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PIK3CA, AKT1, and PTEN Alterations in Breast Cancer

Explore guideline recommendations and actionable best practices for PIK3CA, AKT1, and PTEN testing in breast cancer.

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Reading time: 20 min
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PIK3CA/AKT1/PTEN Alteration Testing Recommendations Aim to Inform Treatment Decisions1

The NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend NGS testing for the detection of actionable biomarkers, such as PIK3CA, AKT1, and PTEN, in HR+/HER2-negative aBC.1,a

Confused individual icon

Whom to test

Patients with HR+/HER2-negative advanced or metastatic breast cancer1–3

Biomarker DNA icon

When to test?

NCCN Guidelines® recommend ordering comprehensive somatic and germline testing (including NGS) during the initial patient work-up for metastatic disease1,2

NGS panel tests can also be ordered after progression on first line treatment2

Laboratory microscope icon

How to test

Utilize NGS testing4,b

aaBC, advanced breast cancer, including locally advanced (inoperable) and metastatic breast cancer.


bAlthough PCR can be used as a single gene test, NGS can provide more comprehensive information about PIK3CA, AKT1 and PTEN alteration status.4

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline Breast Cancer V.6.2024. © 2024 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form or for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. 


NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way

aBC, advanced breast cancer; AKT1, serine/threonine protein kinase 1; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; PCR, polymerase chain reaction; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog.

DNA and patient icon

Abnormal PI3K/AKT/PTEN Pathway Activation Can Mediate Tumor Growth and Treatment Resistance5

The PI3K/AKT/PTEN pathway is a signal transduction pathway that mediates metabolism, proliferation, and survival of cells.5

Overview of the PI3K/AKT/PTEN pathway

Overview of the PI3K/AKT/PTEN pathway

PI3K is an intracellular kinase that stimulates multiple downstream targets of the PI3K/AKT/PTEN pathway through phosphorylation6

PI3K

PTEN acts as a tumor suppressor by preventing AKT from being activated, suppressing PI3K/AKT/PTEN pathway signaling
which will inhibit cell proliferation6

PTEN

AKT is the central downstream protein in the PI3K/AKT/PTEN pathway that regulates various cellular processes such as cell proliferation, cell survival, and cell metabolism7

AKT

mTOR

Survival

Proliferation

Metabolism

Adapted from Paplomata E, et al. 2014.8

Activating mutations of PIK3CA and AKT1 and inactivating alterations of PTEN are common in HR+ breast cancer and result in hyperactivation of the PI3K/AKT/PTEN pathway.5

Hyperactivation of the PI3K/AKT/PTEN pathway can drive treatment resistance and disease progression.5,9–11

GeneKey alterationsConsequence
PIK3CA6Point mutations of PIK3CAGain of function of PI3K
AKT112Point mutation of AKT1Gain of function of AKT
PTEN13Point mutations, large deletions, and genomic rearrangements involving PTENLoss of function of PTEN

AKT, serine/threonine protein kinase; AKT1, serine/threonine protein kinase 1; HR, hormone receptor; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog.

Up to 50% of Patients With HR+ Breast Cancer May Have an Actionable PIK3CA, AKT1, and/or PTEN Alteration7

approximately 40% of patients with HR+ breast cancer may have PIK3CA mutations6, approximately 5% may have PTEN alterations13, and approximately 5% may have AKT1 mutation
40%

PIK3CA mutations6,12

Up to
50%
with PIK3CA,
AKT1, and/or
PTEN alterations7

~5%

PTEN
alterations13

~5%

AKT1 mutation6,12

While PCR can be used to detect PIK3CA status, NGS is the only recommended testing method that can identify PIK3CA, AKT1, and PTEN alterations, and more, with just one test.1,14–19

AKT1, serine/threonine protein kinase 1; HR, hormone receptor; NGS, next-generation sequencing; PCR, polymerase chain reaction; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog.

