| Summary: | Background: LIV1 is a transmembrane protein that may become a new therapeutic target through the development of antibody–drug conjugates (ADCs). Few studies are available regarding the assessment of <i>LIV1</i> expression in clinical breast cancer (BC) samples. Methods: We analyzed <i>LIV1</i> mRNA expression in 8982 primary BC. We searched for correlations between <i>LIV1</i> expression and clinicopathological data, including disease-free survival (DFS), overall survival (OS), pathological complete response to chemotherapy (pCR), and potential vulnerability and actionability to anti-cancer drugs used or under development in BC. Analyses were performed in the whole population and each molecular subtype separately. Results: LIV1 expression was associated with good-prognosis features and with longer DFS and OS in multivariate analysis. However, patients with high <i>LIV1</i> expression displayed a lower pCR rate than patients with low expression after anthracycline-based neoadjuvant chemotherapy, including in multivariate analysis adjusted on grade and molecular subtypes. <i>LIV1</i>-high tumors were associated with higher probabilities of sensitivity to hormone therapy and CDK4/6 inhibitors and lower probabilities of sensitivity to immune-checkpoint inhibitors and PARP inhibitors. These observations were different according to the molecular subtypes when analyzed separately. Conclusions: These results may provide novel insights into the clinical development and use of LIV1-targeted ADCs by identifying prognostic and predictive value of <i>LIV1</i> expression in each molecular subtype and associated vulnerability to other systemic therapies.
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