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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое Not applicable- observational study
  Not Applicable. This is an observational study; no interventions are assigned.

Первичные конечные точки

• Immunohistochemical expression of PI3K pathway activation markers: p-AKT and p-S6. [Срок оценки: At the time of immunohistochemical staining of archived tissue (single time point).]

Вторичные конечные точки (3)

• Correlation of p-AKT and p-S6 expression with endocrine therapy response. [Срок оценки: through study completion, an average of 2 years]
• Correlation of p-AKT and p-S6 expression with histologic features [Срок оценки: through study completion, an average of 2 years]
• Correlation of p-AKT and p-S6 expression with clinicopathologic features [Срок оценки: through study completion, an average of 2 years]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

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• 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
• 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;2 PMID 28446508
• 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
• 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

Идентификаторы

NCT: NCT07387861 · Pending

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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