Liquid biopsies hold promise for the future of cancer care

Caroline Dive, CBE, BPharm, PhD, FMedSci
Caroline Dive,  BPharm, PhD

Using liquid biopsies to detect tumor relapse after curative intent therapy supports earlier intervention when tumor burden is low. This is just one of the possible uses for liquid biopsies in the cancer realm.

More updates on advances in liquid biopsies were discussed during the On Demand session Noninvasive Monitoring of Minimal Residual Disease with Liquid Biopsies: Towards Real-Time Treatment Decision Making. The session’s presentations will be discussed in more detail during a live panel discussion Tuesday, April 13, at 3:30 p.m. EDT. When viewing On Demand sessions, viewers can submit their questions in a Q&A box to the right of the video window. All of the questions for the On Demand sessions will reach the panelists for the live session.

“We know the liquid biopsy field has witnessed rapid improvement in ctDNA sensitivity and specificity,” said session moderator and presenter Caroline Dive, BPharm, PhD, CRUK Manchester Institute. “The challenge for us now is to implement liquid biopsies in prospective trials of minimal residual disease monitoring in order to instruct earlier treatment.”

Colorectal cancer

Alberto Bardelli, PhD
Alberto Bardelli, PhD

Alberto Bardelli, PhD, Candiolo Cancer Center University of Torino, discussed three clinical trials, each addressing a point relevant to the use of liquid biopsies: Drug resistance, follow-up and treatment rechallenge, and minimal residual disease (MRD).

In the area of drug resistance, researchers have long studied have to identify new targeted therapies for patients with colorectal cancer. The HERACLES study enrolled patients with KRAS exon 2 wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care. The researchers used liquid biopsy to help understand why patients had relapsed and discovered metastasis-specific mechanisms of relapse.

The CHRONOS trial is using liquid biopsy in the area of therapeutic rechallenge to help understand the mechanism of resistance and use this knowledge to direct therapy. Specifically, the trial evaluated rechallenge in panitumumab-driven RAS clonal-mediated disease. Initial results showed that if patients were selected based on levels of RAS and eGFR in the blood, rechallenging therapy could lead to a second effective response.

Bardelli also discussed the PEGASUS trial. It will use liquid biopsy to measure the presence of disease upon surgery and see if it can identify patients who needs additional therapy after surgery.

“We give adjuvant therapy because we cannot be sure all lesions are eradicated, and with current imaging modalities it is impossible to determine the actual presence or absence of cancer after surgery,” Bardelli said.

Genomic & epigenomic monitoring

Sarah-Jane Dawson, MBBS, FRACP, PhD
Sarah-Jane Dawson, MBBS, PhD

There are currently no routine tests used in the management of solid malignancies to identify MRD after routine cancer treatment, said presenter Sarah-Jane Dawson, MBBS, PhD, Peter MacCallum Cancer Centre.

An ideal test for MRD would be minimally invasive and repeated regularly following treatment. Tests should be highly sensitive and specific and also able to provide key molecular information about residual cancer cells to understand how these cells have evaded therapy and how they could be eradicated with additional therapy.

Dawson discussed the promise of ctDNA detection using whole genome sequencing (WGS), which she called a promising tool for MRD analysis.

A strength of this approach, she said, is the type of information that can be gained, including mutational profiling, copy number alterations, fragmentomics, and nucleosome footprinting, and it can be coupled with DNA methylation to characterize epigenetic changes.

Dawson further focused her talk on nucleosome footprinting and DNA methylation. Specifically, she detailed a study of plasma samples from patients with breast cancer and healthy controls. These samples were divided into training and test sets. The training set was used to build the classifier for identification of plasma containing ctDNA versus normal cell-free DNA using a range of features including differentially methylated regions, the balance of hypo- and hypermethylation, and the genomic context for where methylations are occurring. Once the classifier is optimized, it is applied to a test set. This is repeated multiple times to refine the model. Finally, the model is applied to an independent validation cohort.

The test showed very high sensitivity and specificity for detecting ctDNA and separating breast cancer samples from those derived from healthy individuals. Not surprisingly, the ability of the model to accurately detect ctDNA is influenced by tumor purity. This research continues in ongoing validation cohorts.

“ctDNA WGS can provide the opportunity for combining a variety of analytical approaches which may increase the sensitivity of detection,” Dawson said. “Analysis of both genomic and epigenomic features may also provide insights into therapeutic resistance in the MRD setting.”

NSCLC recurrence

Dive spoke about predicting risk of non-small cell lung cancer (NSCLC) after surgery with curative intent using circulating tumor cells (CTCs).

“Up to 50 percent of patients with NSCLC who have surgery with curative intent will relapse,” Dive said. “If the CTCs are architects of micrometastatic disease, [which is] non-detectable when the patient has their resection, can CTCs help us predict the risk of recurrence at the point of surgery?”

Dive discussed a pilot study that showed that CellSearch CTCs were detectable in the pulmonary vein at surgery. The study looked at 32 patients and found that a higher level of pulmonary vein CTCs (PV-CTCs) was associated with a higher chance of relapse.

“This tells us that CellSearch CTCs are out and about early,” Dive said.

This hypothesis was validated in the TRACERx Consortium study. Going from baseline to relapse looking at PV-CTCs, the researchers were trying to address two questions: Can CTCs predict recurrence and are those PV-CTCs genetically linked to relapse? Dive showed data from 100 prospectively recruited patients; 48 of 100 of the patients had at least one CellSearch PV-CTC, and the hypothesis was validated. Higher levels of PV-CTCs were associated with lower lung cancer-specific survival.

Dive also presented information from a patient case study that showed that 79 percent of mutations detected in the PV-CTC were also detected in the primary tumor and 91 percent were detected in a metastasis arising 10 months later.

Dive also discussed the use of liquid biopsy for MRD monitoring and for earlier detection of NSCLC.

“I think liquid biopsies for both early detection and MRD monitoring is certainly the future,” Dive said.