Somatic Testing and Germline Genetic Status: Implications for Cancer Treatment Decisions and Genetic Counseling

Abstract

Purpose of Review

We review recent precision oncology literature pertaining to the implications of germline and somatic genetic information in cancer treatment. The goal of this work is to provide a practical resource for oncology practitioners and genetic providers and discuss practice considerations for those on the frontline of precision oncology.

Recent Findings

Understanding germline and somatic tumor alterations, patients can be matched to targeted therapy options attacking the specific genetic makeup of that tumor. This information informs treatment decisions about which therapies the cancer is likely to respond to and which treatment options should be avoided. Timely access to germline and somatic genetic testing is critical to ensure that patients have this information for treatment planning, both at diagnosis and through later lines of therapy.

Summary

The hope of precision oncology is here although significant challenges remain for implementation for routine cancer care.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Gutierrez M, Choi K, Lanman R, et al. Genomic profiling of advanced non-small cell lung cancer in community settings: gaps and opportunities. Clin Lung Cancer. 2017;18(6):651–9.

    Article  Google Scholar 

  2. 2.

    Gutierrez M, Price K, Lanman R, et al. Rates of genotyping for KRAS, NRAS, BRAF, microsatellite instability (MSI), and mismatch repair (MMR) in metastatic colon cancer patients: Gaps and implications. Journal of Clinical Oncology 2019 37:15_suppl, e15123-e15123. https://doi.org/10.1200/JCO.2019.37.15_suppl.e15123.

  3. 3.

    Kurian A, Ward K, Howlander N, et al. Genetic testing and results in a population-based cohort of breast cancer patients and ovarian cancer patients. Clin Oncol. 2019;37(15):1305–15.

    CAS  Article  Google Scholar 

  4. 4.

    National Comprehensive Cancer Network: Non-small cell lung cancer (version 6.2020) https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

  5. 5.

    Aggarwal C, Thompson C, Black T, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(2):173–80. https://doi.org/10.1001/jamaoncol.2018.4305.

    Article  PubMed  Google Scholar 

  6. 6.

    Lazzari C, Gregorc V, Karchaliou N, et al. Mechanisms of resistance to osimertinib. J Thorac Dis. 2019. https://doi.org/10.21037/jtd.2019.08.30 Accepted July 31, 2019.

  7. 7.

    • Hollis RL, Churchman M, Gourley C. Distinct implications of different BRCA mutations: efficacy of cytotoxic chemotherapy, PARP inhibition and clinical outcome in ovarian cancer. Onco Targets Ther. 2017;10:2539–51. https://doi.org/10.2147/OTT.S102569. This is a comprehensive review highlighting the research and outcomes of PARP-based applications specific to the ovarian cancer setting.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    National Comprehensive Cancer Network: Prostate cancer (version 4.2019) https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.

  9. 9.

    Iglehart J, Silver D. Synthetic lethality -- a new direction in cancer-drug development. N Engl J Med. 361:189–91. https://doi.org/10.1056/NEJMe0903044.

  10. 10.

    Lord C, Ashworth A. PARP inhibitors: the first synthetic lethal targeted therapy. Science. 2017;355(6330):1152–8. https://doi.org/10.1126/science.aam7344.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Robson M, Seock-Ah I, Senkus E, Xu B, Domcheck SM, Masuda N, et al. Olaparib for metatatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523–33. https://doi.org/10.1056/NEJMoa1706450.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, et al. Talazoparib in patients with advanced breast cancer and germline BRCA mutation. N Engl J Med. 2018;279:753–63. https://doi.org/10.1056/NEJMoa1802905.

    Article  Google Scholar 

  13. 13.

    Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495–505. https://doi.org/10.1056/NEJMoa1810858.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Golan T, Hammel P, Reni M, van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–27. https://doi.org/10.1056/NEJMoa1903387.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Carneiro B, Collier K, Nagy R, et al. Acquired resistance to poly (ADP-ribose) polymerase inhibitor Olaparib in BRCA2- associated prostate cancer resulting from biallelic BRCA2 reversion mutations restores both germline and somatic loss-of-function mutations. JCO Precis Oncol. 2018. https://doi.org/10.1200/PO.17.00176.

