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Presence of cfDNA, CTCs Predicts Recurrence in Triple-Negative Breast Cancer

NEW YORK – A combined method measuring both circulating tumor DNA and circulating tumor cells can detect lingering residual disease in women with triple-negative breast cancer after neoadjuvant chemotherapy and predicts disease recurrence, according to a new study.

Because this molecular and cellular signal was independently associated with disease recurrence, "above and beyond standard clinical parameters," it could be an important stratification tool for future post-neoadjuvant trials, the researchers, led by a team at Indiana University, wrote in a report in JAMA Oncology yesterday.

Patients with early-stage triple-negative breast cancer are frequently treated with neoadjuvant chemotherapy, based on the increased risk for recurrence and death associated with this category of tumors.

A subset continue to live without recurrence but a significant number still see their disease return despite this added chemotherapy. Blood-based genomic testing, or liquid biopsy, has rapidly become popular for patients with TNBC and other cancers to identify those who may have residual cancer present and whose outcome might be improved with new or existing treatments.

Recent studies of liquid biopsy MRD detection have focused on circulating tumor DNA, including previous studies by the Indiana team, but the authors of the new JAMA Oncology study wrote that because there is evidence that CTCs can be detected in some patients who show no signs of ctDNA, adding this second analyte could help boost the ability to pick up an MRD signal.

Their report describes a preplanned secondary analysis of 196 female patients from a recently completed randomized clinical trial, BRE12-158, which randomized TNBC patients to genomically directed post-neoadjuvant treatment. Investigators discussed some of the study findings in a presentation at the San Antonio Breast Cancer Symposium last December, but shared them in greater detail in their new paper this week.

Using blood samples taken from patients after receiving standard neoadjuvant treatment, the investigators applied Foundation Medicine's liquid biopsy assay to profile ctDNA and enumerated CTCs using an EpCAM-based, positive-selection microfluidic device.

CtDNA was detectable in 142 patients and CTCs in 123 patients, and the presence of ctDNA and CTCs was associated with significantly worse disease-free survival and overall survival rates.

As has been seen in other studies, ctDNA on its own was significantly associated with poor disease-free survival. Although patients who were CTC positive also had inferior outcomes, results did not reach statistical significance, the authors wrote. However, there was a significant association with increasing CTC count and survival.

For the 112 patients for whom both ctDNA and CTC results were available, there was no significant association between CTC positivity and ctDNA positivity. In other words, some patients were positive for one marker and not the other. As a result, the sensitivity to detect recurrences across the cohort was highest when both markers were considered: MRD sensitivity was 79 percent with ctDNA alone, 62 percent with CTCs alone, and 90 percent when combined.

Patients who were both ctDNA positive and CTC positive had significantly inferior distant disease-free survival compared with those who were double-negative. At 24 months, distant DFS probability was 52 percent for patients who were positive for both biomarkers compared with 89 percent for those who were negative. Similar trends were observed for non-distant DFS and for overall survival.

The authors stressed that the results don't yet support the use of liquid biopsy MRD to guide routine clinical practice because there is no evidence, as yet, that early detection of residual disease can inform treatment changes that actually improve patient outcomes.

But they did argue that the data is strong enough to support immediate use of their MRD strategy in post-neoadjuvant clinical trials, which will hopefully collect that evidence.

This concept is now the centerpiece of the PERSEVERE trial, a planned successor trial to BRE12-158, in which patients with TNBC who are ctDNA positive after surgery will be assigned to receive a targeted agent matched to their plasma ctDNA sequencing results.