Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER)

Summary

Background

Breast cancer is characterised by genomic alterations. We did a multicentre molecular screening study to identify abnormalities in individual patients with the aim of providing targeted therapy matched to individuals' genomic alterations.

Methods

From June 16, 2011, to July 30, 2012, we recruited patients who had breast cancer with a metastasis accessible for biopsy in 18 centres in France. Comparative genomic hybridisation (CGH) array and Sanger sequencing on PIK3CA (exon 10 and 21) and AKT1 (exon 4) were used to assess metastatic biopsy samples in five centres. Therapeutic targets were decided on the basis of identified genomic alterations. The primary objective was to include 30% of patients in clinical trials testing a targeted therapy and, therefore, the primary outcome was the proportion of patients to whom a targeted therapy could be offered. For the primary endpoint, the analyses were done on the overall population registered for the trial. This trial is registered with ClinicalTrials.gov, number NCT01414933.

Findings

423 patients were included, and biopsy samples were obtained from 407 (metastatic breast cancer was not found in four). CGH array and Sanger sequencing were feasible in 283 (67%) and 297 (70%) patients, respectively. A targetable genomic alteration was identified in 195 (46%) patients, most frequently in PIK3CA (74 [25%] of 297 identified genomic alterations), CCND1 (53 [19%]), and FGFR1 (36 [13%]). 117 (39%) of 297 patients with genomic tests available presented with rare genomic alterations (defined as occurring in less than 5% of the general population), including AKT1 mutations, and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET high-level amplifications. Therapy could be personalised in 55 (13%) of 423 patients. Of the 43 patients who were assessable and received targeted therapy, four (9%) had an objective response, and nine others (21%) had stable disease for more than 16 weeks. Serious (grade 3 or higher) adverse events related to biopsy were reported in four (1%) of enrolled patients, including pneumothorax (grade 3, one patient), pain (grade 3, one patient), haematoma (grade 3, one patient), and haemorrhagic shock (grade 3, one patient).

Interpretation

Personalisation of medicine for metastatic breast cancer is feasible, including for rare genomic alterations.

Funding

French National Cancer Institute, Breast Cancer Research Foundation, Odyssea, Operation Parrains Chercheurs.

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.