Efrat Levy Lahad : Genetic testing for breast and ovarian cancer
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This document discusses genetic testing guidelines for breast and ovarian cancer. It provides an overview of current guidelines from organizations like USPSTF, NCCN, ACOG, and NICE. The USPSTF recommends testing only for those with a suggestive family history. NCCN guidelines provide more detailed criteria for testing breast cancer patients. Studies have found a high percentage (around 10%) of Ashkenazi Jewish women with breast cancer carry BRCA mutations, suggesting all such women should undergo genetic testing. Overall, the guidelines are evolving to expand testing to more patients as the therapeutic implications of mutations are better understood.
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Efrat Levy Lahad : Genetic testing for breast and ovarian cancer
- 1. Gene$c tes$ng for breast & ovarian cancer Ephrat Levy-‐Lahad, MD Shaare Zedek Medical Center Jerusalem, Israel Israeli-‐French Breast Cancer Update, Jerusalem May 1, 2014
- 2. Disclosures -‐ none Our research is supported by : • The Israel Cancer Associa:on • The Breast Cancer Research Founda:on (NY, USA)
- 3. Gene$c tes$ng for breast and ovarian cancer: Who should be tested and for what genes?
- 4. Why perform gene$c tes$ng? Unaffected women – defining risk • Prevent breast & ovarian cancer (in carriers) • Avoid unnecessary preven:on/surveillance measures (in non-‐carriers) • Enable tes:ng in rela:ves. Affected women (breast or ovarian cancer) • Prevent addi:onal cancers (ovarian, contralateral breast) • Enable tes:ng in rela:ves • Therapeu$c implica$ons – chemotherapy, radiotherapy, targeted therapy (incl. clinical trials). Therapeu$c implica$ons are a game changer: Timeline; Scope of tes:ng: pa:ents & genes
- 5. Who to test? Current guidelines • This recommenda$on applies to asymptoma$c women who have not been diagnosed with BRCA-‐related cancer. • USPSTF recognizes the poten$al importance of further evalua$ng women who have a diagnosis of breast or ovarian cancer. Some women receive gene:c tes:ng as part of a cancer evalua:on at the :me of diagnosis of breast cancer. • The USPSTF did not review the appropriate use of BRCA tes$ng in the evalua$on of women who are newly diagnosed with breast cancer. That assessment is part of disease management and is beyond the scope of this recommenda$on.
- 6. USPSTF – Test asymptoma$c only with sugges$ve family history Family history sugges:ve of BRCA muta:ons includes: • Breast cancer diagnosis at age <50 years, • Bilateral breast cancer • Individual with 2 primary tumors: breast& ovarian/ fallopian/peritoneal cancer • Male breast cancer • Mul:ple cases of breast cancer in the family, Rela:ves with 2 primary BRCA-‐related cancers • Ashkenazi Jewish ethnicity.
- 7. Insufficient evidence to support a specific risk threshold for referral for tes$ng, or a specific carrier probability model. Recommend tes$ng women with sugges:ve family history Recommend against tes:ng women without family history USPSTF – Tes$ng only for sugges$ve family history
- 8. Who to test? Addi:onal guidelines • ACOG (2009), SGO (2007) 20-‐25% cancer risk threshold, suggest tes:ng could be helpful for those with > 5-‐10% chance of inherited cancer predisposi:on. (prior probability approach) • ASCO (2010), NSGC (2013)– no threshold, emphasize counseling and impera:ve that test results affect pa:ent management. • ESMO (2011) – pretest & post-‐test counseling, informed consent. (emphasis on process and clinical u$lity)
- 9. NCCN Guidelines -‐ 2014 Affected persons – detailed criteria for breast cancer + • All breast cancer < 45 • Early onset (<50 yrs) breast cancer+ • Triple nega:ve breast cancer – all < 60, over 60 if + • All mul:ple primaries • All ovarian cancer • All male breast cancer
- 10. NICE Guidelines (UK) June 2013 • Carrier probability at which gene$c tes$ng should be offered • Breast/ovarian cancer cases with combined BRCA1/BRCA2 muta-on carrier probability of >10% (based on acceptable methods) • Person with no personal history of breast or ovarian cancer: 1. If they have a combined BRCA1/BRCA2 muta-on carrier probability > 10%. 2. If they have an an affected rela-ve with carrier probability > 10% who is available for tes-ng.
