Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.
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SUBMITTER: Tankova T
PROVIDER: S-EPMC8997133 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
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Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.
Tankova Tsvetalina T Senkus Elżbieta E Beloyartseva Maria M Borštnar Simona S Catrinoiu Doina D Frolova Mona M Hegmane Alinta A Janež Andrej A Krnić Mladen M Lengyel Zoltan Z Marcou Yiola Y Mazilu Laura L Mrinakova Bela B Percik Ruth R Petrakova Katarina K Rubovszky Gábor G Tokar Margarita M Vrdoljak Eduard E
Cancers 20220322 7
Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), <i>PIK3CA</i>-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. ...[more]
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Project description:PurposeThe combination of fulvestrant with alpelisib, a PI3K inhibitor, improves progression-free survival in metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. This study describes the incidence, risk factors, and treatment of alpelisib-associated hyperglycemia.MethodsPatients with metastatic breast cancer who received alpelisib from 2013 to 2021 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Alpelisib prescription dates and patient/tumor characteristics were abstracted from medical records. Risk factors associated with hyperglycemia and alpelisib dose reduction/discontinuation were evaluated using Pearson's χ2 tests.ResultsAmong 247 patients, baseline median body mass index was 25.4 kg/m2 and median hemoglobin A1c (HbA1c) was 5.5%. A total of 152 patients (61.5%) developed any-grade hyperglycemia and 72 patients (29.2%) developed grade 3-4 hyperglycemia; median time to onset was 16 days. A total of 100 patients (40.5%) received alpelisib on a clinical trial; rates of hyperglycemia were significantly higher in patients treated as standard care versus on a clinical trial (any-grade hyperglycemia 80.3% vs. 34.0%, grade 3-4 hyperglycemia 40.2% vs. 13.0%, p < .001). Baseline HbA1c was significantly associated with development of hyperglycemia (p < .001) and alpelisib dose reduction/discontinuation (p = .015). Among those who developed hyperglycemia, 101 (40.9%) received treatment, most commonly with metformin. A total of 49 patients (19.8%) were referred to an endocrinologist, which was associated with SGLT2 inhibitor prescription (p = .007).ConclusionsRates of hyperglycemia among patients treated with alpelisib as standard care were significantly higher than patients treated on clinical trials. Elevated baseline HbA1c is associated with alpelisib-induced hyperglycemia and requiring dose modification. Optimization of glycemic status before alpelisib initiation should become routine practice.
| S-EPMC10863751 | biostudies-literature
Project description:BackgroundHER2 is amplified or overexpressed in around 20% of breast cancers (BC). HER2-targeted therapies have significantly improved the prognosis of patients with HER2+ BC, however, de novo and acquired resistance to anti-HER2 treatment is common. Activating mutations in the PIK3CA gene are reported in ∼30% of HER2+ BC and are associated with resistance to anti-HER2 therapies and a poor prognosis. Here, we investigated the in vitro and in vivo antitumor efficacy of the alpha-specific PI3K inhibitor alpelisib alone or in combination with anti-HER2 therapy using a panel of HER2+ BC cell lines. We also generated models of acquired resistance to alpelisib to investigate the mechanisms underlying resistance to alpha-specific PI3K inhibition.Materials and methodsPIK3CA mutant (HCC1954, KPL4 and JMT1) and wild-type (BT474 and SKBR3) HER2+ BC cell lines were used. The HCC1954 and KPL4 cells were chronically exposed to increasing concentrations of alpelisib or to alpelisib + trastuzumab in order to generate derivatives with acquired resistance to alpelisib (AR) and to alpelisib + trastuzumab (ATR). The transcriptomic profiles of HCC1954, KPL4 and their AR and ATR derivatives were determined by RNA sequencing. Cell growth was assessed by MTT assay. Changes in the protein levels of key PI3K pathway components were assessed by Western blotting. Gene expression, cellular and patients' data from the Cancer Dependency Map (DepMap) and KMPlot datasets were interrogated.ResultsHER2+ BC cell lines harboring activating mutations in PIK3CA were less sensitive to single or dual anti-HER2 blockade compared to PIK3CA wild-type cells. Alpelisib treatment resulted in dose-dependent inhibition of the growth of cells with or without PIK3CA mutations and enhanced the antitumor efficacy of anti-HER2 therapies in vitro. In addition, alpelisib greatly delayed tumor growth of HCC1954 xenografts in vivo. Functional annotation of the significantly differentially expressed genes suggested the common activation of biological processes associated with oxidation reduction, cell proliferation, immune response and RNA synthesis in alpelisib-resistant models compared with native cells. Eight commonly upregulated genes (log2 fold-change >1, False Discovery Rate [FDR] <0.05) in models with acquired resistance to alpelisib or alpelisib + trastuzumab were identified. Among these, AKR1C1 was associated with alpelisib-resistance in vitro and with a poor prognosis in patients with HER2+ BC.ConclusionsOur findings support the use of an alpha-selective PI3K inhibitor to overcome the therapeutic limitations associated with single or dual HER2 blockade in PIK3CA-mutant HER2+ breast cancer. Future studies are warranted to confirm the potential role of candidate genes/pathways in resistance to alpelisib.
| S-EPMC10353540 | biostudies-literature
Project description:This phase I study aimed to determine tolerability and preliminary efficacy of single-agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28-day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose-limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all-grade treatment-suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression-free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.
| S-EPMC6398875 | biostudies-literature
Project description:BackgroundHyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors.Patients and methodsWe retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method.ResultsThe study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28).ConclusionWhile receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.
| S-EPMC10322119 | biostudies-literature
Project description:BACKGROUND:Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. METHODS:In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. FINDINGS:Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3-4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. INTERPRETATION:Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. FUNDING:Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.
