTEINS HAVE DIFFERENTIAL EFFECTS ON DNA REPAIR PATHWAYS , Anna K. Miller

UNDERSTANDING THE ROLE OF PEROXIREDOXIN IV IN COLORECTAL CANCER DEVELOPMENT , Pratik Thapa

BEYOND MITOSIS, PLK1-MEDIATED PHOSPHORYLATION RE-WIRES CANCER METABOLISM AND PROMOTES CANCER PROGRESSION , Qiongsi Zhang

Theses/Dissertations from 2022 2022

ELUCIDATING THE ROLE OF POLYCOMB REPRESSIVE COMPLEX 2 IN LUNG STEM CELL FATE AND LUNG DISEASE , Aria Byrd

SEX DIMORPHISM IN HEMATOPOIESIS AND BONE MARROW NICHE , xiaojing cui

EXTRACELLULAR VESICLES AND CANCER THERAPY: AN INSIGHT INTO THE ROLE OF OXIDATIVE STRESS , Jenni Ho

OVERCOMING RESISTANCE TO SG-ARIS IN CASTRATION-RESISTANT PROSTATE CANCER , Chaohao Li

Theses/Dissertations from 2021 2021

THE TUMOR SUPPRESSOR PAR-4 REGULATES HYPERTROPHIC OBESITY , Nathalia Araujo

Epigenetic States Regulate Tumor Aggressiveness and Response to Targeted Therapies in Lung Adenocarcinoma , Fan Chen

DELINEATING THE ROLE OF FATTY ACID METABOLISM TO IMPROVE THERAPEUTIC STRATEGIES FOR COLORECTAL CANCER , James Drury

DEVELOPMENT OF TOOLS FOR ATOM-LEVEL INTERPRETATION OF STABLE ISOTOPE-RESOLVED METABOLOMICS DATASETS , Huan Jin

MECHANISMS OF CADMIUM-INDUCED AND EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION-DRIVEN LUNG TUMORIGENESIS , Hsuan-Pei Lin

SCIENCE-BASED REGULATION OF PHARMACOLOGICAL SUBSTANCES IN COMPETITION HORSES , Jacob Machin

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How and Where to Write a Thesis

by Deepti Mathur

To paraphrase Jane Austen, it is a truth universally acknowledged that a Ph.D. student in possession of data must be in want of a thesis. I was in this situation recently myself. I took to the streets of New York City to find the best writing spot in town. In my pursuit, the only criteria were free WIFI — so that I could VPN into university networks for access to scientific papers — and readily available outlets.

Top tips for finding a space to write a thesis

• Work spaces that previously were productive for you may not be so good for a large task like a thesis.
• There are many amazing libraries in NYC, or any city. The below guide can help you find the criteria that best suit your needs.
• Moving to different study spaces on occasion will break up monotony and might help you re-focus if you are not too distracted by the new sights.

While the locations described below are in NYC, the findings can be extrapolated to any city.

At home: “I have total comfort here”

I began in my humble apartment, where I am now writing this post. In fact, most of my previous writing has happened while sitting at this very desk. I have total comfort here. I can regulate the temperature precisely to my liking, can get snacks or make tea whenever I wish. Also, I can go to the bathroom without worrying about someone stealing my laptop.  However, the comfort comes with a price: easy distraction. This has never been an issue with smaller pieces of work, but the thesis was too large and daunting. It was easier to go on YouTube, talk to my roommates, or even clean my apartment rather than face such a formidable task. I needed to get out of the house.

Coffee shops: “inconsistent noisiness”

The workplace: “interrupted writing was not my best writing”.

The most obvious location was at the workplace itself. All of my data at my fingertips without the need for VPN, programs like Adobe Illustrator for making figures, and a large monitor were all perks of working in lab.  However, I have the happy problem of being friends with my labmates, and ended up spending too much time chatting or fiddling with lab work. Interrupted writing was not my best writing.  Disappearing into conference rooms was fruitful until I had to once again move to make room for the actual meetings that required the room.

Libraries: “this is where I struck gold”

I next ventured to several libraries across the city, and this is where I struck gold. My best writing was done at some of these libraries, and, importantly, it was ­ fun .

If you have never been inside the New York Public Library, you must. The grandeur of the high ceilings and beauty of the Rose Reading Room make you feel like whatever you are working on is of supreme importance. It awakens a certain thrill, as if you are cracking the secrets of the Da Vinci Code while unaware tourists peek into the otherwise quiet room.

Heightened enthusiasm about my own work aside, I made each NYPL day into a culinary delight. Breakfast at Grand Central, a lunch break at the food stands in Bryant Park accompanied by a walk to clear the mind, and soup dumplings for dinner a few blocks away left me feeling satisfied rather than tired at the end of a productive day. It is also always nice to escape from one’s own neighborhood. It’s a good thing to shake off any feelings of cabin fever or monotony.

This is not to say that NYPL didn’t have its own cons. The main reading room is quite cold, no matter the season. Studying here also necessitates bringing a friend with you, since you can’t leave your stuff unattended even to go to the bathroom or to get a coffee from downstairs. You also aren’t allowed to bring in your own beverages. Though you can sneak in a water bottle buried in your bag. Inconveniences aside, I accomplished the majority of my background research for the thesis in this library.

Once you have your perfect zone, it’s time to actually write the thesis.

Here’s a few additional helpful tips:.

• Outline the crap out of it. Staring at a blank page is too daunting. The only way to make progress is to write a rough outline and to keep adding more and more details until you’re ready to string it together into sentences. Outlining also vastly helps with organization. This is because a detail from one paper may belong in a different paragraph from other details from the paper depending on its connections to other work.
• Endnote as you go! It’s way harder to go back and add citations later.
• Everything takes longer to do than you think it will. Be realistic while budgeting your time.
• Have fun! Writing the thesis was one of my favorite parts of the entire Ph.D. You get to read other papers, put together all your knowledge about the field, present your own work exactly how you like with no restrictions from journals. Plus, your day is entirely your own to organize as you wish.  Enjoy the literary and scientific freedom!

About the author

Deepti is a postdoctoral fellow at Memorial Sloan Kettering Cancer Center, where she is using mathematical and experimental techniques to investigate metastasis and therapeutic resistance. She is also interested in science communication – she was a finalist for Science magazine’s Dance Your Ph.D. competition, and won her institution’s Postdoc Slam.

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The 150 most important questions in cancer research and clinical oncology series: questions 94–101

Edited by Cancer Communications

Cancer Communications

Cancer Communications volume  38 , Article number:  69 ( 2018 ) Cite this article

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Since the beginning of 2017, Cancer Communications (former title: Chinese Journal of Cancer ) has published a series of important questions regarding cancer research and clinical oncology, to provide an enhanced stimulus for cancer research, and to accelerate collaborations between institutions and investigators. In this edition, the following 8 valuable questions are presented. Question 94. The origin of tumors: time for a new paradigm? Question 95. How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma? Question 96. Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor? Question 97. What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction? Question 98. Is high local concentration of metformin essential for its anti-cancer activity? Question 99. How can we monitor the emergence of cancer cells anywhere in the body through plasma testing? Question 100. Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells? Question 101. Is cell migration a selectable trait in the natural evolution of carcinoma?

Until now, the battle against cancer is still ongoing, but there are also ongoing discoveries being made. Milestones in cancer research and treatments are being achieved every year; at a quicker pace, as compared to decades ago. Likewise, some cancers that were considered incurable are now partly curable, lives that could not be saved are now being saved, and for those with yet little options, they are now having best-supporting care. With an objective to promote worldwide cancer research and even accelerate inter-countries collaborations, since the beginning of 2017, Cancer Communications (former title: Chinese Journal of Cancer ) has launched a program of publishing 150 most important questions in cancer research and clinical oncology [ 1 ]. We are providing a platform for researchers to freely voice-out their novel ideas, and propositions to enhance the communications on how and where our focus should be placed [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. In this edition, 8 valuable and inspiring questions, Question 94–101, from highly distinguished professionals from different parts of the world are presented. If you have any novel proposition(s) and Question(s), please feel free to contact Ms. Ji Ruan via email: [email protected].

Question 94: The origin of tumors: time for a new paradigm?