  16. 16.

    Lin K, Harrell M, Oza A, et al. BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Disc. 2019;9(2):210–9. https://doi.org/10.1158/2159-8290.CD-18-0715.

    CAS  Article  Google Scholar 

  17. 17.

    Ganesan S. Tumor suppressor tolerance: reversion mutations in BRCA1 and BRCA2 and resistance to PARP inhibitor and platinum. JCO Precis Oncol. 2018. https://doi.org/10.1200/PO.18.00001.

  18. 18.

    Bardia A, Rich T, Slavin T, et al. Landscape of BRCA1 and BRCA2 germline, somatic, and reversion alterations detectable by cell-free DNA testing among patients with metastatic breast, ovarian, pancreatic or prostate cancer. J Clin Oncol. 2018:36(suppl; abstr 12097). https://doi.org/10.1200/JCO.2018.36.15_suppl.12097.

  19. 19.

    Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/, based on November 2018 SEER data submission, posted to the SEER web site, April 2019.

  20. 20.

    Harter P, Hauke J, Reuss A, Kommoss S, Marme F, Heimbach A, et al. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS One. 2017;12(10):e0186043. https://doi.org/10.1371/journal.pone.0186043.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    National Comprehensive Cancer Network: Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer (version 1.2020) https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf.

  22. 22.

    Ledermann J, Harter P, Gourley G, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92. https://doi.org/10.1056/NEJMoa1105535.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Moore K, Colombo N, Scambia BG, et al. Maintenance Olaparib in patients with newly diagnosed advanced ovarian cancer. NEJM. 2018;379(26):2495–505. https://doi.org/10.1056/NEJM1810858.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Pujade-Lauraine E, Ledermann JA, Selle F, Febski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–84. https://doi.org/10.1016/S1470-2045(17)30469.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Coleman RL, Ola AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949–61. https://doi.org/10.1016/S0140-6736(17)32440-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Shimelis H, LaDuca H, Hu C, Hart SN, Na J, Thomas A, et al. Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. JNCI. 2018;110(8):855–62. https://doi.org/10.1093/inci/div106.

    Article  PubMed  Google Scholar 

  27. 27.

    • Das S, Salami SS, Spratt DE, Kaffenberger SD, Jacobs MF, Morgan TM. Bringing prostate cancer genetics into clinic practice. J Urol. 2019;202(2):223–30. https://doi.org/10.1097/JU.0000000000000137. This article provides an optimal foundation for prostate cancer genetics and further reviews the clinical implications both from a preventive and treatment perspective.

    Article  PubMed  Google Scholar 

  28. 28.

    de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. NEJM. 2020;832:2091–102. https://doi.org/10.1056/NEJMoa1911440.

    Article  Google Scholar 

  29. 29.

    FDA.gov. FDA approves olaparib for HRR gene-mutated metastatic castration resistant prostate cancer. 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer.

  30. 30.

    FDA.gov. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. 2020. https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate.

  31. 31.

    Abida W, Campbell D, Patnik A, Shapiro JD, Sautois B, Vogelzang NJ, et al. Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in the metastatic castration-resistant prostate cancer: analysis from the phase II triton study. Clin Cancer Res. 2020;26:2487–96. https://doi.org/10.1158/1078-0432.CCR-20-0394.

    Article  PubMed  Google Scholar 

  32. 32.

    Mateo J, Carreira S, de Bono JS. Differential response to olaparib treatment among men with metastatic castration-resistant prostate cancer harboring BRCA1 or BRCA2 versus ATM mutations. Eur Urol. 2019;76:452–8.

    Article  Google Scholar 

  33. 33.

