Squamous Cell Lung Cancer Research Articles

Prognostic significance of CT-determined sarcopenia in older patients with advanced squamous cell lung cancer treated with programmed death-1 inhibitors

Sarcopenia has been associated with higher toxicity induced by anti-cancer treatments and shorter survival in patients with squamous cell lung carcinoma (SqCLC). Over the past few decades, immune checkpoint inhibitors (ICIs) significantly improves the prognosis. However, few clinical studies explored the effectiveness of immunotherapy in the elderly population. Here, we performed a retrospective analysis to determine the prognostic role of sarcopenia in older patients with SqCLC receiving ICIs. We retrospectively assessed SqCLC patients who were treated with PD-1 inhibitors and all patients were at least 70 years old. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index (SMI) with chest CT. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using the Kaplan–Meier method, and the differences in survival were compared using the log-rank test. Among 130 male SqCLC patients, 93 had sarcopenia. Patients with sarcopenia were older and had a lower body mass index (BMI). Over an average follow-up of 20.8 months, 92 patients died. For all 130 patients, the mean OS was 13.3 months. Patients with sarcopenia had a significantly shorter OS and PFS than those without sarcopenia (OS, 12.4 ± 5.2 months vs. 15.5 ± 10.5 months, P = 0.028; PFS, 6.4 ± 2.9 months vs. 7.7 ± 4.2 months; P = 0.035). Multivariable analysis showed that sarcopenia was an independent prognostic factor for shorter OS and PFS. CT-determined sarcopenia is an independent prognostic factor for older patients with SqCLC receiving ICIs.

Different types of tumor microvessels in stage I-IIIA squamous cell lung cancer and their clinical significance.

Lung cancer (LC) is the leading cause of morbidity and mortality among malignant neoplasms. Improving the diagnosis and treatment of LC remains an urgent task of modern oncology. Previously, we established that in gastric, breast and cervical cancer, tumor microvessels (MVs) differ in morphology and have different prognostic significance. The connection between different types of tumor MVs and the progression of LC is not well understood. To evaluate the morphological features and clinical significance of tumor MVs in lung squamous cell carcinoma (LUSC). A single-center retrospective cohort study examined medical records and archival paraffin blocks of 62 and 180 patients with stage I-IIIA LUSC in the training and main cohorts, respectively. All patients underwent radical surgery (R0) at the Orenburg Regional Cancer Clinic from May/20/2009 to December/14/2021. Tumor sections were routinely processed, and routine Mayer's hematoxylin and eosin staining and immunohistochemical staining for cluster of differentiation 34 (CD34), podoplanin, Snail and hypoxia-inducible factor-1 alpha were performed. The morphological features of different types of tumor MVs, tumor parenchyma and stroma were studied according to clinicopathological characteristics and LUSC prognosis. Statistical analysis was performed using Statistica 10.0 software. Univariate and multivariate logistic regression analyses were performed to identify potential risk factors for LUSC metastasis to regional lymph nodes (RLNs) and disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with and without metastases in RLNs and those with and without disease recurrence. The effectiveness of the predictive models was assessed by the area under the curve. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. A value of P < 0.05 was considered to indicate statistical significance. Depending on the morphology, we classified tumor vessels into the following types: normal MVs, dilated capillaries (DCs), atypical DCs, DCs with weak expression of CD34, "contact-type" DCs, structures with partial endothelial linings, capillaries in the tumor solid component and lymphatic vessels in lymphoid and polymorphocellular infiltrates. We also evaluated the presence of loose, fine fibrous connective tissue (LFFCT) and retraction clefts in the tumor stroma, tumor spread into the alveolar air spaces (AASs) and fragmentation of the tumor solid component. According to multivariate analysis, the independent predictors of LUSC metastasis in RLNs were central tumor location (P < 0.00001), the presence of retraction clefts (P = 0.003), capillaries in the tumor solid component (P = 0.023) and fragmentation in the tumor solid component (P = 0.009), whereas the independent predictors of LUSC recurrence were tumor grade 3 (G3) (P = 0.001), stage N2 (P = 0.016), the presence of LFFCT in the tumor stroma (P < 0.00001), fragmentation of the tumor solid component (P = 0.0001), and the absence of tumor spread through the AASs (P = 0.0083). The results obtained confirm the correctness of our previously proposed classification of different types of tumor vessels and may contribute to improving the diagnosis and treatment of LUSC.

Dual mTOR1/2 Inhibitor Sapanisertib (FTH-003/TAK-228) in Combination With Weekly Paclitaxel in Patients With Previously Treated Metastatic Urothelial Carcinoma: A Phase II Open-Label Study

BackgroundThe PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib. Patients and MethodsThis was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8, and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders. Results22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (n = 4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI: 1.8-6.1) and median OS was 6.1 months (95% CI: 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders. ConclusionsAlthough the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.

