In the plasmaMATCH trial, researchers performed circulating tumor DNA testing on patients with advanced breast cancer and matched those with ESR1, HER2, or AKT1 alterations to targeted therapies. Patients with HER2 and AKT1 mutations experienced response rates greater than 22% with durable benefit.
Recent studies in non–small cell lung cancer and colorectal cancer have suggested that circulating tumor DNA (ctDNA) could inform treatment decisions—and now breast cancer could be added to that list. In the plasmaMATCH trial, researchers used ctDNA testing to identify genomic alterations in patients with advanced breast cancer and match them with targeted treatments.
ctDNA indicates the presence of not only the cancer, but also genomic alterations if it's sequenced. However, most studies on ctDNA testing have been retrospective. “What the field has really needed is a large, prospective study to demonstrate that ctDNA testing works in clinical practice,” explains Nicholas Turner, MD, PhD, of the Institute of Cancer Research in London, UK, who presented the results at the 2019 San Antonio Breast Cancer Symposium in Texas. “We wanted to assess if we could detect mutations in ctDNA without tumor testing, and if we could use that to guide therapy.”
As part of plasmaMATCH, which was carried out at 18 sites in the UK, researchers sequenced ctDNA from 1,033 patients with advanced breast cancer, most of whom had received at least three prior treatments. They searched for ESR1, HER2, and AKT1 alterations and enrolled patients in one of three cohorts based on their mutations: Patients with ESR1 mutations received an extended dose of the antiestrogen fulvestrant; those with HER2 mutations received fulvestrant and the tyrosine kinase inhibitor neratinib (Nerlynx; Puma Biotechnology); and those with AKT1 alterations received fulvestrant and the experimental AKT inhibitor capivasertib (AZD5263; AstraZeneca).
In the ESR1 cohort, the response rate was just 8.1% among 74 evaluable patients, and the median progression free survival (PFS) was 2.2 months. However, more—and longer—responses were seen in the other cohorts: Among 20 evaluable patients in the HER2 group, 25% responded, with a median PFS of 5.4 months, and among 18 evaluable patients in the AKT1 group, 22.2% responded, with a median PFS of 10.2 months.
“Despite the fact that we were enrolling a heavily pretreated patient population, we saw durable responses and relatively high median progression-free survival” in patients with HER2 and AKT1 mutations, Turner says. “This provides the prospective validation for ctDNA testing that's been missing in clinical practice,” he adds, positioning it as a viable alternative to repeat biopsies.
Aditya Bardia, MBBS, MPH, of Massachusetts General Hospital in Boston, who is not involved in plasmaMATCH, calls it “a landmark trial” that demonstrates the feasibility of using ctDNA-based genotyping to direct therapy. However, he notes that although response rates were encouraging in the HER2 and AKT1 groups, the limited responses in patients with ESR1 mutations hint that other factors could be involved—including the efficacy of the targeted treatment, coexisting mutations, tumor evolution, and redundant pathways that may lead to therapeutic resistance. Combinations of targeted therapies, he says, might improve response rates and their durability.
For Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, who is also not connected to plasmaMATCH, the trial establishes ctDNA testing as a powerful tool for quickly identifying targetable mutations and directing therapy, but he thinks clinicians should still test tumor tissue to confirm the results and obtain more comprehensive genomic information.
In addition, he wants to see adaptive studies that repeat ctDNA testing to tailor treatment to patients in real time. “You can imagine using ctDNA as a dynamic biomarker to assess response” and guide decisions about escalating or switching therapies, he says. –Catherine Caruso