Abstract
Addition of taxanes to preoperative chemotherapy in breast cancer increases the proportion of patients who have a pathological complete response (pCR). However, a substantial proportion of patients do not respond, and the prognosis is particularly poor for patients with oestrogen-receptor (ER)/progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) disease who do not achieve a pCR. Reliable identification of such patients is the first step in determining who might benefit from alternative treatment regimens in clinical trials. We previously identified genes involved in mitosis or ceramide metabolism that influenced sensitivity to paclitaxel, with an RNA interference (RNAi) screen in three cancer cell lines, including a triple-negative breast-cancer cell line. Here, we assess these genes as a predictor of pCR to paclitaxel combination chemotherapy in triple-negative breast cancer. We derived a paclitaxel response metagene based on mitotic and ceramide genes identified by functional genomics studies. We used area under the curve (AUC) analysis and multivariate logistic regression to retrospectively assess the metagene in six cohorts of patients with triple-negative breast cancer treated with neoadjuvant chemotherapy; two cohorts treated with paclitaxel (n=27, 30) and four treated without paclitaxel (n=88, 28, 48, 39). The metagene was associated with pCR in paclitaxel-treated cohorts (AUC 0.79 [95% CI 0.53-0.93], 0.72 [0.48-0.90]) but not in non-paclitaxel treated cohorts (0.53 [0.31-0.77], 0.59 [0.22-0.82], 0.53 [0.36-0.71], 0.64 [0.43-0.81]). In multivariate logistic regression, the metagene was associated with pCR (OR 19.92, 2.62-151.57; p=0.0039) with paclitaxel-containing chemotherapy. The paclitaxel response metagene shows promise as a paclitaxel-specific predictor of pCR in patients with triple-negative breast cancer. The metagene is suitable for development into a reverse transcription-PCR assay, for which clinically relevant thresholds could be established in randomised clinical trials. These results highlight the potential for functional genomics to accelerate development of drug-specific predictive biomarkers without the need for training clinical trial cohorts. UK Medical Research Council; Cancer Research UK; the National Institute for Health Research (UK); the Danish Council for Independent Research-Medical Sciences (FSS); Breast Cancer Research Foundation (New York); Fondation Luxembourgeoise contre le Cancer; the Fonds National de la Recherche Scientifique; Brussels Region (IRSIB-IP, Life Sciences 2007) and Walloon Region (Biowin-Keymarker); Sally Pearson Breast Cancer Fund; and the European Commission.
Highlights
In the T-FAC treated triple-negative cohorts, the paclitaxel response metagene was highly predictive of pathological complete response (pCR), with an AUC of 0·79 in MDA1 (p=0·0053; 95% CI 0·53–0·93; n=27), an AUC of 0·72 in MDA/MAQC (p=0·031; 0·48–0·90; n=30), and an AUC of 0·74 when the two cohorts were combined (p=0·0013; 0·58–0·86; n=57; table 2, figure 2 A and B, webappendix p 2)
We found that the paclitaxel response metagene was the covariate most significantly associated with pCR (p=0·0039; odds ratio 19·92; 95% CI 2·62–151·57) in T-FAC-treated patients with triple-negative breast cancer, more than nodal status, T stage, tumour grade, and Ki67
By filtering for common paclitaxel resistance pathways through RNA interference (RNAi) screening across three cell lines of different tumour origin, and selecting genes which correlate across independent cohorts, we derived a paclitaxel response metagene that is predictive of T-FAC response in two clinical trial datasets, but not in cohorts treated without paclitaxel
Summary
Despite the use of modern cytotoxic agents, the proportion of patients who achieve a complete pathological response (pCR) to preoperative chemotherapy remains low, at 15–25% for all breast-cancer histopathological subtypes. Rates of pCR in sporadic oestrogen-receptor (ER)/ progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) breast cancer range from 12% for taxane monotherapy to 45% with combination neoadjuvant chemotherapy regimens. Patients who achieve a pCR after chemotherapy have excellent disease-free and overall survival. The outcome for patients who do not achieve a pCR varies, and the prognosis for patients with triple-negative cancers and residual disease after preoperative chemotherapy is poor. Better understanding of breast-cancer biology is likely to expand the list of potentially effective chemotherapeutic agents in the neoadjuvant setting, and will help identify tailored chemotherapy schedules for distinct patient cohorts based on tumour molecular characterisation. Despite the use of modern cytotoxic agents, the proportion of patients who achieve a complete pathological response (pCR) to preoperative chemotherapy remains low, at 15–25% for all breast-cancer histopathological subtypes.. The outcome for patients who do not achieve a pCR varies, and the prognosis for patients with triple-negative cancers and residual disease after preoperative chemotherapy is poor.. Better understanding of breast-cancer biology is likely to expand the list of potentially effective chemotherapeutic agents in the neoadjuvant setting, and will help identify tailored chemotherapy schedules for distinct patient cohorts based on tumour molecular characterisation. If it can be reliably established that patients resistant to one type of therapy are sensitive to a different agent, robust predictors of chemotherapy response will have an essential role in selecting the optimum treatment in the neoadjuvant setting. The identification of patients with disease that is resistant to www.thelancet.com/oncology Vol 11 April 2010
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