Squamous Cell Lung Cancer Patients Research Articles

Cost-effectiveness of additional serplulimab to chemotherapy in metastatic squamous non-small cell lung cancer patients.

To estimate the cost-effectiveness of adding serplulimab to chemotherapy for metastatic squamous non-small cell lung cancer (NSCLC) patients in a first-line setting from a Chinese perspective. A three-health state partitioned survival model was constructed to simulate disease development. The clinical data used in the model were derived from the ASTRUM-004 clinical trial. Only direct medical costs were included, and the utilities were derived from published literature. The quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were employed to evaluate health outcomes. Additionally, a sensitivity analysis was performed to verify the robustness of the results. Compared with chemotherapy alone, the addition of serplulimab resulted in an increase of 0.63 QALYs with an incremental cost of $5,372.73, leading to an ICER of $8,528.14 per QALY. This ICER was significantly lower than 3 times China's per capita GDP. The one-way sensitivity analysis suggested that the utility of PFS was the most sensitive factor on ICERs, followed by the price of serplulimab. The combination of serplulimab and chemotherapy has been shown to be a cost-effective initial treatment option for patients with metastatic squamous NSCLC with the commonly accepted willingness-to-pay threshold of 3 times the GDP per capita per QALY in China.

Transcriptomic Profiling for Prognostic Biomarkers in Early-Stage Squamous Cell Lung Cancer (SqCLC).

Squamous cell lung carcinoma (SqCLC) is associated with high mortality and limited treatment options. Identification of therapeutic targets and prognostic biomarkers is still lacking. This research aims to analyze the transcriptomic profile of SqCLC samples and identify the key genes associated with tumorigenesis, overall survival (OS), and a profile of the tumor-infiltrating immune cells. Differential gene expression analysis, pathway enrichment analysis, and Gene Ontology analysis on RNA-seq data obtained from FFPE tumor samples (N = 23) and healthy tissues (N = 3) were performed (experimental cohort). Validation of the results was conducted on publicly available gene expression data using TCGA LUSC (N = 225) and GTEx healthy donors' cohorts (N = 288). We identified 1133 upregulated and 644 downregulated genes, common for both cohorts. The most prominent upregulated genes were involved in cell cycle and proliferation regulation pathways (MAGEA9B, MAGED4, KRT, MMT11/13), while downregulated genes predominately belonged to immune-related pathways (DEFA1B, DEFA1, DEFA3). Results of the survival analysis, conducted on the validation cohort and commonly deregulated genes, indicated that overexpression of HOXC4 (p < 0.001), LLGL1 (p = 0.0015), and SLC4A3 (p = 0.0034) is associated with worse OS in early-stage SqCLC patients. In contrast, overexpression of GSTZ1 (p = 0.0029) and LILRA5 (p = 0.0086) was protective, i.e., associated with better OS. By applying a single-sample gene-set enrichment analysis (ssGSEA), we identified four distinct immune subtypes. Immune cell distribution suggests that the memory T cells (central and effector) and follicular helper T cells could serve as important stratification parameters.

Expression of AHR-regulated and PD-L1-regulated microRNAs in squamous cell lung cancer

Introduction. Despite modern advances in research into the risk of development, immunological control and treatment options for lung cancer (LC), it is the leading cause of death from cancer. Tobacco smoking remains the predominant risk factor for the development of lung cancer, especially one of its aggressive subtypes, squamous cell lung cancer (SCLC). Benzo[a]pyrene, a component of cigarette smoke, promotes the activation of the aryl-hydrocarbon receptor (AhR). AhR regulates the expression of many oncogenes, including PD-L1, the positive status of which is an indication for immunotherapy, one of the main treatment strategies for SCLC. However, to improve the effectiveness of treatment of SCLC, further search for new diagnostic, prognostic and therapeutic markers is necessary. MicroRNAs (miRs), which are highly stable and present in biological fluids, can act as such markers.Objective. Search for microRNAs that could potentially serve as diagnostic markers or therapeutic targets for SCLC. For this purpose, microRNAs were selected whose promoter regions contain AhR binding sites or whose target is PD-L1.Materials and methods. A biocollection of tumor and conditionally normal lung tissue samples (n = 40) was collected at the thoracic department of the Novosibirsk Clinical Oncology Dispensary. The relative levels of selected miRNAs were examined using real-time reverse transcription-PCR (RT-PCR) technique.Results. The levels of miR-342 and miR-181a in SCLC tissues were reduced by 3 times relative to conditionally normal tissue. The expression of miR-181a and miR-155 is associated with tumor size (lower levels in tumors larger than 3 cm) and the presence of metastases in the lymph nodes (3- and 2-fold lower levels in cases with metastases). The level of miR-146a decreased by 3 times in patients with metastatic lesions of lymph nodes. A significant relationship between the levels of miR-93, miR-181a and miR-155 and the expression status of PD-L1 was also found.Conclusions. The expression profile of miR-146a, miR-93, miR-181a and miR-155 differs in SCLC patients depending on PD-L1 status and the presence or absence of lymph node metastases.

