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• v.8; Jan-Dec 2021

Educational Case: HER-2 Positive Breast Cancer

Julia jennings.

1 Department of Pathology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, MA, USA

Jennifer L. Clark

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040 . 1

Primary Objective

Objective BR2.7: Factors Affecting Response and Prognosis of Breast Cancer . Explain the prognosis and likelihood of recurrence and response to therapy for breast cancer patients based on knowledge of molecular classification and/or gene expression profiling, morphologic classification, grade, prognostic marker studies, and other predictive factors.

Competency 2: Organ System Pathology, Topic: Breast (BR), Learning Goal 2: Molecular Basis of Breast Neoplasms

Patient Presentation

A 65-year-old woman with no relevant past medical history is found to have a spiculated right breast mass measuring approximately 1.6 cm on routine mammogram. She has had unremarkable annual screening mammograms since her first mammogram at age 50. Her family history is significant for breast cancer in her mother and maternal grandmother, both older than 75 years at diagnosis.

Diagnostic Findings, Part 1

The patient undergoes an ultrasound-guided core needle biopsy, shown in Figure 1 . The biopsy demonstrates small clusters and single cells with enlarged and pleomorphic, hyperchromatic nuclei and moderately increased mitoses infiltrating through stroma. A diagnosis of poorly differentiated invasive ductal carcinoma is rendered. There is no evidence of lymphovascular invasion or in situ carcinoma.

Results of breast core needle biopsy. A hematoxylin & eosin–stained tissue section from the breast core needle biopsy demonstrates poorly differentiated invasive ductal carcinoma (10× objective).

Questions/Discussion Points, Part 1

What biomarkers are routinely performed on new diagnoses of breast cancer.

Newly diagnosed cases of breast carcinoma undergo testing for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER-2) receptor.

How Are These Biomarkers Evaluated, and What Is Their Clinical Significance?

Both ER and PR status are evaluated by immunohistochemistry alone, while HER-2 status can be determined by immunohistochemistry and/or fluorescence in situ hybridization (FISH). The expression of these markers contributes to prognosis, as well as targeted therapy. 2

Estrogen receptor and PR are both nuclear hormone receptors that operate as ligand-dependent transcription factors. Approximately 50% to 60% of breast cancers are ER positive. Hormone receptor positivity predicts tumor progression and mortality benefit from endocrine therapies such as tamoxifen. 2

HER-2 is a transmembrane receptor with tyrosine kinase activity that mediates growth, differentiation, and survival of cells via multiple signal transduction pathways. Approximately 15% to 25% of breast cancers overexpress this gene which is typically associated with more aggressive tumor behavior. 3 In fact, the quantitative amount of HER-2 overamplification has been found to be in direct association with worse clinical outcomes. 4 HER-2 overexpression and amplification have also been found in cancers of other sites, such as the stomach, ovary, colon, bladder, and esophagus. 2

The first step in routine evaluation of HER-2 is immunohistochemistry, following a scoring system illustrated in Figure 2A to D . A tumor demonstrating circumferential membrane staining that is complete, intense, and in >10% of the tumor cells is scored immunohistochemistry (IHC) 3+ and is considered HER-2 positive. Conversely, a tumor with incomplete membrane staining that is faint and in >10% of tumor cells is classified as IHC 1+ and is considered HER-2 negative. Weak to moderate complete membrane staining observed in >10% of tumor cells is classified as IHC 2+ and is considered equivocal. In equivocal cases, the sample should be evaluated with FISH.

Human epidermal growth factor (HER-2) immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) guideline summary. (A) No perceptible staining or barely perceptible incomplete membrane staining in <10% of tumor cells (IHC 0; 40× objective), (B) faint, barely perceptible incomplete membrane staining in >10% of tumor cells (IHC 1+; 40× objective), (C) weak to moderate complete membrane staining in >10% of tumor cells (IHC 2+; 40× objective), (D) intense, complete circumferential membrane staining in >10% of tumor cells (IHC 3+; 40× objective), (E) negative HER-2 FISH demonstrating HER-2 copy number <4.0 and HER-2/CEP17 ratio <2.0 (HER-2: red signal, CEP17: green signal; 100× objective), (F) positive HER-2 FISH demonstrating HER-2 copy number >6.0 and HER-2/CEP17 ratio >2.0 (HER-2: red signal, CEP17: green signal; 100× objective).

Fluorescence in situ hybridization is used to identify and quantify amplification of the HER-2-neu gene and is viewed as the “gold standard” for determining which patients would benefit from HER-2-targeted therapy. Fluorescence in situ hybridization is a molecular technique that utilizes fluorescent probes complementary to the nucleic acid sequence of interest, in this case, the HER-2-neu gene. The HER-2-neu copy number can either be evaluated alone or in comparison to the copy number of internal centromeric control (typically the region termed CEP17), as summarized in Table 1 . Under normal circumstances, each cell will demonstrate 2 copies of both the HER-2-neu and CEP17 regions (1:1 ratio), but in the presence of an amplified HER-2-neu gene, there will be an excess of HER-2-neu signals in relation to CEP17 signals. Examples of both negative and positive FISH results are included in Figure 2E and F . A downside of FISH testing is that it is often more expensive than immunohistochemistry. 2 , 5

Summary of HER-2 FISH Reporting Guidelines.

Abbreviations: FISH, fluorescence in situ hybridization; HER-2, human epidermal growth factor; IHC, immunohistochemistry.

* Additional workup varies depending on the HER-2/CEP17 ratio and average HER-2 copy number in a particular case but may include review of HER-2 IHC, repeat FISH scoring by a second observer, and/or use of alternate probe sets.

What Other Factors Affect the Prognosis of Breast Cancer?

Tumor grade (well, moderately, or poorly differentiated), determined through scoring of tubule formation, nuclear atypia, and mitotic count, is a major factor affecting the prognosis of breast cancer. In addition, molecular subtypes, including luminal, normal breast-like, HER-2-enriched, and basal-like types, identified through extensive molecular profiling of a large number of breast cancer samples, play a major role in prognosis and treatment response. These topics are further discussed in a previously published educational case. 6

Diagnostic Findings, Part 2

This patient’s breast cancer is negative for ER and PR. Immunohistochemistry staining results for HER-2 are shown in Figure 3 . HER-2 IHC is scored as 2+ (equivocal) for HER-2, demonstrating weak to moderate complete membrane staining in >10% of tumor cells. Due to this result, the sample is tested reflexively by FISH.

Human epidermal growth factor (HER-2) immunohistochemistry (IHC) on breast core needle biopsy. The HER-2 IHC demonstrates moderate complete membrane staining in >10% of tumor cells (IHC 2+; 10× objective).

Fluorescence in situ hybridization results demonstrate amplification of the HER-2/neu gene. Using the CEP17 gene as an internal centromeric control, the HER-2/CEP17 ratio is 3.7, while the average nucleus contains 9.4 copies of HER-2. This result indicates that this patient’s breast cancer is HER-2 positive.

Questions/Discussion Points, Part 2

Discuss the biology of the her-2 protein and its role in breast cancer.

