Retinoic acid sensitivity in breast cancer

A new study published on Clinical Breast Cancer suggests that a small subgroup of breast cancers with retinoic acid receptor alpha (RARA) amplification could be sensitive to retinoic acid, opening new avenues in targeted therapies for breast cancer.

The study arose from a clinical observation, when authors described a case report of a patient with chemo- and trastuzumab-resistant HER2-overexpressing breast cancer, who presented a concomitant acute promyelocytic leukemia. The patient showed a response in her breast lesions to retinoic acid, arsenic and aracytin. Considering the case of the patient and the vicinity between RARA and HER2 genes, the study was extended to a clinical data set analysis to characterize RARA amplifications and expression in 103 breast cancer samples, together with an in vitro investigation of retinoic acid activity in breast cancer cell lines. Results showed that retinoic acid receptor alpha was gained or amplified in 27% of HER2-positive and 13% of HER2-negative breast cancer samples, and that retinoic acid receptor alpha can be co-amplified with HER2. All-trans-retinoic acid reduced cell viability of RARA-amplified, but not RARA-normal, cell lines through apoptosis. «We provide new evidence that a small subset of breast cancer patients present with RARA amplification that could be associated with sensitivity to retinoic acid derivatives in breast cancers», authors say. «Retinoic acid mechanism to induce apoptosis in these cells is mainly mediated by Interferon Regulatory Factor 1, which activates the caspase pathway. Our results suggest therefore a mechanistic basis for the synergistic antitumor activities of retinoic acid and interferons, arguing for combination therapies with trans-retinoic acid and nonspecific immunotherapy to eradicate tumor cells». Based on these findings, researchers plan to open a phase II biomarker-driven trial, selecting patients with RARA amplification and evaluating the efficacy of retinoic acid when combined with trastuzumab in patients who are resistant to HER2 inhibitors.