👤 Natalia N Taran

Approximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer (ABC) have PIK3CA alterations, which contributes to endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol 3-kinase inhibitor and degrader, given in combination with fulvestrant, is approved for the treatment of PIK3CA-mutated, HR+, HER2- ABC, based on the SOLAR-1 trial. Aside from PIK3CA, other gene alterations are associated with poor prognosis and limited response to treatment in this patient population. In this retrospective analysis, we performed tissue-based next-generation sequencing of 398 patients (237 PIK3CA-altered, 161 PIK3CA-wild type) from SOLAR-1. Progression-free survival (PFS) correlative analysis was performed in the PIK3CA-altered cohort. PIK3CA-altered and PIK3CA-wild type tumors had distinct genomic profiles. In the PIK3CA-altered cohort, patients who received alpelisib plus fulvestrant had a median PFS (mPFS) of 11.01 months versus 5.55 months for those receiving placebo plus fulvestrant (P=0.0004). Patients in the lowest tumor mutational burden quartile as well as those with FGFR1 or FGFR2 alterations derived greater PFS benefit from alpelisib plus fulvestrant versus placebo plus fulvestrant (18.5 versus 3.22 months; HR 0.38; 95% CI 0.21-0.68. FGFR1 12.71 versus 3.75 months; HR 0.38; 95% CI 0.17-0.81; P=0.32. FGFR2: 9.63 versus 2.78 months; HR 0.31; 95% CI 0.1-0.94; P=0.29); patients with MYC or RAD21 alterations derived limited PFS benefit. Cox and multi-task machine learning models identified lower Eastern Cooperative Oncology Group performance status, prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and PTEN or TP53 alterations among the most deleterious factors for PFS in the PIK3CA-altered cohort. Alpelisib plus fulvestrant provides clinical benefit for patients with PIK3CA-altered, HR+, HER2- ABC across a range of concomitant alterations, including those previously implicated in endocrine therapy or CDK4/6i resistance. Machine learning models identified factors including gene mutations that influenced PFS. Show less

Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic genetic variants in LPL, APOC2, LMF1, and APOA5 genes. Case: We present a clinical case of severe primary hypertriglyceridemia (TG level > 55 mmol/L in a 4-year-old boy) in a consanguineous family. The disease developed due to a previously undescribed homozygous deletion in the APOA5 gene (NM₀₅₂₉₆₈: c.579₅₉₂delATACGCCGAGAGCC p.Tyr194Gly*68). We also evaluate the clinical significance of a genetic variant in the LPL gene (NM₀₀₀₂₃₇.2: c.106G>A (rs1801177) p.Asp36Asn), which was previously described as a polymorphism. In one family, we also present a different clinical significance even in heterozygous carriers: from hypertriglyceridemia to normotriglyceridemia. We provide evidence that this heterogeneity has developed due to polymorphism in the LPL gene, which plays the role of an additional trigger. Conclusions: The homozygous deletion of the APOA5 gene is responsible for the severe hypertriglyceridemia, and another SNP in the LPL gene worsens the course of the disease. Show less