No Breast Cancer Risk Reduction with Risk-reducing Salpingo-oophorectomy?

It’s been 24 years since BRCA testing became commercially available, after sequencing was accomplished by the team led by Mark Skolnick (above).  And for 24 years, we’ve been telling BRCA-positive patients that bilateral salpingo-oophorectomy, if performed premenopausally, around age 40, will simultaneously reduce breast cancer risk…substantially.

But now…a multi-center prospective study of risk-reducing salpingo-oophorectomy (RRSO) was just published in Breast Cancer Research (https://doi.org/10.1186/s13058-020-1247-4), concluding no benefit for BRCA-1 patients when it comes to breast cancer risk reduction, and limited benefit for BRCA-2, perhaps increasing over time after the RRSO.

With more authors than I can count, merging multiple cohorts, using epidemiologic terms I’ve never heard before, e.g., “immortal person-time bias,” the results – if valid – are practice-changing for those of us who deal with high-risk gene-positive patients.

For those thousands upon thousands of women who have tested BRCA-1 positive since 1996, and who then opted for early-age RRSO and were told “you also cut your breast cancer risk in half”….SURPRISE – no benefit whatsoever! At least, that’s what this article is telling us, while simultaneously claiming to be the largest and most pure study ever performed. And I can assure you, from now on, many will be quoting “no benefit” for RRSO protecting against breast cancer in BRCA-1 patients without scrutinizing the study design. As always, the devil lives in the fine print.

Granted, one wouldn’t expect as much benefit in BRCA-1, given the ER-negative propensity, but zero benefit is unlikely. And, the benefit of RRSO for BRCA-2 when it comes to breast cancer risk reduction is likely going to be substantial in the long term (this prospective study had a mean f/u of only 5 years).

Here are my quibbles:

1) Counting cancers that occurred shortly after RRSO — if a patient developed breast cancer within 2 months, they were excluded. TWO MONTHS! That’s not near enough to exclude patients with established cancer wherein RRSO cannot possibly benefit. In fact, investigators should have excluded patients for the first two years after RRSO, not months, to truly measure a preventive effect.

2) Postmenopausal women were included. Now how exactly is RRSO supposed to prevent breast cancer in a postmenopausal woman?

3) In the Discussion, a point is made about how “HRT” could cause one to lose any protection from RRSO performed premenopausally.  Let’s consider that “HRT” can be either estrogen alone or estrogen plus progesterone. The prospective, randomized WHI study (see last month’s blog) has been telling us for many years that the two approaches have opposite effects – exogenous estrogen alone lowers breast cancer risk (and mortality) while E+P raises risk (and mortality). To lump these two opposites into “HRT” is misleading. It has always been misleading to tell BRCA+ patients that “HRT” will cause them to lose any breast cancer protection afforded by RRSO. Add-back HRT is lower (and often non-cyclic) than the natural premenopausal state so even in theory, one could make the case for hormonal add-back in low doses.  And now there is confirmatory data that little or nothing is lost when given to BRCA-positive patients after RRSO.

4) As Malcolm Pike, PhD and colleagues have shown us for 30+ years, the most powerful variable in endocrine manipulation when it comes to preventing breast cancer is the number of years of high, cycling hormone levels that can be shaved away through an early, induced menopause. Using age 50 as the predicted age when menopause would occur naturally, inducing menopause at 45 lowers risk a little, but 40 has a much stronger effect, and age 35 stronger still. And, consider that we counsel patients to have RRSO performed at 35-40 for BRCA-1 and 40-45 for BRCA2. These ages are chosen primarily on the age profile of fallopian tube/ovarian cancers. So, if 35 to 40 is the very strong recommendation for BRCA-1 patients, why did the investigators pick the single age of 45 with binary outcomes – above vs. below 45? Rather than stratify outcomes by age, a binary approach was used, based on an age that has no clinical relevance.

The study design would have been more helpful like this – exclude all cancers occurring within the first 2 years (or at least one year). And, stratify impact according to age groups as to when RRSO was performed: under 35, 35-40, 40-45 (no need to include over 45 at all, at least theoretically). Yet, in the binary approach of this study, there were 1,783 person-years over the age of 45 when RRSO was performed (including postmenopausal women) and 2,205 were under the age of 45.  We can say nothing about the impact of SSRO when performed at 40 or younger from this article.

While the study might give us pause for the BRCA-1 patients, as one would not expect the breast cancer risk reduction with RRSO to be as much as BRCA-2, we have to acknowledge that adjusting our risk calculations upwards might result in more preventive mastectomies. And maybe that’s the right thing to do, I don’t know.

I will probably adjust my counseling to a degree – that is, introduce more uncertainty about the impact of RRSO in the BRCA-1 patient when it comes to breast cancer risk. But for BRCA-2 patients who have RRSO performed around age 40, well, this current study doesn’t alter anything. We are counseling patients about lifetime risks, not 5 years, when it comes to making decisions about the age at which to perform RRSO.

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(Will Rogers Airport, OKC) Hosting Mark Skolnick in Oklahoma City (1995), shortly after the sequencing of BRCA-1 and before Myriad Genetics was offering commercial testing.