Background With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune‐related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI). Materials and Methods This is a large, single‐site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non‐small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated. Results Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression‐free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months; p = .294), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months; p = .009). Progression‐free survival times were similarly affected. Conclusion This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics. Implications for Practice Antibiotic use is negatively associated with treatment outcomes of immune checkpoint inhibitors (ICI) in advanced cancer. Cumulative antibiotic use is associated with a marked negative survival outcome. Judicious antibiotic prescribing is warranted in patients receiving treatment with ICI for treatment of advanced malignancy.
For most patients with salivary gland cancer, there are no effective standard systemic therapies. Although clinical trials of biomarker-led drug therapies have delivered significant recent advances, there remains a need to understand the clinical utility of genomic profiling of cancer as a means to match patients with recurrent or metastatic salivary gland cancer to clinical trial therapies. In total, 209 patients with salivary gland cancers were profiled with 24 gene (n = 209)) and >325 gene (n = 32) DNA-based next-generation sequencing panels. A retrospective systematic evaluation was performed to identify the frequency of available matched drug therapies within clinical trials based on the results. The matches were then stratified based upon the level of evidence supporting the drug–biomarker combination being investigated using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) to determine the strength of the clinical rationale for each gene–drug match identified. DNA-based next generation sequencing (NGS) analysis was successful in 175/209 (84%) patients with salivary gland cancer. Using the 24-gene NGS panel, actionable alterations were identified in 27% (48/175) patients. Alterations were most frequent in salivary duct carcinoma (88%) characterized by TP53 and/or PIK3CA mutations, with matched trials available for 63% (10/16). In ACC, biomarker-matched trials were available for 7% (8/115), and no genomic alterations were found in 96/115 (83%) of ACC patients. TP53 was the most frequently altered gene across all subtypes; however, there were no trials recruiting based on TP53 status. In 32 ACC patients with no genomic alterations using the 24-gene panel, a broader (>325 gene) panel identified alterations in 87% (27/32) of cases with biomarker-matched trials available in 40% (13/32) cases. This study identified that genomic profiling using focused (24-gene) NGS panels has potential utility in matching to trial therapies for most patients with non-ACC salivary gland cancer. For patients with ACC, broader genomic profiling has demonstrated added clinical utility. We describe the application of an approach to classification of levels of evidence which may be helpful to inform the clinician and patient decision making around the selection of clinical trial therapies.
6086 Background: For most patients with recurrent or metastatic salivary gland cancer (RM-SGC), there are no standard therapies. Many patients undergo genomic profiling to guide selection of targeted therapy. The MSK-IMPACT study applied a 468 gene next generation sequencing (NGS) panel, identifying actionable mutations in 34/114 patients (30%) with RM-SGC. Minimising cost will facilitate application within publically funded healthcare systems. We therefore sought to determine the utility of genomic profiling using a focused 24 gene targeted NGS panel to identify actionable mutations in RM-SGC with a sub-group analysis in adenoid cystic carcinoma (ACC) and non-ACC sub-types. Methods: From January 2017 to 2018, 125 patients with RM-SGC provided informed consent to an ethically approved study. Clinical and demographic characteristics were collected. DNA was extracted from FFPE samples and analysed using Qiagen GeneRead DNAseq Targeted Panel V2 in the Manchester Centre for Genomic Medicine Diagnostic Laboratory, an NHS clinically accredited lab. A custom bioinformatic pipeline was validated to detect single nucleotide variants and indels ( < 40bp) to 5% mutant allele frequency. Alterations were categorised following American College of Medical Genetics guidelines and Association for Molecular Pathology tiering. Results: DNA from 101 tumours (69 major, 32 minor salivary gland) was sequenced with 95% coverage at > 350x read depth over the target enrichment. 65 patients had adenoid cystic carcinoma (ACC) and 36 had non-ACC SGC. Median age was 55 years (range 18-80). 43 actionable alterations were identified in 33 patients within the following genes: TP53 (21%), PIK3CA (8%), ERBB2 (6%), PTEN (3%), BRAF (2%), EGFR (T790M) (1%), and AKT1 (1%). Targeted therapy was selected based on genomic findings in 12% of these patients. In ACC patients, actionable alterations were seen in 25% compared with 55% of non-ACC patients (9 adenocarcinoma, 5 salivary duct carcinoma, 3 carcinoma ex pleomorphic adenoma, 2 mucoepidermoid carcinoma and 1 myoepithelial carcinoma). Conclusions: This study identified actionable alterations in 33% of SGC patients using focused genomic profiling, demonstrating comparable utility to larger research panels. This focussed panel is being expanded to include emerging biomarkers such as NOTCH gene mutations, with NOTCH inhibitors currently in trials in ACC. Greater access to basket studies incorporating therapies matched to genomic alterations will maximise the clinical utility of this approach.