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Several Clinically Actionable Biomarkers Can be Detected Using NGS1

Breast cancer subtypeBiomarkerCan be detected with NGSOther detection methods
Actionable biomarkers1,3HR+/HER2-negativePIK3CA activating mutations
PCR
AKT1 activating mutation
PCR
PTEN inactivating alterations
PCR
ESR1 mutation
PCR
AnyGermline BRCA1/2 mutation
Germline Sequencing
NTRK-fusion
FISH and PCR
MSI-H/dMMR
IHC and PCR
RET-fusion
Emerging biomarkers1HER2-negativeHER2 activating mutation
AnySomatic BRCA1/2 mutation

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Guideline Breast Cancer V.6.2024. © 2024 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form or for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. 


NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

AKT1, serine/threonine protein kinase 1; BRCA1/2, BReast CAncer susceptibility gene 1/2; dMMR, DNA mismatch repair; ERBB2, receptor tyrosine protein kinase erbB-2; ESR1, estrogen receptor 1; FISH, fluorescence in situ hybridization; HER2-negative, human epidermal growth factor receptor 2 negative; HR, hormone receptor; IHC, immunohistochemistry; MSI-H, microsatellite instability high; NGS, next-generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; PCR, polymerase chain reaction; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RET, rearranged during transfection.

Cells under magnifying glass

Most common commercial NGS panels include PIK3CA, AKT1, and PTEN alterations.14–18,20–25

Send-out (centralized)

Lab/manufacturerNGS test panel nameNumber of genesPI3K/AKT/PTEN pathway biomarker genes included within panel
Foundation MedicineFoundationOne®CDx15324PIK3CA, AKT1, and PTEN
NeoGenomicsNeoTYPE® - Breast Tumor Profile1754
Neo Comprehensive™ – Solid Tumor20517
TempusTempus xT18648
Caris Life Science®Comprehensive Molecular Profiling14~23,000
LabcorpOmniSeq INSIGHT21,22523
Quest Diagnostics™Solid Tumor Core Panel2349

In-house (decentralized)

Lab/manufacturerNGS test panel nameNumber of genesPI3K/AKT/PTEN pathway biomarker genes included within panel
Illumina®TruSight™ Oncology 50016523PIK3CA, AKT1, and PTEN
Thermo Fisher ScientificOncomine™ Precision Assay GX2450
Oncomine™ Focus Assay2552PIK3CA and AKT1

Tips on decreasing tissue insufficiency

Scalpel

When NGS is planned:

  • Proactively communicate to the MDT member to ensure that sufficient tissue is collected4
  • Split tissue into multiple cassettes26
  • Consider using rapid on-site evaluation (ROSE)27
Note taking icon

Look back on previously ordered NGS reports and results

  • Access the online portal of your NGS vendor to identify if patients who have been previously tested have tumors positive for PIK3CA, AKT1, and PTEN alterations
  • NCCN Guidelines are often updated with additional testing guidance for actionable biomarkers. Therefore, the NGS report’s upfront biomarker ‘highlights section’ is only as up to date as the guidelines that were available at the time of testing
Scientist looking at lab samples

Browse a selection of major laboratories offering a range of biomarker testing options.

Find a lab

This information is intended as educational and is not intended as a complete list of available testing options. AstraZeneca is not responsible for any test provider and does not endorse any particular diagnostic test. The accuracy and results of diagnostic tests vary, and AstraZeneca shall have no liability arising from such testing. Information provided herein should in no way be considered a guarantee of coverage, reimbursement, or patient assistance. Providers should contact third-party laboratories for information on their patient assistance programs. While diagnostic testing may assist providers in identifying appropriate treatment for patients, the decision and action should be decided by a provider in consultation with the patient. All products are trademarks of their respective holders, all rights reserved.

AKT, serine/threonine protein kinase; AKT1, serine/threonine protein kinase 1; CDx, companion diagnostic; MDT, multidisciplinary team; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog; ROSE, rapid on-site evaluation.

