A 57-year-old woman with metastatic breast cancer developed Fournier’s gangrene, a life-threatening necrotizing infection of the perineal region, following severe hyperglycemia induced by the targeted cancer therapy inavolisib. Published in Frontiers in Pharmacology, this case report describes the first known instance of this specific complication arising from a PI3Kα inhibitor. The patient, who had PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer, was receiving a combination of fulvestrant, palbociclib, and inavolisib when her blood glucose levels became dangerously uncontrolled. The sequence of events highlights the potential for metabolic side effects of targeted therapies to precipitate severe infectious complications in patients with pre-existing metabolic vulnerabilities.

Inavolisib is a selective inhibitor and degrader of mutant phosphatidylinositol 3-kinase alpha (PI3Kα), approved for advanced breast cancer with specific genetic mutations. Hyperglycemia is the most frequent class effect associated with this drug, occurring in a majority of patients in clinical trials. The mechanism involves the interruption of insulin signaling pathways, which normally facilitate glucose uptake in peripheral tissues and suppress glucose production in the liver. By blocking PI3Kα, the drug induces acute insulin resistance, leading to elevated blood sugar levels. While this metabolic effect is well-documented, its progression to a necrotizing soft tissue infection had not been previously reported in the peer-reviewed literature.

The patient presented with a history of metabolic syndrome, obesity, and impaired fasting glucose, but no known diabetes mellitus. Before starting inavolisib, her fasting plasma glucose was in the range of 110 to 120 mg/dL, and her glycated hemoglobin (HbA1c) was 5.6%, which is within the normal range. Metformin was started pre-emptively to manage her glucose levels. However, after inavolisib was added to her regimen, she developed grade 3 persistent hyperglycemia. Her fasting glucose rose to 348 mg/dL within nine days, necessitating the addition of insulin glargine. Despite rapid escalation of insulin to a ceiling of 50 IU/day, her peak plasma glucose reached 623 mg/dL, indicating a severe and refractory metabolic response to the therapy.

Forty-seven days after initiating inavolisib, the patient was admitted to the intensive care unit with septic shock. Clinical examination revealed malodorous necrosis of the skin over the perianal region and both buttocks, accompanied by erythema, induration, and bullae. Laboratory studies showed acute kidney injury, metabolic acidosis with an elevated anion gap, and marked elevations in inflammatory markers such as C-reactive protein and procalcitonin. Contrast-enhanced computed tomography demonstrated gas within the soft tissue of the perineum and gluteal region, a hallmark sign of necrotizing infection. Polymicrobial cultures and histology confirmed the diagnosis of Fournier’s gangrene, characterized by vascular thrombosis, coagulative fat necrosis, and a dense neutrophilic infiltrate.

The treatment required urgent surgical debridement, followed by four additional debridements and a laparoscopic colostomy for fecal diversion. The patient recovered gradually and was discharged, with reconstructive coverage of the gluteal defect performed subsequently. Inavolisib was permanently withdrawn due to the severity of the toxicity, which was graded as grade 4 necrotizing fasciitis according to the Common Terminology Criteria for Adverse Events. Eight months after the initial presentation, the gluteal defect remained durably healed with no recurrence of soft-tissue infection. However, her metastatic breast cancer progressed, requiring two subsequent lines of systemic therapy, including capecitabine and trastuzumab deruxtecan.

The authors suggest that the convergence of severe hyperglycemia and the patient’s pre-existing risk factors created a susceptible environment for the infection. Sustained hyperglycemia is known to impair neutrophil function, including chemotaxis and phagocytosis, and to dampen complement function, thereby favoring bacterial proliferation in soft tissue. The patient’s background of active malignancy, metabolic syndrome, active smoking, and obesity further compromised local tissue perfusion and lymphatic drainage. Although the causal link between inavolisib-induced hyperglycemia and the gangrene is inferred rather than proven, the temporal sequence and the absence of a local portal of entry support the hypothesis that inadequate glycemic control was a proximate contributor.

To assess the novelty of this case, the researchers interrogated the FDA Adverse Event Reporting System (FAERS) for reports naming inavolisib, alpelisib, or capivasertib as the suspect product. The analysis revealed that Fournier’s gangrene appeared only in reports naming inavolisib, with four entries sharing identical patient data, presumably from the same case notified by different marketing authorization holders. No independent cases of Fournier’s gangrene were registered for any other agent in this class. This absence of independent precedent supports the novelty of the report, although the authors caution that spontaneous reporting data lack a denominator of exposed patients and cannot establish causality or incidence rates.

The case underscores the importance of individualized metabolic and infectious risk stratification before initiating PI3Kα inhibition. The patient’s normal pretreatment HbA1c did not exclude the possibility of catastrophic decompensation, illustrating that baseline glycemic control may not fully predict the severity of drug-induced hyperglycemia. The authors note that an oral glucose tolerance test at baseline might have quantified the patient’s reduced glucose tolerance reserve, potentially justifying closer surveillance or a lower threshold for starting basal insulin. Additionally, the timing of glucose monitoring is critical, as hyperglycemia induced by PI3K inhibitors follows each dose, with glucose peaking within hours of administration. Relying solely on fasting determinations may miss the largest excursions, which could have been detected with more frequent post-dose monitoring.

