Risk-reducing surgery, risk-reducing medication, and surveillance in young BRCA carriers with breast cancer: considering all the options

In their study, “Association between risk-reducing surgeries and survival in young BRCA carriers with breast cancer: an international cohort study” (1), Blondeaux et al. describe improved overall survival (OS) following risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO). The study, conducted through the BRCA BCY Collaboration across 109 countries, was a retrospective cohort study over a 20-year time period recruiting 5,290 women carrying a BRCA1/2 pathogenic variant diagnosed with stages I–III invasive breast cancer before 41 years of age. The primary endpoint of the study was OS, with secondary endpoints disease-free survival (DFS), breast cancer-free interval, incidence of second primary breast cancer, and incidence of ovarian/fallopian tube cancer.

Of the 5,290 patients, 2,910 (55%) underwent RRM and 2,782 (52.5%) RRSO, with 1,804 women (34.1%) undergoing both. It is not described what surveillance or counselling the no-RRM or no-RRSO groups received, apart from follow-up being performed in accordance with the clinical practice of the local centre. OS was significantly better in the RRM group compared to the no-RRM group [adjusted hazard ratio (HR) =0.65; 95% confidence interval (CI): 0.53–0.78], irrespective of BRCA gene, age at diagnosis, tumour subtype, size, nodal status, chemotherapy use, or timing of BRCA testing. DFS, breast cancer-free interval, and reduced incidence of second breast cancers were also significantly better in the RRM group compared to the no-RRM group. The relative reduction of 35% is far greater than predicted by a simulated analysis assuming a 2% incidence of contralateral breast cancer in the no-RRM group (2). It is unfortunate that the authors did not provide the number of contralateral breast cancers experienced in the women in their study, with and without RRM, nor were the causes of death shown. Although they employed models that adjusted for the timing of surgery and genetic testing, there may still have been a survival bias. For instance, patients with co-morbid conditions that could contribute to mortality would be predicted to be less likely to opt for risk-reducing surgery, as well as those that developed metastatic disease during follow-up.

OS was significantly better in the RRSO group compared to no-RRSO (adjusted HR =0.58; 95% CI: 0.48–0.71). This was most significant in the BRCA1-heterozygotes and patients with triple-negative breast cancer (TNBC). DFS, breast cancer-free interval, and reduced incidence of ovarian or fallopian tube cancers were also significantly better in the RRSO group compared to the no-RRSO group. This effect was partially attenuated in the sensitivity analysis that only included women tested for BRCA before or at diagnosis (HR =0.70; 95% CI: 0.49–1.01), suggesting there may be some survival bias at play. The effect of RRM and RRSO appeared to be independent in terms of impact on OS, but not on breast cancer-free interval or DFS, suggesting, understandably, that the addition of RRM to patients having RRSO was impactful in terms of breast-specific disease.

Taking this data at face value, the OS advantage of RRM seems modest after 20 years of overall follow-up, and a median follow-up of 8.2 years per woman, leading to only an average of 1 year advantage of OS in women with young-onset breast cancer. Given that the median time of RRM following breast diagnosis itself was 0.8 years, it is unclear how much the RRM contributed to the better OS despite the conclusions presented. The findings of RRM resulting in improved breast cancer DFS and secondary events having a 4-year advantage when compared with the OS figure of 1 year also raise the question of lead-time bias—does the RRM delay recurrence but not death? Alternatively, there may be competing mortality risks; however, given the young age of this cohort, this is less likely.

The authors suggest that these findings can add to the evidence for tailored counselling of high-risk young women on cancer-risk management strategies. However, realistic counselling of women in this situation involves discussion of all options, beyond surgery vs. ‘no surgery’. The omission of further detail and elaboration of the non-surgical options is an important one. Surveillance is a crucial alternative that was not discussed. Magnetic resonance imaging (MRI) surveillance has been shown to significantly reduce breast cancer mortality in BRCA1-heterozygotes (3), the majority population of this study. While surveillance was no doubt a part of the control RRM and RRSO groups’ management, the details of this are not stated, and given the timespan and geographical variance of the study sites, it is likely these varied significantly across different recruitment sites and the 20 years over which the study was conducted.

Disparities are likely emphasised in surveillance programs offered between high-income and low- and middle-income countries (LMIC). In addition, two-thirds of women from LMIC did not undergo RRM, whereas 58% of women from high-income countries did do so. This in itself has the potential to bias the results in favour of RRM. We are not provided with the number of women in LMIC who had access to standard of care chemotherapy.