Background and implications.

“There is no worse blind man than the one who doesn’t want to see. There is no worse deaf man than the one who doesn’t want to hear. And there is no worse madman than the one who doesn’t want to understand.” —Ancient Proverb

In the past half-century, cancer biologists have focused on a dogma in which cancer was viewed as a proliferative disease due to mechanisms that activate genes (oncogenes) to promote cell proliferation or inactivate genes (tumor suppressor genes) to suppress tumor growth. In retrospect, these concepts were established based on functional selections, by using tissue culture (largely mouse NIH 3T3 cells) for the selection of transformed foci at the time when we knew virtually nothing about the human genome [ 14 ]. However, it is very difficult to use these genes individually or in combinations to transform primary human cells. Further, the simplified view of uncontrolled proliferation cannot explain the tumor as being a malignant organ or a teratoma, as observed by pathologists over centuries. Recently, the cancer genomic atlas project has revealed a wide variety of genetic alterations ranging from no mutation to multiple chromosomal deletions or fragmentations, which make the identification of cancer driver mutations very challenging in a background of such a massive genomic rearrangement. Paradoxically, this increase the evidences demonstrating that the oncogenic mutations are commonly found in many normal tissues, further challenging the dogma that genetic alteration is the primary driver of this disease.

Logically, the birth of a tumor should undergo an embryonic-like development at the beginning, similar to that of a human. However, the nature of such somatic-derived early embryo has been elusive. Recently, we provided evidence to show that polyploid giant cancer cells (PGCCs), which have been previously considered non-dividing, are actually capable of self-renewal, generating viable daughter cells via amitotic budding, splitting and burst, and capable of acquisition of embryonic-like stemness [ 15 , 16 , 17 ]. The mode of PGCC division is remarkably similar to that of blastomere, a first step in human embryogenesis following fertilization. The blastomere nucleus continuously divides 4–5 times without cytoplasmic division to generate 16–32 cells and then to form compaction/morulae before developing into a blastocyst [ 18 ]. Based on these data and similarity to the earliest stage of human embryogenesis, I propose a new theory that tumor initiation can be achieved via a dualistic origin, similar to the first step of human embryogenesis via the formation of blastomere-like cells, i.e. the activation of blastomere or blastomere-like cells which leads to the dedifferentiation of germ cells or somatic cells, respectively, which is then followed by the differentiation to generate their respective stem cells, and the differentiation arrest at a specific developmental hierarchy leading to tumor initiation [ 19 ]. The somatic-derived blastomere-like cancer stem cell follows its own mode of cell growth and division and is named as the giant cell cycle. This cycle includes four distinct but overlapping phases: the initiation, self-renewal, termination, and stability phases. The giant cell cycle can be tracked in vitro and in vivo due to their salient giant cell morphology (Fig.  1 ).

One mononucleated polyploid giant cancer cell (PGCC) in the background of regular size diploid cancer cells. The PGCC can be seen to be at least 100 times larger than that of regular cancer cells

This new theory challenges the traditional paradigm that cancer is a proliferative disease, and proposes that the initiation of cancer requires blastomere-like division that is similar to that of humans before achieving stable proliferation at specific developmental hierarchy in at least half of all human cancers. This question calls for all investigators in the cancer research community to investigate the role of PGCCs in the initiation, progression, resistance, and metastasis of cancer and to look for novel agents to block the different stages of the giant cell cycle.

The histopathology (phenotype) of cancers has been there all the time. It is just the theory of cancer origin proposed by scientists that changes from time to time. After all, trillions of dollars have been invested in fighting this disease by basing on its genetic origin in the past half-century, yet, little insight has been gained [ 14 ]. Here are two quotes from Einstein: “Insanity: doing the same thing over and over again expecting different results”, and “We cannot solve our problems with the same thinking we used when created them”.

In short, it is time to change our mindset and to start pursuing PGCCs, which we can observe under the microscope. But with very little understanding about these cells, it is time for a shift in paradigm.

Jinsong Liu.

Affiliation

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4095, USA.

Email address

[email protected]

Question 95: How can we accelerate the identification of biomarkers for the early detection of pancreatic ductal adenocarcinoma?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the world with a dismal 5-year overall survival rate of less than 5%; which has not been significantly improved since the past decades. Although surgical resection is the only option for curative treatment of PDAC, only 15%–20% of patients with PDAC have the chance to undergo curative resection, leaving the rest with only palliative options in hope for increasing their quality of life; since they were already at unresectable and non-curative stages at their first diagnosis.

The lack of specific symptoms in the early-stage of PDAC is responsible for rendering an early diagnosis difficult. Therefore, more sensitive and specific screening methodologies for its early detection is urgently needed to improve its diagnosis, starting early treatments, and ameliorating prognoses. The diagnosis so far relies on imaging modalities such as abdominal ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP), and positron emission tomography (PET). One may propose to screen for pancreatic cancer in high-risk populations, which is highly recommended, however screening intervention for all the people is not a wise choice; when considering the relatively low prevalence of PDAC, and the difficulty for diagnosing it in its early stage [ 20 ].

Therefore, alternative diagnostic tools for early detection of PDAC are highly expected. Among the biomarkers currently used in clinical practice, carbohydrate antigen 19–9 (CA19–9) is among the most useful one for supporting the diagnosis of PDAC, but it is neither sufficiently sensitive nor specific for its early detection. Yachida et al. reported in 2010 that the initiating mutation in the pancreas occurs approximately two decades before the PDAC to start growing in distant organs [ 21 ], which indicates a broad time of the window of opportunity for the early detection of PDAC. With the advancement in next-generation sequencing technology, the number of reported studies regarding novel potential molecular biomarkers in bodily fluids including the blood, feces, urine, saliva, and pancreatic juice for early detection of PDAC has been increasing. Such biomarkers may be susceptible to detect mutations at the genetic or epigenetic level, identifying important non-coding RNA (especially microRNA and long non-coding RNA), providing insights regarding the metabolic profiles, estimating the tumor level in liquid biopsies (circulating free DNA, circulating tumor cells and exosomes), and so on.

Another approach to identifying biomarkers for the early detection of pancreatic cancer is using animal models. In spontaneous animal models of pancreatic cancer, such as Kras-mutated mouse models, it is expected that by high throughput analyses of the genetic/epigenetic/proteomic alterations, some novel biomarkers might be able to be identified. For instance, Sharma et al. reported in 2017 that the detection of phosphatidylserine-positive exosomes enabled the diagnosis of early-stage malignancies in LSL-Kras G12D , Cdkn2a lox/lox : p48 Cre and LSL-Kras G12d/+ , LSL-Trp R172H/+ , and P48 Cre mice [ 22 ].

These analyses in clinical samples or animal models hold the clues for the early detection of PDAC, however, further studies are required to validate their diagnostic performance. What’s most important, will be the lining-up of these identified prospective biomarkers, to validate their sensitivities and specificities. This will determine their potential for widespread clinical applicability, and hopefully, accelerate the early diagnosis of PDAC.

Mikiya Takao 1,2 , Hirotaka Matsuo 2 , Junji Yamamoto 1 , and Nariyoshi Shinomiya 2 .

1 Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan; 2 Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.

E-mail address

[email protected]; [email protected]; [email protected]; [email protected]

Question 96: Can we improve the treatment outcomes of metastatic pancreatic ductal adenocarcinoma through precision medicine guided by a combination of the genetic and proteomic information of the tumor?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers, and nearly half of the patients had metastatic PDAC when they are initially diagnosed. When they are accompanied by metastatic tumors, unlike most solid cancer, PDAC cannot be cured with primary surgical resection alone [ 23 , 24 ]. Also, since PDAC has poor responses to conventional therapies, improvements in adjunctive treatment approach including chemo- and immuno-therapy are earnestly required. From this standpoint, recent results regarding the differences in the molecular evolution of pancreatic cancer subtypes provide a new insight into its therapeutic development [ 25 ], which may lead to the improvement of the prognosis of not only metastatic PDAC but also of locally advanced or recurrent PDAC.