    • Herbst R, Morgansztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):4460454. https://doi.org/10.1038/nature25183. Comprehensive review of targets and therapies in NCSLC.

    CAS  Article  Google Scholar 

  34. 34.

    Skov B, Rervig S, Jensen T, et al. The prevalence of programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer in an unselected, consecutive population. Mod Pathol. 2020;33(1):109–17. https://doi.org/10.1038/s41379-019-0339-0.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Frey M, Pothuri B. Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature. Gynecol Oncol Res Pract. 2017;4:4. https://doi.org/10.1186/s40661-017-0039-8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Moore K, Secord A, Geller M, et al. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm phase 2 trial. Lancet Oncol. 2019. https://doi.org/10.1016/S1470-2045(19)30029-4.

  37. 37.

    Rodrigues de Cunha Colombo Bonadio R, Fogace R, Miranda V, et al. Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics (Sao Paulo). 2018;73(suppl 1):e450s. https://doi.org/10.6061/clinics/2018/e450s.

    Article  Google Scholar 

  38. 38.

    National Comprehensive Cancer Network: Invasive breast cancer (version 2.2020) https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.

  39. 39.

    André F, Cireulos E, Campone M, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–40.

    Article  Google Scholar 

  40. 40.

    National Comprehensive Cancer Network: Prostate cancer (version 2.2020) https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

  41. 41.

    National Comprehensive Cancer Network: Colon cancer (version 4.2020) file:///C:/Users/SwanK20417/Desktop/Germline%20Somatic%20Article/colon.pdf.

  42. 42.

    Ikeda M, Maruki Y, Ueno M, et al. Frequency and clinicopathological characteristics of biliary tract carcinomas harboring the FGFR2fusion gene: a prospective observational study (PRELUDE study). Ann Oncol. 2019;30(suppl 5;abstr 723P). https://doi.org/10.1093/annonc/mdz247.050.

  43. 43.

    FDA.gov. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion.

  44. 44.

    National Comprehensive Cancer Network: Esophageal and esophagogastric junction cancer (version 2.2020) https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf.

  45. 45.

    National Comprehensive Cancer Network: Gastric cancer (version 2.2020) https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf.

  46. 46.

    National Comprehensive Cancer Network: Soft tissue sarcoma (version 2.2020). https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf.

  47. 47.

    Fader A, Roque D, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/nue. J Clin Oncol. 2018;36(20):2044–51. https://doi.org/10.1200/JCO.2017.76.5966.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    National comprehensive cancer network: Uterine neoplasms (version 1.2020) https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.

  49. 49.

    National Comprehensive Cancer Network: Cutaneous melanoma (version 1.2020) https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf.

  50. 50.

    Loriot Y, Necchi A, Park S, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381:338–48. https://doi.org/10.1056/NEJMoa1817323.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    National comprehensive cancer network: Bladder cancer (version 5.2020) https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.

  52. 52.

    National Comprehensive Cancer Network: Thyroid carcinoma (version 2.2019) https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf.

  53. 53.

    • Le D, Durham J, Smith K, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13. https://doi.org/10.1126/science.aan6733. Review of microsatellite instability across cancer types and efficacy of PD-1 blockade.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    FDA.gov. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. 2017. http://fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.

  55. 55.

    • Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731–47. https://doi.org/10.1038/s41571-018-0113-0. This publication reviews detection of NTRK fusions, current landscape of resistance, and therapies to target.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    FDA.gov. FDA approves an oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor. 2018. https://www.fda.gov/news-events/press-announcements/fda-approves-oncology-drug-targets-key-genetic-driver-cancer-rather-specific-type-tumor.

  57. 57.

    FDA.gov. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc.

  58. 58.

    FDA.gov. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors.

  59. 59.

    American Society of Breast Surgeons: Consensus guidelines on genetic testing for hereditary breast cancer. 2019. https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf.

  60. 60.

    American Cancer Society: Breast cancer facts & figures 2019-2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2019-2020.pdf.

  61. 61.

