Comparison of genetic profiles among primary lung tumor, metastatic lymph nodes and circulating tumor DNA in treatment-naïve advanced non-squamous non-small cell lung cancer patients
Introduction
Lung cancer is the leading cause of cancer-related death worldwide [1], [2]. Targeted therapies, revolutionized the treatment of non-small cell lung cancer (NSCLC), have substantially improve the outcomes of a subpopulation of patients [3], [4], [5]. However, responses are often transient and there are still a significant percentage of patients who do not respond to treatment despite the fact of harboring targeted mutation [6]. Such phenomena can be partly attributed to the expansion of drug resistance clones, which have different genetic profiles, resulting in tumor heterogeneity [7], which imposes serious challenges on the development of therapeutic agents. Therefore, understanding tumor heterogeneity is critically important to the development of targeted therapies.
Metastasis, the main cause of death in individuals with cancer, is often depicted as a multistage process in which malignant cells spread from the tumor of origin to distant organs via blood circulation [8]. The prevailing model of metastasis holds that only a small subset of cells has the ability to metastasize, thus resulting in distinct molecular signature comparing to the primary tumor [9], [10]. In contrast, other studies have reported evidence supporting the notion that genetic changes favoring metastasis is an early event in tumorigenesis [11]. Distinct genotypes and phenotypes are referred to as tumor heterogeneity, which can occur within a primary tumor and its metastasis or between tumors of the same histopathological subtype [12]. Studies have shown the impact of tumor heterogeneity on addressing resistance mechanisms [13], treatment decisions and accurate diagnosis [14].
Although, currently the gold standard for obtaining mutation profile is still from tissue biopsy, either from the primary tumor or from a single metastatic lesion, the potential of probing genetic profile of solid tumors through blood draw—liquid biopsy has been increasingly acknowledged and routinely performed in clinical settings, especially in patients with advanced disease when tissue biopsy is not feasible [15], [16]. The majority of circulating tumor DNA (ctDNA), composed of small fragments of nucleic acid, is released from apoptotic or necrotic tumor cells, thus reflecting genetic profiles of solid tumors [17]. The bias generated by tumor biopsy, which is a temporal and spatial snapshot of a tumor, to some extent can be overcome by liquid biopsy [18]. Numerous studies have demonstrated a high concordance between mutation profiles obtained through ctDNA and tumor biopsy [19].
Currently, in the management of NSCLC, genetic profiles obtained from primary tumor, metastatic lymph nodes or peripheral blood are all used for guiding treatment in clinical practice. However, whether primary tumor and metastatic lymph nodes can be replaced by each other to guide treatment remains controversial. Moreover, whether genetic profiles of plasma ctDNA can reflect the spatial heterogeneity between primary and metastatic lesions is unclear. This is the first prospective study designed to evaluate the mutational profiles of matched primary tumor, metastatic lymph nodes and peripheral blood using capture-based ultra-deep targeted sequencing. This cohort consisted of 35 treatment-naïve patients with advanced NSCLC.
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Patient selection
From May 2015 to July 2016, patients meeting the following inclusion criteria from Shanghai Chest Hospital were enrolled in this study. Inclusion criteria: 1) Treatment-naïve patients suspected to have advanced (IIIA-IV) non-squamous NSCLC according to the 7th edition of the TNM classification. 2) Between the age of 18–80 years old. 3) Chest imaging demonstrating primary lung tumor and at least one metastatic lymph node that can be sampled. 4) Not suitable for surgery as first-line treatment
Patient characteristics
Thirty-five treatment-naïve patients presented with late stage NSCLC, ranging from stage IIIA to IV, were finally enrolled in this study (Fig. 1). Their primary tumor tissue, matched metastatic lymph node tissue and plasma samples were collected from each patient and subjected to capture-based ultra-deep targeted sequencing. The demographic and clinical characteristics of the enrolled patients are shown in Table 1. Of the 35 patients profiled, 8 were females and 27 were males. The median age
Discussion
The similarity and heterogeneity of mutation profiles between primary and metastatic tumors have been investigated in a number of cancers [21], [22], including NSCLC [23], [24], demonstrating conflicting results. Furthermore, whether the genetic divergence between primary and metastatic tumors can be reflected by plasma ctDNA has not been investigated. In this study, we evaluated the concordance in mutation spectrum among primary lung tumor, metastatic lymph nodes and plasma utilizing
Funding
The study was supported by Shanghai Municipal Hospitals’ Rising and Leading Technology Program (grant number SHDC12015115); Scientific Research Program by Science and Technology Commission of Shanghai Municipality (grant numbers 15441900502, 15411964300, 16441900702, 16441903502).
Conflict of interest
The authors have no conflict of interests to declare.
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2021, ChestCitation Excerpt :Concordance at the mutation level has been shown to be 62.2% to 88.8% in patients with NSCLC for EGFR mutations.46-49 Concordance rates varied from 50% to 55% in early-stage cancers and 64% to 83% in late-stage and metastatic cancers.49-54 The lower concordance in early-stage NSCLC may be contributed by a lack of sensitively to DNA shedding of early tumors and overall low tumor mutation burden.16,55
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