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J. Spicer
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MINI 07 - ChemoRT and Translational Science (ID 110)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:D. Raben, B. Kavanagh
- Coordinates: 9/07/2015, 16:45 - 18:15, 201+203
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MINI07.11 - Isotoxic Dose Escalation and Acceleration in Lung Cancer Chemoradiotherapy (ID 1522)
16:45 - 18:15 | Author(s): J. Spicer
- Abstract
Background:
RTOG 0617 investigated standard dose radiotherapy (RT) versus higher dose in the context of concurrent chemoRT with no advantage to higher dose treatment. IDEAL CRT investigated an alternative RT dose-escalation strategy with concurrent chemoRT in locally advanced NSCLC. Dose-per-fraction-escalation was used to achieve intensification without treatment prolongation. The trial would determine the maximum tolerable dose (MTD) deliverable to esophagus, and assess toxicity and early clinical outcomes for the schedule.
Methods:
Patients were enrolled to 2 groups, depending on maximum esophageal dose. Tumor doses were determined by esophageal constraints in Group 1 and other normal tissue constraints in Group 2. Patients received 63-73Gy in 30 once-daily fractions / 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. Group 1 esophageal dose-escalation followed a 6+6 design, increasing maximum dose to 1cc esophagus from 65Gy, 68Gy then 71Gy in successive cohorts, defining MTD by early and late toxicity. Efficacy endpoints were overall survival (OS), progression-free survival (PFS) and tumor response.
Results:
8 centres recruited 84 patients, treating 13, 12 and 10 in 65Gy, 68Gy and 71Gy group 1 cohorts. Prescribed RT doses are shown in figure 1. Median follow-up 24 months. 57 patients (68%) were stage IIIa and 21 (25%) IIIb. 5 grade 3 esophagitis events observed across both groups and 3 grade 3 pneumonitis. Following 1 fatal esophageal perforation in the 71Gy cohort, 68Gy was declared as esophageal MTD. Overall Survival (OS) and Progression Free Survival (PFS) were 87.8% and 72.0% at 1 year, and 67.1% and 50.4% at 2 years, median OS 39.3 months. OS is shown in figure 2. Figure 1 Figure 2
Conclusion:
Acceptable toxicity rates and promising survival were achieved. The isotoxic design proved practical, allowing significant treatment intensification and definition of MTD with relatively few patients. Results from longer follow-up are required and will be presented at the meeting.
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MINI 08 - Prognostic/Predictive Biomarkers (ID 106)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.E. Stinchcombe, N. Pavlakis
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI26.01 - Tumour Molecular Profiling and Quantitative Detection of Circulating Biomarkers in Patients with Non-Small Cell Lung Cancer (NSCLC) (ID 317)
16:45 - 18:15 | Author(s): J. Spicer
- Abstract
- Presentation
Background:
The introduction of targeted therapy has transformed the care of patients with lung cancer by incorporating tumour genotyping into therapeutic decision making. Recent improvements in sequencing technology have allowed for a rapid and broad snapshot of a tumour’s genetic landscape. Circulating cell-free tumour DNA (cfDNA) can be detected in patients with solid organ malignancies and has the potential to be used as a non-invasive biomarker (“liquid biopsy”). By integrating the two approaches, it is possible to detect specific mutational events in diagnostic samples, assess tumour burden, longitudinally monitor the response to therapeutic intervention and detect disease recurrence. As we have shown previously, it may also facilitate the detection of emergent subclonal populations, including variants that confer resistance to specific therapeutic agents.
Methods:
30 unselected treatment-naive patients with lung cancer were recruited from clinic. Paired DNA from tumour biopsies and plasma was obtained. Targeted next-generation sequencing (NGS) was performed on the tumour biopsy DNA. Primer sets and probes for identified mutations were optimised and validated on a microdroplet digital PCR (mdPCR) system.
