The number of circulating tumor cells (CTCs) assessed at baseline and at about 1 month after cancer-directed treatment was strongly associated with overall survival in patients with metastatic breast cancer, according to a large retrospective pooled analysis reported at the 2020 San Antonio Breast Cancer Symposium (SABCS).¹ Monitoring early treatment responses using CTCs was predictive for overall survival in all tumor subtypes: luminal-like, HER2-positive, and triple-negative breast cancer.

“Patients with CTC response had significantly increased overall survival. These results provide clinical validation of CTC monitoring as an early treatment response marker in advanced breast cancer and suggest the potential for clinical utility,” said lead author Wolfgang Janni, MD, PhD, of University Hospital Ulm, Germany. Dr. Janni presented these data at a press conference in advance of the meeting, where the study was one of five abstracts singled out as newsworthy.

“The persistently CTC-negative groups had significantly improved overall survival compared with the other three subgroups.”

— Wolfgang Janni, MD, PhD

Tweet this quote

Response to treatment for metastatic breast cancer is typically monitored by conventional imaging. However, it takes approximately 3 to 4 months after treatment is started for changes to be detectable on scans.

“With the increasing number of treatment options available to patients with metastatic breast cancer, being able to predict and monitor treatment responses rapidly will be critical to aiding treatment decisions. The data from our study indicate that CTC dynamics can predict the trajectory of the disease a little more than 4 weeks after initiating treatment. This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued. It is also very reassuring that CTC dynamics predicted outcomes for all breast cancer subtypes,” Dr. Janni stated.

Study Details

Several studies support the clinical relevance of CTC enumeration as a means of assessing response status in metastatic breast cancer. The study reported by Dr. Janni was a comprehensive pooled analysis of globally collected data that aimed to further define and explore the role of serial CTC monitoring as a tool for early treatment monitoring in patients with metastatic breast cancer. The authors sought to determine the predictive power of CTC monitoring in different breast cancer subtypes.

Data were pooled from 14 different data sets for a total of 4,079 patients with metastatic breast cancer. CTC status was measured in blood by a CellSearch assay at baseline and at a median of 29 days after treatment initiation. Respondents were categorized according to change in CTC status (ie, positive or negative) from baseline to first follow-up. The largest subset was CTC-positive at baseline and CTC-positive approximately 1 month later (CTC-positive/CTC-positive; 1,855 patients, 45.5%); the next largest subset was CTC-positive/CTC-negative and included 1,106 patients (27.1%); 305 patients (7.4%) were CTC-negative/CTC-positive; and 813 patients (19.9%) were persistently negative (CTC-negative/CTC-negative). The cutoff used for CTC positivity in this study was at least one CTC.

Survival Outcomes

Patientswho fared the best were persistently CTC-negative, with a median overall survival of 47 months, whereas survival was shortest in the persistently positive subgroup: median of 18 months.

Median overall survival was 30 months in the CTC-negative/CTC-positive group and 32 months in the CTC-positive/CTC-
negative group.

The hazard ratios from the CTC-negative/CTC-positive and CTC-positive/CTC-negative groups did not differ significantly,” Dr. Janni said. “The persistently CTC-negative groups had significantly improved overall survival compared with the other three subgroups (P < .0001). The evidence is clear that survival is improved in CTC responders.”

Looking at CTC responders alone—those who were positive at baseline but negative thereafter—overall survival was improved by 53% in luminal-like breast cancers, 46% in HER2-positive breast cancer, and 59% in triple-negative breast cancer.

“These results provide clinical validation of CTC monitoring as an early treatment response marker,” Dr. Janni stated.

Timing of CTC Assessment

At the premeeting press conference where these data were discussed, session moderators brought up several important points. Carlos L. Arteaga, MD, Past President of the American Association for Cancer Research and Director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, commented: “This is an important study on the clinical utility of repeated CTC enumeration as an early monitoring tool in metastatic breast cancer. This strikes me as a noninvasive approach that can replace or complement imaging methods that can take up to 4 months to show disease response or progression.”

“I predict that 10 years from now, we will be presenting information on ctDNA that will predict what type of treatment we should switch to.”

— Carlos L. Arteaga, MD

Tweet this quote

“I was trying to identify negatives for this study, and I couldn’t think of any. It’s a positive study across the board. In terms of the timing of CTC assessment, the study used an arbitrary timepoint. The timing of the assessment after about 29 days of treatment may have missed some patients who converted from CTC-positive to CTC-negative. Timing may vary from one subtype to another, so ‘one size fits all’ may not fit in terms of the second measurement,” Dr. Arteaga continued.

Dr. Janni responded: “Doing a pooled analysis meant it was a retrospective analysis, so the timing of the follow-up assessment was not in our hands. The median time was close to 4 weeks. The timing has to be early enough to provide added value compared with conventional imaging. If we waited until later, there would be no advantage. We saw no variation among tumor types, which is also a strength of this study. The method works in luminal cancers and more aggressive cancers.”