In fact, new chemotherapeutic regimens such as the combination of gemcitabine with nab-paclitaxel and FOLFIRINOX have been reported to show improved prognosis despite a lack of examples of past successes in the treatment of patients with metastatic PDAC who had undergone R0 resection [ 26 ]. While many mutations including KRAS , CDKN2A , TP53, and SMAD4 are associated with pancreatic carcinogenesis, no effective molecular targeted drug has been introduced in the clinical setting so far. A recent report of a phase I/II study on refametinib, a MEK inhibitor, indicated that KRAS mutation status might affect the overall response rate, disease control rate, progression-free survival, and overall survival of PDAC in combination with gemcitabine [ 27 ].

While immunotherapy is expected to bring a great improvement in cancer treatment, until now, immune checkpoint inhibitors have achieved limited clinical benefit for patients with PDAC. This might be because PDAC creates a uniquely immunosuppressive tumor microenvironment, where tumor-associated immunosuppressive cells and accompanying desmoplastic stroma prevent the tumor cells from T cell infiltration. Recently reported studies have indicated that immunotherapy might be effective when combined with focal adhesion kinase (FAK) inhibitor [ 28 ] or IL-6 inhibitor [ 29 ], but more studies are required to validate their use in clinical practice.

As such, we believe that if the dynamic monitoring of drug sensitivity/resistance in the individual patients is coupled with precision treatment based on individualized genetics/epigenetics/proteomics alterations in the patients’ tumor, this could improve the treatment outcomes of PDAC.

Mikiya Takao 1,2 , Hirotaka Matsuo 2 , Junji Yamamoto 1 , and Nariyoshi Shinomiya 2.

Question 97: What are the parameters that determine a competent immune system that gives a complete response to cancers after immune induction?

Recently, cancer immunotherapy has shown great clinical benefit in multiple types of cancers [ 30 , 31 , 32 ]. It has provided new approaches for cancer treatment. However, it has been observed that only a fraction of patients respond to immunotherapy.

Much effort has been made to identify markers for immunotherapeutic response. Tumor mutation burden (TMB), mismatch repair (MMR) deficiency, PD-L1 expression, and tumor infiltration lymphocyte (TIL) have been found to be associated with an increased response rate in checkpoint blockade therapies. Unfortunately, a precise prediction is still challenging in this field. Moreover, when to stop the treatment of immunotherapy is an urgent question that remains to be elucidated.

In other words, there is no available approach to determine if a patient has generated a good immune response against the cancer after immunotherapy treatments. All of these indicate the complexity and challenges that reside for implementing novel man-induced cancer-effective immune response therapeutics. A variety of immune cells play collaborative roles at different stages to recognize antigens and eventually to generate an effective anti-cancer immune response. Given the high complexity of the immune system, a rational evaluation approach is needed to cover the whole process. Moreover, we need to perfect vaccine immunization and/or in vitro activation of T cells to augment the function of the immune system; particularly the formation of immune memory.

Edison Liu 1 , Penghui Zhou 2 , Jiang Li 2 .

1 The Jackson Laboratory, Bar Harbor, ME 04609, USA; 2 Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P. R. China.

[email protected]; [email protected]; [email protected]

Question 98: Is high local concentration of metformin essential for its anti-cancer activity?

Metformin was approved as a first line of anti-diabetic drug since decades. Interestingly, the fact that clinical epidemiological studies have shown that metformin can reduce the risk of a variety of cancers stimulates considerable recognition to explore its anticancer activity.

Although the in vitro and in vivo experimental results have demonstrated that metformin can have some potential anti-tumor effects, more than 100 clinical trials did not achieve such desirable results [ 33 ]. We and others believe that the main problem resides in the prescribing doses used. For cancer treatment, a much higher dose may be needed for observing any anti-tumor activities, as compared to the doses prescribed for diabetics [ 34 , 35 , 36 ].

Further, if the traditional local/oral administration approach is favored, the prescribed metformin may not be at the required dose-concentration once it reaches the blood to have the effective anti-cancer activities. We, therefore, propose that intravesical instillation of metformin into the bladder lumen could be a promising way to treat for bladder cancer, at least. We have already obtained encouraging results both in vitro and in vivo experiments, including in an orthotopical bladder cancer model [ 36 , 37 ]. Now, we are waiting to observe its prospective clinical outcome.

Mei Peng 1 , Xiaoping Yang 2 .

1 Department of Pharmacy, Xiangya Hospital, Central South University. Changsha, Hunan 410083, P. R. China; 2 Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Department of Pharmacy, School of Medicine, Hunan Normal University, Changsha, Hunan 410013, P. R. China.

[email protected]; [email protected]

Question 99: How can we monitor the emergence of cancer cells anywhere in the body through plasma testing?

The early detection of cancer is still a relentless worldwide challenge. The sensitivity and specificity of traditional blood tumor markers and imaging technologies are still to be greatly improved. Hence, novel approaches for the early detection of cancer are urgently needed.

The emergence of liquid biopsy technologies opens a new driveway for solving such issues. According to the definition of the National Cancer Institute of the United States, a liquid biopsy is a test done on a sample of blood to look for tumorigenic cancer cells or pieces of tumor cells’ DNA that are circulating in the blood [ 38 ]. This definition implies two main types of the current liquid biopsy: one that detects circulating tumor cells and the other that detects non-cellular material in the blood, including tumor DNA, RNA, and exosomes.

Circulating tumor cells (CTCs) are referred to as tumor cells that have been shed from the primary tumor location and have found their way to the peripheral blood. CTCs were first described in 1869 by an Australian pathologist, Thomas Ashworth, in a patient with metastatic cancer [ 39 ]. The importance of CTCs in modern cancer research began in the mid-1990s with the demonstration that CTCs exist early in the course of the disease.

It is estimated that there are about 1–10 CTCs per mL in whole blood of patients with metastatic cancer, even fewer in patients with early-stage cancer [ 40 ]. For comparison, 1 mL of blood contains a few million white blood cells and a billion erythrocytes. The identification of CTCs, being in such low frequency, requires some special tumoral markers (e.g., EpCAM and cytokeratins) to capture and isolate them. Unfortunately, the common markers for recognizing the majority of CTCs are not effective enough for clinical application [ 41 ]. Although accumulated evidences have shown that the presence of CTCs is a strong negative prognostic factor in the patients with metastatic breast, lung and colorectal cancers, detecting CTCs might not be an ideal branch to hold on for the hope of early cancer detection [ 42 , 43 , 44 , 45 ].

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the circulatory system, which is mainly derived from the tumor cell death through necrosis and/or apoptosis [ 46 ]. Given its origin, ctDNA inherently carries cancer-specific genetic and epigenetic aberrations, which can be used as a surrogate source of tumor DNA for cancer diagnosis and prognostic prediction. Ideally, as a noninvasive tumor early screening tool, a liquid biopsy test should be able to detect many types of cancers and provide the information of tumor origin for further specific clinical management. In fact, the somatic mutations of ctDNA in different types of tumor are highly variable, even in the different individuals with the same type of tumor [ 47 ]. Additionally, most tumors do not possess driver mutations, with some notable exceptions, which make the somatic mutations of ctDNA not suitable for early detection of the tumor.

Increased methylation of the promoter regions of tumor suppressor genes is an early event in many types of tumor, suggesting that altered ctDNA methylation patterns could be one of the first detectable neoplastic changes associated with tumorigenesis [ 48 ]. ctDNA methylation profiling provides several advantages over somatic mutation analysis for cancer detection including higher clinical sensitivity and dynamic range, multiple detectable methylation target regions, and multiple altered CpG sites within each targeted genomic region. Further, each methylation marker is present in both cancer tissue and ctDNA, whereas only a fraction of mutations present in cancer tissue could be detected in ctDNA.

In 2017, there were two inspiring studies that revealed the values of using ctDNA methylation analysis for cancer early diagnosis [ 49 , 50 ]. After partitioning the human genome into blocks of tightly coupled CpG methylation sites, namely methylation haplotype blocks (MHBs), Guo and colleagues performed tissue-specific methylation analyses at the MHBs level to accurately determine the tissue origin of the cancer using ctDNA from their enrolled patients [ 49 ]. In another study, Xu and colleagues identified a hepatocellular carcinoma (HCC) enriched methylation marker panel by comparing the HCC tissue and blood leukocytes from normal individuals and showed that methylation profiles of HCC tumor DNA and matched plasma ctDNA were highly correlated. In this study, after quantitative measurement of the methylation level of candidate markers in ctDNA from a large cohort of 1098 HCC patients and 835 normal controls, ten methylation markers were selected to construct a diagnostic prediction model. The proposed model demonstrated a high diagnostic specificity and sensitivity, and was highly correlated with tumor burden, treatment response, and tumor stage [ 50 ].

