Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common form of breast cancer, comprising up to 70% of all breast cancer cases.¹ Unfortunately, endocrine resistance is common, observed in approximately 60% of patients with recurrent disease.^2,3 Activating mutations along the PI3K/AKT/mTOR pathway decrease a tumor’s dependency on estrogen and increase therapeutic resistance. PIK3CA mutations specifically are common in this patient population and often emerge during endocrine therapy but can be present early in tumor development. Although 5-year survival for patients with localized or regional HR+/HER2- is estimated to be between 87% and 99%,¹ primary endocrine resistance has been associated with a median overall survival of just 27.2 months.³ Although newer therapies are improving overall survival outcomes for patients, all available agents are known to cause hyperglycemia. Hyperglycemia can be serious if not managed appropriately; however,  practitioners often dose adjust or discontinue breast cancer therapy too early, leading to poorer outcomes for patients.

In the Q&A below, Dr. Jason Mouabbi explains recommended approaches to monitoring for and managing hyperglycemia, including use of prophylactic metformin. He also provides insights into appropriate timing for endocrinology and primary care referrals. Advanced practitioner Michelle Butaud offers best practices for ascertaining which patients are at increased risk for hyperglycemia and providing education to patients and caregivers about the importance of dietary and lifestyle modifications.

How and when do you test patients for PI3K/AKT/mTOR alterations?

Dr. Mouabbi: Patients with PIK3CA mutations or other AKT1/PTEN alterations have a difficult biology to treat. When these patients experience disease progression while receiving adjuvant therapy or up to 12 months after its completion, genomic testing is important because PI3K/AKT inhibitors are only used if we find the associated mutations or alterations, which can be equally well detected using either liquid or tissue biopsy.

In terms of timing, we currently test upon diagnosis of stage 4 disease and usually after progression on the first-line therapy in the metastatic setting.

Please discuss the current therapeutic landscape for PI3K/AKT inhibitors.

Dr. Mouabbi: We have three treatments for PI3K or AKT inhibition. AKT sits downstream of PI3K, so the idea is that if there is a mutation upstream and you block downstream, you’ll effectively treat for that upstream mutation.  

Inavolisib is the new kid on the block for patients with HR+/HER2- locally advanced or metastatic breast cancer who harbor a PIK3CA mutation. It is approved for use in the first line in combination with palbociclib, a CDK4/6 inhibitor, and fulvestrant, an endocrine therapy backbone.

Approval was based on results of the phase 3 INAVO120 study, which was designed to simultaneously target PI3K, CDK4/6, and estrogen receptor pathways by combining inavolisib with palbociclib and fulvestrant.⁴ Included patients had measurable disease, disease progression during adjuvant endocrine therapy or within 12 months of completion, and no prior metastatic therapy. Patients also had to have a fasting glucose level <126 mg/dL and a glycated hemoglobin (HbA1C) level <6.0%. Patients with Type 1 or certain criteria related to Type 2 diabetes mellitus were excluded. The results of the study were astonishing. The study showed that the addition of the PI3K inhibitor improved progression-free survival (PFS) by more than double. It went from about 7 months to 15 months, with a hazard ratio of around 0.4, so that’s very exciting to see. In addition, inavolisib is the only agent in class to have overall survival data. Inavolisib with palbociclib and fulvestrant showed a 33% reduction in relative risk of death, with a hazard ratio of 0.67, in INAVO120. The median time to subsequent chemotherapy for the triplet was also improved, at 35.6 months vs. 12.6 for just palbociclib and fulvestrant.

The other drug for patients with PIK3CA mutations, alpelisib, has been around since 2019 and isn’t used as much anymore for reasons I’ll discuss later. This one is usually used in the second line in combination with fulvestrant. The SOLAR-1 study did show a doubling of PFS from about 6 months with placebo plus fulvestrant to 11 months for alpelisib plus fulvestrant. It’s important to note, however, that patients in SOLAR-1 did not receive the current standard of care, as the study was initiated before CDK4/6 inhibitors started to make headway.⁵ Because of this, the phase 2 BYLieve was designed to assess alpelisib plus endocrine therapy after a CDK4/6 inhibitor. At 6 months, 53.8% of patients were alive and progression free, the primary endpoint, but 99.2% of patients had discontinued treatment at the data cutoff.⁶   

The one AKT inhibitor in the mix is capivasertib, which is also mainly used in the second line. The CAPItello-291 trial is more contemporary, so patients did use the standard of care in the first line.⁷ Researchers showed a median PFS of about 7 months for capivasertib with fulvestrant compared to only about 3 months for placebo plus fulvestrant, so it was more than doubled, which is impressive.

