A New Online Tool for Hereditary Cancer Risk: Who Should Have Genetic Testing?

Although all cancers arise from genetic damage, in approximately 10-15% this damage is inherited from parents. These are called hereditary cancers . The Human Genome Project, completed in 2003, and the subsequent Cancer Genome Atlas, completed in 2020, improved understanding of their prevalence and importance. However, major gaps remain in identifying which cancers are hereditary and who is at risk.

If clinical information, such as cancer at an early age or family history, raises suspicion of hereditary cancer, this should be confirmed through genetic testing . Who should undergo genetic testing for hereditary cancer is another important question. To address this need, clinical decision support systems are being developed. This article discusses a study of an online tool designed for this purpose.

A Decision Support System for Hereditary Cancers

A new online tool can quickly and accurately identify individuals likely to carry a mutation in genes associated with hereditary cancers, helping determine who would benefit from genetic testing.

PREMMplus is an online tool developed and validated by Dana-Farber Cancer Institute researchers using multigene hereditary cancer risk testing involving more than 30 thousand people. The latest scientific study of PREMMplus was published on August 15, 2022 in Journal of Clinical Oncology.

Dana-Farber’s Dr. Sapna Syngal said, “Our findings suggest that PREMMplus has the potential to change how patients and family members are referred for genetic testing and counseling” .

Traditionally, someone concerned about a family history of cancer is referred to a genetics clinic, where counselors take a complete history. However, cancer genetic counseling centers are in short supply worldwide.

“At a time of genetic counselor shortages, PREMMplus could help modernize risk assessment and allow counselors to focus their time where it is most needed, helping people understand their genetic test results and the options available when a cancer predisposition gene is found,” Syngal says.

How Does It Work?

The tool uses clinical data (age, sex, ethnicity and personal/family history of 18 cancers) to estimate the probability that a person carries a potential gene alteration (PGD) in 19 cancer susceptibility genes.

A PREMMplus score of 2.5% or higher has 89%–94% sensitivity and a negative predictive value above 97% for identifying individuals with PGDs in 11 well-defined category A, high-penetrance cancer-risk genes. These hereditary cancer-associated genes are APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2 and TP53.

The team says these PGDs “represent a range of hereditary cancer risks” . Knowing that a person carries an alteration increasing hereditary cancer risk can help prevent cancer or enable very early diagnosis if they do not have cancer. If they do, newer drugs targeting hereditary cancer alterations may be appropriate.  

Associated cancers include those comprising Lynch syndrome, as well as breast, ovarian, colorectal, pancreatic and prostate cancer. The team reported slightly lower but still “quite strong” performance for identifying PGDs in moderate-risk genes such as CHEK2 and ATM (84%–90% sensitivity and negative predictive value above 93%).

Syngal said her ultimate vision is to integrate the tool into electronic health records (EHRs). “Through EHRs, it could be sent to people before an oncology or primary care appointment, mammogram or colonoscopy. The doctor or nurse would then have information beforehand and could refer them for genetic testing when appropriate.”

The tool is not currently suitable for routine clinical use. The aim is to make it available online within a few months.

Syngal said two versions would be available:

1. A user-friendly version that patients complete directly, indicating whether they meet the threshold for genetic testing. They would then take this information to their primary care physician.
2. In the other version, the physician and patient complete the information together during an in-person appointment. PREMMplus will be free for patients and healthcare professionals.

“We hope hospital systems will use it. We also hope insurers will use it to see who needs testing and determine whose tests to authorize.”