Who is at risk after risk reduction?

INTRODUCTION In this issue of Cancer, Harmsen et al have provided insight into the characteristics of BRCA1/2 mutation carriers who later develop primary peritoneal carcinoma (PPC) despite undergoing risk-reducing gynecologic surgery. The authors have done a commendable job in trying to shed light on a rare condition, and this effort provides clinicians with information that can guide counseling and surveillance around risk-reducing surgery. Women who carry a deleterious mutation in BRCA1 or BRCA2 have a higher lifetime risk of developing ovarian cancer, cancer of the fallopian tube, and PPC. At the time of diagnosis, these gynecologic cancers tend to be high grade, of serous histology, and of advanced stage. There are no reliable screening methods available and thus these women are counseled to undergo surgical removal of the ovaries and fallopian tubes to mitigate their risk. This procedure, also known as risk-reducing salpingo-oophorectomy (RRSO), reduces the risk of gynecologic cancer development by approximately 80%. The development of metachronous PPC after RRSO has been observed in 1% to 4% of women, but to date, there have been limited data to allow for risk stratification or an understanding of who among these women are at highest risk of this rare outcome. The study by Harmsen et al sought to address this gap in knowledge. The authors performed a Medline literature search and evaluated reference lists to identify studies reporting on cases of PPC in BRCA1/2 carriers after RRSO with no pathologic abnormalities in the ovaries or fallopian tubes. E-mail inquiries were sent to the authors of 28 relevant studies as well as to other national and international experts in the field of hereditary breast and ovarian cancer. These individuals were asked to provide information regarding cases of PPC after RRSO via a 2-page case report form that collected data concerning age, BRCA mutation status, breast cancer history (including stage of disease and tumor histology), type of risk-reducing surgery, histopathologic data, details of the peritoneal carcinoma diagnosis (including age, histology, grade, stage, and treatment), and the patient’s vital status. Case report forms ultimately were retrieved from 6 authors and 2 Dutch colleagues. Six additional cases were added from the authors’ own institution. This effort led to 36 evaluable cases of PPC after RRSO that occurred between 1961 and 2014, of which 8 cases could be recognized from previous publications. The initial casting of a wide net led to a modest return on effort, thereby underscoring the difficulty in putting this type of case series together. Nevertheless, this work represents a reasonably large series for a rare outcome. Among the 36 cases, the median age at the time of RRSO was 52 years, the median age at the time of PPC diagnosis was 60 years, the median interval between RRSO and PPC diagnosis was 54 months, approximately 86.1% of cases occurred in BRCA1 mutation carriers, and 6 cases had histopathologic evidence of serous tubal intraepithelial carcinoma (STIC) lesions (5 cases) or tubal epithelial atypia (1 case) in the RRSO specimen. To provide a comparison group, the authors also included details from their single-institution cohort of all BRCA1/2 mutations carriers who underwent RRSO with no invasive carcinoma identified in the surgical specimen at Radboud University Medical Center in Nijmegen, the Netherlands between 2014 and 2016. As part of their institutional protocol, all specimens were completely embedded and sectioned as per the Sectioning and Extensively Examining the Fimbriated End (SEE-Fim) protocol. In this comparison cohort of 113 patients, there was a lower percentage of BRCA1 mutation carriers (53.1% vs 86.1%), the median age at the time of RRSO was younger (46 years vs 52 years; P 5 .025), and the there was a lower percentage of STIC lesions in the RRSO specimens (0% vs 53.1%). Although the 36-patient PPC cohort and the more recent 113-patient RRSO group differed and were not directly comparable, Harmsen et al made 3 reasonable