With the rapid development of highly sensitive detection methods, especially the technologies of massively parallel sequencing or next-generation sequencing (NGS)-based assays and digital PCR (dPCR), we strongly believe that the identification of a broader “pan-cancer” methylation panel applied for ctDNA analyses, probably in combination with detections of somatic mutation and tumor-derived exosomes, would allow more effective screening for common cancers in the near future.

Edison Liu 1 , Hui-Yan Luo 2 .

[email protected]; [email protected]

Question 100: Can phytochemicals be more specific and efficient at targeting P-glycoproteins to overcome multi-drug resistance in cancer cells?

Though several anticancer agents are approved to treat different types of cancers, their full potentials have been limited due to the occurrence of drug resistance. Resistance to anticancer drugs develops by a variety of mechanisms, one of which is increased drug efflux by transporters. The ATP-binding cassette (ABC) family drug efflux transporter P-glycoprotein (P-gp or multi-drug resistance protein 1 [MDRP1]) has been extensively studied and is known to play a major role in the development of multi-drug resistance (MDR) to chemotherapy [ 51 ]. In brief, overexpressed P-gp efflux out a wide variety of anticancer agents (e.g.: vinca alkaloids, doxorubicin, paclitaxel, etc.), leading to a lower concentration of these drugs inside cancer cells, thereby resulting in MDR. Over the past three decades, researchers have developed several synthetic P-gp inhibitors to block the efflux of anticancer drugs and have tested them in clinical trials, in combination with chemotherapeutic drugs. But none were found to be suitable enough in overcoming MDR and to be released for marketing, mainly due to the side effects associated with cross-reactivity towards other ABC transporters (BCRP and MRP-1) and the inhibition of CYP450 drug metabolizing enzymes [ 52 , 53 ].

On the other hand, a number of phytochemicals have been reported to have P-gp inhibitory activity. Moreover, detailed structure–activity studies on these phytochemicals have delineated the functional groups essential for P-gp inhibition [ 53 , 54 ]. Currently, one of the phytochemicals, tetrandrine (CBT-1 ® ; NSC-77037), is being used in a Phase I clinical trial ( http://www.ClinicalTrials.gov ; NCT03002805) in combination with doxorubicin for the treatment of metastatic sarcoma. Before developing phytochemicals or their derivatives as P-gp inhibitors, they need to be investigated thoroughly for their cross-reactivity towards other ABC transporters and CYP450 inhibition, in order to avoid toxicities similar to the older generation P-gp inhibitors that have failed in clinical trials.

Therefore, the selectivity for P-gp over other drug transporters and drug metabolizing enzymes should be considered as important criterias for the development of phytochemicals and their derivatives for overcoming MDR.

Mohane Selvaraj Coumar and Safiulla Basha Syed.

Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.

[email protected]; [email protected]

Question 101: Is cell migration a selectable trait in the natural evolution of carcinoma?

The propensity of solid tumor malignancy to metastasize remains the main cause of cancer-related death, an extraordinary unmet clinical need, and an unanswered question in basic cancer research. While dissemination has been traditionally viewed as a late process in the progression of malignant tumors, amount of evidence indicates that it can occur early in the natural history of cancer, frequently when the primary lesion is still barely detectable.

A prerequisite for cancer dissemination is the acquisition of migratory/invasive properties. However, whether, and if so, how the migratory phenotype is selected for during the natural evolution of cancer and what advantage, if any, it may provide to the growing malignant cells remains an open issue. The answers to these questions are relevant not only for our understating of cancer biology but also for the strategies we adopt in an attempt of curbing this disease. Frequently, indeed, particularly in pharmaceutical settings, targeting migration has been considered much like trying “to shut the stable door after the horse has bolted” and no serious efforts in pursuing this aim has been done.

We argue, instead, that migration might be an intrinsic cancer trait that much like proliferation or increased survival confers to the growing tumor masses with striking selective advantages. The most compelling evidence in support for this contention stems from studies using mathematical modeling of cancer evolution. Surprisingly, these works highlighted the notion that cell migration is an intrinsic, selectable property of malignant cells, so intimately intertwined with more obvious evolutionarily-driven cancer traits to directly impact not only on the potential of malignant cells to disseminate but also on their growth dynamics, and ultimately provide a selective evolutionary advantage. Whether in real life this holds true remains to be assessed, nevertheless, work of this kind defines a framework where the acquisition of migration can be understood in a term of not just as a way to spread, but also to trigger the emergence of malignant clones with favorable genetic or epigenetic traits.

Alternatively, migratory phenotypes might emerge as a response to unfavorable conditions, including the mechanically challenging environment which tumors, and particularly epithelial-derived carcinoma, invariably experience. Becoming motile, however, may not per se being fixed as phenotypic advantageous traits unless it is accompanied or is causing the emergence of specific traits, including drug resistance, self-renewal, and survival. This might be the case, for example, during the process of epithelial-to-mesenchymal transition (EMT), which is emerging as an overarching mechanism for dissemination. EMT, indeed, may transiently equip individual cancer cells not only with migratory/invasive capacity but also with increased resistance to drug treatment, stemness potential at the expanse of fast proliferation.

Thus, within this framework targeting pro-migratory genes, proteins and processes may become a therapeutically valid alternative or a complementary strategy not only to control carcinoma dissemination but also its progression and development.

Giorgio Scita.

IFOM, The FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Oncology and Hemato-Oncology (DIPO), School of Medicine, University of Milan, Via Festa del Perdono 7, 20122, Italy.

[email protected]

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Cancer Communications. The 150 most important questions in cancer research and clinical oncology series: questions 94–101. Cancer Commun 38 , 69 (2018). https://doi.org/10.1186/s40880-018-0341-9

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Cancer Research Paper

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This research paper on global burden of cancer, its trends and projections, is split into four themes. The first section provides a basic description of the main sources of routine cancer information. The second section describes the international variation in cancer using the latest available cancer incidence, mortality, and prevalence estimates. Global trends of the most commonly occurring tumors are then presented in the third section, primarily based on high-quality incidence data from established cancer registries worldwide. The final section discusses how the global profile of cancer might look around 2020, on the basis of projections of population aging and growth and some assumptions on future cancer trends.

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Get 10% off with 24start discount code, definitions, uses, and caveats, producing global estimates of cancer burden, global burden of cancer 2002, geographical variations in the eight most common cancers, temporal variations in the five most common cancers, predicting cancer in 2020.

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Routine Measures of Cancer Burden

Cancer incidence is the frequency of occurrence of new cases of cancer in a defined population for a given period of time. It can be expressed as the absolute number of cases, although computation of rates is required for comparative purposes, with the denominator the person-time at risk from which the cases in the numerator arose. The statistic is useful in providing clues to the underlying risk factors and in planning and prioritizing resources for primary prevention, where the aim is to reduce incidence via changes in cultural and personal patterns of behavior.

Population-based cancer registries collect and classify information on all new cases of cancer in a defined population and provide statistics on occurrence for the purposes of assessing and controlling the impact of cancer in the community. Registries may cover entire national populations or selected regions. The comparability, completeness, and accuracy of incidence data are essential in making reliable inferences regarding geographical and temporal variations in incidence rates. The Cancer Incidence In Five Continents (CI5) series, first published in 1962, is now in its eighth volume (Parkin et al., 2002) and covers diagnoses of cancer 1993–97 in 186 registries in 57 countries. Inclusion is a good marker of the quality of an individual registry, given that the editorial process includes numerous assessments of data quality.

Mortality provides a measure of the impact of cancer and is expressed either as number of deaths occurring or as a mortality rate: The number of deaths per 100 000 persons per year. Mortality is a product of the incidence and the case fatality from a given cancer. Death rates estimate the average risk to the population of dying from a specific cancer, while fatality, the inverse of cancer survival (the time that elapsed between the diagnosis of cancer and death from it), represents the probability that an individual with cancer will die from it. Data derive from vital registration systems, where usually a medical practitioner certifies the fact and cause of death. The International Classification of Diseases (ICD) provides a standardized system of nomenclature and coding, and a suggested format for the death certificate.

