PIK3CA, AKT1, and PTEN Alterations in Breast Cancer

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  HRRm
  
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Breast cancer
PIK3CA/AKT1/PTEN

PIK3CA/AKT1/PTEN

Jump to:

Testing Recommendations
Role of PIK3CA/AKT/PTEN
Prevalence
Diagnostic Assays
Interpreting & Reporting
NGS Panel Testing
Considerations for Your Practice
Helpful Resources

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

Whom to test

Patients with HR+/HER2-negative advanced or metastatic breast cancer^1–3

When to test?

NCCN Guidelines^® recommend ordering comprehensive somatic and germline testing (including NGS) during the initial patient work-up for metastatic disease^1,2

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

How to test

Utilize NGS testing^4,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.

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

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

Gene	Key alterations	Consequence
PIK3CA⁶	Point mutations of PIK3CA	Gain of function of PI3K
AKT1¹²	Point mutation of AKT1	Gain of function of AKT
PTEN¹³	Point mutations, large deletions, and genomic rearrangements involving PTEN	Loss 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

Up to

50%

with PIK3CA, AKT1, and/or PTEN alterations⁷

~40%

PIK3CA mutations^6,12

~5%

PTEN alterations¹³

~5%

AKT1 mutation^6,12

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.

Several Clinically Actionable Biomarkers Can be Detected Using NGS¹

	Breast cancer subtype	Biomarker	Other detection methods
Actionable biomarkers^1,3	HR+/HER2-negative	PIK3CA activating mutations	PCR
		AKT1 activating mutation	PCR
		PTEN inactivating alterations	PCR
		ESR1 mutation	PCR
	Any	Germline BRCA1/2 mutation	Germline Sequencing
		NTRK-fusion	FISH and PCR
		MSI-H/dMMR	IHC and PCR
		RET-fusion
Emerging biomarkers¹	HER2-negative	HER2 activating mutation
Emerging biomarkers¹	Any	Somatic BRCA1/2 mutation

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.

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

Send-out (centralized)

Lab/manufacturer	NGS test panel name	Number of genes	PI3K/AKT/PTEN pathway biomarker genes included within panel
Foundation Medicine	FoundationOne^®CDx¹⁵	324	PIK3CA, AKT1, and PTEN
NeoGenomics	NeoTYPE^® - Breast Tumor Profile¹⁷	54
NeoGenomics	Neo Comprehensive^™ – Solid Tumor²⁰	517
Tempus	Tempus xT¹⁸	648
Caris Life Science^®	Comprehensive Molecular Profiling¹⁴	~23,000
Labcorp	OmniSeq INSIGHT^21,22	523
Quest Diagnostics^™	Solid Tumor Core Panel²³	49

In-house (decentralized)

Lab/manufacturer	NGS test panel name	Number of genes	PI3K/AKT/PTEN pathway biomarker genes included within panel
Illumina^®	TruSight^™ Oncology 500¹⁶	523	PIK3CA, AKT1, and PTEN
Thermo Fisher Scientific	Oncomine^™ Precision Assay GX²⁴	50	PIK3CA, AKT1, and PTEN
Thermo Fisher Scientific	Oncomine^™ Focus Assay²⁵	52	PIK3CA and AKT1

Tips on decreasing tissue insufficiency

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

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

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.

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 significance²⁸	Tier II: Variants of potential clinical significance²⁸	Tier III: Variants of unknown clinical significance²⁸	Tier 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.		Variants that have no clinical significance.

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.

Consistent NGS Panel Testing Can Help Ensure Appropriate Treatment Decisions^1,31

Sample selection³¹

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

Biomarker testing^4,31

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

Diagnosis and staging³²

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

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.

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.

Helpful Resources

Check out these featured resources on PIK3CA/AKT1/PTEN biomarker testing in breast cancer.

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View more resources

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.

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.
Schwartzberg L, et al. Am Soc Clin Oncol Educ Book. 2017;37:160–169.
Henry NL, et al. J Clin Oncol. 2022;40(27):3205–3221.
Schmid S, et al. ESMO Open. 2022;7(5):100570.
Skolariki A, et al. Explor Target Antitumor Ther. 2022;3(2):172–199.
Miricescu D, et al. Int J Mol Sci. 2020;22(1):173.
Martorana F, et al. Front Pharmacol. 2021;12:662232.
Paplomata E, et al. Ther Adv Med Oncol. 2014;6(4):154–166.
Cogliati V, et al. Life (Basel). 2022;12(3):378.
Lee JS, et al. Cancers (Basel). 2022;14(13):3159.
Rimawi MF, et al. Breast Cancer Res Treat. 2018;167(3):731–740.
Smyth LM, et al. Cancer Discov. 2020;10(4):526–535.
Chen J, et al. Front Oncol. 2022;12:825484.
Caris Life Sciences. Comprehensive Tumor Profiling. August 22, 2024. Available at: https://www.carislifesciences.com/products-and-services/molecular-profiling/testing-menu/
Foundation Medicine. FoundationOne^®CDx. Technical Information. Accessed August 22, 2024. https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170019S006C.pdf
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
Neo Genomics. Test Catalog. Accessed August 22, 2024. https://neogenomics.com/test-menu/neotyper-breast-tumor-profile
Tempus. Tempus xT CDx. Accessed August 22, 2024. https://www.accessdata.fda.gov/cdrh_docs/pdf21/P210011C.pdf
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
Neo Comprehensive – Solid Tumor. Test Menu. Accessed August 22, 2024. https://neogenomics.com/test-menu/neo-comprehensive-solid-tumor
Labcorp. OmniSeq Brochure. Accessed August 22, 2024. https://oncology.labcorp.com/sites/default/files/2023-03/OmniSeq_brochure_DX_BRO_L26428-1222-2.pdf
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
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
ThermoFisher Scientific. Oncomine™ Precision Assay. Accessed August 22, 2024. Available at https://assets.thermofisher.com/TFS-Assets/CSD/Flyers/oncomine-precision-assay-flyer.pdf
ThermoFisher Scientific. Oncomine™ Focus Assay. Accessed August 22, 2024. https://assets.thermofisher.com/TFS-Assets/LSG/Flyers/oncomine-focus-assay-flyer.pdf
Padmanabhan V, et al. Arch Pathol Lab Med. 2017;141(3):402–409.
Schmidt RL, et al. PLoS One. 2015;10(8):e0135466.
Li MM, et al. J Mol Diag. 2017;19(1):4–23.
Richards S, et al. Genet Med. 2015;17(5):405–424.
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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.

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PIK3CA, AKT1, and PTEN Alterations in Breast Cancer

PIK3CA/AKT1/PTEN Alteration Testing Recommendations Aim to Inform Treatment Decisions1

Whom to test

When to test?

How to test

Footnotes

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

Overview of the PI3K/AKT/PTEN pathway

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

Several Clinically Actionable Biomarkers Can be Detected Using NGS1

Footnotes

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

Send-out (centralized)

In-house (decentralized)

Tips on decreasing tissue insufficiency

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

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

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

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

Sample selection31

Biomarker testing4,31

Diagnosis and staging32

Reporting4