investigators wrote in JAMA Oncology.
However, authors of a related editorial suggested CTC counts are not adequate for guiding treatment choice in this population.
In a phase 3 trial, investigators compared the use of CTC counts and the use of clinical factors to guide the decision between chemotherapy and endocrine therapy. Results showed similar progression-free survival (PFS) and overall survival (OS) with both methods but more chemotherapy use with the CTC method.
“The results of this trial demonstrate the reliability and clinical utility of CTC count to guide the choice between single-agent endocrine therapy and chemotherapy as first-line treatment,” but “at the cost of a higher proportion of patients treated with chemotherapy,” study author François-Clement Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues wrote.
The investigators explained that endocrine therapy is the preferred first-line treatment option in this patient population, but chemotherapy is used when women are in visceral crisis, with rapidly progressive, symptomatic disease. The decision usually rests on clinical factors, such as tumor subtype and performance status, but there’s interphysician variability.
The team hoped to find a “more reliable, standardized, and reproducible” biomarker to help remove some of the uncertainty from the situation. They tested CTC count, a well-established prognostic indicator of PFS and OS, as a candidate.
Study results
The trial included 755 patients with hormone receptor–positive, HER2-negative breast cancer in the per-protocol population. The patients’ median age was 63 years (range, 30-88 years).
Among the 377 patients randomized to the CTC arm, those with counts at or above 5 CTCs per 7.5 mL received chemotherapy, while those with a lower count received endocrine therapy.
The 378 patients in the standard-care group received endocrine therapy or chemotherapy based on provider choice guided by clinical factors.
Chemotherapy was given to 37% of patients in the CTC arm and 27% of those in the standard arm.
The median PFS was 15.5 months in the CTC arm and 13.9 months in the standard arm, which meant the primary endpoint of noninferiority was met (hazard ratio, 0.94; 90% confidence interval, 0.81-1.09).
Age older than 60 years was the only baseline characteristic associated with better PFS with CTC-driven decision-making. This may be because of the greater “use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics,” in older subjects, the investigators wrote.
As with PFS, the median OS was similar between the study arms – 47.3 months in the CTC arm and 42.8 months in the standard arm (HR, 0.91; 95% CI, 0.71-1.16).
‘Not good enough’
The investigators behind this study had “a worthy goal,” according to authors of a related editorial.
Without “predictive biomarkers, we are left with our clinical knowledge, experience, and intuition. Patients are left with uncertainty, doubt, and fear,” Tarah Ballinger, MD,, of Indiana University, Indianapolis, and colleagues wrote in the editorial.
However, the editorialists had concerns about the findings. For one thing, the investigators hypothesized that relying on CTC would lead to a deescalation from chemotherapy to endocrine therapy, but use of chemotherapy was actually 10% higher in the CTC arm.
“Adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients. ... We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy. Not worse simply is not good enough,” the editorialists wrote.
In addition, the trial was completed before CDK4/6 inhibitors became a standard add-on with endocrine therapy for hormone receptor–positive, HER2-negative patients.
“The overall response rate to CDK4/6 inhibitor therapy is higher than with traditional chemotherapy, and several randomized trials have failed to show a survival benefit of upfront chemotherapy compared with CDK4/6 inhibitor use. ... Thus, it is even less likely that we can assume that baseline high CTC count corresponds to a need for chemotherapy in a modern treatment landscape that offers more patients more benefit from hormone therapy,” Dr. Ballinger and colleagues wrote.
The editorialists concluded that CTC count “alone at baseline primarily reflects disease bulk, much like anatomic staging, rather than disease biology. As treatments become more rooted in our knowledge of breast cancer biology, decisions based on disease bulk are decidedly out of place.”
Perhaps a better use, they suggested, is for treatment personalization. For instance, patients with persistently elevated CTCs despite standard approaches could consider trials of novel targeted therapies, or CTCs could be sequenced to identify actionable molecular targets, achieving a “clinical utility that merely counting CTCs lacks,” the editorialists wrote.
This study was funded by the Institut Curie, the French National Cancer Institute, and Menarini Silicon Biosystems, the maker of the CTC assay used in the trial. The investigators disclosed relationships with Menarini and many other companies. Dr. Ballinger receives honoraria from Medscape, which is owned by the same company as this news organization.
SOURCE: Bidard FC et al. JAMA Oncol. 2020 Nov 5. doi: 10.1001/jamaoncol.2020.5660.