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ORAL 39 - Potential Biomarkers for CT Screening (ID 149)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
ORAL39.03 - Clinical Utility of a Blood Based Circulating Tumour DNA Signature for the Diagnosis of Lung Cancer (ID 2457)
16:45 - 18:15 | Author(s): A.M. Fernandez
Lung cancer is conventionally diagnosed by confirmatory tissue biopsy, an invasive procedure that involves waiting time, costs and complications. The development push for a blood based liquid biopsy is a less invasive, more readily acceptable means to expedite the diagnosis and management of cancer. Circulating tumour DNA is promising in this regard as cancer specific genetic mutations are not usually found in the circulation of healthy individuals. The aim of our study is to report the performance of a three gene signature in for the diagnosis of cancer.
Pre-operative blood samples were obtained from patients undergoing surgery for known or suspected lung cancer and 1ml aliquots of plasma were extracted from 9ml of EDTA preserved blood. DNA was extracted from the plasma using the QIAamp DNA blood mini kit. High resolution melt analysis was undertaken to identify mutations in hotspots of the TP53, KRAS and EGFR genes in the ctDNA from plasma as well as matching FFPE tissue. A positive test result was defined as a mutation identified in the plasma ctDNA and compared against the reference clinical histopathology report of the resected lung abnormality. Clinical test performance was quantified and reported conventionally using sensitivity and specificity.
Pre-operative blood was analysed in a blinded manner from 223 patients undergoing surgery at our institution, and the pathology reports were issued blinded to the blood test results. In total, 116 (52%) had primary lung cancer, 64 (29%) had secondary cancer, 6 (3%) had primary thoracic (not lung) cancer and 35 (16%) did not have any evidence of cancer. Of the 186 patients with confirmed cancer, a mutation was identified in the FFPE sections of the primary tumour of 113 (61%) and in the plasma ctDNA in 127 (68%) with substantial agreement of 85% and a kappa statistic of 0.70 (P<0.001). The clinical test performance for the blood based diagnostic signature was a sensitivity of 68% (95% CI 61-75), specificity of 91% (77 to 98), positive predictive value 98% (93-100) and a negative predictive value of 35% (25 to 46) when compared to conventional clinical histopathology reporting of the resected tissue.
There is substantial agreement between the detection of ctDNA and FFPE tumour tissue mutations. We postulate higher mutation levels detected in the plasma is due to heterogeneity of tumour and FFPE sections in comparison to a global (plasma based ctDNA) estimate of mutation burden. Our results suggest blood based ctDNA analysis of cancer mutations is a specific, non-invasive test for the diagnosis of cancer. A positive test strongly rules in the diagnosis but a negative test does not have sufficient discriminatory ability to exclude the diagnosis of cancer.