Clinical management of common toxicities with inhibitors targeting the PI3K/AKT/mTOR pathway in breast cancer

KL Jhaveri; NM Iyengar; NC Turner; HS Rugo; J O’Shaughnessy; CH Barrios; G Curigliano; F André; S-A Im; MD Goncalves; ME Lacouture; PA Fasching; R Leung

doi:10.1016/j.esmoop.2025.105936

. 2026 Jan 27;11(2):105936. doi: 10.1016/j.esmoop.2025.105936

Clinical management of common toxicities with inhibitors targeting the PI3K/AKT/mTOR pathway in breast cancer

KL Jhaveri ^1,^2,^∗, NM Iyengar ^2,³, NC Turner ⁴, HS Rugo ⁵, J O’Shaughnessy ⁶, CH Barrios ⁷, G Curigliano ^8,⁹, F André ¹⁰, S-A Im ¹¹, MD Goncalves ^12,¹³, ME Lacouture ¹², PA Fasching ¹⁴, R Leung ¹⁵

PMCID: PMC12865632 PMID: 41604817

Abstract

Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated in oncogenesis, treatment resistance, and disease progression, making it an attractive target for anticancer drug development. Early experiences with PI3K/AKT/mTOR inhibitors have highlighted challenges associated with their modest efficacy, as well as safety and tolerability issues; however, several effective next-generation PI3K/AKT/mTOR inhibitors have now been approved for patients with breast cancer. As a result, there is a growing need to understand the presentation, characteristics, and management of common toxicities (hyperglycemia, rash, stomatitis, and diarrhea). This review summarizes available safety data from phase III randomized clinical trials for approved PI3K/AKT/mTOR pathway-targeted therapies (everolimus, alpelisib, capivasertib, and inavolisib), including incidence, severity, adverse event-related dose modifications, and time to onset. We also provide guidance for preparation, monitoring, and management strategies for integrating these therapies into clinical practice, with the hope that appropriate support will allow patients to tolerate higher PI3K/AKT/mTOR inhibitor dose intensities, which has the potential to translate to improved patient outcomes.

Key words: diarrhea, hyperglycemia, PI3K/AKT/mTOR inhibitors, rash, stomatitis

Highlights

•
Hyperglycemia, rash, stomatitis, and diarrhea are toxicities commonly associated with PI3K/AKT/mTOR inhibitors.
•
We summarize available safety data from PI3K/AKT/mTOR inhibitors in phase III randomized clinical trials.
•
We also provide toxicity preparation and management guidance for integrating these therapies into clinical practice.
•
With appropriate management, we hope to improve tolerability, which may translate into improved patient outcomes.

Introduction

The phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) pathways, collectively known as PI3K/AKT/mTOR, are involved in multiple cellular processes, including growth, survival, and metabolism. PI3K/AKT/mTOR pathway dysregulation contributes to oncogenesis, treatment resistance, and disease progression,¹ making it a target for anticancer drug development. While PI3K/AKT/mTOR pathway-targeted drug development has been ongoing for decades, early experiences with pan-PI3K, pan-AKT, and dual PI3K/mTOR inhibitors have indicated challenges regarding modest efficacy, and safety/tolerability issues. With the introduction of novel, more effective PI3K/AKT/mTOR inhibitors in the clinic, there is a need to understand common toxicity (hyperglycemia, rash, stomatitis, diarrhea) presentation, characteristics,²^,³ and management to optimize patient outcomes. This review summarizes clinical trial safety data for PI3K/AKT/mTOR pathway-targeted breast cancer (BC) therapies and provides guidance for integrating these therapies into clinical practice.

PI3K

Of the four PI3K isoforms (α, β, γ, δ), the most frequently mutated across solid tumors is PIK3CA,⁴ which encodes catalytic subunit α. Approximately 35%-40% of patients with hormone receptor (HR)-positive BC harbor activating PIK3CA mutations.¹^,5, 6, 7 These patients have poor prognosis and survival, and may benefit from effective PI3K-targeted therapies.⁸ Due to high adverse event (AE)-related treatment discontinuation rates with the pan-PI3K inhibitor buparlisib and the PI3Kβ-sparing inhibitor taselisib,9, 10, 11 development of PI3K inhibitors focused on agents with greater α isoform selectivity.

The PI3Kα inhibitor alpelisib, plus fulvestrant, is approved for endocrine therapy-experienced patients with PIK3CA-mutated, HR-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced BC, based on phase III SOLAR-1 results. However, implementation in clinical practice has been challenging due to alpelisib’s safety profile.²^,¹² Inavolisib is a potent and selective PI3Kα inhibitor that also promotes mutated p110α degradation. These properties provide a wider therapeutic window, enabling better drug combinability and sustained pathway inhibition.¹³^,¹⁴ Based on phase III INAVO120 primary analysis results, inavolisib plus palbociclib and fulvestrant was approved by the United States Food and Drug Administration for PIK3CA-mutated, HR-positive, HER2-negative, endocrine-resistant advanced BC following recurrence on or after completing adjuvant endocrine therapy.³^,¹⁵ The combination was also recently approved by the European Medicines Agency for PIK3CA-mutated, estrogen receptor-positive, HER2-negative, locally advanced or metastatic BC, following recurrence on or within 12 months of completing adjuvant endocrine treatment.¹⁶ A significant overall survival benefit was observed at the final analysis.¹⁷

AKT

Capivasertib is a small-molecule inhibitor of all three AKT isoforms¹⁸ that, in combination with fulvestrant, is approved in the United States for HR-positive, HER2-negative locally advanced or metastatic BC with one or more PIK3CA, AKT1, or PTEN alteration in patients who progressed on endocrine-based therapy in the metastatic setting, or who experienced recurrence at or within 12 months of completing adjuvant therapy. In the European Union, it is approved following recurrence/progression on or after endocrine-based therapy. Approval was based on phase III CAPItello-291 results.¹⁹

mTOR

Everolimus is an mTOR inhibitor approved for HR-positive, HER2-negative advanced BC in combination with exemestane, in postmenopausal women after recurrence/progression following a non-steroidal aromatase inhibitor, based on the phase III BOLERO-2 results.²⁰ Everolimus plus tamoxifen or fulvestrant was investigated before cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approvals in the phase II TAMRAD²¹ and PrE0102²² trials, respectively. Results from the ALCINA study of everolimus plus fulvestrant in CDK4/6 inhibitor-treated patients have been published.²³ Some real-world data on everolimus treatment after CDK4/6 inhibitors also exist²⁴^,²⁵; however, data from prospective randomized controlled trials are lacking. Ongoing efforts include the phase III evERA BC study of everolimus plus giredestrant versus everolimus plus physician’s choice of standard-of-care endocrine therapy in CDK4/6 inhibitor-treated patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC.²⁶

Biomarker testing

Testing is vital for ensuring patients receive PI3K/AKT/mTOR inhibitors in the appropriate setting. Testing for PIK3CA mutations in BC commonly occurs after first-line treatment,²⁷ consistent with current treatment algorithms (based on approved treatments).²⁸^,²⁹ The recent inavolisib approval for patients with advanced BC following recurrence on or after completing adjuvant endocrine therapy¹⁵^,¹⁶ highlights the importance of earlier PIK3CA testing. Biomarker testing can also guide treatment assignment: e.g. elacestrant for ESR1 mutations, alpelisib/inavolisib for PIK3CA mutations, and capivasertib or poly (ADP-ribose) polymerase inhibitors for PIK3CA/AKT/PTEN or BRCA mutations, respectively.30, 31, 32, 33, 34, 35 Additionally, testing for loss of PTEN (through PTEN mutation testing or through PTEN immunohistochemistry, although caution should be taken with the latter due to some PTEN mutations still allowing protein synthesis but without the functional phosphatase domain responsible for its tumor suppressor properties³⁶) can help identify patients with PI3K inhibitor resistance or enhanced AKT inhibitor sensitivity.37, 38, 39

A key consideration for biomarker testing is sample type. PIK3CA mutations are truncal and can be tested in primary tumors or metastases using either tissue or plasma samples and approved polymerase chain reaction or next-generation sequencing techniques. In contrast, PTEN alteration testing is more reliable using tissue samples.⁴⁰

Of note, everolimus was approved for use in all patients with HR-positive BC, rather than a particular biomarker group.⁴¹ Everolimus efficacy biomarkers were later investigated.⁴² For upcoming PI3K/AKT/mTOR inhibitors, early biomarker testing is important to guide first-line treatment decisions.

PI3K/AKT/mTOR pathway-mediated side-effect mechanisms of action

The PI3K/AKT/mTOR inhibitor mechanisms of action that cause hyperglycemia, stomatitis, rash, and diarrhea are shown in Table 1.

Table 1.

Mechanisms of action of PI3K/AKT/mTOR pathway-mediated adverse events

Adverse event	Potential mechanisms of action
Hyperglycemia	• Potentially caused by inhibition of insulin-dependent signaling, which affects glycogen synthesis and glucose uptake.⁴³^,⁴⁴ • PI3K/AKT/mTOR pathway inhibitors block AKT-mediated GLUT4 translocation, resulting in reduced glucose uptake into muscles and adipose tissue, which in turn signals increased insulin production in the pancreas.⁴⁵ It also increases glycogenolysis and gluconeogenesis, which further increases blood glucose levels and insulin production.⁴⁵ If the patient is unable to produce enough insulin (undiagnosed prediabetes, due to either subacute beta cell burnout or a chronic loss in beta cell mass) or develops AKT-mediated insulin resistance, hyperglycemia occurs. • Although insulin therapy would correct the hyperglycemia, excess insulin may reduce the effectiveness of PI3K inhibitors on the tumor, representing a disconnect in this setting between treating the tumor and preventing hyperglycemia side effects.
Rash	• Potentially caused by reduction of keratinocyte growth and differentiation upon PI3K/AKT/mTOR pathway inhibition.⁴⁶
Stomatitis	• Potentially caused by a reduction in pro-survival proteins leading to apoptosis of epithelial cells, alongside promoting secretion of pro-inflammatory cytokines and recruitment of macrophages leading to autophagy.⁴⁷
Diarrhea	• Primarily driven by disruption of intestinal homeostasis, reduced enterocyte function and survival, altered mucosal immunity, and inflammation.⁴⁸ • Diarrhea has also been associated with PI3Kδ inhibitors, possibly through T-cell dsyregulation.49, 50, 51

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AKT, protein kinase B; GLUT4, glucose transporter type 4; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase.

