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Purpose The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA- mutated ( PIK3CA mut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2−), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2− advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results Patients with PIK3CA mut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CA mut BC. Among patients with double PIK3CA mut tumors (12% of all PIK3CA mut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CA mut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2− BC were not part of the therascreen panel. Conclusion PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CA mut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.

[This corrects the article DOI: 10.3389/fphar.2023.1212771.].[This corrects the article DOI: 10.3389/fphar.2023.1212771.].

Background PIK3CA -related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA -related disorders. Main body PIK3CA -related disorders include PIK3CA -related overgrowth spectrum (PROS), PIK3CA -related vascular malformations, and PIK3CA -related nonvascular lesions. Somatic activating mutations (predominantly in hotspots in the helical and kinase domains of PIK3CA, but also in other domains), lead to hyperactivation of the PI3K signaling pathway, which results in abnormal tissue growth. Diagnosis is complicated by the variability and overlap in phenotypes associated with PIK3CA -related disorders and should be performed by clinicians with the required expertise along with coordinated care from a multidisciplinary team. Although tissue mosaicism presents challenges for confirmation of PIK3CA mutations, next-generation sequencing and tissue selection have improved detection. Clinical improvement, radiological response, and patient-reported outcomes are typically used to assess treatment response in clinical studies of patients with PIK3CA -related disorders, but objective assessment of treatment response is difficult using imaging (due to the heterogeneous nature of these disorders, superimposed upon patient growth and development). Despite their limitations, patient-reported outcome tools may be best suited to gauge patient improvement. New therapeutic options are needed to provide an alternative or supplement to standard approaches such as surgery and sclerotherapy. Currently, there are no systemic agents that have regulatory approval for these disorders, but the mTOR inhibitor sirolimus has been used for several years in clinical trials and off label to address symptoms. There are also other agents under investigation for PIK3CA -related disorders that act as inhibitors to target different components of the PI3K signaling pathway including AKT (miransertib) and PI3K alpha (alpelisib). Conclusion Management of patients with PIK3CA -related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.

Background Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. Methods In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. Results We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models. Conclusions These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

Background There are many biomarkers associated with breast cancer. Higher expression of PIK3CA (Phosphoinositide 3-kinase Cα), in its upregulated form, is associated with Hr + and Her2 − breast cancer; therefore, many drugs were synthesized against this protein to treat breast cancer patients. FDA recently approved that the drug alpelisib also inhibits PI3KCα (PDB ID-5DXT) in BC patients with Hr + and Her2 − . In present study, we have exploited fourteen coumarin-carbonodithioate derivatives and alpelisib against this protein along with eighteen others which are responsible for causing BC through computational analysis. We have used Schrödinger Maestro 11.2 version for our in silico docking study, and to calculate relative binding energies of ligands, we used prime MM-GBSA module. Result Docking study revealed that among all fourteen compounds, 2f, 2a, 2d, and 2e showed the highest G score than the alpelisib and coumarin against PI3KCα with − 9.3, − 9.0, − 9.0 and − 9.1 kcal/mol respectively, along with individual G score of alpelisib (− 8.9) and coumarin (− 7.9). Prime MM-GBSA analysis gave the relative binding energies of alpelisib, 2f, and 2e with − 19.94864535, − 18.63076296 and − 13.07341286 kcal/mol sequentially. Conclusion This study provides an insight into the coumarin-carbonodithioate derivatives that could act as inhibitors of PI3KCα like alpelisib. Further prime MM-GBSA study revealed ligand binding energies and ligands strain energies.

PurposeActivation of the phosphoinositide 3-kinase (PI3K) pathway is an important resistance mechanism to anti-HER2 therapies. This study aimed to assess the safety and activity of alpelisib (a PI3Kα isoform-specific inhibitor) with T-DM1 in trastuzumab- and taxane-resistant HER2-positive MBC.MethodsPatients with HER2-positive MBC that had progressed on trastuzumab-based therapy were treated with alpelisib daily and T-DM1 3.6 mg/kg every 3 weeks. The dose-limiting toxicity (DLT), maximum tolerated dose (MTD), adverse events, overall response rate (ORR), and clinical benefit rate (CBR = CR + PR + SD > 6 months) were assessed with descriptive statistics. Progression-free survival (PFS) was calculated by the Kaplan–Meier method.ResultsSeventeen patients were enrolled with a median of 3 prior therapies for metastatic disease. The DLT was a maculopapular rash and MTD was 250 mg alpelisib daily. The most frequently occurring toxicities included fatigue, rash, gastrointestinal side effects, thrombocytopenia, anemia, elevated liver enzymes, and hyperglycemia. Fourteen patients were evaluable for response with an ORR of 43%. In patients with prior treatment and progression on T-DM1 (n = 10), the ORR was 30%. The CBR was 71% in evaluable patients and 60% in those with prior T-DM1. The median PFS was 8.1 months.ConclusionsThe combination of alpelisib and T-DM1 is tolerable and demonstrates activity in trastuzumab-resistant HER2-positive MBC. Furthermore, activity was observed in T-DM1-resistant disease. These data suggest that PIK3CA inhibition targets an important resistance pathway to anti-HER2 therapy, providing rationale for further study of PI3K inhibition in refractory HER2-positive MBC to validate these results.

Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway mutations are frequent in BC (20–40%) and are significant causes of aggressive tumor behavior, as well as treatment resistance. Improving knowledge of the PI3K/AKT/mTOR pathway is an urgent need. This review aims to highlight the central role of PI3K-mTORC1/C2 mutations in the different BC subtypes, in terms of clinical outcomes and treatment efficacy. The broad base of knowledge in tumor biology is a key point for personalized BC therapy in the precision medicine era.

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.

Background Everolimus, an mTOR inhibitor, is FDA-approved with endocrine therapy (ET) for hormone receptor-positive (HR+)/HER2- MBC regardless of PI3K/AKT/mTOR pathway mutation status. Alpelisib, a PI3K inhibitor, is FDA-approved with fulvestrant for PIK3CA- mutant HR+/HER2- MBC. The efficacy and safety of sequential treatment with these pathway inhibitors is not well described. Methods This single-center observational study identified patients with PIK3CA -mutant HR+/HER2- MBC treated with everolimus and alpelisib sequentially from 2012 to 2023. We abstracted patient, tumor, and treatment information from medical records. Patients treated first with everolimus then alpelisib were categorized as Group 1 and those treated first with alpelisib then everolimus as Group 2. Median time to treatment failure on 1st pathway inhibitor (TTF1) and TTF on 2nd pathway inhibitor (TTF2) were computed using the Kaplan-Meier method. Results 115 patients were included, with 63 (55%) in Group 1 and 52 (45%) in Group 2. Median age was 61 and 53% of patients had visceral disease. Patients received a median 3 prior lines of metastatic treatment (interquartile range [IQR] 2–4.5) and 71% received prior CDK4/6 inhibitor; more patients in Group 2 received prior CDK4/6 inhibitor than Group 1 (87 vs. 59%, p  = 0.001). In Group 1, 50 (79%) patients discontinued everolimus for progression and 13 (21%) for toxicity. In Group 2, 33 (63%) patients discontinued alpelisib for progression and 19 (37%) for toxicity. Median TTF1 was 9.2 months (95%CI 5.5–12) in Group 1 and 9.7 months (95%CI 7.1–14) in Group 2 ( p =  0.5, Fig. 1, left). In patients who received prior CDK4/6 inhibitor, median TTF1 was 4.3 months (95%CI 3.2–11) in Group 1 and 8.7 months (95%CI 6.4–12) in Group 2 (p  = 0.02). In univariable Cox proportional hazards analyses, factors associated with worse TTF1 included prior CDK4/6 inhibitor use and more prior lines of treatment; these remained significant in multivariable analyses. After adjusting for prior CDK4/6 inhibitor use and prior total/intervening lines of therapy, TTF1 was not significantly different between groups (p =  0.2), nor was TTF2 (p  = 0.1). Presence of GATA3 mutation was significantly associated with poorer alpelisib-specific TTF ( p  = 0.016). Conclusions Prior CDK4/6 inhibitor use was associated with worse TTF1 and TTF2. There were no significant differences in TTF1 nor in TTF2 between Groups 1 and 2 after adjusting for clinical predictors. Given the recent approvals of capivasertib and inavolisib, prospective studies testing optimal sequencing of pathway agents with integration of biomarker analysis are needed.

The pharmacokinetics (PK) and safety of single-dose alpelisib (300 mg) were assessed in participants with moderate to severe hepatic impairment (n = 6 each) compared with their matching healthy controls (n = 11). Blood samples were collected upto 144 hours post-dose and evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary PK parameters (maximum plasma concentration [C ], area under the curve [AUC] and AUC ) and secondary PK parameters (AUC , apparent total body clearance [CL/F], apparent volume of distribution [Vz/F], time of maximum observed concentration [T ], and half-life [T ]) of oral alpelisib 300 mg were determined from individual plasma concentration-time profiles using non‑compartmental analysis. C of alpelisib decreased by approximately 17% in the moderate hepatic impairment group vs. the healthy control group (geometric mean ratio; GMR [90% confidence interval; CI], 0.833 [0.530, 1.31]). C in the severe hepatic impairment group was comparable to that of the healthy control group (GMR [90% CI], 1.00 [0.636, 1.58]). AUC for alpelisib decreased by approximately 27% in the moderate hepatic impairment group vs. the healthy control group (GMR [90% CI], 0.726 [0.487, 1.08]). AUC was 26% higher in the severe hepatic impairment group compared with the healthy control group (GMR [90% CI], 1.26 [0.845, 1.87]). Overall, 3 participants (13.0%) experienced at least 1 adverse event which were either grade 1 or 2. Adverse events did not lead to study drug discontinuation. No grade 3 or 4 adverse events, serious adverse events or deaths were reported. The results indicate that a single dose of alpelisib was well tolerated in this study population. There was no significant impact of moderate or severe hepatic impairment on the exposure of alpelisib.