At this San Antonio Breast Cancer Symposium 2024 we presented an international cohort study that looked into the association between risk-reducing surgeries and survival in the specific cohort of young BRCA carriers with breast cancer. We have looked into a large network, the so-called BRCA BCY Collaboration, a large network of 109 centres worldwide that included young patients diagnosed with invasive breast cancer, early stage breast cancer, between January 2000 and December 2020. All the patients were young at diagnosis, so 40 years or less and all of them were known to carry germline pathogenic or likely pathogenic variants in the BRCA genes. Within this cohort of 5,290 patients, all young BRCA carriers with prior risk of breast cancer, we have looked into the potential beneficial effect of risk-reducing mastectomy as well as risk-reducing salpingo-oophorectomy in terms of reducing mortality as well as disease-free survival and breast cancer free interval.
What was the study design?
The study is a retrospective international multicentre hospital-based cohort study that’s called the BRCA BCY Collaboration. Within this large network we managed to include more than 5,200 young BRCA carriers with breast cancer and in this special analysis we looked into risk-reducing surgeries. However, the network was started many years ago to try to answer the question and the first question that was answered with this study was the safety of having a pregnancy after being diagnosed with breast cancer in this special cohort of patients. These results were published in JCO in 2020 and then [?? 1:52] in JAMA in 2024. At San Antonio 2024 we presented within the same consortium the data on risk-reducing surgery in this special cohort of patients.
What were the key results?
In the study we have seen that around half of the patients included received one or the other risk-reducing surgery and 1,804 patients received both risk-reducing mastectomy and risk-reducing salpingo-oophorectomy. Looking first at the risk-reducing mastectomy, this surgical procedure was associated with a significant improvement in overall survival with an adjusted hazard ratio of 0.65, so a 35% reduced risk of dying for those patients that underwent risk-reducing mastectomy. This result was consistent with all the different models, sensitivity analyses, that we have done to try to counteract the potential biases with this sort of analysis. This benefit was observed across all the subgroups that were analysed and risk-reducing mastectomy was also associated, as expected, with a significant improvement in disease free survival and breast cancer free interval with an adjusted hazard ratio of 0.58 and 0.55 respectively. This is mostly due to the major reduction in the risk of developing a second primary breast cancer for those patients who underwent this surgical procedure.
For the second part of the analysis on risk-reducing salpingo-oophorectomy, in this case also this surgical procedure was associated with a significant improvement in overall survival, an adjusted hazard ratio of 0.58 and again the result was consistent in all the different models that we have used. The main difference with the prior analysis is that the median time from diagnosis of breast cancer to risk-reducing mastectomy was less than one year, it was 0.8 years, in this case it was around three years after diagnosis of breast cancer and the median age of the patient at the time of this procedure was around 40 years, so in line with the guidelines on risk-reducing salpingo-oophorectomy.
Interestingly, in the subgroup analysis we have seen the benefit of risk-reducing salpingo-oophorectomy was greater for BRCA1 carriers and for those with triple negative disease more than BRCA2 carriers or those patients with ER positive HER2 negative disease. The main explanation is that ovarian cancer risk is higher for BRCA1 carriers than BRCA2 carriers and BRCA2 carriers have a risk of ovarian cancer at an older age as compared to BRCA1 carriers. So the patients we included were very young so the follow-up was 18 years but still not probably enough to see ovarian cancer events in the BRCA2 cohort. So that’s why probably the benefit is most observed in the BRCA1 cohort. For the tumour subtype this is probably related to the different distribution of subtypes in the BRCA1 and BRCA2 population, with BRCA1 mostly affected by triple negative disease and BRCA2 mostly by ER positive HER2 negative disease.
The final point on the benefit of risk-reducing salpingo-oophorectomy in improving the disease free survival and breast cancer free interval with adjusted hazard ratios of 0.68 and 0.65 respectively. This is driven by both a reduction in the risk of developing a second primary breast cancer and a second primary ovarian cancer.
In the final analysis we looked into the independent effect of the two surgical procedures, both to see if the benefit was observed also for those patients that underwent one and not the other surgical procedure. For overall survival there was no interaction so the benefit of these two surgical procedures was independent. For disease free survival and breast cancer free interval we observed that the effect of risk-reducing salpingo-oophorectomy on these outcomes was more pronounced in patients who also underwent risk-reducing mastectomy because a second primary breast cancer counts as an event for disease free survival breast cancer free interval. So those patients that underwent also risk-reducing mastectomy had a further reduced risk of developing a second primary breast cancer.
What is the clinical significance of these results?
These results should be applied in the special patient population that we have included in the study, meaning young women with a diagnosis of breast cancer at the age of 40 or less and all known to carry a BRCA pathogenic or likely pathogenic variant, meaning that these results do not apply to BRCA healthy carriers or BRCA carriers with a first breast cancer diagnosed at an age older than 40. So in this special population what we have seen is a clear and strong value in terms of improving the outcomes of these patients for both surgical procedures, so both risk-reducing mastectomy as well as risk-reducing salpingo-oophorectomy. So I believe that the counselling of this patient population on these surgical procedures should be more enforced as compared to what we were used to doing, particularly for the risk-reducing mastectomy which is probably the most important news out of this study.
For the risk-reducing salpingo-oophorectomy I would stick to the guidelines. So the recommended age is 35-40 years for BRCA1 carriers, 40-45 for BRCA2 carriers with important fertility counselling because of all the reproductive implications of this surgical procedure. For the risk-reducing mastectomy, based on this data, it will be a bit more pushy into the counselling of undergoing this surgical procedure for these very young women at the time of diagnosis of their first breast cancer.