What side effects might patients experience on these agents, and which are most concerning?

Dr. Mouabbi: Anytime you target this pathway, there are four side effects that we see across all agents because this pathway is heavily involved in metabolism and with the gastrointestinal tract: diarrhea, rash, hyperglycemia, and stomatitis.

Stomatitis can be managed proactively and reactively with a steroid mouthwash. The rash can be managed with an antihistamine pill, and the diarrhea can be managed with antidiarrheal. The adverse event that’s really concerning, however, is hyperglycemia, and each drug has a unique relationship with it.

Alpelisib is notorious for causing hyperglycemia. In SOLAR-1, one-third of the patients essentially became diabetic, defined as developing grade 3 hyperglycemia per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, on the drug.⁵ This resulted in decreased time on the drug because the drug is held once the grade 3 hyperglycemia is discovered. Patients need to see an endocrinologist to begin insulin therapy before treatment can be continued. At that point though, both doctors and patients are reluctant to restart the alpelisib.

Now, thankfully, the next-generation agents are better. Although inavolisib also causes hyperglycemia in 85% of patients, the problematic grade ≥3 hyperglycemia, as defined by the CTCAE version 5.0, was shown to occur in only around 12% of patients. So here we went from about 30% of alpelisib to 12% with inavolisib.⁴

Capivasertib, the downstream inhibitor, has the best hyperglycemia profile, with grade ≥3 hyperglycemia rare but still important to monitor for. In CAPItello-291, developed grade ≥3 hyperglycemia per the CTCAE version 5.0. In fact, the most common event leading to drug discontinuation was rash, or cutaneous.⁷

So, for the hyperglycemia, we went to about 30% with alpelisib down to less than 10% with capivasertib, which is pretty amazing.

What type of baseline testing and subsequent monitoring is recommended, and how does this inform your therapeutic approach? 

Dr. Mouabbi: Monitoring looks different for each agent because of the different hyperglycemia incidence and severity profiles, but hyperglycemia typically makes itself known early in therapy (within 7 to 90 days) . Patients on alpelisib must be monitored at least weekly. Most of the time, we give them an at-home glucose monitor that we ask them to check daily because we’re really worried about severe hyperglycemia. Whereas, with inavolisib, we test weekly for the first 4 weeks, either at home or in the clinic, and then we reduce it to just once a month. With capivasertib, we just check it even less — every 2 weeks the first month and then monthly thereafter, because it has the least risk to cause more severe hyperglycemia.

Everyone, regardless of agent, needs a baseline HbA1C and a baseline fasting glucose level. The results of these tests can be big determinants for therapeutic selection (see Table 1). The different drugs have different thresholds, which makes the baseline testing essential.

If patients have an HbA1C >6.5% and a fasting glucose >160 mg/dL, we refer them to an endocrinologist, who will help patients quickly lower these levels, and then we can start treatment. I should note that if endocrinology support is not available within your practice system, primary care physicians are fantastic at managing hyperglycemia and diabetes. Physicians should not be afraid to work with primary care for help here, because the primary care practitioners are much better at dealing with the day-to-day management of these issues than we are.

Because of the risk for hyperglycemia, a lot of doctors are more reluctant to start these agents at their recommended full doses. They start at the lower dose, and reduce from there, compromising efficacy. This means that the duration of treatment is shorter, and efficacy is decreased as a result. A lower dose was never meant to be a starting point; a lower dose was meant to be an option in case a more serious side effect was experienced.

The idea that a lower dose will not negatively affect patient outcomes is tied to the idea of tolerability, which is very important. A lower dose should not be used to start because some patients will not experience the side effect a physician is concerned about — as a reminder, only 10% of patients on inavolisib develop the serious hyperglycemia and even fewer with capivasertib. So many patients tolerate the recommended dose, with adverse event support and without issue. Some patients will need dose adjustment because their bodies tend to hold on to the drug longer before metabolizing it. So it is logical and necessary to personalize the dose based on the patient, but everyone should be started at the recommended effective dose.

How can providers ensure that therapeutic selection is informed by a patient’s risk factors for hyperglycemia and best prepare patients in terms of lifestyle and dietary modifications?

