A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer

Abstract

Context: Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies.

Objective: To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer.

Design, setting, and patients: Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response.

Main outcome measures: Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years).

Results: Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy.

Conclusion: A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.

Conflict of interest statement

The authors have the following potential conflicts of interest to disclose:

Hatzis: Employment (Nuvera Biosciences), Equity (Nuvera Biosciences), Patents

Pusztai: Unpaid scientific advisor (Nuvera Biosciences, uncompensated), Patents

Valero: None

Booser: None

Esserman: None

Lluch: None

Vidaurre: None

Holmes: Honoraria (Novartis, Genentech, Philips) with relevance outside the submitted work

Souchon: None

Martin: None

Cotrina: None

Gomez: Honoraria (Glaxo Smith Kline, Bristol Meyers Squibb) with relevance outside the submitted work

Hubbard: None

Chacón: None

Ferrer-Lozano: None

Dyer: None

Buxton: None

Gong: None

Wu: None

Ibrahim: None

Andreopoulou: None

Ueno: None

Hunt: None

Yang: None

Nazario: None

DeMichele: None

O’Shaughnessy: None

Hortobagyi: Paid consultant (Allergan, Genentech, Novartis, SanofiAventis), research funding (Novartis), with relevance outside the submitted work

Symmans: Unpaid scientific advisor (Nuvera Biosciences), Equity (Nuvera Biosciences), Patents, Honoraria (Agendia BV).

Figures

Figure 1

The decision algorithm that was used in the genomic test to predict a patient’s sensitivity to adjuvant chemotherapy or chemo-endocrine therapy from a biopsy of newly diagnosed invasive breast cancer. *, predicted sensitivity to endocrine therapy was defined as high or intermediate genomic sensitivity to endocrine therapy (SET) index; **, predicted resistance to chemotherapy was defined as predicted extensive residual cancer burden (RCB-III) or predicted distant relapse or death within 3 years of diagnosis; ***, predicted sensitivity to chemotherapy was defined as predicted pathologic complete response (pCR) or minimal residual cancer burden (RCB-I).,

Figure 2

Flow chart of biospecimen accrual and testing in the discovery cohort (A) and validation cohort (B).

Figure 3

Kaplan-Meier estimates of distant relapse-free survival according to genomic predictions (before treatment) as treatment-sensitive (Rx Sensitive) or treatment-insensitive (Rx Insensitive) in the discovery (A) and independent validation (B) cohorts. For comparison, the prognosis of the groups stratified by actual pathologic response (pathologic complete response vs residual disease) after completion of all chemotherapy is shown for the validation cohort (C). P-values are from the log-rank test.

Figure 4

Subset analysis of genomic predictions in the validation cohort: ER+/HER2− (A), ER−/HER2−(B), taxane chemotherapy administered as 12 cycles of weekly paclitaxel (C) or 4 cycles of 3-weekly docetaxel (D). P-values are from the log-rank test.

Figure 5

Kaplan-Meier estimates of distant relapse-free survival in the discovery cohort (A–D) and the independent validation cohort (E–H) of patients treated with sequential taxane-anthracycline chemotherapy, then endocrine therapy if hormone receptor-positive, stratified by other signatures reported to be predictive of response to neoadjuvant taxane-anthracycline chemotherapy., , A prognostic signature for genomic grade index predicts pathologic response if high GGI versus low GGI (A, E); the intrinsic subtype classifier predicts pathologic response if basal-like or luminal B versus other subtypes (B, F); a genomic predictor of pathologic complete response (pCR) versus residual disease following taxane-anthracycline chemotherapy (C, G); and the genomic predictor of excellent pathologic response (pCR or RCB-I) versus other residual disease, according to ER status, that we incorporated in the last step of our prediction algorithm (D, H)., , P-values are from the log-rank test.