    Fasching PA, Hu C, Hart SN, Polley EC, Lee KY, Gnanolivu RD, et al. Cancer predisposition genes in metastatic breast cancer- association with metastatic pattern, prognosis, patient and tumor characteristics. Presented at: San Antonio Breast Cancer Symposium. 2017.

  62. 62.

    Litton JK, Scoggins ME, Hess KR, Adrada BE, Murthy RK, Damodaran S, et al. Neoadjuvant talazoparib for patients with operable breast cancer with a germline BRCA pathogenic variant. J Clin Oncol. 2020;38(5):388–94. https://doi.org/10.1200/JCO.19.01304.

    Article  PubMed  Google Scholar 

  63. 63.

    Tutt A, Kaufman B, Garber J, Gelber R, McFadden E, Goessi C, et al. OLYMPIA: a randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BRCA1/2 mutation (GBRCAM). Presented at ESMO 2017 Congress.

  64. 64.

    Giri VN, Knudsen KE, William KK, et al. Implementation of germline testing for prostate cancer: Philadelphia prostate cancer consensus conference 2019. J Clin Oncol. 2020;9;JCO2000046. Online ahead of print. https://doi.org/10.1200/JCO.20.00046.

  65. 65.

    Nicolosi P, Lefet E, Yang S, Michalski S, Freschi B, O’Leary E, et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5(4):523–8. https://doi.org/10.1001/jamaoncol.2018.6760.

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Yurgelun MB, Chittenden AB, Morales-Oyarvide V, Rubinson DA, Dunne RF, Kozak MM, et al. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med. 2019;21(1):213–23. https://doi.org/10.1038/s41436-018-0009-5.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    National Comprehensive Cancer Network: Pancreatic adenocarcinoma (version 1.2020) https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf.

  68. 68.

    Walter JE, Carnevale JC, Pedley C, Blanco A, Chan S, Collisson EA, et al. Referral patterns and attrition rate for germline testing in pancreatic cancer (PC) patients. J Clin Oncol. 2018;36(15):1591. https://doi.org/10.1200/JCO.2018.36.15_suppl.1591.

    Article  Google Scholar 

  69. 69.

    Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;35(10):1086–95. https://doi.org/10.1200/JCO.2016.71.0012.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild type, HER2-positive metastatic colorectal cancer (HERACLES): a proof of concept, multicenter, open-label, phase 2 trial. Lancet Oncol. 2016;17:738–46.

    CAS  Article  Google Scholar 

  71. 71.

    De Groot P, Wu C, Carter B, et al. The epidemiology of lung cancer. Transl Lung Cancer Res. 2018;7(3):220–33.

    Article  Google Scholar 

  72. 72.

    • Hirsch F, Suda K, Wiens J, et al. New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet. 2016;388:1012–24. Thorough review of drivers in NSCLC and various therapies that are being developed.

    Article  Google Scholar 

  73. 73.

    Astor L FDA grants AMG 510 fast track designation for KRAS G12C+ NSCLC. Targeted Oncology News https://www.targetedonc.com/news/fda-grants-amg-510-fast-track-designation-for-kras-g12c-nsclc.

  74. 74.

    Langer CJ. Epidermal growth factor receptor inhibition in mutation-positive non-small-cell lung cancer: is afatinib better or simply newer? J Clin Oncol. 2013;31:3303–6.

    CAS  Article  Google Scholar 

  75. 75.

    •• Girard N. Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when? Future Oncol. 2018;14(11):1117–32. Excellent resource to review the different EGFR TKIs, their mechanism of action and the clinical trial data as well as testing for the various EGFR alterations and additional factors to consider when choosing the right therapy.

    CAS  Article  Google Scholar 

  76. 76.

    Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain. PLoS Med. 2005;2(3):e73. https://doi.org/10.1371/journal.pmed.0020073.

  77. 77.

