Risk of breast cancer in Lynch syndrome: a systematic review

Abstract

IntroductionLynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation carriers have a substantial burden of increased risks of cancers of the colon, rectum, endometrium and several other organs which generally occur at younger ages than for the general population. The issue of whether breast cancer risk is increased for MMR gene mutation carriers has been debated with evidence for and against this association.MethodsUsing the PUBMED, we identified all relevant studies of breast cancer associated with Lynch syndrome that were published by 15 December 2012. In the review, we included: (i) molecular studies that reported microsatellite instability and/or immunohistochemistry in breast cancer tumors of MMR gene mutation carriers; and (ii) risk studies that investigated risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families.ResultsWe identified 15 molecular studies and, when combined, observed 62 of 122 (51%; 95% CI 42 to 60%) breast cancers in MMR gene mutation carriers were MMR-deficient. Of the 21 risk studies identified, 13 did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome while 8 studies found an increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers). There is only one prospective study demonstrating an elevated risk of breast cancer for MMR gene mutation carriers compared with the general population (standardized incidence ratio 3.95; 95% CI 1.59, 8.13).ConclusionsSince breast cancer is a relatively common disease in the general population, more precise estimates of risk and gene-specific risks will need to utilize large prospective cohort studies with a long follow-up. While current data are inconclusive at a population level, individual tumor testing results suggest that MMR deficiency is involved with breast cancers in some individuals with Lynch syndrome.

Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology

“…In addition, there have been suggestions of an increased risk for breast cancer in the Lynch syndrome population 76,77 ; however, there is insufficient evidence to support increased screening above average-risk breast cancer screening recommendations. 42,51 A study of 188 men with Lynch syndrome also showed a 5-fold increase in risk of prostate cancer.…”

Patients Tested at a Laboratory for Hereditary Cancer Syndromes Show an Overlap for Multiple Syndromes in Their Personal and Familial Cancer Histories

“…Although several studies have suggested there is no increased risk for breast cancer with LS, there has been no consensus to date on the correlation between breast cancer and LS [11,12,13,19,20]. This study revealed that 22.4% of the LS patients meeting NCCN criteria for HBOC had a personal history of breast cancer and a family history of early-onset breast cancer.…”

The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?

“…With the experience of gene panels, which included HBOC susceptibility genes among others, some families harboring a mutation in an MMR gene did not meet Amsterdam II or Bethesda criteria for Lynch syndrome testing [37]. To date, it is unclear whether the results in our three families with single-affected earlyonset BC should be regarded as incidental or not since an increased risk of BC in Lynch syndrome is still controversial [38][39][40]. Nevertheless, massively-parallel sequencing targeting multiple candidate genes is changing the paradigm as it gives the opportunity to assess the role of genes that would never have been evaluated in a nonpanel approach.…”