Inhibition of Lung Squamous Cancer Target HMGCS1 Promotes Cellular Ferroptosis

Targeted therapies are ineffective in lung squamous cancer (LUSC), and the low response rate of immunotherapy hampers its application in LUSC, so it is urgent to explore new strategies for LUSC treatment. Ferroptosis plays an important role in tumour suppression. The aim of this study was to investigate the role and mechanism of targeting 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating ferroptosis in LUSC cells, in order to provide a new research direction for LUSC therapy. The expression of HMGCS1 in LUSC was analysed by The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) online databases; the relationship between HMGCS1 and survival time of lung cancer was analysed by the Kaplan-Meier Plotter online survival database; the expression level of HMGCS1 in LUSC tissues was verified by immunohistochemistry. After interfering with HMGCS1 expression by small interfering RNA (siRNA), cell activity and cell migration ability were detected by CCK8 and Transwell assay; apoptosis was detected by flow cytometry after interfering with HMGCS1 or after treatment with the HMGCS1 inhibitor of hymeglusin; Fe2+, reactive oxygen species (ROS) and lipid peroxidation levels were detected by flow cytometry and high-content confocal fluorescence imaging systems, respectively in SKMES cells after inhibition of HMGCS1; and Western blot was performed to detect the expression of ACSL4, GPX4 and SLC7A11, which are markers of the ferroptosis pathway after inhibition of HMGCS1. HMGCS1 mRNA and protein levels were significantly high in LUSC; siRNA interference with HMGCS1 expression inhibited the proliferative activity and migration ability of LUSC cells, but had no significant effect on apoptosis. Interference with HMGCS1 or treatment with the HMGCS1 inhibitor of hymeglusin significantly promoted intracellular Fe2+, ROS and lipid peroxidation levels in SKMES cells, and induced ferroptosis in LUSC cells; Western blot assay showed that inhibition of HMGCS1 significantly promoted the expression of ACSL4. Inhibition of HMGCS1, a target of LUSC, promotes ferroptosis in lung cancer cells and provides a research basis for screening new therapeutic targets for LUSC.

Human papillomavirus infection and the risk of cancer at specific sites other than anogenital tract and oropharyngeal region: an umbrella review

Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and oropharyngeal, the findings are inconsistent and the quality of evidence has not been systematically quantified. We aimed to summarise the existing evidence as well as to evaluate the strength and credibility of these associations. We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, EMBASE, and Web of Science were searched from inception to March 2024. Studies with systematic reviews and meta-analyses that examined associations between HPV or HPV-associated genotypes infection and specific cancers were eligible for this review. The quality of the methodology was evaluated using A Measurement Tool to Assess systematic Reviews (AMSTAR). The credibility of the evidence was assessed using GRADE. The protocol was preregistered with PROSPERO (CRD42023439070). The umbrella review identified 31 eligible studies reporting 87 associations with meta-analytic estimates, including 1191 individual studies with 336,195 participants. Of those, 29 (93.5%) studies were rated as over moderate quality by AMSTAR. Only one association indicating HPV-18 infection associated with an increased risk of breast cancer (odds ratio [OR]=3.48, 95% confidence interval [CI]=2.24-5.41) was graded as convincing evidence. There were five unique outcomes identified as highly suggestive evidence, including HPV infection increased the risk of oral squamous cell carcinoma (OR=7.03, 95% CI=3.87-12.76), oesophageal cancer (OR=3.32, 95% CI=2.54-4.34), oesophageal squamous cell carcinoma (OR=2.69, 95% CI=2.05-3.54), lung cancer (OR=3.60, 95% CI=2.59-5.01), and breast cancer (OR=6.26, 95% CI=4.35-9.00). According to GRADE, one association was classified as high, indicating that compared with the controls in normal tissues, HPV infection was associated with an increased risk of breast cancer. The umbrella review synthesised up-to-date observational evidence on HPV infection with the risk of breast cancer, oral squamous cell carcinoma, oesophageal cancer, oesophageal squamous cell carcinoma, and lung cancer. Further larger prospective cohort studies are needed to verify the associations, providing public health recommendations for prevention of disease. National Key Research and Development Program of China, Natural Science Foundation of China, Outstanding Scientific Fund of Shengjing Hospital of China Medical University, and 345 Talent Project of Shengjing Hospital of China Medical University.

The prognostic value of lymph node to primary tumor standardized uptake value ratio in cancer patients: a meta-analysis.

The lymph node to primary tumor standardized uptake value ratio (NTR) is an innovative parameter derived from positron emission tomography/computed tomography (PET/CT) scans that captures the intricate relationship between primary tumors and associated lymph nodes. This meta-analysis aimed to investigate the prognostic value of NTR in cancer patients. A systematic search of PubMed, Cochrane, and Embase databases was conducted to identify studies investigating the association between NTR and survival outcomes in cancer patients. The pooled adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Twelve studies comprising a total of 2037 patients were included in the meta-analysis. Elevated NTR was significantly associated with worse overall survival aHR (2.21, 95% CI 1.63 to 2.99), disease-free survival aHR (3.27, 95% CI 2.12 to 5.05), and distant metastasis-free survival aHR (2.07, 95% CI 1.55 to 2.78) in cancer patients. Subgroup analyses by cancer type showed consistent results across various malignancies, including head and neck squamous cell carcinoma, endometrial carcinoma, lung cancer, breast cancer, and nasopharyngeal carcinoma. This meta-analysis provides evidence for a significant association between elevated NTR and worse survival outcomes in cancer patients. Elevated NTR may serve as a useful prognostic biomarker for cancer patients and could potentially be used to guide treatment decisions and monitor disease progression. Future studies should aim to validate these findings in larger and more diverse patient populations and investigate the underlying mechanisms for the observed association between NTR and survival outcomes.