The HER-2/neu belongs to a family of 4 human epidermal growth factor receptors: HER-1, HER-2, HER-3, and HER-4. Each is characterized by a cysteine-rich extracellular ligand-binding site, a transmembrane lipophilic segment, and an intracellular domain with tyrosine kinase activity. More specifically, the HER-2 receptor is a 1255 amino acid, 185 kD transmembrane glycoprotein located on the long arm of human chromosome 17 (17q12). It has no direct activating ligand and thus requires heterodimerization with other epidermal growth factor receptor (EGFR) family receptors such as HER-1 and HER-3. Dimerization and autophosphorylation of the HER-2 receptor tyrosine residues initiates various signal transduction pathways including mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphophate 3-kinase, and protein kinase C. 2 When amplified or overexpressed, uncontrolled overactivation of these pathways leads to tumorigenesis and increased tumor aggressiveness. The HER-2 overexpression in breast cancer is related to the amplification of the otherwise normal gene rather than mutation. For this reason, HER-2 targeted therapy does inherently carry the risk of damaging normal tissues which express the protein.

Discuss the Epidemiologic Features of HER-2 Positive Breast Cancer

It has been found that ER/PR+HER-2− breast cancers are associated with better survival rates, followed by ER/PR+HER-2+ breast cancers, while triple-negative cancers (ER/PR-HER-2−) are associated with the shortest survival rates of these categories. Although HER-2 positive breast cancers were historically among the most aggressive cancers with the worst prognosis, the advent of HER-2-targeted therapy has improved survival rates significantly, such that HER-2 positive breast cancers now demonstrate similar or better outcomes than triple-negative breast cancers when matched for stage. The distribution of breast cancer subtypes varies by age, race, ethnicity, and other factors. Compared with women who have ER/PR+/HER-2− breast cancer, those diagnosed with other subtypes (ER/PR+/HER-2+, ER/PR-/HER-2+, or ER/PR-/HER-2−) are more likely to be younger, belong to minority groups, and be diagnosed with cancer at a later stage. 7 BRCA1/BRCA2 mutations are associated with lower rates of HER-2 positive breast cancer. 8

What Is the Prognosis of HER-2 Positive Breast Cancer?

HER-2 positive breast cancers have been found to have a worse overall prognosis than HER-2 negative breast cancers. Population-based studies have shown that overexpression of HER-2 is associated with poorly differentiated, high-grade tumors, high proliferative rates, lymph node involvement, and relative resistance to certain types of chemotherapy. 9

Studies have shown that HER-2 positive breast cancers carry an increased risk of cerebral metastasis compared with ER/PR+ breast cancers and that HER-2-positivity is associated with earlier cerebral metastasis in the disease course. 10 It is believed that once HER-2 amplification occurs, the HER-2 phenotype is fixed throughout the tumor’s lifetime. As a result, testing for HER-2 may be performed on either a primary tumor or a metastatic deposit. 2

Discuss the Management of HER-2 Positive Breast Cancer

The advent of HER-2-targeted therapies has significantly improved the outlook for patients with HER-2 positive breast cancer. Trastuzumab (Herceptin), a monoclonal antibody targeting the HER-2 receptor, has been found to cause internalization and downregulation of the receptor. 11 It has also been found to reduce mortality and recurrence rates in HER-2 positive breast cancers. Studies have shown that the addition of trastuzumab to adjuvant chemotherapeutics such as paclitaxel, doxorubicin, and cyclophosphamide can reduce the rates of recurrence by half. 3 , 11 Due to the persistence of the HER-2 phenotype, trastuzumab has also been found to improve outcomes for both local and distant disease. 2 Additional therapy options include pertuzumab, a monoclonal antibody thought to interrupt HER-2/HER-3 dimerization, and neratinib, a tyrosine kinase inhibitor believed to interact with HER-2 and other EGFR kinases. 12

Approximately half of HER-2 positive breast cancers are also ER positive, PR positive, or both. However, the levels of these hormone receptors are typically lower than in HER-2 negative, hormone receptor positive tumors. For this reason, most HER-2 positive breast cancers are relatively resistant to tamoxifen and other endocrine therapies. 9

Current guidelines do not recommend the use of trastuzumab or other anti-HER-2 therapies in HER-2 negative breast cancers. Treatment for these tumors typically includes endocrine therapy (if ER/PR+) or single-agent chemotherapy.

Diagnostic Findings, Part 3

The patient’s stage is determined to be a clinical stage cT1cN0 based on physical examination and imaging findings.

Questions/Discussion Points, Part 3

How is breast cancer staged.

Breast cancer is staged using the TNM (tumor, node, metastasis) system which assesses the size and local extent of the primary tumor (T), presence or absence and number of axillary lymph node (N) metastases, and presence or absence of metastasis (M) at distant sites. Although clinical staging, designated by the prefix “c” is performed prior to surgery using data gathered from physical examination and imaging studies, including breast, axillary, and whole body imaging as indicated; pathologic staging, designated by the prefix “p,” is performed after surgery using data gathered from the resulting excision specimen. 13 In this patient case, stage cT1cN0 refers to a localized breast cancer measuring 1 to 2 cm on imaging without evidence of nodal metastasis.

How Does the Clinical Stage Affect Initial Management of Breast Cancer?

Treatment of breast cancer is interdisciplinary, utilizing expertise from medical oncology, radiation oncology, and surgery. Although low stage, localized cancer is often treated initially by surgical excision, higher stage cancers may require up-front neoadjuvant chemotherapy to reduce the tumor burden prior to surgery. Patients with known or suspected lymph node metastasis may undergo complete removal of the axillary lymph nodes at the time of surgery, as well. However, patients such as the one in this case without suspected lymph node metastasis may undergo sentinel lymph node biopsy only (the primary node draining from the breast lymphatics, as identified by a blue dye and/or radiotracer injected into the breast at the time of surgery). If the sentinel node is positive for metastatic tumor, further surgery or radiation may be pursued to treat the remaining axillary lymph nodes. The presence of distant metastasis may preclude surgery altogether, with a focus on palliative chemotherapy and radiation.

Teaching Points

• Pathologic factors affecting the prognosis of breast cancer include tumor grade, molecular subtype, and expression of ER, PR, and HER-2.
• HER-2 is part of a family of receptors that work together within various signal transduction pathways to promote growth, differentiation, and survival of cells. Amplification and overexpression of HER-2 may be seen in a subset of breast cancers.
• Primary evaluation for HER-2 status should be performed by immunohistochemical staining, with equivocal results evaluated by FISH. A positive FISH result is the gold standard for determining whether a patient would benefit from HER-2-targeted therapy.
• HER-2 positive breast cancers are often more aggressive, less responsive to treatment, and associated with decreased survival rates, though the advent of HER-2-targeted therapy has significantly improved prognosis.
• Current management recommendations for HER-2 positive breast cancer include HER-2-targeted therapy (such as Trastuzumab) with adjuvant chemoradiation. Endocrine therapies (such as tamoxifen) have not been found to be effective for tumors with HER-2 amplification.

