Tracking longitudinal genetic changes of circulating tumor DNA (ctDNA) in advanced Lung adenocarcinoma treated with chemotherapy

Abstract

Introduction Pemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), however, the efficacy and safety is varying from individuals. There is a need to better understand the genetic variations associated with platinum response. Materials and Methods We performed next-generation sequencing (NGS) based on BGI Oseq-ctDNA panel to analyze 98 longitudinal plasma samples from 32 lung adenocarcinoma patients during platinum-based chemotherapy, and a bioinformatic pipeline was developed to detect point mutations. Results We found that mutation burden was decreased after chemotherapy, which reflected chemotherapy sensitivity, especially the frequency of C>G and C>A substitutions. Moreover, neoplastic cells carrying a specific set of somatic mutations, such as EGFR(L858R), KRAS (p.G12C) were obviously correlated with platinum treatment. In addition, the MAPK pathway was found to have a pivotal role in NSCLC and platinum based response. Finally, we found that smokers benefit less from platinum-based chemotherapy. Conclusions Collectively, this work described the dynamic changes of ctDNA mutation status during platinum-based treatment, which may contribute to advanced lung adenocarcinoma patients stratification and precision treatment.

Circulating Tumor DNA as a Prognostic Biomarker in Localized Non-small Cell Lung Cancer

“…Therefore, our data cannot evaluate the impact of adjuvant chemotherapy on ctDNA. However, previous studies have confirmed the possible role of circulating DNA in judging the efficacy of chemotherapy (24,25). A well-designed clinical trial is needed to verify the role of ctDNA in evaluating the efficacy of neoadjuvant therapy for lung adenocarcinoma.…”

The Polemic Diagnostic Role of TP53 Mutations in Liquid Biopsies from Breast, Colon and Lung Cancers

“…The clinical utility of TP53 mutations in lung cancer is still controversial as some authors showed that a decrease in their VAF after adjuvant chemotherapy was somehow related to better outcomes [ 78 ], whereas others found no correlation between TP53 mutation status with chemotherapy response [ 79 , 80 ]. This might be due to the particular mutation detected, as some seem to be associated with sensitivity to treatment, whereas others are more likely resistant markers [ 79 ].…”

“…The clinical utility of TP53 mutations in lung cancer is still controversial as some authors showed that a decrease in their VAF after adjuvant chemotherapy was somehow related to better outcomes [ 78 ], whereas others found no correlation between TP53 mutation status with chemotherapy response [ 79 , 80 ]. This might be due to the particular mutation detected, as some seem to be associated with sensitivity to treatment, whereas others are more likely resistant markers [ 79 ]. Regarding biological treatments, tyrosine kinase inhibitors (TKIs) are being successfully used to treat lung tumors with ALK rearrangement or when sensitizing EGFR mutations are present [ 80 ], as some mutations such as EGFR T790M are related to Gefitinib and Erlotinib resistance [ 21 ].…”

“…Nevertheless, it is known that TP53 mutations might also arise as consequence of a particular therapy, for example, in metastatic colorectal patients treated with Cetuximab; thus, its appearance may produce resistant clones that need to be monitored [77] and possibly targeted by different drugs. The clinical utility of TP53 mutations in lung cancer is still controversial as some authors showed that a decrease in their VAF after adjuvant chemotherapy was somehow related to better outcomes [78], whereas others found no correlation between TP53 mutation status with chemotherapy response [79,80]. This might be due to the particular mutation detected, as some seem to be associated with sensitivity to treatment, whereas others are more likely resistant markers [79].…”

An electrochemiluminescence resonance energy transfer biosensor for the detection of circulating tumor DNA from blood plasma

“…The blood plasma of patients with cancer often harbors double-stranded (ds) circulating tumor DNA (ctDNA) released from necrotic or apoptotic tumor cells ( van Ginkel et al., 2017 ; Jahr et al., 2001 ). The nucleotide sequence of ctDNA comprises mutations specific to different types of cancer ( Iwahashi et al., 2019 ; Han et al., 2019 ; Said et al., 2020 ; Reece et al., 2019 ). This attribute can be exploited for the non-invasive detection of early- to late-stage cancers and to monitor treatment efficiency via liquid biopsy of blood samples ( Del Re et al., 2019 ; Chen et al., 2020b ; Kelley and Pantel, 2020 ).…”