Diagnostic and Prognostic Biomarkers in Oligometastatic Non-small Cell Lung Cancer

A Literature Review

Diego Cortinovis; Umberto Malapelle; Fabio Pagni; Alessandro Russo; Giuseppe Luigi Banna; Elisa Sala; Christian Rolfo


Transl Lung Cancer Res. 2021;10(7):3385-3400. 

In This Article

Abstract and Introduction


Objective: This review aims to summarize the possibilities of recently discovered molecular diagnostic techniques in lung cancer, by evaluating their impact on diagnosis, monitoring, and prognosis in oligometastatic disease.

Background: Oligometastatic non-small cell lung cancer (OM-NSCLC) is currently defined based on morphological rather than biological features. Major advances in the detection of molecular biomarkers in cell-free tumoral DNA and the models of oncogene addiction make as feasible an early diagnosis and guide the therapeutic decision-making progress to improve the prognosis.

Methods: This narrative review EXAMINES current approaches of diagnosis, monitoring, and prognosis of OM-NSCLC and describes the fast-evolving therapeutic scenario of this disease. We provide an overview of the powerful capability of liquid biopsy techniques applied to blood and fluid and we focus on the technological advancement of circulant biomolecular factors in OM NSCLC pathology, starting from apparently simpler models such as oncogene addicted tumors to evaluate themselves in the light of treatment with immune-checkpoint inhibitors.

Conclusions: A better understanding of spatial and temporal evolution of oligometastatic diseases would contribute to a more accurate diagnosis and tailored treatment. Data from prospective clinical trials in the early stage of disease, coupled with knowledge of genetic characteristics of lung tumors, are warranted. These efforts would lead to improving the possibility to eradicate the residual disease in these low burden tumoral settings, thus enhancing the definitive cure perspectives.


Since the first observations on growth and the metastatic spreading of non-small cell lung cancer (NSCLC), it has been clear that some tumors remained confined and indolent in few organs for a long time.[1] The "oligometastatic" condition—hereafter called oligometastatic NSCLC—was initially defined as an intermediate stage between locally advanced and widely disseminated disease.[1] However, this definition was inaccurate and did not discriminate between primary oligometastatic disease and oligorecurrence, and different cut-off numbers of metastases or organs involved were used.[1]

Recently, the European Organization for Research and Treatment of Cancer Lung Cancer Group (EORTC-LCG) published a consensus about the clinical definition of oligometastatic NSCLC[2] and described different patterns among de-novo status, repeat or induced oligometastatic disease in collaboration with the European Society of Radiotherapy (ESTRO).[3]

All definitions summarize a phenotypic rather than a genotypic condition; however, describing genetic features and microRNA signatures may be pivotal in the diagnostic process of oligometastatic disease.[4] In clinical practice, genotyping to identify oligometastatic-NSCLC (OM-NSCLC) is not feasible, and the diagnosis of a clinical oligometastatic status per se is a prognostic factor.

Indeed, among clinical factors, metachronous versus synchronous metastases, N-stage, and adenocarcinoma histology may stratify the risk of progressive disease and death.[5]

Lacking biomarkers of OM-NSCLC, it is impossible to differentiate an oligometastatic disease that grows slowly and remains in this clinical status from an oligometastatic disease that continues to proliferate and spreads in multiple organs. Furthermore, it is not possible to distinguish the definition of metastasis in multinodular lung disease from multiple primary lung tumors with the prognostic consequences and the therapeutic strategy of the case only from histopathological evidence.[6,7]

Many efforts had been done to discriminate multiple primary lung cancers from intrapulmonary metastasis. The first attempt was based on the expression of four cancer-related proteins—p53, p16, p27, and C-erbB2.[8] Subsequently, the TRACERx program, using the whole-exon sequencing, revealed a more complex genetic scenario.[9] Tissue genetic profiling and liquid biopsies resulted as effective techniques to achieve the correct diagnosis of oligometastatic disease and ameliorate the individualized therapeutic strategy.

Tissue-based biomolecular biomarkers can more accurately identify those patients who might benefit from local therapy, describing mRNA expression, microRNA expression, DNA mutations, epigenetic changes. In these procedures, poor quality of tissue and tumor heterogeneity—spatial and temporal—may be limiting.[10]

Blood-based biomarkers are attractive, since they do not require invasive biopsies and may explore many tumoral components such as proteins, microRNAs, circulating tumor cells, ctDNA, and exosomes. These techniques can be repeated, if necessary, and better reflect tumor molecular heterogeneity, either temporal or spatial, than a single biopsy.[11,12]

ctDNA is quantitively related to tumor burden and is a more objective measure of total body disease burden than imaging. Based on these observations, ctDNA profile can be useful to determine the minimal residual disease (MRD), defined as a small volume of tumor cells remaining after treatment in patients who do not have clinical evidence of disease, in early-stage or oligometastatic solid tumors and may allow predicting the outcomes in oligometastatic patients.[13] In OM-NSCLC, ctDNA profile can be applied both to identify those patients who are eligible for local ablative treatment and to follow them after ablative treatments that completely eradicate metastatic deposits and lead to a definitive cure.

This review summarizes current approaches of diagnosis, monitoring, and prognosis of OM-NSCLC and describes the fast-evolving therapeutic scenario of this disease. We present the following article in accordance with the Narrative Review reporting checklist (available at https://dx.doi.org/10.21037/tlcr-20-1067).