Background: Carboplatin is part of NCCN-preferred neoadjuvant chemotherapy (NAC) for stage II-III triple negative (TN) early-stage breast cancer (eBC) as addition to taxane-containing standard-of-care, and significantly improves pathologic complete response (pCR) rates in multiple trials. In hormone receptor (HR)+/HER2− disease, platinum addition has been explored in investigational settings but is not standard. In I-SPY2 (NCT01042379), high-risk eBC pts were randomized to standard taxane-anthracycline (T-AC) with or without investigational agents. One arm evaluated carboplatin plus the PARP inhibitor veliparib added to T-AC (VC arm; 32 HR+/HER2- and 39 TN pts, n = 71). Two gene signatures, a 205-gene Platin Drug Response Predictor (Platin-DRP) and a 113-gene taxane response predictor, have been validated for association with response to platinum agents and taxane-based regimens, respectively. This study evaluated their combined association with pCR in the I-SPY2 VC arm and their potential to inform platinum benefit in taxane-based NAC.
Methods: Agilent gene expression data (GSE194040) from 987 high-risk eBC tumors were analyzed, focusing on 71 VC-arm pts and 179 HER2- T-AC pts. Samples were scored using each gene signature on a percentile scale (0–100). Associations between a 50-point increase in score and pCR were assessed using logistic regression with one-sided tests and 90% confidence interval (CI) lower bound (LB), unless otherwise specified.
Results: The pCR rate in the VC arm was 38% (27/71), compared with 17.3% (31/179) in the control arm. In the VC arm, both the Platin-DRP (OR = 3.4, p = 0.016, 90% CI LB = 1.36) and the taxane predictor (OR = 3.88, p = 0.01, 90% CI LB = 1.54) were associated with pCR after adjustment for HR status and retained independent predictive value after adjustment for MammaPrint risk. The platinum and taxane scores were moderately correlated (r = 0.53). In a bivariable model, inclusion of the Platin-DRP trended toward improved fit beyond the taxane score alone (two-sided (2s) p = 0.082). Dichotomization at 50 showed highest pCR in double-high pts (55%, 16/29), intermediate rates in discordant pts (33%, 7/21), and lowest rates in double-low pts (19%, 4/21). Quartile stratification further separated outcomes, with 78% pCR (7/9) in the high-high quartile and 0% (0/8) in the low-low quartile.The taxane score showed no evidence of arm-specific effects (control vs VC; 2s p = 0.97), whereas the Platin-DRP showed directionally stronger associations in the VC arm (2s p = 0.12).
Conclusions: Taxane and platinum gene expression signatures showed complementary associations with pCR in the I-SPY2 veliparib-carboplatin arm. Joint modeling and stratification identified subgroups with distinct responses, supporting the potential utility of combining drug-specific biomarkers to refine patient selection for platinum addition in taxane-based NAC.
All authors and affiliations
Jacob Hansen Niklassen, J.H. (presenting author) (1), Beatrice Hahn: Hahn, B. (2) , Urania Dafni (3), Jan Nart: Nart, J. (2), Stephen P Finn (2) , Ulla Hald Buhl: Buhl, U.H. (2), Ida Kappel Buhl: Buhl, I.K. (2) , Steen Knudsen: Knudsen, S. (4) , Thomas Jensen: Jensen, T. (4) , Lydia Tsamtsouri (5), Roswitha Kammler (6) , Sarah Danson (7), Mary O’Brien (8), Peter Buhl Jensen: Jensen, P.B. (2), Fred R. Hirsch (9), Rolf A. Stahel (10), Solange Peters (11)
(1) Chair ETOP Translational Research Working Group, St. James and Trinity and Molecular Diagnostics and Histopathology, St. James’s Hospital and Trinity College Dublin, Dublin, Ireland
(2) CHOSA Oncology, Lund, Sweden
(3) ETOP Statistical Center, Frontier Science Foundation-Hellas & University of Athens, Athens, Greece ,
(4) Allarity Therapeutics, Hørsholm, Denmark
(5) ETOP Statistical Center, Frontier Science Foundation-Hellas Athens, Greece,
(6) Translational Research Coordination, ETOP IBCSG Partners Foundation, Bern, Switzerland
(7) Department of Oncology and Metabolism & Sheffield Experimental Cancer Medicine Centre, University of Sheffield, Weston Park Hospital, Sheffield, United Kingdom
(8) Department of Medical Oncology, Royal Marsden Hospital Sutton, London, United Kingdom
(9) Department of Medicine, Division of Medical Oncology, Mount Sinai Hospital, New York, CO, United States of America
(10) President, ETOP IBCSG Partners Foundation, Coordinating Center, Bern, Switzerland
(11) Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
Contact information:
Peter Buhl Jensen (CHOSA Oncology, CEO): peter@chosa.bio
Contact information:
Peter Buhl Jensen (CHOSA Oncology, CEO): peter@chosa.bio