    Soria J, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR- mutated advanced non-small cell lung cancer. N Engl J Med. 2018;378(2):113–25. https://doi.org/10.1056/NEJMoa1713137.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    •• Leonetti A, Sharma S, Minari R, et al. Resistance to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725–37. https://doi.org/10.1038/s41416-019-0573-8. Comprehensive and up to date review on the mechanisms of resistance to the third generation TKI, osimertinib. It also details various strategies in development to overcome these mechanisms of resistance including ongoing clinical trials.

    Article  PubMed  Google Scholar 

  79. 79.

    Oxnard G, Hu Y, Mileham K, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2018.2969.

  80. 80.

    Schoenfeld A, Yu H. The evolving landscape of resistance to osimertinib. J Thorac Oncol. 2020;15(1):18–21.

    Article  Google Scholar 

  81. 81.

    Oxnard G, Miller V, Robson M. Brief report: screening for germline EGFR T790M mutations through lung cancer genotyping. J Thorac Oncol. 2012;7(6):1049–52. https://doi.org/10.1097/JTO.0b013e318250ed9d.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Veyseh M, Ricker C, Espenschied C. Secondary germline finding in liquid biopsy of a deceased patient; case report and review of the literature. Front. Oncol. 8:259. https://doi.org/10.3389/fonc.2018.00259.

  83. 83.

    Shipley K, Wells A, Nance T et al. Germline BRCA alterations detected by circulating tumor DNA testing among patients with advanced cancer. Platform Presentation D14-4. Presented at 38th Annual NSGC Conference. November 5-8, 2019. Salt Lake City, UT.

  84. 84.

    Vlessis K, Purington N, Chun N, et al. Germline testing for patients with BRCA1/2 mutations on somatic tumor testing. JNCI Cancer Spectr. 2020, 4(1). https://doi.org/10.1093/jncics/pkz095.

  85. 85.

    •• Hargadon K, Johnson C, Williams C. Immune checkpoint blockade therapy for cancer: an overview of FDA approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39. Great review of various immune checkpoint inhibitors and how they function.

    CAS  Article  Google Scholar 

  86. 86.

    Blons H, Garinet S, Laurent-Puig P, Oudart JB. Molecular markers and prediction of response to immunotherapy in non-small cell lung cancer, an update. J Thorac Dis. 2019;11(Suppl 1):S25–36.

    Article  Google Scholar 

  87. 87.

    Dudnik E, Peled N, Nechushtan H, Wollner M, Onn A, Agbarya A, et al. BRAF mutant lung cancer: programmed death ligand 1 expression, tumor mutational burden, microsatellite instability status, and response to immune check-point inhibitors. J Thorac Oncol. 2018;13(8):1128–37.

    CAS  Article  Google Scholar 

  88. 88.

    Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321–8.

    CAS  Article  Google Scholar 

  89. 89.

    • Mhanna L, Guibert N, Milia J, et al. When to consider immune checkpoint inhibitors in oncogene-driven non-small cell lung cancer? Curr Treat Options Oncol. 2019;20:60. https://doi.org/10.1007/s11864-019-0652-3. Great overview of predictors of response to immunotherapy and when it is most appropriate.

    Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Schoenfeld A, Arbour K, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30:839–44.

    CAS  Article  Google Scholar 

  91. 91.

    Skoulidis F, Goldberg M, Greenawalt D, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 2018;8:822–35. https://doi.org/10.1158/2159-8290.CD-18-0099.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Schwaederle M, Parker B, Schwab R, et al. Molecular tumor board: the University of California- San Diego Moores Cancer Center experience. Oncologist. 2014;19(6):631–6.

    Article  Google Scholar 

  93. 93.

    Dalton W, Forde P, Kang H, et al. Personalized medicine in the oncology clinic: implementation and outcomes of the Johns Hopkins Molecular Tumor Board. JCO Precis Oncol. 2017;1:1–19. https://doi.org/10.1200/PO.16.00046.

  94. 94.

