The research interests of Niloy Jewel Samadder, M.D., focus on the role of genetics in cancer development, prevention and therapy and the care of patients with hereditary cancer syndromes. His work concentrates on understanding the role of inherited genes in the predisposition to developing cancer, application of genetic testing in the clinical practice to optimize the care of patients with cancer and opportunities for chemoprevention in patients with an inherited predisposition to colorectal cancer.
Dr. Samadder leads efforts to increase genetic evaluation and testing of patients with cancer. Most recently, he led a multicenter clinical trial of proactive multigene panel testing in all Mayo Clinic patients newly diagnosed with cancer. He is also leading multiple clinical trials using medications to prevent cancer in patients with a genetic predisposition to the disease. His research findings have been published in leading academic journals.
The role and utility of current guideline-based testing
Given the therapeutic and prevention implications, the National Comprehensive Cancer Network and other professional organizations offer guidance on when patients with colorectal cancer should undergo genetic evaluation. Currently, these guidelines advocate an approach based heavily on family cancer history or the use of 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 colorectal cancer, 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.
Role of tumor-based screening approaches
Medical professionals have begun to widely adopt "universal" tumor screening using microsatellite instability, immunohistochemistry showing deficient expression of the mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) or both to identify patients with colorectal or endometrial cancers that are likely to have Lynch syndrome. However, the sensitivity and specificity of immunohistochemistry for Lynch syndrome varies, and there is considerable interobserver variation among pathologists in their interpretations.
Thus, both the current family history-based and phenotype-focused clinical guidelines and examination of tumor molecular features will fail to identify a significant number of patients with inherited cancer predisposition. Dr. Samadder's research is aimed at developing better ways to identify and treat these patients.
Cancer prevention for family members
In individuals with colorectal cancer and hereditary cancer predisposition, implications for family members are clinically meaningful and include increased colorectal and extracolonic surveillance and consideration of risk-reducing hysterectomy, salpingo-oophorectomy and bilateral mastectomy for colorectal, uterine, ovarian, breast and other cancer prevention, depending on the germline mutation.
The goal of these intensive surveillance strategies is to either prevent the occurrence of cancer altogether or detect cancer at an earlier stage when a cure is more likely. Identifying these high-risk groups can thus play a significant role in Dr. Samadder's overall goal of reducing the burden of cancer in society.
Precision targeted treatment and chemoprevention
The treatment implications for patients with colorectal cancer and pathogenic mutations in the MMR genes linked to Lynch syndrome are so far the best characterized and include response to immune checkpoint inhibitor therapy.
Mismatch repair deficiency is highly predictive of response to immunotherapy in patients with metastatic colorectal cancer. This predictive ability led to expedited approval of both pembrolizumab and nivolumab monotherapies with durable response and combination therapy with nivolumab and ipilimumab with likely even greater benefit.
The community of researchers focused on hereditary cancer has long aimed to develop a chemopreventive approach to long-term cancer prevention. The best studied group of patients to date has been those with Lynch syndrome and familial adenomatous polyposis (FAP).
Dr. Samadder has led some of the pivotal studies of chemoprevention in FAP. These studies include recent multicenter trials that have used COX inhibitors, EGFR inhibitors and IL-23 blockade as possible targeted chemoprevention strategies to reduce the risk of developing colorectal and duodenal neoplasia in patients with FAP.
Significance to patient care
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.
A universal strategy for multigene panel testing in all patients with colorectal cancer is an option that shows significant potential to improve upon the current strategy of guideline-based testing using family history and tumor features. In addition, the identification of alterations in patients' normal, healthy DNA (germline DNA) has substantial clinical implications, including the selection of targeted therapies and future cancer prevention in patients and their relatives.
Cancer programs have already started to introduce genomic profiling of patients' germline and tumor DNA into front-line care to help guide precision therapy approaches that optimize disease control, minimize side effects and reduce risk of long-term recurrence.
The approach to genomic profiling of patients with cancer is rapidly changing because of the lack of sensitivity of current approaches focused on family history, clinical phenotype and tumor features. The wide availability of low-cost multigene panel testing has implications for cancer therapy selection and cancer prevention.
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 patients at high risk of developing colorectal cancer. Dr. Samadder is a leader in this research and disseminates finding to others in the field to improve care for patients everywhere.
- Associate medical director, Department of Development, Mayo Clinic, 2020-present
- Participant, ASGE GOLD Leadership Program, American Society for Gastrointestinal Endoscopy, 2020
- Associate program director, Gastroenterology & Hepatology Fellowship, Mayo Clinic School of Graduate Medical Education, 2018-present
- Physician lead, Hereditary Cancers, Mayo Clinic Cancer Center, 2017-present
- Invited speaker, Presidential Plenary Session, Digestive Disease Week, American Gastroenterological Association, 2017
- Member, Future Leaders Program, American Gastroenterological Association, 2017