Abstract P2-03-05: The heterogeneous clinical behavior of luminal breast cancers is associated with different mutational landscapes
Authors: Bianchini Giampaolo , Galeota Eugenia , Jiang Tingting , Callari Maurizio , Zambetti Milvia , Iwamoto Takayuki , Karn Thomas , Hatzis Christos , Pusztai Lajos , Gianni Luca 
Published: May 2015

Background: Genomic studies in estrogen-receptor (ER) positive breast cancer showed few commonly mutated genes and suggested that tumors with higher background of mutation rate were enriched in intrinsic aromatase-inhibitor-resistant tumors (Ellis MJ Nature 2012). Different combinations of proliferation (PROL) and estrogen-receptor related genes (ERS) allow the prediction of the risk of recurrence and endocrine treatment sensitivity (Bianchini G Breast Cancer Res 2013). The highPROL/lowERS is enriched in intrinsic endocrine resistant tumors. We explored whether different genomic alterations could contribute to the different clinical behavior of groups defined by PROL and ERS.

Method: We defined luminal breast cancers by PAM50 and retrieved gene expression and whole-exome sequencing data of 324 luminal breast cancer cases from the Cancer Genome Atlas (TCGA). PROL and ERS were calculated as previously reported. Low and high expression groups were defined by median cut-points (Bianchini G Breast Cancer Res 2013). As a metric of the background mutation rate of each sample, we used the overall mutation frequency in whole exome (Kandoth C Nature 2013). The most frequently mutated genes (TP53, PIK3CA, MAP2K4, MAP3K1, GATA3, CDH1) were also assessed for their association with PROL and ERS defined groups.

Results: The average number of mutations (Nmut) was 44.4 (5-366). High and low proliferation groups had different mutation frequency (average Nmut 53.6 and 35.3, respectively; p=6.1E-06). LowERS group also had a higher Nmut (average Nmut 54.4 vs. 34.5 in high ERS; p=1.2E-06). Notably, neither high or low expression of the ER gene (p=0.89), nor positive and negative progesterone receptor by immunohistochemistry (p=0.69) were associated with Nmut. LowERS group was associated with higher Nmut in luminal A (p=0.005) and B (p=0.006) subtypes. The group with highPROL and lowERS had the highest Nmut (average 62.1), which was not significantly different from basal-like tumors. HighPROL/lowERS was significantly associated with higher frequency of mutTP53 (32.3%) and lower rates of mutPIK3CA (28.1%), mutMAP2K4 and/or mutMAP3K1 (7.2%) and mutCHD1 (3.1%). The lowPROL/highERS had the lowest Nmut (average 29.8), with the higher rate of mutPIK3CA (61.4%) and mutMAP2K4 and/or mutMAP3K1 (29.2%), and lower rate of mutTP53 (6.7%).

Discussion: In ER-positive breast cancers, the highPROL/lowERS group, which is characterized by the highest risk of early recurrences despite endocrine treatment and chemotherapy, poor down-regulation of Ki67 after neoadjuvant aromatase-inhibitor (AI), but the highest rate of pCR after neoadjuvant chemotherapy, was also associated with the highest frequency of mutations, of the same order of magnitude of basal-like tumors. This data is in line with the observation that the number of mutations is linked to intrinsic resistance to neoadjuvant AIs (Ellis MJ Nature 2012). These data could be also informative for interpreting results of the combination of everolimus and endocrine therapy (exemestane or tamoxifen) that suggest higher efficacy in tumors with acquired endocrine resistance (lower mutation rate) compared to intrinsic or primary endocrine resistance (higher mutation rate).

Citation Format: Giampaolo Bianchini, Eugenia Galeota, Tingting Jiang, Maurizio Callari, Milvia Zambetti, Takayuki Iwamoto, Thomas Karn, Christos Hatzis, Lajos Pusztai, Luca Gianni. The heterogeneous clinical behavior of luminal breast cancers is associated with different mutational landscapes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-03-05.