Abstract P3-07-26: Biomarker comparison between androgen receptor – Positive-triple-negative breast cancer (AR+ TNBC) and quadruple-negative breast cancer (QNBC)
Authors: Xiu J , Obeid E , Gatalica Z , Reddy S , Goldstein LJ , Link J , Waisman J 
Published: May 2016

Background: Quadruple-negative breast cancer (QNBC) is a subgroup of triple-negative breast cancer (TNBC) that lacks androgen receptor (AR) expression. While TNBC patients with AR expression have shown a promising response to AR-targeted therapies, QNBC patients' treatment options remain limited, with no targeted therapy We investigated the biomarker profiles of large cohorts of AR+TNBC and QNBC to identify their molecular differences.

Method: TNBC tumors (defined as negative by IHC for ER, PR, Her2 and ISH for Her2) referred to Caris Life Sciences (Phoenix, AZ) between 2009 and 2015 were evaluated by board-certified pathologists with a combination of immunohistochemistry (AR, cKIT, cMET, EGFR, ER, ERCC1, Her2, MGMT, PD-1, PD-L1, PGP, PR, PTEN, RRM1, SPARC, TLE3, TOPO2A, TOPO1, TS and TUBB3), fluorescent/chromogenic in-situ hybridization (cMET, EGFR, Her2, TOP2A), and sequencing (Next-generation and Sanger). Tumors evaluated included a mix of primary tumors and metastases. QNBC tumors were defined as TNBC tumors that showed negative AR expression (&lt;10% of cells staining).

Results: Among 2,071 TNBC tumors identified, 1,952 tumors had AR IHC performed, out of which 1,612 (83%) were QNBC and 340 (17%) were AR+ TNBC tumors. Tumor expression of PD-L1 (Ab: SP142, Spring Bioscience/130021, R&D Systems, cutoff used: 2+, 5%) was significantly higher in QNBC compared to AR+TNBC tumors (18% vs. 8%, p=0.01), while PD-1 (Ab: NAT105, Ventana) expression on tumor-infiltrating lymphocytes was comparable between the two cohorts (60% vs. 62%). QNBC tumors were significantly more likely to express proteins of cKIT (26% vs. 15%, p=0.01), EGFR (69% vs. 56%, p=0.03), TS (49% vs. 33%, p&lt;0.0001) and TOPO2A (85% vs. 65%, p&lt;0.0001) compared to AR+TNBC. TLE3 expression was significantly higher in AR+TNBC cohorts (48% vs. 32%, p&lt;0.0001). Sequencing reveals that QNBC tumors carried significantly higher mutation rate of TP53 (71% vs. 55%, p&lt;0.0001) while AR+TNBC tumors showed significantly higher mutation rates of PIK3CA (42% vs. 12%, p&lt;0.0001), AKT1 (13% vs. 1%, p&lt;0.0001) as well as ERBB2 (5% vs. 1%, p=0.0003).

Conclusion:

Biomarker comparisons between two molecular subgroups of the TNBC tumors confirm the molecular heterogeneity of this aggressive type of breast cancer. Our biomarker results suggests that for AR+TNBC tumors, future clinical trial design can consider fluoropyrimidines, taxanes, and agents targeting PI3K/AKT/mTOR pathway as well as pan-HER inhibitors, and those agents may be combined with anti-androgen therapies. On the other hand, clinical trials for immune checkpoint inhibitors, TOP2A inhibitors, as well as agents that target cKIT and EGFR should be considered for QNBC tumors. Our findings highlight the molecular differences that should be considered in the design of future clinical trial strategies, warranting further investigation for improving targeted therapy and outcomes in TNBC.

Citation Format: Xiu J, Obeid E, Gatalica Z, Reddy S, Goldstein LJ, Link J, Waisman J. Biomarker comparison between androgen receptor – Positive-triple-negative breast cancer (AR+ TNBC) and quadruple-negative breast cancer (QNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-26.