Influence of Tumor Cavitation on Assessing the Clinical Benefit of Anti-PD1 or PD-L1 Inhibitors in Advanced Lung Squamous Cell Carcinoma

PurposeA considerable portion of lung squamous cell cancer (LUSC) displays radiographic signs of cavitation. The cavitation of lesions is not accounted for in the prevailing Evaluation Criteria of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or iRECIST in lung cancer. We hypothesized that cavitation might alter response assessment in these patients. Patients and MethodsWe performed a retrospective radiologic review of 785 patients with stage IV LUSC treated with PD-1/PD-L1 antibody combined with platinum-based doublet chemotherapy. 131 patients exhibited cavitation lesions pre- or after-treatment. Response was assessed by RECIST v1.1 and a modified Evaluation Criteria in Solid Tumors (mRECIST) guidelines in which the longest diameter of any cavity was subtracted from the overall longest diameter of that lesion to measure target lesions. The response rate and PFS and OS between mRECIST and RECIST v1.1 were compared. Survival curves of different response categories in each criterion were prepared using the method of Kaplan-Meier and log-rank tests. Weighted κ statistics were used to assess interobserver reproducibilities and to compare response rates. The chi-square test confirmed the relationship between PD-L1 expression and post-treatment cavitation. ResultsNotable cavitation of pulmonary lesions was seen in 16.7% of 785 patients treated with immunotherapy combined with platinum-based chemotherapy. Using the mRECIST for response assessment resulted in a higher response rate than RECIST v1.1 (66% vs. 57%). mRECIST might better identify patients with PFS and OS benefits who have cavitation. The chi-square test revealed a marginally significant difference between PD-L1 expression and tumor cavitation. Interobserver reproducibility of mRECIST for tumor cavitation evaluation was acceptable (the weighted k coefficients for mRECIST criteria was 0.821). ConclusionCavitation lesions at baseline and after checkpoint treatment are common in LUSC patients. mRECIST records a significantly higher response rate than RECIST for these LUSC patients. Response assessment might be improved by incorporating cavitation into volume assessment for target lesions. These results may inform further modifications to RECIST V1.1 to better reflect efficacy with immunotherapy.

EP06.06-14 High Circulating Activin a Plasma Level Is Associated with Advanced Tumor Stage and Poor Prognosis in Lung Squamous Cell Cancer Patients

EP06.06-14 High Circulating Activin a Plasma Level Is Associated with Advanced Tumor Stage and Poor Prognosis in Lung Squamous Cell Cancer Patients

DNA methylome analysis reveals potential alterations contributing to the progression of bronchial hyperplasia.

Squamous cell lung cancer (SCLC) arises from bronchial changes: basal cell hyperplasia (BCH), squamous metaplasia (SM), and dysplasia. However, the premalignant process preceding SCLC is not inevitable; it can stop at any of the bronchial lesions. Previously, we hypothesized that combinations of premalignant lesions observed in the small bronchi of SCLC patients can reflect the different "scenarios" of the premalignant process: BCHi-the stoppage at the stage of hyperplasia and BCHSM-the progression of hyperplasia to metaplasia. In this study, using whole-genome bisulfite sequencing we analyzed the DNA methylome of two forms of BCH: isolated BCH (BCHi) and BCH co-occurred with SM (BCHSM) in the small bronchi of SCLC patients. It was shown that BCHi harbored differentially methylated regions (DMRs) affecting genes associated with regulating phosphatase activity. In BCHSM, DMRs were found in genes involved in PI3K-Akt and AMPK signaling pathways. DMRs were also found to affect specific miRNA genes: miR-34a and miR-3648 in BCHi and miR-924 and miR-100 in BCHSM. Thus, this study demonstrated the significant changes in DNA methylome between the isolated BCH and BCH combined with SM. The identified epigenetic alterations may underlie different "scenarios" of the premalignant process in the bronchial epithelium.

