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Clinical Impact of Hybrid Capture–Based Next-Generation Sequencing on Changes in Treatment Decisions in Lung Cancer
Anna Belilovski Rozenblum MD, Maya Ilouze PhD, Elizabeth Dudnik MD, Addie Dvir MSc, Lior Soussan-Gutman PhD, Smadar Geva MSc, Nir Peled MD, PhD
Journal of Thoracic Oncology, Volume 12, Issue 2, February 2017, Pages 258 - 268
Commentary by Nir Peled
Precision care in lung cancer has shifted survival and quality of life for many of our patients. With appropriate diagnosis, more than half of our NSCLC may be treated first without chemotherapy (combining targeted therapies and pembrolizumab for eligible patients). This study shows the strong impact of multiplex hybrid capturing NGS above the routine approved PCR-based or ALK IHC/FISH methods. Using hybrid capturing NGS had huge impact on treatment decision which was later translated to 66% response rate and oversall survival benefit. Mis-diagnosis of a driver mutation hits the patients twice. First, patients are treated by chemo- and not by targeted drugs, and later, by immunotherapies where its benefit in patients with a valid driver mutation is very low. In conclusion, the use of sensitive technology is highly important in lung cancer therapy (tissue or ctDNA) and we shell do any possible effort to bring the best technology to our patients.
PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project
Fred R. Hirsch MD, PhD, Abigail McElhinny PhD, Dave Stanforth MBA, James Ranger-Moore PhD, Malinka Jansson MA, Karina Kulangara PhD, William Richardson BA, Penny Towne BS, MBA, Debra Hanks MD, Bharathi Vennapusa MD, Amita Mistry MD, Rasika Kalamegham PhD, Steve Averbuch MD, James Novotny PhD, Eric Rubin MD, Kenneth Emancipator MD, Ian McCaffery PhD, J. Andrew Williams PhD, Jill Walker PhD, John Longshore PhD, Ming Sound Tsao MD, Keith M. Kerr MB, FRCPath
Journal of Thoracic Oncology, Volume 12, Issue 2, February 2017, Pages 208 - 222
Commentary by Nir Peled
Pembrolizumab as first line therapy has become standard of care in NSCLC who express PDL1≥50%. In 2nd line, the survival benefit from all PD1/PDL1 agents is also correlated to PDL1 expression. However, each study used its own PDL1 biomarker. Therefore, tissue is required for primary diagnosis, molecular analysis and PDL1 staining.
The Bluepring study aims to harmonize between the four PDL1 staining methods which were used for the different compounds. This effort is highly important as to avoid tissue exhaustion, if possible. The study shows a good correlation between three of the methods, while the SP142 assay (atezolizumab) stained less cells in comparison to the others which was later compensated by its immune-cell counts. Still, it is too early to jump into conclusions and the current recommendation is to use each biomarker for its related drug. To note, only pembrolizumab has been labeled upon PDL1 staining.
Detection of cancer specific mutations in early-stage non-small cell lung cancer using cell-free DNA by targeted sequencing
He Y, Zhang X, Wang L, Tian Z, Liu Q, Yao J, Liu Y, Li C, Min L, Shan BInternational Journal of Oncology, Volume 49, Issue 6, December 2016, Pages 2351-2358
Commentary by Nir Peled
Screening for lung cancer is now recommended for high risk individuals. However, low dose CT programs do detect numerous nodules, where most of them are benign. Non-invasive biomarkers to support nodule' management are needed to direct clinicians toward a more or less aggressive approach to patients. This study shows the feasibility of cfDNA to detect cancer related gene mutations as another potential and highly specific tool. Next, its incorporation into a clinical setting should be presented.
A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma
Karen L. Reckamp MD, Vladislava O. Melnikova MD, PhD, Chris Karlovich PhD, Lecia V. Sequist MD, MPH, D. Ross Camidge MD, PhD, Heather Wakelee MD, Maurice Perol MD, Geoffrey R. Oxnard MD, Karena Kosco PhD, Peter Croucher PhD, Errin Samuelsz BS, Cecile Rose Vibat PhD, Shiloh Guerrero BS, Jennifer Geis PhD, David Berz MD, Elaina Mann MS, Shannon Matheny PhD, Lindsey Rolfe MB, ChB, Mitch Raponi PhD, Mark G. Erlander PhD, Shirish Gadgeel MD
Journal of Thoracic Oncology, Volume 11, Issue 10, October 2016, Pages 1690 - 1700
Commentary by Tom Stinchcombe
Approximately 60% of patients treated with an EGFR TKI develop a T790M acquired resistance mutation, and these patients are candidates for treatment with a third generation EGFR TKI (e.g. osimertinib). Historically patients have undergone a repeat tumor biopsy to detect the T790M. This study investigated the use of plasma and urine testing. In this phase I/II study plasma, urine, and tumor samples were collected, and 60 patients had evaluable tumor specimens. When the tumor sample was used as a reference the sensitivity for plasma for T790M was 93%, for exon 21 L858R 100% and for exon 19 deletions was 87% When tumor samples were used as a reference the sensitivity of urine for T790M was 72%, for exon 21 L858R was 75%, and for exon 19 deletions was 67%. The urine and plasma together identified an additional 12 patients with a T790M mutation that were undetectable on tumor testing or the sample inadequate tumor tissue. This is a small study and the number of patients in each mutation subset is limited. The potential use of urine will facilitate the detection of additional patients with a T790M resistance mutation, and may assistance in the serial measurement of T790M levels. Importantly if the original EGFR mutation, exon 19 deletion or exon 21 L858R, is not detected on these test this tests cannot be accurately interpreted.
Prospective analysis of oncogenic driver mutations and environmental factors: Japan molecular epidemiology for lung cancer study
Kawaguchi, T., Koh, Y., Ando, M., (...), Saka, H., Matsumura, A.Journal of Clinical Oncology 34, no. 19 (July 2016) 2247-2257
Commentary by Tom Stinchcombe
With the identification of oncogenic drivers of NSCLC there has been increase interest in identifying the potential causative factors, the prevalence and the association of environmental factors and oncogenic events. Many studies are retrospective and the patients tested may not be representative of the lung cancer patient population. This study prospectively collected exposure to active and passive smoke, occupational exposures, reproductive and hormonal risk factors, weight loss, family history of cancer, medication use, and diet and exercise. 72 cancer associated genes, copy number of 5 cancer associated genes, and IHC staining and scoring estrogen receptor and anaplastic lymphoma kinase (ALK) rearrangements were performed. Data on 876 samples (441 ever and 435 never smokers) was analyzed. P53 and KRAS increased proportionally with smoking status, and TP53 and NFE2L2 mutations were observed more frequently in advanced stage. In never smokers no environmental factors were associated with mutational changes. On multivariate analysis KRAS and SMAD4 mutations were associated with high body mass index. Only 3 patients (0.3%) were HPV positive suggesting little contribution of HPV to lung cancer. The prospective collection of prior exposure is a strength of this study, and the limitations are the environmental exposures were patient reported and the use of targeted rather than whole exome or genome sequencing. The study was performed in Japan and the prevalence and associations may vary depending on the patient population studied. Further epidemiological studies are warranted to identify the additional causative agents or environmental exposures associated with NSCLC.