SAN ANTONIO — When choosing between chemotherapy and endocrine therapy for patients with hormone receptor (HR)+/HER2- metastatic breast cancer, allowing the results from a blood test that measures circulating tumor cell (CTC) count to overrule physician’s choice of therapy can significantly improve overall survival.
But are these results enough to change clinical practice? One expert reacting to the findings says probably not, and another pointed out that the CTC count test used in the trial (CellSearch), although approved by the FDA, is not widely used in clinical practice.
The findings comes from updated results from the STIC CTC study.
“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy [in] first-line therapy,” explained study presenter François-Clément Bidard, MD, PhD, professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris, France.
Since then, the first-line treatment has changed and can now can also include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but Bidard said the results are still clinically relevant.
Nowadays, endocrine therapy plus CDK4/6 inhibitors is the “preferred option for treatment-naive patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors, where current guidelines advocate in favor of endocrine therapy, despite its short-lived efficacy.”
“In that scenario, based on the STIC CTC trial results, the CTC count in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” Bidard said.
The research was presented here at the San Antonio Breast Cancer Symposium (SABCS).
The study involved more than 750 patients with HR+/HER2- metastatic breast cancer randomly assigned to physician choice or CTC-guided therapy, although the physician decision and the recommendation based on the CTC count was recorded in both groups.
Using the CellSearch (Menarini Silicon Biosystems) to perform the CTC count at baseline only, the team defined patients as low or high risk, with low-risk patients deemed to need only endocrine therapy and high-risk patients recommended chemotherapy.
Physicians based their decisions on current guidelines and their clinical experience.
In the 25% of cases where CTC count would recommend chemotherapy while the physician would recommend endocrine therapy, following the CTC count-based choice resulted in a 35% improvement in progression-free survival (PFS) and a 47% increase in overall survival.
In all other situations, including those when the CTC count recommended endocrine therapy in contrast to the physicians, or the approximately 60% of cases in which the two were in agreement, there was no difference in survival outcomes between the approaches.
Reacting to the findings, Nancy Chan, MD, medical oncologist and the director of breast cancer clinical research at NYU Langone’s Perlmutter Cancer Center, New York City, told Medscape Medical News that the “goal is really to understand how we can personalize treatment options for patients.”
Another aim is to avoid performing a tumor biopsy, if possible, “as that has increased morbidity for patients.”
She noted also that choosing between endocrine therapy and chemotherapy is a “big decision.” These researchers “really wanted to help some patients get less chemotherapy,” as they felt that “some patients are getting too much” as they are not really that high risk and should get endocrine therapy instead.
However, Chan said that the CTC count is a “complicated concept” and is “not something we’re all using in our clinical practice yet.”
With regard to the approximately 40% discordance between the CTC- and physician-guided choices, Chan said that clinicians are perhaps not as accurate as they believed in predicting risk when relying on the clinical or pathological features of the tumor.
On Twitter, Guilherme Nader-Marta, MD, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium, commented that the question behind the study was whether CTC measurement is a “clinically useful strategy for first-line treatment decision-making.”
“Amazingly,” he continued, the trial went “straight to the point” to answer the question and showed that CTC-based decisions can offer a survival benefit.
Daniel F. Hayes, MD, co-director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center, Ann Arbor, echoed these thoughts, saying that the goals of therapy are to make patients live longer and “better.”
He said that the point of any clinical biomarker is not only to show that testing for it offers “analytical validity” but that it also provides “clinical utility,” in that it can guide treatment decisions to improve outcomes.
Hayes, who was not involved in the study but has worked for many years on the development of CellSearch, said that the results do not make it clear whether measuring CTC counts meets the definition of clinical utility, but it’s “very close.”
On the other hand, the analytical validity of the test is “excellent,” and, in that context, was well-chosen, he said, adding that the endpoint of the trial “is the one most important to us: improvement in overall survival.”
Hayes noted that the magnitude of benefit from CTC-guided therapy was “moderate,” although that is a “matter of perception,” and the “level of evidence is probably 2 or 3.” Although the trial was prospective, he said, the key results were in a “relatively small” subgroup.
The question is, Hayes continued: “Is this enough to change practice? My conclusions are probably not.”
Although patients rated as low risk based on their CTC low count avoided chemotherapy, “it’s not clear to me that this whole thing is sufficient for clinical utility in context of what we know today.”The key issue, however, is who decides whether CTC counts are measured and whether they will be used to guide therapy decisions — will it be the patient, the caregiver, an expert guidelines panel, or third party payers/society?
In his presentation, Bidard explained that CTC count is an FDA-approved standardized liquid biopsy biomarker, with a count of ≥5 cells per 7.5 mL of blood deemed an adverse prognostic marker, regardless of the line of therapy, with a grade 1 level of evidence.
Previous studies have indicated that a high CTC count is strongly associated with overall survival, at a hazard ratio of 2.78.
Crucially, the CTC count “complements” and does not duplicate standard clinicopathological prognostic factors, Bidard said.
