Knowledge of Inherited Gene Mutations Increasingly Can Guide Cancer Treatment

Zsofia Stadler

Medical oncologist Zsofia Stadler is Clinical Director of MSK’s Clinical Genetics Service.

The majority of cancers are caused by random genetic changes and environmental exposures — things like sunlight, tobacco smoke, and the human papillomavirus (HPV). But Memorial Sloan Kettering researchers have found that, at least among people with metastatic or recurrent disease, 17% of cancers are caused by an inherited gene mutation. Cancers caused by hereditary mutations may arise at a younger age; their presence also suggests that the patient — as well as their family members — may be at risk for other cancers.

Research from MSK published June 16, 2021, in the Journal of Clinical Oncology (JCO) shows that about half of those with inherited mutations have genetic changes that can be targeted with either approved or investigational drugs. These so-called therapeutically actionable mutations exist in 8% of cancer patients overall. The study includes data on nearly 12,000 patients with more than 50 different kinds of cancer who had genetic analysis at MSK between 2015 and 2019.

As scientists learn more about the inherited causes of cancer, it’s becoming increasingly important to test people with cancer for these inherited mutations, also called germline mutations. “At MSK, we’re offering germline testing to more and more of our patients,” says medical oncologist Zsofia Stadler, Clinical Director of the Clinical Genetics Service and the paper’s lead author. “In addition to identifying which people with cancer may be at risk for new malignancies, we are now also using inherited-genetic test results to help inform the selection of cancer treatment, thereby ensuring that patients are receiving the best possible therapy.”

At MSK, we're offering germline testing to more and more of our patients.
Zsofia K. Stadler Clinical Director of the Clinical Genetics Service

Growth in Treatments Targeting Inherited Mutations

MSK is able to do wide-ranging germline testing on patients thanks to MSK-IMPACT®, a diagnostic tool that looks for mutations in more than 500 genes linked to cancer. Tests that look for mutations in many cancer genes simultaneously are available at other hospitals, but MSK-IMPACT is unique. That’s because in addition to analyzing tumor tissue, it also scans patients’ normal tissue (usually a blood sample) for comparison. Very early in the development of MSK-IMPACT, MSK’s clinical geneticists realized that having gene sequences of patients’ noncancerous tissue would reveal germline cancer mutations, which are carried in all the cells of the body.

In 2017, a team led by Clinical Genetics Service Chief Kenneth Offit published a study in the Journal of the American Medical Association (JAMA) that for the first time reported the 17% figure. That number has since been confirmed with larger studies, including the new JCO study. At the time the JAMA study came out, the most important implication was that if a patient learned their cancer was caused by an inherited mutation, they knew they could be at risk for additional cancers. They also could inform family members who may also be at risk. Drugs that actually target germline mutations were still very new and were only approved for a few cancers.

Since then, the number of available therapies directed at germline mutations has taken off. Drugs called PARP inhibitors, which target changes caused by mutations in the genes BRCA1 and BRCA2, are now approved for breast, ovarian, prostate, and pancreatic cancers and are being studied in additional cancer types. Immunotherapy drugs like pembrolizumab (Keytruda®) have proven effective against cancers caused by mutations in DNA mismatch repair genes, including in people with Lynch syndrome, a hereditary cancer condition.

Expanding Testing to More Patients

About 40% of patients in the JCO study who had therapeutically actionable germline mutations received therapies that targeted those changes, the investigators reported, but Dr. Stadler says that number is even higher today than it was between 2015 and 2019 when the data for this study was collected. That’s thanks to the increase in the number of such treatments.

MSK is now conducting clinical trials to determine the efficacy of drugs that target germline mutations in the adjuvant setting — to prevent cancer from coming back after surgery in patients with early-stage disease.

“As many of the germline-directed treatments are now being evaluated in clinical trials in the early-stage setting, we believe that the therapeutic impact of germline mutations will continue to expand,” Dr. Stadler says. “Beyond guiding surgical decision-making, we now anticipate that germline genetic testing in some early-stage cancers will also help to identify patients who may benefit from these targeted therapies.”

[OncoKB] helps make sure that the doctor and the patient are aware of all possible treatment options so that they can make an informed choice about which treatments to pursue.
Debyani Chakravarty Assistant Attending, Molecular Diagnostics Service

A Tool for Classifying Mutations

A preliminary analysis of this MSK-IMPACT germline data was presented in 2020 at the American Society of Clinical Oncology annual meeting. What’s noteworthy about the new JCO study is that it represents the first time that another MSK-developed tool, named OncoKB®, has been applied to germline information.

“OncoKB was developed to help clinicians in the point-of-care setting to appropriately interpret the genetic information contained in sequencing reports,” says Debyani Chakravarty, an Assistant Attending in the Molecular Diagnostics Service who co-developed this precision oncology knowledge base with Nikolaus Schultz, Head of Knowledge Systems, and JianJiong (JJ) Gao, an Assistant Attending Computational Oncologist in MSK’s Marie-Josée & Henry R. Kravis Center for Molecular Oncology.

“When specific mutations arise in select cancer types, they guide the use of certain approved targeted therapies,” she adds. “They also may make the patient eligible for enrollment in a clinical trial. In this way, a patient’s tumor sequencing report may inform a patient’s treatment strategy.”

OncoKB, which has been used to annotate MSK-IMPACT reports since April 2017, is essentially a grading scale for mutations that classifies them according to their level of therapeutic actionability:

  • Level 1 means that the mutation is recognized by the US Food and Drug Administration as a biomarker for an FDA-approved drug.
  • Level 2 means the mutation is widely recognized as a standard-of-care marker for an FDA-approved drug and is typically included in professional guidelines, such as the National Comprehensive Cancer Network.
  • Level 3 means there is compelling clinical evidence that a patient with this mutation may benefit from either an FDA-approved drug or a drug that’s currently being studied in a clinical trial and may help guide patients and their oncologists toward clinical trial selection.

Having germline information annotated by OncoKB will enable doctors to more easily match patients with therapies that target those germline mutations, the investigators note. “I think of this tool as a decision-support system,” Dr. Chakravarty says. “It helps make sure that the doctor and the patient are aware of all possible treatment options so that they can make an informed choice about which treatments to pursue.”

This research was supported in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Precision Interception and Prevention Program, the Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Romeo Milio Lynch Syndrome Foundation, and the National Institutes of Health National grant P30 CA008748.

Dr. Chakravarty has consulted for Medendi Medical Travel. Dr. Stadler’s immediate family member serves as a consultant in ophthalmology for Genentech/Roche, Novartis, RegenexBio, Neurogene, Optos Plc, Regeneron, Allergan, Gyroscope Tx, and Adverum outside the submitted work.