PI3K pathway analysis in tumor tissue and circulating DNA to obtain further insight in the efficacy of everolimus when combined with exemestane.
A side-study protocol attached to standard treatment with everolimus and exemestane for postmenopausal patients with hormone receptor-positive advanced metastatic breast cancer, who have progressed on anastrozole or letrozole

Study title:
PI3K pathway analysis in tumor tissue and circulating DNA to obtain further
insight in the efficacy of everolimus when combined with exemestane
A side-study protocol attached to standard treatment with everolimus and
exemestane for postmenopausal patients with hormone receptor-positive advanced
metastatic breast cancer, who have progressed on anastrozole or letrozole

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 side-study proposal we 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 PI3K pathway activation versus patients whose metastatic tumor does
not express PI3K pathway activation (see Attachment 1).
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 side-studies (see Attachment 1).
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 (see
Attachment 2).
4. It is proposed to establish the incidence of mutations in PIK3CA and 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 (see Attachment 3).

Number of patients and centers:
Since the majority of the side-studies involve the use of new techniques,
studies 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.
- 175 patients for blood samples and archived tumor tissue
- 50 for fresh tumor biopsy,
- 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, 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 GCP in the patient*s file.

This study will not provide any direct benefit for the patients participating
in this study. The burden for the patients is low and risks of participating
are negligible to low.