PIK3CA / AKT1 / PTEN

  • PIK3CA encodes the p110α catalytic subunit of PI3K; AKT1 encodes the AKT1 serine/threonine kinase; PTEN is a tumor-suppressor phosphatase that negatively regulates the pathway
  • Gene Location: PIK3CA chromosome 3 (3q26.32); AKT1 chromosome 14 (14q32.33); PTEN chromosome 10 (10q23.31)

Biology

  • The PI3K/AKT/mTOR pathway is a central regulator of cell growth, proliferation, and survival. In breast cancer it is the most frequently altered pathway and a key driver of endocrine-therapy resistance.1
  • Activating PIK3CA or AKT1 mutations, and loss of function of PTEN by mutation or reduced protein expression, all converge to constitutively activate AKT signaling downstream, promoting tumor cell proliferation and survival.1
  • Three drug classes intervene at different nodes: PI3Kα inhibitors (alpelisib), PI3Kα inhibitor-degraders (inavolisib), and pan-AKT inhibitors (capivasertib). All three are given with fulvestrant, and inavolisib additionally with palbociclib.4,5,6

Etiology and Epidemiology

  • PIK3CA is the most commonly altered gene in this pathway, mutated in approximately 40% of HR-positive/HER2-negative breast cancers. The dominant hotspots are H1047R in the kinase domain and E545K and E542K in the helical domain.1
  • AKT1 mutations occur in roughly 3% to 4% of cases, with the E17K hotspot accounting for the large majority. PTEN loss of function is present at a variable frequency.1,2
  • Taken together, about half of HR-positive/HER2-negative metastatic breast cancers carry an alteration in at least one of these three genes, making this the largest biomarker-defined subgroup in the setting.2

Testing

When to Test:

  • Test for PIK3CA, AKT1, and PTEN alterations in HR-positive/HER2-negative advanced or metastatic disease to identify candidates for pathway-directed therapy. Because alterations can be acquired under treatment pressure, retesting at progression is reasonable.3

Testing Methodologies:

  • Next-generation sequencing of tumor tissue or plasma (circulating tumor DNA) is standard. Each agent carries a distinct FDA-approved companion diagnostic, and they are not interchangeable.4,5,6
  • Alpelisib: therascreen PIK3CA RGQ PCR, on tumor tissue or plasma. Capivasertib: FoundationOne CDx (tissue) or FoundationOne Liquid CDx (plasma), covering all three genes. Inavolisib: selection is based on one or more PIK3CA mutations in a plasma specimen, with FoundationOne Liquid CDx used in INAVO120.4,5,6
  • When an alteration is not detected in plasma, testing tumor tissue is recommended, since circulating tumor DNA sensitivity is imperfect and a negative plasma result does not exclude an alteration.3

Guideline Recommendations

  • ASCO recommends testing for PIK3CA mutations, and for capivasertib eligibility AKT1 and PTEN alterations, in HR-positive/HER2-negative metastatic breast cancer to guide selection of pathway-directed therapy.3
  • NCCN includes pathway testing in the workup of HR-positive/HER2-negative recurrent or stage IV disease, with the specific alteration determining which of the three agents applies.7

Targeted Therapy

Approved Agents

  • Three oral pathway-directed agents are FDA-approved in HR-positive/HER2-negative advanced or metastatic breast cancer: alpelisib (2019), capivasertib (2023), and inavolisib (2024). Each requires a distinct companion diagnostic and each is given with fulvestrant.4,5,6
  • The three differ in the alterations they target and in where they sit in the treatment pathway. Alpelisib and capivasertib are used after progression on an endocrine-based regimen; inavolisib is used in first-line endocrine-resistant disease, as a triplet with palbociclib and fulvestrant, in patients who relapsed on or within 12 months of completing adjuvant endocrine therapy.4,5,6
  • Hyperglycemia is a class effect of PI3K/AKT pathway inhibition and the characteristic toxicity of all three agents, requiring baseline and on-treatment glucose monitoring.4,5,6

Alpelisib (Piqray)

  • FDA-Approved Indication:
    • In combination with fulvestrant for adults with HR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer, as detected by an FDA-approved test, following progression on or after an endocrine-based regimen.4
  • Mechanism of Action:
    • Oral alpha-selective inhibitor of phosphatidylinositol 3-kinase (PI3Kα).4

Drug Information:

Learn more about Alpelisib ›

Patient Resources:

https://www.piqray.com/

Capivasertib (Truqap)

  • FDA-Approved Indication:
    • In combination with fulvestrant for adults with HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.5
  • Mechanism of Action:
    • First-in-class oral pan-AKT inhibitor, targeting all three AKT isoforms (AKT1, AKT2, and AKT3).5
    • The only agent in this class covering AKT1 and PTEN alterations in addition to PIK3CA.5

Drug Information:

Learn more about Capivasertib ›

Patient Resources:

https://www.truqap.com/

Inavolisib (Itovebi)

  • FDA-Approved Indication:
    • In combination with palbociclib and fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.6
  • Mechanism of Action:
    • Oral PI3K inhibitor with activity predominantly against PI3Kα that also induces degradation of the mutated p110α protein.6
    • The only agent in this class given as a triplet with a CDK4/6 inhibitor, and the only one indicated in the first-line setting.6

Drug Information:

Learn more about Inavolisib ›

Patient Resources:

https://www.itovebi.com/

References

1. Anderson EJ, Mollon LE, Dean JL, 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;2020:3759179. doi:10.1155/2020/3759179

2. Bhave MA, Quintanilha JCF, Tukachinsky H, et al. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(−) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice. Breast Cancer Res Treat. 2024;207(3):599-609. doi:10.1007/s10549-024-07376-w

3. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for HR-positive, HER2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol. 2021;39(35):3959-3977. doi:10.1200/JCO.21.01392

4. PIQRAY (alpelisib) tablets. Prescribing information. Novartis Pharmaceuticals Corporation. Accessed July 2026.

5. TRUQAP (capivasertib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP. Accessed July 2026.

6. ITOVEBI (inavolisib) tablets. Prescribing information. Genentech, Inc; revised 10/2024. Accessed July 2026.

7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.