Alpelisib 200mg tablets

BackgroundBreast cancer presents with distinct clinical and molecular characteristics in the Middle East and North Africa (MENA) region, where women are diagnosed at younger ages and with more aggressive disease compared to Western populations. Despite the global burden, genomic studies of breast cancer in MENA remain underrepresented. This systematic review provides the first comprehensive analysis of somatic mutations in breast cancer patients across the MENA region.MethodsFollowing PRISMA guidelines, we analyzed 44 studies encompassing 13 MENA countries, representing data from over 2500 breast cancer patients. Studies were rigorously assessed using the Newcastle-Ottawa Scale, with mutation data extracted, standardized, and classified according to pathogenicity using established databases. We employed multiple sequencing methodologies, including next-generation sequencing and targeted gene panels, to identify country-specific and region-wide mutation patterns.ResultsWe identified 559 mutations across 104 genes, with TP53 (23.79%) and PIK3CA (10.19%) emerging as the most frequently altered genes, followed by significant mutations in BRCA1/2, ATM, ESR1, and PTEN. Nearly 43% of variants were classified as pathogenic/likely pathogenic, while 23% remained variants of uncertain significance. Missense mutations predominated (60.29%), followed by frameshift variants (13.06%) and stop-gained mutations (10.91%). We discovered distinctive country-specific mutation profiles, including unique alterations in KLF6 (Turkey) and IL-1β (Iraq), reflecting potential environmental and hereditary influences unique to MENA populations. Notably, all 11 PIK3CA hotspot mutations that predict sensitivity to alpelisib therapy were identified.ConclusionsThis study reveals both shared and distinct somatic mutation patterns in MENA breast cancer patients compared to Western populations. The high prevalence of clinically actionable mutations, particularly in PIK3CA and DNA repair genes, presents immediate opportunities for implementing targeted therapies across the region. Our findings underscore the urgent need for establishing a MENA Breast Cancer Genomics Consortium to standardize sequencing protocols, develop locally validated gene panels, and create regional variant databases that capture the unique mutation spectrum of these populations. This comprehensive genomic landscape of breast cancer in the MENA region addresses a critical gap in global cancer genomics, ultimately improving outcomes for a historically underrepresented patient population.

Abstract licence: CC BY

Abstract Introduction: A new phosphatidylinositol-3-kinase (PI3K) inhibitor, alpelisib (Piqray) has been recently approved for the treatment of breast cancer. Severe hyperglycemia has been reported as an adverse effect. Many breast cancer patients also have diabetes mellitus type 2 which puts them at a higher risk for this adverse effect.1 2 Case description: Patient is a 73 year old Caucasian woman with history of insulin treated type 2 diabetes mellitus and breast cancer who presented to the hospital with a left hip fracture. She has been recently started on alpelisib with worsening glycemic control. Glycemic control improved after alpelisib was held for 5 days. She resumed taking alpelisib and had an up titration of the insulin regimen. During her hospital stay, she suffered from hyperglycemia as high as 558 mg/dl. HbA1c increased to 11.3% from 6.5% reportedly before starting alpelisib. Patient was discharged on an intensified regimen with close follow up. Discussion: Alpelisib is a PI3K inhibitor used in the treatment of postmenopausal women and men with hormone receptor positive, human epidermal growth factor receptor-2 negative, PIK3CA-mutated metastatic breast cancer. It inhibits PI3K which in turn inhibits protein kinase B (AKT). Insulin binds to insulin receptor substrates which activates PI3K, which in turn activates AKT resulting in translocation of the glucose transporter GLUT4 to the plasma membrane causing an uptake of glucose.3 A disruption in this pathway will result in hyperglycemia. Hyperglycemia was reported in 65% of patients with some cases found to be in ketoacidosis. This adverse effect means frequent monitoring of blood glucose is required following initiation of this treatment.4 Conclusion: Alpelisib is a new drug used in the select treatment of breast cancer. It can cause severe hyperglycemia and potential worsening of diabetes. Blood glucose should be monitored closely in patients with diabetes who are treated with alpelisib. References: Giovannucci E et al. Diabetes and Cancer. A consensus report. Diabetes Care 33:1674–1685, 2010. Boyle P et al. Diabetes and breast cancer risk: a meta-analysis. British Journal of Cancer 107, 1608–1617, 2012. Huang, X et al. The PI3K/AKT pathway in obesity and type 2 diabetes. International Journal of Biological Sciences14,1483–1496,2018. Piqray [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp;2019

Abstract licence: CC BY-NC-ND 4.0

Abstract Congenital hyperinsulinism (CHI) is a disorder of unregulated insulin secretion, leading to severe hypoglycemia in most cases. We previously described the adjunct use of alpelisib therapy in a 3-month-old patient with CHI. We now describe our observations in 2 additional patients with severe CHI treated with alpelisib therapy, resulting in discontinuation of all existing treatments and normalization of feeding. Two children (aged 3 and 4 years) with CHI (homozygous ABCC8 and KCNJ11 pathological variants) who were unresponsive to conventional therapies were treated with alpelisib. Treatment was initiated at 12.5 mg daily, with gradual dose adjustments based on clinical responses. Outcome measures included blood glucose variability, frequency of hypoglycemic episodes, need for supplemental feeding, and treatment safety. In both cases, alpelisib significantly improved glucose levels, reducing the frequency of hypoglycemic episodes. This allowed for the tapering and discontinuation of other medications (diazoxide and octreotide) and facilitated a transition to bolus gastrostomy-tube/oral feeding. No significant adverse effects were reported. Alpelisib shows promise as both an adjunctive and primary therapy for CHI, improving glucose levels and reducing dependence on continuous feeding and other medications. Randomized controlled trials are needed to assess its long-term safety and efficacy for CHI.

Abstract licence: CC BY 4.0

Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated in oncogenesis, treatment resistance, and disease progression, making it an attractive target for anticancer drug development. Early experiences with PI3K/AKT/mTOR inhibitors have highlighted challenges associated with their modest efficacy, as well as safety and tolerability issues; however, several effective next-generation PI3K/AKT/mTOR inhibitors have now been approved for patients with breast cancer. As a result, there is a growing need to understand the presentation, characteristics, and management of common toxicities (hyperglycemia, rash, stomatitis, and diarrhea). This review summarizes available safety data from phase III randomized clinical trials for approved PI3K/AKT/mTOR pathway-targeted therapies (everolimus, alpelisib, capivasertib, and inavolisib), including incidence, severity, adverse event-related dose modifications, and time to onset. We also provide guidance for preparation, monitoring, and management strategies for integrating these therapies into clinical practice, with the hope that appropriate support will allow patients to tolerate higher PI3K/AKT/mTOR inhibitor dose intensities, which has the potential to translate to improved patient outcomes.

Abstract licence: CC BY-NC-ND