Results:
25 of 30 patients in our test cohort had stage IIIB/IV non-small cell lung cancer. 25 of 30 patients (83%) of patients had mutations identified in their diagnostic specimen. 4 out of the 5 patients with no identifiable mutation in their diagnostic specimen presented with early disease and underwent curative surgery. The diagnostic specimens included endobronchial ultrasound (EBUS) samples, percutaneous and pleural biopsies, surgical resection specimens and a brain biopsy. The corresponding mutation was then assayed in cfDNA and was detected in the pre-treatment plasma samples in 90% of patients. Results to date from this cohort will be presented in detail. There has been complete concordance between mutations identified as part of the clinical standard-of-care and our targeted NGS data.
Conclusion:
It is feasible to perform a targeted NGS analysis on DNA from standard diagnostic lung cancer specimens and design generic and patient-specific biomarkers for use in a mdPCR assay of cfDNA. We aim to validate this approach and embed it in future clinical trial protocols.
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MS 13 - The Other "-omics" (ID 31)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:I. Laird-Offringa, J. Herman
- Coordinates: 9/08/2015, 14:15 - 15:45, Mile High Ballroom 2a-3b
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MS13.04 - Integrating "omics" for a Unified View of Lung Cancer (ID 1907)
14:15 - 15:45 | Author(s): J. Spicer
- Abstract
- Presentation
Abstract:
Study of genomics, epigenomics and proteomics may contribute to an understanding aetiology, prevention, early diagnosis, classification, treatment selection, and novel trial design in lung cancer. The clinical material available for analysis ranges from tumour biopsy to pleural fluid, bronchoalveolar lavage, saliva and even urine. The available techniques are in many cases sensitive (including PCR and mass spectrometry (MS)), and specificity can be optimised especially with reference to normal material such as germline DNA. The omic landscape of lung cancer has been extensively characterised (The Cancer Genome Atlas Research Network, 2014). This provides insight into disease biology via SNP/exome/whole genome sequencing, CpG DNA methylation, mRNA sequencing and protein expression profiling. Epigenomics is a key component since promoter hypermethylation occurs an early event in lung tumourigenesis (Belinsky, S. et al. 2015), targeting tumour suppressor genes. Indeed epigenomics and genomics are intimately linked, with CpG methylation leading to base substitution through 5-methylcytosine deamination, and enhancing the effect of exogenous carcinogens. Although the contribution of smoking to lung cancer aetiology has long been recognised, genomics is now providing insight into somatic mutagenesis as the mechanism of this causal interaction, as well as into tumourigenesis in non-smokers. However, this wealth of genetic and epigenetic information requires further analysis to establish which of these events really drive the phenotype, and which can be biologically validated as targets for therapy. Both genetic and epigenetic targets for therapy of lung cancer have been identified, in the form of both activated oncogenes and loss of tumour suppressor gene function. In some cases tumour genotype proves valuable as a predictive biomarker for patient selection. Several current biomarker-directed trials (such as Lung-MAP and MATRIX) are seeking to identify further successful genotype/therapy pairings. Despite impressive response rates in genomically stratified populations, regulators seem still to require validation of omics-driven treatment selection in a strategy-testing design, randomising to standard of care or personalised therapy. A further therapeutic application of genomics is characterisation of resistance mechanisms, an understanding of which has already led directly to next generation drugs in several drug classes including inhibitors of EGFR and ALK. It is genetic events that are at the origin of the hallmarks of cancer, but proteins, as the effectors of cellular processes, are key to a full understanding of the cancer phenotype. Some have argued that proteomic markers, as a surrogate for the genetic drivers, may be inferior to genomics. Certainly proteomic biomarkers are the less dynamic because their half life is measured in weeks, compared with a few hours for nucleic acids. Beyond the small number of actionable mutations already described in non-small cell lung cancer, the diagnostic, prognostic, and predictive potential of a large number of omic markers has been studied, and in most cases problems with reproducibility have limited their clinical impact. Indeed the utility of multi-gene predictive markers