Laboratory test results icon

Interpreting and Reporting Requires Multidisciplinary Team Input on the Clinical Significance of the Biomarker Test Results


The reporting of mutations detected by NGS panel testing is complex and may include classifications beyond positive or negative.28

The joint recommendation of the Association for Molecular Pathology (AMP), American Society of Clinical Oncology (ASCO), and College of American Pathologists (CAP) is to categorize biomarkers based on their clinical significance.3,28

Tier I: Variants of strong clinical significance28Tier II: Variants of potential clinical significance28Tier III: Variants of unknown clinical significance28Tier IV: Benign or likely benign clinical significance28
Therapeutic, prognostic, and/or diagnostic.Variants that have not been classified as pathogenic or benign and, therefore, have unknown clinical significance.

While not clinically actionable at the time of the test, the reporting laboratory may follow up on the clinical relevance of VUS if additional studies categorize the mutation as pathogenic.29		Variants that have no clinical significance.
Known actionable and well-studied potentially actionable biomarkers.Actionable biomarkers in other tumor types or potentially actionable biomarkers studied in preclinical trials and few case reports.

Depending on the NGS assay used, the report may look different — it is important to discuss the results and options for treatment with your MDT.30

AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; CAP, College of American Pathologists; MDT, multidisciplinary team; NGS, next-generation sequencing; VUS, variant of unknown significance.

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Consistent NGS Panel Testing Can Help Ensure Appropriate Treatment Decisions1,31

Scalpel icon

Sample selection31

  • Interventional radiologist, oncologist, or surgeon obtains tissue sample
  • Communication helps ensure timely and adequate sample collection
Microscope icon

Biomarker testing4,31

  • Anatomical pathologist manages specimen for testing
  • Molecular pathology lab/Genetics core lab performs testing
  • Oncologist orders NGS panel testing
  • Standardized tissue handling strategies are crucial to ensure samples meet assay and lab criteria
Stethoscope icon

Diagnosis and staging32

  • Physician (pathologist or oncologist, etc.) guides diagnostic confirmation and staging
  • Accurate staging is critical, affecting prognosis and testing/clinical decisions
Laboratory test results icon

Reporting4

  • Pathologist or commercial lab staff send(s) the report to the oncologist
  • Complete and accurate reporting is vital for clinical decision-making

NGS, next-generation sequencing.

Guideline document icon

Considerations for Your Practice

Collaborate with your MDT to ensure PIK3CA, AKT1, and PTEN alteration status is consistently identified and recorded for all patients with HR+/HER2-negative breast cancer.1,33

  • Advocate for NGS test ordering at initial patient work-up at metastatic disease on first line treatment
  • Look back on previously ordered NGS results
  • Utilize NGS testing – patients only need to be positive for at least one PIK3CA, AKT1, or PTEN alteration for their results to be actionable

AKT, serine/threonine protein kinase; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; MDT, multidisciplinary team; NGS, next-generation sequencing; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog.

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Detecting PIK3CA, AKT1, and PTEN alterations using next-generation sequencing (NGS)

Download this concise slide deck for an overview of the PI3K/AKT/PTEN pathway, NGS testing, and finding solutions to common testing challenges.

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AKT, serine/threonine protein kinase; AKT1, serine/threonine protein kinase 1; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor positive; NGS, next-generation sequencing; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog.

