Early CTC assessment can predict survival in metastatic breast cancer

BY ALAN P. LYSS, MD


Early circulating tumor cell (CTC) dynamics can predict survival in patients with metastatic breast cancer, according to a large, retrospective study.

The number of CTCs at baseline and about 30 days after treatment was strongly associated with overall survival in all tumor subtypes.

These results were reported at the 2020 San Antonio Breast Cancer Symposium (Abstract GS4-08) by Wolfgang Janni, MD, PhD, of Ulm (Germany) University Hospital.

Dr. Janni noted that conventional imaging can take months to detect treatment response. He and his colleagues wanted to determine whether response and prognosis could be predicted earlier by measuring CTCs.

Prior research had shown that serial CTC monitoring could be used to assess response and overall survival in metastatic breast cancer (N Engl J Med. 2004;351:781-91). However, there was a lack of robust data that early CTC enumeration was equally prognostic in all breast cancer subtypes.



Dr. Wolfgang Janni

Global pooled analysis of CTCs

Dr. Janni reported an analysis of pooled datasets from peer-reviewed and published studies of 4,079 patients with metastatic breast cancer.

All patients had undergone baseline and follow-up CTC measurements using the CellSearch test (Menarini Silicon Biosystems).

The criterion for CTC positivity was at least 1 CTC per 7.5 mL of whole blood. The median time from baseline to follow-up was 29 days.

Of the 2,961 patients who were CTC positive at baseline, 1,855 (45.5%) patients remained CTC positive after initiating treatment (positive/positive) and 1,106 (27.1%) had converted to CTC negative (positive/negative).

Of the 1,118 patients who were CTC negative at baseline, 813 (19.9%) patients remained free of CTCs during treatment (negative/negative), while 305 (7.5%) had become CTC positive (negative/positive).

Prediction of survival

Log rank tests showed significant differences in overall survival between the four CTC groups (P < .0001 for all pairwise comparisons except the comparison between negative/positive and positive/negative, P = .015).

Median overall survival durations were:

• 47.05 months for negative/negative (reference)
• 29.67 months for negative/positive (hazard ratio, 1.74)
• 32.2 months for positive/negative (HR, 1.52)
• 17.87 months for positive/positive (HR, 3.15).

Results were similar when a cutoff of 5 CTCs per 7.5 mL was used for CTC positivity.

In addition, CTC dynamics were associated with overall survival for all breast cancer subtypes.

Looking at patients who were CTC positive at baseline but negative thereafter, overall survival was improved by 53% in luminal-like breast cancer, 46% in HER2-positive breast cancer, and 59% in triple-negative breast cancer, when compared with patients whose CTCs remained detectable.

Top image credit: doble-d/Getty Images
Image credit: Pr. J. Bernard/CNRI / Science Source


Strengths and weaknesses

In this study, early monitoring of CTCs was a marker of survival in metastatic breast cancer patients of all histologic subtypes. The data are consistent with those from the SWOG S0500 study (J Clin Oncol. 2014 Nov 1;32[31]:3483-9) but are much more robust in each histologic subtype.

The S0500 study was among those incorporated in this global, pooled analysis. S0500 was significant because it examined the effect of making an early treatment change for those patients with persistent CTCs after one cycle of systemic therapy.

Because the pooled analysis was retrospective, several important parameters were not in the control of the investigators, such as the timing of the follow-up testing or clinical assessments, analyzable information regarding tumor burden or metastatic sites, and detailed information about the treatment being administered to patients. As a result, it is difficult to know if testing at about 4 weeks is ideal for all breast cancer subtypes.

In addition, there is an absence of detailed data on whether different types of initial or salvage treatments influence the predictive value of CTC enumeration differently.

In a retrospective, large data analysis, it is proper to assess easily quantified and binary outcomes like “positive versus negative.” However, it is conceivable that patients who have a dramatic decline in CTCs but CTCs that are still detectable after a single cycle of therapy would have favorable outcomes from continuing the therapy that produced the large decline in CTCs.

Clinical utility of CTC enumeration

Although it is intuitively appealing, it remains unproven that patients benefit from changing treatment before the development of clinical or radiographic evidence of progression.

In the S0500 study, patients who were positive/negative for CTCs after one cycle of therapy were randomized to either continue their current treatment or switch to an alternative systemic therapy immediately. The median overall survival and progression-free survival were not significantly different for the continuation (10.7 and 3.5 months, respectively) and switch groups (12.5 and 4.6 months, respectively).

The failure of CTC monitoring to yield information that can improve outcomes probably means that, for now, CTC assessment should be regarded as a promising research tool but not a routine diagnostic test, according to Virginia Kaklamani, MD, of the University of Texas, San Antonio, who commented on Dr. Janni’s study during a press conference. 

At the same press conference, Carlos L. Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, noted that circulating tumor DNA (ctDNA) testing may prove to be a preferred early monitoring technique. Dr. Arteaga said ctDNA testing not only detects persistent cancer, but it can direct treatment to an actionable target, an advantage that CTC monitoring lacks.












Dr. Virginia Kaklamani
In the foreseeable future, artificial intelligence will likely be applied to measuring ctDNA in blood samples in many clinical settings.

As a result, the application and utility of follow-up testing for cancer patients will be markedly different in the future than it is now. The “bar” for approval of diagnostic tests – even those that are measured via blood tests – will likely be set at a high level.

Dr. Janni’s study was supported by Menarini Silicon Biosystems, and Dr. Janni received a research grant from the company. Dr. Kaklamani disclosed relationships with Amgen, Eisai, Puma, Celldex, AstraZeneca, Athenex, Pfizer, Celgene, Genentech, Genomic Health, and Novartis. Dr. Arteaga disclosed relationships with Novartis, Lilly, Merck, Sanofi, Daiichi Sankyo, Puma Biotechnology, Radius, Taiho Oncology, Petra Pharma, Immunomedics, G1 Therapeutics, Athenex, Abbvie, H3Biomedicine, OrigiMed, Clovis, Provista, Y-Trap, Pfizer, Takeda, Bayer, and the Komen Foundation.


Dr. Alan P. Lyss
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.