RE: Breast Cancer Risk After Salpingo-Oophorectomy in Healthy BRCA1/2 Mutation Carriers: Revisiting the Evidence for Risk Reduction

Heemskerk-Gerritsen et al. ( 1 ) questioned the protective effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer (BC) risk in women who carry a BRCA1 or BRCA2 ( BRCA1/2 ) mutation, as previously reported. They proposed that studies addressing this question should ensure: 1) women are eligible only if they do not have breast or ovarian cancer and have both ovaries and breasts intact before DNA testing; 2) each woman is followed from the age of DNA testing; and 3) the time at risk considers RRSO as a time-dependent variable that takes value 0 before RRSO and 1 after. Using this design, their analysis of Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON) data reported a BC hazard ratio (HR) by RRSO of 1.09 (95% confidence interval [CI] = 0.67 to 1.77). They hypothesized that the previously reported protective effect of RRSO on BC was because of failure to conform to one of these three design features.

Domchek et al. ( 2 ) and Kauff et al. ( 3 ) both have reported a protective effect of RRSO on BC for BRCA1/2 mutation carriers ( Table 1 ) in women followed prospectively from ascertainment with breasts and ovaries intact at start of follow-up. These analyses followed women who underwent RRSO from RRSO date. Therefore, these analyses did not conform to feature 2 above and may be subject to “immortal person-time bias.” We updated the Prevention and Observation of Surgical Endpoints (PROSE) dataset reported by Domchek to accommodate additional subjects recruited since the original publication and current follow-up. We then reanalyzed the PROSE and Kauff data using RRSO as a time-dependent variable following each woman from the age at ascertainment, as per Wacholder et al. ( 4 ).

The hazard ratio estimates in the current reanalyses were similar to those previously reported ( Table 1 ): RRSO conferred a protective effect on BC in both the PROSE and Kauff data. In PROSE, all BC cases occurred more than five months following RRSO. In Kauff, BC occurring less than six months after RRSO were excluded. Thus, as in the paper of Heemskerk-Gerritsen, it is doubtful that cases unlikely to be influenced by RRSO biased either analysis. Mavaddat et al. ( 5 ) also reported hazard ratio estimates for RRSO using the same approach as Heemskerk-Gerritsen and found hazard ratios of 0.52 (95% CI = 0.24 to 1.13) in BRCA1 and 0.79 (95% CI = 0.35 to 1.80) in BRCA2 .

In Figure 2, Heemskerk-Gerritsen et al. displayed cumulative BC risk by RRSO based on a “landmark” method ( 6 ). The x-axis of this figure started from age 30 years and risk started to increase at about age 31 years, implying the “landmark time” used was approximately 31 years. As the minimum age at RRSO in HEBON was 31 years, it is likely the estimated curve of the RRSO group was unstable when the number of carriers undergoing RRSO was small at the beginning of the curve. Choice of landmark time can clearly have large impact on the graphical display of the RRSO protective effect ( 6 ). It is not clear how the figure would appear if a different landmark time were used. Finally, if RRSO effects depend on age, then the difference in censoring events in HEBON vs the PROSE or Kauff data may lead to different effect estimates.

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