Breast Cancer Molecular Subtypes Predict Response to Anthracycline/Taxane-Based Chemotherapy.

Abstract

Background: Classifying breast cancer into molecular subtypes (Luminal A/B, Her2-enriched, and Basal-like) has proven to be biologically and clinically informative. Recently, we developed a gene expression based protocol (PAM50) that provides reliable subtype classification as well as independent prognostic utility (Parker et al, J Clin Oncol 2009). In this study, we evaluated the ability of the PAM50 subtypes to predict pathological complete response (pCR) to anthracycline/taxane-based chemotherapy in the neoadjuvant setting.Methods: Gene expression data were combined from three independent neoadjuvant studies totaling 361 subjects. Complete clinical data (hormone receptor levels, tumor size, node status, and grade) were available for 186 subjects. The I-SPY cohort (n=129; fresh-frozen, Agilent) was treated with doxorubicin/cyclophosphamide (ACx4) followed by paclitaxel (Tx4). The NSABP B-27 cohort (n=103; FFPE, Affymetrix) was treated with ACx4 followed by docetaxel (4 cycles). The third cohort from MD Anderson Cancer Center (MDACC) (n=129; fresh-frozen tissue, Affymetrix) was treated with paclitaxel/T followed by sequential fluorouracil-AC (FAC). Subtype assignments and prognosis scores were generated as previously described (Parker et al., 2009). Univariate and multivariate testing for pCR was performed with Fisher's exact test and logistic regression. Statistical learning methods were also implemented in order to identify an improved predictor of pCR.Results: There was no difference between the cohorts/studies with respect to estrogen receptor (ER) status (p=0.23), subtype distribution (p=0.77), or pCR rate (p=0.95). ER, PR, HER2, grade, node status, and subtype were all associated with pCR in univariate analyses. Multivariable logistic regression indicated that molecular subtype is an independent predictor of pCR (p<0.01). We found that molecular subtype contains additional pCR-predictive information beyond that of ER status, and that adding ER status to models containing molecular subtype did not significantly improve the model's performance. This indicates that the information predictive of pCR represented by ER status is largely also present in molecular subtype. Among the subtypes, Basal-like and Her2-enriched tumors demonstrated the highest rate of pCR relative to Luminal A tumors (OR 7.4; 2.2-24.8; OR 6.4; 2.0-20.7). The Risk of Relapse based on the subtype (ROR-S) was also a strong predictor of pCR (auROC=0.74), but was improved when using a novel ridge regression model (auROC=0.77; p<0.01). ROR-S and the different pCR predictors evaluated were generally correlated, however, Luminal B samples were consistently classified as having a poor prognosis and a low likelihood of pCR.Conclusions: In this combined analysis, using ER, PR, HER2, node status, tumor size, and subtype, the intrinsic molecular subtype classification is the most significant predictor of pCR across three anthracycline/taxane-based neoadjuvant cohorts.Interestingly, hormone receptor status is no longer significant when subtype is included in the model. These results indicate robust predictive information provided by the subtype classification, and highlights the chemotherapy insensitivity of the poor prognosis luminal B breast cancer subtype. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2019.

Molecular Stratification of Triple-Negative Breast Cancers

“…Meanwhile, the luminal B group had Abbreviations: ER, estrogen receptor; HER-2, human epidermal growth factor receptor; VEGF, vascular endothelial growth factor. an appreciable pCR rate, but it was still rather low (Table 1) [12].…”

Biological subtypes of breast cancer: Prognostic and therapeutic implications

“…Several studies have suggested that luminal-B breast cancer was relatively insensitive to endocrine therapy compared to luminal-A breast cancer and to paclitaxeland doxorubicin-containing preoperative chemotherapy compared with HER2-positive and basal-like breast cancers. However, luminal-B breast cancer responds better to neoadjuvant chemotherapy than luminal-A subtype, achieving higher pathological complete response rates [25][26][27][28][29] . Increased relapse rates observed in luminal-B tumors are limited to the first 5 years after diagnosis [30] .…”

Research-Based PAM50 Subtype Predictor Identifies Higher Responses and Improved Survival Outcomes in HER2-Positive Breast Cancer in the NOAH Study

“…Since 2009, the PAM50 subtype predictor has shown to provide prognostic and predictive value across multiple cohorts of patients with breast cancer (8,(9)(10)(11)(12)(13). For example, two studies have shown that the PAM50 subtype predictor predicts pathologic complete response (pCR) after neoadjuvant anthracycline-taxane-based chemotherapy (8,14).…”