Reality check for precision oncology in squamous cell lung cancer.

e21221 Background: Squamous cell lung cancer (SqCLC) is the second most common type of pulmonary malignancy after lung adenocarcinoma. Therapeutic advances in Precision Oncology have significantly improved outcomes in subsets of patients with lung adenocarcinoma. However, a significantly different mutational landscape has limited the success of Precision Oncology in SqCLC. Still, NCCN guidelines recommend considering molecular testing in SqCLC, preferably with broad-based molecular profiling like next-generation sequencing (NGS), aiming to identify candidates for FDA-approved targeted therapy. We aim to evaluate the percentage of SqCLC potentially eligible for targeted therapy using NGS by analyzing data from The Cancer Genome Atlas (TCGA). Methods: We filtered cases with a SqCLC diagnosis from the TCGA database. These cases were screened for DNA/RNA alterations in the 9 NCCN-guidelines recommended genes, including EGFR/ALK/ROS1/BRAF/MET/RET/HER2/NTRK/KRAS. Each unique alteration in the genes mentioned above was then analyzed in the oncoKB database to predict clinical benefit with level 1 and 2A evidence from FDA-approved targeted therapy. We then calculated the percentage of patients with SqCLC tested with NGS who could assess approved matched targeted therapy. Results: We identified 501 unique cases of SqCLC diagnosis in the TCGA. In the 9 NCCN-recommended actionable genes, 206 alterations were detected. We reviewed the clinical implication and utility of each of these alterations in the OncoKB database, and only 5 alterations were consistent with level 1/2A clinical benefit from a matched targeted therapy. These included 2 cases with L861Q and one each with EGFR L858R, EGFR E746_A750 exon 19 deletion, and G222C missense in the ERBB2 gene. Conclusions: The percentage of squamous cell cases which are potential candidates for FDA-approved targeted therapy was relatively low, 0.1% (5/501). While next-generation sequencing will not affect the standard of care treatment options for most SqCLC patients, clinicians can use this information to counsel patients for enrollment in clinical trials. [Table: see text]

ER predicts poor prognosis in male lung squamous cell cancer of stage IIIA-N2 disease after sequential adjuvant chemoradiotherapy.

The efficacy of postoperative radiotherapy (PORT) is still unclear in non-small cell lung cancer (NSCLC) patients with pIIIA-N2 disease. Estrogen receptor (ER) was proven significantly associated with poor clinical outcome of male lung squamous cell cancer (LUSC) after R0 resection in our previous study. A total of 124 male pIIIA-N2 LUSC patients who completed four cycles of adjuvant chemotherapy and PORT after complete resection were eligible for enrollment in this study from October 2016 to December 2021. ER expression was evaluated using immunohistochemistry assay. The median follow-up was 29.7 months. Among 124 patients, 46 (37.1%) were ER positive (stained tumor cells≥1%), and the rest 78 (62.9%) were ER negative. Eleven clinical factors considered in this study were well balanced between ER+ and ER- groups. ER expression significantly predicted a poor prognosis in disease-free survival (DFS, HR=2.507; 95% CI: 1.629-3.857; log-rank p=1.60×10-5). The 3-year DFS rates were 37.8% with ER- vs. 5.7% with ER+, with median DFS 25.9 vs. 12.6 months, respectively. The significant prognostic advantage in ER- patients was also observed in overall survival (OS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The 3-year OS rates were 59.7% with ER- vs. 48.2% with ER+ (HR, 1.859; 95% CI: 1.132-3.053; log-rank p=0.013), the 3-year LRFS rates were 44.1% vs. 15.3% (HR=2.616; 95% CI: 1.685-4.061; log-rank p=8.80×10-6), and the 3-year DMFS rates were 45.3% vs. 31.8% (HR=1.628; 95% CI: 1.019-2.601; log-rank p=0.039). Cox regression analyses indicated that ER status was the only significant factor for DFS (p=2.940×10-5), OS (p=0.014), LRFS (p=1.825×10-5) and DMFS (p=0.041) among other 11 clinical factors. PORT might be more beneficial for ER negative LUSCs in male, and the examination of ER status might be helpful in identifying patients suitable for PORT.

