Aiming to Understand the Molecular Aberrations in Metastatic Breast Cancer

Study Objectives

1. To improve the understanding of locally recurrent/advanced BC and MBC by using high-throughput technologies on primary, metastatic, as well as plasma ctDNA samples, to explore tumor heterogeneity, clonal evolution and transcriptional changes associated with mutational and copy number variation (CNV) patterns.
2. To discover biomarkers of response and/or resistance to systemic therapy using genomic and transcriptomic data of “exceptional responders” and “rapid progressors” (collectively referred to as “outliers”, as defined in the AURORA protocol, section 3).
3. To provide evidence that can contribute in assessing the feasibility of implementing a global molecular screening platform of MBC.
4. To identify patients with candidate driver alterations in their tumors that can be matched to biomarker-driven clinical trials.
5. To build new therapeutic hypotheses based on findings generated by Targeted Gene Sequencing (TGS).
6. To evaluate the prognostic relevance of genomic alterations detected in plasma ctDNA samples, tumor metastatic biopsies and archived primary tissue.
7. To correlate molecular alterations in patients with the efficacy endpoints (response rate, progression-free survival and overall survival).

Participation conditions

Inclusion criteria

Patients will be eligible for study participation only if they comply with the following inclusion criteria:

1. Female or male with diagnosis of locally recurrent/advanced BC not amenable to treatment with curative intent or MBC. AURORA Program - Protocol version 3.0 FINAL – 09 February 2017
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or1 (please refer to appendix 20.4).
3. Written informed consent prior to registration into the program.
4. Patients aged ≥ 18 years.
5. Availability of primary tumor tissue for research purposes.
6. Patient must have a metastatic lesion accessible for biopsies and must agree with the biopsy procedure. Biopsies of bone lesions are not accepted. Brain tissue is accepted if provided through surgical excision not planned for the AURORA program, but as part of the routine clinical practice. Up to 100 patients with bone-only disease will be included without a metastatic biopsy provided that a plasma sample is collected at registration in the program for ctDNA analysis and that the patient meets all other eligibility criteria including the availability of primary tumor tissue. Of note, no metastatic lesion biopsies will be collected for patients with bone-only disease.
7. The biopsy of the metastatic lesion must be conducted either at the initial diagnosis of the BC relapse before the initiation of 1st line systemic therapy or at the 1st disease progression before initiation of a second line systemic treatment. Biopsies obtained during as part of routine clinical practice are accepted if both formalin-fixed paraffinembedded (FFPE) and Frozen Tissue (FT) blocks were collected concurrently from the same metastatic lesion and if collected at the pre-specified timelines.
8. Availability of a whole blood, serum and plasma samples collected at the time of screening.
9. There is no restriction in the type of therapeutic modality considered as 1st line systemic treatment, which can consist of any type of treatment administered after the diagnosis of the BC relapse till the 1st disease progression thereafter. 10. Patient agrees to provide blood samples at regular intervals, both at screening as well as during the FU phase of the program

Exclusion criteria

1. The patient has received more than 1 line of systemic therapy (any type) in the metastatic setting.
2. Patients who have received prior palliative radiotherapy to the only site that is accessible to biopsy.
3. Bone biopsy as the only available metastatic sample. Note that up to 100 patients with bone-only disease will be accepted without a metastatic biopsy provided that a plasma sample is collected at screening in the program and that the patient meets all other eligibility criteria.
4. Presence of severe hematopoietic, renal, and/or hepatic dysfunction, including but not restricted to albumin < 3 g/dl.
5. Known increased risk of hemorrhage during biopsy procedure, as evaluated by the treating physician.
6. Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin.

Centre Hospitalier de Luxembourg (CHL)