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Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial
- Source :
- C Turner, N, Kingston, B, S Kilburn, L, Kernaghan, S, M Wardley, A, R Macpherson, I, D Baird, R, Roylance, R, Stephens, P, Oikonomidou, O, P Braybrooke, J, Tuthill, M, Abraham, J, C Winter, M, Bye, H, Hubank, M, Gevensleben, H, Cutts, R, Snowdon, C, Rea, D, Cameron, D A, Shaaban, A, Randle, K, Martin, S, Wilkinson, K, Moretti, L, Bliss, J M & Ring, A 2020, ' Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial ', The Lancet Oncology, vol. 21, no. 10, pp. 1296-1308 . https://doi.org/10.1016/S1470-2045(20)30444-7
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- 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 common grade 3–4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C).INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment.FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology.
- Subjects :
- Adult
0301 basic medicine
Oncology
medicine.medical_specialty
Genotype
Receptor, ErbB-2
Breast Neoplasms
Circulating Tumor DNA
03 medical and health sciences
0302 clinical medicine
Breast cancer
Internal medicine
Biomarkers, Tumor
medicine
Clinical endpoint
Humans
Pyrroles
Molecular Targeted Therapy
Prospective Studies
Prospective cohort study
Fulvestrant
Aged
business.industry
Estrogen Receptor alpha
PTEN Phosphohydrolase
Cancer
Middle Aged
medicine.disease
Clinical trial
Pyrimidines
Treatment Outcome
030104 developmental biology
Receptors, Estrogen
030220 oncology & carcinogenesis
Mutation
Neratinib
Cohort
Quinolines
Female
business
Proto-Oncogene Proteins c-akt
medicine.drug
Subjects
Details
- ISSN :
- 14702045
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- The Lancet Oncology
- Accession number :
- edsair.doi.dedup.....07a5a7ae2a2af9e5ba7c16e614105e61