Breast Cancer: Who Gets It? Who Survives? The Latest Information

Transcription

1 Breast Cancer: Who Gets It? Who Survives? The Latest Information James J. Stark, MD, FACP Medical Director, Cancer Program and Director of Palliative Care Maryview Medical Center Professor of Medicine Eastern Virginia Medical School

2 Case Presentation 56 y.o. lady presented in 2004 with Stage I breast cancer History of Stage III ovarian cancer in 1987 treated with debulking surgery, chemo and intraperitoneal chemotherapy.seemingly cured Had 1.5 cm breast primary: grade 3 Nottingham Score 9. ER and PR negative Her-2/neu 2+ but negative by FISH Axillary lymph nodes negative On premarin before breast cancer dx; discontinued

3 Case Presentation, continued In addition to personal history of breast and ovarian cancer, her mother had breast cancer Ethnic background: Ashkenazi Jewish Has two children: son and daugher Refused BRCA 1 and 2 testing

4 Case Presentation, continued Started on adjuvant chemotherapy with Adriamycin and Cytoxan followed by Neulasta Admitted to Maryview two weeks after chemo with fever, WBC 2000, cellulitis, then pneumonia and staphlococcal bacteremia and almost died Concluded that her marrow was probably damaged from prior therapy and chemo was abandoned Referred to radiation oncology to complete locoregional therapy Remains free of breast and ovarian cancer

5 Case Presentation, continued After 2.5 years of discussion finally agreed to BRCA 1 and 2 testing in February, 2007 BRCA 1: no mutation detected BRCA 2: 6174delT (deleterious mutation) According to Myriad Genetics this mutation confers by age 70 a risk of 84% for breast cancer and 27% for ovarian cancer To date has refused to tell her son and daughter that they have a 50% risk of having this mutation Discussions continue.

6 Who will get breast cancer? How close are we to figuring this out?? Earliest work with BRCA 1 and BRCA 2 mutations Small fraction of all women with breast cancer When mutation is present it is a powerful predictor of the development of cancer Very few patients (<5%) with breast cancer will have one of these mutations

7 The BRCA 1 and 2 Mutations Cancer suppressor genes present in all of us Mutations result in large increased risk of cancer 1/345 in general population 1/40 among Ashkenazi Jews 20 X risk of breast cancer; 9X risk of ovarian Breast cancers occur in younger women and may be more virulent

8 BRCA: who is at risk of having the mutation? More than 2 breast cancers and any ovarian cancer in close relatives More than 3 breast cancers in women under age 50 in close relatives Sister pairs under 50 with breast or ovarian cancer Inheritance autosomal dominant Men have increased risk of cancer as well

9 BRCA 1: BRCA 1 and 2, continued 85% likelihood of breast cancer by age % likelihood of ovarian cancer by 70* Doubling of colon cancer risk (men and women) Tripling of prostate cancer risk BRCA 2: 85% likelihood of breast cancer by 70 10% likelihood of ovarian cancer by 70 No associated risk for other cancers *differences explained by additional mutations Burke et al JAMA 277:997, 1997

10 Beyond BRCA: What Next? For most breast cancer patients, there is no obvious genetic link Do additional (non-brca) mutations in the genome add to the risk of breast cancer? The multigenic approach to breast cancer risk in women with no cancer yet

11 Some of the Genes Examined Angiogenesis Folate Metabolism Apoptosis Detoxification of compounds Cellular Signaling Inflammation CART (Classification Tree Analysis) used to explore gene interactions with various genotypic alleles

12 CART Analysis no Gene 1 yes no Gene 2 no Gene 5 Gene 3 yes Gene 4 After all genes are analyzed risk can be assessed at any given point

13 Study Design 500 women with breast cancer 500 controls Computer generated various node sequences and then analyzed results comparing results with what was known about the women in the study Created pathways that could select for very high likelihood of cancer and no cancer Geiger et al, Breast Cancer Research and Treatment 104 (2):159, 2007

14 Study Results Relative risk of cancer 16 in highest risk groups p<0.05. For certain nodes risk of breast cancer approached 100% Other nodes were purely people with no history of breast cancer With continued discovery of genes contributing to risk, the model will get much better

15 CART Analysis, continued Genes can be studied from sample of blood Currently research tool but with validation will become commercially available within the next few years May be the future way to predict breast cancer risk once validated on much larger sample groups

16 How good are we at predicting outcome in women who already have breast cancer?

17 Breast Cancer Outcome Traditional Prognostic Indicators in Breast Cancer Tumor Size Lymph-Node Status Hormone Receptors Her-2/Neu oncogene overexpression Ki-67 proliferative index Presence of vascular invasion Degree of Differentiation

18 Traditional Outcomes Mapping Adjuvant Online Computer program which integrates huge database of breast cancer patients into predictive software for any individual (next) patient using traditional prognostic indicators Validated versus several databases in literature Predicts outcome based on traditional variables

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20 Improving Outcomes Prediction Much background work done to identify those mutated genes in breast cancer which predict outcome better than the above traditional parameters Oncotype DX assay best studied of the commercially available gene profiling tests

