Abstract
BackgroundPatients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been proven to be a marker of disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).MethodsPlasma was sampled at the initial diagnosis (defined as before NAT) and after breast surgery and neoadjuvant therapy(defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. ctDNA positivity was marked by the detection of alterations, such as mutations and copy number variations.ResultsA total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients exhibited ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, patients who did not achieve pCR were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.ConclusionsThis study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.
Highlights
Breast cancer prognosis has improved during the past two decades, breast cancer-related death remains a major cause of cancer-related mortality in women [1, 2]
To confirm the accuracy of the NSG-based deep sequencing, we checked whether this method could distinguish the existence of low-abundance mutants from background errors arising from the polymerase chain reaction (PCR) or sequencing process
The results demonstrated that the signal from the 0.1% mutant was significantly higher than background errors (Supplementary Figure S1A), suggesting that next-generation sequencing (NGS) testing accurately detected mutants present at 0.1%
Summary
Breast cancer prognosis has improved during the past two decades, breast cancer-related death remains a major cause of cancer-related mortality in women [1, 2]. Early detection of recurrence remains a major unmet need. Pathological complete response (pCR) is a favorable prognostic marker in patients with Her (+) and triple-negative breast cancer (TNBC) [6]. For patients with early-stage breast, lung and colon cancer, studies reported that ctDNA in the plasma can be used to detect minimal residual disease [16,17,18]. Serial detection of ctDNA after surgery and adjuvant chemotherapy of breast cancer could identify recurrent disease earlier than clinical overt tumor presenting in the radiologic images [19, 20]. For breast cancer patients receiving neoadjuvant therapy (NAT), the prognostic value of ctDNA before and after NAT is uncertain. The early detection of recurrent breast cancer remains a major unmet need. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT)
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