    Van der Velden D, Van Herpen C, Van Laarhoven H, et al. Molecular tumor boards: current practice and future needs. Ann Oncol. 2017;28(12):3070–5.

    Article  Google Scholar 

  95. 95.

    Knepper T, Bell G, Hicks J, et al. Key lessons learned from Moffitt’s molecular tumor board: the clinical genomics action committee experience. Oncologist. 2017;22:144–51.

    Article  Google Scholar 

  96. 96.

    Patel M, Kato S, Kurzrock R. Molecular tumor boards: realizing precision oncology therapy. Clin Pharmacol Ther. 2018;103(2):206–9.

    Article  Google Scholar 

  97. 97.

    Simone J. Understanding cancer centers. J Clin Oncol. 2002;20:4503–7.

    Article  Google Scholar 

  98. 98.

    Pishvaian M, Blais E, Bender R, et al. A virtual molecular tumor board to improve efficiency and scalability of delivering precision oncology to physicians and their patients. JAMIA. 2019;2(4):505–15.

    Google Scholar 

  99. 99.

    Walko C, Kiel P, Kolesar J. Precision medicine in oncology: new practice models and roles for oncology pharmacists. Am J Health Syst Pharm. 2016;73(23):1935–42.

    CAS  Article  Google Scholar 

  100. 100.

    Bamshad M, Magoulas P, Dent K. Genetic counselors on the frontline of precision health. Am J Med Genet C Semin Med Genet. 2018;178(1):5–9.

    Article  Google Scholar 

  101. 101.

    Stoll K, Kubendran S, Cohen S. The past, the present and future of service delivery in genetic counseling: keeping up in the era of precision medicine. Am J Med Genet. 2018;178C:24–37.

    Article  Google Scholar 

  102. 102.

    Cohen S, Bradbury A, Henderson V, et al. Genetic counseling and testing in a community setting: Quality, access and efficiency. Am Soc of Clin Onc Educ Book. 2019;39e:34–e44. https://doi.org/10.1200/EDBK_23937.

    Article  Google Scholar 

  103. 103.

    Forman A, Sotelo J. Tumor-Based Genetic Testing and Familial Cancer Risk [published online ahead of print, 2019 Sep 30]. Cold Spring Harb Perspect Med. 2019;a036590. https://doi.org/10.1101/cshperspect.a036590.

  104. 104.

    DeLeonardis K, Hogan L, Cannistra S, et al. When should tumor genomic profiling prompt consideration of germline testing? J Oncol Pract. 2019;15(9):465–73.

    Article  Google Scholar 

  105. 105.

    Pawloski PA, Brooks GA, Nielsen ME, Olson-Bullis BA. A systematic review of clinical decision-making systems for clinical oncology practice. J Natl Compr Cancer Netw. 2019;17(4):331–8. https://doi.org/10.6004/jnccn.2018.7104.

    Article  Google Scholar 

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Correspondence to Kelli Swan.

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Mrs. Dougherty (Chatham), MS, CGC, reports personal fees from Myriad Genetics, outside the submitted work. And declares that she is a stockholder of Myriad Genetics.

Mrs. Swan reports personal fees from Myriad Genetics, personal fees from Guardant Health, and personal fees from PerkinElmer Genomics, outside the submitted work; and declares that she is a stockholder of Myriad Genetics and Guardant Health. And stock in PerkinElmer.

Mrs. Wienke reports personal fees from Guardant Health, and personal fees from Ambry Genetics, outside the submitted work; and declares that she is a stockholder in Guardant Health.

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Swan, K., Dougherty, K.C. & Myers, S.W. Somatic Testing and Germline Genetic Status: Implications for Cancer Treatment Decisions and Genetic Counseling. Curr Genet Med Rep 8, 109–119 (2020). https://doi.org/10.1007/s40142-020-00192-w

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Keywords

  • Targeted therapy
  • Germline
  • Somatic
  • PARP inhibitor
  • Immunotherapy
  • Genetic counseling