Acknowledgments

The authors would like to acknowledge Dr Dina Kandil for her assistance in reviewing the content of this manuscript.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Faculty and Disclosures

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All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated according to Medscape policies. Others involved in the planning of this activity have no relevant financial relationships.

Sara A. Hurvitz, MD, FACP

Professor of Medicine Head, Division of Hematology and Oncology Senior Vice President, Clinical Research Division Department of Medicine UW Medicine Fred Hutchinson Cancer Center Seattle, Washington

Sara A. Hurvitz, MD, FACP, has the following relevant financial relationships: Research funding from: Ambrx; Amgen Inc.; Arvinas; AstraZeneca; Bayer HealthCare; Celcuity; CytomX Therapeutics; Daiichi-Sankyo; Dantari; Dignitana; Genentech/Roche; G1-Therapeutics; Gilead Sciences, Inc.; Greenwich Life Sciences Inc.; GlaxoSmithKline; Immunomedics; Lilly; Macrogenics; Novartis Pharmaceuticals; OBI Pharma; Orinove; Orum; Pfizer, Inc.; Phoenix Molecular Designs, Ltd.; Pieris; PUMA; Radius; Samumed; Sanofi; Seagen; Zymeworks

Joyce A. O’Shaughnessy, MD

Celebrating Women Chair in Breast Cancer Research Baylor University Medical Center Chair, Breast Cancer Committee Texas Oncology Sarah Cannon Research Institute Dallas, Texas

Joyce A. O’Shaughnessy, MD, has the following relevant financial relationships: Consultant or advisor for: AbbVie Inc; Agendia; Amgen Inc.; Aptitude Health; AstraZeneca; Bayer HealthCare; Bristol Myers Squibb Company; Carrick Therapeutics; Celgene Corporation; Daiichi Sankyo; Eisai, Co, Ltd.; Fishawack Health; G1 Therapeutics; GlaxoSmithKline; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.; Immunomedics; Incyte Corporation; Lilly; Merck & Co., Inc.; Novartis Pharmaceuticals; Ontada; Pfizer, Inc.; Pharmacyclics; Pierre Fabre Pharmaceuticals; Puma Biotechnology, Prime Oncology; Roche; Samsung Bioepis; Sanofi; Seagen; Stemline Therapeutics; Synthon

Sara M. Tolaney, MD, MPH

Associate Professor of Medicine Harvard Medical School Chief, Division of Breast Oncology Dana-Farber Cancer Institute Boston, Massachusetts

Sara M. Tolaney, MD, MPH, has the following relevant financial relationships: Consultant or advisor for: 4D Pharma; Aadi Biopharma; ARC Therapeutics; Artios Pharma; AstraZeneca; Bayer HealthCare; BeyondSpring Pharmaceuticals; Blueprint Medicines; Bristol Myers Squibb Company; CytomX Therapeutics; Daiichi Sankyo; Eisai Co., Ltd.; Ellipses Pharma; Genentech/Roche; Gilead Sciences, Inc.; Incyte Corp; Infinity Therapeutics; Lilly; Menarini/Stemline; Merck & Co., Inc.; Myovant; Novartis Pharmaceuticals; OncoSec Medical Inc.; OncXerna; Pfizer, Inc.; Reveal Genomics; Sanofi; Seagen; Umoja Biopharma; Zentalis; Zetagen; Zymeworks Research funding from: AstraZeneca; Bristol Myers Squibb Company; Eisai Co., Ltd.; Exelixis, Inc.; Genentech/Roche; Gilead Sciences, Inc.; Lilly; Merck & Co., Inc.; NanoString Technologies; Novartis Pharmaceuticals; OncoPep; Pfizer, Inc.; Seagen 

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CME / ABIM MOC / CE

Building a continuum of care: case studies in her2-positive breast cancer.

• Authors: Sara A. Hurvitz, MD, FACP; Joyce A. O’Shaughnessy, MD; Sara M. Tolaney, MD, MPH

CME / ABIM MOC / CE Released: 12/29/2023

Valid for credit through: 12/29/2024 , 11:59 PM EST

Credits Available

Physicians - maximum of 0.75 AMA PRA Category 1 Credit(s)™

ABIM Diplomates - maximum of 0.75 ABIM MOC points

Nurses - 0.75 ANCC Contact Hour(s) (0.75 contact hours are in the area of pharmacology)

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Target Audience and Goal Statement

This activity is intended for oncologists, obstetricians & gynecologists, pathologists, surgeons, oncology nurses and nurse practitioners (NPs), oncology pharmacists, and other members of the oncology care team.

The goal of this activity is for learners to be better able to select the most optimal anti-HER2 treatments for patients with HER2-positive breast cancer at every stage of care.

Upon completion of this activity, participants will:

• Clinical data associated with emerging anti-HER2 regimens for patients with HER2-positive breast cancer
• Selecting the most optimal anti-HER2 treatment regimens for patients with HER2-positive breast cancer
• Managing adverse events (AEs) that may present with the use of anti-HER2 therapies for the treatment of HER2-positive breast cancer
• Use the interprofessional team to manage the AEs associated with anti-HER2 therapies for treatment of HER2-positive breast cancer

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Cognition and Return to Work Status 2 Years After Breast Cancer Diagnosis

Affiliations.

• 1 ANTICIPE U1086 INSERM-UCN, Equipe Labellisée Ligue Contre le Cancer, Centre François Baclesse, Normandie Université UNICAEN, Caen, France.
• 2 Services Unit PLATON, Cancer and Cognition Platform, University of Caen Normandy, Caen, France.
• 3 Aix Marseille University, INSERM, IRD, ISSPAM, SESSTIM (Economic and Social Sciences of Health and Medical Information Processing), Marseille, France.
• 4 CHU de Caen, Service de santé au travail et pathologie professionnelle, F-14000 Caen, France.
• 5 INSERM, Gustave Roussy Institute, University Paris Saclay, Unit Molecular Predictors and New Targets in Oncology, Villejuif, France.
• 6 Medical Oncology Department, Gustave Roussy, Villejuif, France.
• 7 Care Support Department, Centre Henri Becquerel, Rouen, France.
• 8 Medical Oncology Department, Centre Henri Becquerel, Rouen, France.
• 9 Institut Normand du Sein, Centre François Baclesse, Caen, France.
• 10 Medical Oncology Department, Institut Curie, Saint Cloud, France.
• 11 UNICANCER, Paris, France.
• 12 Medical Oncology Department, CHU de Caen, Caen, France.
• PMID: 39158915
• PMCID: PMC11333979
• DOI: 10.1001/jamanetworkopen.2024.27576

Importance: Return to work after breast cancer (BC) treatment depends on several factors, including treatment-related adverse effects. While cancer-related cognitive impairment is frequently reported by patients with BC, to date, no longitudinal studies have assessed its association with return to work.

Objective: To examine whether cognition, assessed using objective and subjective scores, was associated with return to work 2 years after BC diagnosis.

Design, setting, and participants: In a case series of the French Cancer Toxicities (CANTO) cohort, a study of patients with stage I to III BC investigated cognition from April 2014 to December 2018 (2 years' follow-up). Participants included women aged 58 years or younger at BC diagnosis who were employed or looking for a job.

