Saturday, 18 Sep 2021

Support for Gene-Specific Risk-Reduction Strategies in Lynch Syndrome

NEW YORK (Reuters Health) – New research supports adoption of a gene-specific approach to risk-reduction strategies for gynecologic cancers in women with Lynch Syndrome, finding such an approach to be cost-effective and associated with improved quality of life.

Lynch syndrome (LS) is a hereditary cancer syndrome caused by germline pathogenic variants in DNA-mismatch-repair genes MLH1, MSH2, MSH6 and PMS2. It is associated with “high but variable” risks for endometrial and ovarian cancers based on genotype, researchers note in JAMA Network Open.

With the expansion of multigene testing for cancer susceptibility, LS has become easier to identify among women. However, current guidelines on preventive strategies are not specific to genotypes, they point out.

Using a simulation model, researchers with Columbia University in New York did a cost-effectiveness analysis in which they evaluated gene-specific surveillance and preventive strategies for LS-associated gynecologic cancers.

Their findings suggest that a two-stage surgical approach with hysterectomy and bilateral salpingectomy (hyst-BSO) at age 40 years and oophorectomy delayed until age 50 years was optimal for individuals with MLH1 and MSH6 variants.

Surgical treatment at age 40 years was best for individuals with MSH2 variants and delay in surgical treatment until age 50 years was optimal for individuals with PMS2 variants.

“All together, these results suggest that a one size fits all approach to gynecologic cancer risk management may not be supported for individuals with LS,” write Dr. Fay Kastrinos and colleagues.

“These findings suggest that surgical decision-making should consider LS genotype for gynecologic cancer prevention and that a novel two-stage approach may be associated with decreased cancer risk while avoiding early menopause in individuals with select genetic variants,” they add.

In an email to Reuters Health, Dr. Kastrinos said, “It would not be hard to adopt this approach in practice.”

“The importance of this study is to offer options presented in the decision-making as far as (1) type of risk-reducing surgery – the two-stage, which we introduce, vs. the current approach which is total hysterectomy and removal of both ovaries (which results in premature menopause); and (2) consideration of delayed surgery based on the type of gene,” she added.

“Giving women with Lynch syndrome options regarding how best to manage their gynecological cancer risks is what our study supports and this dialogue is needed during routine clinical care. Currently, the one and only option presented is hysterectomy and bilateral ovary removal when childbearing is completed,” Dr. Kastrinos said.

Writing in an editorial, Dr. Lara Petelin and Dr. Alison Trainer of the Peter MacCallum Cancer Centre, in Melbourne, Australia, say these results “strengthen the proposal that management of Lynch syndrome as 4 distinct inherited cancer syndromes may be associated with benefits among individuals with MMR pathogenic variants.”

They say the researchers “should be commended for making the model source code publicly available for review, given that lack of transparency is a common issue in complex cost-effectiveness models.”

They also note that a recent report from the Manchester International Consensus Group highlighted the lack of comprehensive clinical guidance regarding management of gynecological cancer among individuals with Lynch syndrome.

“As universal screening of colorectal and endometrial cancers for individuals with Lynch syndrome becomes more widespread, it will likely lead to increased identification of individuals with lower-penetrance MSH6 and PMS2 pathogenic variants,” they point out.

“Ensuring appropriate gene-specific guidelines for clinical management will be increasingly important. By using clinical evidence generated through trials and observational studies, models such as that developed by (Dr. Kastrinos and colleagues) may assist in delivering value-based health care to maximize clinical outcomes in a cost- effective way,” the editorialists conclude.

SOURCE: https://bit.ly/3C4tQd3 and https://bit.ly/3tC9eFW JAMA Network Open, online September 9, 2021.

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