Oncology Live®
Vol. 20/No.3
Volume 20
Issue 3

Online Tool Estimates the Risk for Lynch Syndrome

Because specific risk-reducing interventions may be available, it is important to identify individuals with germline variants in cancer susceptibility genes.

Matthew B. Yurgelun, MD

Matthew B. Yurgelun, MD

Gastrointestinal Medical Oncologist

Dana-Farber Cancer Institute

Brigham and Women's Hospital

Harvard Medical School

New Diagnostic Approaches for Identifying Lynch Syndrome and Hereditary Pancreatic Cancer

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.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 promoter hypermethylation).7

Therapeutic Implications—Lynch Syndrome and Hereditary Pancreatic Cancer

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).8 PREMM5 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.9,12-14In 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 or BRCA2 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 or BRCA2 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).25,26 Randomized trials are ongoing in BRCA1 and BRCA2 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.2,27-29Germline 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.


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