Published guidance recommends interrupting the drug when fasting glucose exceeds 250 mg/dL despite optimized antidiabetic therapy, with reintroduction at a reduced dose only after values fall below 160 mg/dL. In this case, the patient followed this approach, yet drug withdrawal reversed the metabolic abnormality without preventing the infectious complication, which appeared 19 days after inavolisib was permanently discontinued. This delay suggests that the period of greatest vulnerability may precede the decision to interrupt treatment, and that the reversibility of a laboratory value does not guarantee clinical safety. The authors emphasize that perineal or perianal pain accompanied by uncontrolled glucose warrants immediate assessment rather than empirical outpatient antibiotics.

The study has limitations inherent to a single case report. Causality is inferred rather than proven, and the concurrent exposure to antidiabetic agents, alongside a background of predisposing conditions, precludes attribution to any single factor. The Naranjo scale graded the inavolisib–hyperglycemia relationship as definite, but this scale addresses only the direct drug–reaction link and not the subsequent gangrene. The authors suggest that systematic pharmacovigilance reporting and multicenter registry or cohort studies coupled with protocolized prospective glycemic monitoring would be necessary to establish whether this association is reproducible. Such studies could provide a clearer understanding of the risk factors and mechanisms underlying this rare but severe complication.

For clinicians prescribing inavolisib, this case highlights the need to anticipate hyperglycemia and monitor glycemic status closely from the outset. Aggressive treatment of refractory hyperglycemia is essential, and any signs of perineal infection should prompt immediate evaluation. The patient’s perspective, shared in the report, reflects the frightening nature of the illness and the long recovery, while expressing hope that sharing her experience will help doctors recognize this complication early. The case serves as a reminder that even common, generally manageable class effects can escalate into rare and potentially lethal complications in routine practice, particularly in patients with underlying metabolic vulnerabilities.

The contrasting glycemic profiles observed across clinical trials reflect distinct pharmacological mechanisms within the PI3K signaling pathway. In the phase III INAVO120 trial, inavolisib combined with palbociclib and fulvestrant yielded an overall hyperglycemia rate of 63.4 percent, yet grade 3 or 4 elevations occurred in only 5.6 percent of participants. By comparison, the phase III SOLAR-1 trial evaluating the alpha-selective inhibitor alpelisib documented a 63.7 percent overall rate with 36.6 percent developing grade 3 or 4 hyperglycemia, leading to drug discontinuation in 6.3 percent of patients. Conversely, the AKT inhibitor capivasertib in CAPItello-291 produced lower rates, with 16.9 percent any-grade and 2.3 percent severe hyperglycemia. These disparities align with isoform selectivity: insulin-stimulated glucose uptake in adipocytes and skeletal muscle depends specifically on the p110α catalytic subunit, whereas beta, delta, and gamma isoforms are not implicated. Inavolisib selectively degrades mutant p110α, which may partially preserve wild-type metabolic regulation, although cross-trial comparisons remain confounded by INAVO120’s stricter enrollment ceiling requiring fasting glucose below 126 mg/dL and glycated hemoglobin below 6.0 percent.

The case also illustrates the complex interplay of dual toxicities arising from combination targeted regimens. In INAVO120, grade 3 or 4 neutropenia occurred in 80.2 percent of the inavolisib group and 78.4 percent of the placebo group, establishing that severe hematologic suppression stems from palbociclib rather than PI3Kα blockade. Prior to beginning inavolisib for her p.(E542K)-mutated tumor, the patient experienced grade 2 neutropenia requiring a temporary pause in palbociclib dosing. The combination regimen thereby converges a frequent bone-marrow insult with unpredictable metabolic disruption, jointly compromising host defenses. Furthermore, the extensive local tissue loss directly altered subsequent oncology care: when systemic therapy resumed after surgical resolution, gluteal debridement and reconstructive surgery precluded further intramuscular gluteal injections of fulvestrant, necessitating a switch to oral exemestane alongside palbociclib.

Initial emergency and intensive care evaluation also required ruling out classical metabolic crises. Although the patient presented with an arterial pH of 7.22 and acute renal failure, diabetic ketoacidosis and hyperosmolar hyperglycemic state were excluded by a normal beta-hydroxybutyrate level below 0.6 mmol/L and effective serum osmolality of 290 mOsm/kg.

Subject of Research: Case report: Fournier’s gangrene occurring after inavolisib-induced hyperglycemia in a patient with metastatic breast cancer

Article Title: Case report: Fournier’s gangrene occurring after inavolisib-induced hyperglycemia in a patient with metastatic breast cancer

Article References: Santa-Catalina, P. G., Feito, J., Espinal-Matos, S., Pazmiño-Zambrano, M. B., Pinto-Valdivia, R., Abad, M., Fonseca-Sánchez, E., Rodríguez-Sánchez, C. A., & Figuero-Pérez, L. (2026). Case report: Fournier’s gangrene occurring after inavolisib-induced hyperglycemia in a patient with metastatic breast cancer. Frontiers in Pharmacology, 17, Article 1953086. https://doi.org/10.3389/fphar.2026.1953086

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1953086

Keywords: Case, report, Fournier, gangrene, occurring, inavolisib-induced, hyperglycemia, patient, metastatic, breast, cancer