Main outcomes and measures: The outcome was return to work assessed 2 years after BC diagnosis. Objective cognitive functioning (tests), cognitive symptoms, anxiety, depression, and fatigue were prospectively assessed at diagnosis (baseline), 1 year after treatment completion, and 2 years after diagnosis. Multivariable logistic regression models were used to explain return to work status at year 2 according to each cognitive measure separately, adjusted for age, occupational class, stage at diagnosis, and chemotherapy.

Results: The final sample included 178 women with BC (median age: 48.7 [range, 28-58] years), including 37 (20.8%) who did not return to work at year 2. Patients who returned to work had a higher (ie, professional) occupational class and were less likely to have had a mastectomy (24.1% vs 54.1%; P < .001). Return to work at year 2 was associated with lower overall cognitive impairment (1-point unit of increased odds ratio [1-pt OR], 0.32; 95% CI, 0.13-0.79; P = .01), higher working memory (1-pt OR, 2.06; 95% CI, 1.23-3.59; P = .008), higher processing speed (1-pt OR, 1.97; 95% CI, 1.20-3.36; P = .01) and higher attention performance (1-pt OR, 1.63; 95% CI, 1.04-2.64; P = .04), higher perceived cognitive abilities (1-pt OR, 1.12; 95% CI, 1.03-1.21; P = .007), and lower depression (1-pt OR, 0.83; 95% CI, 0.74-0.93; P = .001) at year 2 assessment. Return to work at year 2 was associated with several measures assessed at baseline and year 1: higher processing speed (1-pt OR, 2.38; 95% CI, 1.37-4.31; P = .003 and 1.95; 95% CI, 1.14-3.50; P = .02), higher executive performance (1-pt OR, 2.61; 95% CI, 1.28-5.75; P = .01, and 2.88; 95% CI, 1.36-6.28; P = .006), and lower physical fatigue (10-pt OR, 0.81; 95% CI, 0.69-0.95; P = .009 and 0.84; 95% CI, 0.71-0.98; P = .02).

Conclusions and relevance: In this case series study of patients with BC, return to work 2 years after diagnosis was associated with higher cognitive speed performance before and after BC treatment. Cognitive difficulties should be assessed before return to work to propose suitable management.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Vaz-Luis reported receiving nonfinancial support to the institution from Pfizer, AstraZeneca, Novartis, and Amgen, and grants from Resilience outside the submitted work. Dr Pistilli reported receiving grants to the institution from AstraZeneca, Gilead, Seagen, Novartis, Lilly, MSD, and Daiichi-Sankyo; and personal fees from Daiichi-Sankyo, AstraZeneca, Pfizer, and MSD outside the submitted work. Dr Lerebours reported receiving personal fees from Astra Zeneca, Gilead, Novartis, Lilly, and Seagen; and nonfinancial support from Daiichi-Sankyo, MSD, and Pfizer outside the submitted work. Dr Joly reported receiving grants from Ruban rose outside the submitted work. No other disclosures were reported.

Figure.. Patient Flowchart

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• Published: 14 August 2024

Cancer evolution

Tracing the evolutionary history of breast cancer

• Jiwon Koh 1 &
• Seock-Ah Im   ORCID: orcid.org/0000-0002-5396-6533 1  

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• Breast cancer
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Recent advances in genome sequencing technologies have enabled a better understanding of genetic alterations in both cancer and non-neoplastic cells. Breast cancer is commonly accompanied by benign breast lesions (BBLs) in the adjacent parenchyma, and it has long been reported that a subset of such BBLs already have acquired genetic alterations such as 1q gains, 16q losses and PI3K–AKT pathway mutations. However, the exact clonal relationship between the alterations found in BBLs and breast cancer has not been fully elucidated.

To begin to understand this relationship, Nishimura et al. performed multi-regional whole genome sequencing on variable areas within breast tissue from patients with breast cancer using laser capture microdissection. Sequenced areas encompassed normal breast lobules, non-proliferative lesions, proliferative lesions with or without atypia, in situ lesions, and invasive carcinomas. The phylogenetic reconstruction revealed that clones carrying the derivative chromosome der(1;16) were the common precursor clones. Multiple most recent common ancestor (MRCA) clones evolved from der(1;16) clones, often giving rise to independent in situ and invasive carcinomas, thereby contributing to intratumoural heterogeneity.

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Nishimura, T. et al. Evolutionary histories of breast cancer and related clones. Nature 620 , 607–614 (2023)

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Breast Cancer: Survivorship Care Case Study, Care Plan, and Commentaries

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This case study highlights the patient’s status in care plan format and is followed by commentaries from expert nurse clinicians about their approach to manage the patient’s long-term or chronic cancer care symptoms. Finally, an additional expert nurse clinician summarizes the care plan and commentaries, emphasizing takeaways about the patient, the commentaries, and additional recommendations to manage the patient. As can happen in clinical practice, the patient’s care plan is intentionally incomplete and does not include all pertinent information. Responding to an incomplete care plan, the nurse clinicians offer comprehensive strategies to manage the patient’s status and symptoms. For all commentaries, each clinician reviewed the care plan and did not review each other’s commentary. The summary commentary speaks to the patient’s status, care plan, and nurse commentaries.

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Advances in Breast Cancer Research

A polyploid giant cancer cell (PGCC) from triple-negative breast cancer.

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat breast cancer. They are also looking at how to address disparities and improve quality of life for survivors of the disease.

This page highlights some of what's new in the latest research for breast cancer, including new clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Early Detection of Breast Cancer

Breast cancer is one of a few cancers for which an effective screening  test, mammography , is available. MRI ( magnetic resonance imaging ) and  ultrasound  are also used to detect breast cancer, but not as routine screening tools for people with average risk.

Ongoing studies are looking at ways to enhance current breast cancer screening options. Technological advances in imaging are creating new opportunities for improvements in both screening and early detection.

One technology advance is 3-D mammography , also called breast tomosynthesis . This procedure takes images from different angles around the breast and builds them into a 3-D-like image. Although this technology is increasingly available in the clinic, it isn’t known whether it is better than standard 2-D mammography , for detecting cancer at a less advanced stage.

NCI is funding a large-scale randomized breast screening trial, the Tomosynthesis Mammographic Imaging Screening Trial (TMIST) , to compare the number of advanced cancers detected in women screened for 5 years with 3-D mammography with the number detected in women screened with 2-D mammography. 

Two concerns in breast cancer screening, as in all cancer screening, are:

• the potential for diagnosing tumors that would not have become life-threatening ( overdiagnosis )
• the possibility of receiving false-positive test results, and the anxiety that comes with follow-up tests or procedures

As cancer treatment is becoming more individualized, researchers are looking at ways to personalize breast cancer screening. They are studying screening methods that are appropriate for each woman’s level of risk and limit the possibility of overdiagnosis.

For example, the Women Informed to Screen Depending on Measures of Risk (WISDOM) study aims to determine if risk-based screening—that is, screening at intervals that are based on each woman’s risk as determined by her genetic makeup, family history , and other risk factors—is as safe, effective, and accepted as standard annual screening mammography.

