Liquid Biopsy Predicts Colon Cancer Recurrence

Roxanne Nelson, BSN, RN

July 14, 2016

A simple blood test may be able to predict the likelihood of disease recurrence in colorectal cancer, according to a new report.

The genetic test can detect circulating tumor DNA (ctDNA) after patients with stage II colon cancer undergo surgical resection, which, in turn, appears to identify many of those at the highest risk for recurrence.

The test results could help physicians decide about use of adjuvant therapy.

In a study of 230 patients with stage II colon cancer, the test results demonstrated that those who were ctDNA positive postoperatively were at extremely high risk for radiologic recurrence (hazard ratio [HR], 18; P = 2.6 × 10–12).

The findings were published in the July 6 issue of Science Translational Medicine.

No ctDNA tests for cancer have been approved, but growing evidence suggests that ctDNA is a viable approach for both the earlier detection of cancer recurrence and evaluating response to therapy.

"There are multiple potential applications for this test, and further studies are required to determine which has the biggest impact on outcomes," said study author Peter Gibbs, MBBS, MD, an associate professor at the Walter + Eliza Hall Institute of Medical Research, Parkville, Australia.

"At this point the strongest data are for defining which stage II patients need only surgery," he told Medscape Medical News.

Dr Gibbs explained that prospective studies are required to demonstrate that selecting the patients with detectable ctDNA for chemotherapy improves outcomes. Currently, there is only anecdotal evidence about chemotherapy benefitting these patients.

Being able to detect early recurrence with ctDNA could also affect survival. "But again, this needs to be demonstrated in prospective studies of ctDNA-guided follow-up," said Dr Gibbs.

Liquid Biopsy

The idea of using "liquid biopsy" has created quite a buzz in the cancer community because it is a faster and less invasive method than tissue biopsies.

In the largest studies to date, more than 17,000 liquid biopsies from 15,191 patients with more than 50 different types of advanced cancer have revealed genetic mutations similar to those found with traditional tissue biopsy.

For example, a blood test to measure ctDNA in women with early-stage breast cancer who had undergone neoadjuvant chemotherapy and surgery detected ctDNA in blood samples as early as 2 to 4 weeks after surgery in some patients. Most of these women (89%) went on to experience a relapse.

The US Food and Drug Administration, in fact, has just approved the first blood-based genetic test that can detect epidermal growth factor receptor (EGFR) gene mutations in patients with non-small cell lung cancer.

Not a Perfect Test

In the current study, study, the authors performed parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples that were obtained prospectively from 230 patients with resected stage II colon cancer.

Among the 178 patients who did not receive adjuvant chemotherapy, ctDNA was detected postoperatively in 14 (7.9%) patients.

Of this small group, disease recurred in 11 (79%) at a median follow-up of 27 months. Conversely, there was a recurrence in only 16 (9.8%) of 164 patients with negative ctDNA results (HR, 18; P < .001).

In the 52 patients who received chemotherapy, the presence of ctDNA after they completed their treatment was also associated with an inferior recurrence-free survival (HR, 11; P = .001).

Overall, patients who were ctDNA positive postoperatively had a markedly reduced recurrence-free survival (RFS) compared with those who had a ctDNA-negative status (HR, 18; P = 2.6 × 10–12).

Estimates of being recurrence free at 3 years were 0% for the ctDNA-positive group vs 90% for the ctDNA-negative patients.

Notably, cancer recurred in 14 patients whose blood tests showed no cancer-linked DNA. This indicates that the test is not flawless.

Clinicopathologic variables significantly associated with RFS in univariate analysis included T stage, lymph node yield, and lymphovascular invasion. But postoperative ctDNA status, note the authors, had a greater effect on RFS than did any of the other individual clinicopathologic risk factors in any combination.

On multivariable analysis, postoperative ctDNA status continued to remain an independent predictor of RFS both for patients who did not receive adjuvant chemotherapy (HR, 28) and for all patients in the cohort (HR, 14).

ctDNA can often detect disease recurrence Yuxuan Wang

"We showed in our study that ctDNA can often detect disease recurrence before it becomes evident radiographically," commented study author Yuxuan Wang, from the Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland.

"For patients in whom we can detect early recurrence with ctDNA, there is a larger window of opportunity to initiate or modify treatment for better outcomes," she told Medscape Medical News.

She added that they expect ctDNA to have the same utility for predicting recurrence for other stages of colon cancer.

As for next steps, Dr Gibbs pointed out that the test is moving into phase 3 clinical trials. The researchers have initiated a randomized study in stage II colon cancer in which 450 patients are being randomly assigned to ctDNA-guided adjuvant therapy (therapy is given if ctDNA is detected and not given if ctDNA is not given) vs standard of care.

The study was funded by Ludwig Cancer Research, the Conrad N. Hilton Foundation, the Sol Goldman Sequencing Facility at Johns Hopkins, the National Institutes of Health's National Cancer Institute (CA43460, CA152753, CA006973), and the Victorian Cancer Agency. Several of the authors have indicated competing interests as noted in the paper.

Sci Translat Med. Published online July 6, 2016. Abstract

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