Background: BC is the most common malignant disease and leading cancer-related cause of death in women. Despite significant achievements in the treatment, advanced BC (aBC) is still an incurable disease. HR+/HER2- subtype accounts for 70% of all BC. One of the most common mutations in BC is the PIK3CA gene mutation which can induce endocrine and chemo- resistance. In early BC, patients (pts) with PIK3CA mutations mostly have better, but in aBC worse prognosis. Standard first-line treatment for HR+/HER2- aBC is a combination of CDK4/6i and endocrine therapy. PIK3CA status is most often assessed in this group of pts and combination of alpelisib - PIK3CA inhibitor and fulvestrant is second-line treatment option in PIK3CA mutated pts. Methods: Medical records of HR+/HER2- aBC pts who started CDK4/6i therapy between 01.08.2018. and 01.10.2020. were analyzed with prior University Hospital Center Zagreb Ethics Committee approval. Demographics, tumor characteristics, clinical presentation and therapy information were collected. Molecular analysis of PIK3CA mutations was performed on tumor tissue samples. Time to treatment failure (TTF) was analyzed using the Kaplan-Meier method and the data cut-off was 31.12.2022. Results: Of the 103 pts with determined PIK3CA status, 45 (43.7%) had a detectable mutation. Median follow-up was 35 months. CDK4/6i were first line therapy in 31 (68.9%) pts with and 29 (50%) pts without PIK3CA mutation. Endocrine resistance, de novo metastatic disease and bone marrow infiltration were more common in PIK3CA mutated subgroup. The incidence of visceral metastases was similar in both groups, whereas liver metastases were more common in the unmutated group. Disease progression was observed in 69 (67%) pts, 28 (40.6%) of whom were PIK3CA mutated. Median TTF in mutated subgroup was 24 months (95% CI 21-33) and 25 months in unmutated subgroup (95% CI 19-36). During the follow-up period, 35 (34%) pts died, 14 (40%) of whom were PIK3CA mutated. Odds ratios in pts with a PIK3CA mutation. Conclusions: There was no relevant difference in TTF between two groups. However, PIK3CA mutated subgroup had more aggressive clinical features - more often presented with bone marrow infiltration and de novo aBC, statistically relevant OR 5.158 and 2.323 respectively, which is related to lower quality of life and highlights the importance of treatment improvement for this subgroup of pts.

*Statistically significant p<0.05.