Abstract
Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. To evaluate the predictive and prognostic values of circulating tumor DNA (ctDNA) in this setting, we analyzed tumor and serial bloods from 26 TNBC patients collected prior, during, and after NAC. Individual digital droplet PCR assays were developed for 121 variants (average 5/patient) identified from tumor sequencing, enabling ctDNA detection in 96% of patients at baseline. Mutant allele frequency at baseline was associated with clinical characteristics. Levels drastically fell after one cycle of NAC, especially in patients whose tumors would go on to have a pathological complete response (pCR), but then rose significantly before surgery in patients with significant residual tumor at surgery (p = 0.0001). The detection of ctDNA early during treatment and also late at the end of NAC before surgery was strongly predictive of residual tumor at surgery, but its absence was less predictive of pCR, especially when only TP53 variants are considered. ctDNA detection at the end of neoadjuvant chemotherapy indicated significantly worse relapse-free survival (HR = 0.29 (95% CI 0.08–0.98), p = 0.046), and overall survival (HR = 0.27 95% CI 0.075–0.96), p = 0.043). Hence, individualized multi-variant ctDNA testing during and after NAC prior to surgery has prognostic and predictive value in early TNBC patients.
Highlights
Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery
Patients consented to pre and post-chemotherapy biopsies and surgical tissue collection [for whole exome sequencing (WES)] as well as to serial blood sampling at 5 time points: prior to NAC, after 1 cycle of NAC, at mid-treatment, after 1 cycle of the 2nd chemo regimen and at the end of NAC before surgery (Fig. 1). 60 patients were enrolled in this study but only 26 were eligible for this study with high quality tumor DNA sufficient for WES, as well as at least 2 serial blood samples collected according to established SOPs (Supplementary Fig. S1 and Supplementary Table S1)
We evaluated the effect of cell free tumor DNA (ctDNA) detection on relapse-free survival (RFS) and overall survival (OS) using only the 80 variants detected at baseline in the remaining 23 patients, since these are the variants that can be followed throughout the treatment course
Summary
Response to neoadjuvant chemotherapy (NAC) in triple negative breast cancer (TNBC) is highly prognostic and determines whether adjuvant chemotherapy is needed if residual tumor is found at surgery. We recently completed the Q-CROC-03 clinical trial, in which patients with TNBC undergoing NAC were consented for biopsies pre-chemotherapy and post-chemotherapy as well as serial bloods before, during and after NAC14 to determine molecular factors of response or resistance to standard NAC both in tumor tissue and plasma. We recently reported on optimized protocols for cfDNA extraction and digital droplet polymerase chain reaction (ddPCR) a nalysis[15] We applied these protocols to the analysis of serial plasma from 26 patients enrolled in Q-CROC-03, by developing personalized ddPCR assays based on whole exome sequencing (WES) of each tumor. We present our findings, which confirm the power of ctDNA as a strong potential prognostic and predictive biomarker in the early stages of this aggressive disease
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