Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets

Justin M. Balko, Jennifer M. Giltnane, Kai Wang, Luis J. Schwarz, Christian D. Young, Rebecca S. Cook, Phillip Owens, Melinda E. Sanders, Maria G. Kuba, Violeta Sánchez, Richard Kurupi, Preston D. Moore, Joseph A. Pinto, Franco D. Doimi, Henry Gómez, Dai Horiuchi, Andrei Goga, Brian D. Lehmann, Joshua A. Bauer, Jennifer A. PietenpolJeffrey S. Ross, Gary A. Palmer, Roman Yelensky, Maureen Cronin, Vincent A. Miller, Phillip J. Stephens, Carlos L. Arteaga

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206 Scopus citations

Abstract

Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defined TNBCs after NAC, including nextgeneration sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micrometastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC.

Original languageEnglish (US)
Pages (from-to)232-245
Number of pages14
JournalCancer discovery
Volume4
Issue number2
DOIs
StatePublished - Feb 1 2014

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ASJC Scopus subject areas

  • Oncology

Cite this

Balko, J. M., Giltnane, J. M., Wang, K., Schwarz, L. J., Young, C. D., Cook, R. S., Owens, P., Sanders, M. E., Kuba, M. G., Sánchez, V., Kurupi, R., Moore, P. D., Pinto, J. A., Doimi, F. D., Gómez, H., Horiuchi, D., Goga, A., Lehmann, B. D., Bauer, J. A., ... Arteaga, C. L. (2014). Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer discovery, 4(2), 232-245. https://doi.org/10.1158/2159-8290.CD-13-0286