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Genetic testing for breast cancer PowerPoint Presentation

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Description : Check out this medical presentation on Familial Pancreatic Cancer, which is titled "Genetic testing for breast cancer", to know about genetic testing in case of breast cancer.

Tags : Familial Pancreatic Cancer, Genetic testing, breast cancer

Published on : May 18, 2021 | Views : 2413 | Downloads : 4

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Slide 1-

Genetic testing for breast cancer Susan M. Domchek, MD Basser Professor of Oncology University of Pennsylvania
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Sex Age Family history Depends on specific of family history Depends on whether there is a known genetic susceptibility Reproductive history Early first period Late last period Postmenopausal estrogen use Late first child No breast feeding ETOH Obesity Lack of exercise Risk Factors for Breast Cancer
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Germline – the genes you are born with Can be passed on to relatives Does not mean that disease will happen Increased risk of disease There is no one “breast cancer gene” Somatic – changes in tumors that are acquired over time Can not pass on to relatives Can be tested as part of decision making for therapy for cancer Germline vs Somatic Genetics
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Allele Frequency Relative Risk 1 2 5 ≥10 Common Variants Rare variants (moderate) Rare variants (high) Genetics :Cancer Risk Variants Single nucleotide polymorphisms CHEK2, ATM, NBN BRCA1, BRCA2, TP53
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Adapted from Couch, Nathanson, & Offit, Science 2014 Hereditary breast cancer
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Risk Assessment Disease Prevention Therapeutics Germline genetic testing as a paradigm for individualized care
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Increased risk of other cancers: Male breast cancer BRCA2>BRCA1 Pancreatic cancer BRCA2 Prostate cancer BRCA2 Melanoma BRCA2 Breast cancer: 50%-70% Second primary breast cancer: 40%-50% Ovarian cancer: 15-55% BRCA1>BRCA2 BRCA1/2-associated cancers: lifetime risk
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Breast cancer <45 Ovarian cancer cases (particularly high grade serous) Male Breast Cancer Breast and ovarian cancer in a single lineage 2 or more women with breast cancer <50 Ashkenazi Jewish with breast or ovarian cancer Breast cancer < 60 and triple negative Bilateral breast cancer <60 Pay attention to pancreatic cancer and high grade prostate cancer Ashkenazi Jewish individuals? All women at age 30? Many issues related to population screening Who should be considered for testing?
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Estimates of breast cancer risk in BRCA1 carriers: Significant variability in penetrance
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Kuchenbaecker et al in press 2016 Genetic modifiers: CIMBA BRCA1 carriers Polygenic risk scores (PRS) using BC susceptibility SNPs identified through population-based GWAS 15,252 BRCA1 8,211 BRCA2
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Domchek et al, JAMA 2010 Risk Reducing Salpingo-Oophorectomy and the risk of breast cancer RRSO and the risk of ovarian cancer PROSE Consortium
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Domchek et al, JAMA 2010 Domchek et al, JAMA 2010 RRSO and all-cause mortality
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Olaparib Veliparib Rucaparib Niraparib BMN-673 Tutt et al, Lancet 2010 Audeh et al, Lancet 2010 Gelmon et al, Lancet Oncology 2011 Treatment of BRCA1/2-associated cancers: Platinum and PARP inhibitors Poly ADP ribose polymerase (PARP) plays a role in the repair of single strand breaks through base excision repair Significant responses observed in patients with germline BRCA1/2-associated breast and ovarian cancer
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Tutt et al, Lancet 2010 Tumor shrinkage
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Approval is for germline BRCA1 and BRCA2 associated ovarian cancer after treatment with >3 lines of therapy The FDA did not approve maintenance therapy EMA did approve maintenance
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Multiple tumor types Cisplatin-resistant ovarian cancer Breast cancer with >3 lines of therapy in metastatic setting Pancreatic and prostate cancer Kaufman et al, JCO 2015 Domchek et al, Gyn Onc 2016
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Kaufman et al JCO, 2015
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Data from the gyn onc paper Platinum resistance and PARP treatment Domchek et al, Gyn Onc 2016
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Genetic testing has become complicated…. Single nucleotide polymorphism panels
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Not comprehensive sequencing of genes – such as BRCA1/2 Not a stand alone for those with a strong family history Some change in reclassification (change in how you consider someone from a risk perspective) Calibration: How closely the predicted probabilities agree with the actual outcome Clinical utility (or actionability?) Will more women take tamoxifen? How should this impact screening in the era of changing screening recommendations? Ongoing studies Key Points
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In the US - this has become very complicated….
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*Rest of genes on Fulgent: BLM, BUB1B, CTNNB1, CYLD, DDB2, DICER1, EGFR, EGLN1, ERCC2, ERCC3, ERCC4, ERCC5, EXO1, EXT1, EXT2, FANCA, FANCB, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, GPC3, HRAS, KIF1B, KIT, MC1R, MPL, MSH3, NF2, PDGFRA, PICALM, PMS1, PRKAR1A, PRKDC, PTPN11, RB1, RBBP8, RBM15, RECQL4, ROBO2, SBDS, SLX4, SMARCB1, SUFU, TERT, TSHR, TYR, WRN ,WT1, XPA, XPC, XRCC3
Slide 25-