WISDOM is also making a focused effort to enroll Black women in the trial. Past studies  tended to contain a majority of White women and therefore, there is less data on how screening can benefit Black women. Researchers are taking a number of steps to include as many Black women as possible in the study while also increasing the diversity of all women enrolled.

Breast Cancer Treatment

The mainstays of breast cancer treatment are surgery , radiation , chemotherapy , hormone therapy , and targeted therapy . But scientists continue to study novel treatments and drugs, along with new combinations of existing treatments.

It is now known that breast cancer can be divided into subtypes based on whether they:

• are hormone receptor (HR) positive which means they express  estrogen and/or progesterone receptors  ( ER , PR )

Shortening Radiation Therapy for Some with Early Breast Cancer

A condensed course was as effective and safe as the standard course for women with higher-risk early-stage breast cancer who had a lumpectomy.

As we learn more about the subtypes of breast cancer and their behavior, we can use this information to guide treatment decisions. For example:

• The NCI-sponsored TAILORx clinical trial. The study, which included patients with ER-positive, lymph node-negative breast cancer, found that a test that looks at the expression of certain genes can predict which women can safely avoid chemotherapy.
• The RxPONDER trial found that the same gene expression test can also be used to determine treatment options in women with more advanced breast cancer. The study found that some postmenopausal women with HR positive, HER-2 negative breast cancer that has spread to several lymph nodes and has a low risk of recurrence do not benefit from chemotherapy when added to their hormone therapy. 
• The OFSET trial is comparing the addition of chemotherapy to usual treatment ( ovarian function suppression plus hormone therapy) to usual treatment alone in treating premenopausal estrogen receptor (ER)-positive/HER2-negative breast cancer patients who are at high risk of their cancer returning. This will help determine whether or not adding chemotherapy helps prevent the cancer from returning.  

Genomic analyses, such as those carried out through  The Cancer Genome Atlas (TCGA) , have provided more insights into the molecular diversity of breast cancer and eventually could help identify even more breast cancer subtypes. That knowledge, in turn, may lead to the development of therapies that target the genetic alterations that drive those cancer subtypes.

HR-Positive Breast Cancer Treatment 

Hormone therapies have been a mainstay of treatment for HR-positive cancer. However, there is a new focus on adding targeted therapies to hormone therapy for advanced or metastatic HR-positive cancers. These treatments could prolong the time until chemotherapy is needed and ideally, extend survival. Approved drugs include:

Drug Combo Effective for Metastatic Breast Cancer in Younger Women

Ribociclib plus hormone therapy were superior to standard chemotherapy combos in a recent trial.

• Palbociclib (Ibrance) ,  ribociclib (Kisqali) , and  everolimus (Afinitor) have all been approved by the FDA for use with hormone therapy for treatment of advanced or metastatic breast cancer. Ribociclib has been shown to increase the survival of patients with metastatic breast cancer . It has also shown to slow the growth of metastatic cancer in younger women when combined with hormone therapy.
• Elacestrant (Orserdu) is approved for HR-positive and HER2-negative breast cancer that has a mutation in the ESR1 gene, and has spread. It is used in postmenopausal women and in men whose cancer has gotten worse after at least one type of hormone therapy.
• Abemaciclib (Verzenio) can be used with or after hormone therapy to treat advanced or metastatic HR-positive, HER2-negative breast cancer. In October 2021, the Food and Drug Administration ( FDA ) approved abemaciclib in combination with hormone therapy to treat some people who have had surgery for early-stage HR-positive, HER2-negative breast cancer.
• Alpelisib (Piqray)  is approved to be used in combination with hormone therapy to treat advanced or metastatic HR-positive, HER2-negative breast cancers that have a mutation in the PIK3CA gene .
• Sacituzumab govitecan-hziy (Trodelvy) is used for HR-positive and HER2-negative breast cancer that has spread or can't be removed with surgery. It is used in those who have received hormone therapy and at least two previous treatments. It has shown to extend the amount of time that the disease doesn't get worse ( progression-free survival ) and also shown to improve overall survival .

HER2-Positive Breast Cancer Treatment 

The FDA has approved a number of targeted therapies to treat HER2-positive breast cancer , including:

• Trastuzumab (Herceptin) has been approved to be used to prevent a relapse in patients with early-stage HER2-positive breast cancer. 
• Pertuzumab (Perjeta) is used to treat metastatic HER2-positive breast cancer, and also both before surgery ( neoadjuvant ) and after surgery ( adjuvant therapy ). 
• Trastuzumab and pertuzumab together can be used in combination with chemotherapy to prevent relapse in people with early-stage HER2-positive breast cancer.  Both are also used together in metastatic disease, where they delay progression and improve overall survival. 
• Trastuzumab deruxtecan (Enhertu) is approved for patients with advanced or metastatic HER2-positive breast cancer who have previously received a HER2-targeted treatment. A 2021 clinical trial showed that the drug lengthened the time that people with metastatic HER2-positive breast cancer lived without their cancer progressing. The trial also showed that it was better at shrinking tumors than another targeted drug, trastuzumab emtansine (Kadcyla).
• Tucatinib (Tukysa) is approved to be used in combination with trastuzumab and capecitabine (Xeloda) for HER2-positive breast cancer that cannot be removed with surgery or is metastatic. Tucatinib is able to cross the blood–brain barrier, which makes it especially useful for HER2-positive metastatic breast cancer, which tends to spread to the brain. 
• Lapatinib (Tykerb)  has been approved for treatment of some patients with HER2-positive advanced or metastatic breast cancer, together with capecitabine or letrozole.
• Neratinib Maleate (Nerlynx) can be used in patients with early-stage HER2-positive breast cancer and can also be used together with capecitabine (Xeloda) in some patients with advanced or metastatic disease.
• Ado-trastuzumab emtansine (Kadcyla) is approved to treat patients with metastatic HER2-positive breast cancer who have previously received trastuzumab and a taxane . It's also used in some patients with early-stage HER2-positive breast cancer who have completed therapy before surgery ( neoadjuvant ) and have residual disease at the time of surgery.

HER2-Low Breast Cancer

 A newly defined subtype, HER2-low, accounts for more than half of all metastatic breast cancers. HER2-low tumors are defined as those whose cells contain lower levels of the HER2 protein on their surface. Such tumors have traditionally been classified as HER2-negative because they did not respond to drugs that target HER2. 

However, in a clinical trial, trastuzumab deruxtecan (Enhertu) improved the survival of patients with HER2-low breast cancer compared with chemotherapy , and the drug is approved for use in such patients. 

Immunotherapy Improves Survival in Triple-Negative Breast Cancer

For patients whose tumors had high PD-L1 levels, pembrolizumab with chemo helped them live longer.

