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Circulating Tumor DNA in Checkpoint Inhibitor treated Lung Cancer

ABSTRACT: BackgroundImmune checkpoint inhibitors (ICI) are increasingly used to treat non-small cell lung cancer (NSCLC) and there is a critical need for novel predictive/prognostic biomarkers. We evaluated whether dynamics of circulating tumor (ctDNA) can identify NSCLC patients who benefit from single agent ICI.MethodsCirculating cell-free DNA (cfDNA) from 177 patients was analyzed prior ICI and at first treatment evaluation using a Commercial 77-gene panel. We performed de novo mutation calling and corrected for variants related clonal hematopoiesis. ctDNA changes were evaluated as predictors of tumor response estimated with PET/diagnostic CT and survival.ResultsMutations were detected in 159 of 174 (91.4%) analyzable patients. Most responders presented decreasing ctDNA levels, while non-responders had mixed molecular responses. Patients with a >50% molecular ctDNA decrease or no detectable ctDNA demonstrated improved PFS (5.9 versus 1.8 months; HR 0.49, 95%CI, 0.35-0.67, P < .001), and OS (18.9 versus 9.9 months; HR 0.41, 95%CI, 0.30-0.57, P < .001) compared to patients not achieving these endpoints. Clearance of mutations (and no detected ctDNA) had a similar effect (PFS HR 0.45, 95%CI, 0.32-0.61, P < .001; OS 0.37,95%CI, 0.27-0.52, P < .001) compared to patients having stable or additional mutations. After adjusting for clinical factors both >50% ctDNA decrease (HR 0.4, 95% CI, 0.3-0.6, P < .001) and clearance of mutations (HR 0.42, 95% CI, 0.3-0.6, P < .001) remained independent predictors for PFS and OS.ConclusionsctDNA testing reveals significant prognostic albeit not predictive information in ICI treated advanced NSCLC. This relevant information can be obtained with a commercial easy-to-implement ctDNA test that will facilitate extensive testing.

PROVIDER: EGAS00001004847 | EGA |

REPOSITORIES: EGA

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Project description:Introduction: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented. Methods: The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n=71) or no adjuvant treatment (OBS, n=62) [GSE14814] and 2) formalin-fixed paraffin-embedded (FFPE) pre-treatment tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine. Results: The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p=0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p=0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR=0.138 (95% CI:0.035-0.537), p=0.004) and multivariate analysis (HR=0.14 (95% CI:0.030-0.6), p=0.0081). No discrimination was found in the OBS cohort (HR=1.328, p=0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p=0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p=0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis. Conclusions: Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.

Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.485, 95% CI 0.265 to 0.889, p = 0.019; OS: HR 0.314, 95% CI 0.155 to 0.637, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.

Project description:Background: Accurate survival stratification in early-stage NSCLC could inform the use of adjuvant therapy. We developed a clinically-implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables. Methods: Gene expression profiles from 1106 non-squamous NSCLCs were used for generation and internal validation of a 9-gene molecular prognostic index (MPI). Expression of the MPI genes was determined within sorted tumor cell subpopulations. A quantitative PCR (qPCR) assay was developed and validated on an independent cohort of FFPE tissues. A prognostic score using clinical variables was generated using Surveillance Epidemiology and End Results (SEER) data and combined with the MPI. Results: The MPI stratified stage I patients into prognostic categories in four independent validation datasets, including three microarray and one FFPE qPCR cohorts (HR=2.4, 95% CI, 1.8-3.3, P=7x10-9 in the largest microarray cohort; and HR=2.5, 95% CI 1.1-6.0, P=.03 in stage I patients of the qPCR validation cohort). Prognostic genes were expressed in distinct tumor cell subpopulations and expression of genes implicated in cellular proliferation and stem cells portended poor outcomes, while expression of genes involved in normal lung differentiation and immune infiltration was associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR=3.3, 95% CI 2.4-4.6; P=2x10-15 in the largest microarray cohort; and HR=3.6, 95% CI 1.5-8.8, P=.003 in stage I patients of the qPCR validation cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK. Conclusion: The MPI incorporates genes expressed in the tumor and its microenvironment, and designates risk of death for patients with early-stage non-squamous NSCLC. The MPI can be implemented clinically using qPCR assays on FFPE tissues and a composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

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Circulating Tumor DNA in Checkpoint Inhibitor treated Lung Cancer

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