Michelle Butaud: Anytime we start patients on these agents, we always first assess for risk factors or comorbid conditions. Factors that put patients at high risk for hyperglycemia include diabetes, obesity, steroid use, and older age. We can, working with our endocrinology colleagues as necessary, optimize patients’ blood glucose levels once we evaluate the baseline test results prior to starting the medication.

Our pharmacists also play a critical role with these patients. The pharmacists help with patient education and with determining risk factors, especially when the patient has comorbidities and is on other medications.

In addition to the pharmacist and an endocrinologist, we might have the patient meet with a nutritionist as well because dietary changes are essential to managing hyperglycemia. It’s important to help the patient understand that we’re not really trying to restrict calories, but we do want them to follow a low carbohydrate diet because of the relationship between carbs and sugar. The ideal carbohydrate intake is <100 grams per day. Everyone loves a good app for their phone, so I tell my patients to find a carb tracker they like because these types of apps really help with accurate tracking. Patients should also avoid sweets, of course, limit alcohol, and eat foods high in fiber. It’s critical that they stay hydrated with water — no soda or surgery drinks!

As far as lifestyle changes, regular exercise is very important for these patients as well.

Dr. Mouabbi: I totally agree with Michelle about how critical it is to educate patients about the importance of adhering to dietary and lifestyle changes, especially in the United States. Most of the studies associated with these agents included just a small proportion of US patients, with the majority of patients being from Europe and Asia. We know that those populations tend to have lower rates of metabolic syndrome and glucose impairment compared with the US population. It’s important to remember that, for these reasons, whatever incidence and severity of hyperglycemia  are seen on study gets amplified in the United States.

For example, I can tell you here in Texas, the vast majority of patients are considered pre-diabetic, if they aren’t already diabetic, when we check their HbA1C. So there can be regional differences like this that also drive monitoring and provision of patient education.

In 2025, the FDA updated the label for capivasertib to include glucose monitoring irrespective of HbA1C level. They updated the label to mandate the HbA1C check at least every 2 weeks the first month, and then monthly thereafter. They did this because they noticed that the drug was causing more hyperglycemia for US patients than was reported for the study patient population.

I treat everyone as at high risk for hyperglycemia, until the patient’s lab work proves otherwise. I prefer to be a little bit overcautious because I understand my patient population.

Regarding glucose monitoring, what are some best practices for providing patient education about the importance of testing and encouraging patient–provider communication?

Michelle Butaud: We provide high-risk patients with the prescription for the glucose monitoring device at diagnosis and emphasize the importance of daily monitoring to our ability to optimize or even begin therapy. I usually like them to check their levels every day, prior to their start of therapy. We don’t want the level to creep up right before dosing but, if it does, we emphasize the importance of communication of this information with the clinic. Because patients can be overwhelmed by the amount of information they receive at diagnosis and into the start of therapy, having the caregiver present to hear this information and understand the importance of these measures can sometimes be critical to adherence to glucose monitoring.

All patients are required to monitor at home, and we also draw labs when they come in for their clinic visits for toxicity checks. During these visits and during the initial discussion, I emphasize the importance of the at-home glucose checks by educating on the poor outcomes associated with high blood glucose levels, such as diabetic ketoacidosis and risk of infections. I also tell patients that by monitoring at home, we can identify potential problems early and intervene appropriately to prevent these complications.

We provide patients and caregivers with educational sheets about their specific therapies but also about hyperglycemia in general. We discuss with them the common signs and symptoms that are noted in the educational materials such as excessive thirst, dry mouth, increased urination or unusual fatigue. Patients also might have an increased appetite but experience weight loss simultaneously. We want them to report anything that is out of the ordinary for them — anything that is persistent or getting worse — along with their blood glucose levels. We emphasize communication because prevention of adverse events is the key to their overall outcomes. 

Dr. Mouabbi: I also want to add that the continuous glucose monitoring systems are fantastic. If a patient has a prescription from a doctor, they can get 3 months for free, which is when the bulk of the monitoring would need to happen. I started doing this a lot more in my practice, and some of my colleagues are adopting the practice because it makes patient communication so streamlined during visits. Patients can set alerts based on glucose level, so I can take a quick look at the corresponding app on their phone to see a quick review of the alerts. I tell patients that a level >150 mg/dL warrants a call to the treating physician, and patients should seek emergent care if their level hits >200 mg/dL.