6072 Background: ACC is a rare salivary cancer for which effective drug therapies remain lacking. The highest rates of disease recurrence are in patients with NOTCH pathway activation, which is reported in 10-20% of ACC tumors. Novel drugs targeting NOTCH signaling are under investigation in the recurrent and metastatic setting. To understand their clinical utility, there is an urgent need to better characterize the disease course and outcomes following current standard of care treatment from diagnosis and following recurrence. Methods: 120 patients with ACC underwent clinical review at a single UK Cancer Centre from 2017-19. Patients were retrospectively assessed for tumor NOTCH pathway activation using next generation sequencing (NGS) targeting NOTCH1/2/3 genes (n = 98) and/or by immunohistochemistry (IHC) for the NOTCH1 intra-cellular domain (NICD1) (n = 87). To understand the disease course with NOTCH pathway activation, treatment data including surgery, radiotherapy and systemic therapies were extracted and presented as swimmer plots. Kaplan-Meier survival analysis was performed and a difference in survival with/without NOTCH activation was calculated with log rank test. Overall survival (OS) was calculated both from diagnosis and from first confirmed disease recurrence or metastasis, and recurrence free survival (RFS) calculated from diagnosis. Results: Of 120 patients, median age was 46 years (22-74 years). 114/120 patients (95%) had confirmed disease recurrence at clinical review. The primary site was major salivary gland in 58/120 (48%), the others were minor salivary. NOTCH1/3 activating somatic mutations were identified in 11% by NGS (11/98) and NICD1 diffuse nuclear staining was seen in 6% by IHC (5/87) for overall NOTCH activation in 11% (13/120). In NOTCH activated ACC, primary site was major salivary gland in 7/13 (54%), and non-pulmonary visceral/bone metastases were present in 6/13 (46%). Consistent with other reports, patients with NOTCH activation (n = 13) had shorter RFS (0.9 vs 3.6 years, p = 0.11) and significantly reduced OS from diagnosis (4.0 vs 16.3 years, p < 0.0001). Critically, as therapies targeting NOTCH signaling are being evaluated in recurrent/metastatic ACC, there was significantly reduced OS from time of first confirmed disease recurrence or metastasis (1.5 vs 9.6 years, p < 0.0001). This reduction in OS for NOTCH activation following recurrence was seen consistently whether patients were classified using NGS (1.9 vs 9.6 years, p = 0.0009) or NICD1 IHC (0.8 vs 8.5 years, p < 0.0001). Conclusions: This is the first study to report clinical outcomes for patients with NOTCH pathway activated ACC following disease recurrence. Although ACC is frequently considered an indolent disease, the short survival in this sub-group of ACC patients demonstrates the urgent need to develop effective drug therapies in this setting.