Abstract 6029: Multi-omic landscape of squamous cell lung cancer

Abstract Patients with squamous cell lung cancer (SCC) have high unmet medical need. Knowledge of these tumors is limited, and a lack of targetable genomic drivers means patients have few treatment options. To provide a detailed analysis on the influence of genomic alterations to proteome-level changes in SCC, we previously integrated DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 SCC patients. A major finding was identification of three proteomic subtypes, two of which made up the majority (87%) of tumors: the “Inflamed” subtype was enriched for B-cell rich tertiary lymphoid structures (TLS), and the “Redox” subtype was enriched for redox pathways and NFE2L2/KEAP1 alterations but had significantly less immune infiltration. We hypothesized these proteomic subtypes would give rise to distinct metabolic signatures. Therefore, we performed untargeted metabolomics on 87 tumors from the same cohort using chromatographic separation on a HILIC column, followed by analysis on a Q Exactive HF mass spectrometer. This analysis yielded 7,344 features corresponding to 7,072 unannotated metabolites and 272 identified metabolites. Glutathione, a key redox metabolite, was anticorrelated with immune score (R = -0.44, padj = 0.004) calculated from our transcriptomic data with the ESTIMATE algorithm, and glutathione was elevated in the Redox proteomic subtype (0.58 log2 ratio, padj = 9.87E-04). Consensus clustering was next used to identify novel metabolomic subtypes of SCC. Surprisingly, none of the five metabolomic subtypes we identified corresponded to proteomic subtype or NFE2L2/KEAP1 alteration (Fisher’s Exact test p-values &amp;gt; 0.05). The fifth subtype had 332 metabolites (26 identified) differentially expressed (&amp;gt; 1.5 fold-change, padj &amp;lt; 0.05) with ascorbate and aldarate metabolism as the top enriched pathway (padj = 3.36E-04). Interestingly, this fifth metabolomic subtype had significantly higher DNp63-alpha (p = 2.40E-05), a primary transcript of delta-N p63 that is known to promote non-small cell lung cancer. Ongoing integrative analyses across omic types will determine how p53, p63, and p73 transcripts influence these metabolomic subtypes, how these transcripts relate to the poor immune infiltration in some SCC tumors, and if these transcripts relate to novel metabolic vulnerabilities in SCC. Citation Format: Paul Stewart, Ashley Lui, Eric Welsh, Dalia Ercan, Vanessa Rubio, Hayley Ackerman, Guohui Li, Bin Fang, Steven Eschrich, John Koomen, Elsa Flores, Eric Haura, Gina DeNicola. Multi-omic landscape of squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6029.

Immune-related histologic phenotype in pretreatment tumour biopsy predicts the efficacy of neoadjuvant anti-PD-1 treatment in squamous lung cancer

BackgroundAlthough neoadjuvant anti-PD-1 immunotherapies have shown good efficacy in non-small cell lung cancer (NSCLC) patients, there is still a lack of effective predictive markers. We aimed to develop a pretreatment histologic scoring system to predict the efficacy of neoadjuvant immunotherapy.MethodsOne hundred forty NSCLC cases were evaluated in this study. Initially, surgical specimens from 31 squamous cell lung cancer patients treated with neoadjuvant anti-PD-1 therapy and their eligible paired pretreatment biopsies were used for pathologic evaluation and developing the pretreatment scoring system, immune-related histologic phenotype assessment criteria (irHPC). Three trained pathologists independently scored the haematoxylin-eosin (HE) slides of the pretreatment tumour biopsies according to irHPC. The follow-up was from 07 March 2018 to 31 December 2021, mainly focusing on disease-free survival (DFS) and overall survival (OS). Second, 109 biopsies of lung squamous cell carcinoma were evaluated to explore the relationship between eosinophils and PD-L1 expression.ResultsSuperior 2-year DFS rates and 2-year OS rates were observed in patients who achieved major pathologic response (MPR) (MPR vs. non-MPR: 92.9% vs. 78.6%; 100.0% vs. 93.3%). Whether necrosis was included in the calculation of the per cent of residual viable tumour (%RVT) or not had almost no effect on the consistency of pathologic assessment and the histological response grouping. The interpathologist variability in assessing %RVT with immune-activated phenotype was not statistically significant (P = 0.480). Four immune-related features of pretreatment biopsies were included for calculating the predictive score. The trained pathologist accurately predicted most cases according to irHPC. For interobserver reproducibility using “2 points” as the cutoff, the overall per cent agreement was 77.8%. The reliability between pathologists for a binary tumour evaluation showed “moderate” agreement (κ = 0.54). Patients with scores ≥ 2 points tended to have better 2-year DFS rates and 2-year OS rates than those with scores < 2 points (85.7% vs. 71.4%; 100.0% vs. 87.5%).ConclusionsThe irHPC scoring system reflecting the preexisting immune response could be used to predict pathologic response to neoadjuvant immunotherapy, possibly further predicting the long-term prognosis, but larger trials are needed for verification.

