Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657)

Abstract

Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with ≥ 3 cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group.

Fig. 1

CONSORT diagram: patients available for analysis. Of the 237 patients enrolled in the study, 16 patients withdrew. Of the 221 patients available for analysis, six decided not to undergo surgery after completing neoadjuvant chemotherapy, leaving 215 patients available for pathologic response analysis

Fig. 2

Stratification, by molecular classifier, of the hormone receptor positive HER2 negative subgroup that did not achieve a pathologic complete response. The patients in the HR+/HER2− subgroup that did not achieve a pathologic complete response are stratified by the molecular subtypes as shown: a 70-gene prognosis profile (Blue line low risk/gold line high risk); b wound healing signature (Blue line quiescent; gold line activated); c risk of relapse subtype score (ROR-S) (Blue line low risk/Gold line medium and high risk); d p53 predicted mutation (Blue line predicted wild type/Gold line predicted mutation); e clinical stage (Blue line clinical stage 2/Gold line clinical stage 3). Stratification of the “no pCR” HR+/HER2− patient group by molecular signatures and clinical stage

Fig. 3

Heat map by molecular features and outcomes for all patients