Findings With Comparative Genomic Hybridization Array and DNA Sequencing Indicate Feasibility of Personalized Treatment for Metastatic Breast Cancer
In the SAFIR01/UNICANCER study reported in The Lancet Oncology, André et al used comparative genomic hybridization and Sanger sequencing on metastatic breast cancer biopsy samples to determine the proportion of cases in which targeted therapy could be offered. They found that screening procedures could be completed in most patients, resulting in the ability to select targeted therapy in many, including those with infrequently observed genomic alterations.
Study Details
In the study, 423 patients with breast cancer metastasis accessible to biopsy were recruited between June 2011 and July 2012 from 18 centers in France. Comparative genomic hybridization array and Sanger sequencing on PIK3CA (exon 10 and 21) and AKT1 (exon 4) were used to assess metastatic biopsy samples in five genomic centers, with therapeutic targets being selected on the basis of identified genomic alterations.
The primary objective was to include 30% of patients in clinical trials testing a targeted therapy. Thus, the primary outcome was the proportion of patients that could be offered targeted therapy.
Identification of Targetable Alterations
Of the 423 patients included, biopsy samples were obtained from 407. The most frequent biopsy sites were liver (42%), lymph nodes (18%), skin (16%), and lungs (5%). Comparative genomic hybridization array and Sanger sequencing were feasible in 283 (67%) and 297 patients (70%), respectively.
A targetable genomic alteration was identified in 195 patients (46%), with the most frequently identified alterations being those in PIK3CA (25% of 297 identified alterations), CCND1 (19%), and FGFR1 (13%). A total of 117 (39%) of 297 patients with genomic tests available had genomic alterations occurring in < 5% of the general population, including AKT1 mutations, and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET high-level amplifications.
Personalized Therapy
Overall, therapy could be personalized in 55 (13%) of the 423 patients, with selection based on genomic alterations in 52 and HER2 amplification on comparative genomic hybridization array in 3. Of the 52 patients with genomic alterations, 4 were included in randomized trials of targeted therapies that could be matched to their alteration.
Aggressive disease was characteristic of the remaining 48 patients, with 56% having received at least two lines of chemotherapy, and 56% of the 43 assessable for antitumor activity having grade III tumors. Seventeen of these patients were screened for inclusion in phase I trials but did not meet eligibility criteria and were treated with conventional chemotherapy or endocrine therapy.
A total of 16 different regimens including 19 drugs were used in the 48 patients who received targeted therapy. The most common treatments were PI3K, AKT, or mTOR inhibitors in patients with PIK3CA mutation or amplification (12 patients) and FGFR inhibitors in patients with FGFR1 amplification (9 patients), but targeted treatments were also given to patients with AKT1 mutation and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET amplifications. Among the 48 patients, 28 (58%) received treatment in phase I or II trials. Overall, 13 (30%) of 43 evaluable patients had either objective response (n = 4) or stable disease for > 16 weeks (n = 9).
Grade 3 adverse events related to biopsy occurred in four patients (1%), and consisted of pneumothorax, pain, hematoma, and hemorrhagic shock in one patient each.
The investigators concluded, “Personalisation of medicine for metastatic breast cancer is feasible, including for rare genomic alterations.”
Fabrice André, MD, of Gustave Roussy Cancer Campus, Villjeuif, France, is the corresponding author for The Lancet Oncology article.
The study was funded by the French National Cancer Institute, Breast Cancer Research Foundation, Odyssea, and Operation Parrains Chercheurs. For full disclosures of the study authors, visit www.thelancet.com.
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