Determination of EGFR Mutation Prevalence in Advanced and Metastatic Lung Squamous Cell Carcinoma in Vietnam

Abstract: This paper aims to determine the rate of epidermal growth factor receptor (EGFR) gene mutations in advanced and metastatic squamous cell lung cancer in Vietnamese patients. EGFR mutation testing was performed on 559 formalin-fixed paraffin-embedded tissue samples from advanced and metastatic squamous cell lung cancer patients by real-time PCR. The results showed that EGFR mutations were found in 8.4%. Most of them were exon 19 deletions, approximately 51.1%. Multivariate analysis showed that EGFR mutations were more prevalent in gender (p&lt;0.0001). In conclusion, EGFR mutation testing should be performed in patients with squamous cell lung cancer.&#x0D; Keywords: Lung squamous cell carcinoma, EGFR gene. &#x0D; &#x0D;

TLR5 Variants Are Associated with the Risk for COPD and NSCLC Development, Better Overall Survival of the NSCLC Patients and Increased Chemosensitivity in the H1299 Cell Line.

Chronic obstructive pulmonary disease (COPD) is considered as the strongest independent risk factor for lung cancer (LC) development, suggesting an overlapping genetic background in both diseases. A common feature of both diseases is aberrant immunity in respiratory epithelia that is mainly regulated by Toll-like receptors (TLRs), key regulators of innate immunity. The function of the flagellin-sensing TLR5 in airway epithelia and pathophysiology of COPD and LC has remained elusive. We performed case–control genetic association and functional studies on the importance of TLR5 in COPD and LC development, comparing Caucasian COPD/LC patients (n = 974) and healthy donors (n = 1283). Association analysis of three single nucleotide polymorphisms (SNPs) (rs725084, rs2072493_N592S, and rs5744174_F616L) indicated the minor allele of rs2072493_N592S to be associated with increased risk for COPD (OR = 4.41, p < 0.0001) and NSCLC (OR = 5.17, p < 0.0001) development and non-small cell LC risk in the presence of COPD (OR = 1.75, p = 0.0031). The presence of minor alleles (rs5744174 and rs725084) in a co-dominant model was associated with overall survival in squamous cell LC patients. Functional analysis indicated that overexpression of the rs2072493_N592S allele affected the activation of NF-κB and AP-1, which could be attributed to impaired phosphorylation of p38 and ERK. Overexpression of TLR5N592S was associated with increased chemosensitivity in the H1299 cell line. Finally, genome-wide transcriptomic analysis on WI-38 and H1299 cells overexpressing TLR5WT or TLR5N592S, respectively, indicated the existence of different transcription profiles affecting several cellular pathways potentially associated with a dysregulated immune response. Our results suggest that TLR5 could be recognized as a potential biomarker for COPD and LC development with functional relevance.

Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1; however, resistance mechanisms originally existing in patients or acquired during treatment have so far led to limited treatment efficiency in clinical trials. In this study we performed a wide-scale phosphoproteomic mass-spectrometry analysis to explore signaling pathways that lead to resistance toward FGFR1 inhibition in lung cancer cells that display (i) intrinsic, (ii) pharmacologically induced and (iii) mutationally induced resistance. Additionally, we correlated AKT activation to CD44 expression in 175 lung cancer patient samples. We identified a CD44/PAK1/AKT signaling axis as a commonly occurring resistance mechanism to FGFR1 inhibition in lung cancer. Co-inhibition of AKT/FGFR1, CD44/FGFR1 or PAK1/FGFR1 sensitized ‘intrinsically resistant’ and ‘induced-resistant’ lung-cancer cells synergetically to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated with AKT activation in SQCLC patients. Collectively, our phosphoproteomic analysis of lung-cancer cells resistant to FGFR1 inhibitor provides a large data library of resistance-associated phosphorylation patterns and leads to the proposal of a common resistance pathway comprising CD44, PAK1 and AKT activation. Examination of CD44/PAK1/AKT activation could help to predict response to FGFR1 inhibition. Moreover, combination between AKT and FGFR1 inhibitors may pave the way for an effective therapy of patients with treatment-resistant FGFR1-dependent lung cancer.

