Abstract P2-13-12: High CD36 expression predicts worse event free survival in HER2-positive breast cancer patients treated with neoadjuvant trastuzumab-based therapy: An exploratory analysis of the NeoALTTO study

Abstract

Background: Despite great efforts to identify tumor-related prognostic biomarkers in early-stage Human Epidermal growth factor Receptor 2 (HER2)-positive Breast Cancer (HER2+ BC), reliable determinants of long-term clinical outcomes are lacking. HER2+ BC is a lipogenic malignancy, and HER2-driven fatty acid (FA) biosynthesis plays a crucial role in sustaining cancer cell growth, proliferation, and metastatization. Recently, FA uptake, a process mediated by the transmembrane transporter CD36, has emerged as a new determinant of acquired resistance to anti-HER2 treatments in preclinical studies. Methods: The phase III NeoALTTO (NCT00553358) trial randomized 455 HER2+ BC patients to receive lapatinib, trastuzumab, or the combination of both drugs with weekly paclitaxel, followed by surgery, adjuvant fluorouracil, epirubicin, and cyclophosphamide and the same anti-HER2 therapy received before surgery. In the present analysis, we tested the hypothesis that higher intratumor CD36 mRNA levels could be associated with worse Event Free Survival (EFS) in a cohort of NeoALTTO patients for whom global gene expression analysis of baseline tumor samples through ClariomS platform was available. Results: A total of 180 patients were included (trastuzumab arm: n=66; lapatinib arm: n=65; combination arm: n=49). Higher baseline CD36 expression levels were associated with significantly worse EFS in patients treated with trastuzumab-based therapy, at both univariate (continuous scale, HR:1.73, 95% CI 1.20-2.49) and multivariable (HR:1.72, 95% CI 1.20-2.46) analysis, but not in patients treated with lapatinib- or trastuzumab plus lapatinib (HR:1.01; 95% CI: 0.69-1.47; p=0.98 and HR:1.02; 95% CI:0.54-1.95; p=0.94, respectively). CD36 levels did not predict pathological Complete Response (pCR) probability, while combining CD36 expression (based on median levels) with pCR status identified two subsets of patients with especially bad or good prognosis (7-year EFS rates in patients with high CD36/no pCR: 47%, 95% CIs: 0.26-0.66 vs. 79%, 95% CIs: 0.62-0.88 in patients with low CD36/any pCR status (Yes/No) OR high CD36/pCR; Log-Rank test p= 0.006). Conclusions: This is the first study to show that high CD36 expression is independently predictive of worse long-term clinical outcomes in HER2+ BC patients treated with neoadjuvant trastuzumab-based therapy. Along with recent preclinical data highlighting CD36 role in tumor resistance to anti-HER2 therapies, our findings point to CD36 as a novel promising target for HER2+ BC treatment. Citation Format: Francesca Ligorio, Serena Di Cosimo, Paolo Verderio, Chiara Maura Ciniselli, Sara Pizzamiglio, Lorenzo Castagnoli, Tiziana Triulzi, Elda Tagliabue, Sarra El-Abed, Miguel Izquierdo, Evandro de Azambuja, Paolo Nuciforo, Jens Huober, Luca Moscetti, Wolfgang Janni, M Coccia-Portugal, Paola Corsetto, Antonino Belfiore, Daniele Lorenzini, Maria Grazia Daidone, Andrea VIngiani, Serenella M Pupa, Giancarlo Pruneri, Claudio Vernieri. High CD36 expression predicts worse event free survival in HER2-positive breast cancer patients treated with neoadjuvant trastuzumab-based therapy: An exploratory analysis of the NeoALTTO study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-12.

Resistance to Trastuzumab

“…This potential metabolic switch was recently exemplified by Feng et al, who showed that acquired resistance to the HER2 inhibitor lapatinib is mediated by upregulation of CD36, a transmembrane glycoprotein that acts as a transporter for, among other ligands, long-chain fatty acids [ 158 ]. Although that study did not conclusively demonstrate that trastuzumab resistance was also accompanied by upregulation of CD39, a subsequent report by Ligorio showed that high baseline expression of CD39 was associated with poorer event-free survival in patients treated with a combination of paclitaxel and trastuzumab, suggesting an increased uptake of long-chain fatty acids contributes to primary resistance to trastuzumab [ 159 ].…”