High risk of in-breast tumor recurrence after BRCA1/2-associated breast cancer

In this cohort study, we report that the risk of LR was substantially higher after BCT than after M for BRCA1/2 mutation carriers. The cumulative incidence of LR 15 years after BCT was 32 %, which was significantly higher than after M and is more than two-fold higher than after BCT in the general population, where most tumors are sporadic and the patients on average are older [19, 20]. Apart from type of surgery, younger age was also associated with an increased risk of LR. This can probably be explained by the fact that carriers who get breast cancer when they are very young are likely to have other predisposing or modifying factors of genetic or environmental nature, and thus an increased risk of new primary breast cancers [10, 15, 21].

Most of the case–control and cohort studies that have been conducted to compare the outcome of BCT between carriers and sporadic cases have reported point estimates of LR that have been higher for carriers, although the difference in the majority of the studies have not obtained a significant difference at p values <0.05, and it is therefore difficult to draw firm conclusions from them. The largest such study was reported by Pierce et al. in 2006 [12]. BRCA1/2 mutation carriers were matched with sporadic cases, all treated with BCT. The 15-year risk of LR was 24 % for carriers and 17 % for sporadic cases (p = 0.19). When patients that had done an oophorectomy were excluded from the analysis, carriers had an increased risk of LR (HR 1.9; p = 0.03). The same collaborative group published a different type of study in 2010, which is very similar to ours in study design and is the only previous study that has compared BCT and M for BRCA1/2 mutation carriers [13]. No difference in survival was seen between BCT and M, but patients treated with BCT had a higher risk of LR: the 15-year risk of LR was 23.5 versus 5.5 %. Interestingly, chemotherapy decreased the risk, so in the subgroup of BCT patients treated with chemotherapy, the risk of LR was only 11.9 % after 15 years; a level of risk comparable to what it is for sporadic cases and very relevant for counseling and treatment of carriers today, since a majority of them will receive chemotherapy if diagnosed with a breast cancer. With the limitations of a smaller number of patients and, therefore, no analyses of modifying factors conducted separately in the BCT subgroup, we also found a trend for a decreased risk of LR after use of chemotherapy.

Metcalfe et al. [11] reported data from a large cohort of carriers treated with partial mastectomy without any group for comparison and found the 15-year risk of LR to be 15.8 %. Use of chemotherapy, oophorectomy, and postoperative radiotherapy decreased the risk.

The age at diagnosis and uptake of oophorectomy was similar, but the proportion of patients that received chemotherapy was lower in our cohort than in the above-mentioned studies, which could partly explain the higher absolute risk of LR after BCT seen in our study. A study that reported a higher risk of LR after BCT than what we do, is a retrospective cohort study by Haffty et al., in which the cumulative risk of LR 12 years after BCT was 49 %. Of note, no mutation carriers in that cohort were treated with adjuvant endocrine therapy or oophorectomy, and the mean age at diagnosis was only 34 years [9].

In a recent meta-analysis by Valachis et al., no significant difference in LR after BCT was seen between BRCA1/2 mutation carriers and controls; however, a significant difference was observed when the analysis was restricted to studies with a median follow-up of ≥7 years [17].

A hypothesis that has been corroborated in a number of studies is that early LRs are true recurrences and that late LRs are in fact new primary breast cancers; the latter group probably accounts for the majority of LR [9, 13]. We point out that our cohort consists of mutation carriers ascertained through a cancer genetic center, and a majority of them belong to multiple-case families. Under a model where the risk of late LR is modified by genetic and environmental factors, this risk of LR is higher for these carriers than for carriers ascertained through population-based programs. The decreased risk of LR conferred by adjuvant therapy could be mediated not only through killing of breast cancer cells from the primary tumor, but also through an effect on breast cancer precursors and changes in the microenvironment of the breast, making new tumor formation less likely. The difference in the risk of LR between carriers and sporadic cases is less clear in studies where more adjuvant treatment has been used and a majority of the patients have done an oophorectomy, supporting the notion that these measures reduce the risk for new primary breast cancers in the ipsilateral, as well as the contralateral, breast.

Neither our cohort nor any of the other cohorts in published studies is large enough to properly adjust for all possible biases and confounders. Furthermore, in observational studies of surgical decisions, bias can never be fully accounted for.

In the general population, large randomized trials of breast cancer patients have not shown a difference in survival between BCT and M. Still, in the general population, patients that are diagnosed with a LR have an inferior survival compared to patients without a LR [22]. Despite the fact that some studies of BRCA1/2 mutation carriers have shown a very high risk of LR, no study to date has shown a difference in survival. This contradiction could possibly be explained by a larger proportion of new primary breast cancers among carriers, which are less aggressive than early true recurrences, and more often curable [13]. However, given large enough sample sizes and a cohort with a high rate of LR following BCT, a difference in long-term survival between BCT and M would be expected for carriers, since not all new primary breast cancers are curable.

Apart from the inability to make reliable survival comparisons, there are other limitations to our study. First, the follow-up is too short to estimate cumulative lifetime risks of LR, which has not been done in previous studies either. Second, a small number of patients result in point estimates with wide confidence intervals and the inability to include some potentially important variables in the multivariable models. Still, our study confirms some of the findings from the larger collaborative study by Pierce et al. Third, by including breast cancer patients from 1975 and onwards, the proportion of patients receiving adjuvant treatment is lower than what it is today, which can overestimate the risk of LR after BCT. Fourth, we were not able to separate true local recurrences from new primary breast cancers by means of pathology or localization in the breast.

The number of mutation carriers opting for M and BM has increased over the last decade, and the number opting for BCT has decreased [23]; the trend is expected to continue further with evidence of a survival benefit with BM now starting to emerge [5, 24, 25]. In the future, studies on the risk of LR after BCT in mutation carriers will therefore be harder to carry out and randomized trials are very unlikely. Still, there is a need for more studies, since BCT is considered an acceptable option for mutation carriers today. Data from retrospective studies can give relatively unbiased estimates of LR, but cannot properly measure psychosocial endpoints. In future studies, for an optimal generalizability to current standards, a very high proportion of patients treated with chemotherapy and prophylactic oophorectomy is needful. Furthermore, a long-term follow-up is demanded for estimation of cumulative lifetime risks of LR, which are pivotal for carriers with newly diagnosed breast cancer to know in order to make informed decisions about type of surgery.