644P BRCA2 Status and Intraductal [IDC] and Cribriform [CRIB] Histologic Variants: Partners in Prostate Cancer (PC)?

Small series have shown that IDC histology is more common in prostate tumors harboring germline mutations in BRCA2 (gBRCA2mut) and other DDR genes than in sporadic PC. If confirmed, it may lead to guide genetic testing for PC patients. We carried out a case-control study to examine the association of gBRCA2mut and/or IDC/CRIB. 174 primary prostate tumors were reviewed by two expert pathologists blinded to genetic status, including 58 gBRCA2mut and 116 non-carriers (NC) matched 1:2 by Gleason (<8 vs >8) and specimen type (biopsy/prostatectomy). Molecular characterization was performed: a)somatic mono/bi-allelic BRCA2 alterations by FISH, NGS and/or aCGH; b)PTEN expression by IHC; c)TMPRSS2-ERG by FISH/qRT-PCR. Chi-square test were used to compare IDC/CRB prevalence in gBRCA2mut vs NC. MVA was used to identify independent factors associated with IDC/CRIB and gBRCA2mut. gBRCA2mut carriers were slightly younger (median 61.3 vs 64, p = 0.004) and more frequently T3-4 stage than NC (31% vs 10.5%, p<0.001), but not significant (NS) differences were observed when other clinical-pathologic characteristics were included (PSAvalue, N+, M1 disease). 79 cases demonstrated IDC and 81 CRIB histology. There were NS differences in the prevalence of IDC (36% gBRCA2 vs 50% NC, p=0.09) or CRIB (53% gBRCA2 vs 43% NC, p=0.20). But IDC probability was higher in PC with bi-allelic BRCA2 alterations (OR 5.1, 95%CI 2.1-12.6), PTEN loss (OR 5.1, 95%CI 1.9-13.5) or both (OR 23.0, 95%CI 4.9-107.2).The independent association of bi-allelic BRCA2 alteration (p=0.031) and PTEN homozygous loss (p<0.001) with IDC was confirmed by MVA. Also bi-allelic BRCA2 alterations were associated with CRIB higher probability(OR 7.2, 95%CI 3.1-16.4). Bi-allelic BRCA2 (p<0.01) and Gleason >8 (p<0.01) were independent risk factors for CRIB, but there was NS association with PTEN loss and CRIB (p=0.265). TMPRSS2-ERG fusions were NS associated with IDC/CRIB. We found a significant correlation between IDC/CRIB and bi-allelic BRCA2 alterations in primary prostate tumors, independent of other clinical-pathologic factors (while gBRCA2 status alone was not). PTEN loss was also independently associated with IDC.