Is tissue still the issue in detecting molecular alterations in lung cancer?

Abstract

Molecular biomarker testing of advanced‐stage NSCLC is now considered standard of care and part of the diagnostic algorithm to identify subsets of patients for molecular‐targeted treatment. Tumour tissue biopsy is essential for an accurate initial diagnosis, determination of the histological subtype and for molecular testing. With the increasing use of small biopsies and cytological specimens for diagnosis and the need to identify an increasing number of predictive biomarkers, proper management of the limited amount of sampling materials available is important. Many patients with advanced NSCLC do not have enough tissue for molecular testing and/or do not have a biopsy‐amenable lesion and/or do not want to go through a repeat biopsy given the potential risks. Molecular testing can be difficult or impossible if the sparse material from very small biopsy specimens has already been exhausted for routine diagnostic purposes. A limited diagnostic workup is recommended to preserve sufficient tissue for biomarker testing. In addition, tumour biopsies are limited by tumour heterogeneity, particularly in the setting of disease resistance, and thus may yield false‐negative results. Hence, there have been considerable efforts to determine if liquid biopsy in which molecular alterations can be non‐invasively identified in plasma cell‐free ctDNA, a potential surrogate for the entire tumour genome, can overcome the issues with tissue biopsies and replace the need for the latter.

Detection of KRAS G12/G13 Mutations in Cell Free-DNA by Droplet Digital PCR, Offers Prognostic Information for Patients with Advanced Non-Small Cell Lung Cancer

“…In 48.6% (N = 17/35 cases) of patients with KRAS mutations in tumor tissues, no mutations were detected in cfDNA. Possible causes that limit the detection sensitivity of ctDNA in liquid biopsy samples include the low contribution of ctDNA originating from tumor cells into plasma, as well as the short half-life time of ctDNA in the blood circulation [9,25]. Moreover, we also found seven cases (N = 7/61, 11.5%) that were KRAS wild-type in tumor tissue and KRAS mutant in plasma.…”

“…To date, the majority of studies are based on tumor tissue genotyping [7]. Although tissue biopsy is considered as the "gold standard" source for the molecular profiling of cancer, in advanced NSCLC, access to tumor tissue is often limited [8,9]. Additionally, the procedure is invasive and cannot capture the temporal and spatial heterogeneity of the tumor [9].…”

“…Although tissue biopsy is considered as the "gold standard" source for the molecular profiling of cancer, in advanced NSCLC, access to tumor tissue is often limited [8,9]. Additionally, the procedure is invasive and cannot capture the temporal and spatial heterogeneity of the tumor [9]. To this end, circulating tumor DNA (ctDNA), the fraction of circulating cell-free DNA (cfDNA) that derives from cancer cells, represents a valuable analyte within "liquid biopsy" by providing an alternative, reliable and non-invasive source of clinically valuable information [10,11].…”

Next Generation Sequencing for Gene Fusion Analysis in Lung Cancer: A Literature Review

“…In NSCLC tissue biopsies or FNA specimens are not always available and are barely representative of intra-tumor heterogeneity. Moreover, up to 10–20% of biopsies are inadequate for molecular testing [ 55 , 56 ]. Over the last few years, ctDNA has acquired a great relevance in the context of precision medicine of advanced lung ADC.…”

“…Over the last few years, ctDNA has acquired a great relevance in the context of precision medicine of advanced lung ADC. It consists of short DNA fragments released in the circulation by tumor cells due to mechanisms like apoptosis or necrosis [ 55 , 57 ]. The use of ctDNA is approved to assess the presence of EGFR -activating mutations in advanced lung ADC patients whenever tumor tissue is not available, and to monitor EGFR TKI treatment [ 58 ].…”