New Insight Into Hyperglycemia Risk With PI3K Inhibitor for Breast Cancer

Severe hyperglycemia has emerged as a common side effect among patients with PIK3CA-mutated breast cancer treated with the PI3K inhibitor alpelisib (Piqray), especially patients treated outside a clinical trial, a retrospective study showed.

Overall, 61.5% of 247 patients developed any degree of hyperglycemia, which reached grade 3/4 severity in 29%. Any grade of hyperglycemia occurred in 34.0% of patients who received alpelisib in a clinical trial versus 80.3% of patients treated in the community. Severe hyperglycemia occurred in 40.2% versus 13.0% of patients treated in community and clinical trial settings, respectively.

An elevated HbA1c level at baseline was associated with an increased likelihood of developing hyperglycemia, highlighting the need to optimize blood sugar levels before starting treatment with alpelisib, reported Sherry Shen, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, and colleagues in Cancer.

“This needs to be done months before initiating alpelisib, because once alpelisib is started, hyperglycemia usually develops within the first 2 weeks of treatment,” Shen said in a statement. “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.”

More than 40% of hormone receptor (HR)-positive breast cancers and almost a fourth of HER2-positive breast cancers harbor PIK3CA mutations. PIK3CA encodes the p110-alpha subunit of PI3K, which mediates insulin signaling and cell growth. Cancer cells exploit the pathway to increase nutrient uptake and trigger uncontrolled proliferation and cell survival, Shen and co-authors noted in their introduction.

Alpelisib is the only PI3K inhibitor approved for breast cancer (in combination with fulvestrant). Hyperglycemia is a known frequent adverse effect of PI3K inhibition. In the phase III SOLAR-1 trial, 63.7% of patients treated with alpelisib developed hyperglycemia, including 36.6% with grade 3/4 severity. Metformin was the standard antihyperglycemic agent used to treat patients in the trial. Ultimately, 6.3% of patients discontinued treatment because of hyperglycemia.

Data on the frequency and severity of hyperglycemia in community-treated patients remain sparse. Additionally, “we didn’t really know what the risk factors were for developing hyperglycemia with alpelisib,” Shen told MedPage Today.

To inform decision making about using the PI3K inhibitor to treat breast cancer, investigators at MSKCC reviewed records of patients with breast cancer treated with alpelisib from Jan. 1, 2013 to Oct. 15, 2021. They identified 247 patients who had confirmed treatment with alpelisib (not just evidence of a prescription). The patients had a baseline median body mass index (BMI) of 25.4 and median HbA1c of 5.5%.

Overall, 152 of 247 patients developed hyperglycemia during treatment with alpelisib, including 72 who had grade 3/4 hyperglycemia. The median time to onset of hyperglycemia was 16 days. Significantly more patients treated in the community developed hyperglycemia and severe hyperglycemia as compared with those treated in clinical trials (P<0.001).

Baseline HbA1c had significant associations with development of hyperglycemia (P<0.001) and for alpelisib dose reduction or discontinuation (P=0.015). Among patients who developed hyperglycemia, 40.9% received treatment, which most often was metformin. Additionally, 19.8% of patients were referred to an endocrinologist, which was associated with a prescription for an SGLT2 inhibitor (P=0.007).

“We identified prediabetes and diabetes, as determined by an abnormal hemoglobin A1c, as putting patients at high risk of developing high blood sugar,” said Shen. “There are patients in whom I would be very reluctant to use alpelisib, particularly patients who have a known diagnosis of diabetes that requires several different types of medications to control their blood sugar, and those in whom, despite those medications, their blood sugar is still not well controlled. I wouldn’t want to give them alpelisib for fear of causing that side effect, which can be dangerous.”

For patients deemed at too high of a risk to give the PI3K inhibitor, the mTOR inhibitor everolimus (Afinitor) is an option, Shen added.

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