ctDNA Analysis Feasible For Breast Cancer Targetable Mutations

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The results of the plasmaMATCH study suggest that circulating tumour (ct)DNA analysis can be used to direct the treatment of breast cancer patients with HER2 or AKT1 mutations. 

“The high sensitivity of ctDNA testing for tissue mutations calls into question the need for reflex tissue testing for negative ctDNA results, within the pretreated metastatic breast cancer patient population studied”, the investigators remark in The Lancet Oncology. 

“This study also shows the potential of a novel liquid biopsy platform to screen for rare oncogenic mutations in breast cancer, and how this approach could transform clinical trials with efficient and rapid mutation screening”, the authors say. 

The open-label phase IIa study included advanced breast cancer patients who had previously received at least one neoadjuvant or adjuvant chemotherapy regimen in the past 12 months, or relapsed after treatment, and had tested positive for ctDNA-identified mutations in one of four genes with an associated targeted therapy. 

The investigators report that there was 96–99% agreement between ctDNA digital polymerase chain reaction testing and analysis of tissue samples that were available for 800 patients. Overall, ctDNA testing was 93% sensitive for mutations identified using tissue sequencing, rising to 98% for patients whose biopsies were taken within 60 days of plasma sampling. 

The researchers took a closer look at the response rates for four cohorts of patients in the study after a median of 14.4 months of follow-up.  

The target objective response rate of 25% was achieved among the 20 patients with HER2 mutations who received neratinib 240 mg, with those individuals with oestrogen receptor-positive cancer also given intramuscular fulvestrant 500 mg every 28 days after an initial loading dose. 

In addition, 22% of the 18 oestrogen receptor-positive patients with an AKT1 mutation responded to treatment with capivasertib 400 mg plus intramuscular fulvestrant 500 mg. This rate approached but did need meet the cohort’s target response rate of 25%. 

By contrast, just 8% of the 74 patients with an ESR1 mutation responded to treatment with extended-dose intramuscular fulvestrant 500 mg, a rate below the 10% required for acceptability and the 20% target rate for response.  

And only 11% of the 19 patients with AKT1 mutations and oestrogen receptor-negative cancer or a PTEN mutation responded to capivasertib 480 mg – this rate was above the threshold for acceptability but again below the 25% target rate. 

Safety analysis identified one treatment-related death caused by grade 4 dyspnoea in an oestrogen receptor-positive patient with an AKT1 mutation. The most common grade 3–4 adverse events were rash (26%) in those with an AKT1 mutation plus oestrogen receptor-negative disease or a PTEN mutation, diarrhoea in those with a HER2 mutation (25%), fatigue in the oestrogen receptor-positive AKT1 cohort (22%) and elevated gamma-glutamyltransferase in the ESR1 mutation cohort (16%). 

“[T]he degree of sensitivity observed in this study suggests that, within the patient population of advanced disease patients recruited, ctDNA testing could replace tissue-based mutation analysis”, postulate Nicholas Turner, from the Institute of Cancer Research in London, UK, and colleagues. 

“However, we note that tissue biopsy will remain important for immunohistochemistry, and for copy number-based assessment”, they conclude. 

Reference 

Turner NC, Kingston B, Kilburn LS, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol; Advance online publication 10 September 2020. https://doi.org/10.1016/S1470-2045(20)30444-7