Mortality data are affected by both the degree of detail and the quality of the information, that is, the accuracy of the recorded cause of death and the completeness of registration. These are known to vary considerably between countries and over time. Mortality data are, however, more comprehensively available than incidence: The WHO mortality databank contains national cancer mortality data on over 70 countries, and for many, over extended periods of time. This availability partly explains its common application as a surrogate for incidence in both geographic and temporal studies of cancer, although its use must be guarded where survival differences are suspected between the groups being compared.

Prevalence is a more complex measure of cancer incidence, fatality, and other influences operating in affected individuals prior to death or cure. Partial prevalence is a useful measure for quantifying the resource requirements needed for treating and supporting cancer patients, as it limits the number of patients to those diagnosed during a fixed time in the past. Prevalence for cases diagnosed within a certain number of years are of relevance to initial treatment (within 1 year), clinical follow-up (2–3 years) and possible cure (4–5 years). There are some exceptions, primarily that of female breast cancer, for which the risk of death remains higher than the general population for many more years.

For several decades, the International Agency for Research on Cancer (IARC) has complied and published estimates of global cancer burden. The first publication in 1984 estimated cancer incidence for 12 common cancers in 1975 in 24 world areas (Parkin et al., 1984); the most recent estimates (for 2002) were compiled as part of IARC’s GLOBOCAN series published in 2004 (Parkin et al., 2005). This database contains regional and country-specific estimates of the cancer incidence, mortality, and prevalence worldwide for 26 cancer sites (Ferlay et al., 2004).

National cancer incidence and mortality data are available for a minority of countries of the world, so estimation procedures are necessary to obtain a comprehensive global picture of cancer. The available sources and methods used to derive the GLOBOCAN 2002 estimates are summarized in Table 1 and Figure 1 (incidence) and Figure 2 (mortality). The baseline data for the compilation are the cancer incidence, mortality, and survival data sets considered the best available within a given country. Incidence rates for a country are obtained wherever possible from cancer registries serving the whole population, or a representative sample of it. The most recent national mortality data from the WHO databank are used to obtain information on cancer deaths. As cancer registries record mortality as well as incidence, a country’s incidence may be estimated by applying a registry-based incidence: mortality ratio to its national mortality data. As mortality data are available for many more countries than incidence (Figures 1 and 2), there are known problems of accuracy and completeness. Adjustments are made where underrecording of mortality is suspected, and deaths recorded as uterus cancer are reallocated back to the specific sites of cervix or corpus uteri. Global prevalence is estimated from combining the estimated incidence data with appropriate estimates of survival (Pisani et al., 2002) (Table 1).

Geographical Variations in Cancer Worldwide

To provide a recent profile of global cancer burden as well as highlight some of the international variations, incidence, mortality, and prevalence estimates are presented from GLOBOCAN 2002. As well as describing the numbers of persons affected, comparisons of risk in different groups are described by the age-standardized rate using the weights from the world standard. Such an adjustment for age allows for the differing population age structures between countries and regions.

The international variability of cancer burden is briefly presented here according to 23 geographical areas for which the United Nations provides population estimates. In the following text, the terms developed and more developed refer to the regions or countries of North America, Europe (including all of the former USSR),

Australia and New Zealand, and Japan, and developing or less developed, the remainder. According to this classification and the corresponding United Nations (UN) population estimates, just over 5.1 billion people of the global population of 6.3 billion were living in less developed regions of the world in 2002, four times the number resident in developed areas (1.2 billion).

Almost 11 million people were diagnosed with cancer in 2002, over 6.5 million died from cancer, and approximately 24.5 million were living with cancer worldwide (Table 2). These total cancer estimates exclude nonmelanoma skin cancers, given difficulties in their accurate measurement and resultant lack of data. In terms of incidence, the leading four cancers, lung (12.4% of global total), female breast (10.6%), colorectum (9.4%), and stomach (8.6%) comprise over 40% of the world cancer burden. A similar percentage emerges for mortality, although lung cancer alone is responsible for one in every six of the deaths from cancer worldwide in 2002 (17.5%). Half of the global cancer mortality burden is explained by five cancers on adding liver cancer (responsible for 8.9% of all cancer deaths) to the above list. The relative magnitude of prevalence reflects both incidence and prognosis, and therefore the most prevalent cancers are female breast (17.9%) followed by colorectum (11.5%) and prostate (9.6%).

The distribution and frequency of the different cancer types varies by sex and region as well by the measure used to profile disease burden. In women, breast and cervical cancer rank first and second in frequency above colorectal, lung, and stomach cancers worldwide, while liver cancer in men ranks as the fifth most frequent cancer globally and the third most common cause of cancer death (Figure 3 and Table 3). Previous estimates for 1990 showed that the division of cancer burden between less and more developed countries was quite similar (Parkin et al., 1999). The more recent estimates indicate a disproportionate number of cancer cases occur in the developing world (53%), while in terms of mortality, closer to two-thirds of the burden now occurs in less developed regions (Table 4). The shift partly reflects increasing incidence rates of some common cancers in these areas, but the numbers of cases are also profoundly affected by the demographic phenomenon of continuing rapid population growth and aging, particularly in the developing world (see the section titled ‘Predicting cancer in 2020’). According to world area, about one-fourth of the global incidence (2.9 million new cases) and one-fifth of the global mortality (1.4 million deaths) occurs within Eastern Asia, which includes China; in contrast, an estimated 1400 new cases occurred in the Micronesia and Polynesia regions combined. On adjusting for population size and age structure, the comparison reveals a fourfold and threefold variation in age-standardized rates between regions in men and women, respectively (Figure 3). Overall rates are highest in North America, Australia/New Zealand, and Western Europe, and lowest in Northern and Western Africa (Figure 3).

The relative importance of different cancer sites also varies between and within the developing and developed regions (Table 3). Liver and cervical cancer are the fourth and fifth most common new cancers after lung, stomach, and female breast in less developed regions, while the incidence of esophageal cancer (ranking sixth) is more common than colorectal cancer. In developed areas, prostate cancer ranks above stomach cancer as the fourth most frequent cancer in 2002 (after lung, colorectal, and female breast), while cervical and esophageal cancer only rank 16th and 18th in frequency, respectively. The overall risk in different regions evidently reflects the additive contribution of different forms of cancer (Figure 4), so that in Northern Africa, for instance, rates are low for most cancer types other than bladder cancer in men and breast cancer in women. In contrast, in Southern Africa where rates are twice as high, there are elevated rates of a number of neoplasms including prostate, lung, and esophagus in men, and cervix and breast cancer in women.

Lung cancer has ranked as the most common neoplasm globally for several decades. In 2002, over 1.3 million new cases were diagnosed, of which almost one million were in men, making it the most frequent cancer to affect men and the third most common among women (Figure 3). Lung cancer incidence and mortality rates rank first in many developed and developing regions. Age-adjusted incidence rates are highest in Northern America (in both sexes) and in Europe, particularly among Eastern European men (Figure 5). Moderately high rates of lung cancer are seen in Eastern Asia (including China and Japan) and Oceania, with rates lowest in Africa.

Among women, breast cancer dominates in both developing and developed regions, with over 1.1 million new cases per year worldwide (Figure 3). Thus, close to one in four of the five million women diagnosed with a cancer in 2002 were diagnosed with breast cancer (Table 3), making it the second most frequent cancer when both sexes are considered together. In terms of mortality, breast cancer ranks lower (fifth) and given the high incidence and relatively favorable prognosis, it is by far the most prevalent form of cancer, with almost 4.5 million women diagnosed and living with breast cancer within the 5-year period up to 2002 (Table 2). More than half the incident cases occur in the developed world, with the highest incidence seen in Northern America, Oceania, and Northern and Western Europe (Figure 6). The disease tends to be less common in developing countries, although incidence rates are increasing in many (see the section titled ‘Cancer trends worldwide’).

