DCIS in BRCA1 and BRCA2 mutation carriers: prevalence, phenotype, and expression of oncodrivers C-MET and HER3.
BACKGROUND
Studies report conflicting evidence regarding the existence of a DCIS-associated premalignant pathway in BRCA mutation carriers. We aimed to examine the prevalence, phenotype, and expression of oncodrivers in pure DCIS (pDCIS) and invasive breast cancer with concurrent DCIS (IBC + DCIS) in mutation carriers.


METHODS
A cohort of BRCA1 and BRCA2 mutation carriers >18 years old who underwent surgery for breast cancer at an academic hospital (1992-2011) and had pathology available for review were included for study. Invasive breast cancer (IBC) and DCIS were stained for ER, PR, HER1, HER2, and HER3, and C-MET. DCIS prevalence was evaluated. Correlation of IBC and DCIS phenotypes was evaluated in patients with IBC + DCIS. DCIS and IBC expression of tumor markers were examined by BRCA mutation.


RESULTS
We identified 114 breast tumors. Of all BRCA1-associated tumors, 21.1 % were pDCIS and 63.4 % were IBC + DCIS. Of all BRCA2-associated tumors, 23.3 % were pDCIS and 60.5 % were IBC + DCIS. In BRCA1 and BRCA2 mutation carriers with IBC + DCIS, there was a significant correlation in ER, PR, and HER3 expression between the DCIS and IBC components. Most BRCA1-associated DCIS did not express ER, PR or HER2, while most BRCA2-associated DCIS did express ER and PR. BRCA1- as well as BRCA2-associated DCIS had expression of HER3 and C-MET.


CONCLUSIONS
The majority of BRCA-associated tumors had DCIS present. Concordance of DCIS and IBC phenotypes was high, arguing for the existence of a DCIS-associated premalignant pathway. Oncodrivers HER3 and C-MET were expressed in the DCIS of mutation carriers, suggesting an opportunity for prevention strategies.
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rlyang@stanford.edu.
Rachel L
RL
Yang
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rmick@mail.med.upenn.edu.
Rosemarie
R
Mick
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Kathreen.Lee@uphs.upenn.edu.
Kathreen
K
Lee
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. holly.graves@uphs.upenn.edu.
Holly L
HL
Graves
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. knathans@exchange.upenn.edu.
Katherine L
KL
Nathanson
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. susan.domchek@uphs.upenn.edu.
Susan M
SM
Domchek
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. rachel.kelz@uphs.upenn.edu.
Rachel R
RR
Kelz
Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. pjz@mail.med.upenn.edu.
Paul J
PJ
Zhang
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. brian.Czerniecki@uphs.upenn.edu.|Abramson Cancer Center, 3rd Floor West 3400 Civic Center, Boulevard, Philadelphia, PA, 19104, USA. brian.Czerniecki@uphs.upenn.edu.
Brian J
BJ
Czerniecki
D001943:Breast Neoplasms / Q000235:genetics*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006580:Genetic Carrier Screening; D006801:Humans; D009154:Mutation; D010641:Phenotype; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000235:genetics*
C581292:ERBB3 protein, human; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3