ctDNA analysis permits matched therapy to breast cancer mutations
December 2019
By Wayne Kuznar for oncoXchange
Circulating tumor (ct) DNA testing can efficiently and relatively quickly genotype breast tumors, identifying some rare mutations that may be matched to targeted therapies, according to results from the plasmaMATCH study. The findings were presented at the 2019 San Antonio Breast Cancer Symposium by Nicholas Turner, MD, PhD, team leader in the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, U.K.
Rare activating mutations in advanced breast cancer include AKT1 and ERBB2 (HER2), which occur in <5% of cancers. In addition, mutations may be acquired in advanced breast cancer, which is observed in the estrogen receptor itself (ESR1 mutations) acquired through prior aromatase Inhibitor therapy. AKT1 and ERBB2 mutations may be acquired as well. So these mutations may not be present in the primary cancer; they may not even be present in the cancer at first relapse; they may be acquired through treatment. There is a need to be able to genotype the tumor without needing to repeat biopsies.
ctDNA analysis may allow noninvasive tumor genotyping, but there has been a need to do prospective studies to assess the accuracy of ctDNA testing in routine practice and the potential to guide targeted therapy without conducting tissue testing.
The plasmaMATCH trial was designed to assess the clinical utility of ctDNA testing. Patients with advanced breast cancer with measurable disease were enrolled after they had progressed on prior therapy for advanced breast cancer or if they had relapsed within 12 months of adjuvant chemotherapy. Up to two prior lines of chemotherapy were allowed for advanced breast cancer. ctDNA testing was performed using two technologies: digital polymerase chain reaction and sequencing.
If patients had actionable mutations identified, they were able to enroll in the treatment cohort in which their mutation was matched to a treatment.
- Cohort A included patients with ESR1 mutation, who were treated with extended-dose fulvestrant.
- Cohort B comprised patients with HER2 mutation, who were treated with neratinib (with fulvestrant added if estrogen receptor [ER]-positive).
- Cohort C included patients with AKT1 mutation and ER-positive disease, enrolled on their ctDNA result, who were treated with capiversatib and fulvestrant.
- Cohort D was a basket cohort that included patients with activating AKT1 mutation by ctDNA or tumor sequencing and ER-negative breast cancer or a PTEN inactivating mutation, who were treated with capivasertib.
- Cohort E consisted of patients with TNBC without mutations who were treated with olaparib and AZD6738; results from this cohort were not presented.
The primary endpoint was the confirmed objective response rate of targeted therapies matched to mutations in ctDNA without tissue testing.
A total of 1,044 patients registered for ctDNA testing from 18 centers in the U.K., with ctDNA results obtained in 98.9%. The most frequent mutations by digital PCR were ESR1 (27.7%), HER2 (2.7%), and AKT1 (4.2%). By ctDNA, the most frequent mutations for patients entering the treatment cohort were 38% for ESR1, 58% for HER2, and 54% for AKT1.
Most patients who underwent ctDNA analysis had ER-positive, HER2-negative breast cancer (64.6%) and 17% had triple-negative breast cancer. Three fourths (78%) of patients had visceral disease.
The patient population was heavily pretreated, with 69% having had prior chemotherapy for advanced disease and 65% had had two or more lines of prior therapy for advanced disease, and 36% had had two or more lines of chemotherapy for advanced disease.
In cohort A (ESR1 mutations), 74 of the 84 patients who entered were evaluable for the primary endpoint, and the confirmed ORR with extended-dose fulvestrant was 8.1%, not meeting the number of responses required to infer efficacy.
The ORR in patients with clonally dominant ESR1 mutations was 12.2%, whereas in those patients with subclonal ESR1 mutations, no responses were observed. Median progression-free survival (PFS) was 2.2 months in this cohort.
In cohort B (HER2 mutations), 21 patients were entered and 20 were evaluable. The confirmed ORR with neratinib with or without fulvestrant was 25.0%, “exceeding the number of responses required to infer efficacy,” said Dr. Turner.
“There appeared to consistency in benefit across different HER2 mutations.” The median PFS was 5.4 months.
In cohort C (AKT1 mutation), 18 patients were entered and all were evaluable. The confirmed ORR with capivasertib with or without fulvestrant was 22.2%, reaching the target number of responses to infer efficacy. The median PFS was 10.2 months.
In cohort D, 19 patients were entered, six with AKT1 mutation and 13 with PTEN alterations, and all were evaluable. The confirmed ORR with single-agent capivasertib was 10.5%, not meeting the predefined efficacy criterion. In patients with AKT1 mutations, the ORR was 33.3%, whereas there were no confirmed responses to treatment in those with PTEN mutations. The median PFS in this cohort was 3.4 months.
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