Michelle Butaud: There’s so much technology out there that patients can use. Even for patients not using the continuous glucose monitoring systems, there are glucose-monitoring apps that are easy for patients to add their personal data into, and then the apps create charts and graphs of their levels over a time period. These visuals can be really helpful for patients in terms of seeing the effects of dietary and lifestyle changes.

If hyperglycemia of any grade develops, how do you personally decide dose modification, interruption, or discontinuation?

Dr. Mouabbi: Drug-modification strategies have actually been standardized for us based on the fasting glucose level, monitored monthly once therapy has started (see Table 2).

Table 2. General Dose-modification Strategy Based on Fasting Glucose Levels

Grade	Fasting glucose level (mg/dL)	Management strategy
1	≤160     ≥126 but ≤160	Begin lifestyle modifications, such as reaffirming diets and limiting carbohydrates Consider prophylactic metformin, especially for those patients whose HbA1C is in the pre-diabetic range
2	160-250	Asymptomatic — maintain dose and start metformin Symptomatic — hold the dose and send for endocrinology referral
3	≥250	Hold treatment, send for emergency endocrinology evaluation, begin insulin. Administer hydration (if needed). • If levels rebalance within 7 days, the previous dose may be resumed. • If levels rebalance in 8 days or more, a lower dose may be initiated. • If the fasting glucose was > 500 and returns to > 500 at any point in the 30 days after returning to ≤160, discontinue drug.

In my experience, if the elevated fasting glucose level does not resolve as quickly as I would like, you rarely wind up reducing the dose and continuing therapy. As my practice’s patient population is predisposed to hyperglycemia and diabetes, when the scale tips to above 250 mg/dL, stored or fasting, it takes a longer time to control it and keep it under control.

Metformin is recommended both prophylactically and reactively, depending on the HbA1C level of the patient. What is your preferred strategy for incorporating metformin?

Dr. Mouabbi: The METALLICA study evaluated prophylactic metformin as a way to decrease risk for serious hyperglycemia for patients initiating alpelisib. All patients received prophylactic metformin, regardless of risk profiles. By the end of week 8, researchers saw a huge drop in grade ≥3 hyperglycemia and discontinuation rates due to hyperglycemia.⁸

Since the publication of that study, I am much more willing to prescribe prophylactic metformin for the majority of my patients, unless the patient really doesn’t want to be on metformin for some reason. I explain that the risk for serious hyperglycemia is really within the first few months, after which the body adapts. The guidelines for the individual PI3K/AKT inhibitors, however, say to consider prophylaxis if the patient has grade 1 hyperglycemia, meaning a fasting glucose level of ≥160 mg/dL. But, again, we have the METALLICA study that showed us that this was a safe and effective strategy for everyone from the beginning.

Metformin is a more benign drug because it only works in the gut. It keeps carbohydrates in the gut, and, because carbohydrates retain water, diarrhea results. So it’s a very local process because the drug doesn’t get absorbed by the body. As a medical oncologist, however, I am not comfortable with prescribing other antihyperglycemic agents outside of metformin; I would rely on my endocrinology or primary care colleagues to help with that, if necessary.

Michelle Butaud: Just to add, when we prescribe metformin, we set expectations with patients that diarrhea may occur. We make sure that they have antidiarrheals on hand so that they aren’t miserable in the middle of the night.

References:

1. National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Female Breast Cancer Subtypes. Accessed January 19, 2026. https://seer.cancer.gov/statfacts/html/breast-subtypes.html#:~:text=When%20all%20subtypes%20are%20combined,Unknown%20(6%25)
2. Jeselsohn R, Chen L, Chaudhary N, et al. Endocrine therapy resistance (ETR) in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+, HER2- mBC): prevalence, biomarker characteristics, and outcomes. Poster presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL.
3. Lambertini M, Blondeaux E, Bisagni G, et al. Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies. EClinicalMedicine. 2023;59:101931.
4. Jhaveri KL, Im S-A, Saura C, et al. Overall Survival with Inavolisib in PIK3CA-Mutated Advanced Breast Cancer. N Engl J Med. 2025;393:151-161.
5. André F, Ciruelos EM, Juric D, et al. Alpelisibl plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2–negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-217.
6. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2024;25(12):e629-638.
7. Turner NC, Oliveira SJ, Howell F, et al. Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer. N Engl J Med. 2023;388:2058-2070.
8. Llombart-Cussac A, Pérez-Garcia JM, Ruiz Borrego M, et al. Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial. eClinicalMedicine. 2024;71:102520.