Triple-Negative Breast Cancer Treatment 

Triple-negative breast cancers (TNBC) are the hardest to treat because they lack both hormone receptors and HER2 overexpression , so they do not respond to therapies directed at these targets. Therefore, chemotherapy is the mainstay for treatment of TNBC. However, new treatments are starting to become available. These include:

• Sacituzumab govitecan-hziy (Trodelvy)  is approved to treat patients with TNBC that has spread to other parts of the body . Patients must have received at least two prior therapies before receiving the drug.
• Pembrolizumab (Keytruda)  is an immunotherapy drug that is approved to be used in combination with chemotherapy for patients with locally advanced or metastatic TNBC that has the PD-L1 protein. It may also be used before surgery (called neoadjuvant ) for patients with early-stage TNBC, regardless of their PD-L1 status.
• PARP inhibitors, which include olaparib (Lynparza) and talazoparib (Talzenna) , are approved to treat metastatic HER2-negative or triple-negative breast cancers in patients who have inherited a harmful BRCA gene mutation. Olaparib is also approved for use in certain patients with early-stage HER2-negative or triple-negative breast cancer. 
• Drugs that block the androgen receptors  or prevent androgen production are being tested in a subset of TNBC that express the androgen receptor.

For a complete list of drugs for breast cancer, see Drugs Approved for Breast Cancer .

NCI-Supported Breast Cancer Research Programs

Many NCI-funded researchers working at the NIH campus, as well as across the United States and world, are seeking ways to address breast cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some are more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in breast cancer.

TMIST is a randomized breast screening trial that compares two Food and Drug Administration (FDA)-approved types of digital mammography, standard digital mammography (2-D) with a newer technology called tomosynthesis mammography (3-D).

The  Breast Specialized Programs of Research Excellence (Breast SPOREs)  are designed to quickly move basic scientific findings into clinical settings. The Breast SPOREs support the development of new therapies and technologies, and studies to better understand tumor resistance, diagnosis, prognosis, screening, prevention, and treatment of breast cancer.

The NCI Cancer Intervention and Surveillance Modeling Network (CISNET) focuses on using modeling to improve our understanding of how prevention, early detection, screening, and treatment affect breast cancer outcomes.

The Confluence Project , from NCI's Division of Cancer Epidemiology and Genetics (DCEG) , is developing a research resource that includes data from thousands of breast cancer patients and controls of different races and ethnicities. This resource will be used to identify genes that are associated with breast cancer risk, prognosis, subtypes, response to treatment, and second breast cancers. (DCEG conducts other breast cancer research as well.)

The Black Women’s Health Study (BWHS) Breast Cancer Risk Calculator allows health professionals to estimate a woman’s risk of developing invasive breast cancer over the next 5 years. With the NCI-funded effort, researchers developed a tool to estimate the risk of breast cancer in US Black women. The team that developed the tool hopes it will help guide more personalized decisions on when Black women—especially younger women—should begin breast cancer screening. 

The goal of the Breast Cancer Surveillance Consortium (BCSC) , an NCI-funded program launched in 1994, is to enhance the understanding of breast cancer screening practices in the United States and their impact on the breast cancer's stage at diagnosis, survival rates, and mortality.

There are ongoing programs at NCI that support prevention and early detection research in different cancers, including breast cancer. Examples include:

• The  Cancer Biomarkers Research Group , which promotes research in cancer biomarkers and manages the Early Detection Research Network (EDRN) . EDRN is a network of NCI-funded institutions that are collaborating to discover and validate early detection biomarkers. Within the EDRN, the Breast and Gynecologic Cancers Collaborative Group conducts research on breast and ovarian cancers.
• NCI's Division of Cancer Prevention  houses the Breast and Gynecologic Cancer Research Group which conducts and fosters the development of research on the prevention and early detection of  breast and gynecologic cancers.

Breast Cancer Survivorship Research

NCI’s Office of Cancer Survivorship, part of the Division of Cancer Control and Population Sciences (DCCPS), supports research projects throughout the country that study many issues related to breast cancer survivorship. Examples of studies funded include the impact of cancer and its treatment on physical functioning, emotional well-being, cognitive impairment , sleep disturbances, and cardiovascular health. Other studies focus on financial impacts, the effects on caregivers, models of care for survivors, and issues such as racial disparities and communication.

Breast Cancer Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for breast cancer prevention , screening , and treatment . 

Breast Cancer Research Results

The following are some of our latest news articles on breast cancer research and study updates:

• How Breast Cancer Risk Assessment Tools Work
• Can Some People with Breast Cancer Safely Skip Lymph Node Radiation?
• Study Adds to Debate about Mammography in Older Women
• Pausing Long-Term Breast Cancer Therapy to Become Pregnant Appears to Be Safe
• A Safer, Better Treatment Option for Some Younger Women with Breast Cancer
• Shorter Course of Radiation Is Effective, Safe for Some with Early-Stage Breast Cancer

View the full list of Breast Cancer Research Results and Study Updates .

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Genetic testing advances help women with high risk of breast cancer avoid surgery

by Vittoria D'Alessio, Horizon: The EU Research & Innovation Magazine

Researchers are discovering new genes linked to breast cancer and refining evaluation of risk to help spare women from life-changing surgery.

They call it the Angelina Jolie effect: the popular belief that only a preventative double mastectomy can safeguard a woman from developing a tumor if she carries gene mutations linked to breast cancer.

Celebrity actress Jolie made headlines in 2013 when she underwent radical breast surgery after genetic testing revealed she carried a gene—BRCA1—that significantly increased her odds of developing breast and/or ovarian cancer .

Fast forward a decade and eight more genes known to raise a woman's susceptibility to breast cancer have been discovered. Among these are BRCA2, which also greatly increases the chances of developing breast cancer, and four genes discovered by BRIDGES, an international research project.

Thanks in large part to groundbreaking work by researchers, prophylactic surgery is no longer seen as inevitable for a woman to stay healthy if she carries a gene that increases her risk of breast cancer.

In parallel to these discoveries, medical understanding of risk—the likelihood of a woman developing breast cancer if she carries specific mutations—has also evolved significantly.

Avoiding surgery where possible

Greater clarity around the level of risk and the treatment options available is welcomed by women 's cancer support groups.

"The ideal outcome of genetic screening is for women to get an accurate picture of their risk and be offered a personalized approach to tumor prevention," said Marzia Zambon, executive director of Europa Donna, Europe's largest breast cancer advocacy group.

"We're pushing for genetic testing to always be done with the professional guidance of a genetic counselor. If testing isn't done right, it can cause a lot of stress and an unnecessary escalation of treatment."

Researchers involved in BRIDGES and B-CAST—another research initiative—have made huge advances in showing how both genes, lifestyle and environmental factors influence the risk of breast cancer. These non-genetic factors include a woman's exposure to pollution, excess body weight, breast tissue density, low physical activity, alcohol consumption, exposure to birth control and other hormones, and the number of children born.

"Until recently, genetic testing could identify women carrying genes linked to breast cancer, but estimates of the risk these women were facing were quite imprecise," said Professor Peter Devilee, BRIDGES research coordinator and cancer geneticist at Leiden University in the Netherlands. This matters because imprecise risk evaluation can result in inaccurate treatment advice.

