Matthew B. Yurgelun, MD
Gastrointestinal Medical Oncologist
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Harvard Medical School
Because specific risk-reducing interventions may be available, it is important to identify individuals with germline variants in cancer susceptibility genes. For patients with a diagnosis of cancer in the setting of a known inherited syndrome, the management of that cancer often involves different systemic therapy options, surgical decisions, and posttreatment surveillance and survivorship considerations. Advances in next-generation sequencing (NGS) technologies have drastically improved both the cost and efficiency of germline genetic testing, and a wide array of multigene panels have become commercially available to clinically assess patients for a broad spectrum of inherited cancer risks. Recent data produced by such improved NGS technologies have demonstrated that roughly 10% of colorectal cancers and 4% to 10% of pancreatic cancers originate from germline cancer gene mutations.1-6
What follows is an overview of recent progress in the diagnosis of Lynch syndrome—the most common form of inherited gastrointestinal cancer—and hereditary pancreatic cancer and the treatment of patients.
New Diagnostic Approaches for Identifying Lynch Syndrome and Hereditary Pancreatic Cancer
Although the above-mentioned advances in NGS offer a new paradigm for germline testing, older tools for hereditary gastrointestinal cancer risk assessment (tumor testing for microsatellite instability [MSI] and family history assessment) remain essential for the identification of individuals with possible Lynch syndrome, which genetically predisposes those individuals to higher risks for certain types of cancer. A recent analysis of more than 15,000 tumors (including more than 50 different primary tumor types) reaffirmed the critical importance and high sensitivity of MSI status in identifying potential for Lynch syndrome among individuals with colorectal, endometrial, urothelial, small bowel, and other Lynch-associated cancers.7
Surprisingly, the same study also demonstrated a small but intriguing subset of patients with MSI-high (MSI-H) status in tumors not classically linked to Lynch syndrome (eg, melanoma, mesothelioma, germ cell tumors) who were ultimately confirmed to be carriers of Lynch syndrome.7
Such data strongly suggest that any patient whose tumor is MSI-H should be referred for germline Lynch syndrome testing, excluding instances in which MSI-H status can be explained as sporadic (eg, somatic MLH1
Although the use of MSI status to identify individuals who should undergo germline Lynch syndrome testing is well established, clinical history remains key to the identification of Lynch syndrome, particularly for patients with concerning clinical histories but no tumor available for analysis. The PREMM5
clinical prediction model, developed at Dana-Farber Cancer Institute, is a free, efficient online tool that enables individuals to obtain a numeric estimate of the likelihood of having Lynch syndrome, based on 10 questions about personal and family histories of cancer (Figure
is currently the only available tool to effectively predict for the presence of a mutation in any of the 5 genes associated with Lynch syndrome. Germline Lynch syndrome testing is recommended for any individual whose PREMM5
result indicates a ≥2.5% likelihood of having Lynch syndrome, even for those who have never had cancer.8
On the other hand, the use of clinical information to identify patients with pancreatic cancer who have germline cancer susceptibility has continued to present challenges. Results from studies have consistently shown that patients with pancreatic cancer who have underlying germline mutations typically do not receive diagnoses of cancer at particularly young ages and often lack classic family histories of cancer.2,3,5,9-11
This is not the case with Lynch syndrome and other forms of inherited gastrointestinal cancer risk. Recent NGS data have demonstrated that 4% to 10% of all comers with pancreatic cancer harbor germline mutations in cancer susceptibility genes, most commonly BRCA1
, BRCA2, ATM, PALB2
, and other genes related to homologous recombination (HR) deficiency.3,5,6,9
Because such genes predispose individuals to high risks of breast cancer and other malignancies beyond pancreatic cancer, there is now growing support for recommending germline genetic testing for all patients with pancreatic cancer, regardless of age or family history of cancer.9-11
Reflecting this, the National Comprehensive Cancer Network formally added such a consideration to its clinical practice guidelines, although significant questions persist about to how implement such systematic testing in routine clinical care.9,12-14
Therapeutic Implications—Lynch Syndrome and Hereditary Pancreatic Cancer
In addition to its value in helping to recognize individuals with possible underlying Lynch syndrome, MSI has recently been identified as a critically important biomarker for response to immune checkpoint blockade in metastatic cancers. In single-arm phase II studies, the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) have demonstrated significant activity in the treatment of chemotherapy-refractory, metastatic, MSI-H colorectal cancer, with objective response rates of 31% to 52% and median durations of response that were not yet reached at the time of publication. These results led to the FDA approval of both agents in this setting.15,16
Pembrolizumab has shown similar efficacy in MSI-H cancers regardless of primary tumor site, leading to its FDA approval for any chemotherapy-refractory, MSI-H cancer.15
More recent data have suggested that combined immune checkpoint inhibitor therapy with nivolumab and the anti–CTLA-4 antibody ipilimumab (Yervoy) may be particularly efficacious in treating metastatic, chemotherapy-refractory, MSI-H colorectal cancer, although this combination has not been compared directly with single-agent treatment with a PD-1 inhibitor.17
Data to date suggest that the likelihood of benefit from immune checkpoint inhibitor therapy in metastatic MSI-H cancer is not dependent on whether the patient’s cancer arises in the setting of Lynch syndrome or is a sporadic malignancy.15,16
Ongoing randomized phase III clinical trials are investigating immune checkpoint inhibitors as monotherapy in first-line treatment for metastatic MSI-H colorectal cancer (NCT02563002) and in combination with chemotherapy for adjuvant treatment of resected stage III colon cancer (NCT02912559).