21 Gene-Expression Profiling

22 Defining Risk Using Oncotype DX

23 Probability That Patients Would Remain Free of Distant Metastases among 151 Patients with Lymph-Node-Negative Breast Cancer with the Use of Gene-Expression Profiling, the St. Gallen Criteria, and the National Institutes of Health (NIH) Consensus Criteria) Biggest difference van de Vijver, M. et al. N Engl J Med 2002;347:

24 Adjuvant Online vs. Genetic Mapping Uses Mammaprint 70-gene signature

25 Use of Oncotype DX assay in NSABP B-20* All Patients with or without Chemo Low Risk R<18 Intermediate Risk 18 R 30 High Risk R>30 Tam vs. CMF+Tam in ER+ node negative patients

26 Observations Extended at Recent ASCO Meeting Intergroup trial E2197 Purpose of trial was to compare 2 different drug regimens in adjuvant therapy of breast cancer Adriamycin/Taxotere Adriamycin/Cytoxan Oncotype DX assay was done on subset of all tumors (776/2,885)

27 Results. Oncotype DX assay validated in much larger group of patients than had ever been studied Validation helped predict which hormonereceptor positive patients should get aggressive therapy Should encourage more widespread use of assay

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29 Circulating Tumor Cells Key finding is presence of CK-19 m-rna Uses PCR technology Can detect very small number of cells What is the value of this test to prognosis in: Newly diagnosed patients? Patients with first onset of metastatic disease?

30 Disease-free interval in node-negative cytokeratin-19 (CK-19) mrna-positive and CK-19 mrna-negative patients Xenidis, N. et al. J Clin Oncol; 24:

31 Relation of Circulating Tumor Cells to Survival in Patients with Metastatic Breast Cancer Hayes, D. F. et al. Clin Cancer Res 2006;12:

32 Circulating Tumor Cells Data are clear that CTC s have prognostic significance at initiation of therapy and at first onset of metastatic disease The next challenge is to figure out how to best use this data to design therapy Stay tuned.

33 Summary Risk of getting breast cancer within certain kindreds has been well-defined for several years (BRCA-1 and BRCA-2) New ways of looking at other genetic alleles is yielding a potentially very useful methodology in predicting who will get breast cancer needs validation Understanding who will relapse and die of breast cancer has undergone a revolution with the advent of genetic fingerprinting of the tumor itself Role of circulating tumor cells in predicting outcome is in evolution

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35 Background: Current Trends in Breast Cancer Research New chemo drug development always ongoing but not emphasis of current interest Targeted therapy is at the forefront of clinical cancer research What is targeted therapy??

36 Targeted Therapy Relies on physical and chemical characteristics that differentiate normal versus cancer cell Original targeted therapies were monoclonal antibodies against surface proteins on lymphoma cells Rituximab (Rituxan) an antibody against the CD-20 protein on the surface of B-cell lymphoma

37 Other Examples of Targeted Therapy Infliximab (Remicade) for inflammatory bowel disease and rheumatoid arthritis Antibody against Tumor Necrosis Factor keeping it from attaching to target cell Imatinib (Gleevec) for Chronic Myelogenous Leukemia Binds to novel tyrosine kinase created by translocation of two pieces of chromosomes 9 and 22 Trastuzumab (Herceptin) in breast cancer Binds to protein product (also tyrosine kinase) of overexpressed gene in 25-30% of breast cancer cells

38 The HER (erb) gene family with its protein products (DNA encodes for RNA which encodes for proteins) Receptor end of protein e Cell membrane Ross, J. S. et al. Oncologist 2003;8: Effector end

39 Normal cell Artist s Representation of the Overexpressed Her-2/neu Oncogene Cancer cell with overexpressed oncogene

40 How Herceptin Works Herceptin molecule: Light blue:light chains Dark blue: heavy chains Antibody slides into blue groove Extracellular domain of Her-2/neu

41 Targeted Therapy, continued Other new anticancer targeted therapies Bevacizumab (Avastin) for colorectal and lung cancer Cetuximab (Erbitux) for colorectal and headand-neck cancer Erlotinib (Tarceva) for lung and pancreatic cancer Current challenge is how to use these drugs either in combinations or with chemotherapy

42 ASCO Highlights Update on the use of Trastuzumab (Herceptin) in the adjuvant setting in breast cancer Background. Chemotherapy has been known for 30 years to help prevent development of metastases in Stages I-III breast cancer Addition of Herceptin to patients with Her- 2/neu + metastatic breast cancers improves outcome over chemotherapy alone

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44 Next Question about Herceptin If it works to prolong survival when added to chemo in patients with metastases will it improve outcome in newly diagnosed patients? The combined NSABP/NCCTG clinical trial

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46 ASCO Update 2007

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49 What About the Safety of Herceptin? Cardiac toxicity has been recognized as complication since the early days of this drug ASCO meeting provided updates and insights into cardiac risk factors with use of Herceptin

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51 Further Analysis of Data

52 Further Analysis of Cardiac Data

53 Risk Factors for Cardiac Toxicity

54 Development of Risk Model

55 Validation of Risk Model

56 Summary Exciting work is being done in new therapeutics involving non-chemo drugs Toxicity and efficacy are being better defined Predictors of outcome are being refined

57 For a copy of this talk Visit us on the web ( or at the office