Common toxicity characteristics and monitoring

We have summarized phase III clinical trial (Table 2) data for common toxicities for everolimus, alpelisib, capivasertib, and inavolisib. Cross-trial comparisons should be made with caution, given differences in trial designs, patient populations, analyses, and reporting methods. Notably, these trials differ in the AE reporting guidelines used. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3 (used in BOLERO-2) and v4 (used in SOLAR-1) grades hyperglycemia based on fasting blood glucose (FBG) levels, whereas v5 grading (used in CAPItello-291 and INAVO120) reflects interventions.²^,³^,¹⁹^,²⁰^,⁵²^,⁵³ v5 leads to fewer high-grade events, since grade 3 is assigned only if patients require hospitalization or intravenous therapy. Events managed with oral medication [e.g. metformin or sodium-glucose cotransporter-2 (SGLT2) inhibitors] are grade 1-2, which reclassifies many previously high-grade events. Many agree that v5 better reflects patient burden, as many patients with cancer experience transient or mild treatment-related hyperglycemia with no urgent intervention required. Exclusion criteria for glycated hemoglobin (HbA_1c) and FBG levels also differed between trials (Table 3).²^,³^,¹⁹^,²⁰ Finally, INAVO120 used grouped terms for AEs, and SOLAR-1 and CAPItello-291 used both preferred and grouped terms (BOLERO-2 did not specify which terms were reported).²^,³^,¹⁹^,²⁰^,⁵²^,⁵³ Table 3 summarizes the characteristics of hyperglycemia, rash, stomatitis, and diarrhea observed in phase III clinical trials. While long-term safety data from INAVO120 are not yet available, the phase I/Ib GO39374 study of inavolisib as a single agent and in combination with palbociclib and/or endocrine therapy in patients with PIK3CA-mutated, HR-positive, HER2-negative metastatic BC with HbA_1c <7% collected safety data for patients treated for >1 year (AEs graded based on CTCAE v4) (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105936).⁶⁶

Table 2.

Phase III randomized clinical trials of PI3K/AKT/mTOR inhibitors in advanced breast cancer (showing study populations and primary endpoint results)

Study	Population	N	HbA_1c inclusion criterion	FBG inclusion criterion	Setting	Treatment	INV-PFS (primary endpoint)
BOLERO-2²⁰ NCT00863655	HR-positive, HER2-negative nonamplified	724 (everolimus: n = 485; placebo: n = 239)	NR	NR	2L+	Everolimus (10 mg daily) or placebo plus 0exemestane (25 mg daily)	Investigator-assessed: 6.9 months versus 2.8 months (hazard ratio 0.43) Central assessment:10.6 months versus 4.1 months (hazard ratio 0.36)
SOLAR-1² NCT02437318	HR-positive, HER2-negative	572 (alpelisib: n = 284; placebo: n = 288)	≤6.4%	≤140 mg/dl	2L+	Alpelisib (300 mg orally once daily) or placebo plus fulvestrant (500 mg intramuscular injection on cycle 1 days 1 and 15 and on day 1 for subsequent cycles)	PIK3CA-mutated: 11.0 months versus 5.7 months (hazard ratio 0.65) PIK3CA-wild-type: 7.4 months versus 5.6 months (hazard ratio 0.85)
CAPItello-291¹⁹ NCT04305496	HR-positive, HER2-negative	708 (capivasertib: n = 355; placebo: n = 353)	<8.0%	NR	2L+	Capivasertib (400 mg orally twice daily for 4 days, followed by 3 days off) or placebo plus fulvestrant (500 mg intramuscular injection on cycle 1 days 1 and 15 and on day 1 for subsequent cycles)	Overall population: 7.2 months versus 3.6 months (hazard ratio 0.60) AKT pathway-altered population: 7.3 months versus 3.1 months (hazard ratio 0.50)
INAVO120³ NCT04191499	HR-positive, HER2-negative, PIK3CA-mutated	325 (inavolisib: n = 161; placebo: n = 164)	<6.0%	<126 mg/dl	1L	Inavolisib (9 mg orally once daily) or placebo plus palbociclib (125 mg orally once daily on days 1-21 of each 28-day cycle) and fulvestrant (500 mg intramuscular injection on cycle 1 days 1 and 15 and on day 1 for subsequent cycles)	15.0 months versus 7.3 months (hazard ratio 0.43)

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1L, first line; 2L+, second or later line; AKT, protein kinase B; FBG, fasting blood glucose; HbA_1c, glycated hemoglobin; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; INV-PFS, investigator-assessed progression-free survival; mTOR, mammalian target of rapamycin; NR, not reported; PI3K, phosphatidylinositol 3-kinase.

Table 3.

Summary of the characteristics of hyperglycemia, rash, stomatitis, and diarrhea in phase III clinical trials

	Everolimus²⁰^,54, 55, 56, 57, 58, 59 (BOLERO-2: CTCAE v3^a)	Alpelisib²^,⁵² (SOLAR-1: CTCAE v4^a)	Capivasertib¹⁹^,⁶⁰^,⁶¹ (CAPItello-291: CTCAE v5^b)	Inavolisib³^,⁵³^,⁶² (INAVO120: CTCAE v5^b)
Hyperglycemia
All grade	13%	63.7%	16.3%	58.6%
Grade 3-4	<5%	36.6%	2.3%	5.6%
Dose reductions	NR	NR	0.5%	2.5%
Dose interruptions	NR	NR	2.5%	27.2%
Discontinuation rates	0.2%^c	6.3%	0.3%	0.6%
Time to onset	NR	Grade ≥3: 15 days	15 days	7.0 days
Additional information	• 9% of patients had diabetes at study entry and 11% developed grade ≥2 hyperglycemia or new-onset diabetes • Any-grade hyperglycemia incidence was numerically higher in patients with visceral metastases versus those without, non-Asian patients versus Asian patients, and in patients <70 years old versus those who were ≥70 years old (although severe hyperglycemia occurred more often in the older group) • In patients whose last treatment before study entry was in the neoadjuvant setting, hyperglycemia occurred in 17% (grade 3-4: 8%)	• 31.9% with PIK3CA mutations who received hyperglycemia medication required insulin, including patients with a history of diabetes mellitus • FBG peaked within 2 weeks of treatment, and was higher in the prediabetic and diabetic groups than the normal FBG group^d • Patients in the prediabetic group had more frequent (74% versus 52%) and higher-grade hyperglycemia than the normal group^d	• Serious hyperglycemia and hyperglycemia leading to hospitalization occurred in 0.8% of patients each. Hyperglycemia was more frequent in patients with a history of diabetes at baseline (29.4% versus 15.6% for patients with no history of diabetes) or with a BMI ≥30 kg/m² (21.2% versus 16.1% for patients with a BMI <30 kg/m²)	NA
Rash
All grade	36%	35.6%	38.0%	25.3%
Grade 3-4	1%	9.9%	12.1%^e	0%
Dose reductions	NR	NR	4.5%	0.6%
Dose interruptions	NR	NR	11.8%	1.2%
Discontinuation rates	1.7%^f	3.2%	4.5%	0%
Time to onset	NR	Grade ≥3: 13 days	12 days	29.0 days
Additional information	• Incidence of any-grade rash was numerically higher in patients with visceral metastases versus those without, Asian versus non-Asian patients, and in patients <70 years old versus those who were ≥70 years old • Rash occurred in 37% (none grade 3-4) of patients whose last treatment before study entry was in the neoadjuvant setting	NA	• Serious rash and rash leading to hospitalization occurred in 2.0% of patients	NA
Stomatitis
All grade	56%	24.6%	14.6%	51.2%
Grade 3-4	8%	2.5%	2.0%	5.6%
Dose reductions	23.7%	NR	NR	3.7%
Dose interruptions		NR	NR	9.9%
Discontinuation rates	2.7%^g	1.4%	0.3%	0.6%
Time to onset	NR	NR	NR	13.0 days
Additional information	• Incidence of any-grade stomatitis was comparable in patients with visceral metastases versus those without, and was numerically higher in Asian versus non-Asian patients and in patients <70 years old versus those who were ≥70 years old • Stomatitis occurred in 68% (grade 3-4: 4%) of patients whose last treatment before study entry was in the neoadjuvant setting	NA	NA	NA
Diarrhea
All grade	30%	57.7%	72.4%	48.1%
Grade 3-4	<3%	6.7%	9.3%^h	3.7%
Dose reductions	NR	NR	7.9%	1.2%
Dose interruptions	NR	NR	9.9%	6.8%
Discontinuation rates	NR	2.8%	2.0%	0%
Time to onset	NR	Grade ≥3: 139 days	8 days	15.0 days
Additional information	• Incidence of any-grade diarrhea was comparable in patients with visceral metastases versus those without, and was numerically lower in Asian versus non-Asian patients and in patients <70 years old versus those who were ≥70 years old • Diarrhea occurred in 40% (grade 3-4: 4%) of patients whose last treatment before study entry was in the neoadjuvant setting	NA	• Serious diarrhea and diarrhea resulting in hospitalization occurred in 1.7%	NA

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BMI, body mass index; CTCAE, Common Terminology Criteria for Adverse Events; FBG, fasting blood glucose; HbA_1c, glycated hemoglobin; NA, not applicable; NR, not reported.

CTCAE v3 and v4 hyperglycemia grading is based on FBG levels (grade 1: >the upper limit of normal to 160 mg/dl; grade 2: >160-250 mg/dl; grade 3: >250-500 mg/dl; grade 4: >500 mg/dl).⁶³^,⁶⁴

CTCAE v5 hyperglycemia grading is based on required interventions (grade 1: no intervention required; grade 2: oral any hyperglycemic agent; grade 3: insulin and hospitalization; grade 4: urgent intervention).⁶⁵

All occurred in patients with grade 3-4 hyperglycemia events.

Normal: FBG, <5.6 mmol/l and HbA_1c, <5.7%; prediabetic: FBG, 5.6 to <7.0 mmol/l and HbA_1c, 5.7 to <6.5%; diabetic: FBG, ≥7.0 mmol/l or HbA_1c, ≥6.5%.

None were grade 4 rash events.

Grade 1-2 rash occurred in 1.0% of patients and grade 3-4 rash in 0.6% of patients.

Grade 1-2 stomatitis occurred in 1.9% of patients and grade 3-4 stomatitis in 0.8%.

None were grade 4 diarrhea events.

Hyperglycemia

Hyperglycemia typically occurs within the first month of treatment with alpelisib, capivasertib, and inavolisib.⁵²^,⁵³^,⁶⁰^,67, 68, 69 With everolimus treatment, more than half of grade ≥2 hyperglycemia events occurred within the first 6 weeks and 46% of grade 3-4 events had resolved to grade ≤1 after a median of 29.1 weeks in BOLERO-2.⁵⁴ A retrospective study showed that real-world rates of hyperglycemia with alpelisib were significantly higher than those observed in clinical trials.⁷⁰ The low hyperglycemia incidence and severity with capivasertib were possibly due to the drug’s intermittent dosing schedule (4 days on, 3 days off).¹⁹ In 54 patients who experienced high FBG (>160 mg/dl) in INAVO120, 52 (96%) saw an improvement of ≥1 grade, with an 8-day median time to improvement from the first event (range 2-43 days).³²

Patients’ FBG levels should be frequently and carefully monitored to identify hyperglycemia.⁷¹ Patients must fast overnight for 8-12 h before drawing blood and samples obtained before drug administration for FBG testing. For alpelisib, testing was originally at least once every week for the first 2 weeks of treatment, then at least every 4 weeks, and as clinically indicated. HbA_1c levels should also be monitored every 3 months and as clinically indicated.²^,³¹ The SOLAR-1 protocol was amended to add a clinic visit at day 8 to identify possible hyperglycemia.²^,⁵² The inavolisib United States prescribing information states that FBG and HbA_1c should be evaluated, and that blood glucose should be optimized, before treatment initiation and at regular intervals throughout.³² The label also recommends FBG monitoring once every 3 days for the first week, then once weekly for the next 3 weeks, then once every 2 weeks for the next 8 weeks, then once every 4 weeks thereafter, and as clinically indicated, in patients who experience hyperglycemia after initiating treatment. HbA_1c should be monitored every 3 months and as clinically indicated. In the INAVO120 protocol, FBG monitoring was mandated on days 1, 4, 8, 15, and 22 in the first treatment cycle; days 1 and 15 in the second and third cycles; and on day 1 of subsequent cycles.³ The protocol also scheduled HbA_1c monitoring every three treatment cycles and fasting blood insulin monitoring every treatment cycle. Capivasertib’s United States prescribing information was recently updated based on post-marketing evidence to include FBG monitoring on day 3 or 4 of weeks 1, 2, 4, 6, and 8, then monthly thereafter, and HbA_1c monitoring every 3 months during treatment.³³

