Circulating tumor DNA dynamics using patient-customized assays are associated with outcome in neoadjuvantly treated breast cancer

Abstract

Pathological complete response (pCR) is an accurate predictor of good outcome following neoadjuvant chemotherapy (NAC) for locally advanced breast cancer. The presence of circulating-tumor DNA (ctDNA) has recently been reported to be strongly predictive of poor outcome in similar patient groups. We monitored ctDNA levels from 10 women undergoing NAC for locally advanced breast cancer using a patient-specific, hybrid-capture sequencing technique sensitive to the level of one altered allele in 10,000. Plasma was collected prior to the start of NAC, prior to each infusion of NAC, and during follow-up for between 350 and 1150 d after the start of NAC. Prior to the start of NAC, ctDNA was detectable in 3/3 triple negative, 3/3 HER2 + , and 2/4 HER2 − , ER + breast cancer patients. Total cell-free DNA levels were considerably higher when patients were on NAC than at other times. ctDNA dynamics during NAC showed that patients with pCR experienced rapid declines in ctDNA levels, whereas patients without pCR typically showed evidence of residual ctDNA after initiation of treatment. Intriguingly, two of three patients that showed marked increases in ctDNA while on NAC experienced rapid recurrences (<2 yr following start of NAC). The third patient that had increases in ctDNA levels while on NAC had low-grade ER + disease and showed residual ctDNA after surgery, which became undetectable after local radiation. Taken together, these results demonstrate the ability of our approach to sensitively serially monitor ctDNA during NAC, and identifies a need to further investigate the possibility of stratifying patients who need additional treatment or identify therapies that are ineffective.

Prognostic and predictive value of circulating tumor DNA during neoadjuvant chemotherapy for triple negative breast cancer

“…Our results are similar to those of McDonald et al, who developed a multiplex targeted digital sequencing approach for the detection of very low abundance ctDNA. At a timepoint similar to our T4, they reported that ctDNA was detected in 12 of 13 patients without pCR and in 5 of 9 patients with pCR 19 . Our analogous numbers are 13 of 17 without pCR and 2 of 7 with pCR.…”

“…Indeed, the early decrease in ctDNA levels appears to be mostly the result of the effect of chemotherapy on the primary tumor's ability to generate ctDNA, and not on initial tumor response. Butler et al 19 , who showed similar results, suggest that chemotherapy may selectively kill actively dividing cells, which are the majority secretors of ctDNA. Nevertheless, those patients whose tumors eventually showed complete pathological response were less likely to have detectable ctDNA at this early stage of neoadjuvant treatment (33% vs 83%).…”

Early circulating tumour DNA kinetics measured by ultra-deep next-generation sequencing during radical radiotherapy for non-small cell lung cancer: a feasibility study

“…2 Line graphs depicting the VAF of mutations (labelled on each graph) detected in patients 1 to 5 (a-e, respectively) at baseline, 3 days and 7 days mid-treatment exhibited a transient rise prior to the eventual decrease (3/14 [23] and 2 /10 [24]). In addition, transient rises in ctDNA have been observed following systemic therapy, such as immunotherapy in melanoma [39], neoadjuvant combined cytotoxic/biologic combination therapy in breast carcinoma [40] and tyrosine kinase inhibition in EGFR-mutant NSCLC [41]. This pilot study demonstrates the feasibility of applying ctDNA-optimised NGS protocols through specified time-points in a small, homogenous cohort of patients treated with modern radiotherapy planning for locally advanced NSCLC.…”

Circulating biomarkers in patients with glioblastoma

“…63 A liquid biopsy may be able to reveal tumour information prior to clinical progression. 133,134 However, the tumour morphological features and the microenvironment are more readily available in the tissue biopsy. Therefore, a liquid biopsy aims to provide additional and complementary data to improve upon the diagnosis and follow-up of GBM patients.…”