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

Assiut University

Status: Begins enrollment this month

Conditions: Breast Cancer - ER+, HER2-, PIK3CA Gene Mutation

Treatments: Other: Not applicable- observational study

Study type: Observational

Funder types: Other

Identifiers

NCT07387861

Pending

Details and patient eligibility

About

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.

Full 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.

Enrollment: 70 estimated patients

Sex: All

Volunteers: No Healthy Volunteers

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.

Trial design

70 participants in 2 patient groups

Endocrine-Resistant Breast Cancer

Description:

Patients with ER-positive, HER2-negative invasive breast carcinoma who developed primary or secondary resistance to adjuvant endocrine therapy.

Treatment:

Other: Not applicable- observational study

Endocrine-Sensitive Breast Cancer

Description:

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.

Treatment:

Other: Not applicable- observational study