Abstract P1-10-01: Caveolin gene expression predicts for response and clinical outcomes of patients treated with preoperative paclitaxel-based chemotherapy regimens in early stage breast cancer
Authors: Williams Terence , Schneeweiss Andreas , Jackisch Christian , Shen Changxian , Weber Karsten , Fasching Peter , Denkert Carsten , Furlanetto Jenny , Heinmoller Ernst , Schmatloch Sabine , Karn Thomas , Szeto Christopher , van Mackelenbergh Marion , Nekljudova Valentina , Stickeler Elmar , Soon-Shiong Patrick , Schem Christian , Fleige Barbara , Muller Volkmar , Marme Frederik , Untch Michael , Loibl Sibylle 
Published: March 2020

Abstract
Background: Biomarkers are needed to prognosticate and predict efficacy of therapy for patients undergoing neoadjuvant chemotherapy for HER2-negative breast cancer (BC). Caveolin genes (CAV1, CAV2) are responsible for formation of caveolae, which are 50-100 nM membrane invaginations implicated in endocytosis and transcytosis of nutrients and substances, including albumin. Overexpression of caveolin family genes has been implicated in driving BC progression, but also in predicting response to nab-paclitaxel. We hypothesized that high CAV1/2 expression would correlate with poor clinical outcomes, but that patients with high CAV1/2 expression would have better outcomes with nab-paclitaxel based chemotherapy. Methods: We correlated tumor CAV1/2 RNA expression from available RNA-Seq data with pathologic complete response (pCR) and clinical outcomes (disease-free survival, DFS, and overall survival, OS) in the GeparSepto (G7) clinical trial, which randomized patients with early stage BC to preoperative paclitaxel versus nab-paclitaxel-based chemotherapy regimens. CAV1/2 log-transformed values were analyzed as a continuous variable and dichotomized about the mean for each gene. Multivariable logistic regression models were generated, and included age, T-stage, N-stage, tumor grade (G3 vs G1-2), Ki67 (continuous), and histology (non-ductal versus ductal). Results: There was RNA-Seq expression data available for 279 out of 810 HER2-negative patients, of whom 26.5% were hormone receptor (HR)-negative (triple negative). CAV1 and CAV2 expression values were directly correlated with each other (Pearson coefficient 0.452). There was no difference in CAV1 expression between HR-negative and HR-positive patients, but there was significant up-regulation of CAV2 expression (mean) in HR-negative patients (p=0.003). With regards to pCR, high CAV1/2 expression was associated with a strong benefit from nab-paclitaxel compared to paclitaxel (OR(CAV1)=4.92 (1.70-14.22) and OR(CAV2)=5.39 (1.76-16.47)) in contrast to low CAV1/2 expression (OR(CAV1)=0.94 (0.38-2.34) and OR(CAV2)=0.95 (0.39-2.29)) in multivariate modeling (tests for interaction p=0.023 and p=0.019). For CAV1 this effect continued beyond pCR with regards to survival: high CAV1 expression was associated with superior survival in the nab-paclitaxel arm (HR(DFS)=0.53 (0.27-1.05), HR(OS)=0.29 (0.11-0.77)) but not low CAV1 expression (HR(DFS)=1.37 (0.62-3.04), HR(OS)=2.47 (0.78-7.80)) in multivariate modeling (test for interaction p=0.077 (DFS) and p=0.005 (OS)). No significant interactions in hazard ratios for DFS and OS were detected for CAV2. With regard to prognostic effects, CAV2 expression was significantly associated with worse DFS and OS for all patients. In particular, high CAV2 expression was associated with poor prognosis for HR-negative patients in multivariate modeling (OR(DFS)=4.40 (1.44-13.46), OR(OS)=9.38 (1.13-77.75)), but not for HR-positive patients (OR(DFS)=1.60 (0.84-3.05), OR(OS)=2.05 (0.92-4.58)) (test for interaction p=0.125 and p=0.186). Conclusions: Higher CAV2 expression is associated with worse DFS and OS, in particular for HR-negative patients, confirming potential prognostic roles for CAV1/2. No significant differences in DFS and OS based on CAV1/2 expression were noted for patients who received nab-paclitaxel based treatment, but the odds of obtaining pCR were improved for patients with high CAV1/2 expression. Taken together, these findings suggest that CAV1/2 expression may offset the negative prognostic factor associated with higher CAV1/2 expression in patients treated with nab-paclitaxel regimens by enhancing the efficacy of treatment, perhaps through increased nab-paclitaxel endocytosis/transcytosis.
Citation Format: Terence Williams, Andreas Schneeweiss, Christian Jackisch, Changxian Shen, Karsten Weber, Peter Fasching, Carsten Denkert, Jenny Furlanetto, Ernst Heinmoller, Sabine Schmatloch, Thomas Karn, Christopher Szeto, Marion van Mackelenbergh, Valentina Nekljudova, Elmar Stickeler, Patrick Soon-Shiong, Christian Schem, Barbara Fleige, Volkmar Muller, Frederik Marme, Michael Untch, Sibylle Loibl. Caveolin gene expression predicts for response and clinical outcomes of patients treated with preoperative paclitaxel-based chemotherapy regimens in early stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-01.