A prespecified circulating tumor cell count (CTC) threshold appeared to be reliable for selecting treatment with chemotherapy instead of hormone therapy in women with a certain metastatic breast cancer phenotype, a non-inferiority trial indicated.
In the phase III STIC CTC trial, 755 women with hormone receptor-positive, ERBB2-negative metastatic breast cancer were randomly assigned to receive first-line treatment based on CTC count or treatment based on clinician choice. In the CTC-count arm, women with CTC count of 5 CTCs/7.5 mL or greater were automatically assigned to chemotherapy instead of endocrine therapy, reported François-Clément Bidard, MD, PhD, of Institut Curie in Saint-Cloud, France, and colleagues.
Chemotherapy was given to 37% of patients assigned to the CTC arm and 27% of patients assigned to clinician choice. Median progression-free survival (PFS) was 15.5 months in the CTC arm compared with 13.9 months in the clinician-choice arm, meeting the study’s primary endpoint (hazard ratio 0.94, 95% CI 0.81-1.09), they stated in JAMA Oncology.
The threshold for non-inferiority was met, but not for superiority, the authors noted. They concluded that use of CTC count as a single biomarker was “a reliable, standardized option to guide the treatment choice between single-agent endocrine therapy and chemotherapy in hormone receptor-positive, ERBB2-negative MBC.”
Age older than 60 was the only independent factor found to be associated with a PFS benefit when using CTC-driven treatment selection (HR 0.76, 95% CI 0.61-0.94), which the researchers noted “might stem from the observed significant association between older age and more systematic use of endocrine therapy as the clinically favored treatment, whatever the other clinicopathologic characteristics.”
In addition, more than one-third of patients had discordant CTC and clinical assessments. When these patients with clinical low risk and high CTC counts were pooled with clinical high risk/low CTC counts in a multivariable analysis, PFS and overall survival were higher for those treated with chemotherapy versus endocrine therapy. Overall survival in the per-protocol population was 47.3 months (95% CI 43.8-51.3) in the CTC arm and 42.8 months (95% CI 39.5-47.4) in the standard arm.
The prespecified non-inferiority margin of 1.25 used in the study was described as “generous” by Tarah J. Ballinger, MD, of Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis, and colleagues.
The study met its non-inferiority endpoint, but in an accompanying editorial, Ballinger’s group “contend that adding to or replacing the parameters we use to make a clinical decision should help us improve the lives of patients, whether through superior survival outcomes, improved quality of life, reduced cost, or lessened toxicity.”
The trial design by Bidard and colleagues reasoned that some patients — those with high clinical risk but low CTCs — would be deescalated from chemotherapy to hormone therapy, but others — those with low clinical risk but high CTCs — were escalated to chemotherapy, they wrote.
“We should demand an improvement in outcomes before accepting a strategy that exposes more patients to more toxic therapy,” Ballinger’s group wrote. “Not worse simply is not good enough.”
They pointed out that the trial was conducted before cyclin-dependent kinase (CDK 4/6) inhibitors were added to hormone therapy in this patient population. Bidard and colleagues noted that CDK 4/6 inhibitors have been reimbursed in France since 2015, meaning that most patients in this trial likely received them in a later line of therapy.
“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,” Ballinger and colleagues wrote, concluding that “CTC count is not a replacement for shared clinical decision-making.”
Data for the open-label STIC CTC trial were collected at 17 French cancer centers from February 2012 to July 2016, and analyzed June 2019 to October 2019. Both premenopausal and postmenopausal patients were included in the trial, along with those who relapsed during adjuvant endocrine therapy. The median age was 63 in both arms, and a little over 38% of the patients were CTC high.
“Capecitabine was overall more often used in the CTC arm compared with the standard arm (23.9% vs 7.9%), as it was frequently prescribed to clinical low, CTC high patients allocated to the CTC arm and switched from endocrine therapy to chemotherapy,” the authors explained.
The authors reported that there was a higher rate of chemotherapy-related adverse events of any grade in the CTC arm, most commonly anemia at 20.4% vs 14.6% in the standard arm.
Disclosures
Bidard disclosed relevant relationships with, and/or support from, Menarini Silicon Biosystems, Lilly, Novartis, Pfizer, Freenome, Archer DX, and Radius. Co-authors disclosed multiple relevant relationships with industry.
Ballinger disclosed a relevant relationship with Medscape. A co-author disclosed serving as a member and chair of the advocates committee for the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group.