Bardia A.Parton M.Kummel S.Estevez L.G.CHIUN-SHENG HUANGCortes J.Ruiz-Borrego M.Telli M.L.Martin-Martorell P.Lopez R.Beck J.T.Ismail-Khan R.Chen S.-C.Hurvitz S.A.Mayer I.A.Carreon D.Cameron S.Liao S.Baselga J.Kim S.-B.2020-03-232020-03-2320180732-183Xhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85055808241&doi=10.1200%2fJCO.2017.74.8392&partnerID=40&md5=241315e5b15c521d4ac8fef6d3b989bfhttps://scholars.lib.ntu.edu.tw/handle/123456789/477700Purpose There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor a (TNFa)-based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist,was translated into a clinical assay and evaluated in a neoadjuvant trial. Patients and Methods Women with localized TNBC (T2/N0-2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800mg once per week) and intravenous paclitaxel (80mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by . 7.5% increase in the pathologic complete response (PCR, breast) rate, stratified by GS. Results Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, PCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of . 7.5% increase in PCR. However, in the GS-negative group, the PCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of . 7.5% increase in PCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm. Conclusion This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC. ? 2018 by American Society of Clinical Oncology.[SDGs]SDG3BRCA1 protein; BRCA2 protein; n [1 cyclohexyl 2 [2 [4 (4 fluorobenzoyl) 2 thiazolyl] 1 pyrrolidinyl] 2 oxoethyl] 2 (methylamino)propanamide; paclitaxel; tumor necrosis factor; adult; aged; alopecia; anemia; Article; cancer combination chemotherapy; cancer patient; cancer surgery; chill; comparative effectiveness; constipation; controlled study; coughing; diarrhea; drug efficacy; drug hypersensitivity; drug potentiation; drug safety; dysgeusia; dyspnea; fatigue; female; fever; gene expression; headache; human; hyponatremia; hypotension; insomnia; lung embolism; major clinical study; myalgia; nausea; neoadjuvant chemotherapy; neutropenia; peripheral neuropathy; phase 2 clinical trial; Pneumocystis pneumonia; priority journal; pruritus; randomized controlled trial; rash; sensory neuropathy; stomatitis; treatment duration; treatment response; triple negative breast cancer; virus pneumoniajournal article10.1200/JCO.2017.74.83922-s2.0-85055808241