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New Insights on a Potentially Serious Side Effect of the Cancer Drug Alpelisib

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New research has uncovered elevated rates of high blood sugar, or hyperglycemia, among patients with breast cancer who are treated with the oral medication alpelisib. The results are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

Alpelisib targets the phosphoinositide 3-kinase (PI3K) protein that is involved in cell growth. When mutated, the protein can contribute to cancer. In 2019, the US Food and Drug Administration approved the use of this drug in combination with fulvestrant, an oestrogen receptor blocker, for certain cases of metastatic breast cancer that have mutations in the gene that codes for a PI3K subunit.

Unfortunately, targeting PI3K can lead to hyperglycemia as a side effect which, if severe, can result in dehydration or kidney damage and can require hospitalisation. Sherry Shen, MD, of Memorial Sloan Kettering Cancer Center, and her colleagues set out to describe the incidence, risk factors, and treatment patterns of alpelisib-associated hyperglycemia in patients with metastatic breast cancer treated in a clinical trial or as standard care at their institution.

Among 147 patients treated with alpelisib as standard care, the rate of hyperglycemia was 80.3% and the rate of serious hyperglycemia was 40.2%. Among 100 patients who were treated during a clinical trial, rates were lower (34.0% any grade and 13.0% serious hyperglycemia). The median time to onset of hyperglycemia after initiating alpelisib was 16 days. An initially elevated hemoglobin A1c, an indicator of high blood sugar such as in prediabetes or diabetes, was a risk factor for later developing hyperglycemia.

Among patients who developed hyperglycemia, 66.4% received treatment, most commonly with the diabetes drug metformin.

“If a patient is identified to have a PI3KCA mutation and [is] thus eligible for treatment with alpelisib, we should be checking hemoglobin A1c level and partnering with the patient’s primary care physician and/or endocrinologist to optimise their blood sugar levels,” said Dr Shen. “This needs to be done months before initiating alpelisib, because once alpelisib is started, hyperglycemia usually develops within the first two weeks of treatment. Being pre-emptive about improving glycemic status and treating prediabetes/diabetes will hopefully lower the patient’s risk of developing hyperglycemia and, thus, lower their risk of needing to discontinue a drug that could be effective for their cancer.”

Senior author Neil Iyengar, MD, noted that optimising a patient’s blood sugar levels often involves changes to dietary and exercise patterns, and potentially introducing certain medications. “Improving metabolic risk factors through lifestyle interventions may also improve dose delivery of alpelisib, and ongoing clinical trials by our group and other groups are testing whether metabolic interventions, such as the ketogenic diet or newer medications used to treat diabetes, could also improve the treatment efficacy of cancer therapies that target the PI3K pathway,” he commented.

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