Abstract 1985: Ipilimumab and nivolumab induced reactivation of hepatitis B (HBVr) in patient with metastatic squamous cell lung cancer

Abstract Background: Unique adverse events caused by immunological perturbation of immune checkpoint inhibitor (ICI) treatment were reported. Recently, it came into light that ICI can increase the risk of HBVr. Immune-mediated adverse events including immune-mediated hepatitis have been widely reported. However, HBVr is an extremely rare adverse event that has been seldom reported. Herein, we report the first case of ipilimumab/nivolumab induced HBVr in metastatic squamous cell lung cancer patient. Case Presentation: 71-year-old Asian gentlemen with stage IIIB poorly differentiated squamous cell carcinoma of the lung (PD-L1 immunohistochemistry 5-10%) was initially treated with 4 cycles of carboplatin/paclitaxel/pembrolizumab and one dose of maintenance pembrolizumab. The treatment was complicated by immune-related adverse events of thyroiditis and adrenal insufficiency and followed by surgical resection of the tumor. Unfortunately, he developed recurrent metastatic disease of the brain which provoked craniotomy and resection followed by multiple courses of radiation therapy. The patient was then started on treatment with ipilimumab/nivolumab maintenance therapy following 2 cycles of carboplatin/paclitaxel/nivolumab/ipilimumab combined therapy (every 3 weeks). Bevacizumab was added for cerebral edema associated with brain metastasis. The patient was initially noted to be positive for hepatitis B Antigen. However, he was asymptomatic and liver function test (LFT) and liver ultrasound were unremarkable. He had been monitored for LFT at every visit. After 5.5 months from starting the treatment (after seven cycles of ipilimumab/nivolumab and six cycles of bevacizumab), transaminitis was noted and treatment was held. He was admitted for abdominal pain with labs demonstrating hepatocellular injury with ALT 1761 units/L, AST 607 units/L, and total bilirubin 3.3 mg/dL. Hepatitis work-up revealed HBVr (positive for HBs Ag, hepatitis B viral load 11,745). Patient was started on tenofovir daily and LFT was normalized after three weeks without synthetic dysfunction or metabolic encephalopathy. Ipilimumab/nivolumab treatment was held for six weeks and reintroduced without any further significant events. Conclusion: It has recently been reported that pembrolizumab had a strong signal associated with HBVr. However, to our knowledge, this is the first case report for HBVr in squamous cell carcinoma of lung patient treated with ipilimumab/nivolumab. ASCO recommends universal screening for hepatitis B for patients anticipating systemic anticancer therapy. As illustrated by our case, it is important to have hepatitis B screening before starting systemic therapy including immunotherapy. Additional larger studies are warranted to validate the role of each type of ICI in HBVr. Citation Format: Leeseul Kim, Horyun Choi, Yeun Ho Lee, Jinah Kim, Young Kwang Chae. Ipilimumab and nivolumab induced reactivation of hepatitis B (HBVr) in patient with metastatic squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1985.

Abstract 3911: Proteomic and transcriptomic subtypes of KRASG12C mutant lung cancer

Abstract Sotorasib (AMG510) is the first KRASG12C covalent inhibitor (KRASG12Ci) approved by the FDA in lung cancers harboring oncogenic KRASG12C mutation. However, it remains unclear why some patients show upfront resistance to the KRASG12Ci, and the mechanisms of adaptive resistance. To enhance the efficacy of the KRASG12Ci, several combination regimens are in clinical trials which includes Sotorasib combination with MEK, PD1, SHP2, pan-HER, PD-L1, and EGFR inhibitors. However, it remains unclear how to precisely identify an appropriate cohort for analysis and predict tumor-centric combination strategies that would be effective in the clinic. We hypothesized that subsets of KRASG12C lung cancer could be identified using transcriptomics and proteomics. To test our hypothesis, we performed hierarchical clustering of the microarray dataset on 87 NSCLC KRASG12C tumors and identified three novel transcriptomic subtypes - Subtype 1 had higher expression of extracellular matrix (ECM) genes, which are related to cellular adhesion, and lower expression of EMT genes. Subtype 2 had low ECM expression, high expression in EMT and cell cycle pathway genes suggesting that this is a more invasive subtype. Subtype 2 had lowest expression of small molecule metabolism, suggesting it may be more responsive to KRASG12Ci. Subtype 3 had the lowest expression in interferon gamma/cytotoxic T-cell, T-cell, and B-cell pathways. Subtype 3 had the highest expression of small molecule metabolism, suggesting that it could be more resistant to KRASG12Ci. Having observed these unique clusters, we next hypothesized that mass spectrometry-based expression and phosphoproteomic analysis (pY and pS/T/Y) will further refine these clusters and help identifying new subsets. Our previous work by Stewart et al., demonstrated the importance of proteomics integrated with genomic and transcriptomic analyses to define molecular subtypes in a cohort of 108 squamous cell lung cancer patients. We believe that a similar integrated proteogenomic study is important in context of KRASG12C tumors to understand the signaling diversity and phenotypically categorized them to optimize patient enrichment schemes for effective combination therapy. For that purpose, we performed an integrative proteogenomic analysis of 75 KRASG12C tumors (55 lung, 12 large bowel adenocarcinomas and 8 PDXs) with full clinical follow up and pathology data. We are presently classifying the 75 KRASG12C tumors into phosphoproteomic subtypes. We also carried out targeted exome sequencing for cancer-specific genes. Next, we plan to leverage existing gene expression microarray data and add exome sequencing proteomics, and phosphoproteomics for a comprehensive, protein-centric characterization on these tumors. Importantly, the inclusion of 8 PDXs being co-processed and co-analyzed along with the tumors will enable rapid follow-up experiments to validate the findings into preclinical therapy trials. Citation Format: Hitendra Singh Solanki, Paul A. Stewart, Eric A. Welsh, Victoria Izumi, Bin Fang, Sean J. Yoder, John M. Koomen, Eric B. Haura. Proteomic and transcriptomic subtypes of KRASG12C mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3911.

