Learning Objectives. Page 1

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1 Learning Objectives 1. Outline the role of the DNA damage response (DDR) pathway in tumor suppression and describe how mutations in DDR genes lead to tumor proliferation. 2. Explore recent advances in the discovery of actionable mutations in DDR (e.g., BRCA1/2) and the developments in precision medicine targeting these mutations, including poly (ADP-ribose) polymerase (PARP) inhibitors. 3. Assess current guideline recommendations for genetic testing and counseling in patients with possible or known pathogenic DNA damage response mutations. 4. Using a case-based approach, evaluate challenging questions encountered in the genetic testing and counseling of BRCA1/2 and other DDR mutations and discuss the evolving role of the genetic counselor in the interprofessional oncology care team. Page 1

2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of April 10, All materials contained herein reflect the views of the faculty, and not those of Creative Educational Concepts, Inc. or the commercial supporter(s). Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for specific patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review or any applicable manufacturer s product information, and comparison with recommendations of other authorities. Usage Rights: This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply. BRCA and Beyond Identifying Genomic Targets in DDR and the Emergence of Precision Medicine in Cancer Nadine M. Tung, MD Beth Israel Deaconess Medical Center Harvard Medical School Boston, MA Page 2

3 Pathways DNA Damage Repair PARPi BRCA1/2 Platinum Lynch MSI BER=base excision repair; HR=homologous recombination; MMR=mismatch repair; MSI=microsatellite instability; NER=nucleotide excision repair; NHEJ=non-homologous end joining Cervelli T. Int J Mol Sciences Pathways DNA Damage Repair PARPi BRCA1/2 Platinum Lynch MSI Cervelli T. Int J Mol Sciences Page 3

4 Relative Risk BRCA1/2 Repair Double Strand Breaks in DNA Homologous Recombination (FA-BRCA) ATM BRCA2 BRCA1 CHEK2 PALB2 FA=Fanconi anemia Pennington KP, et al. Gynecol Oncol Breast Cancer Susceptibility Genes RR >5 High Clinical SNPs/PRS RR <2 Low risk: GWAS RR 2 5 Moderate PRS=polygenic risk scores; Minor Allele Frequency (%) SNP=single-nucleotide polymorphism; GWAS=genome-wide association study Foulkes WD. N Engl J Med Page 4

5 Gene Mutations Associated with a Hereditary Predisposition to Breast Cancer High penetrance (RR >5; Lifetime Risk >40%) Gene Syndrome Breast Cancer Risk (to 70) BRCA1 Breast-ovarian 57% 87% BRCA2 Breast-ovarian 57% 87% TP53 Li-Fraumeni >90% PTEN Cowden Syndrome 25% 50% STK11/LKB1 Peutz-Jeghers 45% 54% CDH1 Diffuse gastric cancer 39% Robson M. N Engl J Med. 2007; Graffeo R, et al. Breast Cancer Res Treat Breast Cancer Risk with Moderate Risk Genes Gene Breast PALB2 Y (RR 5.3) ATM Y (RR 2.8) CHEK2 (truncating) Y (RR 3.0) NBN Y (RR 2.7) NF1 Y (RR 2.6) BRIP1 RAD51C RAD51D BARD1 No evidence No evidence No evidence Insufficient evidence High Risk Easton DF, et al. N Engl J Med. 2015; Pelttari LM, et al. Hum Mol Gen. 2011; Meindl A, et al. Nat Gen. 2010; Couch FJ, et al. JAMA Oncol. 2017; Loveday C, et al. Nat Genet. 2011; Loveday C, et al. Nat Genet. 2012; Pelttari LM, et al. J Med Genet. 2012; Kurian AW, et al. JCO Pres Oncol. 2017; Easton DF, et al. J Med Genet. 2016; Weber-Lassalle N, et al. Breast Cancer Res. 2018; Couch FJ, et al. J Clin Oncol. 2015; NCCN Breast/Ovarian Genetic Assessment Guidelines, v Page 5

6 Risk of Breast Cancer Associated with Inherited Mutations High penetrance Moderate penetrance Gene Breast Cancer Risk (by age 70) BRCA1 57% 87% BRCA2 57% 87% PALB2 33% 58% ATM 20% 30% CHEK2 20% 30% Antoniou AC, et al. N Engl J Med. 2014; Tung N, et al. Nat Rev Clin Oncol. 2016; Graffeo R, et al. Breast Cancer Res Treat Breast Cancer Risk Estimates Affected by Family History Even true for BRCA1/2 Higher risks for breast or ovarian cancer for carriers with strong family history PALB2 35% risk of breast cancer by age 70 33% (no family history) and 58% (2 first-degree relatives diagnosed by age 50) Antoniou AC, et al. N Engl J Med Page 6

