PI3K Pathway Activation Markers in ER-Positive, HER2-Negative Breast Cancer: A Clinicopathologic Study (p-AKT p-S6)

January 30, 2026 updated by: Roaa Ahmed Mohamed Elnaffar, Assiut University

Immunohistochemical Evaluation of p-AKT and p-S6 as Surrogate Markers of PI3K/AKT/mTOR Pathway Activation in ER-Positive, HER2-Negative Breast Carcinoma

The goal of this observational study is to examine whether markers of PI3K pathway activation are associated with endocrine therapy response and clinicopathologic features in estrogen receptor-positive, HER2-negative breast cancer. The main questions it aims to answer are:

Are immunohistochemical levels of phosphorylated AKT (p-AKT) and phosphorylated S6 (p-S6) different between endocrine-sensitive and endocrine-resistant breast cancer cases? Do different levels of p-AKT and p-S6 show distinct clinicopathologic and histologic characteristics, including features of the tumor microenvironment?

Archived tumor tissue from patients who received adjuvant endocrine therapy as part of routine clinical care will be analyzed. Biomarker expression will be correlated with clinicopathologic parameters, including tumor-infiltrating lymphocyte density, tumor budding, and other histologic features, to explore associations with tumor behavior and outcomes.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Endocrine therapy is the cornerstone of treatment for estrogen receptor-positive breast cancer; however, a substantial proportion of patients develop resistance during the disease course. Activation of the PI3K/AKT/mTOR signaling pathway has been implicated as a key mechanism underlying resistance to endocrine therapy and disease progression. While genomic alterations in PI3K pathway-related genes are commonly assessed, they do not consistently reflect pathway activation or predict therapeutic response, highlighting the need for practical surrogate biomarkers.

The aim of this study is to evaluate immunohistochemical markers of PI3K pathway activation in estrogen receptor-positive, HER2-negative invasive breast carcinoma and to explore their associations with endocrine therapy response and clinicopathologic characteristics. Specifically, the study examines whether levels of phosphorylated AKT (p-AKT) and phosphorylated S6 (p-S6) differ between endocrine-sensitive and endocrine-resistant cases and whether these markers correlate with histologic features related to tumor biology and the tumor microenvironment.

This is a retrospective observational study including patients with estrogen receptor-positive, HER2-negative invasive breast carcinoma who received adjuvant endocrine therapy as part of routine clinical care. Archived formalin-fixed, paraffin-embedded (FFPE) tissue blocks from excisional surgical specimens will be retrieved, and clinicopathologic and follow-up data will be collected from medical records.

Cases will be classified into endocrine-sensitive and endocrine-resistant groups based on international consensus definitions using the timing of disease recurrence relative to endocrine therapy. Immunohistochemical staining for p-AKT and p-S6 will be performed on FFPE tissue sections and evaluated using a semi-quantitative scoring system. Histopathologic assessment will include standard reporting parameters as well as additional features such as tumor-infiltrating lymphocyte density, tumor budding, lymphovascular invasion, perineural invasion, and tumoral necrosis. Associations between biomarker expression, clinicopathologic features, and follow-up outcomes will be explored.

Study Type

Observational

Enrollment (Estimated)

70

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Noha A Abo-elhaggag, MD
  • Phone Number: +20 100 7509759
  • Email: nohah@aun.edu.eg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Patients with estrogen receptor-positive (ER+), HER2-negative invasive breast cancer who received adjuvant endocrine therapy and have available formalin-fixed, paraffin-embedded (FFPE) tumor tissue archived in the Surgical Pathology Laboratory of Assiut University Hospital, as well as corresponding clinical follow-up data in the medical records of the Oncology Department at Assiut University Hospital.

Description

Inclusion Criteria:

  • Patients diagnosed with invasive breast carcinoma.
  • ER-positive and HER2-negative tumor status.
  • Received adjuvant endocrine therapy as part of routine clinical care.
  • Archived formalin-fixed paraffin-embedded (FFPE) tumor tissue available from excisional specimens (mastectomy).
  • Available medical records documenting treatment history and follow-up outcomes.

Exclusion Criteria:

  • Cases with missing or unavailable FFPE tissue blocks.
  • Cases with insufficient tissue quality for immunohistochemistry (e.g., severely degraded or exhausted FFPE block).
  • Cases with unknown or incomplete follow-up or treatment data.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Endocrine-Resistant Breast Cancer
Patients with ER-positive, HER2-negative invasive breast carcinoma who developed primary or secondary resistance to adjuvant endocrine therapy.
Other: Not applicable- observational study
Not Applicable. This is an observational study; no interventions are assigned.
Endocrine-Sensitive Breast Cancer
Patients with ER-positive, HER2-negative invasive breast carcinoma who remained relapse-free during adjuvant endocrine therapy and for ≥12 months after completion, with sufficient follow-up.
Other: Not applicable- observational study
Not Applicable. This is an observational study; no interventions are assigned.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Immunohistochemical expression of PI3K pathway activation markers: p-AKT and p-S6.
Time Frame: At the time of immunohistochemical staining of archived tissue (single time point).
Semi-quantitative assessment of phosphorylated AKT (Ser473) and phosphorylated S6 ribosomal protein in FFPE breast carcinoma tissue sections, scored using H-score, to compare expression levels between endocrine-sensitive and endocrine-resistant ER-positive, HER2-negative cases.
At the time of immunohistochemical staining of archived tissue (single time point).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation of p-AKT and p-S6 expression with endocrine therapy response.
Time Frame: through study completion, an average of 2 years
Description: Association of biomarker expression with endocrine therapy response (sensitive vs resistant) and time to recurrence or progression.
through study completion, an average of 2 years
Correlation of p-AKT and p-S6 expression with histologic features
Time Frame: through study completion, an average of 2 years
Association of biomarker expression with tumor grade, histologic type, luminal subtype, tumor budding, tumor-infiltrating lymphocyte (TIL) density, lymphovascular invasion, perineural invasion, and tumor necrosis.
through study completion, an average of 2 years
Correlation of p-AKT and p-S6 expression with clinicopathologic features
Time Frame: through study completion, an average of 2 years
Description: Association of biomarker expression with patient age, menopausal status, tumor size, nodal status, and stage at presentation.
through study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assiut University

Investigators

  • Principal Investigator: Roaa A Elnaffar, MBBS, Assiut University, Faculty of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 1, 2026

Primary Completion (Estimated)

January 1, 2028

Study Completion (Estimated)

March 1, 2028

Study Registration Dates

First Submitted

January 25, 2026

First Submitted That Met QC Criteria

January 30, 2026

First Posted (Actual)

February 4, 2026

Study Record Updates

Last Update Posted (Actual)

February 4, 2026

Last Update Submitted That Met QC Criteria

January 30, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pending (Clinical Research Information Service)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Individual participant-level data will not be publicly shared because the study uses archived clinical and pathology records containing sensitive patient information. Although the data will be de-identified, sharing it broadly could risk patient privacy and confidentiality. Data may be shared on a case-by-case basis with qualified researchers after institutional review and approval.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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