"Women with a family history of breast cancer are being referred to labs for genetic testing, and mutations are being identified, but if you can't translate a result into a fairly precise breast cancer risk, it can lead to improper risk management advice. We wanted to help clinics interpret results properly."

Predicting with precision

In their quest to estimate the risk posed by any given gene mutation more precisely, the BRIDGES researchers sequenced all suspected breast cancer genes in the genomes of 113,000 women. Of these women, half were known to have had a breast cancer diagnosis, while the other half had not.

The genetic profiles of these patients were then crosslinked with data from 20,000 breast tumors analyzed by the B-CAST team. In addition, the B-CAST researchers contributed information about the genetic profiles of patients' close family members and those all-important lifestyle and environmental risks.

The BRIDGES team contributed an added tranche of data on genes that hadn't yet been implicated in breast cancer, but that might affect the risk of developing breast cancer when appearing in a mutated form.

Finally, all this information was combined with the findings of earlier research efforts that had set out to find common DNA variations in the same cohort of women, including COGS, the world's largest project on genome-wide association studies to predict cancer risk.

The result of all this data crunching? The BRIDGES and B-CAST teams were able to make vast improvements to a pre-existing tool that estimates the risk posed by any given gene mutation or combination of mutations.

Named CanRisk, this online tool, available in seven EU languages, is designed to give an expert—usually a clinical geneticist—an accurate estimate of a woman's risk of developing a specific type of tumor. The higher the score, the greater the risk.

The hope is that more women with moderate-to-high risk of breast cancer will be identified early. CanRisk factors in the subtype of cancer linked to each cancer gene or gene combination. This is important as some tumor subtypes are far more dangerous than others and treatment options , as well as likely health outcomes, differ from subtype to subtype.

A handful of European clinics are currently piloting the user-friendly, CE-marked CanRisk tool. The researchers are hopeful that more will come on board in the years ahead.

More choices, better screening

Being informed of an elevated risk of developing breast cancer is important, but what actions should a woman take upon receiving this information?

"Better precision in predicting breast cancer makes it easier for women to make informed choices about their bodies and their health," said Dr. Marjanka Schmidt, B-CAST coordinator and an epidemiologist with expertise in breast cancer genetics based in the Netherlands. "Ultimately, it cuts overtreatment and reduces the incidence of unnecessary, life-changing surgery."

Typically, women who are identified as at-risk using the CanRisk tool are offered mammograms from an earlier age than other women and/or more frequent mammograms. MRI scans might also be added to their screening protocol.

"CanRisk has brought clear benefits to many, leading to reductions in the occurrence, severity and mortality of breast cancer. And as we continue to refine the tool, it's likely to save more and more lives," said Schmidt, who leads a research group at the Netherlands Cancer Institute and is a professor of genetic epidemiology of (breast) cancer at Leiden University Medical Center.

The research carried out by the BRIDGES and B-CAST teams between 2015 and 2021 has continued.

The B-CAST team is now developing a tool that will help cancer doctors more accurately predict the health benefits of a specific course of treatment for a given woman with a given subtype of breast cancer.

"Some treatments have quite serious side-effects, so it's important for women and clinicians to know how much impact a particular treatment is likely to have on the tumor, and for decisions to be based on the survival benefits of this treatment," said Schmidt.

Meanwhile, the BRIDGES researchers continue in their quest to identify further genes associated with breast cancer.

"We know about 55-60% of the genetic risk factors, but that leaves 40-45% that still need to be discovered," said Devilee.

The combined impact of their research is already being felt. It will continue to help guide both doctors and patients on the best way to decrease both the incidence of breast cancer and the human toll of this disease.

This article was originally published in Horizon the EU Research and Innovation Magazine.

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Scientists obtain real-time look at how cancers evolve

This year, approximately 4,060 British Columbians will be diagnosed with breast cancer. While many forms of breast cancer can be treated successfully, triple negative breast cancer (TNBC) remains the most deadly subtype because it is resistant to most forms of treatment.

A new study co-led by researchers at BC Cancer and Memorial Sloan Kettering Cancer Center New York suggests that one day it might be possible to predict how triple negative breast cancer tumours evolve over time. The study, led by Dr. Samuel Aparicio , distinguished scientist at BC Cancer Research Institute and Dr. Sohrab Shah , computational biologist at Memorial Sloan Kettering showed that a machine learning approach, built using principles from population genetics theory, could accurately predict how breast cancer tumours will evolve.

“Ultimately, the approach could provide a means to predict whether a patient’s tumour may stop responding to a treatment and identify the cells that are responsible for the relapse,” says Dr. Aparicio. “This could mean highly tailored treatments, delivered at the optimal time, to produce better outcomes for people with triple negative breast cancer.”

From amoebas to zebras, all living things evolve.  Cancer cells are no different. Within a growing tumour, cancer cells are vying for top spot in a campaign of “survival of the fittest” on a microscopic scale. But fitness, meaning how well suited any living thing is to its environment, can change when the environment changes. The cancer cells that might do best in an environment saturated with chemotherapy drugs are likely to be different than the ones that will thrive in an environment without those drugs. So, predicting how tumours will evolve over time, especially in response to treatment, is a major challenge for scientists.

“Population genetic models of evolution match up nicely to cancer, but for a number of practical reasons it’s been a challenge to apply these to the evolution of real human cancers,” says Dr. Shah, who is an affiliated scientist with the BC Cancer Research Institute. “In this study, we show it’s possible to overcome some of those barriers.”

A Trifecta of Innovations

Three innovations came together to make these findings possible. Scientists analyzed realistic tumour models repeatedly over extended timeframes of up to 3 years, exploring the effects of platinum-based chemotherapy treatment and treatment withdrawal.

“Historically, the field has focused on the evolutionary history of a cancer from a single snapshot,” Dr. Aparicio says. “That approach is inherently error prone. By taking many snapshots over time, we can obtain a much clearer picture.”

The second key innovation was applying single cell sequencing technology to characterize the genetic make-up of thousands of individual cancer cells in the tumour at the same time. A previously developed platform allowed the team to perform these operations in an efficient and automated fashion.

The final component was a machine-learning tool, developed in collaboration with UBC statistics professor Alexandre Bouchard-Côté, which applies the mathematics of population genetics to cancer cells in the tumour. These equations describe how a population will evolve given certain starting frequencies of individuals with different fitnesses within that population.

With these innovations in place, the scientists were able to create a model of how individual cancer cells, known as or clones, will behave. In other words, how the cancer will evolve is predictable.

“The beauty of this model is it can be run forwards to predict what clones are likely to expand and which clones are likely to get outcompeted,” Dr. Shah says.

The model bears a close resemblance to reality: when the team conducted experiments to measure evolution in comparison to what they predicted would happen, there was close agreement.

A Foundation for the Future

The particular types of genetic changes the team looked at are called copy number changes. These are differences in number — more or less — of segments of DNA in cancer cells. Up until now, the significance of these sorts of changes hasn’t been clear, and researchers have had doubts about their importance in cancer progression.

“Variants in copy number can have a large effect on cells - a single copy number variant can directly affect whether hundreds of genes are switched on or off,” Dr Aparicio says.