  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.6.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed November 20, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org.
  2. Schwartzberg L, et al. Am Soc Clin Oncol Educ Book. 2017;37:160–169.
  3. Henry NL, et al. J Clin Oncol. 2022;40(27):3205–3221.
  4. Schmid S, et al. ESMO Open. 2022;7(5):100570.
  5. Skolariki A, et al. Explor Target Antitumor Ther. 2022;3(2):172–199.
  6. Miricescu D, et al. Int J Mol Sci. 2020;22(1):173.
  7. Martorana F, et al. Front Pharmacol. 2021;12:662232.
  8. Paplomata E, et al. Ther Adv Med Oncol. 2014;6(4):154–166.
  9. Cogliati V, et al. Life (Basel). 2022;12(3):378.
  10. Lee JS, et al. Cancers (Basel). 2022;14(13):3159.
  11. Rimawi MF, et al. Breast Cancer Res Treat. 2018;167(3):731–740.
  12. Smyth LM, et al. Cancer Discov. 2020;10(4):526–535.
  13. Chen J, et al. Front Oncol. 2022;12:825484.
  14. Caris Life Sciences. Comprehensive Tumor Profiling. August 22, 2024. Available at: https://www.carislifesciences.com/products-and-services/molecular-profiling/testing-menu/
  15. Foundation Medicine. FoundationOne®CDx. Technical Information. Accessed August 22, 2024. https://​​www​.​accessdata​.​fda​.​gov​/​cdrh_docs​/​pdf17​/P170019S006C.pdf
  16. Illumina®. TruSight™ Oncology 500 and TruSight Oncology 500 High-Throughput. Accessed August 22, 2024. https://​www.​illumina.​com/​content/​dam/​illumina/gcs/assembled-assets/marketing-literature/trusight-oncology-500-data-sheet-m-gl-00173/trusight-oncology-500-and-ht-data-sheet-m-gl-00173.pdf
  17. Neo Genomics. Test Catalog. Accessed August 22, 2024. https://neogenomics.com/test-menu/neotyper-breast-tumor-profile
  18. Tempus. Tempus xT CDx. Accessed August 22, 2024. https://www.accessdata.fda.gov/cdrh_docs/pdf21/P210011C.pdf
  19. Thermo Fisher Scientific. Oncomine™ Dx Target Test Part I: Sample Preparation and Quantification: User Guide. Accessed August 22, 2024. https://​​www​.​accessdata​.​fda​.​gov​/​cdrh​_docs​/pdf16​/p160045c​.pdf
  20. Neo Comprehensive – Solid Tumor. Test Menu. Accessed August 22, 2024. https://neogenomics.com/test-menu/neo-comprehensive-solid-tumor
  21. Labcorp. OmniSeq Brochure. Accessed August 22, 2024. https://oncology.labcorp.com/sites/default/files/2023-03/OmniSeq_brochure_DX_BRO_L26428-1222-2.pdf
  22. Labcorp. OmniSeq Gene List. Accessed August 22, 2024. https://oncology.labcorp.com/sites/default/files/2023-03/OmniSeq_gene_list_DX_SS_L26488-1222-2.pdf
  23. Quest Diagnostics™. Solid Tumor Core Panel Test Detail. Accessed August 22, 2024. https://testdirectory.questdiagnostics.com/test/tes-detail/93234/solid-tumor-core-panel?q=93234&cc=MASTER
  24. ThermoFisher Scientific. Oncomine™ Precision Assay. Accessed August 22, 2024. Available at https://assets.thermofisher.com/TFS-Assets/CSD/Flyers/oncomine-precision-assay-flyer.pdf
  25. ThermoFisher Scientific. Oncomine™ Focus Assay. Accessed August 22, 2024. https://assets.thermofisher.com/TFS-Assets/LSG/Flyers/oncomine-focus-assay-flyer.pdf
  26. Padmanabhan V, et al. Arch Pathol Lab Med. 2017;141(3):402–409.
  27. Schmidt RL, et al. PLoS One. 2015;10(8):e0135466.
  28. Li MM, et al. J Mol Diag. 2017;19(1):4–23.
  29. Richards S, et al. Genet Med. 2015;17(5):405–424.
  30. Guan YF, et al. Chin J Cancer. 2012;31(10):463–470.
  31. Cree IA, et al. J Clin Pathol. 2014;67(11):923–931.
  32. Gennari A, et al. Ann Oncol. 2021;32(12):1475–1495.
  33. Cerma K, et al. Biomedicines. 2023;11(1):109.

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.