There were just over one million new cases of colorectal cancer in 2002. Similar numbers of men and women are affected, with one in ten cancer patients diagnosed with this cancer. Approximately 50% fewer colorectal deaths (5.3 million) were estimated worldwide in the same year, making it the second most prevalent cancer globally (2.8 million). In more developed countries, two-thirds of a million colorectal cancer cases were estimated for 2002, ranking it second to lung cancer in global frequency (Table 2). It is the most common cause of cancer in Australia and New Zealand, and rates tend to be high in most developed regions (Figure 7 and Table 5). In formerly low-risk Japan, markedly increasing trends in colorectal cancer incidence have been observed in recent decades, to the extent that Japanese populations now have among the highest incidence rates in the world.

Stomach cancer has historically ranked as the second most frequent cancer worldwide, but according to the 2002 estimates, the disease ranked fourth (0.9 million new cases) behind lung, breast, and colorectum. It remains the second most common cause of mortality from cancer, however, with 0.7 million deaths occurring worldwide in the same year (Table 2). Roughly two-thirds of the new cases and deaths in 2002 occurred in men (Table 3), with a similar fraction occurring in developing countries. Rates are highest in Eastern Asia (Figure 8), notably in Japan, where one in five cancers diagnosed were stomach cancer. Rates are also elevated in Eastern Europe and in some South American countries, notably Uruguay and Argentina.

An estimated 0.7 million new cases of prostate cancer occurred worldwide in 2002 (Table 2), making this the fifth most common cancer globally and second in importance in males (Table 3). Mortality is much lower than incidence, with an estimated 0.2 million deaths in the same year (Figure 9). Three-quarters of the prostate cancer incidence worldwide occurred in the developed regions where the disease affects one in five male cancer patients. Incidence rates are notably elevated in North America, with rates considerably higher than next placed Australia/New Zealand, Northern and Western Europe. In contrast, rates in many developed countries are low: There is at least a 75fold variation in the incidence if one compares rates in the United States and China in 2002. The magnitude of such variations reflects more the high prevalence of prostate specific antigen (PSA) testing in some Western countries – as a means to detect latent cancers in asymptomatic individuals – than real differences in risk. In this respect, mortality rates may be a better guide to true geographical differences than incidence.

Liver cancer is the fifth most frequent cancer globally: Over 0.6 million new cases were estimated in 2002 (Table 2). Due to its poor prognosis, it is also the third most common cause of cancer death after lung and stomach cancer, with just under 0.6 million deaths in the same year. Much of the burden is observed among men and populations residing in developing regions: It is the third most common cancer of cancer incidence and the second most common cause of cancer death among males. Rates are highest in Eastern Asia, with China having half of the global liver cancer burden (Figure 10). Rates are also elevated in Central and Eastern Asia.

Esophageal cancer was responsible for approximately 0.45 million of the global cancer incidence and has a rather poor prognosis, almost 0.4 million deaths (Table 2). Over four-fifths of the burden is borne by the less developed world, where it is the fourth most common cause of cancer death after lung, liver, and stomach cancer. The geographic variability in the risk of esophageal cancer worldwide is striking, with the highest risk areas of the world in the so-called esophageal cancer belt, which extends from northern Iran through central Asia to north-central China. Rates are thus elevated in Eastern Asia, but are also high in sub-Saharan Africa (Figure 11).

Cervix cancer is the second most common cancer among women worldwide in 2002, with almost 0.5 million new cases and about 0.25 million deaths (Table 3). Over 80% of the burden occurs in the less developed regions, where cervix cancer accounts for 15% of female cancers. The highest incidence rates are observed in Southern and Eastern Africa, Melanesia, and the Caribbean (Figure 12). Rates in most developed countries are low, and overall, cervix cancer accounts for less than 4% of the total cancer incidence burden.

Kaposi’s sarcoma is a very rare form of cancer in most world regions but is now one of the most common cancers in sub-Saharan Africa as a result of the AIDS epidemic. Approximately 57 000 new cases occurred in Africa in 2002 and, due to poor survival associated with AIDS, approximately 52 000 deaths.

Cancer Trends Worldwide

Investigations of cancer trends have important applications in epidemiological research and in planning and evaluating cancer control strategies. Analyses of how rates of different cancers are changing in different populations over time can provide clues to the underlying determinants and serve as an aid to formulating, implementing, or further developing population-based preventative strategies. Genetic factors have only a minor impact on time trends of cancer in the absence of large migrational influxes and exoduses within the population under study.

Issues concerning data quality and other detectable artifacts in interpreting time trends have been comprehensively addressed (Saxen, 1982; Muir et al., 1994). Truly valid studies would require, for instance, that the definition and content, criteria of malignancy, and likelihood of diagnosis of cancer have not changed with time, that case ascertainment has been equally efficient throughout the study period, that ICD indexing has not changed, and the accuracy and specificity of coding is consistent with time (Muir et al., 1994). Although few data series would meet each of these criteria, cancerspecific artifacts and their likely effects on time trends are reasonably well understood. The efforts of cancer registries in standardizing procedures and data definitions have been important in establishing consistently the high quality and comparability of cancer incidence data over time.

Global trends in the five most common cancers are presented as age-adjusted incidence rates by 5-year calendar period using data from 16 cancer registries representing countries within four regions complied in successive volumes of CI5. While these figures can only provide a broad overview of trends, references are made to trends in cancer mortality (where the trends diverge from incidence), in the age-specific rates by calendar period or birth cohort (where the age-adjusted trends are partially misleading), and according to subsite or histological groups (where they differ from the overall trend).

Lung Cancer

Temporal studies of lung cancer incidence and mortality have played an important role in validating smoking as the primary cause of the disease. The contrasting trends observed in different parts of the world largely reflect the changing profile of tobacco use – the number of cigarettes smoked, the duration of habit, and the composition of the tobacco – within different populations over time. Among males (Figure 13), overall rates in many developed countries – in Northern Europe, Northern America, and Australia – have tended to peak and subsequently decline, although there is a distinct variability in the magnitude of the rates and the year of peak incidence. There have been dramatic increases in rates in many Eastern European countries including Hungary, which presently has the highest rate worldwide. In contrast, there are the beginnings of a decline in some European countries, as observed in Spain and Slovakia (Figure 13). Uniform increases are observed in Japan, with rates of lung cancer doubling within 20 years. In the developing countries displayed in Figure 13, rates tend to be reasonably stable or decreasing; there is, however, a consistent and large variation in lung cancer risk: Rates in Cali are, for instance, five times those of Mumbai.

The global profile of female lung cancer trends is somewhat different. Rates tend to be steadily increasing with time in most countries, an observation that reflects the more recent acquisition of the smoking habit among women (Figure 14). In some Western populations – in the United States and United Kingdom, where the downturn in the prevalence of smoking among women has been established longest – plateaus and recent declines are emerging in the trends. In Spain, as in many (mostly developing) countries, lung cancer rates have been historically low. However, recent increases – as can be can now be detected in the Zaragoza population – illustrate the shift in smoking activity among women during the past two or three decades. A similar pattern can possibly be seen in Mumbai, India.

Recent estimates of the proportion of lung cancer cases due to smoking indicate about 85% of cases in men and 47% in women are due to smoking worldwide, although there is considerable regional variation, and these figures are more representative of countries/regions with a long history of smoking: The current fraction is much lower, for example in Africa and Southern Asia. With transnational tobacco companies using a global tactic to expand their sales, however, a smoking epidemic is emerging in many developing countries and the corresponding attributable fraction is likely to increase. The extent of the projected increases in lung cancer and other tobacco-related diseases have been quantified in China, the pattern of substantially increased burden will likely be repeated in many countries in Asia, Africa, and South America (Peto et al., 1999).

Since the 1950s, its has been established that lung cancer incidence or mortality trends by age are primarily a birth cohort phenomenon, that is, incidence rates in a given birth cohort can be related to the smoking habits of the same generation. The smoking epidemic therefore produces changes in rates first observed within younger age groups that lead to increasingly higher overall rates as these generations reach the older age groups, where lung cancer is most common. Figure 15 depicts lung cancer mortality rates plotted against birth cohort by age for U.S. men and women according to race (Devesa et al., 1989), and provides an illustrative example of the importance of these generational influences. Successive cohort-specific declines in mortality can be observed in men born in the 1930s and in women born 10–15 years later, as they begin to relinquish the smoking habit. The impact of the phenomenon in the overall age-adjusted rates can be seen in Figures 13 and 14.

