乌鸦传媒

Personalized circulating tumor DNA (ctDNA) assays identified women with HR-positive, HER2-negative breast cancer who had late recurrences, suggesting that these high-risk patients can be identified for potential interventions, researchers said.

"To our knowledge, these are the first data on plasma ctDNA analysis for MRD [minimal residual disease] detection in late adjuvant HR+ breast cancer, a major and understudied cause of more than 40,000 annual breast cancer-related deaths in the United States," Heather Parsons, MD, MPH, of Dana-Farber Cancer Institute in Boston, and colleagues wrote in a "Rapid Communication" article in the .

Parson's group performed whole-exome sequencing on primary tumor samples from 103 patients with high-risk stage II-III HR+ breast cancer who were diagnosed more than 5 years prior and had no clinical evidence of recurrence. The somatic mutations detected were used to design, for each patient, a personalized ctDNA [residual disease and recurrence] assay.

Over the next 2 years, the team collected plasma and performed the personalized ctDNA tests at routine visits every 6-12 months. Eight patients (10%) had positive MRD testing. Of these, six (7.2%) developed distant metastatic recurrence. The median ctDNA lead time was 12.4 months. One patient had a local recurrence not identified by the test.

"Here, 10% of patients were MRD-positive more than 5 years from diagnosis despite no clinical evidence of metastatic recurrence at the time of first plasma sample," Parsons and colleagues said. "Importantly, ctDNA analysis identified MRD in all cases of distant recurrence. ctDNA analysis did not identify MRD in the case of local recurrence in this study, consistent with previous reports. Additionally, ctDNA was detected in two patients who had not experienced clinical recurrence at the time of last follow-up, although imaging had not been obtained in these cases."

In addition, "these data suggest that there may be a period in which MRD is detectable via ctDNA before overt, late breast cancer recurrences. This will inform future studies of liquid biopsy to personalize treatment and prevent or delay late recurrence of early-stage breast cancer," the researchers concluded.

In the following interview, Parsons discussed additional details of the study and other relevant ongoing research.

Can you give us more details on how the individualized RaDaR assay is created for each patient?

Parsons: RaDaR is a tumor-informed, patient-specific assay. First, each patient's archival primary tumor sample underwent whole exome sequencing (WES). Then, from mutations identified in the WES, up to 51 variants were selected for assay design.

Next, each patient-specific assay was applied to cell-free DNA isolated from a patient's plasma, to the leukocyte DNA and to the tumor DNA. Samples underwent high-depth sequencing, variants were confirmed, and ChIP [clonal hematopoiesis of indeterminate potential] was filtered. Each test was then reported as either MRD+ or MRD-. For positive MRD tests, eVAF (estimated variant allele fraction) was reported.

Do you plan to continue this study with longer follow-up or additional patients?

Parsons: Yes, we are continuing to follow these patients clinically and to draw research blood samples. We believe this is an important, understudied group of patients – those with a history of HR+ breast cancer diagnosed more than 5 years prior.

Have the two patients who were MRD positive but without recurrence during the study period experienced recurrence subsequently?

Parsons: We have not yet gone back to assess follow-up for the overall cohort but plan to do this in the coming months.

You mentioned that several clinical trials are underway to investigate the efficacy of interventions based on MRD detection. Are there any results yet from these trials, or any information about when can we expect them?

Parsons: In HR+ breast cancer, there are a few trials underway evaluating intervention based on MRD detection. The and studies are both enrolling patients with history of HR+ breast cancer with an MRD positive test. Patients are screened and then undergo staging scans if the MRD test is positive. If metastatic disease is not detected, they enter the study.

In both trials, investigators are evaluating the efficacy of a CDK4/6 inhibitor together with hormonal therapy.

You mentioned that researchers at the Dana Farber Cancer Institute are investigating patient understanding of and attitudes toward late recurrence in a survey study. Can you tell us more about this study and what it hopes to find?

Parsons: This is the POWER study, led by Shoshana Rosenberg. In investigating patients with HR+ breast cancer with risk of late recurrence, we found very little data available evaluating patient understanding of and attitudes toward this risk. The POWER study, which is complete and undergoing data analysis currently, enrolled participants at least 5 years from diagnosis with HR+ breast cancer.

We look forward to the results of this study to help us design patient-centered interventions and approaches to the problem of late recurrence in HR+ breast cancer.

Read the study here and expert commentary about the clinical implications here.