described to date, most likely to be of clinical value in therapy, is limited. An eight-peak MALDI-MS proteomic profile has been developed as a predictive tool (Taguchi, F. et al. 2007). Long suspected, the contribution of tumour heterogeneity to an analysis of tumour omics is now proven to be potentially problematic (Bedard, P. et al. 2013). The study of circulating genomic (eg circulating free DNA, cfDNA) and proteomic tumour markers provides an opportunity for integration of this heterogeneity. Nevertheless, further questions remain. For example, do primary and metastatic sites release similar amounts of DNA and protein into the circulation? However, potential advantages of these liquid biopsies are obvious, as they can be repeated over time without risk or inconvenience to the patient. Still to be fully clarified is the clinical utility of this approach. Possible applications include early discontinuation of toxic failing therapy, evaluation of an emerging resistance mechanism and selection of next therapy, and prognostication (for example, selection for adjuvant therapy). Earlier liquid biopsy methods required initial analysis of potential biomarkers in a tumour, to identify what to look for, followed by detection of this marker in blood samples. This approach requires personalisation for each patient. Newer techniques allow direct analysis, for example next generation sequencing of cfDNA. It is also possible to study the methylation status of cfDNA, so these liquid biopsies may in addition be relevant to the study of tumour epigenomics. cfDNA may be superior to circulating tumour cells (CTCs) as a biomarker since in some patients cfDNA but not CTC is detectable (Bettegowda, C. et al. 2014) The most prominent recent therapeutic advance in lung cancer is the validation of immunotherapy in the context of checkpoint inhibition. While this approach appears to target the tumour only indirectly, via host immunity, there is already good evidence that the genomic context of the target tumour is critically significant (Gubin, M. et al. 2015) The optimum strategy for selection of patients for clinical omic testing remains to be finalised. Should this be for all patients, from the time of diagnosis, or only after completion of standard care? And what material is ideal for testing (archival or contemporaneous biopsy, for example)? Guidelines on what, when and how to test are available (Lindeman, N. et al. 2013), but this advice quickly becomes out of date given the pace of change in the field. Further practical concerns include access to technology, turnaround time for testing, interpretation of molecular pathology results and bioinformatics, and clinical relevance. Fundamental questions arise about which changes are actionable, and the importance of any findings in the germline sequence (incidental or deleterious). Finally, quality control and regulation of omic technologies is demanding and not necessarily well served by existing approaches and infrastructure (Evans, B. et al. 2015), and these aspects must be developed alongside the emergence of these novel technologies. Progress in development of these techniques has been rapid, but maximum utility to patients is still to be developed. Omics have made major contributions to the understanding of lung cancer biology, and to the identification of a growing spectrum of therapeutic targets, but more work remains to be done. References Bedard, P et al. (2013). Tumour heterogeneity in the clinic. Nature 501; 355-364 Belinsky S, et al. (2015). Gene promoter methylation in plasma and sputum increases with lung cancer risk. Clin Cancer Res 11; 6505-11 Bettegowda, C et al. (2014). Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6, 224ra24 Evans, B et al. (2015). The FDA and genomic tests - getting regulation right. New Engl J Med 372; 2258-2264 Gubin, M et al. (2015). PD-1 blockade in tumors with mismatch-repair deficiency. New Engl J Med 372; 2509-2520 Lindeman, N et al. (2013). Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. J Thoracic Oncol 8; 823-59 Pastor, M et al. (2013). Proteomic biomarkers in lung cancer. Clin Transl Oncol 15; 671-682 Taguchi F et al. (2007). Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst 99; 838-46 The Cancer Genome Atlas Research Network (2014). Comprehensive molecular profiling of lung adenocarcinoma. Nature 511; 543-550
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ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, S. Lee
- Coordinates: 9/07/2015, 10:45 - 12:15, 401-404
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ORAL01.07 - Discussant for ORAL01.05, ORAL01.06 (ID 3290)
10:45 - 12:15 | Author(s): J. Spicer
- Abstract
- Presentation
Abstract not provided
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