Predictive Role of CD36 Expression in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Trastuzumab

Abstract

Background Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage Human Epidermal growth factor Receptor 2 (HER2)-positive Breast Cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty Acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. Methods Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival (EFS) in 180 patients enrolled in the phase 3 trial NeoALTTO, which randomized stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pre-treatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase 2 trial NeoSphere. Results In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse EFS in patients treated with trastuzumab-based therapy (HR: 1.72, 95% CI: 1.20–2.46), but not with lapatinib- (HR: 1.02, 95% CI: 0.68–1.53) or trastuzumab-lapatinib-based (HR: 1.08, 95% CI: 0.60–1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient Disease-Free Survival (DFS) both in the whole study cohort (HR = 1.197, 95% CI: 1.002–1.428) and in patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI: 1.049–1.568). Conclusion High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy.

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer

“…Moreover, CD36 overexpression might correlate with poor clinical outcomes in human breast cancer. From the phase III trial NeoALTTO, patients treated with trastuzumab-based therapy showed an independently associated between worse event-free survival and CD36 expression, however, this result was not fit for the patients that treated with lapatinib-based or trastuzumab-lapatinib-based therapy [119].…”

Lipid metabolic reprogramming in tumor microenvironment: from mechanisms to therapeutics

“…Particularly, CD36-mediated metabolic reprogramming in breast cancer, has been linked to resistance to HER2-targeted therapies. Recent clinical studies have confirmed that higher CD36 expression correlates with poorer outcomes in early-stage HER2 + breast cancer patients undergoing trastuzumab-lapatinib therapy [ 230 ]. Furthermore, JC63.1C, an anti-CD36 monoclonal antibody, was found to resensitize lapatinib-resistant xenograft tumors to HER2-targeted therapy [ 231 ], providing a novel direction for combinatorial treatment strategies in breast cancer.…”

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

“…Expression of CD36 is also a poor prognostic marker in BC [ 141 ]. It provides FA, an alternative energy source, for cancer cells to grow and proliferate.…”