The past year has been an exciting time for medical applications of genetic testing. We are entering an era when germline genetic status is no longer focused solely on risk stratification to guide surveillance and risk-reducing options, but is increasingly influencing treatment selection.
Typically, the genes associated with hereditary cancer syndromes produce proteins that repair DNA. When a gene has a mutation and does not function correctly, the ability of the cell to repair DNA damage is diminished, which may result in errors and, in some instances, cancer. The main mechanisms by which DNA damage is repaired are base excision repair, mismatch repair, nucleotide excision repair, single-strand annealing, homologous recombination, and nonhomologous end joining.1 Cancer treatments are beginning to focus on specific defects in DNA repair pathways that may be applicable across a variety of malignancies rather than focusing on specific organs. Two examples related to hereditary cancer are patients with BRCA1/2 mutations and patients with mutations associated with Lynch syndrome.
BRCA Mutations and DNA Damage Repair
Cells containing a BRCA mutation are unable to repair double-strand breaks through homologous recombination. As a result, an accumulation of genetic mutations and cancer may occur. In an attempt to repair damage, cells with mutant BRCA genes rely on other DNA repair methods, such as base excision repair. By impairing the pathway on which the mutated cells rely for repair, the cells can be directed to death. In the case of cancer cells with BRCA mutations, poly (ADP-ribose) polymerase (PARP) inhibitors can be used to impair the base excision repair pathway. The unrepaired single-strand breaks turn into double-strand breaks, and ultimately, cell death.1
The first PARP inhibitor to treat patients with BRCA mutations, olaparib (Lynparza; AstraZeneca) was approved in 2014 for use in germline BRCA-mutated advanced ovarian cancer in patients who had received 3 or more previous lines of chemotherapy.2 Since this approval, indications and approvals for PARP inhibitor drugs in patients with mutations have expanded. Most recently in 2018, olaparib was approved for maintenance therapy in BRCA-mutated advanced ovarian, fallopian tube, or primary peritoneal cancer,3,4 as well as for certain patients with BRCA-mutated metastatic breast cancer.5 In addition, a different PARP inhibitor, talazoparib (Talzenna; Pfizer Oncology) was approved for patients with germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer,6 and rucaparib (Rubraca; Clovis Oncology) was granted breakthrough therapy designation for use in men with BRCA1/2-mutated metastatic castration-resistant prostate cancer who have received at least 1 previous androgen receptor–directed treatment and taxane-based chemotherapy.7
Mutations and the MMR Pathway
Another DNA damage repair pathway linked to hereditary cancers is the mismatch repair (MMR) pathway. Germline mutations in genes associated with Lynch syndrome cause the MMR pathway to not work correctly. Such defects place patients at risk for early-onset and multiple tumors. A characteristic feature of tumors in these individuals is MMR deficiency (dMMR) and/or high microsatellite instability (MSI-H). These tumors have a much higher mutational burden than the average cancer cell. The high number of mutations makes the tumor look even more foreign to the immune system, and checkpoint inhibitors can be used to target the increased level of tumor antigens resulting from the mutational burden.8 One such immunotherapy is pembrolizumab (Keytruda; Merck), which was granted accelerated approval in 2017 for certain patients with dMMR or MSI-H solid tumors. This agent works by blocking the PD-1 pathway.9
Historically, genetic testing for Lynch syndrome relied on criteria focusing on a tumor spectrum, which included colorectal, endometrial, small bowel, ureter, or renal pelvis.10 However, we now know that a variety of cancers may fall under the Lynch syndrome spectrum, and a recent study suggests the spectrum may be even broader than previously considered.11
In this study, 33 of 66 participants with Lynch syndrome had tumors other than colorectal and endometrial, including sarcoma, mesothelioma, melanoma, and germ-cell tumors. Of concern, approximately half of the patients without colorectal and/or endometrial cancer did not meet Lynch syndrome genetic testing criteria based on personal or family history. However, almost all were detected by immunohistochemical staining for proteins associated with Lynch syndrome. Therefore, it was recommended that any patient with a dMMR and/or MSI-H tumor undergo germline assessment for Lynch syndrome. Given the growing role of immunotherapies in dMMR and/or MSI-H tumors, the need to identify patients with Lynch syndrome and/or Lynch-like tumors will become even more important.
In addition to targeted therapies for carriers of BRCA1/2 mutations and Lynch-like tumors, therapies are emerging for von Hippel-Lindau disease and familial adenomatous polyposis, and clinical trials for other gene mutation carriers are ongoing.12,13 PARP inhibitors for patients with BRCA1/2 mutations now have a recognized role in ovarian, breast, and prostate cancers. An indication for pancreatic cancer, as well as for other cancers in gene mutation carriers, may also be on the horizon. No longer are therapies limited to solely targeting a specific cancer, but rather underlying genetic causes across various cancer types. Research is ongoing to further advance our understanding of the potential of these agents to improve patient outcomes.
- Anwar M, Aslam HM, Anwar S. PARP inhibitors. Hered Cancer Clin Pract. 2015;13:4.
- AstraZeneca. Lynparza approved by the US Food and Drug Administration for the treatment of advanced ovarian cancer in patients with germline BRCA-mutations. December 19, 2014. www.astrazeneca-us.com/media/press-releases/2014/lynparza-approved-by-the-us-fda-20141219.html#. Accessed March 16, 2019.
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505.
- US Food and Drug Administration. FDA approves olaparib for first-line maintenance of BRCA-mutated advanced ovarian cancer. December 19, 2018. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628876.htm. Accessed March 16, 2019.
- US Food and Drug Administration. FDA approves first treatment for breast cancer with a certain inherited genetic mutation. January 12, 2018. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm592347.htm. Accessed March 16, 2019.
- The ASCO Post. Talazoparib approved for BRCA-mutated, HER2-negative breast cancer. October 25, 2018. www.ascopost.com/issues/october-25-2018/talazoparib-approved-for-brca-mutated-her2-negative-breast-cancer/. Accessed March 16, 2019.
- Prostate Cancer Foundation. Clovis Oncology receives breakthrough therapy designation for Rubraca (rucaparib) for treatment of BRCA1/2-mutated metastatic castration resistant prostate cancer (mCRPC). October 2, 2018. www.pcf.org/news/clovis-oncology-receives-breakthrough-therapy-designation-for-rubraca-rucaparib-for-treatment-of-brca1-2-mutated-metastatic-castration-resistant-prostate-cancer-mcrpc/. Accessed March 16, 2019.
- Hampel H, Hofner B. Lynch syndrome and immunotherapy. J Adv Pract Oncol. 2017;8:7-21.
- US Food and Drug Administration. FDA approves first cancer treatment for any solid tumor with a specific genetic feature. May 23, 2017. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm560167.htm. Accessed March 16, 2019.
- Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology. 1999;116:1453-1456.
- Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol. 2019;37:286-295.
- Jonasch E, McCutcheon IE, Gombos DS, et al. Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. Lancet Oncol. 2018;19:1351-1359.
- Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018;379:2417-2428.