The oncological impact of surgical injury during the perioperative period has been demonstrated to be crucial in determining the risk of post-operative recurrence in cancer,. Around 30% of breast cancer patients present with disease recurrence at follow-up assessment. Indeed, the risk of disease recurrence is highest during the first 5 years (10.4%), with a peak occurring between years 1 and 2 (15.2%). Early detection of recurrence is crucial to survival in breast cancer. Identification of reliable and cost-effective assays from an easily accessible source, such as blood could have an inherent role in routine testing for recurrence risk and adjuvant treatment requirements in surgically resectable cancer. Circulating nucleic acids in the form of cfDNA released by tumour cells may provide crucial information relevant to several aspects of cancer biology. Quantification of cfDNA is a simple non-invasive blood-based test and appears to have diagnostic and prognostic relevance in breast cancer, ,. In this study, we sought to explore whether peri-operative cfDNA quantification holds any prognostic significance as it relates to disease recurrence in breast cancer patients undergoing curative surgery. We observed that high cfDNA concentrations in the peri-operative period and after surgery correlate with shortened recurrence free survival (RFS).
In breast cancer, optimum timings for measurement of cfDNA in perioperative period are unclear. So, we study dynamics of cfDNA concentrations and its association with outcome of recurrence in breast cancer before and after surgery. In the preoperative period, high concentrations of cfDNA were observed consistent with the presence of tumour burden in breast cancer patients with subsequent drop in cfDNA levels following surgery. Agassi et al and by Lin et al reported similar findings in breast cancer and oral cancer respectively. Intriguingly, significant correlation was observed upon subgroup analysis, between high cfDNA concentrations in the pre-operative period and inferior recurrence free survival in our cohort of breast cancer patients. Bastian et al and He Y et al, have also reported an association between preoperative cfDNA concentration and increase risk of recurrence in prostate cancer and colorectal cancer. Following cancer surgery, identification of patients at high risk of recurrence is imperative for adjuvant therapy decisions. Overall, we observed a fall in cfDNA levels following surgical removal of tumour burden. Importantly, in first week after surgery, there was increase in cfDNA concentration among those at higher risk of disease recurrence compared to those who were at lower risk of recurrence. These findings were also observed by our group in a cohort of colon cancer patients where cfDNA concentrations from 48 hours to day 5 after surgery predicted those at risk of recurrence at 2 years. Another study by Hu et al highlighted the significant association between higher cfDNA concentrations on post-operative day 30 and increased risk of disease recurrence in lung cancer patients. The possible explanation for high cfDNA concentrations in cancer patients could arise from accumulation of DNA derived from the primary tumour and metastatic deposits in blood. This combined with the reduced clearance of cfDNA contribute to cfDNA elevation in the blood of patients with cancer. Therefore, monitoring concentrations of cfDNA following surgery could aid clinicians in assessing risk stratification during follow up
The diagnostic and prognostic value of cfDNA in breast cancer has been demonstrated in the available literature. However, there is limited evidence about its significance in the context of the peri-operative period in breast cancer. Although the number of patients in our study was small, we observed that cfDNA concentrations in the peri-operative period could discriminate among patients at risk of recurrence with reasonable sensitivity and specificity. In addition, there was a positive correlation between high cfDNA concentration and shortened recurrence-free survival in breast cancer. We highlighted the significance of cfDNA concentrations in the peri-operative period in breast cancer in our proof-of-concept study but it needs to be validated in larger cohort of patients.
Our study provides insights into the dynamics of cfDNA specific to the perioperative period in breast cancer in detecting and characterizing localized disease before clinical symptoms or radiological evidence of progression. The future of this work will involve exploration of different aspects of the cfDNA biology in the context of immediate peri-operative period with objectives and strategies to minimize perioperative surgical stress response which might affect long-term outcomes in breast cancer. Recently, researchers also explored other aspects of cfDNA including combined mutation detection in cfDNA with serum protein biomarkers, machine learning model DELFI (DNA evaluation of fragments for early interception) to incorporate genome-wide fragmentation of cfDNA to identify differences in cfDNA fragment lengths between cancer and non-cancer participants and use of targeted methylation analysis of cfDNA to detect and localize multiple cancer types across all stages at high specificity.
There are some limitations to our study. The sample size of 63 patients was small. To evaluate the effect of perioperative cfDNA concentrations on breast cancer in our study, we only enrolled cohort of breast cancer patients with known 5-year recurrence outcomes (DF and DR subgroups) and availability of paired perioperative blood samples. Furthermore, there is heterogeneity in patients’ subgroups and third of patients had neoadjuvant therapy. However, there is now a platform to investigate this research even further in a larger prospective study group. The role of cfDNA for prediction of recurrence in cancer is one of the most challenging endeavours, so future research should focus on defining the time points in the perioperative period as well as standardizing cfDNA assessment techniques to approve its clinical utility as biomarker in breast cancer.