- 11. Should all women with breast or ovarian cancer undergo germline gene$c tes$ng?
- 12. Ashkenazi Women with Breast Cancer IBCS (Israel Breast Cancer Study) –Results NYBCS (King et al. Science 2003) N=1008 42 25 37 104 4.2% 2.5% 3.7% 10.3% BRCA1 BRCA1 BRCA2 Total 185delAG 5382insC 6174delT 44 20 48 112 4.2% 1.9% 4.5% 10.6% N=1,046 consecu:ve, Ashkenazi Jewish women with breast cancer
- 13. 83 52 48Br 39 79 * BRCA1 5382 insC 84 74 48Br 42 * BRCA2 6174 ΔT VN" VN" VN" VN"NN" NN" NN" NN" NN" Small families" Paternal inheritance" Female relatives carry wildtype alleles by Mendelian chance" 50% of patients with BRCA1 or BRCA2 mutations" No close family history of breast or ovarian cancer" V – Variant (mutation) N- normal Courtesy of MC King, UW
- 14. Carriers Non-carrier controls Family History- How suggestive? 77* (45%)119 (70%)Not 31 (18%)32 (19%)Low 34** (20%)15 (9%)Moderate 25 (15%)4 (2%)High 3 (2%)0 (0%)Lack of information 170 (100%)170 (100%)Total Do carriers have family history? Carriers vs. Non-carriers – p<.001 BRCA2 vs. BRCA1 p=0.015 Assessment of family history in BRCA1/2 and control families *one double heterozygote ** two double heterozygotes
- 15. Should all women with ovarian cancer undergo germline gene$c tes$ng?
- 16. Hirsch-Yecehzkel et al, Gyn Oncol 2003 BRCA1/BRCA2 muta$ons in ovarian cancer NISOC study – all ovarian cancer cases in Israel 3/1994-‐6/1999 – 779 invasive epithelial ovarian cancers.
- 17. TP53 BRCA1 BRCA2 BRIP1 CHEK2 BARD1 MRE11 MSH6 NBN PALB2 RAD51C RAD50 40 23 1 4 5 1 2 1 2 1 2 3 Ovarian cancer: BRCA1/BRCA2 mutations in 63/360 (18%) patients not selected for family history or age at onset Walsh, Swisher et al. PNAS 2011 BRCA1/BRCA2 muta$ons in ovarian cancer (UW, Seaile, USA) Courtesy of MC King, UW
- 18. Should all women with breast or ovarian cancer undergo germline gene$c tes$ng? BRCA1/BRCA2 Ovarian cancer – Yes > 10% probability Breast cancer– Ashkenazi Jews – Yes ~10% probability other founder popula$ons, all? (7-‐8%)
- 19. Advantages and disadvantages of general tes$ng in affected women Advantages • Management – planning surgery and radia:on, chemotherapy choice • Preven:on/early detec:on of second primary • Clinical trials Disadvantages • Variants of unknown significance 10-‐15%
- 20. For what genes? • BRCA1/BRCA2 • Syndrome specific – PTEN (Cowden/PTEN hamartoma synd.), TP53, CDH1 • Popula:on specific – PALB2 in Finland Game changer – mul$-‐gene panels Available as a consequence of NGS (next genera:on sequencing). Most now include BRCA1/BRCA2
- 21. Hereditary breast/ovarian gene panels – Gene list Hiraki S, et al, J Genet Counsel, 2014
- 22. Hiraki S, et al, J Genet Counsel, 2014
- 23. Panel genes: pathways and risk categories
- 24. Panel genes: pathways and risk categories Hiraki S, et al, J Genet Counsel, 2014
- 25. Mul$-‐gene panel tes$ng -‐ results 1. Deleterious muta$ons in high-‐risk genes 2. Deleterious muta$ons in moderate-‐risk genes? • No clinical guidelines for management of moderate penetrance genes. • Life:me breast cancer risk > 20%, breast MRI • Risk reducing surgeries???? 3. Variants of unknown signficance (VOUS)
- 26. What is the added yield of mul$-‐gene panels?
