Researchers have reported the results of the first large-scale, whole-genome study of advanced breast cancer. The analysis of the sequences has resulted in identification of a subset of patients who have a higher chance of benefiting from specific personalized therapy.
Comprehensive Whole-Genome Breast Cancer Study Identifies Patients Who May Benefit From New Treatments
Researchers have reported the results of the first large-scale, whole-genome study of advanced breast cancer. The analysis of the sequences has resulted in the identification of a subset of patients who have a higher chance of benefiting from specific personalized therapy. These personalized therapy approaches are currently being tested in clinical trials in 13% of the 423 patients that were included in the study. The results are published in Lancet Oncology.
The analysis could help physicians choose treatments with better precision, based on the genetic landscape of the tumor.
“The key finding is that it is feasible to deliver personalized medicine using a genome-wide approach at a large-scale, nationwide level,” said lead study author Fabrice AndrÃ©, MD, PhD, of the Institut Gustave Roussy in Villejuif, France. The study demonstrated that analyzing the entire genome could identify frequent and rare genetic aberrations and that this could be done in a clinical practice setting. Previous studies have only analyzed a small subset of genes to identify potential therapy options for patients, which could miss novel mutations or mutations that could be targeted with experimental or available therapies.
“The major implication is that we must stop running single gene tests, and we should move to multigenic assays that can screen for a higher number of targets,” said AndrÃ©.
These analyses were part of UNICANCER’s SAFIR-01 trial, which aimed to address the feasibility of implementing molecular screening in order to identify patients eligible for early-stage targeted agent clinical trials. Eighteen centers in France recruited 423 patients and analyzed their metastatic breast cancer biopsy samples. Of the 423 patients, 407 underwent a biopsy, with 4 patients (1%) reporting grade 3 or 4 adverse events.
Whole-genome analysis by array comparative genomic hybridization (CGH) was successful for 67% (283) of patients, and Sanger sequencing was successful for 70% (297) of patients. Forty-six percent of the 423 patients were found to have a targetable genomic alteration, and 39% had a rare alteration for which there are no available therapies or even therapies in development. The most frequently identified mutation (in 25% of patients) was in the PIK3CA gene.
Fifty-five (13%) of the patients had genetic aberrations in their tumors that made them eligible for clinical trials of targeted agents. This proportion of patients did not meet the study steering committee’s predefined threshold (30%) of patients who should be recruited into targeted treatment studies based on the genomic analysis.
Of the 55 patients eligible for a treatment clinical trial, 43 could be treated. Patients were treated with EGFR, AKT2, IGF1R, or FGF-pathway targeted inhibitors. Four patients had an objective response. According to Charles Swanton, MD, FRCP, PhD, of the Cancer Research UK London Research Institute, the low response rate may reflect the number of previous lines of therapy the patients had already received to treat their cancer.
Although no significant clinical benefit was derived in this study, AndrÃ© said that he and his colleagues were even skeptical that the genomic analysis study could be executed. The authors were able to set up an intricate 10-step process, from patient identification to biopsy collection, and then to treatment. Each step had to be completed by a different expert. “This was done on a large scale of 18 centers and 423 patients, and we succeeded in a span of 16 months,” said AndrÃ©.
“In view of the challenges highlighted by SAFIR-01, efforts to accelerate genomic analyses for personalized medicine must continue to be embedded within the context of clinical trials, and integrated with scientific and clinical collaborative structures to deliver measurable benefits to patients,” concluded Swanton in his editorial. “The findings of SAFIR-01 represent an important first step on this journey.”
AndrÃ© and colleagues are now conducting a randomized trial that compares this precision approach based on genomic analysis with standard of care. “[We] need randomized trials before implementing the approach-and also to integrate other biological pathways such as DNA repair and patients’ immune pathways-in the diagnosis and treatment decision process.”