By: Tony Hagen
At the 2018 San Antonio Breast Cancer Symposium, data demonstrated that use of circulating tumor-cell (CTC) counts had strong value for selecting endocrine therapy compared to chemotherapy in patients with estrogen receptor–positive, HER2-negative metastatic breast cancer.
A CTC cutoff value was used to determine first-line treatment in this double-arm, randomized trial. There was high concordance between clinician’s choice of therapy and therapy based on CTC counts with little difference in both progression-free survival (PFS) and overall survival (OS).
However, in cases of high discordance between the CTC recommended therapy and clinician’s choice, there was a trend toward superior results for frontline chemotherapy versus hormone treatment.
“In the ‘90s, we had trials that showed that chemotherapy was not superior to endocrine therapy, and since that time endocrine therapy has been the preferred first-line treatment for most patients in the absence of primary endocrine resistance or serious concern about patient prognosis,” said lead author Francois-Clement Bidard, MD, PhD, professor of medical oncology at Institut Curie in Saint Cloud and the University of Versailles, France.
Patients were randomized 1:1 to the clinically driven versus CTC arms. In the latter arm, the CTC cutoff values for therapy choice were <5 CTC/7.5mL for hormone therapy and ≥ 5 CTC/7.5mL for chemotherapy. Patients with low CTC values were viewed as having a good prognosis and were treated only with hormone therapy; otherwise, they received chemotherapy.
The primary endpoint of the trial was to demonstrate PFS noninferiority between clinically-driven and CTC-driven arms in the trial, which enrolled 778 patients. Secondary endpoints were OS and subgroup analyses, which evaluated concordance versus discordance in recommended therapies.
The primary objective of PFS noninferiority was met, with the trial demonstrating an overall median PFS of 15.6 months in the CTC arm and 14.0 months in the control group (HR 0.92; 90% CI, 0.80-1.06).
Respective OS rates were 82.1% versus 81.4%. “The main point is, if you are in the overall population, you are not making any mistake if you rely on the CTC count to make a decision,” Bidard said.
In the analysis of the concordant groups where clinicians’ choice of therapy agreed with the CTC-based selection, outcomes were also similar. For patients with CTC scores <5 and those whose clinicians chose was hormone therapy, the median PFS was 17 months versus 18 months, respectively, and the OS was 88.4% versus 89.0%. For those who received chemotherapy, median PFS was 11.1 months for the CTC arm versus 12.4 months for control, and OS was 71.0% versus 62.7%, respectively.
In the clinically low-risk versus CTC high-risk discordant subgroups, PFS was 10.5 months versus 15.6 months, respectively (HR 0.62; P = .002); and OS was 73.7% versus 77.6% (HR .069; P = .12). In the clinically high-risk versus CTC low-risk subgroups, median PFS was 14.6 months versus 8.1 months, respectively (HR 1.24; P = .32), and OS was 89.8% versus 77.7% (HR 1.14; P = .71).
In a pooled exploratory analysis of the discordant groups that evaluated for superiority of therapy alone, investigators found a trend toward better frontline results with chemotherapy for both PFS and OS. Median PFS was 15.6 months versus 10.5 months for chemotherapy versus hormone therapy, respectively (HR 0.66; P = .001); and OS was 82.9% for chemotherapy versus 74.4% for hormone therapy (HR 0.65; P = .04).
Taking the results for the discordant groups together, there is a slight advantage for chemotherapy in the equivocal setting, or where CTC-based recommendations and clinicians’ choices disagree, Bidard said. “Basically, if you use frontline chemotherapy, which has been dismissed for a long time, it can be a very suitable option for patients with unfavorable characteristics, such as a high CTC count.”
Bidard said that another reason this finding is important for physicians and patients is because from country to country and practice to practice and physician to physician, choices of hormone versus chemotherapy tend to vary widely and there is a need for clearer guidelines and standards. CTC counts, based on the results of this study, should be incorporated into the selection process and have the potential to change the standard of care, he said.
However, session moderator Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, advised caution. Kaklamani said she would like to see further trials of CTC values versus clinician’s choice, adding that moving chemotherapy to the frontline for this setting constitutes a radical idea. “In the metastatic setting, what we are trying to do is de-escalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is a little foreign to us. These are the first results where you are seeing survival benefit by doing CTC.”
Bidard noted that the trial opened in 2012 and was challenged in part by the arrival and increasing use of the CDK4/6 inhibitors palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), which in combination with hormone therapy have become a much-used frontline treatment.
Kaklamani said that despite that new class of agents and its value in the frontline setting, CDK4/6 inhibitors are costly, at around $10,000 per month, and carry a high toxic burden; therefore, if CTC tests can recommend efficacy with chemotherapy upfront, that might be the preferred course of action. “If there is a group I can save from taking CDK4/6 inhibitors in the first-line setting, I would love to do that,” she said.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.