Abstract P5-20-19: PAM50 intrinsic subtype predicts survival outcome in HER2-positive/hormone receptor-positive metastatic breast cancer treated with palbociclib and trastuzumab: a correlative analysis of the PATRICIA (SOLTI 13-03) trial
Authors: Ciruelos E , Villagrasa P , Paré L , Oliveira M , de la Peña L , Pernas S , Cortés J , Soberino J , Adamo B , Vazquez S , Martínez N , Perelló A , Bermejo B , Martínez E , Garau I , Melé M , Morales S , Galvan P , Pascual T , Nuciforo P , Gonzalez X , Prat A 
Published: February 2018

Abstract
Background. In HER2+/HR+ breast cancer (BC), CDK4/6 inhibition combined with anti-HER2 therapy is currently being explored in phase II/III trials. However, we and others have shown that Luminal A and B subtypes (i.e. luminal disease) defined by gene expression only represent 30-50% in this group. Identification of the luminal subtype in HER2+/HR+ disease might be important since the median IC50 of palbociclib in HER2+ BC cell lines falling into the luminal subtype is lower than in non-luminal HER2+ cell lines (47.5 vs. 300 nM; Finn BCR 2011). Here, we explored, for the first time, the efficacy (progression-free survival [PFS]) of palbociclib and trastuzumab and its association with subtype in HER2+/HR+ BC.
Methods. PATRICIA is an exploratory, prospective, open-label, multicenter phase II trial in advanced HER2+ BC. Patients (pts) had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of trastuzumab 6 mg/kg every 3w and palbociclib 200 mg daily for 2w and 1w off. The study was based on a Simon 2-stage design comprising 3 cohorts: ER-negative cohort A (still recruiting) and ER+ cohorts B1 and B2 (both completed). Patients in cohort B2 also received letrozole by randomization. Safety run-in phase was made for first 12 pts. For stage 1 to be successful, at least 6 pts of 15 had to be progression-free at 6 months (PFS6) in each cohort. In stage 2, up to 46 pts per cohort will be included to show a PFS6 &gt;50%. As a secondary objective, research-based PAM50 intrinsic subtype was performed from FFPE samples using the nCounter platform. Estimates of PFS were from Kaplan-Meier curves. Univariate Cox regression analyses evaluating luminal subtype, age, performance status, treatment line, type of biopsy and endocrine treatment were evaluated.
Results. Thirty-one pts with HER2+/HR+ disease were recruited in stage 1 in cohorts B1 (n=16) and B2 (n=15). Median age was 59.8y, and median number of prior lines was 3.0. The rate of PFS6 was 40.0% (6/15) and 53.3% (8/15) in cohorts B1 and B2, respectively. A total of 26 (83.9%) tumors samples (15 primary and 11 metastatic tumors) were profiled. Subtype distribution was as follows: 46.2% HER2-enriched, 23.1% Luminal B, 19.2% Luminal A and 11.5% Normal-like. Median PFS in this subgroup of patients with PAM50 data was 3.71 months. Compared to non-luminal disease, luminal disease showed a statistically significantly longer median PFS (10.37 vs. 3.53 months, p-value=0.023). The PFS hazard ratio of luminal versus non-luminal groups was 0.34 (95% CI 0.13-0.92, p-value=0.033). In addition, Luminal A signature score, as a continuous variable, was also found associated with PFS (adjusted hazard ratio=0.54, 0.31-0.92, p-value=0.023). No clinical-pathological variable was found associated with PFS.
Conclusion. PAM50 subtype predicts PFS in HER2+/HR+ advanced BC treated with palbociclib and trastuzumab. Patients with non-luminal disease might not derive a large benefit from this treatment strategy concordant with the preclinical in vitro data. Our results might have important implications for current and future clinical trials evaluating CDK4/6 inhibitors in HER2+/HR+ disease.
Citation Format: Ciruelos E, Villagrasa P, Paré L, Oliveira M, de la Peña L, Pernas S, Cortés J, Soberino J, Adamo B, Vazquez S, Martínez N, Perelló A, Bermejo B, Martínez E, Garau I, Melé M, Morales S, Galvan P, Pascual T, Nuciforo P, Gonzalez X, Prat A. PAM50 intrinsic subtype predicts survival outcome in HER2-positive/hormone receptor-positive metastatic breast cancer treated with palbociclib and trastuzumab: a correlative analysis of the PATRICIA (SOLTI 13-03) trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-19.