Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial

Abstract

Summary Background Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. Methods We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0–2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov , NCT03182634 ; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. Findings Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96–99% (n=800, kappa 0·89–0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83–98) overall and 98% (87–100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0–23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9–49]) of 20 patients in cohort B and four (22% [6–48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3–17]) of 74 in cohort A and two (11% [1–33]) of 19 patients in cohort D having a response. The most c...

Association of plasma cell-free DNA with survival in patients with IDH wild-type glioblastoma

“…Blood-based liquid biopsy has become part of routine clinical care for detection of therapeutically targetable mutations in nonsmall cell lung cancer, 20 breast cancer, 21 and other solid tumors. While the detection rate of somatic mutations in the plasma of patients with GBM has been relatively low, 22 , 23 we and others have demonstrated the prognostic value of total cell-free DNA (cfDNA) concentration for GBM and other solid tumors, irrespective of the proportion of cfDNA that is tumor-derived.…”

A Closer Look at Estrogen Receptor Mutations in Breast Cancer and Their Implications for Estrogen and Antiestrogen Responses

“…Improving the detection of ERα mutations (notably by noninvasive methods) is critical as well to enable better patient care by adapting the therapeutic strategy faster in a personalized way [ 94 , 95 ]. In fact, the relevance of analyzing circulating DNA isolated from plasma samples to select therapy for breast cancer patients was recently assessed by Turner and colleagues [ 96 ].…”

Clinical Perspectives in Addressing Unsolved Issues in (Neo)Adjuvant Therapy for Primary Breast Cancer

“…Genomic profile analysis revealed various genomic mutations in primary breast tumors, including those of PIK3CA, AKT1, estrogen receptor 1 (ESR1), and checkpoint kinase 2, and more frequent mutations in metastatic lesions [ 22 ]. In a recent phase-II trial, tumor genomic profiles were evaluated using ctDNA for the administration of mutation-directed therapies; the mutations considered involved ESR1, HER-2, AKT1, P53, and phosphatase and tensin homolog deleted from chromosome 10 [ 23 ]. That study revealed that patients treated for advanced and recurrent breast cancers responded well to HER-2- and AKT1-directed therapy [ 23 ], suggesting that the mutation-directed targeted treatment of residual tumor cells improves survival in patients with early-stage breast cancer after NAC and adjuvant chemotherapy or during ET.…”