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Genetic testing for breast cancer Susan M. Domchek, MD Basser Professor of Oncology University of Pennsylvania Risk Factors for Breast Cancer • 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 Germline vs Somatic Genetics • • 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 Genetics :Cancer Risk Variants Single nucleotide polymorphisms Allele Frequency Common Variants CHEK2, ATM, NBN BRCA1, BRCA2, TP53 Rare variants (moderate) 1 2 Rare variants (high) 5 Relative Risk ≥10 Hereditary breast cancer Predicted SNP , 14% Known SNPs, 14% Unknown, 50% Moderate penetrance , 4% Other high penetrance, 3% BRCA1/2, 15% Adapted from Couch, Nathanson, & Offit, Science 2014 Germline genetic testing as a paradigm for individualized care • Risk Assessment • Disease Prevention • Therapeutics BRCA1/2 as the prototype BRCA1/2-associated cancers: lifetime risk Breast cancer: 50%-70% Second primary breast cancer: 40%-50% Ovarian cancer: 15-55% BRCA1>BRCA2 Increased risk of other cancers: Male breast cancer BRCA2>BRCA1 Pancreatic cancer BRCA2 Prostate cancer BRCA2 Melanoma BRCA2 Who should be considered for testing? • 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 % Affected with Breast Cancer Estimates of breast cancer risk in BRCA1 carriers: Significant variability in penetrance Easton, 1995 all mutations linkage families 100% 90% 80% Penn Clinic Brose et al JNCI 2002 70% Streuwing, 1997 185delAG, 5382insC 60% 50% Hopper, 1999 consecutive breast ca cases 40% 30% Fodor, 1998 185delAG, 5382insC consecutive breast ca cases 20% 10% 0% 30 40 50 60 AgeAge 70 80 85 5%, 95% 10%, 90% Average 0.6 0.8 Polygenic risk scores (PRS) using BC susceptibility SNPs identified through population-based GWAS 0.4 15,252 BRCA1 0.2 8,211 BRCA2 0.0 Breast cancer risk BRCA1 carriers 1.0 Genetic modifiers: CIMBA 30 40 50 60 Age 70 80 Kuchenbaecker et al in press 2016 Risk Reducing Salpingo-Oophorectomy and the risk of breast cancer No Prior Breast Cancer Total Participants HR (95% CI) Total BRCA1 BRCA2 1,370 869 501 0.54 (0.37-0.79) 0.63 (0.41-0.96) 0.36 (0.16-0.82) RRSO and the risk of ovarian cancer Breast cancer prior Total Participants HR (95% CI) PROSE Consortium Total BRCA1 BRCA2 1060 684 376 0.14 (0.04-0.59) 0.15 (0.04-0.63) No cancer events Domchek et al, JAMA 2010 RRSO and all-cause mortality All eligible women Total Participants HR (95% CI) All BRCA1 BRCA2 2,482 1587 895 0.40 (0.26-0.61) 0.38 (0.24-0.62) 0.52 (0.22-1.23) Domchek et al, JAMA 2010 Domchek et al, JAMA 2010 Treatment of BRCA1/2-associated cancers: Platinum and PARP inhibitors • • • • • Olaparib Veliparib Rucaparib Niraparib BMN-673 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 BRCA1/2associated breast and ovarian cancer Tutt et al, Lancet 2010 Audeh et al, Lancet 2010 Gelmon et al, Lancet Oncology 2011 Tumor shrinkage Tutt et al, Lancet 2010 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 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 Ovarian (n=193) Breast (n=62) Pancreas (n=23) Prostate (n=8) Other (n=12) All (n=298) 148 (76.7) 44 (22.8) 1 (0.5) 37 (59.7) 25 (40.3) 0 5 (21.7) 17 (73.9) 1 (4.3) 1 (12.5) 7 (87.5) 0 7 (58.3) 5 (41.7) 0 198 (66.4) 98 (32.9) 2 (0.7) Median (SD) prior regimens for advanced disease 4.3 (2.2) 4.6 (2.0) 2.0 (1.6) 2.0 (1.0) 2.2 (1.3) 4.0 (2.2) Tumor response rate 60 (31.1) 8 (12.9) 5 (21.7) 4 (50) 1 (8.3) 78 (26.2) Complete response 6 (3.1) 0 1 (4.3) 0 0 7 (2.3) Partial response 54 (28) 8 (12.9) 4 (17) 4 (50) 1 (8.3) 71 (23.8) Stable (>8wks) Stable disease Unconfirmed PR 78 (40) 