With the emerging data about the frequency of germline HR gene variants in unselected patients with pancreatic cancer, there has been rapidly growing interest in the use of PARP inhibitors to treat such patients. To date, results from small, nonrandomized trials using PARP inhibitors as singleagent therapy have shown objective response rates of 0% to 22% in patients with germline BRCA1
mutations who were pretreated for pancreatic cancer. These rates are lower than what has been seen in patients with breast and ovarian cancer with the same germline mutations.18-24
Combination of platinum-based chemotherapy with PARP inhibitors in patients with pancreatic cancer and germline BRCA1
mutations may be promising, although existing data are extremely limited at this point, and there are likewise minimal data regarding the efficacy of PARP inhibitors in patients with pancreatic cancer and germline mutations in other HR genes (eg, ATM, PALB2
Randomized trials are ongoing in BRCA1
mutation carriers with advanced pancreatic cancer to examine platinum-based chemotherapy with and without PARP inhibitors (NCT01585805), as well as the role of PARP inhibitors as maintenance therapy after an initial response to platinum-based chemotherapy (NCT02184195). Limited data do suggest that pancreatic cancers arising in the setting of germline HR gene mutations have superior prognoses and improved responses to platinum-based chemotherapy compared with other pancreatic cancers.2,27-29
Germline genetic testing for inherited cancer susceptibility is increasingly becoming a standard component of the oncologic management of individuals with gastrointestinal cancers. There is a growing array of diagnostic tools for identifying patients with Lynch syndrome, hereditary pancreatic cancer, and other forms of inherited cancer risk, and insights into the appropriate therapeutic management of such patients are rapidly evolving. Such progress underscores the notion that the modern oncologist must be prepared to diagnose gastrointestinal cancer in patients with inherited forms of cancer risk and treat them appropriately.
- Yurgelun MB, Kulke MH, Fuchs CS, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;35(10):1086-1095. doi: 10.1200/JCO.2016.71.0012.
- Yurgelun MB, Chittenden AB, Morales-Oyarvide V, et al. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med. 2019;21(1):213-223. doi: 10.1038/s41436-018-0009-5.
- Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319(23):2401-2409. doi: 10.1001/jama.2018.6228.
- Brand R, Borazanci E, Speare V, et al. Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. Cancer. 2018;124(17):3520-3527. doi: 10.1002/cncr.31628.
- Shindo K, Yu J, Suenaga M, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017;35(30):3382-3390. doi: 10.1200/JCO.2017.72.3502.
- Grant RC, Selander I, Connor AA, et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. 2015;148(3):556-564. doi: 10.1053/j.gastro.2014.11.042.
- Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer [published online October 30, 2018]. J Clin Oncol. doi: 10.1200/JCO.18.00283.
- Kastrinos F, Uno H, Ukaegbu C, et al. Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome. J Clin Oncol. 2017;35(19):2165-2172. doi: 10.1200/JCO.2016.69.6120.
- Yurgelun MB. Germline testing for individuals with pancreatic cancer: the benefits and challenges to casting a wider net. J Clin Oncol. 2017;35(30):3375-3377. doi: 10.1200/JCO.2017.74.7535.
- Syngal S, Furniss CS. Germline genetic testing for pancreatic ductal adenocarcinoma at time of diagnosis. JAMA. 2018;319(23):2383-2385. doi:10.1001/jama.2018.6227.
- Schwark AL, Stadler ZK. Should we lower our threshold for germline genetic assessment in pancreatic adenocarcinoma [published online January 19, 2018]? JCO Precis Oncol. doi: 10.1200/PO.17.00227.
- Pancreatic adenocarcinoma, version 2.2018. National Comprehensive Cancer Network website. Accessed October 31, 2018.
- Genetic/familial high-risk assessment: breast and ovarian, version 2.2019. National Comprehensive Cancer Network website. Accessed October 31, 2018.
- Walker EJ, Carnevale J, Pedley C, et al. Referral frequency, attrition rate, and outcomes of germline testing in patients with pancreatic adenocarcinoma [published online September 28, 2018]. Fam Cancer. doi: 10.1007/s10689-018-0106-2.
- Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. doi: 10.1126/science.aan6733.
- Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study [erratum in Lancet Oncol. 2017;18:1182-1191. doi: 10.1016/S1470-2045(17)30638-1]. Lancet Oncol. 2017;18(9):1182-1191. doi: 10.1016/S1470-2045(17)30422-9.
- Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi: 10.1200/JCO.2017.76.9901.
- Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation [erratum in N Engl J Med. 2017;377(17):1700. doi: 10.1056/NEJMx170012.]. N Engl J Med. 2017;377:(6)523-533. doi: 10.1056/NEJMoa1706450.
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- Lowery MA, Kelsen DP, Capanu M, et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018;89:19-26. doi: 10.1016/j.ejca.2017.11.004.
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- Kim G, Ison G, McKee AE, et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015;21(19):4257-4261. doi: 10.1158/1078-0432.CCR-15-0887.
- Yarchoan M, Myzak MC, Johnson BA III, et al. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Oncotarget. 2017;8(27):44073-44081. doi: 10.18632/oncotarget.17237.
- O’Reilly EM, Lee JW, Lowery MA, et al. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer. 2018;124(7):1374-1382. doi: 10.1002/cncr.31218.
- Golan T, Sella T, O’Reilly EM, et al. Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. Br J Cancer. 2017;116(6):697-702. doi: 10.1038/bjc.2017.19.
- Kondo T, Kanai M, Kou T, et al. Association between homologous recombination repair gene mutations and response to oxaliplatin in pancreatic cancer. Oncotarget. 2018;9(28):19817-19825. doi: 10.18632/oncotarget.24865.
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