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MD Anderson Researchers Using Liquid Biopsy to Predict Melanoma Relapse

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NEW YORK – A group of researchers at the University of Texas MD Anderson Cancer Center has applied a blood-based circulating tumor cell (CTC) assay to potentially predict relapse in stage III melanoma cancer patients.

The team plans to develop a combined assay that integrates both CTCs and circulating tumor DNA (ctDNA) to potentially eliminate the need for repeated positron emission tomography (PET) image surveillance for melanoma patients at risk of recurrence.

PET and other radiologic surveillance such as computed tomography scans are frequently used for melanoma recurrence testing after treatment. However, issues with these methods include false-positive results, cumulative radiation exposure, and a significant increased cost of care.

"Currently, follow-up with melanoma patients is inaccurate and expensive," explained Anthony Lucci, a breast surgical oncology and surgical oncology professor at MD Anderson and lead author on a Clinical Cancers study published this week describing the team’s work. "If we could figure out how far CTCs or ctDNA predates finding of metastasis using imaging, it could be sensitive and minimize costs."

In the prospective study, Lucci and his team initially collected 7.5-ml blood samples from 243 cutaneous stage III melanoma patients within three months of clinically identifying a positive sentinel lymph node biopsy.

The researchers applied Menarini Silicon Biosystem's Celltrack's Circulating Melanoma Cell assay to collect CTCs, later comparing relapse-free survival (RFS) between patients with one or more baseline CTCs versus those with no CTCs.

The Celltrack assay, which runs on the firm's CellSearch platform, uses ferrofluids coated with antibodies to enrich melanoma cells, as well as a melanoma-specific antibody to fluorescently label the CTCs. The assay then identifies  circulating melanoma cells using a fluorescence-based microscope.

"We hypothesized that identification of CTCs within the blood at baseline would independently predict shorter survival, irrespective of [clinical staging], or the extent of lymph node metastases," the study authors noted. "If this hypothesis is validated, it would warrant larger studies to facilitate the incorporation of easily obtained, blood-based CTC assessments into standard practice."

Lucci's team then collected follow-up blood samples from melanoma patients after 6 and 54 months, searching for CTCs using the CellSearch assay.  

The researchers identified at least one baseline CTC in 90 patients, of which 23 relapsed within six months compared to 12 of 153 patients who lacked CTCs. In addition, the cohort with at least one CTC had a lower RFS rate six months after baseline (76 percent) compared to the cohort with no CTCs (92 percent).

Importantly, the researchers found that more patients with at least one or more CTCs at baseline showed significantly decreased RFS than those without CTCs in the long run. By 54 months, 43 of the 90 patients with CTCs relapsed during the follow-up period, compared to 56 of the 153 patients without CTCs at baseline. The study authors also noted that the assay had an AUC of 0.66 for detecting circulating melanoma cells.

While 132 patients received some form of adjuvant therapy, the team did not identify any significant links between adjuvant therapy or type of therapy and CTC detection at baseline.

Acknowledging that the study's data did not indicate whether altering patients' therapy affected their outcome, Lucci noted that his team will see if it can determine dynamic changes with treatment in further studies.

"One of the limitations of the [current] study was that it was done in an era before immunotherapy was routine, so only half the patients had [any] amount of adjuvant therapy," Lucci explained. "But now, we can see which patients are receiving therapy and see their responses using CTC numbers, [as well as] copy number aberrations (CNAs) and single nucleotide variants (SNVs) in ctDNA."

Lucci and his team also were unable to perform routine tumor molecular profiling while initially collecting stage III patient samples, preventing them from determining if CTC detection was linked to specific tumor mutations or molecular signatures.

Because the CellSearch assay uses a single enrichment marker — CD146 — to enrich CTCs from the blood, the study authors also acknowledged that the assay might have missed some cancer cells that did not express the biomarker.

Although Lucci's team performed parallel studies that searched for ctDNA and CTCs, Lucci said that the group had published the results of CTC study due to the assay's ease of analysis and lower cost to perform.

"The issues with ctDNA are that there's no standardized test and the cost is often pretty high," Lucci explained. "[Since we] were looking for a relatively easy and standardized technology, we thought to use a [CTC-based] method, especially if it's [US Food and Drug Administration]-approved."

The researchers have launched a prospective trial examining both serial CTCs and ctDNA measurements in additional high-risk stage II/IIIA melanoma patients receiving immunotherapy. Lucci said he hopes to find both CTC and ctDNA signals in the patients and potentially determine their relapse risk.

"Right now, we have hundreds of plasma samples from patients with node-positive melanoma that we want to … figure out what's going with them dynamically during their treatment course." Lucci explained. "We'd like to run all of those with known outcomes to collect data at the same time and work on collecting more prospective samples and data."

The researchers are now designing a customized cell-free DNA panel based on Thermo's Ion AmpliSeq next-generation sequencing technology. Lucci said his team will select target genes based on SNV and CNV data from the prospective study's patient tumor results. He believes the selection will help the group focus on clinically relevant genes before, during, after treatment, as well as at the time of disease progression.

While unable to disclose much about potential commercial plans, Lucci hopes that MD Anderson may partner with industry groups in the future — following the results of the prospective studies — to improve the blood-based biomarker assay.

"For the assay to be optimal, it would not only [need to] be prognostic but also predictive of who would be likely to respond or is resistant to different therapies," Lucci said. "By combining both ctDNA and CTCs, you could get that goal … and [establish] the holy grail for clinical management."

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