“My next concern is whether the threshold of one CTC is enough to be a positive result,” Dr. Arteaga said.

“The results are very similar with one CTC and five CTCs, so we restricted the definition to one,” Dr. Janni replied.

Magnitude of Reduction

C. Kent Osborne, MD, questioned the relationship between the magnitude of reduction and benefit in any magnitude of reduction. “Let’s say you had a patient with a very high CTC value that goes down by 25% with treatment and that patient is still CTC--positive. Was a reduction in percentage of any value?” he asked. Dr. Osborne is Founding Director, Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston.

C. Kent Osborne, MD

“We looked at the relative number and prognosis at baseline and follow-up. We did different types of comparisons—absolute numbers, negative and positive, and percentages, and for all these analyses, the fewer CTC cells you see, the better, and a reduction indicates treatment response,” Dr. Janni said.

Implications for Patient Care

Virginia Kaklamani, MD, Professor of Medicine at UT Health San Antonio and Leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center, asked, “How do these results translate to patient care, and how would [oncologists] use them in the clinic?”

Virginia Kaklamani, MD

“We can use this tool in daily practice when we need information from monitoring; for example, in aggressive disease, in patients treated with checkpoint inhibitors to determine if they are working, and in other situations where early information is needed. Imaging will give you the information later on,” Dr. Janni said.

“In the SWOG 0500 study, CTCs were not helpful in showing that changing the type of chemotherapy based on CTCs improves prognosis,” Dr. Kaklamani continued. “This is not a failure of CTCs. I see it as failure of our treatments. Assessment of CTCs may help in the adjuvant setting, where we can change or alter treatments to affect outcome.”

“We are planning a large study of liquid biopsy in 3,000 patients in the adjuvant setting in Germany,” Dr. Janni noted.

“There are limitations on how to use this to optimize patient outcomes,” Dr. Kaklamani stated. “I would consider CTC measurement as a research tool as we move forward. I’d be hard pressed to monitor CTCs in the clinical setting, as it hasn’t been shown to improve patient outcomes.”

Dr. Arteaga pointed out that circulating tumor DNA (ctDNA) is the wave of the future. “I would encourage your colleagues to use ctDNA together with CTCs. This study [of CTCs] may tell you to be worried or not to be worried about the patient’s response to treatment but doesn’t necessarily tell you how to treat. There could be an actionable target that ctDNA could detect. I predict that a few years from now, we will be listening to information on ctDNA that will predict what type of treatment we should switch to.”

“I agree that we are entering the era of ctDNA. We will look at that in our next study,” Dr. Janni said. 

DISCLOSURE: Financial support for the pooled analysis was provided by Menarini Silicon Biosystems. Dr. Janni has received honoraria from AstraZeneca, Lilly, Novartis, Pfizer, and Roche; has served as a consultant or advisor to AstraZeneca, Daiichi Sankyo, Lilly, Menarini Silicon Biosystems, Novartis, Pfizer, Roche, and Seattle Genetics; has received research funding from Janssen Diagnostics and Menarini Silicon Biosystems; has received institutional research funding from Amgen, Janssen Diagnostics, Lilly, Menarini Silicon Biosystems, Novartis, Pfizer, and Roche. Dr. Arteaga has served in a leadership role for the American Association for Cancer Research; holds minor stock options in Provista Diagnostics and Y-Trap Inc; has served as a consultant or advisor to Athenex, Clovis Oncology, Daiichi Sankyo, AstraZeneca, G1 Therapeutics, H3 Biomedicine, Immunomedics, Lilly, Merck, Novartis, OrigiMed, Puma Biotechnology, Radius Health, Sanofi, and Taiho Oncology; has received research funding from Bayer, Lilly, Pfizer, Puma Biotechnology, Radius Health, and Takeda; and serves on the scientific advisory board of the Susan G. Komen for the Cure Foundation. Dr. Osborne holds stock or other ownership interests in GeneTex; has served as a consultant or advisor to AstraZeneca, Genentech/Roche, Lilly, Tolmar Pharmaceuticals, and Ventana Medical Systems; holds patents or other intellectual property as Co-Editor of Diseases of the Breast; and has provided expert testimony on behalf of AstraZeneca. Dr. Kaklamani has received honoraria from AstraZeneca Celgene, Daiichi Sankyo, Eisai, Genentech, Genomic Health, Novartis, Pfizer, Puma Biotechnology, and Seattle Genetics; has served as a consultant or advisor to Amgen, AstraZeneca, Athenex, Celldex, Eisai, and Puma Biotechnology; has participated in a speakers bureau for Celgene, Eisai, Genentech, Genomic Health, Novartis, Pfizer, and Puma Biotechnology; and has received research funding from Eisai.

REFERENCE

1. Janni WJ, Yab TC, Hayes DF, et al: Clinical utility of repeated circulating tumor cell enumeration as early treatment monitoring tool in metastatic breast cancer: A global pooled analysis with individual patient data. 2020 San Antonio Breast Cancer Symposium. Abstract GS4-08. Presented December 11, 2020.