Circulating tumor DNA testing is feasible in routine clinical practice and can be used to identify rare targetable genetic alterations in women with advanced breast cancer, according to study results presented at the 2019 San Antonio Breast Cancer Symposium.

Previous research has suggested that circulating tumor DNA testing may be more effective than primary tumor analysis in assessing the genetic profile of advanced breast cancer and locating genetic mutations for which targeted therapies can be used.

Photo by © MedMeetingImages/Todd Buchanan 2018

Nicholas Turner, of the Institute of Cancer Research and Royal Marsden NHS Foundation Trust, and colleagues launched the plasmaMATCH trial to determine whether circulating tumor DNA can identify patients in four parallel cohorts with actionable alterations. All patients were prospectively tested with digital droplet PCR at a central laboratory, with Guardant360 used for error-corrected sequencing prospectively from the recruitment midway point and retrospectively for all remaining patients.

Appropriate patients entered cohorts based on their screening results, which included:

• Extended-dose fulvestrant (500 mg every 2 weeks) for patients with ESR1 mutations (Cohort A);

• Neratinib with or without fulvestrant (standard dosing) for patients with HER2 mutations (Cohort B);

• Capivasertib with fulvestrant (standard dosing) for patients with estrogen receptor-positive breast cancer and AKT1 mutations (Cohort C); and

• Capivasertib for patients with AKT1 in estrogen receptor-negative breast cancer or PTEN inactivating mutations.

Objective response rate by cohort served as the primary endpoint. Secondary endpoints included progression-free survival (PFS), clinical benefit rate, safety and frequency of mutation detection by circulating tumor DNA.

In total, 1033 patients were screened and 142 patients entered a treatment cohort (Cohort A, n = 84; Cohort B, n = 21; Cohort C, n = 18; Cohort D, n = 19).

The researchers reported high concordance between digital PCR screening and error-corrected sequencing, with individual gene level agreement ranging between 95.5% and 99.4%.

Cohorts B and C met their predefined efficacy rates, with confirmed response rates of 25% (95% CI, 8.7-49.1) and 22.2% (95% CI, 6.4-47.6).

Cohort A did not meet predefined efficacy criteria, with a confirmed response rate of 8.1% (95% CI, 3-16.8). An exploratory analysis showed capivasertib activity in patients with AKT1 mutations in Cohort D.

Cohort B achieved a median PFS of 5.4 months (interquartile range, 3.4-9.1) and Cohort C achieved a median PFS of 10.2 months (interquartile range, 3.2-18.2). Safety results were consistent previous reporting.

“This approach can be used to identify patients with rare HER2 and AKT1 mutations, who have clinically relevant response rates with matched targeted therapies,” the researchers concluded.