Multigene panel testing for colorectal cancer


Dear colleagues and friends,

I write to introduce to you the new Perspectives section of GI & Hepatology News.

A more appropriate description is perhaps old-new, because Perspectives is the continuation and legacy of AGA Perspectives, the content of which has been consolidated into GI & Hepatology News. Perspectives will continue to feature the point/counterpoint expert debates about an important GI topic, which has historically been immensely popular with readers. In this edition, experts from Mayo Clinic and Cleveland Clinic discuss the pros and cons of universal multigene panel testing for colorectal cancer. These debates never end with the publication itself, and I hope they will continue to stimulate further thought and discussion. As always, I welcome your comments and suggestions for future topics.

–Charles I. Kahi, MD, MS, AGAF, is professor of medicine at Indiana University School of Medicine, Indianapolis. He is also an Associate Editor for GI & Hepatology News.

For everyone

By N. Jewel Samadder, MD, MSC

Traditionally, health care structure has been directed predominantly toward treatment rather than prevention. Advances in genomic medicine offer the opportunity to deliver a more personalized, predictive, and preventive strategy toward colorectal cancer. Approximately 150,000 men and women are diagnosed with colorectal cancer (CRC) every year in the United States.1 An estimated 10%-15% of these cancers are likely attributable to hereditary (germline) causes.2 Several genes are associated with an increased risk of developing CRC, and those of key interest include those for Lynch syndrome, MLH1, MSH2, MSH6, PMS2, EPCAM; adenomatous polyposis conditions (APC), MUTYH, POLE, POLD1, NTHL1; hamartomatous polyposis syndromes PTEN, SMAD4, STK11, and other rare cancer predisposition states where colorectal cancer is part of the phenotype, CHEK2 and TP532.

Dr. N. Jewel Samadder is a gastroenerologist at Mayo Clinic, Phoenix

Dr. N. Jewel Samadder

A universal strategy for multigene panel testing in all patients with CRC is an option versus the current strategy of guideline-based testing using family history and tumor features. In addition, the identification of germline alterations has substantial clinical implications including targeted therapies and future cancer prevention in the patient and relatives. This article will focus on the benefits of universal strategy for germline genetic evaluation in all patients with colorectal cancer.

The role and utility of current guideline-based testing
Given the therapeutic and prevention implications, the National Comprehensive Cancer Network (along with other professional organizations) has guidance on when patients with CRC should undergo genetic evaluation.3 Currently, these guidelines advocate an approach based heavily on family cancer history or utilizing colorectal phenotype based on the number and histology of polyps or tumor-based molecular features. Although family history is important for the diagnosis of hereditary CRC, the ability to accurately capture extended family cancer history in routine practice, from multiple generations and for different cancer types can be a challenge. The largest drawback of all such approaches is the focus on Lynch syndrome or only a few of the cancer predisposition syndromes. Recent studies have reported a substantial number (7%-10%) of CRC patients will have mutations in non–Lynch syndrome–associated genes and over half of these would be missed by using standard criteria for genetic evaluation.

Role of tumor-based screening approaches
More recently, health care institutions have begun to widely adopt “universal” tumor screening using microsatellite instability and/or immunohistochemistry (IHC) showing deficient expression of the mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) to identify patients with colorectal or endometrial cancers that are likely to have Lynch syndrome. However, the sensitivity and specificity of IHC for Lynch syndrome ranges between 60% and 75% and there is considerable interobserver variation by pathologists in their interpretation.

Thus, both clinical guidelines (largely focused around family history and patient phenotype) and tumor molecular features will fail to identify a significant number of patients with inherited cancer predisposition.

Cost and availability of genetic testing
In the past, cost and availability of genetic testing were an impediment to such care. This has rapidly changed in the last few years. With modern next-generation sequencing technology and an ever increasing number of testing laboratories, the cost of genetic testing has dropped to below $500 and multigene panels can now test for dozens of genes in parallel offering comprehensive testing of genetic predisposition across multiple cancer types. The popularity of direct-to-consumer health-related genetic testing (with the inclusion of certain BRCA variants on these panels) has also fueled the public interest in cancer genetic testing.

Cancer prevention for family members
In individuals with CRC and hereditary cancer predisposition, implications for family members are clinically meaningful and include increased colorectal and extracolonic surveillance, consideration of risk-reducing hysterectomy, salpingo-oophorectomy, and bilateral mastectomy for colorectal, uterine, ovarian, breast, and other cancer prevention depending on the germline mutation.2 The goal of these intensive surveillance strategies is to either prevent the occurrence of cancer altogether or detect cancer at an earlier stage when cure is likely. Identifying these high-risk groups can thus play a significant role in our goal to reduce the burden of cancer in society.

Precision targeted treatment and chemoprevention
The treatment implications for patients with CRC and pathogenic mutations in the Lynch syndrome MMR genes are the best characterized and include response to immune checkpoint inhibitor therapy.4 Mismatch repair deficiency is highly predictive of response to immunotherapy in metastatic CRCs and led to expedited approval of both pembrolizumab and nivolumab monotherapies with disease control rates of 69%-77% with durable response and combination therapy with nivolumab and ipilimumab with likely even greater benefit. Multiple clinical trials are examining the role of immune checkpoint inhibitor therapy for first-line palliative treatment of MSI-high CRC ( ID NCT02563002; NCT02997228), adjuvant therapy ( ID NCT02912559), and even as potential chemoprevention in those with Lynch syndrome ( ID NCT03631641).

Long-term cancer prevention using a chemopreventive approach has long been a desire in the hereditary cancer community.5 The most well-studied group to date has been Lynch syndrome, where a large randomized clinical trial showed the effect of high-dose aspirin in decreasing the incidence of colorectal and other Lynch-associated cancers by nearly 60%.6 Similar smaller (earlier-phase) studies in familial adenomatous polyposis have suggested targeted chemoprevention options for the regression of colorectal or duodenal polyposis with COX inhibitors, EGFR inhibitors, DFMO (NCT01483144), and IL-23 blockade ( ID NCT03649971) may all be possible.

Cancer programs have already started to introduce genomic profiling (germline and tumor somatic) into the frontline care of their patients to help guide precision therapy approaches that optimize disease control, minimize side effects, and reduce risk of long-term recurrence.

The future
The approach to genomic profiling of cancer patients is rapidly changing because of the lack of sensitivity for the identification of these hereditary cancer predisposition syndromes utilizing current approaches focused on family history, clinical phenotype, and tumor features. The wide availability of low-cost/affordable multigene panel testing has implications for cancer therapy selection and cancer prevention. This supports establishing a universal approach to multigene panel testing of all patients with CRC.

It will be important for physicians of many different specialties – including gastroenterology and oncology – to become more adept in this changing landscape of genomic medicine and to work closely with the genetic counseling resources available in their communities to provide the best care for these high-risk cancer patients.


1. Siegel RL et al. CA Cancer J Clin. 2017;67:177-93.

2. Kanth P et al. Am J Gastroenterol. 2017;112:1509-25.

3. Gupta S et al. J Natl Compr Canc Netw. 2019;17:1032-41.

4. Ribas A, Wolchok JD. Science. 2018;359:1350-5.

5. Ramamurthy C et al. Surg Oncol Clin N Am. 2017;26:729-50.

6. Burn J et al. Lancet 2011;378:2081-7.

Dr. Samadder is a gastroenterologist in the division of gastroenterology and hepatology, Mayo Clinic, Phoenix. He is a consultant for Janssen Research & Development and Cancer Prevention Pharmaceuticals.


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