STARD3: A New Biomarker in HER2-Positive Breast Cancer

SIMPLE SUMMARY: One out of 8 breast cancers is of a particular type called “HER2-positive”, which is more aggressive and is treated by surgery and a medical treatment associating chemotherapy and a targeted drug against the protein HER2, possibly followed by radiotherapy and endocrine therapy. When the medical treatment is performed before others (neoadjuvant) and that all cancer cells are gone, this is called “pathological complete response”, which is an important good-prognosis marker. This article studied on a group of 112 patients with HER2-positive breast cancer, the presence of a protein called STARD3, which has a strong biological and genetic association with HER2. It found that STARD3 was strongly associated with pathological complete response and could predict this response. It also investigated if the presence of STARD3 had an impact on prognosis (such as survival and the risk of cancer recurrence). This work suggests that the study of STARD3 for HER2-positive breast cancers could lead to a better treatment planning, and further studies are needed. ABSTRACT: Pathological complete response (pCR) after neoadjuvant systemic treatment (NST) is an important prognostic factor in HER2-positive breast cancer. The majority of HER2-positive breast cancers are amplified at the HER2 gene locus, several genes are co-amplified with HER2, and a subset of them are co-expressed. The STARD3 gene belongs to the HER2 amplicon, and its role as a predictive marker was never addressed. The objective of this study was to investigate the predictive value of STARD3 protein expression on NST pathological response in HER2-positive breast cancer. In addition, we studied the prognostic value of this marker. Methods. We conducted a retrospective study between 2007 and 2020 on 112 patients with non-metastatic HER2-positive breast cancer treated by NST and then by surgery. We developed an immunohistochemistry assay for STARD3 expression and subcellular localization and determined a score for STARD3-positivity. As STARD3 is an endosomal protein, its expression was considered positive if the intracellular signal pattern was granular. Results: In this series, pCR was achieved in half of the patients. STARD3 was positive in 86.6% of cases and was significantly associated with pCR in univariate analysis (p = 0.013) and after adjustment on other known pathological parameters (p = 0.044). Performances on pCR prediction showed high sensitivity (96%) and negative predictive value (87%), while specificity was 23% and positive predictive value was 56%. Overall, specific, relapse-free, and distant metastasis-free survivals were similar among STARD3 positive and negative groups, independently of other prognosis factors. Conclusion: NST is an opportunity for HER2-positive cancers. In this series of over a hundred HER2-positive and non-metastatic patients, a STARD3-negative score was associated with the absence of pathological complete response. This study suggests that determining STARD3 overexpression status on initial biopsies of HER2-positive tumors is an added value for the management of a subset of patients with high probability of no pathological response.