As an alternative to measuring FBG levels, continuous glucose monitoring could be used to track glucose levels in real time, with the aim being to keep blood glucose between 70 and 250 mg/dl for >90% of the day. Home glucose monitoring should be considered, particularly for patients with a high hyperglycemia risk. Hyperglycemia symptoms include excessive thirst, more frequent urination, higher than usual urine volumes, and increased appetite with weight loss. In the rare event that patients develop diabetic ketoacidosis, this should be managed with fluid replacement using saline solution, followed by insulin treatment and potassium replacement, as well as bicarbonate or phosphate therapy in patients whose pH remains low or who have severe phosphate deficiency.⁷²

Rash

Rash typically occurs within the first month of treatment with alpelisib, capivasertib, and inavolisib; however, no severe rash (e.g. toxic epidermal necrolysis, erythema migrans, or Stevens–Johnson syndrome) has been reported with inavolisib treatment.⁵²^,⁵³^,⁶⁰^,67, 68, 69 The SOLAR-1 protocol included a clinic visit at day 8 to identify possible skin toxicities.²^,⁵² Patients should be advised to report symptoms immediately, and clinicians should monitor for potential skin reactions at patient visits. Figure 1 shows a patient with alpelisib-induced rash. The most frequent presentation is maculopapular rash, which is characterized by the presence of macules (flat) and papules (elevated); it frequently affects the upper trunk, spreading centripetally, and is associated with pruritus (an intense itching sensation).

Stomatitis

In BOLERO-2, more than one-third of grade ≥2 stomatitis events occurred within the first 2 weeks of treatment; 97% of grade ≥3 events had resolved to grade ≤1 after a median of 3.1 weeks with dose interruption/reduction and 82% had completely resolved after a median of 7.4 weeks.⁵⁴ In INAVO120, stomatitis typically occurred within the first month of inavolisib treatment.⁵³ Clinicians should monitor for potential stomatitis at patient visits; patients should be advised to report symptoms immediately. Stomatitis is characterized by oral mucosal ulceration or inflammation, and usually appears as red, burn-like, or as ulcer-like sores in the mouth.

Diarrhea

With alpelisib, diarrhea was seen over the course of treatment, as shown in SOLAR-1 and real-world data analyses.⁵²^,⁶⁸ In CAPItello-291 and INAVO120, diarrhea typically occurred within the first month of treatment with inavolisib and capivasertib, respectively.⁵³^,⁶⁰ Clinicians should ask their patients if they experience diarrhea or related symptoms at the beginning of each treatment cycle; patients should be advised to report symptoms immediately.

Common toxicity preparation strategies

Hyperglycemia

In SOLAR-1 and INAVO120, patients with FBG ≥100 mg/dl were recommended to have small frequent meals, a low-carbohydrate and high-fiber diet, balancing carbohydrates over the course of the day, and exercise, as appropriate.²^,³ The METALLICA trial demonstrated that use of prophylactic metformin resulted in lower incidence and severity of alpelisib-induced hyperglycemia.⁶⁹ Prophylactic metformin was recommended in INAVO120 for patients with high hyperglycemia risk,³ and the inavolisib United States prescribing information recommends testing FBG and HbA_1c before initiating treatment, and optimizing FBG.³²

The American Diabetes Association identifies several risk factors for developing diabetes, including age, sex, history of gestational diabetes, family history, high blood pressure, physical activity levels, race/ethnicity, and BMI.⁷³ Clinicians should account for these factors, as well as elevated baseline HbA_1c and monocytes, and FBG levels, when treating patients with PI3K/AKT/mTOR inhibitors and consider consulting a diabetologist.⁵²^,⁷¹ Current clinical data are limited to those from specific trial populations; therefore, there is a lack of data representing patients excluded from trials based on eligibility criteria surrounding diabetes status, and HbA_1c and FBG levels (Table 3). The recommendations in this review are based on available evidence and clinicians should take into consideration the individual patient and disease characteristics when applying them in clinical practice. Existing American Diabetes Association guidelines to reduce hyperglycemia risk during treatment include dietary and lifestyle changes,⁷⁴ similar to the SOLAR-1 and INAVO120 recommendations.²^,³ Medical interventions can also be considered, such as prophylactic metformin use. The authors recommend starting metformin treatment and titrating up to the maximum tolerated dose. If needed, an SGLT2 inhibitor can be used alongside metformin. A glucagon-like peptide-1 receptor agonist can be used for patients with a BMI >30 kg/m²; however, the risk of cachexia and malnutrition should be considered. After this, other treatments can then be used in the following order: addition of dipeptidyl peptidase-4 or thiazolidinediones, then sulfonylurea, and finally insulin.

Rash

Prophylactic use of nonsedating antihistamines was recommended in SOLAR-1 to reduce the severity of alpelisib-induced rash; 26.7% of patients who received a prophylactic anti-rash medication experienced rash.⁵² Patients who received prophylactic rash treatment had fewer any-grade and grade 3 events than those who received no prophylactic rash treatment.⁵² As rash observed with inavolisib is typically low grade due to the drug’s high α isoform selectivity, the INAVO120 protocol included no prophylaxis for rash.³^,⁵³ As expected, no grade ≥3 rash was observed in INAVO120.³ Similarly, no primary rash prophylaxis was permitted in CAPItello-291; however, rash was the most frequent grade ≥3 AE in this study, occurring in 12.1% of patients.¹⁹

Prophylactic use of nonsedating antihistamines for rash is recommended for patients receiving alpelisib during the first 4 weeks of treatment.⁷¹ Prophylaxis with cetirizine 10 mg daily during the first 45-60 days of alpelisib treatment showed a potential reduction in rash severity.⁷⁵ No rash preparation strategies were recommended in the INAVO120 protocol, or are listed in inavolisib’s or capivasertib’s United States prescribing information.³^,³²^,³³

Stomatitis

Based on the SWISH trial results, prophylactic dexamethasone mouthwash has become the standard treatment for preventing stomatitis in patients receiving everolimus.²⁸^,⁷⁶ The SOLAR-1 protocol included no prophylaxis for stomatitis.²^,⁵²

Prophylactic dexamethasone mouthwash for stomatitis was recommended for patients receiving inavolisib per the INAVO120 protocol,³ and 20% of the patients who were treated with dexamethasone mouthwash in INAVO120 received it prophylactically⁵³; if dexamethasone was not available, combinations of local anesthetics, antihistamines, corticosteroids, antacids, antifungals, and/or antibiotics could have been used. The United States prescribing information recommends treating stomatitis with a corticosteroid-containing mouthwash, rather than prophylactic use.³² For everolimus, use of topical treatments, such as alcohol-free corticosteroid mouthwash, is also recommended for use prophylactically in the United States prescribing information,⁴¹ and has been shown to eliminate all grade 3 and most grade 2 stomatitis associated with treatment.⁷⁷ Patients should also make dietary and lifestyle modifications, such as avoiding spicy/acidic/salty foods and harsh mouthwashes, to reduce stomatitis risk when receiving a PI3K inhibitor.²

Diarrhea

In SOLAR-1, patient history was reviewed for any previous medication (e.g. laxatives) or diarrhea-inducing disease/condition (e.g. colon surgery, abdominal and pelvic irradiation, nocturnal diarrhea, pain, ulcerative colitis) within the past 12 months that could indicate a risk of diarrhea while receiving alpelisib; patients were to stop all antidiarrheal agents before treatment, and baseline clinical/laboratory studies were carried out to rule out carrier state of Salmonella spp., Clostridium difficile, Campylobacter spp., Giardia, Entamoeba, or Cryptosporidium, which can lead to opportunistic infections in immunosuppressed patients.²^,⁵² The INAVO120 protocol did not permit antidiarrheal medications to be administered prophylactically before initiating study treatment; however, their use was permitted to manage diarrhea events during treatment.⁵³ Consistent with this, prophylactic antidiarrheal medications are not included in inavolisib’s United States prescribing information.³² No primary prophylaxis for diarrhea was permitted in CAPItello-291.¹⁹

Common toxicity management

Supplementary Tables S2-5, available at https://doi.org/10.1016/j.esmoop.2025.105936, summarize guidance from alpelisib’s, inavolisib’s, capivasertib’s, and everolimus’ drug labels and/or study protocols for the management of each common toxicity.

Hyperglycemia

The main aim of hyperglycemia management is to detect and treat patients who develop acute hyperglycemia during the first few weeks of therapy before they develop complications. Metformin was the most common treatment for hyperglycemia in clinical trials.²^,³^,⁵²^,⁵³^,⁶⁰ Metformin treatment should be started at 500 mg daily (1000 mg for patients who develop early significant hyperglycemia) and titrated up every 3-4 weeks in 500-mg intervals to a maximum dose of 2000 mg, until loss of tolerability. An extended-release formulation is preferred; immediate-release formulations should be administered as a split dose two times a day for doses above 500 mg daily. If hyperglycemia cannot be managed with metformin and potentially also an SGLT2 inhibitor (according to oncologist experience/confidence), an endocrinologist should be consulted for guidance. Other treatments used in trials included SGLT2 inhibitors, sulfonylurea, dipeptidyl peptidase-4 inhibitors, and insulin, as well as diets such as carbohydrate restriction.²^,³^,⁵²^,⁵³^,⁶⁰^,⁷⁸ Observational data have shown that SGLT2 inhibitors, which are taken orally once daily, may reduce hyperglycemia more quickly than metformin.⁷⁹ Generally, sulfonylurea should be avoided in PI3K-induced hyperglycemia management due to the risk of rebound hypoglycemia. To manage hyperglycemia in SOLAR-1, insulin was used by 5 of 12 patients with diabetes, 34 of 159 patients with prediabetes, and 13 of 113 patients with normal glycemic status at baseline; 33 patients received it as long-term insulin treatment (>2 days), while 19 received insulin as rescue medication.⁵²

Following the acute phase during the first few weeks, hyperglycemia management is similar to that of type II diabetes mellitus, and monitoring and treatment decisions should be undertaken in collaboration with a diabetologist. The European Society for Medical Oncology (ESMO) guidelines state that clinicians should follow the international recommendations for diabetes mellitus treatment for grade 1-2 hyperglycemia [FBG > the upper limit of normal (ULN) to 250 mg/dl in CTCAE v4], including oral antidiabetics and basal insulin. Treatment interruptions and dose reductions are to be used to manage grade 2 (FBG >160-250 mg/dl) and 3 (FBG >250-500 mg/dl) hyperglycemia, and treatment should be discontinued for grade 4 (FBG >500 mg/dl) hyperglycemia.⁷¹ However, guidance on management of hyperglycemia by severity is complicated by the fact that hyperglycemia grade no longer corresponds to specific glucose ranges in CTCAE v5 (as used in CAPItello-291 and INAVO120³^,¹⁹). Furthermore, although measurement of FBG is the standard approach in oncology, post-prandial glucose levels are considered a better indicator of hyperglycemia in clinical practice. The American Diabetes Association recommends HbA_1c <8% for older patients with coexisting health conditions.⁸⁰ As this equates to an average blood glucose of 183 mg/dl,⁸¹ a post-prandial blood glucose of <250 mg/dl would be a reasonable goal to prevent catabolic wasting and hyperglycemia complications. Oral glucose tolerance tests may also be used if recommended by an endocrinologist, with normal glucose control indicated by 2-h blood glucose levels of <140 mg/dl after consumption of a glucose solution. Continuous glucose monitoring to track glucose levels in real time is recommended by the authors to keep blood glucose between 70 and 250 mg/dl for >90% of the day.

