ArticlesComparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER)
Introduction
Metastatic breast cancer is a leading cause of cancer death worldwide. 39 620 women died from this disease in the USA in 2013.1 Although advances have been made in the management of breast cancer, metastatic disease is still largely viewed as incurable. With the exception of eribulin,2 no chemotherapy or endocrine therapy developed in the past 10 years has led to improvement in overall survival in patients with metastatic breast cancer. By contrast, targeted therapies, such as those directed against HER2 (also known as ERBB2) overexpression, have improved patients' outcomes.3 Studies of molecular characterisation have shown that, besides HER2 amplification, breast cancers include many genomic alterations located in oncogenes or tumour suppressor genes.4, 5 Each specific oncogenic event could potentially be blocked by a targeted therapy. For instance, AKT1 and FGFR1 are mutated or amplified in 4% and 10% of breast cancers, respectively, and might be sensitive to targeted inhibitors.6, 7 Screening for targetable genomic alterations could help to identify subpopulations of patients who will benefit from specific treatments.
The development of drugs for rare genomic alterations first requires identification of patients carrying an alteration that can be targeted by a drug. Many patients must be screened to identify those who stand to benefit, which impairs the development of drugs for rare genomic alterations. To overcome these challenges, complex genomic testing strategies with multiple approaches have been proposed to enable optimum patient screening.8 Molecular screening programmes could identify relevant genomic targets that will show some antitumour activity and warrant further investigation, and would also increase the likelihood of a patient receiving targeted therapy.
Since molecular screening programmes use high-throughput technologies and bioinformatics to interpret cancer biology at the individual patient level, they might also be useful to assess whether the concept of personalised medicine could translate into benefits for patients. This hypothesis has been applied in a few pilot studies. We used array comparative genomic hybridisation (CGH) and hotspot sequencing on PIK3CA and AKT1 in 108 patients with metastatic breast cancer, and showed that 17 (16%) could be treated with targeted therapy on the basis of their genomic profile.9 Von Hoff and colleagues10 used RT-PCR to detect targets in 86 patients with metastatic cancer, and noted that progression-free survival during genomics-driven treatment was higher than that during the previous line of therapy in some patients. The pilot studies, however, included small numbers of patients and could not draw definitive conclusions. Therefore, we did a prospective, multicentre molecular screening study to investigate whether genomic abnormalities could be identified in individual patients that would lead to targeted therapy.
Section snippets
Patients
From June 16, 2011, to July 30, 2012, we recruited 423 patients in 18 centres in France who had metastatic breast cancer, a metastasis at a site accessible for a biopsy, performance status of 0 or 1, and stable disease or response. After 170 patients had been enrolled, the eligibility criteria were changed to allow no more than two lines of previous chemotherapy, to preclude rejection from phase 1 studies because of poor performance status, and to limit biopsy to non-bone lesions because of the
Results
423 patients were included in the trial (figure 1, table 1, appendix). The study population was representative of patients with hard-to-treat breast cancers, reflected by the high proportion of patients who had liver metastases, or who had previously received chemotherapy for metastatic disease (table 1). Biopsies were done in 407 (96%) of 423 enrolled patients. Serious adverse events related to biopsy were noted in nine (2%) patients, including pneumothorax (grade 2, n=3; grade 3, n=1), pain
Discussion
In this trial, we have shown that CGH array and Sanger sequencing are feasible methods to identify targetable genomic alterations in patients with metastatic breast cancer (panel). Genomic analyses led to matching of therapy in 55 (13%) of 423 patients. New strategies to guide therapy are urgently needed in patients who have metastatic cancer that is refractory to standard treatments. Targeting oncogenic drivers has been proposed as a possible approach to improve outcomes for these
References (23)
- et al.
Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study
Lancet
(2011) - et al.
Array CGH and PIK3CA/AKT1 mutations to drive patients to specific targeted agents: a clinical experience in 108 patients with metastatic breast cancer
Eur J Cancer
(2012) Optimal two-stage for phase II clinical trials
Control Clin Trials
(1989)- et al.
Breast cancer statistics
CA Cancer J Clin
(2013) - et al.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2
N Engl J Med
(2001) - et al.
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
Nature
(2012) - et al.
The landscape of cancer genes and mutational processes in breast cancer
Nature
(2012) - et al.
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
Nature
(2007) - et al.
Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer
Clin Cancer Res
(2013) - et al.
Biology-driven phase II trials: what is the optimal model for molecular selection?
J Clin Oncol
(2011)
Pilot study using molecular profiling of patients' tumours to find potential targets and select treatments for their refractory cancers
J Clin Oncol
Cited by (340)
Developing therapies for triple-negative breast cancer subtypes
2024, The Lancet OncologyA GATE Monte Carlo framework for dosimetric evaluation in mammography in an Algerian hospital
2023, Applied Radiation and IsotopesLiquid biopsy accelerates precision medicine
2023, Annals of Oncology