64 (33) 12 (6) 29 (47) 22 (36) 7 (11) 8 (35) 5 (22) 3 (13) 2 (25) 2 (25) 0 7 (58) 6 (50) 1 (8.3) 124 (42) 99 (33) 25 (9) BRCA status, n (%) BRCA1 mutation BRCA2 mutation Both Kaufman et al JCO, 2015 Platinum resistance and PARP treatment Platinum sensitivity status (N= with measurable disease) Confirmed responders n ORR, % (95% CI) • Data from the gyn onc paper Median DoR, months (95% CI) Total (N = 137) 46 34 (26–42) 7.9 (5.6–9.6) Platinum sensitive (N = 39) 18 46 (30–63) 8.2 (5.6–13.5) Platinum resistant (N = 81) 24 30 (20–41) 8.0 (4.8–14.8) Platinum refractory (N = 14) 2 14 (2–43) 6.4 (5.4–7.4) Platinum status unknown (N = 3) 2 67 (9–99) 6.3 (4.7–7.9) Domchek et al, Gyn Onc 2016 Genetic testing has become complicated…. Single nucleotide polymorphism panels Key Points • 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 In the US - this has become very complicated…. Ambry Myriad Uwash Fulgent Cancer Invitae GeneDx MyRisk BROCA * Next # of genes 25 28 28 30 50 110 Gene APC ATM BMPR1A BRCA1 BRCA2 BRIP1 CDH1 CDK4 CDKN2A CHEK2 EPCAM MLH1 MSH2 MSH6 MUTYH NBN PALB2 PMS2 PTEN RAD51C SMAD4 STK11 TP53 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x Gene BARD1 RAD51D MRE11A RAD50 NF1 VHL MEN1 RET PTCH1 PALLD XRCC2 CHEK1 AXIN2 FANCC ATR BAP1 GALNT12 HOXB13 POLD1 PRSS1 RAD51A SDHB SDHC SDHD AKT1 CTNNA1 FAM175A GEN1 GREM1 PIK3CA POLE PPM1D TP53BP1 Ambry Myriad Uwash Fulgent Cancer Invitae GeneDx MyRisk BROCA * Next x x x x x x x Renal/PGL PGL Renal/PGL Renal/PGL Renal/PGL x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x Gene FH FLCN MAX MET MITF SDHA SDHAF2 TMEM127 TSC1 TSC2 Ambry Fulgent Renal or * PGL x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x *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 Revolution of genetic testing Assess patient Test for most likely gene(s) Test for most likely gene(s) Disclose result and reassess New approach? Assess patient Send multigene panel Disclose result and reassess Why do this? • 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? Potential Issues • 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 What will we find? BRCA1/2 negative patients with BC <40 N=278 Patients with Class 4 VUS & Class 5 Mutations N=31 (11%) 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%) TP53 N=4 MSH2 N=1 CDKN2A N=1 MUTYH N=1 Class 3 VUS(s) only N=49 (18%) 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%) ATM & CHEK2 N=18 Other genes N=6 MUTYH Heterozygotes N=6 (2.2%)* No Class 3-5 Variants N=192 (69%) 6% 13% 13% 74% White 31% 63% Non-white Class 4/5 Mutation Class 3 VUS No Class 3-5 Variants Maxwell et al GIM, 2014 What do we do? ACCE Framework Parameter Definition Analytic validity How well test measures property or characteristic it is intended to measure Clinical validity Accuracy of the test in diagnosing or predicting risk for the health condition (sensitivity, specificity, PPV, NPV) Clinical Utility • Evidence of improved measurable clinical outcomes • Usefulness and added value to patient management ELSI • Ethical, legal and social implications 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 Summary of Clinical Validity Gene Breast Ovary Other ATM Y N ?Pancreas CHEK2 Y N ?Colon PALB2 Y N ?Pancreas NBN Y (657del5) N BRIP1 N Y RAD51C/D N Y RAD51B N ? BARD1 N N MRE11A/RAD50 N N Easton et al, NEJM 2015 Clinical utility • 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 • 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 • 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? Conclusions • 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