If a patient receiving alpelisib experiences hyperglycemia, FBG should be monitored as clinically indicated, and at least twice weekly until FBG decreases to normal levels.²^,³¹ Patients being treated with alpelisib who are receiving antihyperglycemic medication should have their FBG monitored at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Information from the United States prescribing information or summaries of product characteristics on the management of hyperglycemia during treatment with everolimus, alpelisib, capivasertib, and inavolisib is shown in Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.105936, and a workflow is shown in Figure 2A. In terms of practical guidance, if a patient receiving a PI3K/AKT/mTOR pathway inhibitor experiences hyperglycemia, clinicians should consider consulting an endocrinologist or diabetologist. Patients at high risk of hyperglycemia should be provided with home glucose monitoring, receive education on checking their FBG at home, and consider a diabetic diet or lifestyle changes. Before starting treatment with capivasertib, testing for FBG should be carried out and blood glucose levels optimized; further testing is then carried out at weeks 1, 2, 4, 6, and 8 after starting treatment and then monthly thereafter.³³ Monitoring for hyperglycemia is also required before initiating everolimus and periodically thereafter, with more frequent monitoring required when everolimus is co-administered with other medicinal products associated with hyperglycemia.⁴¹

Rash

The most frequently used anti-rash medications in clinical trials were steroids (topical, oral, intravenous, and transdermal) and antihistamines (fexofenadine, desloratadine, hydroxyzine, and loratadine).²^,⁵²^,⁵³^,⁶⁰ Of 153 patients who developed rash during alpelisib treatment in SOLAR-1, 33.3% used topical steroids and 72.5% used oral, intravenous, or transdermal; antihistamines were the most common treatment in patients who received anti-rash medication before the onset of rash (60 of 86 patients; 69.8%).⁵² Interleukin-5 inhibition with benralizumab demonstrated significant reduction in rash severity among patients receiving alpelisib and upon rechallenge, patients experienced attenuated dermatologic reactions, improved quality of life, and extended duration of therapy adherence.⁸⁷ In patients treated with capivasertib in CAPItello-291, 109 patients required treatment for rash; of these, antihistamines, topical steroids, and systemic steroids were used in 75, 64, and 28 patients, respectively.⁶⁰ Topical steroids were the most common rash medication used in INAVO120, with 19.2% of patients who experienced rash receiving treatment.⁵³

Specific management strategies based on the presentation of the rash are reported in Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.105936, for alpelisib, capivasertib, and inavolisib (no specific rash management strategies exist for everolimus due to its relative infrequency), and a workflow is shown in Figure 2B. For capivasertib, consultation with a dermatologist should be considered for all grades of rash, and secondary prophylaxis with continuing oral antihistamines and/or topical steroids should be considered for patients with persistent rash and/or previous grade 3 rash.⁸⁸ In terms of practical guidance, dermatology consultations are an important aspect of rash management during treatment with any PI3K/AKT/mTOR pathway inhibitor.

Stomatitis

Dexamethasone mouthwash and lidocaine were reported as common medications to treat stomatitis in SOLAR-1 and INAVO120.⁵²^,⁵³

Early intervention of stomatitis is recommended by the ESMO clinical practice guidelines, which state that treatment should be delayed until resolution, and dose reductions are recommended for grade >2 stomatitis; mild toothpaste and gentle hygiene are recommended to treat stomatitis, and the use of steroid dental paste to treat developing ulcerations should be considered.⁷¹ In addition to this, based on results from the SWISH trial demonstrating a reduction in the incidence of grade ≥2 stomatitis with 8 weeks of dexamethasone mouthwash used alongside everolimus plus exemestane compared with historical data from BOLERO-2 (2% versus 33%),⁷⁶ prophylactic use of dexamethasone mouthwash should now be considered the standard of care for reducing stomatitis risk from PI3K/AKT/mTOR inhibitors.

If patients experience stomatitis when receiving inavolisib, clinicians should intervene early, initiate treatment with dexamethasone mouthwash (or other available treatments) if not already used prophylactically (avoiding alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products), and encourage patients to make dietary and lifestyle modifications. Strategies to manage stomatitis are reported in Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2025.105936, for everolimus, alpelisib, and inavolisib (no specific stomatitis management strategies exist for capivasertib), and a workflow is shown in Figure 2C.

Diarrhea

Antipropulsives, such as loperamide, are the most common medications to treat diarrhea in SOLAR-1, CAPItello-291, and INAVO120.⁵²^,⁵³^,⁶⁰

If patients receiving alpelisib experience diarrhea, they should stop all lactose-containing products, alcohol, laxatives, bulk fiber, stool softeners, and high-osmolar food supplements, drink 8-10 large glasses of clear liquids per day, and eat frequent small meals. In SOLAR-1, patients were provided with loperamide tablets at the start of each cycle to manage symptoms of diarrhea at home [initial administration of 4 mg, then 2 mg every 4 h (maximum of 16 mg/day)] at the first sign of loose stool or symptoms of abdominal pain.² Secondary prophylaxis should be considered for patients treated with capivasertib who have recurrent diarrhea.⁶⁰ Strategies to manage diarrhea are reported in Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2025.105936, for alpelisib, capivasertib, and inavolisib (no specific diarrhea management strategies exist for everolimus), and a workflow is show in Figure 2D.

Other notable toxicities

Pneumonitis

In BOLERO-2, pneumonitis occurred in 12% of patients receiving everolimus and was among the most common grade 3-4 AEs (3% of patients).²⁰ The BOLERO-2 protocol recommended monitoring for pneumonitis using pulmonary function tests (spirometry, diffusing capacity for carbon monoxide, and room air O₂ saturation at rest) and chest computed tomography scans, with bronchoscopy with biopsy and/or a bronchoalveolar lavage being carried out only when medically necessary for ensuring patient care.²⁰ Consultation with a pulmonologist was recommended for non-infectious pneumonitis diagnoses.²⁰ Pre-existing pneumonitis was an exclusion criterion in both the SOLAR-1 and the INAVO120 trials and guidance was provided in both protocols for managing pneumonitis that occurred during treatment.²^,³ For alpelisib, this guidance included immediate treatment interruption for any suspected pneumonitis, tests and initiation of treatment for pneumonitis, and permanent discontinuation of alpelisib for patients with confirmed pneumonitis.² For inavolisib, no action was required for grade 1 pneumonitis, treatment was held during corticosteroid treatment for grade 2/3 pneumonitis and was only resumed when pneumonitis had resolved to grade ≤1, and treatment was permanently discontinued for stage 4 pneumonitis.³ In SOLAR-1, serious pneumonitis occurred in 1.1% (serious grade 3-4: 0.4%) of patients in the alpelisib arm.² No grade 3-4 pneumonitis occurred in inavolisib-treated patients in INAVO120.³

Elevated creatinine levels

Guidelines for managing elevated serum creatinine levels were provided in the SOLAR-1 protocol.² These include maintenance of the alpelisib dose for levels <2× the ULN, dose interruption until the event has resolved to grade ≤1 then either maintenance of the dose level if resolved within 7 days or reduction of the dose by one level if resolved in >7 days for levels 2-3× ULN, and permanent discontinuation for levels >3× ULN.² In SOLAR-1, serious increases in blood creatinine occurred in 0.7% (grade 3-4: 0.7%) of alpelisib-treated patients.²

Decreased weight

Any-grade and grade 3 weight loss occurred in 19% and 1% of patients, respectively, with everolimus in BOLERO-2²⁰; 26.8% and 3.9% of patients, respectively, with alpelisib in SOLAR-1²; and 17.0% and 3.7% of patients, respectively, with inavolisib in INAVO120.³² No grade 4 weight loss events were reported in any of these trials and no specific guidelines for managing decreased weight are given in the prescribing information.

Conclusions

Historically, the main challenges with PI3K/AKT/mTOR pathway-targeting inhibitors in BC have been their low therapeutic index and toxicity. Buparlisib and taselisib development was discontinued due to low tolerability.9, 10, 11 The focus has now changed to isoform-specific inhibitors. The extent and duration of PI3Kα inhibition and mutant selectivity are important to minimize on-target side effects, such as hyperglycemia, which occur due to wild-type inhibition. Future directions include allele-specific PI3K/AKT/mTOR inhibitors that could alleviate some of the AEs associated with pathway inhibition.

The next generation of mutant-selective PI3K inhibitors are in the clinic following the recent approval of inavolisib; as such, we focused on the management of common toxicities and prevention strategies for currently approved agents. While we focused on PI3K/ATK/mTOR pathway inhibitor-related toxicities, it is important to note that AEs associated with the four drugs discussed in this article are distinct due to differences in the pathway nodes (PI3K versus AKT versus mTOR). For example, mTOR and AKT have other input pathways aside from PI3K. Therefore, consideration of PI3K/AKT/mTOR as only one pathway may overly simplify the biology such that it limits our understanding of the drugs and cross-resistance. However, they do have common features with respect to practical management in the clinic. With appropriate guidance, education, communication, management, and prevention strategies, we hope that patients will tolerate higher dose intensities, which could optimize outcomes.

Acknowledgments

Funding

This work was supported by research funding, in the form of third-party medical writing support, furnished by Katie Wilson, PhD, of Nucleus Global, an Inizio Company, from F. Hoffmann-La Roche Ltd (no grant number).

