PI3K Pathway Activation Markers in ER-Positive, HER2-Negative Breast Cancer: A Clinicopathologic Study

NCT07387861 | Not Yet Recruiting

• 1 other identifier: Pending
• Study Type: observational
• Target: 70
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

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

Keywords

Breast Cancer; PI3K/AKT/mTOR pathway; Phospho-AKT; Phospho-S6; Endocrine therapy; Tumor budding; TILs

Outcome Measures

Primary Outcomes (1)

• Immunohistochemical expression of PI3K pathway activation markers: p-AKT and p-S6.

  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 Outcomes (3)

• Correlation of p-AKT and p-S6 expression with endocrine therapy response.

  through study completion, an average of 2 years

• Correlation of p-AKT and p-S6 expression with histologic features

  through study completion, an average of 2 years

• Correlation of p-AKT and p-S6 expression with clinicopathologic features

  through study completion, an average of 2 years

Study Arms (2)

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

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

Interventions

Not applicable- observational study OTHER

Not Applicable. This is an observational study; no interventions are assigned.

Endocrine-Resistant Breast Cancer; Endocrine-Sensitive Breast Cancer

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Assiut University: lead

Related Publications (14)

• Lv W, Du C, Zhang Y, Wu F, Jin Y, Chen X, Liu X, Feng C, Ma X, Zhang S. Clinicopathological characteristics and prognostic analysis of PIK3CA mutation in breast cancer patients in Northwest China. Pathol Res Pract. 2022 Oct;238:154063. doi: 10.1016/j.prp.2022.154063. Epub 2022 Aug 10.

  PMID: 35994807 BACKGROUND

• Adamo B, Deal AM, Burrows E, Geradts J, Hamilton E, Blackwell KL, Livasy C, Fritchie K, Prat A, Harrell JC, Ewend MG, Carey LA, Miller CR, Anders CK. Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases. Breast Cancer Res. 2011;13(6):R125. doi: 10.1186/bcr3071. Epub 2011 Dec 1.

  PMID: 22132754 BACKGROUND

• Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S. Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):408-14. doi: 10.1158/1078-0432.CCR-06-0267. Epub 2007 Jan 3.

  PMID: 17202311 BACKGROUND

• Sakr RA, Weigelt B, Chandarlapaty S, Andrade VP, Guerini-Rocco E, Giri D, Ng CK, Cowell CF, Rosen N, Reis-Filho JS, King TA. PI3K pathway activation in high-grade ductal carcinoma in situ--implications for progression to invasive breast carcinoma. Clin Cancer Res. 2014 May 1;20(9):2326-37. doi: 10.1158/1078-0432.CCR-13-2267. Epub 2014 Mar 14.

  PMID: 24634376 BACKGROUND

• Rasti AR, Guimaraes-Young A, Datko F, Borges VF, Aisner DL, Shagisultanova E. PIK3CA Mutations Drive Therapeutic Resistance in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. JCO Precis Oncol. 2022 Mar;6:e2100370. doi: 10.1200/PO.21.00370.

  PMID: 35357905 BACKGROUND

• Pierobon M, Ramos C, Wong S, Hodge KA, Aldrich J, Byron S, Anthony SP, Robert NJ, Northfelt DW, Jahanzeb M, Vocila L, Wulfkuhle J, Gambara G, Gallagher RI, Dunetz B, Hoke N, Dong T, Craig DW, Cristofanilli M, Leyland-Jones B, Liotta LA, O'Shaughnessy JA, Carpten JD, Petricoin EF. Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer. Clin Cancer Res. 2017 Aug 15;23(16):4919-4928. doi: 10.1158/1078-0432.CCR-16-2656. Epub 2017 Apr 26.

  PMID: 28446508 BACKGROUND

• Creighton CJ, Fu X, Hennessy BT, Casa AJ, Zhang Y, Gonzalez-Angulo AM, Lluch A, Gray JW, Brown PH, Hilsenbeck SG, Osborne CK, Mills GB, Lee AV, Schiff R. Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res. 2010;12(3):R40. doi: 10.1186/bcr2594. Epub 2010 Jun 22.

  PMID: 20569503 BACKGROUND

• Cascardo F, Vivanco M, Perrone MC, Werbach A, Enrico D, Mando P, Amat M, Martinez-Vazquez P, Burruchaga J, Mac Donnell M, Lanari C, Zwenger A, Waisberg F, Novaro V. Higher risk of recurrence in early-stage breast cancer patients with increased levels of ribosomal protein S6. Sci Rep. 2024 Oct 24;14(1):25136. doi: 10.1038/s41598-024-75154-1.

  PMID: 39448637 BACKGROUND

• Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13(6):224. doi: 10.1186/bcr3039. Epub 2011 Nov 1.

  PMID: 22114931 BACKGROUND

• Skolariki A, D'Costa J, Little M, Lord S. Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic. Explor Target Antitumor Ther. 2022;3(2):172-199. doi: 10.37349/etat.2022.00078. Epub 2022 Apr 24.

  PMID: 36046843 BACKGROUND

• Toska E, Osmanbeyoglu HU, Castel P, Chan C, Hendrickson RC, Elkabets M, Dickler MN, Scaltriti M, Leslie CS, Armstrong SA, Baselga J. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science. 2017 Mar 24;355(6331):1324-1330. doi: 10.1126/science.aah6893.

  PMID: 28336670 BACKGROUND

• Vasan N, Toska E, Scaltriti M. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann Oncol. 2019 Dec 1;30(Suppl_10):x3-x11. doi: 10.1093/annonc/mdz281.

  PMID: 31859348 BACKGROUND

• Lei JT, Anurag M, Haricharan S, Gou X, Ellis MJ. Endocrine therapy resistance: new insights. Breast. 2019 Nov;48 Suppl 1(Suppl 1):S26-S30. doi: 10.1016/S0960-9776(19)31118-X.

  PMID: 31839155 BACKGROUND

• Hanker AB, Sudhan DR, Arteaga CL. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell. 2020 Apr 13;37(4):496-513. doi: 10.1016/j.ccell.2020.03.009.

  PMID: 32289273 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Roaa A Elnaffar, MBBS

  Assiut University, Faculty of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Roaa A Elnaffar, MBBS

CONTACT

+20 1281071748; roaaelnaffar@aun.edu.eg

Noha A Abo-elhaggag, MD

CONTACT

+20 100 7509759; nohah@aun.edu.eg

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Demonstrator

Study Record Dates

• First Submitted: January 25, 2026
• First Posted: February 4, 2026
• Study Start: March 1, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): March 1, 2028
• Last Updated: February 4, 2026

Record last verified: 2026-01