| S-EPMC7025391 | biostudies-literature
Project description:PurposePIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and methodsEligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.ResultsA total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.ConclusionsThe alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.
| S-EPMC8282704 | biostudies-literature
Project description:BackgroundHyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib. Here, we characterize incidence of grade 3/4 alpelisib-related hyperglycemia, along with time to event, management, and outcomes using a machine learning model.MethodsData for the risk model were pooled from patients receiving alpelisib ± fulvestrant in the open-label, phase 1 X2101 trial and the randomized, double-blind, phase 3 SOLAR-1 trial. The pooled population (n = 505) included patients with advanced solid tumors (X2101, n = 221) or HR+/HER2- advanced breast cancer (SOLAR-1, n = 284). External validation was performed using BYLieve trial patient data (n = 340). Hyperglycemia incidence and management were analyzed for SOLAR-1.ResultsA random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA1c, monocytes, age). This model was used to derive a score to classify patients as high or low risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib and fulvestrant in SOLAR-1 showed higher incidence of hyperglycemia (all grade and grade 3/4), increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (16.7% vs. 2.6% of discontinuations) in the high- versus low-risk group. Among patients in SOLAR-1 (alpelisib + fulvestrant arm) with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs. 10.9 months). For external validation, the model was applied to the BYLieve trial, for which successful classification into high- and low-risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed.ConclusionsA risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes.RegistrationClinicalTrials.gov: NCT01219699 (registration date: October 13, 2010; retrospectively registered), ClinicalTrials.gov: NCT02437318 (registration date: May 7, 2015); ClinicalTrials.gov: NCT03056755 (registration date: February 17, 2017).
| S-EPMC10913434 | biostudies-literature
Project description:Germline mutations in the tumor suppressor gene PTEN cause PTEN Hamartoma Tumor Syndrome (PHTS). Pediatric patients with PHTS frequently develop lipomas. Treatment attempts with the mTORC1 inhibitor rapamycin were unable to reverse lipoma growth. Recently, lipomas associated with PIK3CA-related overgrowth syndrome were successfully treated with the novel PI3K inhibitor alpelisib. Here, we tested whether alpelisib has growth-restrictive effects and induces cell death in lipoma cells. We used PTEN-haploinsufficient lipoma cells from three patients and treated them with alpelisib alone or in combination with rapamycin. We tested the effect of alpelisib on viability, proliferation, cell death, induction of senescence, adipocyte differentiation, and signaling at 1-100 µM alpelisib. Alpelisib alone or in combination with rapamycin reduced proliferation in a concentration- and time-dependent manner. No cell death but an induction of senescence was detected after alpelisib incubation for 72 h. Alpelisib treatment led to a reduced phosphorylation of AKT, mTOR, and ribosomal protein S6. Rapamycin treatment alone led to increased AKT phosphorylation. This effect could be reversed by combining rapamycin with alpelisib. Alpelisib reduced the size of lipoma spheroids by attenuating adipocyte differentiation. Since alpelisib was well tolerated in first clinical trials, this drug alone or in combination with rapamycin is a potential new treatment option for PHTS-related adipose tissue overgrowth.
| S-EPMC6826943 | biostudies-literature
Project description:Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a compensatory increase in insulin release, which has been shown to reduce the efficacy of treatment by reactivating the PI3K pathway in preclinical models. Patients with an absolute or relative deficiency in insulin, and those with insulin resistance or pancreatic dysfunction, may experience exacerbated or prolonged hyperglycemia. Therefore, the effective management of PI3Ki-associated hyperglycemia depends on early identification of patients at risk, frequent monitoring to allow prompt recognition of hyperglycemia and its sequelae, and initiating appropriate management strategies. Risk factors for the development of hyperglycemia include older age (≥75 years), overweight/obese at baseline, and family history of diabetes. Consultation with an endocrinologist is recommended for patients considered high risk. The management of PI3Ki-induced hyperglycemia requires an integrative approach that combines diets low in carbohydrates and glucose-lowering medications. Medications that do not affect the PI3K pathway are preferred as the primary and secondary agents for the management of hyperglycemia. These include metformin, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors. Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect of PI3K signaling. Clinical studies show that alpelisib-associated hyperglycemia is reversible and manageable, rarely leading to treatment discontinuation. Management of PI3Ki-associated hyperglycemia in patients with breast cancer should focus on the prevention of acute and subacute complications of hyperglycemia, allowing patients to remain on anticancer treatment longer.
| S-EPMC8793384 | biostudies-literature
Project description:Breast cancer is one of the most common types of cancer among women globally. It is caused by mutations in the estrogen/progesterone receptors and conventional treatment methods are commonly utilized. About 70-80 percent of individuals with the early-stage non-metastatic disease may be cured. Conventional treatment is far less than the optimal ratio, as demonstrated through the high mortality rate of women with this cancer. However, conventional treatment methods like surgery, radiotherapy, and chemotherapy are not as effective as expected and lead to concerns about low bioavailability, low cellular uptake, emerging resistance, and adverse toxicities. A nanomedicine-based approach is a promising alternative for breast cancer treatment. The present era is witnessing rapid advancements in nanomedicine as a platform for investigating novel therapeutic applications and modern intelligent healthcare management strategies. This paper focuses on nanomedicine-based therapeutic interventions that are becoming more widely accepted for improving treatment effectiveness and reducing undesired side effects in breast cancer patients. By evaluating the state-of-the-art tools and taking the challenges involved into consideration, various aspects of the proposed nano-enabled therapeutic approaches have been discussed in this review.
| S-EPMC8911433 | biostudies-literature