To the best of our knowledge this is the largest high-risk population based study to date describing the genotypic, conventional clinicopathological and intrinsic phenotypic characteristics of MBCs arising within breast cancer families. Previous studies have either not contained large numbers of patients with a significant family history [30, 34, 35, 37, 43, 47], not commented or examined family history [6–8, 28, 29, 36, 39, 40], or have contained large numbers of such cases with strong family pedigree but not described clinicopathological features  (Table 4). As a large proportion of MBCs are purported to arise in families with breast cancer and in particular BRCA2 mutation carriers, further description of this cohort is of significance in understanding and characterising the disease.
The incidence of MBC in BRCA2, BRCA1 and BRCAX males is significantly higher than the lifetime cumulative incidence of 0.1% in the general population [17, 48] confirming this group as a high risk for MBC. However, the representation of carriers is different to that of familial FBC with direct comparison within the kConFab registry  showing an increased proportion of BRCA2 male carriers and underrepresentation of BRCA1 male tumours. This suggests that significant gender associated modifiers such as high estrogen levels may affect BRCA1 penetrance over BRCA2. Comparing studies of sporadic MBC [6–8, 28–32, 35, 37–40, 44], the median and mean age of onset in our patients is also younger, and this together with the observation of frequent multifocality or bilateral disease reflects the pattern of cancer often seen with underlying genetic predisposition as seen in familial FBC. A recent large population based study by Ottini et al.  containing 46 BRCA2 mutation carriers also observed a high rate (15.2%) of contralateral breast cancer in these carriers, thus supporting this observed pattern.
Compared with other MBC groups, our study appeared to have a higher proportion of high grade tumours with only 3.3% of tumours of BRE grade I, the lowest within any MBC cohort reported to date. We also reported the highest proportion of invasive papillary carcinomas with 6.7% of cases, the next highest in the literature being 5.5% by Ottini et al.. The histopathological tumour characteristics of our group otherwise is comparable to that seen in previous studies of sporadic MBC with the majority of cancers being invasive ductal carcinoma. This is higher than that seen in FBCs from kConFab . Unlike FBC, we also observed proportionately less lobular carcinoma which is thought to reflect paucity of lobular and acinar units in males .
We also report a relatively higher proportion of tumours with invasive micropapillary areas particularly within BRCA2-associated tumours, an association not previously reported. Recent studies suggest that these lesions are a distinct entity with more aggressive behaviour than IDC-NST . The distinct histological features of these tumours correlate with distinct molecular genetic profiles , however, in female cancer a correlation with BRCA2 mutation has not been described or suggested . Ottini et al, also describe a BRCA2 MBC phenotype with a high proportion of BRE grade 3 tumours (54.8%), loss of PgR expression (67.9%) and HER2 amplification (63.2%). Similar to them, our BRCA2 carriers contained a large proportion of BRE grade 3 but was not significantly different to the BRCA1 and BRCAX population. The expression of ER and PgR in our familial MBCs is similar to that seen in sporadic MBC, with proportionately higher levels than seen in FBC, and absence of PgR expression did not discriminate a BRCA2 phenotype. Subsequently, the majority of our cases were also of the luminal subtype. Reported HER2 amplification in MBC has been more variable than ER and PgR with studies demonstrating between 3.3%  to 28.4%  of cases showing HER2 amplification. While our study and Ottini are the only to date to examine the association with BRCA status, using routine diagnostic testing for HER2 we see lower frequency of HER2 amplification both overall (9.1%) and within our BRCA2 carriers (8.3%) as a subgroup. Our results are consistent with most MBC studies that suggest HER2 amplification is seen half as frequently as that in FBC .
The few numbers of BRCA1 MBCs in our cohort precludes extensive clinicopathological analysis, however, in contrast and unlike tumours seen in BRCA1 female carriers [27, 51], cancers of medullary/basal cell phenotype in BRCA1 males has not been reported in the literature and was also not observed in our cohort of BRCA1 males. The paucity of tumours of basal phenotype in our cohort overall also reflected observations of other MBC studies.
Several prognostic markers in our study are also reported in both FBC and sporadic MBC. In our study, we confirmed many but also identified PNI as being of prognostic significance, which has not been reported previously in MBC. Its presence, being double most rates reported in FBC [52, 53], may be due to frequent subareolar tumour location which is less frequently seen in women, and comparable to frequent perineural involvement seen in other epithelial tumours such as pancreatic  and prostatic  adenocarcinoma where the organs have closer proximity to nerve bundles. While mixed prognostic significance of PNI has been seen in FBC studies , PNI positive tumours have been shown to be more often associated with positive nodal status and hormonal positivity , both of which are more commonly seen in MBC in general, and in our study cohort when compared with FBC.
While our numbers are not large, a considerable proportion (16.6%) of the BRCA2 and BRCAX patients developed a second non-breast primary malignancy. The onset or histological type of these tumours did not correlate with mutation carrier status. These findings are consistent with those previously reported in MBC cohorts where the range of second cancer incidence varies between 5.9% to 22.8% when reported [8, 28, 30, 31, 34, 35]. Notably, the studies with higher rates of breast cancer families such as Ding  (60% either BRCA2 pathogenic mutation carrier or strong family history of breast cancer), Liukkonen (33.1% with significant familial history) and Kiluk  (29% with significant familial history) had 22.8%, 19% and 19.4% of their patients reporting a second primary respectively. Of the types reported, prostate cancer was the most common followed by bladder cancer, a tumour type not seen in our cohort. In recent studies we and others have demonstrated the relative risk for developing prostate cancer in male BRCA2 mutation carriers as between 2.9 to 4.8 times the general population [56–59]. Comparing our study with the age related rate of Australian males in the 60–64 year age group, there is an increased relative risk of prostate cancer of 19.08 (p<0.0001, 95%CI 4.50-80.91) and 20.56 (p<0.0001, 95%CI 6.30-67.12) times the normal population for BRCA2 and BRCAX male patients with breast cancer respectively. These data show that patients with MBC may be a high-risk group for developing second malignancies, even when comparing with BRCA2 carriers without MBC. Whether this is due to hormonal influence driving both tumour types or underlying genetic factors requires further study in a larger data set.