The question of what happened to those not undergoing RRM and/or RRSO is crucial, as whilst many women who undergo risk reduction surgery are happy with their decision, there are significant numbers who exhibit regret. Studies regarding acceptability and satisfaction after contralateral RRM suggest that up to 14% of women undergoing bilateral prophylactic surgery describe regret (4,5). This appears to be affected by a number of psychological factors surrounding body image, and also impact on sexual relationships (6). There is also a consequence in terms of potential repeated surgical procedures and hospital visits (7). It has been suggested that the choice of bilateral mastectomy may be more common in individuals more motivated by negative emotion and driven by the negative emotional experiences of a breast cancer diagnosis rather than a cognitive decision to reframe future cancer-related fear (8,9). A meta-analysis of eight studies on decision-making regarding contralateral prophylactic mastectomy (CPM) found that feelings about the effects of CPM varied significantly; while most patients were happy in the short-term, the long-term effects were unknown (6).

It is important that all options, including non-surgical options, are presented to women to allow them to make the most informed choice. A recent study by our group compared long-term oncology outcomes in women with BRCA1/2 pathogenic variants (but without breast or ovarian cancer at testing) who chose RRM (n=460) and those who opted for imaging surveillance (n=745). Breast cancer-specific deaths were similar in both groups, suggesting that this and OS are unlikely to be compromised in those choosing surveillance. However, breast cancer incidence rates were significantly lower [odds ratio (OR) =0.07] in the RRM group compared to the surveillance group (currently in press). Admittedly, this study population differs significantly in that these women had not received a breast cancer diagnosis at the initial time of testing.

The impact of RRSO in women so young also needs considering. Currently, RRSO is recommended for pre-menopausal women with BRCA1/2 PVs who have completed childbearing (10,11). It is of note that the RRSO group had a higher median number of pregnancies of two vs. one in the no RRSO group. The National Comprehensive Cancer Network (NCCN) and National Institute for Health and Care Excellence (NICE) recommend offering RRSO to RAD51C, RAD51D, BRIP1, and BRCA2-heterozygotes at 45–50 years, and in particular, NICE guidance specifies no earlier than 40 years for BRCA2-heterozygotes and 35–40 years for BRCA1-heterozygotes (11,12). In terms of ovarian and primary peritoneal cancer, RRSO has been shown to reduce risk by 95% and may be higher if conducted in specialist centres (13). The impact of RRSO on breast cancer risk has been more disputed, an initial meta-analysis of ten studies reviewing cancer outcomes post-RRSO describing a 51% reduction in breast cancers (HR =0.49; 95% CI: 0.37–0.65) as well as 79% reduction in ovarian or fallopian tube cancers (HR =0.21; 95% CI: 0.12–0.39) especially in BRCA2 heterozygotes (14). Despite subsequent studies also finding ~50% risk reduction of breast cancer following RRSO, these studies were criticised for heavy survivor bias (15), and a subsequent study using methodology to minimise this found no evidence of a protective effect (HR =1.09; 95% CI: 0.67–1.77) (16). Although subsequent longer follow-up studies have shown a benefit after 5–10 years.

There are also significant risks and side effects associated with RRSO that merit consideration, primarily related to premature menopause. Surgical complications are low with an intraoperative complication rate of 1.3% and post-operative complication rate of 3.1%, conversion rate of 0.6%, and median hospital stay of 1 day in a study of 159 women (17). Menopausal symptoms include hot flushes, vaginal dryness, and sexual dysfunction. Higher levels of sexual dysfunction and urogenital symptoms have been described (18), although fatigue and overall quality of life have been shown to be unaffected by RRSO (19,20). The use of hormone replacement therapy (HRT) in the first year after RRSO has been shown to minimise endocrine and sexual symptoms (21), although in the context of breast cancer, this would not be universally recommended. It is not clear from the current study what proportion of women undergoing RRSO received HRT.