7 Mutation-Specific Risks Risks still emerging; may depend on type of mutation more than on highrisk genes CHEK2 Frameshift mutations: 1100delC (RR ) Missense mutations: I157T (470 T>C) and S428F (1283 C>T): lower risks (RR 1.5) ATM Some missense mutations: high risk of breast cancer ATM c.7271t>g; RR Easton DF, et al. N Engl J Med. 2015; Han FF, et al. DNA Cell Biol. 2013; Goldgar DE, et al. Breast Cancer Res. 2011; Southey MC, et al. J Med Genet. 2016; Tung N, et al. Nat Rev Clin Oncol Risk of Ovarian Cancer Gene Estimated Lifetime Risk of Ovarian Cancer Recommended Age for RRSO BRCA1 31% 59% BRCA2 18% 34% by age 45 BRIP1 13% >45 RAD51C 6% >45 RAD51D 14% >45 PALB2 2.3% 11%? Unknown or insufficient evidence BARD1 Insufficient data? (OR 4.2) Unknown or insufficient evidence NCCN Breast/Ovarian Genetic Assessment Guidelines v1.2018; Hartmann LC, et al. N Engl J Med. 2016; Antoniou AC, et al. N Engl J Med. 2014; Norquist BM, et al. JAMA Oncol. 2016; Ramus SJ, et al. J Natl Cancer Inst. 2015; Song H, et al. J Clin Oncol. 2015; Chen S, Parmigiani G. J Clin Oncol. 2007; Mavaddat N, et al. J Natl Cancer Inst Page 7

8 Cancer Risks with Novel Genes Gene Breast Ovary Other PALB2 Y (RR 5.3)? (RR ) Pancreas ATM Y (RR 2.8) Pancreas CHEK2 (truncating) Y (RR 3.0) Colon NBN Y (RR 2.7) NF1 Y (RR 2.6) NF1-related BRIP1 N Y (RR ) RAD51C Insuff data Y (OR 5.2) RAD51D Insuff data Y (OR 12) BARD1 Insuff data (TNBC)? (OR 4.2) Easton DF, et al. N Engl J Med. 2015; Antoniou AC, et al. N Engl J Med. 2014; Couch FJ, et al. J Clin Oncol. 2015; Norquist BM, et al. JAMA Oncol. 2016; Ramus SJ, et al. J Natl Cancer Inst. 2015; Song H, et al. J Clin Oncol. 2015; NCCN Breast/Ovarian Genetic Assessment Guidelines v Tung N, et al. Nat Rev Clin Oncol Page 8

9 Why Do Genetic Testing of a Cancer Patient? Identify other cancers to screen for or to prevent Family members Treatment Platinum chemotherapy PARP inhibitors Tumors in BRCA Carriers Cancers in BRCA carriers cannot repair DS DNA breaks Any therapy (platinum or PARPi) that increases the number of DS DNA breaks in the tumor may lead to cell death DS=double strand Cervelli T. Int J Mol Sciences Page 9

10 Pathways DNA Damage Repair PARPi BRCA1/2 Platinum Lynch MSI Cervelli T. Int J Mol Sciences Pathways DNA Damage Repair PARPi BRCA1/2 Platinum Lynch MSI Cervelli T. Int J Mol Sciences Page 10

11 Platinum is Effective in Treating Cancers in Patients with BRCA1/2 Mutations Ovarian cancer patients with BRCA mutations have a higher cure rate In part due to higher sensitivity to platinum Breast cancer in gbrca carriers Platinum is effective: most data for TNBC Better than standard chemo? Platinum > docetaxel chemo (TNT trial) in gbrca+ carriers with TNBC Pancreatic cancer in gbrca carriers Improved survival with and sensitivity to platinum Alsop. K, et al. J Clin Oncol. 2012; Yang D, et al. JAMA. 2011; Reiss KA, et al. JCO Precision Oncol. 2018; Blair AB, et al. J Am Coll Surg. 2018; Smith AL, et al. JCO Precision Oncol. 2018; Byrski T, et al. Breast Cancer Res Treat. 2014; Tutt A, et al. SABCS Abstract S3-01. Pathways Mechanism of Action PARPis inhibit repair of single strand (SS) DNA breaks in a tumor Unrepaired SS breaks become DS breaks in a replicating tumor Cancers in gbrca carriers cannot repair DS DNA breaks Thus, PARPis lead to cell death in BRCA-associated cancers by creating more DS breaks in the tumor that cannot be repaired. Murai J, et al. Cancer Res Page 11