To determine the potential of the CTC count as an aid to treatment decisions, Bidard and colleagues conducted a trial in pre- and postmenopausal women with untreated HR+/HER2- metastatic breast cancer who were able to receive either endocrine therapy or chemotherapy.
They were randomly assigned to either a standard group, in which the treatment decision followed the physician’s choice, regardless of their CTC count, or to a CTC group, in which the physicians made a treatment recommendation but the choice was driven by the CTC count.
Bidard reminded the audience that the primary endpoint of PFS to demonstrate the non-inferiority of CTC vs physician treatment decisions has already been met, with the results published in 2020. Those results came from an analysis of 788 patients enrolled between February 2012 and July 2016 at 17 sites in France, and showed after 42 months of follow-up that the median PFS in the CTC arm was 15.6 months vs 14 months in the physician choice arm, at a hazard ratio of 0.92.
The current pre-planned analysis involved 755 patients who were followed up for a median of 57 months by the time the trial was stopped in 2021.
In the standard treatment arm, endocrine therapy was favored by physicians in 72.7% of cases (Clin-low), while 27.3% were given chemotherapy (Clin-high).
In the CTC group, 73.5% of patients were recommended to have endocrine therapy by their physician based on their clinical characteristics (Clin-low), whereas 26.5% were suggested to have chemotherapy (Clin-high).
In contrast, 60.1% of patients in the standard arm would have received endocrine therapy based on their CTC count (CTC-low), and 39.9% chemotherapy (CTC-high), while 63.4% of those in the CTC arm were given endocrine therapy based on their CTC count (CTC-low), and 36.6% were assigned to chemotherapy (CTC-high).
Once the allocated treatment was known in both treatment groups, the physicians were free to choose between endocrine therapy (mostly a single-agent aromatase inhibitor or fulvestrant) and chemotherapy (mostly paclitaxel or capecitabine).
Although CDK4/6 inhibitors were not approved at the time of enrollment, 42.2% of patients across both treatment groups received one of these drugs as a second-line or later therapy.
Guiding Treatment Decisions
Bidard said that, overall, more patients in the CTC arm were assigned to chemotherapy, at a difference of 9.7%. There was approximately 60% concordance between physician- and the CTC-guided treatment choices; in other words, patients were recommended the same treatment by the two approaches in both treatment groups.
In these patients, there was no significant difference in overall survival between the physician choice and CTC groups, at a median of 45.5 months vs 51.3 months (hazard ratio [HR], 0.85; P = .11).
The updated PFS data revealed a median PFS of 15.7 months in the CTC group vs 13.8 months, again at a nonsignificant HR of 0.94.
These results, Bidard said, indicate that CTC-based treatment choices are “safe.”
However, there was discordance between physician and CTC-based treatment choices in around 40% of cases, meaning that the two approaches recommended different therapies.
The physician recommended endocrine therapy, in contrast to the CTC count indicating chemotherapy, in 25% of patients (Clin-low/CTC-high), whereas 13.6% of cases were recommended chemotherapy while their CTC count indicated otherwise (Clin-high/CTC-low).
In Clin-low/CTC-high patients, this resulted in 26.1% of patients in the standard group receiving endocrine therapy when their CTC count indicated chemotherapy, while 23.9% of patients in the CTC group received chemotherapy even though their physician did not recommended it.
Comparing these two groups, the researchers found that patients in the CTC group had a significantly longer PFS, at 15.7 months vs 10 months (HR, 0.65; P = .005). They also had a significantly longer median overall survival, at a median of 51.8 months vs 35.4 months with physician choice (HR, 0.53; P = .001).
Among Clin-high/CTC-low, there was no benefit from physician’s choice of chemotherapy over the CTC-guided recommendation of endocrine therapy, at an HR for PFS of 1.14 for CTC- vs physician-guided therapy (P = .54), and an HR for overall survival of 0.88 (P = .64).
Bidard highlighted that the treatment effects were seen across prespecified subgroups.
The study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. Bidard reports relationships with Menarini Silicon Biosystems, AstraZeneca, Daichii Sankyo, Exact Sciences, General Electric Healthcare, GSK, Eli Lilly, Menarini/Stemline, Novartis, ProLynx, Rain Therapeutics, Roche, Seagen, and Sanofi. Chan reports no relevant financial relationships.
Hayes reports relationships with Immunicon, Veridex, Janssen Diagnostics, Menarini Silicon Biosystems, Merrimack Pharmaceuticals, Eli Lilly, Puma Biotechnology, Pfizer, AstraZeneca, InBiomotion, Agendia, BioVeca, CellWorks, Cepheid, EPIC Sciences, Freenome, Guardant, Lexent Bio, Predictus, Salutogenic Innovations, L-Nutra, Macrogenics, OncoCyte, Predictus, BioSciences, Turnstone, Tempus, and Xilis.
San Antonio Breast Cancer Symposium (SABCS) 2022: Abstract GS3-09. Presented December 8, 2017.