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ELCC 2016 News: Comprehensive Molecular Profiling Shows Disparity Between Primary NSCLC Tumours and Metastases

Biomarkers targetable by currently existing agents were also identified
15 Apr 2016
Pathology/Molecular Biology
Thoracic Malignancies

Important differences of up to 47% in the expression rates of biomarkers between the primary tumour and metastatic sites were detected using comprehensive molecular profiling of non-small-cell lung cancer (NSCLC) samples.
Zoran Gatalica of the Department of Pathology, Caris Life Sciences, Phoenix, USA, presented findings on behalf of colleagues at the European Lung Cancer Conference (ELCC), held in Geneva, Switzerland, 13 to 16 April, 2016.

The investigators analysed 10,764 profiled NSCLC samples from a tumour bank at Caris Life Sciences and categorised them as primary tumours, lymph node (LN) metastases, and distant organ metastases to determine site-specific biomarkers for actionable targets. The biomarkers were detected using immunohistochemistry (IHC), in-situ-hybridisation (ISH) and by Sanger and next generation sequencing (NGS) methods. Biomarkers that could be targeted by current therapeutic agents were compared between primary tumours, LN metastases, and distant organ metastases in this large, non-paired cohort and confirmation was done in a cohort of 154 patients with paired samples.

Numerous biomarkers were detected in both squamous cell and adenocarcinomas that could be acted upon by current targeted biological therapies. These samples had a 2.4% and 1.0% ALK and ROS1 rearrangement rate, respectively, 2.9% and 4.0% of samples contained HER2 and cMET amplification, respectively, EGFR overexpression (H-score) was detected in 49.2% of these samples, 29.5% showed gene amplification, and 12.3% of samples showed mutations.

Biomarkers targetable by inhibitors of immune checkpoints were also detected, including 25% PD-L1 expression, as well as biomarkers targetable by chemotherapeutic agents, such as BRCA1 and 2, ERCC1, TUBB3, RRM1, TOPO1, and thymidylate synthase (TS).

Heterogeneity/discordance observed between the expression rates of biomarkers in primary tumours and metastases

Several actionable alterations occurred at higher frequency in the LN metastases of lung adenocarcinomas than in the primary tumours and included: ALK positivity by IHC (8% versus 1%), PD-L1 rates (36% versus 25%), and ROS-1 re-arrangement rates (3% versus 1%). EGFR detection in LN metastases versus primary tumour was 50% versus 42% by IHC and 39% versus 28% by ISH, respectively.

Distant organ metastases displayed higher cMET amplification of 7% compared with 3% in primary tumours.

In squamous cell carcinomas, higher ALK expression at a rate of 10% was seen in LN metastases than in the primary site where the ALK expression rate was 1%. The PD-L1 expression rate in squamous cell carcinomas was also higher at 42% in LN metastases compared with 33% in the primary tumour.

Trends of expression rates that were observed in the non-paired cohort were confirmed in the cohort of patients with paired tissue samples, where gains in PD-L1 expression, cMET amplification, and TP53 mutations and losses in KRAS mutations were observed.


Biomarkers that display significantly different rates of expression, amplification/fusion and mutation in matched primary vs. metastases (lymph node or distant metastasis) in NSCLC (n=154; 130 ADC, 14 SCC)


These findings highlight the importance of the extent and timing of tissue sampling for molecular profiling. The authors concluded that comprehensive genomic profiling can be used successfully to identify actionable targets in tumours, but spatial and temporal differences (heterogeneity) in the expression of predictive biomarkers between primary NSCLC tumours and metastases to the lymph node or distant organs may be substantial.

They stated that the availability of recently-developed targeted therapies and the predictive value of their biomarkers, together with the heterogeneity displayed between primary tumours and metastases mandate thoughtful profiling of tumour samples in order to achieve maximum therapeutic response.


This study was funded by Caris Life Sciences, Phoenix, USA


1PD. Differences in expression of predictive biomarkers between primary and metastatic non-small cell lung cancer tumors

Last update: 15 Apr 2016

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