Disclosure

KLJ reports a consulting/advisory role for Novartis, Pfizer, Taiho Oncology, Genentech, Inc., AbbVie, Eisai, AstraZeneca, Blueprint Medicines, Seattle Genetics, Olema Pharmaceuticals, Daiichi Sankyo, Sun Pharma Advanced Research Company Ltd, Menarini-Stemline, Merck Pharmaceuticals, Gilead, Scorpion Therapeutics, Lilly/Loxo Oncology, Bicycle Therapeutics, and Zymeworks; and institutional research funding from Novartis, Genentech, Inc., AstraZeneca, Pfizer, Lilly/Loxo Oncology, Zymeworks, Immunomedics/Gilead, Puma Biotechnology, Merck Pharmaceuticals, Eisai, Scorpion Therapeutics, and Blueprint Medicines. NMI reports grants or contracts (institutional) from the National Cancer Institute/NIH, the American Cancer Society, Novartis, SynDevRx, the Breast Cancer Research Foundation, and the American Institute for Cancer Research; consulting fees from Pfizer, Novartis, Genentech/Roche, AstraZeneca, Seattle Genetics, Gilead, SynDevRx, TerSera Therapeutics, BD Life Sciences, Daiichi Sankyo, Bayer, Menarini-Stemline, Puma, and Complement Theory; honoraria from MJH Life Sciences, OncLive, Curio Science, Cardinal Health, Physicians Education Resources, and DAVA Oncology; stock or stock options in Complement Theory and The Bettering Company; and is Editor-in-Chief of Oncology. NCT reports advisory board honoraria from AstraZeneca, Lilly, Pfizer, Roche/Genentech, Novartis, GlaxoSmithKline, Repare Therapeutics, Relay Therapeutics, Gilead Sciences, Inivata, Guardant, and Exact Sciences; and research funding from AstraZeneca, Pfizer, Roche/Genentech, MSD, Guardant Health, Invitae, Inivata, Personalis, and Natera. HSR reports honoraria from Mylan, Puma Biotechnology, and Samsung Bioepis; a consulting/advisory role for Napo Pharmaceuticals; and research funding (institutional) from Astellas Pharma, AstraZeneca, Ayala Pharmaceuticals, Daiichi Sankyo, Genentech, Inc., Gilead Sciences, Lilly, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Sermonix Pharmaceuticals. JOS reports honoraria for consulting and/or advisory boards from AADI Bioscience, Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, BioNTech, Bristol Myers Squibb, Daiichi Sankyo, Duality, Eisai, Eli Lilly, Ellipses, Exact Sciences, G1 Therapeutics, Genentech, Inc., Gilead Sciences, Guardant Health, Hibercell, Jazz Pharmaceuticals, J&J, Menarini-Stemline, Merck, Mersana, Natera, Novartis, Pfizer, Pierre Fabre Pharmaceuticals, Puma Biotechnology, RayzeBio, Roche, Sanofi, Seagen, Stemline Therapeutics, Summitt Therapeutics, Tempus, and TerSera Therapeutics. CHB reports grants/research support (institutional) from Amgen, AstraZeneca, Aveo Oncology, BioNTech, BMS, Daiichi Sankyo, Dizal Pharma, Exelixis, Fortrea, Gilead Sciences, GSK, ICON, IQVIA, Janssen, Labcorp, Lilly, Medpace, MSD, Novartis, Novocure, Nuvisan, OBI Pharma, Parexel, Pfizer, PharmaMar, PPD, PSI, Regeneron, Roche/Genentech, Samsung, Sandoz, Sanofi, Seagen, Servier, Stemline, Syneos Health, Taiho, Takeda, Tolmar, TRIO, and Worldwide; ownership or stocks in Tummi, MEDSir, and CPO; and advisory boards, consulting, travel, and presentation honoraria from Adium, Novartis, Pfizer, Roche/Genentech, MSD, AstraZeneca, Lilly, Daiichi Sankyo, and Gilead. GC reports consulting or advisory roles for Roche, Novartis, Lilly, Pfizer, AstraZeneca, Daiichi Sankyo, Ellipsis, Veracyte, Exact Science, Merck, BMS, Gilead, Sanofi, and Menarini. FA reports research grants or advisory boards, paid to institution (hospital), from AstraZeneca, Daiichi Sankyo, Lilly, Novartis, BMS, Pfizer, Relay Tx, and Roche; and honoraria (self) from Relay Therapeutics, Lilly, and AstraZeneca. SAI reports a consulting or advisory role for AstraZeneca, Daiichi Sankyo Company, Eisai, Eli Lilly and Company, F. Hoffmann-La Roche Ltd, MSD Korea, Novartis, and Pfizer; and research funding from AstraZeneca, Boryung Corporation, Daiichi Sankyo Company, Eisai Korea, F. Hoffmann-La Roche Ltd, and Pfizer. MDG reports equity in Faeth Therapeutics and Skye Biosciences; consulting or advisory roles with Almac Discovery, Faeth Therapeutics, Genentech, Inc., Scorpion Therapeutics, and Skye Biosciences; and patents, royalties, and other intellectual property with Weill Cornell Medicine and Faeth Therapeutics. MEL reports research support and honoraria from Hoth Therapeutics; and consulting fees from Pfizer and Daiichi Sankyo. PAF reports advisory board and invited speaker roles for Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme Lilly, Seagen, Roche, Gilead, and Mylan; institutional funding from BioNtech and Cepheid; research grants from Pfizer; advisory board roles for Agendia and Menarinil; personal fees from Veracyte; invited speaker roles for Guardant Health; and has a relationship with Translational Research in Oncology (TRIO). RL has declared no conflicts of interest.

