The presence of circulating tumor DNA or ctDNA, tumor-derived fragments of DNA in the bloodstream that are not associated with cells, in early-stage triple-negative breast cancer (TNBC) helped predict the risk of recurrence in women who had undergone surgery after neoadjuvant (presurgery) chemotherapy.
This is the conclusion reached by Milan Radovich, Ph.D, and Bryan P. Schneider, MD, two researchers at Indiana University Melvin and Bren Simon Cancer Center and the Vera Bradley Foundation Center for Breast Cancer Research, presented at the 2019 San Antonio Breast Cancer Symposium (SABCS), held December 10–14, 2019.
Triple negative breast cancer is among the most aggressive and deadliest types of breast cancer because it lacks common traits used to diagnose and treat this disease seen in most other types of breast cancer. This type of caner tests negative for estrogen receptors (ER), progesterone receptors (PR), and the HER2 protein.
As a result, the growth of triple negative breast cancer is not fueled by estrogen and progesterone, or by the HER2 protein. This also means that patients with this type of breast cancer will not respond to any of the targeted therapies developed to treat other forms of breast cancer. Treatment options usually include treated with a combination of (neoadjuvant or adjuvant) chemotherapy, surgery and radiation. Immunotherapy has also shown to improves survival in some patients with metastatic triple negative breast cancer.
About 10-20% of breast cancers are triple-negative breast cancers.
On average sixty percent of patients with triple-negative breast cancer survive more than five years without disease. However, four out of ten women will have a rapid recurrence of the disease. Unfortunately no clinical tests to exist to assess an individual patient’s prognosis and risk of recurrence.
Radovich and Schneider discovered a method that will help physicians predict whether triple negative breast cancer will recur, and which women are likely to remain disease-free.
“For patients who have triple-negative breast cancer with residual disease, the risk of recurrence is exceptionally high,” noted Schneider, the study’s senior author, and professor of Medicine and Medical and Molecular Genetics.
“Novel therapies and technologies are critical, including those that can potentially predict the risk of relapse,” he added.
In their presentation during the San Antonio Breast Cancer Symposium, the two scientists explain how ctDNA is being explored as a way detect cancer, guide treatment, and monitor patients during remission. They emphasized that the presence of ctDNA may signal the presence of cancer.
“If you are a woman with triple-negative breast cancer, after surgery you are in a constant ‘watch and wait’ scenario, in fear of the cancer coming back,” explained Milan Radovich, Ph.D, the study’s first author and associate professor of Surgery and Medical and Molecular Genetics.
“We know that a significant proportion of these women will have disease relapse after surgery. ctDNA is a powerful tool to be able to predict recurrence and could help us identify the best ways to manage care for women diagnosed with this disease,” Radovich added.
Reduce post-surgical treatment
Conversely, Radovich and Schneider noted that superior outcomes for patients who did not have ctDNA could potentially set the stage for clinical studies evaluating the ability to reduce post-surgical treatment for these patients.
The study, funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative and managed by the Hoosier Cancer Research Network with patients enrolled at 26 sites across the United States, analyzed plasma samples that had been collected from patients enrolled in the BRE12-158 clinical trial. This phase II study investigated genomically directed therapy versus physician’s choice of treatment after preoperative (neoadjuvant) chemotherapy in patients with early stage triple-negative breast cancer with residual disease. 
The trial enrolled 196 women, and ctDNA was sequenced in 142 patients using the FoundationOne Liquid Test.
Mutated ctDNA was detected in 90 of the patients, representing 63%. TP53 was the most commonly mutated gene, followed by others that are commonly associated with breast cancer.
At 17.2 months of follow-up, detection of ctDNA was significantly associated with inferior distant disease-free survival (DDFS). Patients with ctDNA had a median DDFS of 32.5 months, while the patients without ctDNA had not reached the median (median DDFS 32.5 months vs. Not Reached, p=0.0030).
At 24 months, the DDFS probability was 56% in ctDNA-positive patients, compared with 81% in ctDNA-negative patients. In multivariate analysis, when the researchers controlled for factors including residual cancer burden; tumor size, grade, and stage; age; and race, detection of ctDNA remained independently associated with inferior DDFS (HR=3.1, CI: 1.4-6.8, p=0.0048). Overall, ctDNA-positive patients were three times as likely to have distant disease recurrence than ctDNA-negative patients.
Detection of ctDNA was also associated with inferior overall survival (OS) in univariate (p=0.021) and multi-variate analysis (HR=2.7, CI:1.1-6.2, p=0.022); ctDNA-positive patients had 4.1 times increased risk of death compared with ctDNA-negative patients.
“This study establishes that triple-negative breast cancer patients who have ctDNA after neoadjuvant therapy have a higher risk of recurrence,” Schneider said.
“This may set the stage for further clinical trials for these high-risk patients, evaluating novel ways to prevent recurrence,” he further noted.
“[But we also] found is that if patients were negative for both ctDNA and CTC, 90% of the women with triple negative breast cancer remained cancer-free after two years,” Radovich added.
Based on this study, the researchers concluded that the detection of ctDNA in early-stage TNBC after neoadjuvant chemotherapy is an independent predictor of disease recurrence, and represents an important novel stratification factor for future post-neoadjuvant trials.
“The implications of this discovery will change the lives of thousands of breast cancer patients,” noted Nadia E. Miller, a breast cancer survivor and president of Pink-4-Ever, a breast cancer advocacy group in Indianapolis, Indiana.
“This is a huge leap toward more favorable outcomes and interventions for triple negative breast cancer patients. To provide physicians with more information to improve the lives of so many is encouraging,”> Miller added.
The authors noted that a clinical trial expected to begin in 2020 will further examine ctDNA’s potential in guiding therapy for those patients who are at high risk of recurrence. They also noted that sequencing technology is developing rapidly, and will likely become more sensitive and more specific over time.
Schneider and Radovich said that one of the limitation of this study was that the follow-up period is still ongoing. They warned that the results may change in future analysis.
Randomized Controlled Trial of Genomically Directed Therapy in Patients With Triple Negative Breast Cancer – NCT02101385
 Radovich M, Jiang G, Chitambar C, Nanda R, Falkson C, Lynce FC, Gallagher C, Isaacs C, et al. Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158 | GS5-02. Presented during the 2019 San Antonio Breast Cancer Symposium (SABCS) [Abstract]