- 27. TP53 BRCA1 BRCA2 BRIP1 CHEK2 BARD1 MRE11 MSH6 NBN PALB2 RAD51C RAD50 40 23 1 4 5 1 2 1 2 1 2 3 Ovarian cancer: BRCA1/BRCA2 muta:ons in 63/360 (18%) pa:ents not selected for family history or age at onset Muta$ons in 10 other genes: 19/360 – 5% Walsh, Swisher et al. PNAS 2011 BRCA1/BRCA2 muta$ons in ovarian cancer (UW, Seaile, USA) Courtesy of MC King, UW
- 28. Patient’s genotype determines treatment Implications for relatives Almost all these cases are preventable Patients w ovarian cancer BRCA1/BRCA2 Other genes Total with inherited risk 360 63 19 82 0.18 0.05 0.23 N Proportion Walsh, Swisher et al. PNAS 2011 Ovarian cancer: Inherited mutations in 12 genes in 23% of unselected patients
- 29. 18 genes with actionable mutations in 191 breast cancer families 25% of families negative by commercial BRCA1 and BRCA2 testing Courtesy of MC King, UW
- 30. Families with negative results from commercial BRCA1 and BRCA2 testing – Sequencing 20 breast cancer genes 0 0.1 0.2 0.3 All families (N = 741) Female and male breast cancer (N = 83) Breast and ovarian cancer (N = 279) Female breast cancer only (N = 401) Proportionoffamiliesresolved Courtesy of MC King, UW
- 31. NGS panels in “real life” (Mauer CB, et al, GIM 2013) Retrospec:ve review of all NGS cancer panels ordered by a large academic cancer gene:cs program (University of Texas, Dallas) 4/2012 -‐1/ 2013 Various panels (not including BRCA1/2) • 1,233/1,521 (81.1%) new cancer gene:cs pa:ents evaluated had gene:c tes:ng. • NGS panels were ordered on 60 (4.9%) of these pa:ents.
- 32. • Breast cancer pa:ents – 36/37 previously nega:ve BRCA1/BRCA2 tes:ng. • Most other tested pa:ents were also personally affected with cancer • Deleterious results: • 5/50 (10%) of those who had an NGS panel • Compare to: 131/1,233 (10.6%) single-‐gene tests ordered at the same center in the study :me frame-‐deleterious result NGS panels in “real life” (Mauer CB, et al, GIM 2013)
- 35. Clinical U$lity of NGS panels (Mauer CB, et al, GIM 2013) 30 (60%) – no effect on management decisions. 15 (30%) introduced uncertainty regarding the pa:ents’ cancer risks. 5 (10%)-‐ directly influenced management decisions. “The CHEK2 posi-ve pa-ents were counseled according to the management guideline previously established at our ins:tu:on.” “The RAD51C, ATM, and MUTYH muta:on results prompted a thorough review of the literature”
- 36. Suggested Criteria for NGS – Breast cancer (aper nega$ve BRCA1/2 tes$ng)
- 37. Criteria for NGS – Ovarian cancer (aper nega$ve BRCA1/2 tes$ng)
- 38. Conclusions • Who – all women with ovarian cancer, and probably all women with breast cancer. • What – Ideally – BRCA1/BRCA2 + syndromic genes separately, NGS as research. (NCCN – NGS as second :er, with gene:cist) • Not clearly possible as BRCA1/BRCA2 are incorporated into NGS panels. • DATA COLLECTION – reclassify VUS, understand cancer risks.
