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Circulating tumor DNA (ctDNA) shows talent in sleuthing out mutations in women with certain types of advanced breast cancer and matching them to precision treatments. According to British researchers, who reported these findings in The Lancet, this makes a strong case for using liquid biopsy routinely in clinical practice for patients with advanced-stage cancer.
High-sensitivity assays have come on the market in recent years to evaluate ctDNA, which releases into plasma as cancer cells die. These tests represent a convenient, noninvasive approach for assessing tumors for aberrations. Previous studies have shown a definitive correlation between ctDNA and tumor tissue analyses of advanced cancer, but discordant results among commercial ctDNA assays have raised questions about using this tool in clinical practice.
Investigators in the plasmaMATCH trial explored ctDNA’s ability to identify targeted treatments without any previous tissue testing, as well as the clinical validity of liquid biopsy tests. This open label, multicohort, phase 2a platform trial took place in 18 hospitals in the United Kingdom, enlisting women 18 or older with advanced breast cancer. Participants had either relapsed following a year of neoadjuvant or adjuvant chemotherapy or previously completed one line of treatment for advanced cancer.
Investigators assigned 142 patients to four treatment groups based on the mutations found by ctNDA testing. Women with ESR1 mutations (cohort A) received 500 mg doses of fulvestrant, whereas patients with HER2 mutations (cohort B) received 240 mg doses of oral neratinib and intramuscular standard-dose fulvestrant if they were estrogen receptor-positive. Women with AKT1 mutations were split into two groups. Those with estrogen receptor-positive cancer (cohort C) received 400 mg doses of oral capivasertib and intramuscular standard-dose fulvestrant. Estrogen receptor-negative cancer or patients with PTEN mutations (cohort D) received 480 mg doses of oral capivasertib alone.
Digital polymerase chain reaction (PCR) ctDNA testing for mutations found in tissue sequencing scored an overall sensitivity of 93% and a 98% sensitivity with contemporaneous biopsies. Agreement between ctDNA digital PCR and targeted sequencing ranged from 96% to 99%. However, not all of the patients responded to the treatments chosen for them by ctDNA. Five out of 20 women with rare HER2 mutations matched to neratinib saw cancer growth either shrink or cease. Four out of 18 patients with AKT1 mutations responded to capivasertib. Treatments for cohorts A and D were not as successful, however. Only 6 out of 74 patients in the ESR1 mutation group and just 2 out of 19 patients in the D group had responses to therapies.
Liquid biopsy-guided treatment could transform the way physicians select therapies for advanced cancer patients, said lead study author Nicholas Turner, MD, professor of molecular oncology at The Institute of Cancer Research in London and head of the Ralph Lauren Center for Breast Cancer Research at The Royal Marsden Hospital. “Our study shows that these liquid biopsies can pick up the mutations that drive a patient’s breast cancer and can successfully match patients with the best available precision medicine for their cancer,” said Turner in a statement.
Next steps are to take a closer look at the targeted drugs that showed initial success in this trial. Larger studies would assess their clinical validity in comparison to existing treatments.