Supplementary data

Supplementary Material

mmc1.docx^{(63.2KB, docx)}

References

1.LoRusso P.M. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol. 2016;34(31):3803–3815. doi: 10.1200/JCO.2014.59.0018. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.André F., Ciruelos E., Rubovszky G., et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–1940. doi: 10.1056/NEJMoa1813904. [DOI] [PubMed] [Google Scholar]
3.Turner N.C., Im S.A., Saura C., et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584–1596. doi: 10.1056/NEJMoa2404625. [DOI] [PubMed] [Google Scholar]
4.Gerstung M., Jolly C., Leshchiner I., et al. The evolutionary history of 2,658 cancers. Nature. 2020;578(7793):122–128. doi: 10.1038/s41586-019-1907-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Anderson E.J., Mollon L.E., Dean J.L., et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2- metastatic breast cancer. Int J Breast Cancer. 2020;2020 doi: 10.1155/2020/3759179. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Miller T.W., Balko J.M., Arteaga C.L. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29(33):4452–4461. doi: 10.1200/JCO.2010.34.4879. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Martínez-Sáez O., Chic N., Pascual T., et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020;22(1):45. doi: 10.1186/s13058-020-01284-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Fillbrunn M., Signorovitch J., André F., et al. PIK3CA mutation status, progression and survival in advanced HR + /HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022;22(1):1002. doi: 10.1186/s12885-022-10078-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Baselga J., Im S.A., Iwata H., et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(7):904–916. doi: 10.1016/S1470-2045(17)30376-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Di Leo A., Johnston S., Lee K.S., et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(1):87–100. doi: 10.1016/S1470-2045(17)30688-5. [DOI] [PubMed] [Google Scholar]
11.Dent S., Cortés J., Im Y.H., et al. Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial. Ann Oncol. 2021;32(2):197–207. doi: 10.1016/j.annonc.2020.10.596. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Sarfraz H., Bari S., Whiting J., et al. A cohort study of the antitumor efficacy and toxicity profile of alpelisib for metastatic or locally advanced HR+, HER2− breast cancer: a single-institution experience. Oncology. 2023;102(5):414–424. doi: 10.1159/000534953. [DOI] [PubMed] [Google Scholar]
13.Song K.W., Edgar K.A., Hanan E.J., et al. RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (inavolisib) efficacy. Cancer Discov. 2022;12(1):204–219. doi: 10.1158/2159-8290.CD-21-0072. [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Hanan E.J., Braun M.G., Heald R.A., et al. Discovery of GDC-0077 (inavolisib), a highly selective inhibitor and degrader of mutant PI3Kα. J Med Chem. 2022;65(24):16589–16621. doi: 10.1021/acs.jmedchem.2c01422. [DOI] [PubMed] [Google Scholar]
15.U.S. Food and Drug Administration (FDA) FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive Available at.
16.F. Hoffmann-La Roche Ltd European Commission approves Roche’s Itovebi for people with ER-positive, HER2-negative, advanced breast cancer with a PIK3CA mutation. 2025. https://www.roche.com/media/releases/med-cor-2025-07-23 Available at.
17.Jhaveri K., Im S.-A., Saura C., et al. Overall survival with inavolisib in PIK3CA-mutated advanced breast cancer. N Eng J Med. 2025;393:151–161. doi: 10.1056/NEJMoa2501796. [DOI] [PubMed] [Google Scholar]
18.Davies B.R., Greenwood H., Dudley P., et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012;11(4):873–887. doi: 10.1158/1535-7163.MCT-11-0824-T. [DOI] [PubMed] [Google Scholar]
19.Turner N.C., Oliveira M., Howell S.J., et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058–2070. doi: 10.1056/NEJMoa2214131. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Baselga J., Campone M., Piccart M., et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529. doi: 10.1056/NEJMoa1109653. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Bachelot T., Bourgier C., Cropet C., et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718–2724. doi: 10.1200/JCO.2011.39.0708. [DOI] [PubMed] [Google Scholar]
22.Kornblum N., Zhao F., Manola J., et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol. 2018;36(16):1556–1563. doi: 10.1200/JCO.2017.76.9331. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Vasseur A., Cabel L., Hego C., et al. Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis. Oncogene. 2024;43(16):1214–1222. doi: 10.1038/s41388-024-02986-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Mo H., Renna C.E., Moore H.C.F., et al. Real-world outcomes of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors. Clin Breast Cancer. 2022;22(2):142–148. doi: 10.1016/j.clbc.2021.10.002. [DOI] [PubMed] [Google Scholar]
25.Sánchez-Bayona R., Lopez de Sa A., Jerez Gilarranz Y., et al. Everolimus plus endocrine therapy beyond CDK4/6 inhibitors progression for HR+ /HER2- advanced breast cancer: a real-world evidence cohort. Breast Cancer Res Treat. 2024;206(3):551–559. doi: 10.1007/s10549-024-07324-8. [DOI] [PubMed] [Google Scholar]
26.ClinicalTrials.gov A study evaluating the efficacy and safety of giredestrant plus everolimus compared with the physician’s choice of endocrine therapy plus everolimus in participants with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer (evERA Breast Cancer) 2024. https://clinicaltrials.gov/study/NCT05306340 Available at. Accessed November 2024.
27.Park L., Thompson S.L., Roose J., et al. Testing patterns and prevalence of PIK3CA, AKT1, and PTEN alterations among patients (pts) with HR+/HER2- metastatic breast cancer (mBC) in the US. J Clin Oncol. 2024;42(suppl 16) 1041-1041. [Google Scholar]
28.Gennari A., André F., Barrios C.H., et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32(12):1475–1495. doi: 10.1016/j.annonc.2021.09.019. [DOI] [PubMed] [Google Scholar]
29.Burstein H.J., Somerfield M.R., Barton D.L., et al. Endocrine treatment and targeted therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: ASCO Guideline Update. J Clin Oncol. 2021;39(35):3959–3977. doi: 10.1200/JCO.21.01392. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Stemline Therapeutics Inc . Prescribing information; 2023. ORSERDU™ (elacestrant)https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217639Orig1s000correctedlbl.pdf Available at. [Google Scholar]
31.Novartis Pharmaceuticals Corporation . Prescribing information; 2024. PIQRAY® (alpelisib)https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212526s009lbl.pdf Available at. Accessed May 2024. [Google Scholar]
32.F. Hoffmann-La Roche Ltd . Prescribing information; 2024. ITOVEBI (inavolisib)https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/219249s000lbl.pdf Available at. Accessed October 2024. [Google Scholar]
33.AstraZeneca Pharmaceuticals LP . Prescribing information; 2025. TRUQAP™ (capivasertib)https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218197s002lbl.pdf Available at. Accessed May 2025. [Google Scholar]
34.AstraZeneca. LYNPARZA® (olaparib) Prescribing information; 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208558s024lbl.pdf Available at. Accessed December 2, 2022. [Google Scholar]
35.Food and Drug Administration (FDA) Niraparib: FDA label. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf Available at.
36.Lee Y.-R., Chen M., Pandolfi P.P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19(9):547–562. doi: 10.1038/s41580-018-0015-0. [DOI] [PubMed] [Google Scholar]
37.Juric D., Castel P., Griffith M., et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2015;518(7538):240–244. doi: 10.1038/nature13948. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Costa C., Wang Y., Ly A., et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov. 2020;10(1):72–85. doi: 10.1158/2159-8290.CD-18-0830. [DOI] [PubMed] [Google Scholar]
39.Kingston B., Bailleux C., Delaloge S., et al. Exceptional response to AKT inhibition in patients with breast cancer and germline PTEN mutations. JCO Precis Oncol. 2019;3 doi: 10.1200/PO.19.00130. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Vasan N., Chaki M., Benrashid M., et al. Concordance between tissue (tumor DNA) and liquid (ctDNA) biopsy next-generation sequencing (NGS) data in detection of PIK3CA, AKT1, and PTEN alterations in breast cancer: a retrospective analysis. J Clin Oncol. 2024;42(suppl 16) [Google Scholar]
41.Novartis Pharma GmbH Afinitor® (everolimus). Summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/afinitor-epar-product-information_en.pdf Available at.
42.Voutsadakis I.A. Biomarkers of everolimus efficacy in breast cancer therapy. J Oncol Pharm Pract. 2022;28(4):945–959. doi: 10.1177/10781552211073673. [DOI] [PubMed] [Google Scholar]
43.Whiteman E.L., Cho H., Birnbaum M.J. Role of AKT/protein kinase B in metabolism. Trends Endocrinol Metab. 2002;13(10):444–451. doi: 10.1016/s1043-2760(02)00662-8. [DOI] [PubMed] [Google Scholar]
44.Chen X.W., Leto D., Xiong T. A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Mol Biol Cell. 2011;22(1):141–152. doi: 10.1091/mbc.E10-08-0665. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Goncalves M.D., Farooki A. Management of phosphatidylinositol-3-kinase inhibitor-associated hyperglycemia. Integr Cancer Ther. 2022;21 doi: 10.1177/15347354211073163. [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Calautti E., Li J., Saoncella S., Brissette J.L., Goetinck P.F. Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. J Biol Chem. 2005;280(38):32856–32865. doi: 10.1074/jbc.M506119200. [DOI] [PubMed] [Google Scholar]
47.Sonis S., Villa A. A new hypothesis describing the pathogenesis of oral mucosal injury associated with the mammalian target of rapamycin (mTOR) inhibitors. Cancers. 2024;16(1):68. doi: 10.3390/cancers16010068. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Sheng H., Shao J., Townsend C.M., Jr., Evers B.M. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut. 2003;52(10):1472–1478. doi: 10.1136/gut.52.10.1472. [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Weidner A.S., Panarelli N.C., Geyer J.T., et al. Idelalisib-associated colitis: histologic findings in 14 patients. Am J Surg Pathol. 2015;39(12):1661–1667. doi: 10.1097/PAS.0000000000000522. [DOI] [PubMed] [Google Scholar]
50.Gadkar K., Friedrich C., Hurez V., et al. Quantitative systems pharmacology model-based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3-kinase inhibitors. CPT Pharmacometrics Syst Pharmacol. 2022;11(5):616–627. doi: 10.1002/psp4.12749. [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Balagoni H., Chaudhari D., Reddy C., Young M. Idelalisib: a rare cause of enterocolitis. Ann Gastroenterol. 2016;29(2):233–235. doi: 10.20524/aog.2016.0022. [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Rugo H.S., André F., Yamashita T., et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol. 2020;31(8):1001–1010. doi: 10.1016/j.annonc.2020.05.001. [DOI] [PubMed] [Google Scholar]
53.Juric D., Kalinsky K., Turner N.C., et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 phase III randomized trial additional analyses. J Clin Oncol. 2024;42(suppl 16) 1003-1003. [Google Scholar]
54.Rugo H.S., Pritchard K.I., Gnant M., et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014;25(4):808–815. doi: 10.1093/annonc/mdu009. [DOI] [PMC free article] [PubMed] [Google Scholar]
55.Campone M., Bachelot T., Gnant M., et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. Eur J Cancer. 2013;49(12):2621–2632. doi: 10.1016/j.ejca.2013.04.011. [DOI] [PubMed] [Google Scholar]
56.Noguchi S., Masuda N., Iwata H., et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer. 2014;21(6):703–714. doi: 10.1007/s12282-013-0444-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Pritchard K.I., Burris H.A., Ito Y., et al. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor–positive breast cancer in BOLERO-2. Clin Breast Cancer. 2013;13(6):421–432.e428. doi: 10.1016/j.clbc.2013.08.011. [DOI] [PubMed] [Google Scholar]
58.Beck J.T., Hortobagyi G.N., Campone M., et al. Everolimus plus exemestene as first-line therapy in HR+, HER2- advanced breast cancer in BOLERO-2. Breast Cancer Res Treat. 2014;143(3):459–467. doi: 10.1007/s10549-013-2814-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Yardley D.A., Noguchi S., Pritchard K.I., et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870–884. doi: 10.1007/s12325-013-0060-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
60.Rugo H.S., Oliveira M., Howell S.J., et al. Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study. ESMO Open. 2024;9(9) doi: 10.1016/j.esmoop.2024.103697. [DOI] [PMC free article] [PubMed] [Google Scholar]
61.Rugo H.S., Oliveira M., Howell S.J., et al. Capivasertib (c) and fulvestrant (f) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2- advanced breast cancer (ABC): characterization and management of common adverse events (AES) from the phase 3 CAPItello-291 trial. J Clin Oncol. 2023;41(suppl 16):1067. [Google Scholar]
62.Jhaveri K.L., Im S.-A., Saura C., et al. Abstract GS03-13. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: phase III INAVO120 primary analysis. Cancer Res. 2024;84(suppl 9):GS03–GS13. [Google Scholar]
63.National Cancer Institute Common terminology criteria for adverse events v3.0 (CTCAE) 2006. https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v3.pdf Available at.
64.National Cancer Institute Common terminology criteria for adverse events (CTCAE) Version 4.0. 2009. https://www.eortc.be/services/doc/ctc/ctcae_4.03_2010-06-14_quickreference_5x7.pdf Available at.
65.National Cancer Institute Common terminology criteria for adverse events (CTCAE) Version 5.0. 2017. https://www.ctc.ucl.ac.uk/TrialDocuments/Uploaded/Common%20Terminology%20Criteria%20for%20Adverse%20Events%20(CTCAE)%20v5.0_14092023_0.pdf Available at.
66.Bedard P.L., Accordino M.K., Cervantes A., et al. Long-term safety of inavolisib (GDC-0077) in an ongoing phase 1/1b study evaluating monotherapy and in combination (combo) with palbociclib (palbo) and/or endocrine therapy in patients (pts) with PIK3CA-mutated, hormone receptor-positive/HER2-negative (HR+/HER2–) metastatic breast cancer (BC) J Clin Oncol. 2022;40(suppl 16):1052. [Google Scholar]
67.Wang D.G., Barrios D.M., Blinder V.S., et al. Dermatologic adverse events related to the PI3Kα inhibitor alpelisib (BYL719) in patients with breast cancer. Breast Cancer Res Treat. 2020;183(1):227–237. doi: 10.1007/s10549-020-05726-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
68.Miller J., Armgardt E., Svoboda A. The efficacy and safety of alpelisib in breast cancer: a real-world analysis. J Oncol Pharm Pract. 2022;28(5):1152–1156. doi: 10.1177/10781552221096413. [DOI] [PubMed] [Google Scholar]
69.Llombart-Cussac A., Pérez-Garcia J.M., 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 doi: 10.1016/j.eclinm.2024.102520. [DOI] [PMC free article] [PubMed] [Google Scholar]
70.Shen S., Chen Y., Carpio A., Chang C., Iyengar N.M. Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer. Cancer. 2023;129(24):3854–3861. doi: 10.1002/cncr.34928. [DOI] [PMC free article] [PubMed] [Google Scholar]
71.Cardoso F., Paluch-Shimon S., Senkus E., et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) Ann Oncol. 2020;31(12):1623–1649. doi: 10.1016/j.annonc.2020.09.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
72.Joint British Diabetes Societies The management of diabetic ketoacidosis in adults. 2023. https://abcd.care/sites/default/files/site_uploads/JBDS_Guidelines_Current/JBDS_02_DKA_Guideline_with_QR_code_March_2023.pdf Available at. Accessed November 2024. [DOI] [PubMed]
73.Joint British Diabetes Societies for Inpatient Care Take the type 2 risk test. 2025. https://diabetes.org/diabetes-risk-test Available at.
74.American Diabetes Association 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2018;42(suppl 1):S46–S60. doi: 10.2337/dc19-S005. [DOI] [PubMed] [Google Scholar]
75.Gallagher E.J., Moore H., Lacouture M.E., et al. Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique. NPJ Breast Cancer. 2024;10(1):12. doi: 10.1038/s41523-024-00613-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Rugo H.S., Seneviratne L., Beck J.T., et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. 2017;18(5):654–662. doi: 10.1016/S1470-2045(17)30109-2. [DOI] [PubMed] [Google Scholar]
77.Hattori M., Hagiwara S., Kotani H., et al. A single-arm, phase 2 study of steroid-containing mouthwash for the prevention of everolimus-associated stomatitis in multiple tumor types. Int J Clin Oncol. 2019;24(10):1320–1327. doi: 10.1007/s10147-019-01476-0. [DOI] [PubMed] [Google Scholar]
78.Blow T., Hyde P.N., Falcone J.N., et al. Treating alpelisib-induced hyperglycemia with very low carbohydrate diets and sodium-glucose co-transporter 2 inhibitors: a case series. Integr Cancer Ther. 2021;20 doi: 10.1177/15347354211032283. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Weintraub M.A., Liu D., DeMatteo R., Goncalves M.D., Flory J.H. Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition. Breast Cancer Res Treat. 2024;203(1):85–93. doi: 10.1007/s10549-023-07110-y. [DOI] [PubMed] [Google Scholar]
80.American Diabetes Association Professional Practice Committee 13. Older adults: standards of medical care in diabetes – 2022. Diabetes Care. 2022;45(suppl 1):S195–S207. doi: 10.2337/dc22-S013. [DOI] [PMC free article] [PubMed] [Google Scholar]
81.American Diabetes Association What is the A1C test? https://diabetes.org/about-diabetes/a1c Available at.
82.Rodón J., Demanse D., Rugo H.S., et al. A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer. Breast Cancer Res. 2024;26(1):36. doi: 10.1186/s13058-024-01773-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
83.National Institute of Diabetes and Digestive and Kidney Diseases Risk factors for diabetes. 2015. https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/diabetes/game-plan-preventing-type-2-diabetes/prediabetes-screening-how-why/risk-factors-diabetes Available at.
84.Moore H.N., Goncalves M.D., Johnston A.M., et al. Effective strategies for the prevention and mitigation of phosphatidylinositol-3-kinase inhibitor-associated hyperglycemia: optimizing patient care. Clin Breast Cancer. 2025;25(1):1–11. doi: 10.1016/j.clbc.2024.09.017. [DOI] [PubMed] [Google Scholar]
85.Ellis S.L., Moser E.G., Snell-Bergeon J.K., et al. Effect of sitagliptin on glucose control in adult patients with type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med. 2011;28(10):1176–1181. doi: 10.1111/j.1464-5491.2011.03331.x. [DOI] [PubMed] [Google Scholar]
86.Kim N.H., Kim D.L., Kim K.J., et al. Effects of vildagliptin or pioglitazone on glycemic variability and oxidative stress in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a 16-week, randomised, open label, pilot study. Endocrinol Metab (Seoul) 2017;32(2):241–247. doi: 10.3803/EnM.2017.32.2.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
87.Lacouture M.E., Maier T., Pan A., et al. Abstract 3412: Benralizumab for treatment of eosinophil-related cutaneous adverse events associated with checkpoint inhibitors and anticancer targeted therapies: phase 2 study. Cancer Res. 2024;84(suppl 6):3412. [Google Scholar]
88.AstraZeneca. TRUQAP (capivasertib) summary of product characteristics. 2024. https://www.ema.europa.eu/en/documents/product-information/truqap-epar-product-information_en.pdf Available at.

