CTCs Predict Overall Survival in Metastatic Breast Cancer

Level-One Evidence of Benefit Is Lacking

Nick Mulcahy

December 09, 2020

A new meta-analysis adds to the data supporting the use of a blood test that measures circulating tumor cells (CTCs) as a quick way to find out whether or not a treatment for metastatic breast cancer is working.

The CTC results are available about 4 weeks after start of therapy. Conventional imaging is carried out after about 3 months.

But an expert is not convinced that this approach is currently ready for clinical use and suggests that for now, it should remain a tool for use in research.

The new meta-analysis, which involved data on more than 4000 patients, showed that the presence or the absence of CTCs "strongly" predicts overall survival (OS).

Median OS was greatest (47 months) for patients who had no CTCs at baseline and at follow-up. In contrast, the median OS was shortest (17.8 months) for patients who had CTCs at both time points.

The risk for death was more than 200% greater for patients in the latter group than in the former group.

Dr Wolfgang Janni

The results "suggest the potential for clinical utility" of CTC monitoring as an early response marker in metastatic breast cancer, said lead author Wolfgang Janni, MD, PhD, of the Ulm University Hospital, Ulm, Germany. He was speaking at an online press conference for the virtual San Antonio Breast Cancer Symposium (SABCS) 2020, where the new study will be presented this week.

The investigators say the findings from this meta-analysis add to literature in which "several studies suggest clinical utility" of measuring CTC levels as a means of assessing response status for patients with metastatic breast cancer.

Unfortunately, the new study does not show that assessing CTCs over time improves clinical outcomes, which is an ongoing problem in the literature, said Virginia Kaklamani, MD, University of Texas Health Sciences Center, San Antonio, Texas, who is also a meeting co-director.

"Previous randomized clinical trial data have shown that assessing CTCs does not benefit patients (vs not assessing)," Kaklamani told Medscape Medical News.

Kaklamani explained how CTC assessments have worked in practice. "You do these circulating tumor cell tests and you find, for example, that the number increases. The assumption is the treatment's not working. So you switch treatments around," she explained. That pattern can be repeated every 3 to 4 weeks, resulting in more toxicity, which in turn may nullify any treatment benefit.

However, she noted that so far, key data have come from the era of chemotherapy and do not reflect targeted therapies, which may make a difference. In addition, the more recent ability to assess and identify circulating tumor DNA may allow clinicians to match drugs to mutations, which may have greater impact on cancer outcomes.

Currently, CTCs are best used by researchers, said Kaklamani during the press conference, because they have not been definitively proven to improve patient results.

Investigator Janni did not object to that description.

But in a press statement, he suggested that CTCs can be used currently by clinicians.

"These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment," Janni said in the press statement. "This provides an advantage over conventional imaging methods and can help physicians determine very early on whether a treatment should be continued."

But, to Kaklamani's point, an article published last month in JAMA Oncology showed that use of CTCs did not yield significant clinical benefit in comparison with use of other clinical factors in determining whether to choose endocrine therapy or chemotherapy. In that randomized trial, which was conducted in Europe and included women with HR-positive, HER-negative breast cancer, progression-free survival was similar in both arms, as reported by Medscape Medical News. However, use of chemotherapy (and attendant toxicity) was greater among women in the CTC arm, which was considered an undesirable outcome by experts not involved with the trial.

Details of the Study Results

For their study, Janni and colleagues conducted a comprehensive pooled analysis of globally available data. They identified 4079 metastatic breast cancer patients who had undergone baseline and follow-up CTC measurements (at least one, at a median of 29 days later) in previous clinical trials.

The investigators analyzed changes in CTC levels between baseline and follow-up to determine whether they were associated with OS.

Of the 2961 patients who were CTC-positive at baseline, 1855 remained CTC-positive after treatment was initiated (positive/positive), and 1106 patients had converted to CTC-negative status (positive/negative).

Of the 1118 patients who were CTC-negative at baseline, 813 remained CTC-negative (negative/negative), and 305 had become CTC-positive (negative/positive).

As noted above, median OS was greatest for patients who were negative/negative (47 months), followed by patients who were positive/negative (32.2 months), negative/positive (29.6 months), and positive/positive (17.8 months).

Hazard ratios in which the reference group was negative/negative were 1.52 for the positive/negative group, 1.74 for the negative/positive group, and 3.15 for the positive/positive group (P < .0001 for all groups).

These CTC dynamics were found across all breast cancer subtypes, said Janni.

"These data indicate that CTC dynamics can predict the trajectory of the disease a little more than four weeks after initiating treatment," said Janni in the press statement. "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."

The study was supported by Menarini Silicon Biosystems, the makers of CellSearch, the CTC test used for all of the patients and studies in the meta-analysis. Janni received a research grant from Menarini Silicon Biosystems. Other study authors have financial ties to healthcare industries. Kaklamani has received consulting fees from Amgen, Eisai, Puma, Celldex, AstraZeneca, and Athenex; fees for non-CME services received directly from commercial interest or their agents from Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, and Novartis; and has contracted research with Eisai.

San Antonio Breast Cancer Symposium (SABCS) 2020: Abstract GS4-08. Presented December 9, 2020.

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay and MedPageToday and had bylines in WashingtonPost.com, MSNBC, and Yahoo. Email: nmulcahy@medscape.net and on Twitter: @MulcahyNick.

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