Format

Send to

Choose Destination
See comment in PubMed Commons below
Breast Cancer Res. 2017 Aug 1;19(1):88. doi: 10.1186/s13058-017-0877-7.

AKT1low quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer.

Author information

1
Massachusetts General Hospital Cancer Center, Richard B. Simches Research Building, 185 Cambridge Street, Boston, MA, 02114, USA.
2
Harvard Medical School, Boston, MA, USA.
3
Present address: Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, Barcelona, Spain.
4
Dana-Farber Cancer Institute, Boston, MA, USA.
5
Massachusetts General Hospital Cancer Center, Richard B. Simches Research Building, 185 Cambridge Street, Boston, MA, 02114, USA. sridhar@mgh.harvard.edu.
6
Harvard Medical School, Boston, MA, USA. sridhar@mgh.harvard.edu.
7
Broad Institute of Harvard & MIT, Cambridge, MA, USA. sridhar@mgh.harvard.edu.
8
Harvard Stem Cell Institute, Cambridge, MA, USA. sridhar@mgh.harvard.edu.
9
Harvard-Ludwig Center for Cancer Research, Boston, MA, USA. sridhar@mgh.harvard.edu.

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. AKT1low 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 AKTlow/H3K9me2low/HES1high 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 AKT1low quiescent cancer cells as a non-genetic cell state that persists after neoadjuvant chemotherapy in triple negative breast cancer patients and warrants further study.

KEYWORDS:

AKT1low quiescent cancer cells; Chemotherapy resistance; Quantitative immunofluorescence microscopy

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for BioMed Central Icon for PubMed Central
    Loading ...
    Support Center