Early surgical menopause is also associated with osteoporosis, cardiovascular disease, and dementia (22). This is especially relevant to this cohort of women for whom the median age at RRSO was 39.7 years, as the risk of cardiovascular disease is significantly increased in women who undergo RRSO under 50 years, and cardiovascular-related mortality is higher if performed in women who undergo RRSO under 45 years (23). Women undergoing RRSO under 45 years are at increased risk of osteopenia, osteoporosis, and fracture (24), which can occur remarkably quickly; the mean time from RRSO to osteopenia or osteoporosis has been reported to be as short as 29 months (22). Fragility fractures are associated with significant morbidity and mortality, and risk can be reduced with administration of bisphosphonates or monoclonal antibodies such as denosumab (25). It is not clear if the women in the RRSO group received counselling or plans for monitoring for cardiovascular or bone health. It has been described that while the majority of female BRCA1/2-heterozygotes post-RRSO qualify for dual-energy X-ray absorptiometry (DEXA) scanning, less than half receive one (22). Overall, more long-term survival in the RRSO group may be affected by higher fracture and myocardial infarction rates after age 55 years.

Due to the significant implications of RRSO, alternatives such as risk-reducing salpingectomy (RRS) and risk-reduction early salpingectomy with delayed oophorectomy (RRESDO) have been considered, and the timing of these interventions has to be carefully considered. Opportunistic salpingectomy is currently recommended at the time of hysterectomy for benign conditions in the general population (26). This has been demonstrated to reduce the risk of ovarian cancer in a retrospective study of 57,969 individuals undergoing relevant surgical procedures in British Columbia (27). The TUBA clinical trial (TUBectomy with delayed oophorectomy to improve quality of life as Alternative for RRSO in BRCA1/2 mutation carriers) in the Netherlands compared menopause-related quality of life using the Greene Climacteric Scale from 557 women who underwent RRSO with those who underwent RRS after completing childbearing with delayed oophorectomy (28). After RRSO, women were offered HRT unless contraindicated. Menopause-related quality of life was better after RRS than RRSO, regardless of HRT use.

In the UK, the PROTECTOR (Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal) trial is underway, which aims to compare women’s views and the impact of RRSO and delayed oophorectomy on sexual function, hormone levels, quality of life, and overall satisfaction with women undergoing RRSO or no surgery at all (29).

The outcomes from tailored surveillance and risk-reducing medication/chemoprevention studies are also vital to be able to accurately discuss risk with women at high-risk for breast cancer. Outcomes from studies such as the BCAN-RAY (Breast CANcer Risk Assessment in Younger women) study, which involves a comprehensive risk assessment involving risk factors, mammography to assess breast density, and polygenic risk in women aged 30–39 years, will be informative (30).

As the authors discuss, a major limitation of their study is that standard of care treatments, in addition to varying over the geographical locations in the study, have also evolved significantly over time, most crucially that of neoadjuvant immunochemotherapy for early TNBC. As the phase 3 KEYNOTE-522 trial concluded, neoadjuvant pembrolizumab plus chemotherapy for patients with early TNBC followed by adjuvant pembrolizumab is associated with a significant improvement in OS compared to neoadjuvant chemotherapy alone (86.6% compared with 81.7%, P=0.002) (31).

Patients with TNBC made up almost half of the cohort in the Blondeaux et al. study. While immunochemotherapy is associated with toxicity in its own right, it would be the standard of care currently for the largest subgroup, and stated benefits to OS from risk-reducing surgery may arguably be smaller given the benefit from systemic treatment. The impact of a high proportion of this cohort having TNBC in regards to survival is also worthy of discussion; women BRCA1/2-heterozygotes with TNBC diagnosed by 40 years of age have been observed to have a survival advantage over similar patients with TNBC who are BRCA-wild type (32). A further concern in such a large multicentre study is how vital status was ascertained at final follow-up. This could add a further bias that favours the surgical groups.

This study does add to the body of evidence to discuss with high-risk patients when considering risk-reducing surgery, particularly in women who already have a breast cancer diagnosis. The authors should also be congratulated on building such a large cohort. However, this does have to be tempered with a frank discussion that we do not know enough about how this may impact a young woman’s quality of life, and particularly for the triple-negative subtype population, surgical benefits from this trial may not be applicable. Further studies on surveillance and chemoprevention may provide more information on the non-surgical options and their risks and benefits. In addition, the overall benefits may still have been overestimated in both the RRM and RRSO groups due to survivor bias. Stratifying women in terms of future risk and a nuanced discussion on the timing of potential interventions will provide women with the most tailored treatment options.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0067/prf

Funding: This work was supported by the National Institute for Health Research to the Manchester Biomedical Research Centre (No. NIHR203308 to N.F. and S.H.). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0067/coif). A.G. reports research grants from Gilead Science and Greater Manchester Cancer Alliance (paid to institution). D.G.E. reports consulting fees from Antegenes. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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