Nandini Dey MS, PhD, Fred Ashbury, PhD, MACE
Most cancer-related deaths are caused by metastatic progression and/or resistance-associated treatment failure. Circulating Tumor Cell (CTC) testing quantifies any free-roaming cancer cells in the blood and lymph vessels and provides a real-time prognostic readout of the cellular disease. In patients presenting advanced progressive disease (e.g., lung cancers) with insufficient or unavailable tissue for comprehensive genomic profiling, the need for a non-invasive assay, like CTC in longitudinal format, might be of critical clinical relevance. Longitudinal CellSearch CTC testing can be done in conjunction with other clinical methods for monitoring metastatic breast, colorectal, and prostate cancers. Evaluation of CTC at any time during the course of the disease allows assessment of patient prognosis and is predictive of progression-free survival and overall survival. The power of the predictive and prognostic value of identifying CTC in the context of a minimal residual disease to metastatic progression remains undeniable. Yet routine enumeration of CTC remains far from widespread practice for post-surgery follow- ups or in the adjuvant therapy setting. The CELLSEARCH CTC test  is the only FDA- cleared [510(k) review] blood test to identify CTC. In recent years, a user-friendly and cost-effective CTC enumeration has been reported  from the community-based Cancer Center of Avera McKennan, Sioux Falls, SD. The study determined CTC in gynecological cancers and evaluated its clinical relevance. The strength of CTC determination is it requires a simple collection of 7.5 ml of peripheral blood that can be used at any time during a patient’s course of disease management. The clinical relevance of the test was assessed in a case study of a patient with low-grade (G2) and stage (IA) endometrioid endometrial adenocarcinoma. The patient had favorable pathological features, including 6% MI, absence of LVI, absence of LN status, andno uterine serosal and cervical stromal involvement. Surprisingly, the patient presented a high baseline of >100 CTCs in 7.5 ml of her peripheral blood at the time of surgery. In a single microscopic field, a total of 13 CTCs were observed with mitotic figures and 3-cell CTC clusters. During surveillance, the biopsy from a lesion demonstrated recurrent endometrioid adenocarcinoma. A CT scan of the chest, abdomen, and pelvis revealed an area of poorly defined but somewhat mass-like enhancement in the region of the right vaginal cuff, suspicious of disease recurrence. The patient had an event within 6 months of the date of surgery .
We need to consider two key issues in order to improve the uptake of CTC enumeration in the community oncology setting. First, do we needto improve awareness/knowledge of CTC testingin community oncology? The short answer is yes,as CTC testing remains very low throughout the United States. Longitudinal CTC tests present an actionable “liquid biopsy;” it facilitates evidence- based decision-making and treating patients with breast, prostate, or colorectal cancers. While the baseline evaluation of CTC can be helpful for patient stratification and early detection, longitudinal CTC evaluation during and after treatment could be beneficial for monitoring treatment response andearly indicators of disease progression/drug resistance, respectively. The second issue to consider is who pays for CTC testing. There is reimbursement for the CELLSEARCH® CTC test through various public and private payers in most states [See footnote]. The CTC assay has four CPT codesa: 86152, 86153, 0091U [For Oncology (colorectal) screening], and 0338U. The latter two codes are included in the Anthem Blue Cross, LAB.00015 Detection of CTC. The CPT codes for CTC tests for androgen-receptor variant 7 prostate cancer and for colorectal cancer include 81479, 86152, 86153, and S3711 (Oncology: Circulating Tumor DNA and CTC, Liquid Biopsy; Concert Genetics). Phenotypic Biomarker Detection from CTC (L38584) has been referred to in LCD-MolDX (https://www.cms.gov/medicare-coverage-database/search.aspx).
A laboratory-friendly and cost-effective option of longitudinal monitoring of CTC detection as a companion entity combined with the standard prognostic tests in clinics, like ctDNA, promises to advance information-driven decision-making at clinics in community-based cancer centers. Oncologists should consider this tool as part of routine practice in the approved settings.
Footnote: aExamples of CTC reimbursement include: United Health plans, University of Utah (https:// uhealthplan.utah.edu/medicalpolicy/pdf/mp-038.pdf) refers to Circulating Tumor DNA and CTC for cancer management (Liquid Biopsy) in their Medical policy mentioning applicable coding [(CPT code 86152; CPT code 86153].
References 1Sabath DE, et.al. Clinical Validation of a Circulating Tumor Cell Assay Using Density Cen- trifugation and Automated Immunofluorescence Microscopy. Am J Clin Pathol. 2022 Aug 4;158(2):270-276. doi: 10.1093/ajcp/aqac040. 2https://www.cellsearchctc.com/about-cellsearch/what-is-cellsearch-ctc-test)(Veridex, LLC; visit www.veridex.com) 3Sulaiman R, et.al. A Laboratory-Friendly CTC Identification: Comparable Double-Immuno- cytochemistry with Triple-Immunofluorescence. Cancers (Basel). 2022 Jun 10;14(12):2871. doi: 10.3390/cancers14122871.
Fredrick D. Ashbury, PhD
Chief Scientific Officer, VieCure Professor (Adj), Department of Oncology University of Calgary Professor (Adj), DLSPH, University of Toronto
Nandini Dey MS, PhD,
Translational Oncology Laboratory, Avera Research Institute, Sioux Falls, SD, USA
Department of Internal Medicine, University of South Dakota SSOM, USD, Sioux Falls, SD, USA