- 39. Institute of Medical Genetics, Shaare Zedek Medical Center: Sari Lieberman, Ariela Tomer, Vered Koltuv, Carmit Cohen Dr. Efrat Gabai-Kapara , Chaya Hackett, Lab: Dr. Rachel Beeri, Doris Goldschmidt, Dr. Esther Korzin-Bez, GCs: Hila Fridman, Sivan Koka, Dr. Adi Ben-Yehuda, Dr. Galit Lazer- Derbeko, Shachar Zuckerman, Yulia Grinshpun-Cohen. CoordinationL Sara Ribak, Liora Bruchim, Ronit Eliahu, Noam Zaslansky Dr. Avraham Ben-Chetrit, Dr. Oded Olsha, Dr. Amnon Lahad Sheba Medical Center, Tel Hashomer Prof. Bella Kaufman, Dr. Shlomo Segev, Michal Chami, Prof. Raphael Catane, Dr. Miri Sklair, Prof. Eitan Friedman Terem Medical Center Hala Breast Clinic Dr. Keren Djemal, Toby Davidian Dr. Strano, Judy Kopp Efrat Medical Center Terem Modiin Medical Center Dr. Ben Zev, Dr. Yitchak Glick Dr. Todd Zalut, Chaviv Gabai Thank you: Supported by the Breast Cancer Research Founda$on, (BCRF), NY, USA Israel Cancer Associa$on (Israel Breast Cancer Consor$um)
- 40. Which genes? NICE Recommenda:on (2013, unchanged from 2004) • Muta$on tests • 1.5.5 Tests aimed at muta:on finding should first be carried out on an affected family member where possible. [2004] • 1.5.6 If possible, the development of a gene:c test for a family should usually start with the tes:ng of an affected individual (muta:on searching/screening) to try to iden:fy a muta:on in the appropriate gene (such as BRCA1, BRCA2 or TP53) (see recommenda-ons 1.5.8–1.5.13). [2004] • 1.5.7 A search/screen for a muta:on in a gene (such as BRCA1, BRCA2 or TP53) should aim for as close to 100% sensi-vity as possible for detec-ng coding altera-ons and the whole gene(s) should be searched. [2004]
- 41. In the American College of Medical Gene:cs and Genomics (ACMG) recommenda:ons (1) sequence varia$on is previously reported and is a recognized cause of the disorder. (2) sequence varia:on is previously unreported and is of the type which is expected to cause the disorder. (3) sequence varia:on is previously unreported and is of the type which may or may not be causa:ve of the disorder. (4) sequence varia:on is previously unreported and is probably not causa:ve of disease. (5) sequence varia$on is previously reported and is a recognized neutral variant. (6) sequence varia:on is previously not known or expected to be causa:ve of disease, but is found to be associated with a clinical presenta:on
- 42. ACMG results report guideline • (1) the gene • analyzed and the presence or absence of a variant, the nature • of the muta:on, and whether it is conserva:ve or nonconserva:ve; • (2) The category (1–6) within which the variants • falls; (3) The basis upon which this classifica:on was made; • (4) Tes:ng methodology and analy:c sensi:vity; (5) Available • data on penetrance and expressivity of previously reported • variants; (6) Strategies for further classifica:on of novel • variants (Richards et al. 2008). It is recommended that novel • variants with unknown pathogenicity not be reported to the • pa:ent, but be studied within the research context in efforts to • further refine the classifica:on (Berg et al. 2011).
- 43. • GeneDx categorizes genes based on level of risk, with “Significantly • Increased Risk” genes having a rela:ve risk≥4, • “Moderately Increased Risk” genes having a rela:ve risk of • 2–4, and genes that confer an increased risk, the exact magnitude • of which is unknown due to lack of data.