12 Pathways Mechanism of Action Inhib of PARP enzyme activity SSBs PARP trapping Persistent unrepaired SSBs PARPi PARP Trapping of PARP- DNA complexes Synthetic Lethality in HR deficient tumors e.g., BRCA+ tumor Lethality not restricted to HR deficiency SSB=single strand break Murai J, et al. Cancer Res Pathways DNA Damage Repair PARPi BRCA1/2 Platinum Lynch MSI Cervelli T. Int J Mol Sciences Page 12

13 PARP Inhibitor Synthetic Lethality in BRCA Breast Cancers PARPi BRCA1/2 Platinum Lynch MSI X X Cervelli T. Int J Mol Sciences PARPi FDA Approval Which Cancers, Which Setting? Ovarian Breast FDA Prescribing Information. Page 13

14 Current FDA Status of PARPis FDA-approved Olaparib Rucaparib Niraparib Not yet FDA-approved Veliparib Talazoparib FDA Prescribing FDA Prescribing Information; Information; Clinicaltrials.gov. PARPis Approved for Maintenance after First Recurrence in Platinum-sensitive OC For all ovarian cancer (BRCA mutation or not) Including both germline and somatic BRCA-mutated OC More effective if BRCA mutation Studies that led to approval Niraparib (NOVA, FDA approved) Olaparib (SOLO-2/Study-19, FDA approved)) Rucaparib (ARIEL-3, NOT yet FDA approved)) FDA Prescribing Information; Clinicaltrials.gov. FDA Prescribing Information; Coleman RL, et al. Lancet Page 14

15 ENGOT-OV16/NOVA Niraparib Maintenance Niraparib maintenance after achieving CR or PR in patients with platinum-sensitive, relapsed ovarian cancer Median PFS, mo Niraparib (n=234) Placebo (n=116) gbrca cohort Non-gBRCA cohort Non-gBRCA cohort with HRD HR Mirza MR, et al. N Engl J Med PARPis as Single Agents for Treatment of Recurrence (i.e., not maintenance) Olaparib December 19, 2014; accelerated approval gbrca mutation 3 prior lines Olaparib tablets: 300 mg PO BID Rucaparib December 19, 2016; accelerated approval Deleterious BRCA mutation (gbrca and/or sbrca) 2 prior lines Rucaparib tablets: 600 mg PO BID Swisher EM, et al. Lancet Oncol. 2017; Kaufman B, et al. J Clin Oncol. 2015; Page 15

16 Olaparib FDA Approval Breast Cancer January 12, 2018 gbrca+ metastatic HER2-neg breast cancer Prior chemo in (neo)adjuvant or metastatic setting OlympiAD (Olaparib) Phase III Trial gbrca+ Metastatic Breast Cancer HER2-negative metastatic breast cancer and germline BRCA1 or BRCA2 mutation N=302 R 2:1 Olaparib 300 mg PO BID Standard Chemo: MD choice Capecitabine or Vinorelbine or Eribulin Primary Endpoint PFS Robson M, et al. N Engl J Med Page 16

17 OlympiAD (Olaparib) Phase III Trial gbrca+ Metastatic Breast Cancer 3 month significant improvement in PFS Median PFS 7.0 vs 4.2 months; HR 0.58; P<0.001 No improvement in overall survival FDA approved Robson M, et al. N Engl J Med EMBRACA (Talazoparib) Study Design Patients with: locally advanced or metastatic HER2- negative breast cancer and germline BRCA1 or BRCA2 mutation N=431 R 2:1 Talazoparib 1 mg PO daily Standard Chemo: MD choice Capecitabine or Vinorelbine or Eribulin or Gemcitabine Primary Endpoint PFS Phase 3, international, open-label study randomized 431 patients in 16 countries and 145 sites Litton J, et al. SABCS Abstract GS6-07. Page 17

18 EMBRACA Talazoparib in BRCA+ MBC 3 month significant improvement in PFS Median PFS: 8.6 vs 5.6 mos; HR 0.54; P< No improvement in overall survival Not yet FDA approved MBC=metastatic breast cancer Litton J, et al. SABCS Abstract GS6-07. Updated NCCN Breast Cancer Guideline v Footnote suggests testing all treatment eligible patient population Patients with HER2-negative disease eligible for single-agent therapy are eligible for germline BRCA1/2 testing. Page 18

