Multifocal breast cancers are more prevalent in BRCA2 versus BRCA1 mutation carriers

Abstract

Multifocal (MF)/multicentric (MC) breast cancer is generally considered to be where two or more breast tumours are present within the same breast, and is seen in~10% of breast cancer cases. This study investigates the prevalence of multifocality/multicentricity in a cohort of BRCA1/2 mutation carriers with breast cancer from Northern Ireland via cross-sectional analysis. Data from 211 women with BRCA1/2 mutations (BRCA1-91, BRCA2-120) and breast cancer were collected including age, tumour focality, size, type, grade and receptor profile. The prevalence of multifocality/ multicentricity within this group was 25% but, within subgroups, prevalence amongst BRCA2 carriers was more than double that of BRCA1 carriers (p = 0.001). Women affected by MF/MC tumours had proportionately higher oestrogen receptor positivity (p = 0.001) and lower triple negativity (p = 0.004). These observations are likely to be driven by the higher BRCA2 mutation prevalence observed within this cohort. The odds of a BRCA2 carrier developing MF/MC cancer were almost four-fold higher than a BRCA1 carrier (odds ratio: 3.71, CI: 1.77-7.78, p = 0.001). These findings were subsequently validated in a second, large independent cohort of patients with BRCA-associated breast cancers from a UK-wide multicentre study. This confirmed a significantly higher prevalence of MF/MC tumours amongst BRCA2 mutation carriers compared with BRCA1 mutation carriers. This has important implications for clinicians involved in the treatment of BRCA2-associated breast cancer, both in the diagnostic process, in ensuring that tumour focality is adequately assessed to facilitate treatment decision-making, and for breast surgeons, particularly if breast conserving surgery is being considered as a treatment option for these patients.No conflicts of interest were declared.

Multifocality, Multicentricity, and Bilaterality of Breast Cancer

“…A lower incidence of metachronous bilateral breast cancer was observed, likely due to the introduction of systemic adjuvant therapy. In the study on incidence of bilateral breast cancers in Sweden, conducted by Hartman and co-authors reported that the incidence of BSBC was approximately 100 times greater than what can be explained as coincidence or a cumulative effect of exogenous carcinogens [22], Women with MF/MC breast cancers are often of younger age at the time of diagnosis and with positive oestrogen (ER) receptors expression than women with a unifocal condition [50]. Patients with MF/MC tumours are prevalently premenopausal and with a lower body mass index [51].…”

“…Family history of breast carcinoma, younger age at the time of initial diagnosis, or mutation of BRCA1 and BRCA2 genes are linked to a higher risk of developing contralateral tumours, placing them in the higher risk group [45]. Higher prevalence of multifocality/multicentricity than expected occurs in women diagnosed with cancer who are BRCA2 mutation carriers [50].…”

“…Many authors continue to support breast-conserving surgery for MC/MF tumours [96]. Furthermore, when breast-conserving surgery is proposed as a treatment option for patients who carry BRCA2 mutations and have ER positive receptor status, the surgeons should bear in mind the increased incidence of multifocality and plan the surgical procedure accordingly, ensure that the complete excision is performed in one procedure, as well as minimise the consequences related to repeated surgery due to marginal involvement [50]. Oncoplastic surgery enables a more precise resection of the tumour mass and free resection margin as compared to standard quadrantectomy or lumpectomy [97].…”

“…Certain data supports the claim that multifocality/multicentricity is not an independent prognostic factor for BC. Although it is suggested that MF/MC can predict the outcome, it is a fact that the size of the tumour bears greater significance in these patients, rather than the presence of multifocality/multicentricity itself [50]. There is controversy in the literature relating to MF/MC prognosis.…”

Regulation of breast cancer oncogenesis by the cell of origin’s differentiation state

“…Human breast cancers which arise from the effects of exogenous estrogen from hormone replacement therapy are also largely solitary. Even in the setting of inherited germline mutated BRCA1 or BRCA2, which is present in all the cells of the breast, only solitary cancers or multifocal cancers limited to 2 or 3 foci at most arise [7][8][9]. Attempts to explain the rareness of breast cancer at a cellular level have invoked the multi-hit theory of carcinogenesis, which basically opines that breast cancers do not occur unless there has been an accumulation of all of the necessary hits within the cell of origin [10,11].…”