Liquid Biopsy for Small Cell Lung Cancer either De Novo or Transformed: Systematic Review of Different Applications and Meta-Analysis

Abstract

Background: The potential added value of liquid biopsy (LB) is not well determined in the case of small cell lung cancer (SCLC), an aggressive tumor that can occur either de novo or from the histologic transformation of non-small cell lung cancer (NSCLC). Methods: A systematic review of studies adopting LB in patients with SCLC have been performed to assess the clinical utility of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). Results: After a screening of 728 records, 62 studies (32 evaluating CTCs, 27 ctDNA, and 3 both) met predetermined eligibility criteria. Only four studies evaluated LB in the diagnostic setting for SCLC, while its prognostic significance was evaluated in 38 studies and prominently supported by both ctDNA and CTCs. A meta-analysis of 11 studies as for CTCs enumeration showed an HR for overall survival of 2.63 (1.71–4.05), with a potential publication bias. The feasibility of tumor genomic profiling and the predictive role of LB in terms of response/resistance to chemotherapy was assessed in 11 and 24 studies, respectively, with greater consistency for those regarding ctDNA. Intriguingly, several case reports suggest that LB can indirectly capture the transition to SCLC in NSCLC treated with EGFR tyrosine kinase inhibitors. Conclusions: While dedicated trials are needed, LB holds potential clinical roles in both de novo and transformed SCLC. CtDNA analysis appears the most valuable and practicable tool for both disease monitoring and genomic profiling.

Histologic transformation in lung cancer: when one door shuts, another opens

“…Although a tissue biopsy is crucial for the diagnosis of HTs in patients with lung cancer, it can be difficult and invasive. 134 In a previous report, elevated tumor markers, such as neuron-specific enolase and pro-gastrin-releasing peptide were reported at the time of HTs to SCLC; however, tumor markers are not precise indicators of HTs. 135 , 136 Liquid biopsy is a recently developed, non-invasive technique used in cancer treatment.…”

“…In a previous study, a tissue and plasma analysis of EGFR, TP53 , and RB1 contributed to the early detection of HTs to SCLC. 99 , 134 , 137 Moreover, liquid biopsy techniques have been used in the previously mentioned clinical trial (NCT03567642). Furthermore, the use of a serum digital droplet PCR (ddPCR) might be helpful in identifying high-risk patients.…”

Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions

“…Meanwhile, in patients with an accessible pleural effusion, thoracentesis is recommended to facilitate diagnosis 155 . Finally, given the high amount of circulating tumor DNA and CTCs in the bloodstream of patients who have SCLC, liquid biopsy also holds a potential diagnostic role, especially concerning monitoring disease progression 159,160 …”

“…155 Finally, given the high amount of circulating tumor DNA and CTCs in the bloodstream of patients who have SCLC, liquid biopsy also holds a potential diagnostic role, especially concerning monitoring disease progression. 159,160 Radiologic diagnosis of distant metastases varies according to their anatomic localization (Figure 5C). However, except for brain metastases, PET-CT remains the imaging approach of choice in identifying extrathoracic metastases, especially bone and adrenal lesions.…”

Liquid biopsy and non-small cell lung cancer: are we looking at the tip of the iceberg?

“…The most common mutations associated with SCLC transformation included TP53 , RB1 and PIK3CA . Small experiences, applying complementary testing of tumour tissue and liquid biopsy, showed how ctDNA analysis could suggest neuroendocrine evolution, when typical SCLC-associated genetic alterations become detectable [ 99 , 100 ]. Squamous cell carcinoma transformation has also been described in different case reports after EGFR-TKI treatment [ 101 ].…”