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[bib1] 1.LoRusso P.M. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol. 2016;34(31):3803–3815. doi: 10.1200/JCO.2014.59.0018. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib2] 2.André F., Ciruelos E., Rubovszky G., et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–1940. doi: 10.1056/NEJMoa1813904. [DOI] [PubMed] [Google Scholar]

[bib3] 3.Turner N.C., Im S.A., Saura C., et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584–1596. doi: 10.1056/NEJMoa2404625. [DOI] [PubMed] [Google Scholar]

[bib4] 4.Gerstung M., Jolly C., Leshchiner I., et al. The evolutionary history of 2,658 cancers. Nature. 2020;578(7793):122–128. doi: 10.1038/s41586-019-1907-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib5] 5.Anderson E.J., Mollon L.E., Dean J.L., et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2- metastatic breast cancer. Int J Breast Cancer. 2020;2020 doi: 10.1155/2020/3759179. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib6] 6.Miller T.W., Balko J.M., Arteaga C.L. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29(33):4452–4461. doi: 10.1200/JCO.2010.34.4879. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib7] 7.Martínez-Sáez O., Chic N., Pascual T., et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020;22(1):45. doi: 10.1186/s13058-020-01284-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib8] 8.Fillbrunn M., Signorovitch J., André F., et al. PIK3CA mutation status, progression and survival in advanced HR + /HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022;22(1):1002. doi: 10.1186/s12885-022-10078-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib9] 9.Baselga J., Im S.A., Iwata H., et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(7):904–916. doi: 10.1016/S1470-2045(17)30376-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib10] 10.Di Leo A., Johnston S., Lee K.S., et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(1):87–100. doi: 10.1016/S1470-2045(17)30688-5. [DOI] [PubMed] [Google Scholar]

[bib11] 11.Dent S., Cortés J., Im Y.H., et al. Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial. Ann Oncol. 2021;32(2):197–207. doi: 10.1016/j.annonc.2020.10.596. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib12] 12.Sarfraz H., Bari S., Whiting J., et al. A cohort study of the antitumor efficacy and toxicity profile of alpelisib for metastatic or locally advanced HR+, HER2− breast cancer: a single-institution experience. Oncology. 2023;102(5):414–424. doi: 10.1159/000534953. [DOI] [PubMed] [Google Scholar]

[bib13] 13.Song K.W., Edgar K.A., Hanan E.J., et al. RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (inavolisib) efficacy. Cancer Discov. 2022;12(1):204–219. doi: 10.1158/2159-8290.CD-21-0072. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib14] 14.Hanan E.J., Braun M.G., Heald R.A., et al. Discovery of GDC-0077 (inavolisib), a highly selective inhibitor and degrader of mutant PI3Kα. J Med Chem. 2022;65(24):16589–16621. doi: 10.1021/acs.jmedchem.2c01422. [DOI] [PubMed] [Google Scholar]

[bib15] 15.U.S. Food and Drug Administration (FDA) FDA approves inavolisib with palbociclib and fulvestrant for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, advanced breast cancer. 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inavolisib-palbociclib-and-fulvestrant-endocrine-resistant-pik3ca-mutated-hr-positive Available at.

[bib16] 16.F. Hoffmann-La Roche Ltd European Commission approves Roche’s Itovebi for people with ER-positive, HER2-negative, advanced breast cancer with a PIK3CA mutation. 2025. https://www.roche.com/media/releases/med-cor-2025-07-23 Available at.

[bib17] 17.Jhaveri K., Im S.-A., Saura C., et al. Overall survival with inavolisib in PIK3CA-mutated advanced breast cancer. N Eng J Med. 2025;393:151–161. doi: 10.1056/NEJMoa2501796. [DOI] [PubMed] [Google Scholar]

[bib18] 18.Davies B.R., Greenwood H., Dudley P., et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012;11(4):873–887. doi: 10.1158/1535-7163.MCT-11-0824-T. [DOI] [PubMed] [Google Scholar]

[bib19] 19.Turner N.C., Oliveira M., Howell S.J., et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058–2070. doi: 10.1056/NEJMoa2214131. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib20] 20.Baselga J., Campone M., Piccart M., et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529. doi: 10.1056/NEJMoa1109653. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib21] 21.Bachelot T., Bourgier C., Cropet C., et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol. 2012;30(22):2718–2724. doi: 10.1200/JCO.2011.39.0708. [DOI] [PubMed] [Google Scholar]

[bib22] 22.Kornblum N., Zhao F., Manola J., et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol. 2018;36(16):1556–1563. doi: 10.1200/JCO.2017.76.9331. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib23] 23.Vasseur A., Cabel L., Hego C., et al. Fulvestrant and everolimus efficacy after CDK4/6 inhibitor: a prospective study with circulating tumor DNA analysis. Oncogene. 2024;43(16):1214–1222. doi: 10.1038/s41388-024-02986-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib24] 24.Mo H., Renna C.E., Moore H.C.F., et al. Real-world outcomes of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors. Clin Breast Cancer. 2022;22(2):142–148. doi: 10.1016/j.clbc.2021.10.002. [DOI] [PubMed] [Google Scholar]

[bib25] 25.Sánchez-Bayona R., Lopez de Sa A., Jerez Gilarranz Y., et al. Everolimus plus endocrine therapy beyond CDK4/6 inhibitors progression for HR+ /HER2- advanced breast cancer: a real-world evidence cohort. Breast Cancer Res Treat. 2024;206(3):551–559. doi: 10.1007/s10549-024-07324-8. [DOI] [PubMed] [Google Scholar]

[bib26] 26.ClinicalTrials.gov A study evaluating the efficacy and safety of giredestrant plus everolimus compared with the physician’s choice of endocrine therapy plus everolimus in participants with estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer (evERA Breast Cancer) 2024. https://clinicaltrials.gov/study/NCT05306340 Available at. Accessed November 2024.

[bib27] 27.Park L., Thompson S.L., Roose J., et al. Testing patterns and prevalence of PIK3CA, AKT1, and PTEN alterations among patients (pts) with HR+/HER2- metastatic breast cancer (mBC) in the US. J Clin Oncol. 2024;42(suppl 16) 1041-1041. [Google Scholar]

[bib28] 28.Gennari A., André F., Barrios C.H., et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32(12):1475–1495. doi: 10.1016/j.annonc.2021.09.019. [DOI] [PubMed] [Google Scholar]

[bib29] 29.Burstein H.J., Somerfield M.R., Barton D.L., et al. Endocrine treatment and targeted therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: ASCO Guideline Update. J Clin Oncol. 2021;39(35):3959–3977. doi: 10.1200/JCO.21.01392. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib30] 30.Stemline Therapeutics Inc . Prescribing information; 2023. ORSERDU™ (elacestrant)https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217639Orig1s000correctedlbl.pdf Available at. [Google Scholar]

[bib31] 31.Novartis Pharmaceuticals Corporation . Prescribing information; 2024. PIQRAY® (alpelisib)https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212526s009lbl.pdf Available at. Accessed May 2024. [Google Scholar]

[bib32] 32.F. Hoffmann-La Roche Ltd . Prescribing information; 2024. ITOVEBI (inavolisib)https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/219249s000lbl.pdf Available at. Accessed October 2024. [Google Scholar]

[bib33] 33.AstraZeneca Pharmaceuticals LP . Prescribing information; 2025. TRUQAP™ (capivasertib)https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218197s002lbl.pdf Available at. Accessed May 2025. [Google Scholar]

[bib34] 34.AstraZeneca. LYNPARZA® (olaparib) Prescribing information; 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208558s024lbl.pdf Available at. Accessed December 2, 2022. [Google Scholar]

[bib35] 35.Food and Drug Administration (FDA) Niraparib: FDA label. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf Available at.

[bib36] 36.Lee Y.-R., Chen M., Pandolfi P.P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19(9):547–562. doi: 10.1038/s41580-018-0015-0. [DOI] [PubMed] [Google Scholar]

[bib37] 37.Juric D., Castel P., Griffith M., et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2015;518(7538):240–244. doi: 10.1038/nature13948. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib38] 38.Costa C., Wang Y., Ly A., et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov. 2020;10(1):72–85. doi: 10.1158/2159-8290.CD-18-0830. [DOI] [PubMed] [Google Scholar]

[bib39] 39.Kingston B., Bailleux C., Delaloge S., et al. Exceptional response to AKT inhibition in patients with breast cancer and germline PTEN mutations. JCO Precis Oncol. 2019;3 doi: 10.1200/PO.19.00130. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib40] 40.Vasan N., Chaki M., Benrashid M., et al. Concordance between tissue (tumor DNA) and liquid (ctDNA) biopsy next-generation sequencing (NGS) data in detection of PIK3CA, AKT1, and PTEN alterations in breast cancer: a retrospective analysis. J Clin Oncol. 2024;42(suppl 16) [Google Scholar]

[bib41] 41.Novartis Pharma GmbH Afinitor® (everolimus). Summary of product characteristics. https://www.ema.europa.eu/en/documents/product-information/afinitor-epar-product-information_en.pdf Available at.

[bib42] 42.Voutsadakis I.A. Biomarkers of everolimus efficacy in breast cancer therapy. J Oncol Pharm Pract. 2022;28(4):945–959. doi: 10.1177/10781552211073673. [DOI] [PubMed] [Google Scholar]

[bib43] 43.Whiteman E.L., Cho H., Birnbaum M.J. Role of AKT/protein kinase B in metabolism. Trends Endocrinol Metab. 2002;13(10):444–451. doi: 10.1016/s1043-2760(02)00662-8. [DOI] [PubMed] [Google Scholar]

[bib44] 44.Chen X.W., Leto D., Xiong T. A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Mol Biol Cell. 2011;22(1):141–152. doi: 10.1091/mbc.E10-08-0665. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib45] 45.Goncalves M.D., Farooki A. Management of phosphatidylinositol-3-kinase inhibitor-associated hyperglycemia. Integr Cancer Ther. 2022;21 doi: 10.1177/15347354211073163. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib46] 46.Calautti E., Li J., Saoncella S., Brissette J.L., Goetinck P.F. Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. J Biol Chem. 2005;280(38):32856–32865. doi: 10.1074/jbc.M506119200. [DOI] [PubMed] [Google Scholar]

[bib47] 47.Sonis S., Villa A. A new hypothesis describing the pathogenesis of oral mucosal injury associated with the mammalian target of rapamycin (mTOR) inhibitors. Cancers. 2024;16(1):68. doi: 10.3390/cancers16010068. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib48] 48.Sheng H., Shao J., Townsend C.M., Jr., Evers B.M. Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells. Gut. 2003;52(10):1472–1478. doi: 10.1136/gut.52.10.1472. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib49] 49.Weidner A.S., Panarelli N.C., Geyer J.T., et al. Idelalisib-associated colitis: histologic findings in 14 patients. Am J Surg Pathol. 2015;39(12):1661–1667. doi: 10.1097/PAS.0000000000000522. [DOI] [PubMed] [Google Scholar]