Assess patient Test for most likely gene(s) Disclose result and reassess Test for most likely gene(s) Revolution of genetic testing
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Assess patient Send multigene panel Disclose result and reassess New approach?
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More cost effective (for the testing) to do multigene rather than serial testing Patients (and providers!) can get testing fatigue The same cancer can be seen with different genes mutations Ovarian cancer in both BRCA1/2 and Lynch Uterine cancer in Lynch and Cowden Breast in Li-Fraumeni and BRCA1/2 Isn’t more better? Why do this?
Slide 28-

High penetrance and moderate penetrance genes are on one panel Implications for counseling Keeping track of it all Don’t we recognize clinical syndromes? (And if we don’t – what does it mean?) Variants of uncertain significance Clinical utility: order tests you will act on At least actionability Domchek et al, JCO 2013 Potential Issues
Slide 29-

Maxwell et al GIM, 2014 BRCA1/2 negative patients with BC <40 N=278 Patients with Class 4 VUS & Class 5 Mutations N=31 (11%) Class 3 VUS(s) only N=49 (18%) MUTYH Heterozygotes N=6 (2.2%)* Bin A Genes TP53, PTEN, STK11, CDH1, CDKN2A, MLH1, MSH2, MSH6, PMS2, MUTYH (AR) Risk established for breast or other cancers Guidelines available *Clinically actionable* N=7 (2.5%) Bin B Genes ATM, BARD1, BRIP1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD50, RAD51C Risk established for breast and some other cancers Less clear actionability N=24 (8.6%) No Class 3-5 Variants N=192 (69%) TP53 N=4 MSH2 N=1 CDKN2A N=1 ATM & CHEK2 N=18 Other genes N=6 White Non-white 6% 31% 63% 13% 13% 74% Class 4/5 Mutation Class 3 VUS No Class 3-5 Variants MUTYH N=1 What will we find?
Slide 30-

What do we do? ACCE Framework
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What is actionable? Something that potentially could be acted upon It does not mean that it is acted upon It does not mean that such action benefits a patient Actionability = clinical utility Critically important that all this be studied
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Summary of Clinical Validity Easton et al, NEJM 2015
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Risk assessment Value of the true negative Risk of breast and as well as risk of second primary cancer Risk of other cancers (Ovarian cancer risk for BRCA1/2 was a major reason for rapid uptake of testing) Clinical utility
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Screening and prevention Need to understand risks and benefits What age to start screening? What screening? What age to have preventative surgery? What to do with “unexpected” high penetrance mutation When we find things we don’t expect, what should we do? Clinical utility
Slide 35-

Therapeutics Prognosis: may impact administration of adjuvant therapy Drug development/selection Will tumors with mutations in these other genes be sensitive to specific types of drugs? Clinical utility
Slide 36-

Genetic testing can be very useful to patients and their family members Both the prevent and to treat cancer Genetic testing is continuously evolving BRCA1 and BRCA2 mutations are the most commonly found and we have reasonable data on how to manage New genetics tests are often less clear in terms of how to change patients care – and improve patient outcome Variants of unknown significance should NOT be managed as mutations In the face of rising prophylactic mastectomies, we need to emphasize to patients how mutations in these genes are different from those in BRCA1/2 Conclusions