Skip to main content
Premium Trial:

Request an Annual Quote

New Data Suggests Liquid Biopsy Provides Early ID of Breast Cancer Patients Destined to Recur

Premium
Circulating Tumor DNA

NEW YORK – New research has provided evidence that monitoring early-stage breast cancer patients for the emergence of circulating tumor DNA could pick up the first signs of late recurrence, long before clinical symptoms emerge.

The study, called CHiRP (Circulating tumor DNA and late recurrence in high-risk, hormone receptor–positive, HER2-negative breast cancer) was highlighted this week at the American Society of Clinical Oncology annual meeting and published in parallel in the Journal of Clinical Oncology.

Although the study was small, meeting speakers said the results are exciting, considering the possibility that this earlier notice could translate to opportunities for better, potentially curative interventions.

The possibility to prognosticate recurrence "would really give us a lot of opportunities to intervene and potentially cure more patients if we have enough lead time," said Vanderbilt-Ingram Cancer Center researcher Ben Ho Park, who was not involved with the study. "We now know that we have a number of agents that [are] effective in patients with metastatic disease that's HR-positive HER2-negative, so there's hope that this could also afford a change in outcomes," he added.

This potential benefit has generated significant excitement in the field around genomic minimal residual disease (MRD) technologies with studies across a variety of tumor types, including colorectal and lung cancers.

Presenting the CHiRP data at the ASCO meeting, Dana-Farber Cancer Institute fellow Marla Lipsyc-Sharf said that in HR-positive HER2-negative breast cancer, recurrences are relatively rare compared to other oncology settings. When they do happen, they also tend to come out of the blue, emerging more than five years after diagnosis.

In their study, Lipsyc-Sharf and her colleagues studied patients with early-stage breast cancer across tumor subtypes, testing their blood using a tumor-informed, personalized MRD technology called RaDaR, which was developed by Inivata, now a part of NeoGenomics.

While many studies have now confirmed that MRD status is associated with distant recurrence-free survival, Lipsyc-Sharf said that relatively little is known about ctDNA in the late adjuvant setting in HR+ breast cancers.

The group identified 103 patients with stage II or III HR+ tumors diagnosed at least five years prior, with a known higher risk of recurrence based on clinical feature like tumor size, grade, lymph node involvement, and genomic risk markers.

The tumor tissue exome sequencing necessary to create RaDaR MRD assays was successful in 83 out of 85 tumors that had archival samples available, and these became the study's subjects.

Investigators collected plasma samples from all patients during routine follow-up visits every 6 to 12 months, using patient-specific primer panels of between 12 and 51 variants gleaned from the initial tumor exome sequencing data.

The median clinical follow-up for the cohort was 10.4 years from diagnosis and two years from the first study plasma sample. By the study cutoff, six individuals had developed distant metastatic recurrence, all of whom had earlier tested positive for ctDNA, with a median lead time of 12.4 months.

One patient developed locoregional recurrence, but was ctDNA negative, and two others tested positive but had not had a clinical recurrence as of their last follow-up. Lipsyc-Sharf said that recurrence-free survival appeared to be worse for patients testing positive for ctDNA than patients testing negative, but the study's small event rate precludes statistical analysis of that difference.

Among the patients who did recur, two tested positive in their first study sample and the other four in subsequent samples. The lead time ranged from just two days in one individual to 37.6 months, but Lipsyc-Sharf noted that the patient with a two-day lead time had not had blood collection in the preceding year and a half.

She also said the data highlight the importance of individualized MRD assays and the targeting of multiple variants. "If only one or a few of the mutations were tracked for each patient, not all of the eight MRD-positive patients in this cohort would have been identified," she said.

RaDaR is currently up for review by Medicare, and is poised to compete with a similar assay, Natera's Signatera, in the clinic. The current market also includes Guardant Health's Guardant Reveal, which uses a different, fixed-panel epigenetic approach, and multiple companies are now expected to launch analogous assays in both categories.

As these tests have begun to be promoted more aggressively, there has been some pushback by clinicians skeptical of whether MRD tests would notably shift the detection of recurrence in clinical practice, and whether earlier recurrence detection would necessarily lead to better outcomes.

Lipsyc-Sharf said that the fact that patients in the study were not being assessed with other things like radiological scans is certainly a caveat. It is possible subjects identified as having positive ctDNA might also have been detected via imaging or other blood biomarkers just as early.

Despite this, she said the CHiRP study is an "important first step," with multiple prospective trials either already underway or in planning to establish actual clinical utility — "that intervention after MRD detection improves patient outcomes, such as survival or quality of life."

"There was a limited sample size, but I think most of us saw this as very striking data that you could actually predict who's going to recur and that all patients who did recur were in fact ctDNA-positive," added Park.

"To me, it's very encouraging that we can develop assays now that detect minimal residual disease with serial monitoring [and] I think this really opens up the floodgates for designing studies, looking at who to treat with additional adjuvant therapies while they're still on the endocrine therapy phase of their breast cancer treatment," he said.

The Scan

CRISPR's Softer Side

A homologous chromosome-templated repair approach to gene editing relies on versions of the Cas9 enzyme that cut a single DNA strand.

Pickled? No Problem

Researchers come up with an approach for extracting DNA from archived museum specimens. 

Nature Papers on Long Reads for Bacterial Genomes, Zebrafish Atlas, Hypothalamic Aging in Mammals

In Nature this week: near-finished microbial genomes without polishing, zebrafish functional annotation program, and more. 

Rise of BA.5

The New York Times reports that the Omicron subvariant BA.5 has become the dominant version of SARS-CoV-2 in the US.