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Open Access 01-12-2017 | Research article

AKT1^low quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer

Authors: Sheheryar Kabraji, Xavier Solé, Ying Huang, Clyde Bango, Michaela Bowden, Aditya Bardia, Dennis Sgroi, Massimo Loda, Sridhar Ramaswamy

Published in: Breast Cancer Research | Issue 1/2017

Abstract

Background

Absence of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) correlates with poor long-term survival in patients with triple negative breast cancer (TNBC). These incomplete treatment responses are likely determined by mechanisms that enable cancer cells to resist being killed. However, the detailed characterization of a drug-resistant cancer cell state in residual TNBC tissue after NACT has remained elusive. AKT1^low quiescent cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy-resistant subpopulation initially identified in experimental cancer models. Here, we asked whether QCCs exist in primary tumors from patients with TNBC and persist after treatment with NACT.

Methods

We obtained pre-treatment biopsy, post-treatment mastectomy, and metastatic specimens from a retrospective cohort of TNBC patients treated with NACT at Massachusetts General Hospital (n = 25). Using quantitative automated immunofluorescence microscopy, QCCs were identified as AKT^low/H3K9me2^low/HES1^high cancer cells using prespecified immunofluorescence intensity thresholds. QCCs were represented in 2D and 3D digital tumor maps and QCC percentage (QCC-P) and QCC cluster index (QCC-CI) were determined for each sample.

Results

We showed that QCCs exist as non-random and heterogeneously distributed clusters within primary breast tumors. In addition, these QCC clusters persist after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors and nodal and distant metastases in patients with triple negative breast cancer.

Conclusions

These first-in-human data potentially qualify AKT1^low quiescent cancer cells as a non-genetic cell state that persists after neoadjuvant chemotherapy in triple negative breast cancer patients and warrants further study.

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Title: AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer
Authors: Sheheryar Kabraji
Xavier Solé
Ying Huang
Clyde Bango
Michaela Bowden
Aditya Bardia
Dennis Sgroi
Massimo Loda
Sridhar Ramaswamy
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-017-0877-7

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