Survival analysis of patients with non-small cell lung cancer in Novosibirsk region from 2015 to 2019

Rationale: Lung cancer is the leader in high mortality rates among other malignancies. This is largely due to the asymptomatic course of the disease and, as a consequence, to its late diagnosis. To optimize the oncology service of the Novosibirsk region in terms of diagnosis, treatment, follow-up and management of this patient category, it seems prudent to study the epidemiological characteristics of non-small cell lung cancer (NSCLC) with consideration of its histologic types.&#x0D; Aim: To perform the survival analysis in patients with squamous cell lung cancer (SCLC) and adenocarcinoma of the lung (ACL) depending on their age, sex and disease stage.&#x0D; Materials and methods: We analyzed medical files of patients diagnosed with SCLC (n = 3007) and ACL (n = 3049) who were treated in the Novosibirsk Regional Oncologic Dispensary from 2015 to 2019. The study included 4758 men and 1298 women (mean age, 68 years; men 66.8 years, women 69.1 years).&#x0D; Results: The majority (96%) of the NSCLC patients were above 50 years of age. The 5-year survival rate of the patients with SCLC and ACL was below 20%. Median survival of the SCLC patients was 443 days (interquartile range [IQR] 138; 1241), of those with ACL, 552 (IQR 107; 1511) days. At the diagnosis of NSCLC, 67% of the patients had stage III/IV of the disease. Maximal survival (10 to 15 years) was found in the NSCLC patients aged 61 years who had been diagnosed at stage III of the disease. Testing of the hypothesis on the impact of histological type of NSCLC on survival at a particular disease stage (Wilcoxon-Gehan test for unpaired samples) showed an association between the survival and histological type only for stage IV (p = 0.000001); median survival in ACL IV was 80 days and in SCLC IV, 104 days.&#x0D; Men comprised 87% of the SCLC group and 73% of the ACL one. In SCLC, there was no gender difference in the median survival rates (log rank test, p = 0.48). The median survival of the female patients with ACL was longer than that of the male ones (329 vs 169 days, log rank test, p = 0.000001).&#x0D; The major proportion of the SCLC and ACL patients was in the age range of 61 to 75 years (59% and 50%, respectively). The least favorable outcomes were seen in the patients below 50 years of age, and the most favorable, in those above 75 years. In SCLC, the median survival was 156 days in the patients below 50 years of age, 238.5 days in those aged from 51 to 60 years, 300 days in the age of 61 to 75 years, and 487 days in the patients above 75 years of age (chi-square test 98.77097; df = 3; p = 0.000001). In ACL, the respective values were 143, 201, 210.5, and 230 days (chi-square test 23.93492; df = 3; p = 0.00003).&#x0D; Conclusion: The analysis of survival of the patients with SCLC and ACL in the Novosibirsk region has shown that the disease stage and age significantly impact the median survival. These are the characteristic features of the general morbidity and mortality from NSCLC.

A Case of Iodine 125 Seeds (I-125) Responding to Lung Squamous Cell Carcinoma.

