ITPKC as a Prognostic and Predictive Biomarker of Neoadjuvant Chemotherapy for Triple Negative Breast Cancer

SIMPLE SUMMARY: Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene is a negative regulator of T cell activation and is a proven promoter of Kawasaki disease. Given the critical role of immune response in breast cancer, we aimed to determine the clinical relevance of ITPKC expression in breast cancer. ITPKC expression was highest in triple negative breast cancer, associated with its survival, and was its independent prognostic factor. Although high ITPKC expression was not associated with immune function nor with any immune cell fraction, low ITPKC triple negative breast cancer was significantly associated with activated cell proliferation, and they achieved a significantly rate in pathological complete response (disappearance of tumor) after neoadjuvant chemotherapy. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in triple negative breast cancer. ABSTRACT: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher mortality than the others. Pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered as a surrogate to predict survival. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is a negative regulator of T cell activation, and reduction in ITPKC function is known to promote Kawasaki disease. Given the role of tumor infiltrating lymphocytes in NAC and since TNBC has the most abundant immune cell infiltration in breast cancer, we hypothesized that the ITPKC expression level is associated with NAC response and prognosis in TNBC. The ITPKC gene was expressed in the mammary gland, but its expression was highest in breast cancer cells among other stromal cells in a bulk tumor. ITPKC expression was highest in TNBC, associated with its survival, and was its independent prognostic factor. Although high ITPKC was not associated with immune function nor with any immune cell fraction, low ITPKC significantly enriched cell proliferation-related gene sets in TNBC. TNBC with low ITPKC achieved a significantly higher pCR rate after NAC. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in TNBC.