[bib50] 50.Gadkar K., Friedrich C., Hurez V., et al. Quantitative systems pharmacology model-based investigation of adverse gastrointestinal events associated with prolonged treatment with PI3-kinase inhibitors. CPT Pharmacometrics Syst Pharmacol. 2022;11(5):616–627. doi: 10.1002/psp4.12749. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib51] 51.Balagoni H., Chaudhari D., Reddy C., Young M. Idelalisib: a rare cause of enterocolitis. Ann Gastroenterol. 2016;29(2):233–235. doi: 10.20524/aog.2016.0022. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib52] 52.Rugo H.S., André F., Yamashita T., et al. Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol. 2020;31(8):1001–1010. doi: 10.1016/j.annonc.2020.05.001. [DOI] [PubMed] [Google Scholar]

[bib53] 53.Juric D., Kalinsky K., Turner N.C., et al. First-line inavolisib/placebo + palbociclib + fulvestrant (Inavo/Pbo+Palbo+Fulv) in patients (pts) with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer who relapsed during/within 12 months (mo) of adjuvant endocrine therapy completion: INAVO120 phase III randomized trial additional analyses. J Clin Oncol. 2024;42(suppl 16) 1003-1003. [Google Scholar]

[bib54] 54.Rugo H.S., Pritchard K.I., Gnant M., et al. Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol. 2014;25(4):808–815. doi: 10.1093/annonc/mdu009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib55] 55.Campone M., Bachelot T., Gnant M., et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. Eur J Cancer. 2013;49(12):2621–2632. doi: 10.1016/j.ejca.2013.04.011. [DOI] [PubMed] [Google Scholar]

[bib56] 56.Noguchi S., Masuda N., Iwata H., et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer. 2014;21(6):703–714. doi: 10.1007/s12282-013-0444-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib57] 57.Pritchard K.I., Burris H.A., Ito Y., et al. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor–positive breast cancer in BOLERO-2. Clin Breast Cancer. 2013;13(6):421–432.e428. doi: 10.1016/j.clbc.2013.08.011. [DOI] [PubMed] [Google Scholar]

[bib58] 58.Beck J.T., Hortobagyi G.N., Campone M., et al. Everolimus plus exemestene as first-line therapy in HR+, HER2- advanced breast cancer in BOLERO-2. Breast Cancer Res Treat. 2014;143(3):459–467. doi: 10.1007/s10549-013-2814-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib59] 59.Yardley D.A., Noguchi S., Pritchard K.I., et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870–884. doi: 10.1007/s12325-013-0060-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib60] 60.Rugo H.S., Oliveira M., Howell S.J., et al. Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study. ESMO Open. 2024;9(9) doi: 10.1016/j.esmoop.2024.103697. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib61] 61.Rugo H.S., Oliveira M., Howell S.J., et al. Capivasertib (c) and fulvestrant (f) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2- advanced breast cancer (ABC): characterization and management of common adverse events (AES) from the phase 3 CAPItello-291 trial. J Clin Oncol. 2023;41(suppl 16):1067. [Google Scholar]

[bib62] 62.Jhaveri K.L., Im S.-A., Saura C., et al. Abstract GS03-13. Inavolisib or placebo in combination with palbociclib and fulvestrant in patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer: phase III INAVO120 primary analysis. Cancer Res. 2024;84(suppl 9):GS03–GS13. [Google Scholar]

[bib63] 63.National Cancer Institute Common terminology criteria for adverse events v3.0 (CTCAE) 2006. https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events/ctcae-v3.pdf Available at.

[bib64] 64.National Cancer Institute Common terminology criteria for adverse events (CTCAE) Version 4.0. 2009. https://www.eortc.be/services/doc/ctc/ctcae_4.03_2010-06-14_quickreference_5x7.pdf Available at.

[bib65] 65.National Cancer Institute Common terminology criteria for adverse events (CTCAE) Version 5.0. 2017. https://www.ctc.ucl.ac.uk/TrialDocuments/Uploaded/Common%20Terminology%20Criteria%20for%20Adverse%20Events%20(CTCAE)%20v5.0_14092023_0.pdf Available at.

[bib66] 66.Bedard P.L., Accordino M.K., Cervantes A., et al. Long-term safety of inavolisib (GDC-0077) in an ongoing phase 1/1b study evaluating monotherapy and in combination (combo) with palbociclib (palbo) and/or endocrine therapy in patients (pts) with PIK3CA-mutated, hormone receptor-positive/HER2-negative (HR+/HER2–) metastatic breast cancer (BC) J Clin Oncol. 2022;40(suppl 16):1052. [Google Scholar]

[bib67] 67.Wang D.G., Barrios D.M., Blinder V.S., et al. Dermatologic adverse events related to the PI3Kα inhibitor alpelisib (BYL719) in patients with breast cancer. Breast Cancer Res Treat. 2020;183(1):227–237. doi: 10.1007/s10549-020-05726-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib68] 68.Miller J., Armgardt E., Svoboda A. The efficacy and safety of alpelisib in breast cancer: a real-world analysis. J Oncol Pharm Pract. 2022;28(5):1152–1156. doi: 10.1177/10781552221096413. [DOI] [PubMed] [Google Scholar]

[bib69] 69.Llombart-Cussac A., Pérez-Garcia J.M., 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 doi: 10.1016/j.eclinm.2024.102520. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib70] 70.Shen S., Chen Y., Carpio A., Chang C., Iyengar N.M. Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer. Cancer. 2023;129(24):3854–3861. doi: 10.1002/cncr.34928. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib71] 71.Cardoso F., Paluch-Shimon S., Senkus E., et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) Ann Oncol. 2020;31(12):1623–1649. doi: 10.1016/j.annonc.2020.09.010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib72] 72.Joint British Diabetes Societies The management of diabetic ketoacidosis in adults. 2023. https://abcd.care/sites/default/files/site_uploads/JBDS_Guidelines_Current/JBDS_02_DKA_Guideline_with_QR_code_March_2023.pdf Available at. Accessed November 2024. [DOI] [PubMed]

[bib73] 73.Joint British Diabetes Societies for Inpatient Care Take the type 2 risk test. 2025. https://diabetes.org/diabetes-risk-test Available at.

[bib74] 74.American Diabetes Association 5. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2018;42(suppl 1):S46–S60. doi: 10.2337/dc19-S005. [DOI] [PubMed] [Google Scholar]

[bib75] 75.Gallagher E.J., Moore H., Lacouture M.E., et al. Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique. NPJ Breast Cancer. 2024;10(1):12. doi: 10.1038/s41523-024-00613-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib76] 76.Rugo H.S., Seneviratne L., Beck J.T., et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol. 2017;18(5):654–662. doi: 10.1016/S1470-2045(17)30109-2. [DOI] [PubMed] [Google Scholar]

[bib77] 77.Hattori M., Hagiwara S., Kotani H., et al. A single-arm, phase 2 study of steroid-containing mouthwash for the prevention of everolimus-associated stomatitis in multiple tumor types. Int J Clin Oncol. 2019;24(10):1320–1327. doi: 10.1007/s10147-019-01476-0. [DOI] [PubMed] [Google Scholar]

[bib78] 78.Blow T., Hyde P.N., Falcone J.N., et al. Treating alpelisib-induced hyperglycemia with very low carbohydrate diets and sodium-glucose co-transporter 2 inhibitors: a case series. Integr Cancer Ther. 2021;20 doi: 10.1177/15347354211032283. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib79] 79.Weintraub M.A., Liu D., DeMatteo R., Goncalves M.D., Flory J.H. Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition. Breast Cancer Res Treat. 2024;203(1):85–93. doi: 10.1007/s10549-023-07110-y. [DOI] [PubMed] [Google Scholar]

[bib80] 80.American Diabetes Association Professional Practice Committee 13. Older adults: standards of medical care in diabetes – 2022. Diabetes Care. 2022;45(suppl 1):S195–S207. doi: 10.2337/dc22-S013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib81] 81.American Diabetes Association What is the A1C test? https://diabetes.org/about-diabetes/a1c Available at.

[bib82] 82.Rodón J., Demanse D., Rugo H.S., et al. A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer. Breast Cancer Res. 2024;26(1):36. doi: 10.1186/s13058-024-01773-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib83] 83.National Institute of Diabetes and Digestive and Kidney Diseases Risk factors for diabetes. 2015. https://www.niddk.nih.gov/health-information/professionals/clinical-tools-patient-management/diabetes/game-plan-preventing-type-2-diabetes/prediabetes-screening-how-why/risk-factors-diabetes Available at.

[bib84] 84.Moore H.N., Goncalves M.D., Johnston A.M., et al. Effective strategies for the prevention and mitigation of phosphatidylinositol-3-kinase inhibitor-associated hyperglycemia: optimizing patient care. Clin Breast Cancer. 2025;25(1):1–11. doi: 10.1016/j.clbc.2024.09.017. [DOI] [PubMed] [Google Scholar]

[bib85] 85.Ellis S.L., Moser E.G., Snell-Bergeon J.K., et al. Effect of sitagliptin on glucose control in adult patients with type 1 diabetes: a pilot, double-blind, randomized, crossover trial. Diabet Med. 2011;28(10):1176–1181. doi: 10.1111/j.1464-5491.2011.03331.x. [DOI] [PubMed] [Google Scholar]

[bib86] 86.Kim N.H., Kim D.L., Kim K.J., et al. Effects of vildagliptin or pioglitazone on glycemic variability and oxidative stress in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a 16-week, randomised, open label, pilot study. Endocrinol Metab (Seoul) 2017;32(2):241–247. doi: 10.3803/EnM.2017.32.2.241. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib87] 87.Lacouture M.E., Maier T., Pan A., et al. Abstract 3412: Benralizumab for treatment of eosinophil-related cutaneous adverse events associated with checkpoint inhibitors and anticancer targeted therapies: phase 2 study. Cancer Res. 2024;84(suppl 6):3412. [Google Scholar]

[bib88] 88.AstraZeneca. TRUQAP (capivasertib) summary of product characteristics. 2024. https://www.ema.europa.eu/en/documents/product-information/truqap-epar-product-information_en.pdf Available at.

PERMALINK

Clinical management of common toxicities with inhibitors targeting the PI3K/AKT/mTOR pathway in breast cancer

KL Jhaveri

NM Iyengar

NC Turner

HS Rugo

J O’Shaughnessy

CH Barrios

G Curigliano

F André

S-A Im

MD Goncalves

ME Lacouture

PA Fasching

R Leung

Abstract

Highlights

Introduction

PI3K

AKT

mTOR

Biomarker testing

PI3K/AKT/mTOR pathway-mediated side-effect mechanisms of action

Table 1.

Common toxicity characteristics and monitoring

Table 2.

Table 3.

Hyperglycemia

Rash

Figure 1.

Stomatitis

Diarrhea

Common toxicity preparation strategies

Hyperglycemia

Rash

Stomatitis

Diarrhea

Common toxicity management

Hyperglycemia

Figure 2.

Rash

Stomatitis

Diarrhea

Other notable toxicities

Pneumonitis

Elevated creatinine levels

Decreased weight

Conclusions

Acknowledgments

Funding

Disclosure

Supplementary data

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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