Incidence, risk factors, and management of alpelisib‐associated hyperglycemia in metastatic breast cancer

Shen, Sherry; Chen, Yuan; Carpio, Andrea; Chang, Cassandra; Iyengar, Neil M.

doi:10.1002/cncr.34928

Cited by 8 publications

(2 citation statements)

References 42 publications

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“…In metabolism and nutriton disorders, the top three PTs reported cases are hyperglycaemia, decreased appetite and dehydration. These PTs were also reported by other studies [ 23 , 24 ]. Diabetic ketoacidosis and feeding disorder were not reported in the FDA specification or other literature.…”

Section: Discussionsupporting

confidence: 90%

Alpelisib-related adverse events: The FDA Adverse Event Reporting System Database (FAERS) pharmacovigilance study

Li,

Xiang

2024

Heliyon

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Section: Discussionsupporting

confidence: 90%

Alpelisib-related adverse events: The FDA Adverse Event Reporting System Database (FAERS) pharmacovigilance study

Li,

Xiang

2024

Heliyon

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“…However, approximately half of patients receiving alpelisib undergo dose reduction or treatment discontinuation due to severe toxicity related to WT PI3Kα inhibition such as hyperglycemia, diarrhea, and skin rash. These toxicities have made orthosteric inhibitors challenging to use in practice ( 20, 21 ), with intensive glucose monitoring and antidiabetic management limiting broader clinical adoption, and have made some potential combinations intolerable, such as with the CDK4/6 inhibitor ribociclib ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

Varkaris,

Pazolli,

Gunaydin

et al. 2023

Cancer Discovery

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PIK3CA (PI3Ka) is a lipid kinase commonly mutated in cancer, including ~40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Ka inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Ka. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Ka activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Ka. RLY-2608 inhibited tumor growth in PIK3CA mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Ka-related toxicities.

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Optimal hyperglycemia thresholds in patients undergoing chemotherapy: a cross sectional study of oncologists’ practices

Salgado,

Birari,

Alshahawey

et al. 2024

Support Care Cancer

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Purpose Neither the United States nor the European oncology guidelines include details for appropriate management of hyperglycemia in cancer patients. The aim was to identify fasting and random blood glucose thresholds, and hemoglobin A1c (HbA1c) targets used by oncologists in clinical practice when managing hyperglycemia in patients with cancer undergoing chemotherapy. Methods This national, cross sectional study utilized a questionnaire to collect oncologists’ perceptions about optimal blood glucose thresholds and HbA1c targets in patients with cancer undergoing chemotherapy. Descriptive statistics were calculated to summarize glucose thresholds, HbA1c targets, and sample characteristics. Responses to an open-ended question about oncologists’ approach to hyperglycemia management were analyzed via thematic analysis using an inductive approach. Results Respondents (n = 229) were on average 52.1 years of age, 67.7% men, and 91.3% White. For patients without diabetes but experiencing hyperglycemia, oncologists targeted lower and upper fasting blood glucose levels between 75-121 mg/dL and 105-135 mg/dL, respectively. For patients with diabetes, the targets for lower and upper fasting blood glucose levels ranged between 100-130 mg/dL and 128-150 mg/dL, respectively. Fasting blood glucose (95.6%) and HbA1c (78.6%) were the most commonly used clinical indicators to consider chemotherapy dose reduction, delay, or discontinuation due to hyperglycemia in patients receiving chemotherapy with curative intent. Among those receiving palliative intent chemotherapy, the preferred clinical parameters were random blood glucose (90.0%), patient-reported blood glucose readings (70.7%), continuous glucose monitoring readings (65.1%), and patient-reported symptoms of hyperglycemia (65.1%). Three main themes emerged about oncologists’ approach to hyperglycemia management: 1) identification of high-risk patients; 2) need for early identification, screening, and diagnosis of hyperglycemia; and 3) multiple hyperglycemia management strategies. Conclusion Oncologists reported a wide variation of target blood glucose ranges considered appropriate in patients undergoing chemotherapy. Lack of clear guidance for hyperglycemia management during chemotherapy in the United States may be contributing to a lack of consistency in clinical practice.

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Incidence, risk factors, and management of alpelisib‐associated hyperglycemia in metastatic breast cancer

Cited by 8 publications

References 42 publications

Alpelisib-related adverse events: The FDA Adverse Event Reporting System Database (FAERS) pharmacovigilance study

Alpelisib-related adverse events: The FDA Adverse Event Reporting System Database (FAERS) pharmacovigilance study

Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia

Optimal hyperglycemia thresholds in patients undergoing chemotherapy: a cross sectional study of oncologists’ practices

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