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

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.

Early, On-Treatment Levels and Dynamic Changes of Genomic Instability in Circulating Tumor DNA Predict Response to Treatment and Outcome in Metastatic Breast Cancer Patients

“…The detection of such common variants provides an alternative to sequencing of the tumor tissue in contexts in which the prevalence of these variants is frequent, such as the detection of KRAS mutations in colorectal cancers [ 11 ] and Epidermal Growth Factor Receptor (EGFR)mutations in lung cancer [ 12 ]. The detection of private mutations or infrequently mutated genes is more difficult to apply in the clinic because of the necessity of first sequencing the tumor [ 13 ]. Moreover, the primary tumor may have evolved during the metastatic process, and accessing metastatic tumors is difficult [ 14 , 15 ].…”

Circulating Biomarkers in Breast Cancer

“…116 , 120 , 143-145 Prognostically, the presence of ctDNA correlates with worse outcomes in early breast cancer. [146][147][148][149][150][151][152] Using data from 196 early-stage TNBC patients, Radovich et al compared ctDNA and CTCs in predicting disease recurrence; detection of ctDNA was significantly associated with inferior DDFS, DFS, and OS at 24 months, and the combination of ctDNA and CTCs increased sensitivity and discriminatory capacity. 150 Because of the lack of prospective trials and consensus in detection methods, ctDNA's prognostic potential for widespread use in early disease is currently limited.…”

Development of novel agents for the treatment of early estrogen receptor positive breast cancer

“…Detection of circulating tumor DNA using a variety of techniques following definitive therapy has been strongly associated with risk of subsequent recurrence in early stage breast cancer. [73][74][75] While additional study of ctDNA MRD is required to fully characterize its performance, prevalence, lead time to clinical recurrence, relationship with standard imaging (i.e. clinically occult but radiologically detectable metastatic disease), and the relative performance of various assays, the opportunity to target escalated strategies to individuals at extreme risk of recurrence in an "interception" approach is attractive.…”

“…The development of circulating tumor DNA applications is an area of intense clinical investigation [ 69 ], including in ER+ breast cancer. Detection of circulating tumor DNA using a variety of techniques following definitive therapy has been strongly associated with risk of subsequent recurrence in early stage breast cancer [ [73] , [74] , [75] ]. While additional study of ctDNA MRD is required to fully characterize its performance, prevalence, lead time to clinical recurrence, relationship with standard imaging (i.e.…”