FLYWCH1 differentially expressed between normal as well as between different stages of colorectal cancers. However, we have just started exploring the biological functions and mechanisms of FLYWCH1 in colon/ intestinal development, homeostasis and tumor formation. Methods: Loss-and gain-of-function analysis, CRISPR-Cas9, RNA-Seq, Western blotting, Immunoprecipitation, qRT-PCR, and immunofluorescence techniques. Results: Endogenous b-catenin physically interacts with the C-terminal domain of FLYWCH1 protein in human CRC cell lines. FLYWCH1 overexpression negatively regulates the expression of some but not all bb-catenin/TCF4 target genes in CRC cell lines. R-spondin1 synergizes with Wnt-3A in repressing of FLYWCH1 in CRC cell lines. Conclusions: a) FLYWCH1 protein binds to the endogenous bb-catenin protein while negatively regulates the transcription of a specific-subset of bb-catenin /TCF target genes, regardless of Wnt signaling status. b) Activation of Wnt signaling forms a negative feedback loop during FLYWCH1 repressed b-catenin/TCF4 target gene in carcinogenesis. c) Our current and future studies with focuses on the in vivo role(s) of FLYWCH1 will provide insights on a novel molecular mechanism mediated by FLYWCH1 and the canonical Wnt/bb-catenin pathway in CRC carcinogens, where may offer a new potential approach(s) and implications for future therapeutics.Legal entity responsible for the study: University of Nottingham. Funding: Saudi Government. Disclosure: The author has declared no conflicts of interest.66P Adapting a prescreening program to match molecular alterations in over 5,000 patients' tumors with targeted agents and immunotherapies in early clinical trials over the last 8 years
e18016 Background: Immune checkpoint blockade of the programmed death-1 receptor (PD1) with nivolumab improves survival for patients with platinum resistant recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, response rates are only 15-20% and the majority of patients do not have prolonged clinical benefit. Established predictive biomarkers such as PDL1 are not reliable in this context and there remain no reliable predictors of response to nivolumab in R/M HNSCC. We therefore sought to evaluate a panel of clinical, haematology and biochemistry parameters to develop a nomogram to predict the duration of clinical benefit following treatment with nivolumab. Methods: Ninety-one patients treated with nivolumab for R/M HNSCC were included. Nivolumab was administered as standard of care management and tumour response was evaluated every 8-12 weeks using CT or MRI. The electronic clinical records were reviewed and all clinical and demographic data were extracted in addition to baseline haematology and clinical biochemistry values. Using Cox proportional hazard analysis these variables were used to create a predictive model for duration of clinical benefit. Patients were dichotomised based upon duration on nivolumab treatment. Backwards elimination with a p-value threshold of 0.05 was used to create a predictive nomogram. For the final model, patients were assigned to two groups (< 3 months and ≥ 3 months on therapy) calculated from the date of first nivolumab dose to the date of discontinuation. Progression free survival (PFS) and overall survival (OS) were calculated from the date of the first dose of nivolumab. Results: Of the 91 patients, 82 had stopped treatment at the time of analysis with a median time on treatment of 2.5 months (95% CI 1.8 to 3.6). Median PFS was 3 months with 1-year PFS rate of 15%. Median OS was 9 months with 1 year OS rate of 40%. Multivariable analysis identified multiple pre-treatment factors that correlate with time on treatment; age (HR 0.97; 95% CI 0.93-1.00, p = 0.029), oropharyngeal tumour location (HR 0.51; 95% CI 0.31-0.85, p = 0.01), N stage (HR 1.84; 95% CI 0.97-3.5, p = 0.061), M stage (HR 2.44; 95% CI 1.27-4.7, p = 0.007), and pre-treatment peripheral blood markers which included monocyte count (HR 2.83; 95% CI 1.05-7.6, p = 0.04), sodium (HR 0.94; 95% CI 0.88-1.00, p = 0.057) and calcium (HR 7.6; 95% CI 1.46-39.7, p = 0.016) levels. These were included in the final nomogram which had a concordance index of 0.69. Conclusions: We have developed a novel nomogram to predict the duration of clinical benefit from nivolumab in platinum resistant R/M HNSCC for subsequent independent validation. This may assist clinicians in counselling patients and clinical decision making and could also be used to identifying poor responders for whom alternative treatment options are required.
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