There are intriguing differences in time trends by histological type of lung cancer. Squamous cell carcinoma incidence rates among men have declined in North America and in some European countries, whereas among women they have generally increased. In contrast, lung cancer adenocarcinoma rates have increased in both sexes in many world areas. Such observations are probably explained by shifts in cigarette composition, towards low-tar, low-nicotine, and filtered cigarettes (Wynder and Muscat, 1995).

Female breast cancer incidence and mortality rates have been increasing in many populations in both developed and developing regions in the last few decades. The temporal patterns are complex, however, in view of the numerous and interactive risk factors involved, as well as the introduction of screening (affecting both incidence and mortality) and improving therapy (affecting mortality) in some Western countries. In several Nordic countries, England and Wales, and The Netherlands, incidence rates had been rising before the introduction of national screening programs in the mid to late 1980s (e.g., Sweden in Figure 16) (Botha et al., 2003). Mean annual incremental increases of 1–3% were observed in a number of European countries in the 1980s and 1990s, including those that had either not introduced programs, had implemented them recently, or had only regional or pilot programs under way (e.g., Slovakia in Figure 16).

The pattern observed in North America resembles that of Europe, with similar increases in incidence in both white and black women (Figure 16). Most of the increase in the United States occurred in the early to mid-1980s and is related to the escalation of screening during this time. The overall rate of increase slowed in the late 1980s. Early studies of Connecticut incidence trends prior to widespread mammography emerging documented the importance of birth cohort effects (Stevens et al., 1982).

Increasing mortality rates were observed in many Western countries from the 1950s to 1980s, particularly in eastern and southern Europe. A plateau and subsequent decline in mortality in the 1980s in several northern European countries has also been noted in the United States and Canada. The decrease was seen in both younger and older women (Figure 17). Despite the international consensus that there is sufficient evidence for the efficacy of screening women aged 50–69 by mammography in reducing breast cancer mortality (International Agency for Research on Cancer, 2002), quantification of its contribution to the observed mortality declines has been problematic. While some of the overall reduction in breast cancer mortality has been attributed directly to screening via prediction models, the observed declines – a 25% reduction by 2000 – started in 1986, before screening was introduced. In addition to mammography, a number of improvements have probably contributed to the trend, and include the establishment of treatment protocols, improved chemotherapeutic options, and better therapeutic guidelines. Some recent decreases in mortality are also seen in several countries without national screening programs, although these tend to be confined mainly to younger age groups. Mortality is increasing in several eastern European countries, including the Russian Federation, Estonia, and Hungary.

Some of the largest increases in breast cancer mortality are observed in non-Western countries historically at relatively low risk (Figure 17). Breast cancer remains relatively rare in Japan for instance, although rates of both incidence and mortality have been increasing fairly rapidly (Figures 16 and 17), an observation consistent with the reported increasing risk among successive generations of women (Wakai et al., 1995). In less developed countries, increases in breast cancer incidence and mortality are evident and are often more marked in younger generations of women (Parkin, 1994). There have been reported increases in Bombay, Shanghai, Singapore, and Hong Kong in the last few decades, although in relatively highrisk South American countries such as Uruguay and Chile, the observed mortality rates are reasonably stable among younger women (Parkin, 1994). These increases are often attributed to the westernization of lifestyles, an ill-defined surrogate for changes in factors such as childbearing, dietary habits, and exposure to exogenous estrogen, toward a distribution closer in profile to that of women of the industrialized countries in the West. In Japan, for instance, decreasing age at menarche, increasing age at menopause, decreasing fertility, increasing age at first birth, and increases in both height and weight have been noted (Wakai et al., 1995).

While there are some important differences in the epidemiological characteristics of colon and rectal cancer, Figures 18 and 19 depict the sex-specific trends for colon and rectum combined, thus avoiding the recognized problems of varying subsite allocation of cancers found at the rectosigmoid junction. The most notable features of global trends are the rather rapid increases in male and female rates in countries formerly at low risk. The greatest increases in incidence of colorectal cancer are in Hong Kong, Singapore, Israel, and particularly in the presently high-risk Japan, where there has been a threefold increase in incidence in men in just two decades (Figures 18 and 19). There have also been large rises in several Eastern European countries, including Slovakia, Hungary, and Poland as well as in parts of South America, including Colombia and Puerto Rico. In the high-risk countries, incidence trends are either gradually increasing (South Thames, Sweden), stabilizing (New South Wales), or declining with time (North America). Such moderation has been noted particularly in younger age groups (Coleman et al., 1993). In contrast to the recent attenuation of rates seen in some Western and Northern European countries, relatively large increases have been also observed in Spain (Figures 18 and 19).

Declines in mortality may be a consequence of changes in incidence, a result of progress in therapy or a result from the effects of improved early detection. The pattern in the United States is probably due to more widespread screening, resulting in stage-specific shifts in incidence and a subsequent increase in survival (Troisi et al., 1999).

In high-risk Western countries, there has been a notable shift in the subsite distribution within the colorectum, with increases in incidence of proximal (ascending colon) relative to distal cancer (descending and sigmoid colon) (Thorn et al., 1998; Troisi et al., 1999). In low-risk populations such as Singapore, however, the reverse effect has been reported (Huang et al., 1999), while the trend in proximal and distal rates was similar in Shanghai ( Ji et al., 1998). For rectal cancers, the countries with the most rapid increases tend to be in Eastern Europe and Japan. In the United States, there has been a decline in incidence and mortality for several decades in females of both races and in white men, although a recent increase in rectal cancer is apparent in black males (Troisi et al., 1999).

The risk factors that could explain the geographical and temporal variations in colorectal cancer are likely numerous and interactive. The observed declines in distal cancer incidence in some Western populations may be the result of increasing detection and treatment of premalignant polyps, although some improvements in the quality of the diet in younger generations may explain the observation, notably in the United States and some European populations, and the result of cohort-led declines in incidence rates among younger age groups (Coleman et al., 1993). Where rates are increasing, in Asia and in Eastern Europe, a westernization of lifestyle may in part be responsible, particularly with respect to a Western diet. The rapid increases in some populations in Asia imply the importance of genetic susceptibility.

Uniform declines in rates during the last half century in most populations worldwide remain the central epidemiological feature of stomach cancer; the effect can be seen in both men (Figure 20) and women (Figure 21). While the decreases are more marked in more affluent countries, trends in those developing countries with suitable data also portray downward trends (Figures 20 and 21). The temporal profile is consistent with improved food preservation techniques and better nutrition, particularly the invention of refrigeration for the transport and storage of food, making obsolete salting, smoking, and pickling. There is also evidence that, at least in Western countries, there is a progressive decline in infection rates with Helicobacter pylori between successive birth cohorts, likely a result of continual changes within the childhood environment.

Some studies have reported that the declines in gastric cancer are restricted to intestinal-type adenocarcinoma, with rather stable incidence trends observed for the diffuse-type carcinomas. There has been particular interest in the distinct trends of cancers of the gastric cardia, where rising rates are observed in several populations (Powell et al., 2002). While explanations are not yet established, there have been concomitant increases in the prevalence of Barrett’s esophagus and adenocarcinoma of the lower third of the esophagus. It is possible, therefore, that much of the increase in cardia incidence represents misclassification of cancers at the gastroesophageal junction (Ekstrom et al., 1999).

The large increases in prostate cancer incidence in highrisk countries shown in Figure 22 can be attributed mainly to increasing detection following transurethral resection of the prostate (TURP), and, more recently, due to the use of PSA. In the United States, incidence rates were increasing slowly up to the 1980s (Figure 23), probably due to a genuine increase in risk, coupled with an increasing diagnosis of latent, asymptomatic cancers in prostatectomy specimens, due to the increasing use of TURP (Potosky et al., 1990). Beginning in 1986, and accelerating after 1988, there was a rapid increase in incidence, coinciding with the introduction of testing with PSA, allowing the detection of preclinical (asymptomatic) disease (Potosky et al., 1995).

