Fragments of tumor DNA circulating in the bloodstream of patients with breast cancer may predict whether they are likely to experience relapse—especially when samples are taken after the patients have received treatments prior to surgery. Findings presented at the 15th European Breast Cancer Conference (EBCC15) in Barcelona included the largest number of events reported so far for circulating tumor DNA (ctDNA) in individual patients (Abstract 12). Events could include the tumor starting to grow again, metastasis, death, or a new tumor in the same or the other breast.
The findings mean that doctors could analyze ctDNA in patients when they complete neoadjuvant therapy to assess the risk of relapse and plan appropriate, individualized treatments after surgery.
Study Methods and Findings
Elisa Agostinetto, MD, a medical oncologist and researcher at the Institut Jules Bordet in Brussels, Belgium, worked with colleagues from her institution and researchers coordinated by Serena Di Cosimo, MD, PhD, of the Instituto Nazionale dei Tumori in Milan, Italy, to analyze ctDNA in blood plasma samples taken from 81 patients with early breast cancer enrolled in two prospective studies, one at each center.
The women’s ages ranged from 27 to 75 years (median age = 48 years); most had tumors smaller than 5 cm that had spread to the lymph nodes, and more than half (60%) had triple-negative disease.
The researchers took ctDNA samples at three time points: when the patients entered the studies and before they started neoadjuvant treatment; at the end of the treatment and before surgery; and during the follow-up period (median of approximately 7 years). During this time, 1 patient died without their cancer recurring, 21 patients experienced a recurrence, and 4 patients died after a recurrence.
The researchers found ctDNA in 57% of plasma samples at the start of the studies, but at the end of neoadjuvant treatment, this dropped to 17%. There was a trend toward cancer recurring in patients who had ctDNA in their blood at the start of treatment, but this was not statistically significant. However, patients who had ctDNA in their blood at the end of their neoadjuvant treatment were 3.5 times more likely to have their cancer return during the follow-up period, even after adjusting for variables that could affect the analyses, such as tumor size, age, and hormone receptor status.
Even if there was no sign of the tumor after the neoadjuvant treatment—a pathologic complete response—ctDNA still predicted whether the cancer would recur.
The presence of ctDNA, both at the start of the two studies and after neoadjuvant treatment, was significantly associated with hormone receptor–negative disease, which is often more aggressive and harder to treat. Sixty-four percent of patients had hormone receptor–negative disease at the beginning of the studies and 36% had hormone receptor–positive disease.
Dr. Agostinetto said, “The results from this large, prospective study conducted in a real-world setting showed that finding ctDNA was linked to a higher chance of breast cancer coming back, especially when ctDNA was detected at the end of presurgery treatment. These results suggest that ctDNA could be useful in identifying patients at higher risk after neoadjuvant therapy, and to guide additional treatment if needed.”
She continued, “We know already that ctDNA has prognostic relevance, and its detection is consistently associated with a higher risk of recurrence and a worse survival, often anticipating clinical relapse by months. It is good at reflecting [measurable] residual disease and tumor burden. However, until now, there has been limited evidence about its usefulness in the neoadjuvant setting, mainly due to small numbers of patients in available clinical studies. Our analysis includes the largest number of events following neoadjuvant treatment and shows that ctDNA can be useful in guiding further treatments. At present, it is not used as a standard clinical practice for prognosis outside of clinical trials.”
She said the use of ctDNA in the neoadjuvant setting should be tested in prospective clinical trials where treatments decisions were guided by ctDNA results to show whether intervening early in ctDNA-positive patients actually improved outcomes.
Strengths of the study include the long follow-up period and the inclusion of consecutive series of patients in more than one cancer center.
“This is the only way that biomarker research is truly feasible, and I would like to thank all the colleagues involved in this collaboration between Institut Jules Bordet and Istituto Nazionale dei Tumori for their efforts,” noted Dr. Agostinetto.
DISCLOSURE: For full disclosures of the study authors, visit cm.eortc.org/cmPortal/Searchable/ebcc15.
