title: Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Juul
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Li
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Burrell
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.forename: Eleni
authors.initials: E
authors.lastname: Andreopoulou
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D006801:Humans; D016015:Logistic Models; D056186:Metagenomics / Q000379:methods*; D008875:Middle Aged; D008938:Mitosis / Q000235:genetics; D008957:Models, Genetic; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011237:Predictive Value of Tests; D034622:RNA Interference; D012189:Retrospective Studies
chemical_list: D002518:Ceramides; D017239:Paclitaxel