Prostate cancer mortality rates in the United States had been increasing slowly since the 1970s (Figure 23). With the introduction of PSA screening, and the dramatic surge of incidence induced by it, there was an increase in the rate of increase in mortality, but this was very much less marked than the change in incidence. More recently (since 1992 in white men, 1994 in black men), mortality rates have decreased. The contribution that PSA screening and/or improved treatment has made to the slow, steady decline continues to be the subject of much debate. The increased mortality is probably partly due to miscertification of cause of death among the large number of men who had been diagnosed with latent prostate cancer in the late 1980s and early 1990s. The later decline may be partly attributable to a reversal of this effect; it seems unlikely that screening was entirely responsible. The lead-time (between screen detection and usual clinical presentation) would have to be very short, if screening were to have such a rapid effect on mortality. Similar mortality trends have been reported in Australia, Canada, the UK, France, and the Netherlands, although, in general, they are less pronounced, or occurred later, than in the United States. In some of the countries concerned (Canada, Australia), there has been considerable screening activity, but this is not the case in others where the falls in mortality are just as marked (France, Germany, Italy, UK) (Oliver et al., 2001).

Predictions of future cancer burden have become established tools in planning health policy and allocating future resources, as well as in measuring the success (or failure) of specific interventions. Commonly, predicted rates are obtained by extrapolating recent trends forward into the future via a simple statistical model, with the corresponding population projections applied to this to obtain the predicted number of cases. On a global scale, however, it is not easy, even for the major cancer sites, to predict burden in 2020 by such means. Historical patterns are not always a sound basis for future projections, and past trends of the common cancer forms are often different between and within world regions. Further, it is impossible to achieve in practical terms, given the insufficient availability of data for most of the world.

It is assumed, therefore, that current overall cancer incidence rates will be the same in 2020, with the predicted numbers presented by applying sex and age-specific population forecasts for the same year. Irrespective of changing risk, population growth and aging are extremely important in determining likely future burden, and demographic changes will continue to have major consequences over the next half century, particularly in the developing world. One illustrative scenario that allows for changing risk of several common cancers is also examined.

Table 6 displays the predicted number of new cases of all cancers based on the estimated incidence rates in 2002 applied to population projections in 2020. In the absence of changing risk or intervention, it is projected that by 2020, there will be about 15.8 million new cases of cancer worldwide, an approximately 45% increase from 2002. Three fifths of the total burden will reside in less developed regions as a result of a more rapid aging and population growth. The greatest relative increase in developing countries will occur among the elderly (defined here as aged 65 or over): An 80% increase is projected from the 2 million cases in 2002 to 3.7 million by 2020. Worldwide, roughly half of the predicted 5 million additional incident cases in 2020 will occur in this age group.

To give an indication of the impact of changing risk on future numbers, Table 7 shows the additional burden that would occur if the generally observed (increasing) breast, colorectal, and prostate cancer incidence trends and (decreasing) stomach cancer trends were to continue at a rate of growth/reduction of 1% per annum. While the increases are modest compared to the demographic component, a nearly 0.75 million additional new cases would be expected in 2020 given the combined 1% increases in breast, colorectal, and prostate cancer rates. This would be partially offset by a quarter million drop in incidence were stomach cancer rates to decline with the equivalent rate of change.

In practice, the net effect of time trends on future worldwide burden is difficult to guess. For several sites, trends are in different directions in different world regions and can change direction even on the short term, as has been observed for lung cancer in the last decade. The foreseeable demographic changes are projected to substantially increase the magnitude of global cancer incidence in the next decades. Other than making provisions for an older and disproportionately larger number of persons diagnosed with cancer within the developing regions, effective cancer control activities – including the capacity to reduce and nullify the tobacco epidemic – can limit its impact. This is particularly the case among the vast populations living in Asia, Africa, and South America, where the destructive effects of tobacco to health are beginning to be realized.

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Lung Cancer Research Results and Study Updates

See Advances in Lung Cancer Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

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Dr. John Bell awarded lifetime achievement prize by Canadian Cancer Society

The prize recognizes an individual who, “through vision and leadership, has enhanced the Canadian cancer research landscape to benefit people with cancer.”

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One of Ottawa’s most distinguished scientists, Dr. John Bell, has received a lifetime achievement award from the Canadian Cancer Society.

Bell, 71, will receive the society’s Lifetime Contribution Prize, which recognizes an individual who, “through vision and leadership, has enhanced the Canadian cancer research landscape to benefit people with cancer.”

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A leading international expert on the use of viruses to infect and kill cancer cells, Bell has published more than 400 research papers while leading a host of capacity-building initiatives to bolster Canada’s ability to offer cutting-edge immunotherapies.

He has helped launch The Ottawa Hospital’s Biotherapeutics Manufacturing Centre, BioCanRx, a network of immunotherapy researchers, the Canadian Oncolytic Virus Consortium and the Canadian Pandemic Preparedness Hub.

Bell has also sought to leverage the power of private sector investment to develop cancer-killing viruses through his work with biotech firms such as Turnstone Biologics, Jennerex Biotherapuetics and Transgene.

He is a senior scientist at The Ottawa Hospital and professor at the University of Ottawa.

“Dr. Bell is not only a brilliant and creative researcher, but he is passionately dedicated to ensuring that promising therapies find their way to the Canadian patients who need them,” said Dr. Rebecca Auer, executive vice-president of research and innovation at The Ottawa Hospital.

Born and raised in Hamilton, Bell attended Westmount Secondary School, where he played football — “I wanted a career as a professional football player, but I was too small and too slow,” he said — before studying science at McMaster University. In the fourth year of his undergraduate degree, he joined a lab as part of his thesis work.

Ever since, the lab has been part of Bell’s life.

“I found that doing research was really stimulating for me, really interesting, so I continued to pursue that,” he explained in an interview.

As a PhD student, his thesis examined the biology of the vesicular stomatitis virus (VSV). He would return to virology again and again during his career.

“Viruses need the cell in order to replicate, so I always felt, if you could understand viruses, it would help us gain inroads into helping us understand how cells work,” Bell said. “Viruses were really a tool at that time to understand how they use cellular machinery to replicate. Almost everything we know about cells is from studying viruses and host cell interactions.”

After McMaster, Bell spent three years as a post-doctoral fellow at the University of Ottawa, where he worked on a research team led by Prof. Mike McBurney, a cell biologist who was comparing the behaviour of cancer cells to normal cells. The lab was the first in the city to use stem cells for that purpose.

After more post-doctoral work at the Medical Research Council in London, England, Bell began his independent research career in 1986 at McGill University as a biochemistry professor. He studied the molecular biology of cancer cells.

As part of that work, he cloned protein-tyrosine kinases, and discovered that one of the enzymes mutated in cancer cells to better defend the organism against viruses.

It led him to believe that cancer cells could be susceptible to viral infection — an insight that launched the defining pursuit of his career.

In 1989, he moved to uOttawa’s Department of Medicine where a new program in developmental biology promised an emphasis on translational research — science that moves from the lab bench to patient clinics.

“I wanted to be able to take my discoveries and translate them to the clinic as best I could, as quickly as I could,” he said.

Bell discovered that as cancer cells evolve, they develop genetic defects that make them more susceptible to viruses, which have the added benefit of activating the body’s immune system in the fight against cancer.

Seeking to capitalize on his findings, Bell developed a number of targeted, genetically engineered viruses to kill cancer cells without harming healthy ones.

Bell was part of a research team that proved in a clinical trial that administering cancer-killing viruses in the blood of people with cancer was safe and effective. Later, they showed that these oncolytic virotherapies are most successful in cancer’s early stages. Additional studies have demonstrated the potential of combining viruses with other cancer drugs and biotherapeutics.

Unusually collaborative, Bell has brought a team-minded approach to science. He points to those collaborations — and his many mentorships — as his proudest achievements.

“It’s really exciting to come to work every day with all of these bright young people that I work with,” he said, adding: “That’s pretty inspirational so I don’t really see a reason to retire.”

Andrew Duffy is a National Newspaper Award-winning reporter and long-form feature writer based in Ottawa. To support his work, including exclusive content for subscribers only, sign up here:  ottawacitizen.com/subscribe

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