19 TO-PARP Trial PARPi in Prostate Cancer Olaparib worked in metastatic prostate cancer patients 14/16 (88%) response if mutations/biallelic loss in DNA repair gene, especially ATM, BRCA1/2 Responses with inherited and somatic mutations Mateo J, et al. N Engl J Med PARPis and Prostate Cancer Olaparib: FDA breakthrough therapy designation in castration resistant prostate cancer BRCA1/2 (germline or somatic) mutation ATM (germline or somatic) mutation Helleday T. Ann Oncol Page 19

20 Summary PARPi FDA Approvals Ovarian Cancer All patients: maintenance after first platinum-sensitive relapse g/s BRCA+: treatment for relapse if 2 prior chemo Breast Cancer gbrca+: metastatic HER2-negative, with prior chemotherapy g=germline; s=somatic FDA Prescribing Information. What, When, Who and How? Keeping Up with Genetic Testing Guidelines Justine Cooper Pickarski, MS, LGC University of Kentucky Markey Cancer Center Lexington, KY Page 20

21 Somatic Testing vs Germline Testing Somatic Identifies mutations in the tumor (i.e., acquired changes) Is performed on tumor tissue The patient has cancer The purpose is to identify treatment options and determine prognosis Is ordered by oncologist The patient is not often consented Germline Identifies mutations in the germline (i.e., mutations you are born with) Is performed on blood/saliva The patient may be unaffected The purpose is to identify patients with inherited cancer predisposition syndromes Is often ordered by GC, sometimes by oncologist, surgeon, PCP, etc. The patient often receives counseling Available Testing Technologies and Proper Interpretation of Results Tumor only Only the tumor tissue is analyzed Unable to filter out germline mutations Tumor normal Tumor tissue and normal tissue (i.e., blood) is analyzed May filter out germline mutations when reporting results Liquid biopsy Circulating tumor DNA in blood is analyzed May filter out germline mutations when reporting results Jones S, et al. Sci Transl Med. 2015; Page 21

22 Prostate Cancer Consensus Conference 2017 Confirmatory germline genetic testing for prostate cancer predisposition should occur for men with prostate tumor sequencing that shows mutations for the following cancer-risk genes: BRCA1/BRCA2 DNA MMR genes (MLH1, MSH2, MSH6, PMS2, EPCAM) HOXB13 ATM Giri VN, et al. J Clin Oncol. 2018; Richman S. Int J Oncol Page 22

23 ASCO Policy Statement ASCO supports the communication to patients of medically relevant incidental germline findings from somatic mutation profiling conducted in the clinical setting. Oncology providers should communicate the potential for incidental and secondary germline information to patients before conducting somatic mutation profiling and should review the potential benefits, limitations, and risks before testing. Robson ME, et al. J Clin Oncol Discussion Prior to Testing Risk group based on Pre-NGS probability Description of Pre-NGS groups High Strong family or personal history of malignancy, per current tumor-specific genetic counseling guidelines Ashkenazi Jewish heritage Intermediate May have family history of malignancy or other high risk features (e.g., very early age at diagnosis), but does not meet current guidelines for referral to genetic counseling/testing Low Unimpressive family history (either no known history of malignancy or remote, isolated cases) Recommendations to the oncologist before/after ordering NGS Emphasize the implications of NGS testing, including the possibility of identifying a somatic mutation that would be suspicious for germline potential Prior to testing: ask the patient about their preferences regarding disclosure of this information Prior to obtaining NGS results: strongly consider referral to a genetic counselor Discuss the implications of NGS testing and the possibility of identifying a somatic mutation that would be suspicious for germline potential Prior to testing: ask the patient about their preferences regarding disclosure of this information After NGS testing: use post-ngs risk to determine whether referral to genetic counselor and germline testing is warranted. When in doubt, discuss the case with a genetic counselor to clarify whether referral is recommended Briefly mention the implications of NGS testing and the rare possibility of identifying a somatic mutation that would be suspicious for germline potential Prior to testing: ask the patient about their preferences regarding disclosure of this information After NGS testing: use post-ngs risk to determine whether referral to genetic counselor and germline testing is warranted. When in doubt, discuss the case with a genetic counselor to clarify whether referral is recommended Catenacci D, et al. Int J Cancer Page 23

