47P - Defining prognostic and therapeutic selective classes of TNBC

Date 07 May 2015
Event IMPAKT 2015
Session Welcome reception and Poster Walk
Topics Breast Cancer
Translational Research
Presenter Erik Knudsen
Citation Annals of Oncology (2015) 26 (suppl_3): 15-24. 10.1093/annonc/mdv117
Authors E. Knudsen, J. Franco, U. Balaji, A.K. Witkiewicz
  • Pathology, University of Texas Southwestern Medical Center at Dallas, 75390 - Dallas/US

Abstract

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Purpose: Triple negative breast cancer (TNBC) is a heterogeneous disease for which more targeted interventions are needed. Here we employed an integrated combination of biomarker analyses and targeted drug screening to define actionable subtypes of TNBC.

Methods: A cohort of 218 TNBC cases annotated for survival were analyzed for the expression of multiple markers by immunohistochemistry (IHC). Markers included were associated with immune function (e.g. CD163), cell cycle (e.g. RB), and defined subtypes (e.g. vimentin and AR). Affinity propogation clustering and random forest approaches defined specific subtypes of TNBC that were highly enriched for prognosis. Models that mimicked these subtypes were evaluated for sensitivity to established cancer drugs using high-throughput approaches and in selected combinations based on marker profile.

Results: Using unsupervised methods, IHC defined classes of TNBC with particularly preferable and poor prognosis that remained significant in multivariate analysis. For example, tumors with combined loss of RB and PTEN had a 5-year survival of >85% (p < 0.01), while mesenchymal tumors with expression of vimentin exhibited a 5-year survival of <25% (p < 0.005). Two exclusive classes of TNBC (RB-negative and AR-positive) that represent ∼50% of cases were evaluated for therapeutic sensitivities. RNA sequencing of clinical cases demonstrated that tumors deficient in RB express high levels of genes activating CDK5, PLK1, AURK, CHK kinases. Concordantly, RB-deficient tumor models are selectively sensitive to agents targeting these kinases. In contrast, AR positive tumors retain RB and exhibit low proliferation index in clinical cases. TNBC models of AR positive disease were particularly sensitive to CDK4/6 inhibitors alone and in combination with AR-antagonists.

Conclusions: These data indicate that with a limited collection of markers that it is possible to delineate prognostic subtypes of TNBC. Within TNBC cases, select classes of tumors have distinct vulnerabilities that can be targeted therapeutically.

Disclosure: All authors have declared no conflicts of interest.