Abstract P2-12-01: BRCA1 and BRCA2 in multifocal cancers: Results from the POSH study
Authors: Eccles BK , Maishman T , Copson E , Stanton L , Eccles DM 
Published: August 2014

Background:

Multifocal (MF) breast cancers are more common in pre and perimenopausal women and in estrogen receptor (ER) positive disease. Young onset breast cancer and a positive family history of breast/ovarian cancer are characteristic of BRCA1 and BRCA2 carriers, but tumour receptor status and other pathological features may also be helpful in identifying BRCA gene carriers, particularly where family history is negative or unknown. Multifocal cancer may either be clonal in origin or unrelated multiple primaries (multicentric) and in a patient with a strong genetic predisposition the latter might be expected due to a field change effect. There are few data on whether multifocality is a predictor of an underlying BRCA 1 or BRCA2 mutation. A mutation frequency of 18% (combined BRCA1 and 2) in 61 multifocal cancers has been previously reported.

We sought evidence of an association between multifocality and BRCA carrier status in young women both with and without a relevant cancer family history.

Methods:

POSH, the UK population based cohort study recruited breast cancer patients aged ≤40 at diagnosis. Family history data were collected by patient questionnaire (positive family history defined as any number of first or second degree relatives diagnosed with breast or ovarian cancer). Genetic testing occurred either as part of clinical breast cancer management or the research study.

Results:

MF cancer was present in 797 of 2956 patients (27.0%) of the whole POSH cohort, more frequent in ER positive (34.9%) than ER negative (19.9%) cancers (p&lt;0.001). Genetic testing results are available for 760 patients of whom 196 had MF disease; the majority of those tested had a positive family history (57.4%). For those with genetic testing results there was no significant difference in ER, Her2, PR, high grade or multifocal tumours between patients with or without a family history. In total 214/760 patients had a pathogenic BRCA mutation (136 BRCA1, 78 BRCA2). In patients with MF disease a BRCA2 mutation was more likely than a BRCA 1 mutation (68.8% vs 36.2%, p&lt;0.001).

Type of BRCA mutation with distribution of breast cancer by ER status Localised n = 150Multifocal n = 47Missing n = 17Total n = 214BRCA1110 (73.3%)17 (36.2%)9136 (63.6%)ER pos23 (20.9%)6 (35.3%)029 (21.3%)ER neg87 (79.1%)11 (64.7%)9107 (78.7%)BRCA240 (26.7%)30 (68.8%)878 (36.4%)ER pos33 (82.5%)27 (90.0%)666 (84.6%)ER neg7 (17.5%)3 (10.0%)212 (15.4%)

Conclusions:

Multifocal disease is associated with an increased probability of BRCA2 mutations in our data and may be an indicator of BRCA2 genetic status. The ratio of multifocal to unifocal disease in BRCA1, BRCA2 carriers and non BRCA1/2 cases was highest in BRCA2 cases for both ER positive and ER negative tumours. With the caveat of small numbers and incomplete testing of the cohort, there is some evidence pointing to BRCA2 causing a field effect rather than just as a function of predominantly ER positive cancers, and this characteristic may be useful in an algorithm to predict BRCA2 status incorporating further adjustment for other potential confounders. We plan to conduct further genetic testing across the whole cohort to refine the algorithm and to confirm the observed multifocal/BRCA2 association.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-12-01.