The scientists found that treatment of tumours with platinum chemotherapy led to the eventual emergence of drug-resistant tumour cells — similar to what happens in patients undergoing treatment. These drug-resistant cells had distinct copy number variants.

The team wondered: What would happen to the tumour if they stopped treatment? Turns out the cells that took over the tumour in the presence of chemotherapy declined or disappeared when the chemotherapy was taken away; the drug-resistant cells were outcompeted by the original drug-sensitive cells. This paradoxical behavior indicates that drug resistance has an evolutionary cost. In other words, the traits that are good for resisting drugs aren’t necessarily the best for thriving in an environment without those drugs.

Ultimately, Drs. Aparicio and Shah say, the goal is to one day be able to use this approach on blood samples— perhaps obtained through liquid biopsies — to identify the particular clones in a person’s tumour, predict how they are likely to evolve, and tailor medicines accordingly.

This research is supported through funding from the BC Cancer Foundation and Cycle for Survival supporting Memorial Sloan Kettering Cancer Center. Additional funding provided by the Terry Fox Research Institute, Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, Breast Cancer Research Foundation, MSK Cancer Center Support Grant, National Institutes of Health Grant, the Cancer Research UK Grand Challenge Program, and the Canada Foundation for Innovation.

A version of this story was originally published by the Memorial Sloan Kettering Cancer Center .

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An unconventional case study of neoadjuvant oncolytic virotherapy for recurrent breast cancer.

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Forčić, D.; Mršić, K.; Perić-Balja, M.; Kurtović, T.; Ramić, S.; Silovski, T.; Pedišić, I.; Milas, I.; Halassy, B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines 2024 , 12 , 958. https://doi.org/10.3390/vaccines12090958

Forčić D, Mršić K, Perić-Balja M, Kurtović T, Ramić S, Silovski T, Pedišić I, Milas I, Halassy B. An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer. Vaccines . 2024; 12(9):958. https://doi.org/10.3390/vaccines12090958

Forčić, Dubravko, Karmen Mršić, Melita Perić-Balja, Tihana Kurtović, Snježana Ramić, Tajana Silovski, Ivo Pedišić, Ivan Milas, and Beata Halassy. 2024. "An Unconventional Case Study of Neoadjuvant Oncolytic Virotherapy for Recurrent Breast Cancer" Vaccines 12, no. 9: 958. https://doi.org/10.3390/vaccines12090958

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March 22, 2017

Case Study: A Delay in the Diagnosis of Breast Cancer

Lawsuits commenced against physicians in a variety of medical specialties continue to contain allegations of the failure to timely diagnose breast cancer. Often, the targets of these lawsuits are obstetricians/gynecologists, general surgeons, radiologists and general medical practitioners. Frequent allegations include:

• the failure to take a complete family and medical history;
• poor documentation;
• failure to communicate;
• the failure to review and follow up on abnormal test results;
• misread mammograms;
• the failure to recommend further studies;
• and delayed referrals.

The lead article in MLMIC’s Winter 2017 Case Review illustrates some of these problems. It analyzes a case involving a 53-year-old married mother of three who had a family history of maternal breast and ovarian cancer. The patient was post-menopausal and taking hormonal supplementation.

For one of her annual mammograms, the radiologist’s report noted that additional imaging was recommended for what appeared to be a developing nodule. However, the radiology practice had no documentation that any telephone calls were made or letters were sent to the patient requesting her to return for additional studies. Further, neither her gynecologist nor her internist was contacted about this finding. The gynecologist and his staff did not even realize that a mammography report was outstanding until the patient returned for her annual examination one year later. When the results of a CA-125 test ordered at that time showed elevated levels, the patient was promptly referred to a cancer treatment center. She was subsequently diagnosed with stage IV breast cancer with metastasis to the liver and bone, which originated from the breast.

The patient commenced a lawsuit against both the radiologist and his entity and her gynecologist and his entity. The allegations in the lawsuit included the failure to notify the patient of the need for further mammography studies and the failure of both the gynecologist and radiologist to communicate regarding the abnormal findings seen on the initial mammogram. Finally, the patient alleged that her gynecologist negligently failed to review the radiologist’s report until a year after it had been sent to his office.

In light of these serious problems, the lawsuit was settled by both physicians and their professional entities for a combined $1.85 million. Experts who reviewed this case were particularly concerned that because of the delay in diagnosis, the continuous use of estrogen fueled this cancer. This made the other deficits in her care seem even more egregious. The patient was alive at the time of the settlement. However, she subsequently died of metastatic breast cancer.

For the complete case study, including a more detailed summary of the patient’s medical history and a legal perspective, visit the Winter 2017 Case Review here .

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Recurrence of Breast Cancer : A Management Dilemma

There is always a word of advice on the management of early breast cancer, locally advanced breast cancer as well as metastatic breast cancer. Not much is spoken or written about Locally Recurrent breast cancer.

Recurrence is a unique case scenario where it is not possible to have clear-cut guidelines. Precise and personalized treatment is the need of the hour.

Patient Concern

Mrs. N Sampat (name changed), a 55-year-old postmenopausal lady, diabetic and hypertensive presented with a 3 x 3 cms hard lump in her right breast .

Mammography was done  & confirmed it to be a BIRADS V (malignant) lesion; also another 2 x 2 cms, BIRADS V lesion was also seen. FNAC confirmed it to be ductal carcinoma.

She underwent modified radical mastectomy (removal of the breast and axillary nodes). On her final histopathology report, she had hormone receptor-positive, multicentric Infiltrative ductal carcinoma of the breast with four positive nodes.

As an adjuvant treatment, she received 6 cycles of chemotherapy followed by radiation therapy over four weeks.

She had been taking Tab Letrozole for last 5 years. Now after a disease-free interval of 5 years, at the age of 60 years in April 2020, she noticed a swelling just below the clavicle.

Within three months this swelling rapidly increased to 7 x 7 cm. A pet scan showed it to be an isolated tumour recurrence site.

A core biopsy confirmed it to be hormone receptor-positive recurrent breast cancer. A local MRI was done, which showed involvement of Pectoralis major and Minor muscle, and tumour-causing compression of the axillary vein with 90-degree contact. The axillary artery and brachial plexus were free.

She was concerned about the inoperable and incurable status labelled to the disease by the local doctors.

Treatment Offered

On the scan, the tumor mass appeared to be operable with adequate margins. Wide excision of this lump was planned.

Wide excision of tumour mass with adequate margins was done and sent for final histopathology.

On histopathology, it was confirmed to be Recurrent Infiltrative ductal carcinoma with positive ER, and PR receptors. The patient is planned for further chemotherapy and hormonal therapy.

Clinical pictures are shown below:

Core Message

It is possible to offer safe and curative treatment for recurrent breast cancer. Recurrence of breast cancer needs a patient-tailored treatment approach.

Also let’s look at another case study, where 30 year old lady who had multiple lumps in her breast & pain for more than 6 months . It was not cancer but treated successfully with surgery.

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Contact the breast cancer treatment center in mumbai today. schedule a consultation, about author, dr. jay rashmi anam.

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