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Cell-Free DNA Can Help Predict Pathological Complete Response, Gauge Minimal Residual Disease

NEW YORK — Liquid biopsies could help determine which treatment approaches cancer patients might be best suited to receive, three new studies have found.

In one study, researchers from Washington University in St. Louis examined whether tumor DNA isolated from urine could predict which bladder cancer patients had a pathological complete response to chemotherapy and might not need radical cystectomy. That team also used a liquid biopsy approach to distinguish malignant peripheral nerve sheath tumors from benign precursors. In another study, a Fudan University Shanghai Cancer Center-led team investigated whether analyzing circulating tumor DNA within blood samples in combination with MRI analysis could predict pathological complete response among rectal cancer patients receiving radiochemotherapy.

The studies all found that liquid biopsy-based assessments could identify patients who might benefit from particular treatment approaches. "The advantage of this approach is that it is noninvasive and, in the future, could be applied to assess response to neoadjuvant treatment, enabling better personalization of regimentation, and potentially even help select patients who could be managed nonoperatively," WUSTL's Aadel Chaudhuri, an author on two of the studies, said in an email.

For one study appearing in PLOS Medicine, Chaudhuri and his colleagues used a urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq) approach to analyze cell-free DNA samples from 42 individuals with localized bladder cancer and 15 healthy adults. The samples were collected from patients just before they underwent curative-intent radical cystectomy.

Within this cohort, 38 percent of patients had a pathological complete response, while 62 percent had residual disease, as gauged by their surgical samples. Using a focused minimal residual disease gene panel of 49 genes often mutated and known to drive bladder cancer, the researchers found a set of 52 non-silent and 17 silent mutations within samples from patients with residual disease. A positive MRD detection was correlated with an absence of pathological complete response with a sensitivity and a specificity of 81 percent. Additionally, patients with minimal residual disease as gauged by utDNA analysis had worse progression-free survival than those without.

Further, the researchers found that tumor mutational burden could be inferred from utDNA, suggesting urine-based tumor DNA analysis could help personalize bladder cancer treatments by both identifying patients who could potentially undergo bladder-sparing surgeries as well as identify patients who might benefit from targeted or immunotherapies.

In a separate study in PLOS Medicine, Chaudhuri and his colleagues also examined whether ultra-low-pass whole-genome sequencing of cell-free DNA could distinguish patients with malignant peripheral nerve sheath tumor (MPNST) from those with a benign precursor condition. MPNST is a common cause of mortality among individuals with neurofibromatosis type 1 cancer predisposition syndrome but distinguishing it from its benign precursor, plexiform neurofibroma, can be difficult.

They analyzed cell-free plasma samples from 14 individuals with MPNST, 23 with plexiform neurofibroma, and 16 healthy individuals. From this, researchers developed a classifier that used genome-wide copy number alterations to estimate the portion of cell-free DNA originating from the tumor, which then could indicate whether a patient had MPNST or plexiform neurofibroma with 91 percent specificity and 75 percent sensitivity.

According to Chaudhuri, this showed "for the first time to our knowledge, proof-of-concept that we can delineate malignancy from pre-malignancy in a hereditary cancer predisposition syndrome via liquid biopsy cell-free DNA analysis."

Further, by conducting this analysis serially, they could track patients and detect minimal residual disease earlier than it would be caught by imaging, Chaudhuri added.

Meanwhile, the Fudan-led team analyzed blood plasma samples from 119 patients with locally advanced rectal cancer and described in PLOS Medicine their efforts to gauge whether circulating tumor DNA could help stratify patients' risk of relapse after treatment. Currently, MRIs are used to determine treatment response, but their ability to predict complete pathological response could be improved, according to the researchers.

Patients with complete clinical response to chemoradiotherapy could take a watch-and-wait approach, rather than undergo total mesorectal excision surgery, the standard treatment.

The researchers analyzed serial blood samples from 119 patients with locally advanced rectal cancer who were treated with neoadjuvant chemoradiotherapy and total mesorectal excision surgery. They conducted deep targeted panel sequencing of 422 cancer-related genes for each of the 531 plasma samples. They found that a higher ctDNA clearance rate correlated with complete pathological response and that patients who acquired mutations during chemoradiotherapy had a higher probability of non-complete pathological response.

Researchers noted that about half the patients misclassified as having a complete clinical response by MRI could be accurately classified using ctDNA information. Then, by folding ctDNA data in with MRI-gleaned information, the researchers developed a model that could better predict pathological response over MRI alone.

This, the researchers added, could help identify patients suited for a watch-and-wait approach, as well as guide treatments for patients with various recurrence risks.

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