Circulating tumor DNA predicts recurrence in early-stage triple-negative breast cancer
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SAN ANTONIO — Detection of circulating tumor DNA after neoadjuvant chemotherapy appeared to independently predict disease recurrence among women with early-stage triple-negative breast cancer, according to preplanned analyses of results from the randomized phase 2 BRE12-158 trial presented at San Antonio Breast Cancer Symposium.
“We are obviously very excited by these findings,” Milan Radovich, PhD, associate professor of surgery and medical and molecular genetics at Indiana University School of Medicine, told Healio. “Circulating tumor DNA and circulating tumor cells [are] a powerful prognostic indicator for [these patients] but, more so, [they are] an important new stratification factor for future post-neoadjuvant trials.”
Triple-negative breast cancer accounts for a small percentage of breast cancers, but it is an aggressive subtype.
“Unfortunately, women with triple-negative disease have not benefited from the advances in hormonal targeted therapy seen in other breast cancer types, and most are treated with chemotherapy plus radiation and surgery,” Radovich said during a press conference. “These cancers tend to recur at a very high rate, which peaks during the first 3 years after surgery. This, unfortunately, causes an untenable situation for our patients, who live in constant fear and uncertainty of their cancer recurring after surgery.”
Researchers have explored circulating tumor DNA (ctDNA) to detect cancer, guide treatment and monitor patients during remission.
Radovich and colleagues sought to determine whether patients with detectable ctDNA and circulating tumor cells after neoadjuvant chemotherapy and surgery for triple-negative breast cancer are at high risk for recurrence.
The researchers analyzed plasma samples from 148 women with triple-negative breast cancer in the BRE12-158 trial who had been randomly assigned to post-neoadjuvant genomically directed therapy or physician’s choice of treatment.
Radovich and colleagues pooled and assessed the plasma samples using the FoundationOne Liquid test (Foundation Medicine).
At median follow-up of 17.2 months, 64% of the women (n = 94) had detectable ctDNA. The investigators identified TP53 as the most common mutation.
Women who tested positive for ctDNA achieved shorter median distant DFS than those who tested negative for ctDNA (32.5 months vs. not reached).
Researchers estimated 2-year distant DFS rates of 56% for ctDNA-positive women compared with 81% for ctDNA-negative women (HR = 2.99; 95% CI, 1.38-6.48).
Results of multivariate analysis — which accounted for covariates such as residual cancer burden, number of positive lymph nodes and tumor size, stage and grade, as well as age and race — showed detection of ctDNA remained independently associated with shorter distant DFS (HR = 3.1; 95% CI, 1.4-6.8). Moreover, ctDNA correlated with inferior OS in both univariate (P = .021) and multivariate analyses (HR = 2.7; 95% CI, 1.1-6.2).
Women who tested positive for ctDNA and circulating tumor cells achieved shorter distant DFS (median, 32.5 months vs. not reached) and were less likely to achieve 2-year distant DFS (52% vs. 89%; HR = 5.29; 95% CI, 1.5-18.62) than those who tested negative for both.
The absence of both ctDNA and circulating tumor cells had superior ability to predict RFS, Radovich said.
The results “are absolutely striking,” Radovich said.
“These findings have significant implications for future clinical trials,” Radovich told Healio. “The use of ctDNA or CTC testing for standard clinical practice in the post-neoadjuvant setting is not ready [to be used in the clinic] yet, mainly because we do not know if having this information improves outcomes. However, upcoming trials — like our PERSEVERE trial — will answer this important question of whether therapeutically intervening in this population that is positive for molecular minimal residual disease will improve survival.”
The PERSEVRE study — the successor trial to BRE12-158 — will enroll patients with triple-negative breast cancer who have residual disease after neoadjuvant chemotherapy.
“This time, we will harness the powerful information provided by ctDNA to stratify patients,” Radovich said.
Patients who are positive for ctDNA will be assigned to one of four arms in an umbrella trial design based on the genomic alterations observed. Patients will receive a targeted agent or agents matched to the genomic alterations. All patients also will receive therapy in combination with capecitabine, the current standard of care for these patients.
Patients who are positive for ctDNA but lack a prespecified genomic alteration will be assigned to capecitabine or physician’s choice of treatment. Patients who are negative for ctDNA will be assigned to physician’s choice of treatment.
Radovich and colleagues plan to open the trial in the first half of 2020. – by Jennifer Southall
Reference:
Radovich M, et al. Abstract GS5-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative supported the study. Radovich reports contracted research with Arqule, Immunomedics, LifeOmic and MacroGenics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Virginia Kaklamani, MD, DSC
We need clinical trials like this so that we can figure out if we can salvage these patients with our novel therapies. For now, these results should impact clinical research. We do not have predictive data as to how we will act on this and improve patient outcomes. So, we need a trial — which these investigators have designed — to see whether these results can further help us treat our patients and improve their outcomes. Of note, ctDNA was collected from blood, which is very easy to collect, and this is extremely important for our patients.
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