Analysis of Tumor Tissue and Circulating Genetic Material in the Blood to Obtain Further Insight in the Effectiveness of Everolimus When Combined With Exemestane

Clinical Trial Summary

The purpose of this study is to determine whether biomarkers could be found to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival. Postmenopausal patients with advanced metastatic breast cancer who have progressed on anastrozole or letrozole will be eligible for this study.

Rationale of study:

Everolimus combined with exemestane has shown to improve progression-free survival compared to exemestane monotherapy in patients with hormone receptor-positive breast cancer previously treated with non-steroidal aromatase inhibitors. Since January 1st, 2013, everolimus is being reimbursed for this category of patients. For many patients this means, that an interesting treatment possibility has become available. However, some patients do not benefit from everolimus and exemestane, while others have to deal with side-effects requiring adjustment of the dose or even discontinuation of treatment.

In this study proposal the investigators plan to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival.

Study objectives:

1. It is proposed to compare progression-free survival on the combination of everolimus and exemestane between patients whose metastatic tumor expresses markers of phosphatidylinositol 3-kinase (PI3K) pathway activation versus patients whose metastatic tumor does not express PI3K pathway activation.

2. It is proposed to carry out immunohistochemistry on activated members of the PI3K pathway in primary tumor tissue of patients treated with everolimus and exemestane and compare the findings with the outcome of treatment and more specifically, with the results from other studies.

3. It is proposed to associate protein expression/ phosphorylation by proteomics in tumor biopsies to cancer mutations, PI3K pathway activation and progression-free survival on the exemestane and everolimus combination.

4. It is proposed to establish the incidence of mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and protein kinase B (AKT) in peripheral blood of advanced breast cancer patients amenable for treatment with everolimus and exemestane and to explore whether the presence of such mutations is associated with outcome to treatment in these patients.

Study population:

Postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer whose disease is refractory to non steroidal aromatase inhibitors (NSAIs) and have a documented recurrence or progression on last therapy for breast cancer.

Number of patients and centers:

- 175 patients for blood samples and archived tumor tissue, 50 for fresh tumor biopsy, another 30 for fresh tumor biopsy upon progressive disease

- 30 hospitals in the Netherlands.

Treatment phase:

Patients will be treated with 10 mg daily doses of everolimus (either 2 x 5 mg or 1 x 10 mg tablets) in combination with exemestane (25 mg daily tablets).

Dose adjustment (reduction, interruption) according to safety findings will be allowed.

Treatment will continue until one of the following conditions apply and whichever comes first: tumor progression, unacceptable toxicity according to investigator's judgment, patient's wish, death, discontinuation from the study for any other reason. Further treatment after progression will be at the investigator's discretion.

Physicians will collect data on demographics, previous treatments, efficacy of everolimus and exemestane as well as on toxic effects of this combination according to good clinical practice (GCP) in the patient's file.

Statistical considerations:

Since the majority of the studies involve the use of new techniques, the study will be mainly explorative in design. For blood sample analysis and analysis of archival tumor tissue at least 175 patients will be required. For tumor tissue biopsies a number of 50 patients is expected to give insight in differences between patients with clinical benefit ant those with early progressive disease; from 30 of these patients a tumor biopsy will be collected upon progressive disease. ;

Study Design

Related Conditions & MeSH terms

• Breast Neoplasms
• Hormone Receptor Positive Malignant Neoplasm of Breast
• Metastatic Breast Cancer
• Neoplasms