Could Liquid Biopsies Bring Early Warning of Breast Cancer Relapse?

Field: Medicine (Health Sciences)

DNA: DNAHopes were raised at the 2022 American Society of Clinical Oncology Annual Meeting that a blood test could potentially predict recurrence of breast cancer after initial therapy up to a year or so earlier than standard examinations. An observational study of circulating tumor DNA (ctDNA) and late recurrence in high-risk hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (the CHiRP study) found a striking association between the detection of minimal residual disease (MRD) 5 years or longer after diagnosis of breast cancer—as indicated by the presence of ctDNA—and the subsequent risk of relapse (Abstract 103). “We found that ctDNA in the late adjuvant setting of hormone receptor-positive breast cancer patients was associated with distant metastatic recurrence. And we could encourage patients and their doctors to consider enrolling patients in clinical trials to study intervention after ctDNA detection to see if this improves patient outcomes, such as survival or quality of life,” said lead author of the study, Marla Lipsyc-Sharf, MD, Clinical Oncology Fellow at the Dana-Farber Cancer Institute.Marla Lipsyc-Sharf, MD: Marla Lipsyc-Sharf, MDBut she told Oncology Times it was important to take great care not to make big claims yet about the clinical value of doing routine ctDNA testing when such testing became available to cancer teams. This was because the study was small and not randomized—being intended to discover basic facts about any association of ctDNA-detected MRD and relapse beyond 5 years. But the basic headline finding from CHiRP made the concept of ctDNA detection from liquid biopsies seem very attractive. And Lipsyc-Sharf was clearly excited about the possibility that such assays could perhaps soon become predictive tools. But she insisted this remained to be proven by interventional studies. “We are trying to detect minimal residual disease in early-stage breast cancer patients, and this particular study was done in the late adjuvant setting in hormone-receptor positive breast cancer. [These were patients diagnosed over 5 years prior.] Our question in this study was whether ctDNA was associated with clinical recurrence. Our hope is that this will be used in the future to plan clinical trials,” she said. Study Details The CHiRP investigators identified a cohort of 103 patients with early-stage (Stage II and III) breast cancer that overall had higher risk of recurrence—as measured by having bigger tumors, more involved lymph nodes, higher grade tumors, or higher genomic risk scores. Additionally, study subjects needed to have had HR-positive breast cancer. “We used these patients' archival primary tumor tissue—with their consent—to create personalized liquid biopsy tests for 83 patients,” Lipsyc-Sharf said. Liquid biopsy tests were then conducted every 6-12 months to check if any positive tests were correlated with clinical recurrence. The CHiRP study recruited HR-positive patients because this patient subgroup was known to be at high relative risk for late recurrence, she noted. “The majority of recurrences in hormone receptor-positive breast cancers happen more than 5 years after initial diagnosis.” But she warned: “This was an observational study—not an interventional trial—and now this data is being used to plan ongoing clinical trials that will then study intervention based on ctDNA results.” Lipsyc-Sharf explained that not all ctDNA assays were alike. Some are “tumor-naïve” and could theoretically detect breast cancer DNA from a range of primary tumors, but the tests used in the CHiRP study were personalized for each individual patient. “The testing used in this study is called the RaDaR assay. [It is] not a tumor-naïve assay, but a tumor ‘informed’ assay. It uses whole exome sequencing on patients' primary tumors—archival primary tumors from their initial diagnosis—to identify somatic mutations that are then tracked in plasma liquid biopsy tests for these patients,” she explained. Patient-specific “primer panels” were created by the study (with over 50 variants in some cases) to be used for testing every 6-12 months. Eight out of 83 patients analyzed in the study were found to have ctDNA in their plasma samples, and six out of those eight subsequently had recurrences. When Lipsyc-Sharf was asked what she inferred from this striking association, she paused and sighed. “I think that it is quite compelling. Of course, I'm biased! But I think it's quite compelling that the ctDNA detection in this setting appears to be associated with clinical recurrence,” she said. But she admitted CHiRP had been a relatively small study. So, saying that the method could “predict recurrence” needed to be avoided. But she was comfortable with describing the headline finding of the study as an “association” of ctDNA was with recurrence. The CHiRP investigators concluded that in the late adjuvant setting, ctDNA had been identified a median of 1 year before all cases of distant metastasis. “We are hopeful that in studying many more patients, and understanding the clinical utility, we will one day be able to use the test to predict recurrence. But I don't think we're there yet,” Lipsyc-Sharf noted. The ASCO session on ctDNA in breast cancer heard about possible interventions after initial therapy for early breast cancer that could be informed by better predictive testing. “I am thrilled that there are multiple clinical trials in hormone positive breast cancer that are studying intervention after ctDNA detection. Many of these include the addition of CDK 4/6 inhibitors—after the detection of MRD—to see if this could prevent recurrence, delay recurrence, improve recurrence-free survival, [and] improve survival ultimately for these patients. I think that's one particularly promising intervention in this space. But there are, fortunately, others that will be investigated soon,” she said. Peter M. Goodwin is a contributing writer.