24 How Often are Germline Findings Identified in the Tumor? Meric-Bernstam F, et al. Ann Oncol advanced cancer patients offered tumor-normal sequencing with 202-gene panel (19 clinically actionable in germline) at MD Anderson 422/1000 (42%) had pathogenic somatic variant in one of 19 genes 43/1000 (4.3%) had a likely pathogenic germline variant identified Tumor types included breast, colon, brain, melanoma, sarcoma, ovary, and head and neck Schrader KA, et al. JAMA Oncol advanced cancer patients offered tumor-normal sequencing with MSK-IMPACT panel (341-gene panel) 198/1566 (12.6%) had pathogenic germline variant in cancer susceptibility gene Germline findings concordant with cancer type in only 81/198 (40.9%) cases Seifert BA, et al. Clin Cancer Res unselected cancer patients offered tumor-normal sequencing of 247 genes (36 genes strongly associated with hereditary cancer) at UNC 19/439 (4.3%) had pathogenic germline variant 12/19 (63%) were concordant with cancer type Suggestive of Germline Finding All BRCA1 and BRCA2 pathogenic variants regardless of tumor type (NCCN guideline) Founder mutations (i.e., MSH2 exon 1 6 deletion,tp53 R337H, CHEK2 1100delC) Uncommonly somatically mutated genes (i.e., MSH6, PALB2) Lynch HT, et al. JAMA. 2004; Tishkowitz A, Xia B. Cancer Res. 2010; Raymond VM, et al. J Natl Cancer Inst. 2015; Silva FC, et al. BMC Med Genet. 2014; NCCN Breast/Ovarian Genetic Assessment Guidelines v Page 24

25 Percentage of Somatic vs Germline Variants Meric-Bernstam F, et al. Ann Oncol Suggestive of Germline Finding All BRCA1 and BRCA2 pathogenic variants regardless of tumor type (NCCN guideline) Founder mutations (i.e., MSH2 exon 1 6 deletion, TP53 R337H, CHEK2 1100delC) Uncommonly somatically mutated genes (i.e., CHEK2, PALB2) Gene consistent with phenotype Same mutation detected in multiple primary tumors Underlying mutation pattern (i.e., hypermutated tumor) High mutant allele frequency (MAF) Lynch HT, et al. JAMA. 2004; Tishkowitz A, Xia B. Cancer Res. 2010; Raymond VM, et al. J Natl Cancer Inst. 2015; Silva FC, et al. BMC Med Genet. 2014; Li MM, et al. J Mol Diagn. 2017; NCCN Breast/Ovarian Genetic Assessment Guidelines v Page 25

26 Mutant Allele Frequency MAF can be suggestive of a germline mutation MAF >50% suggest loss of heterozygosity (LOH) Germline mutations in tumor suppressor genes often undergo LOH events High MAF also seen in normal course of tumor development without a germline mutation Do not use low MAF to rule OUT a germline mutation! Merajver SD, et al. Clin Cancer Res. 1995; Li MM, et al. J Mol Diagn Mutant Allele Frequencies AF=allelic frequency Meric-Bernstam F, et al. Ann Oncol Page 26

27 Refer if Tumor Testing is Normal? Regardless of tumor results, if the patient meets criteria for germline testing (NCCN guidelines), REFER! Large deletion in somatic can mask germline point mutation Somatic vs germline labs cover different areas of the genes Rearrangement not done on all genes Pathogenic variant in germline may not be considered pathogenic in tumor, therefore not reported or reported as VUS Testing is not completed for all clinically relevant genes VUS=variant of unknown significance Schrader KA, et al. JAMA Oncol. 2016; NCCN Breast/Ovarian Genetic Assessment Guidelines v Barriers and Clinical Challenges Insurance coverage Becoming less of an issue with lower patient-pay prices Single-site vs full panel Patient may have previously declined counseling/testing Patients often confused about germline vs somatic testing Sick patients Often need to be seen relatively quickly Everett JN, et al. J Genet Counsel Page 27

28 Abbreviations ADP adenosine diphosphate GC genetic counselor AF allelic frequency GWAS genome-wide association study ASCO American Society of Clinical Oncology HER2 human epidermal growth factor BER base excision repair receptor 2 BID twice daily HR hazard ratio; or homologous CR complete response recombination DDR DNA damage response HRD homologous repair deficiency DS double strand LOH loss of heterozygosity FA Fanconi anemia MAF mutant allele frequency FDA U.S. Food and Drug Administration MBC metastatic breast cancer gbrca germline BRCA MMR mismatch repair MSI microsatellite instability Abbreviations NCCN National Comprehensive Cancer Network NER nucleotide excision repair NGS next-generation sequencing NHEJ non-homologous end joining OC ovarian cancer OR odds ratio PARP poly (ADP-ribose) polymerase PARPi PARP inhibitor PCP primary care provider PFS progression-free survival PO by mouth PR partial response PRS polygenic risk scores RR relative risk RRSO risk-reducing salpingo-oophorectomy sbrca somatic BRCA SNP single-nucleotide polymorphism SS single strand SSB single strand break TNBC triple negative breast cancer VUS variant of unknown significance Page 28