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Investigating the feasibility of tumour molecular profiling in gastrointestinal malignancies in routine clinical
S Y Moorcraft1, D Gonzalez de Castro2, D Cunningham1
1Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London and Sutton, UK.
Background:
Targeted capture sequencing can potentially facilitate precision medicine, but the feasibility of this approach in gastrointestinal (GI) malignancies is unknown.
Patients And Methods:
The FOrMAT (Feasibility of a Molecular Characterisation Approach to Treatment) study was a feasibility study enrolling patients with advanced GI malignancies from February 2014 to November 2015. Targeted capture sequencing (mainly using archival formalin-fixed paraffin-embedded diagnostic/resection samples) was carried out to detect mutations, copy number variations and translocations in up to 46 genes which had prognostic/predictive significance or were targets in current/upcoming clinical trials.
Results:
Of the 222 patients recruited, 215 patients (96.8%) had available tissue samples, 125 patients (56.3%) had ≥16 genes successfully sequenced and 136 patients (61.2%) had ≥1 genes successfully sequenced. Sample characteristics influenced the proportion of successfully sequenced samples, e.g. tumour type (colorectal 70.9%, biliary 52.6%, oesophagogastric 50.7%, pancreas 27.3%, P = 0.002), tumour cellularity (high versus low: 78.3% versus 13.3%, P ≤ 0.001), tumour content (high versus low: 78.6% versus 27.3%, P = 0.001) and type of sample (resection versus biopsy: 82.4% versus 47.6%, P ≤ 0.001). Currently, actionable alterations were detected in 90 (40.5%) of the 222 patients recruited (66% of the 136 patients sequenced) and 2 patients subsequently received a targeted therapy. The most frequently detected currently actionable alterations were mutations in KRAS, BRAF, TP53 and PIK3CA. For the 205 patients with archival samples, the median time to obtain sequencing results was 18.9 weeks, including a median of 4.9 weeks for sample retrieval and 5.1 weeks for sequencing.
Conclusions:
Targeted sequencing detected actionable alterations in formalin-fixed paraffin-embedded samples, but tissue characteristics are of critical importance in determining sequencing success. Routine molecular profiling of GI tumours outside of clinical trials is not an effective use of healthcare resources unless more targeted drugs become available.
Clinicaltrials.Gov Identifier:
NCT02112357.
Insights
Targeted sequencing of gastrointestinal (GI) tumors identified actionable alterations in archival samples. However, success depends heavily on tissue quality, limiting routine clinical use currently.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Targeted capture sequencing offers potential for precision medicine in gastrointestinal (GI) malignancies.
- The feasibility of using this approach in GI cancers was previously unknown.
Purpose of the Study:
- To assess the feasibility of targeted capture sequencing in advanced GI malignancies.
- To identify actionable molecular alterations in GI tumors using archival samples.
Main Methods:
- The FOrMAT study enrolled patients with advanced GI malignancies between February 2014 and November 2015.
- Targeted capture sequencing was performed on archival formalin-fixed paraffin-embedded samples to detect mutations, copy number variations, and translocations in up to 46 genes.
Main Results:
- Of 222 patients, 96.8% had available tissue samples, and 61.2% had at least one gene successfully sequenced.
- Actionable alterations were detected in 40.5% of patients, with KRAS, BRAF, TP53, and PIK3CA being the most frequent.
- Sequencing success was significantly influenced by tumor type, cellularity, content, and sample type (resection vs. biopsy).
Conclusions:
- Targeted sequencing can detect actionable alterations in archival GI tumor samples.
- Tissue characteristics critically impact sequencing success, and routine molecular profiling is not yet cost-effective for GI tumors outside clinical trials.
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