Lung squamous cell cancer (SCC) and accounts for approximately 20%–30% of all lung cancers. Surgery, chemotherapy and radiotherapy are the main treatments for lung SCC patients. A case with lung SCC patient who was treated using iodine 125 seeds (I-125) because the location of the tumor was adjacent to the great vessels. I-125 is an ideal brachytherapy for lung SCC patients with large masses who lost the chance of operation. I-125 is an adjuvant therapy, combined with chemotherapy and molecular targeting therapy might serve to improve the prognosis of lung SCC patients.

Pembrolizumab-Induced Steven-Johnson Syndrome in an NSCLC Patient: A Case Report

Background: Immune checkpoints inhibitors (ICIs) are widely used in various therapy of tumors. With the increasing usage of them, immune-related adverse events (irAEs) have been known and become common events, especially in the dermatologic system. However, the rare and severe immune-related cutaneous adverse events (irCAEs) still lack enough knowledge. Case presentation: We described a rare case of Steven-Johnson syndrome (SJS) induced by pembrolizumab in an advanced squamous non-small cell lung cancer (NSCLC) patient. SJS is a rare irCAE that could happen at any time after immunotherapy while this case happened from the 3rd day. The patient had influence-like symptoms and several mucous lesions including oral, eye, and skin. With a gradually severer condition, a stoss therapy of intravenous immunoglobulin (IVIG) had a mild effect. It was a long process and failed to respond to usual dermatologic treatment. Conclusion: We share this case in order to enhance clinicians’ ability to early recognition and diagnosis in severe irCAEs. Early recognition and appropriate management are important to evade the termination of immunotherapy. Such severe irCAE should be paid more attention to in clinical medicine when using ICIs.

A Case Report of Korean Medicine Treatment of a Lung Cancer Patient with Chemotherapy-induced Peripheral Neuropathy

The purpose of this study is to report the effect of Korean medicine on a squamous cell lung cancer patient with chemotherapy induction peripheral neuropathy (CIPN). A 61-year old male patient, who had received 4 cycles of chemotherapy after lung surgery from squamous cell lung cancer, was treated with acupuncture and herbal medicines, including Uchasingi-hwan and Samchilchoongcho-capsule, to control CIPN and dyspnea on exertion. The degree of pain was assessed by a numeric rating scale (NRS). After receiving acupuncture and herbal medicines, the NRS score for CIPN symptoms was reduced from 4 to 1 and the NRS score for dyspnea on exertion decreased from 3 to less than 1. Korean medicine could therefore be useful in reducing peripheral neuropathy occurring after chemotherapy and dyspnea after lobectomy.

Relationship between Kita-Kyushu Lung Cancer antigen-1 expression and prognosis of cases with lung squamous cell carcinoma.

BackgroundPreviously, we identified the highly immunogenic cancer testicular antigen named Kita-Kyushu Lung Cancer antigen-1 (KK-LC-1). In this study, we analyzed the effect of KK-LC-1 expression on the prognosis of patients with resected squamous cell lung cancer.MethodsFifty squamous cell lung cancer patients, who received complete resection, were enrolled in this study. The expressions of KK-LC-1, CD8, human leukocyte antigen (HLA) class I, and programmed cell death protein ligand-1 (PD-L1) were assessed via immunohistochemistry staining using the specimens obtained from the participants. The association between the expression of the abovementioned molecules and patient prognosis was investigated.ResultsKK-LC-1 expression was observed in 21 of 50 recruited cases (42%). However, no significant correlation was found between KK-LC-1 expression and patient prognosis. The prognosis was significantly better in lung cancer cases with KK-LC-1 expression in which CD8+ T cells infiltrated the tumor. Regardless of the HLA class I expression or the PD-L1 expression, the KK-LC-1 expression in squamous cell lung cancer could not be detected as a significant prognostic factor. Furthermore, considering the polarity of the cancer tissue as epithelium, staining of KK-LC-1 tended to be strong in the area corresponding to the basal side of the tumor tissue. The Ki-67 expression was frequently observed in cancer cells on the basal side, which was consistent with the KK-LC-1 expression in representative four cases with KK-LC-1-positive squamous cell lung cancer.ConclusionsOur results indicated that lung squamous cell cancer patients with KK-LC-1 expression and the tumor infiltrating CD8+ T cells might exhibit better prognosis. KK-LC-1 might be highly expressed in cancer cells with high proliferative capacity. Larger cohort analysis is still required for further elucidation and validation of the results of this study.