Risk-Reducing Surgery in Women with Lynch Syndrome has Merit

Abstract & Commentary

By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.

Synopsis: These findings suggest that prophylactic hysterectomy with bilateral salpingo-oophorectomy is an effective strategy for preventing endometrial and ovarian cancer in women with the Lynch syndrome.

Source: Schmeler KM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354:261-269.

The Lynch Syndrome (hereditary non-polyposis colorectal cancer) is a cancer susceptibility syndrome highlighted by early age onset of cancers of the colon and rectum, endometrium, ovary, small bowel, ureter and renal pelvis. It is mediated via autosomal dominant transmission of germ-line mutations in DNA-mismatch repair genes. In recent years, it has become recognized that lifetime risk of cancers of the endometrium is similar to that of colon cancer. Since prophylactic surgery in women with BRCA mutations reduces their risk of ovarian and breast cancer, it was hypothesized that similar reductions in endometrial, ovarian and colon cancer may be levied by prophylactic hysterectomy and/or oophorectomy. To test this hypothesis, Schmeler and colleagues performed a case-control retrospective study of 315 women with known germ-line mutations associated with the Lynch syndrome. Approximately 20% had undergone prophylactic hysterectomy (with or without oophorectomy); age-match controls were identified. There were no cases of endometrial, ovarian or primary peritoneal cancer in the group undergoing surgery. Endometrial cancer was identified in 33% of the controls and ovarian cancer in 5% of the controls.

The cumulative risk reduction of these cancers imposed by surgery was 100%. Eighty-eight percent of synchronous or metachronous colon cancers were diagnosed after age 35 supporting the authors recommendation that such surgery could be performed after childbearing. They also concluded that prophylactic hysterectomy is an effective strategy to reduce the risk of endometrial and ovarian cancers in affected women.

Commentary

The article by Schmeler and colleagues is provocative even though retrospective in nature and subject to the usual biases of ascertainment. The authors essentially report (and somewhat obviously) that prophylactic hysterectomy prevents lifetime occurrence of endometrial cancer and (less obviously) in the presence of oophorectomy nearly significantly reduces the lifetime risk of ovarian cancer. In this study, no cases of gynecologic cancer were diagnosed subsequent to the procedure. This is an important observation as the lifetime risk of endometrial cancer among affected individuals is as high, if not higher, than their risk of colon cancer, for which this syndrome is commonly referred to (hereditary non-polyposis colorectal cancer [HNPCC]). A small number of cases of ovarian cancer limited the statistical inference of hysterectomy and oophorectomy on subsequent primary peritoneal cancer.

In the accompanying editorial to the article, Offit and Kauff point out that over-estimation of the risk-reduction potential may indeed be occurring in this case-control study largely from higher than expected disease density in the controls. The reported incidence was nearly 3 times the previously reported risk in other HNPCC studies. However, a reduction to zero from just about any baseline value needs to be seriously considered in counseling at-risk patients. This is further underscored by the fact that effective screening for the disease processes, namely endometrial and ovarian cancer in those in whom surgery is not performed is limited and not validated. However, since surgery may be associated with morbidity, the careful risk-benefit ratio must be objectively presented.

Ultimately, any risk-reduction surgery should translate into improved survival of the treated cohort. This has been preliminarily demonstrated in one ovarian cancer population-based screening study. However, since endometrial cancers are frequently diagnosed in older women, at early stages, with attendant comorbidities, this may not be overtly obvious. However, the age of onset of cancers identified in women with a germ-line mutation is substantially younger and presents a potential life expectancy within which such an effect may be measured. Subsequent prospective cohort trials, as planned within the Gynecologic Oncology Group will hopefully shed light on this important effect.

References

  1. Burke W, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA. 1997;277:915-919.
  2. Skates SJ, et al. Calculation of the Risk of Ovarian Cancer From Serial CA-125 Values for Preclinical Detection in Postmenopausal Women. J Clin Oncol. 2003;21:206-210.
  3. Vasen HF, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19:4074-4080.