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Genomic predictor of residual risk of recurrence after adjuvant chemotherapy and endocrine therapy in high risk estrogen receptor-positive breast cancers

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Abstract

A subset of early stage estrogen receptor (ER)-positive breast cancers considered “high risk” for recurrence with endocrine therapy alone by current genomic prognostic predictors, such as Oncotype DX, is no longer high risk after receiving adjuvant chemotherapy. We hypothesized that a recently described gene expression-based outcome predictor adjuvant chemotherapy and endocrine therapy sensitivity (ACES) could re-stratify these patients into high and low risk groups for relapse when treated with both chemo- and endocrine therapies. ACES involves four separate modules (endocrine sensitivity, chemotherapy sensitivity, chemotherapy resistance, and survival prediction) that yield a prediction for good or poor outcome with current standard of care multimodality therapy. ACES was applied to Affymetrix gene expression data from 2 retrospectively collected ER-positive and HER2-negative patient cohorts that were uniformly treated with adjuvant endocrine and chemotherapy (n = 250). Each sample was first risk stratified by a genomic surrogate of Oncotype DX, and the high risk patients (n = 76) were re-stratified by ACES. Recurrence-free survival (RFS) was evaluated with ACES risk categories. The Oncotype DX high risk but ACES good prognosis patients (n = 24, 32 %) had an RFS of 95 % compared to 76 % in the poor prognosis group (n = 52; log-rank p = 0.033) at 5 years. ACES risk category remained an independent predictor in multivariate analysis after adjusting for age, T-stage, and lymph node involvement at diagnosis (hazard ratio 0.15; p = 0.072). Tertiary risk prediction that takes into account chemotherapy and endocrine sensitivity, and baseline prognosis may help identify high risk ER-positive patients who have excellent survival after chemotherapy.

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Fig. 1
Fig. 2

Abbreviations

ACES:

Adjuvant chemotherapy and endocrine sensitivity

ARR:

Absolute risk reduction

DLR:

Diagnostic likelihood ratio

ER:

Estrogen receptor

GGI:

Genomic grade index

HR:

Hazard ratio

NPV:

Negative predictive value

OR:

Odds ratio

PAM50:

Prediction analysis of microarray 50-gene signature

pCR:

Pathologic complete response

PPV:

Positive predictive value

RCB:

Residual cancer burden

REMARK:

Reporting documentation for tumor marker prognostic studies

RFS:

Recurrence-free survival

RS:

Recurrence score

SET:

Sensitivity to endocrine therapy

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Acknowledgments

This research was supported by grants from the Breast Cancer Research Foundation (to LP), the H.W & J. Hector foundation (to TK), and the Lion Heart Foundation (to CH).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Yale University School of Medicine, New Haven, CT, USA

    Sabrina S. Khan, Lajos Pusztai & Christos Hatzis

  2. Goethe University, Frankfurt, Germany

    Thomas Karn, Uwe Holtrich & Sven Becker

  3. MD Anderson Cancer Center, Houston, TX, USA

    W. Fraser Symmans

  4. Yale Cancer Center, 333 Cedar St, PO Box 208032, New Haven, CT, 05620, USA

    Lajos Pusztai & Christos Hatzis

  5. University Hospital Lübeck, Lübeck, Germany

    Achim Rody

  6. University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Volkmar Müller

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  1. Sabrina S. Khan
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  2. Thomas Karn
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  3. W. Fraser Symmans
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Correspondence to Christos Hatzis.

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Khan, S.S., Karn, T., Symmans, W.F. et al. Genomic predictor of residual risk of recurrence after adjuvant chemotherapy and endocrine therapy in high risk estrogen receptor-positive breast cancers. Breast Cancer Res Treat 149, 789–797 (2015). https://doi.org/10.1007/s10549-015-3277-7

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