Multigene Panels Important for Precision Cancer Care, Variance and Coverage Barriers Remain

While we have long forgotten the Mendelian models and single-gene testing panels in the field of oncology, we have not yet reached agnostic testing or population screening for cancer—although we are headed in that direction, according to Kenneth Offit, MD, MPH, from Memorial Sloan Kettering Cancer Center (MSKCC).

Speaking at the 22nd Annual Conference of the National Comprehensive Cancer Network: Improving the Quality, Effectiveness, and Efficiency of Cancer Care, held March 23-25, 2017, in Orlando, Florida, Offit explained that hereditary factors are responsible for 16% of cancers, behind smoking (33%) and obesity (20%). Paying attention to these known risk factors of cancer can reduce the possibility of cancer-related deaths by 60%.

The Utah genealogical experiment led to the discovery of the BRCA gene and its importance in familial cancers, Offit explained, and paved the way for the role of BRCA in cancer development among Ashkenazi Jewish women. While a single BRCA1 mutation has been noted in 20% of Ashkenazi Jewish women with early onset breast cancer; add to that a frameshift mutation in BRCA2 could lead to 25% of all early-onset breast cancer cases in Ashkenazi Jewish women who have a personal or family history of ovarian cancer.

Knowledge of personal and inherited predisposition to mutations can help oncologists device a more informed approach to treatment decisions.

A more recent study, published in JAMA Oncology, followed BRCA1-positive women and found they have an increased risk of serous or serous-like endometrial cancer. These findings bring into perspective the need to discuss the advantages of preventive hysterectomy in these women, Offit explained.

In the case of familial adenomatous polyposis, where a 100% penetrance of adenomas is seen, and there is a high risk of extracolonic tumors.

“If left untreated, these polyps can lead to cancer,” said Offit. “Testing for a mutation in APC becomes important, and a prophylactic colectomy may be needed in teen years.”

Offit then provided a list of the various tumor sites and the known mutations associated with that form of cancer:

• Gastrointestinal stromal tumor (KIT)
• Thyroid (RET)
• Stomach (CDH1)
• Kidney (STK11, VHL, BHD, TS)
• Basal cell (PTCH)
• Colon (MLH1, MSH2)
• Colon (APC)
• Breast/ovary (BRCA1/2, PALB2, CHEK2)

He explained that while multiple genes may be mutated with a specific cancer type, the risks vary.

“For example, in breast cancer, mutations in BRCA1/2 have a significant bearing on the risk on developing the cancer, while mutation in ATM have a lower risk.” Despite this knowledge, the “Forces of change have led to commercialization of multigene testing,” he said.

Offit explained that scientists like himself were concerned with the rate at which these tests were being developed and introduced in the market. They raised their voices through editorials and at meetings, warning against inadequate knowledge to use these panels in decision making.

About 20% to 30% of multigene panels yield variants of uncertain significance, which may not necessarily affect protein function or be clinically relevant, Offit said. This might be because not many sequencing studies have been conducted, he added.

The Prospective Registry of MultiPlex Testing or PROMPT registry, developed by MSKCC in collaboration with other academic research institutions and laboratories, allows patients to input information from their multiplex genetic testing and have a mutation in any gene other than BRCA1/2.

“This will provide healthcare providers and researchers better access to uncommon or rare gene variants,” Offit said.

But will payers provide coverage for these tests?

A study recently published in the Journal of the National Comprehensive Cancer Network, which conducted semi-structured interviews with 11 major US payers found that main barriers to coverage for hereditary cancer panels included poor fit with coverage frameworks, insufficient evidence, departure from pedigree-based testing for genetic screening, and lack of clinical testing rigor.

Offit concluded his talk by stating that next generation sequencing has made multigene panel testing possible. “While the time for agnostic testing may be approaching, it’s not here yet, mainly because of variance and lack of payer coverage.”