Abstract PO5-20-07: A Case of Metastatic Breast Cancer to Soft Tissue of the Thigh

Abstract Breast cancer is the most diagnosed cancer in women worldwide. The predominant cause of breast cancer mortality is metastatic disease with bone, lung, liver and brain being most common sites of metastasis. After melanoma, breast cancer is the most common cancer to have cutaneous metastatic disease and this presentation represents half of all cutaneous metastases. We are presenting a case of a 70-year-old female with distant recurrence of breast cancer to the left thigh. A 70-year-old female presented to clinic with a palpable left breast mass noted July 2022. Her medical history was notable for right sided upper lobe stage IIIB squamous cell lung cancer diagnosed in 2013 treated with chemotherapy and chest radiation (RT), menopause at 25 years old following TAH/BSO for fibroids. Family history included prostate cancer and genetic testing was negative for pathogenic mutation. Diagnostic mammogram showed a lesion in the left breast at 9:00 of 1.4 cm x 1.2 cm x1.4 cm, and biopsy showed grade 3 triple negative invasive ductal carcinoma (IDC). Her nodes were clinically and radiologically negative. She opted for breast conservation. In September of 2020 the patient had a left lumpectomy with sentinel lymph node biopsy. Final pathology (path) was pT1cN0 with two foci of IDC, grade 3, measuring 1.9 × 1.9 × 1.1 cm and 0.4 × 0.2 × 0.2 cm with negative margins. Two sentinel lymph nodes were negative for carcinoma. She received 4 cycles of doxorubicin and cyclophosphamide and started paclitaxel, but only completed 5/12 planned cycles. During these treatment cycles she was admitted twice for shortness of breath and found to have an exudative pleural effusion, repeat cytology was negative for malignancy at which point fluid did not recur. There was no CT evidence of lung nodules or plural thickening. Echocardiogram showed normal ejection fraction of 45%. PET scan was negative. Chemotherapy was stopped in February of 2021. Initial pre-operative discussion with radiation oncology indicated no contraindication to adjuvant RT. However, after simulation, it was deemed by radiation oncology that the patient was no longer a candidate for RT as during her lung cancer treatment, she had received RT of 69.4 Gy including the area of the current lumpectomy cavity. She then opted for bilateral mastectomy with immediate reconstruction in June 2021. Final path from both breasts showed no carcinoma. In November of 2021 she was admitted for shortness of breath and on CT scan was noted to have a left sided lung nodule. The patient declined biopsy and underwent a left wedge resection in January of 2022. Final path showed a 2.2. cm carcinoma consistent with breast primary that was ER 0, PR 0, and Her 2 neu 1+. She was started on capecitabine with plan for 6 months of treatment but stopped taking this after one month due to severe pain in her hands and feet. In November 2022 the patient noted a left thigh mass. Exam showed a firm, palpable thigh mass without overlying skin changes and core needle biopsy showed adenocarcinoma, favoring breast primary, ER 0, PR 0, HER 2 neu 2+ and FISH negative. PET scan showed no uptake in the chest abdomen or pelvis, however a 2.6 × 2.3 × 3.1 cm round mass in the left thigh was seen with SUV max of 8.6. She was started on traztuzumab-deruxtecan by medical oncology in December of 2022. The thigh tumor shrank significantly, however, patient discontinued after two infusions, citing intolerable hand weakness. She then received RT to the thigh. She was treated using 3D technique and 6 MV photons for a total dose of 5400 cGY, from February to March of 2023. Repeat PET June 2023 showed no avid uptake in the thigh. She has declined any additional systemic therapy. Soft tissue metastasis in distant recurrent breast cancer is uncommon and little guidance exists on clinical management. In cases of metastatic disease to the skin, hormone positive lesions can be managed with hormonal therapy. Early detection and biopsy for receptor studies may help guide therapy in cases of distant soft tissue recurrence. Citation Format: Rangel Melissa, Julia Alexieva, Alison Coogan, Lily Hussein, Elizabeth Marcus, Julie Wecsler. A Case of Metastatic Breast Cancer to Soft Tissue of the Thigh [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-07.

Analysis of Methylome of Different Forms of Basal Cell Hyperplasia and Squamous Cell Metaplasia of Bronchial Epithelium.

Squamous cell lung cancer (SCLC) occurs as a result of dysregenerative changes in the bronchial epithelium: basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia. We previously suggested that combinations of precancerous changes detected in the small bronchi of patients with SCLC may reflect various "scenarios" of the precancerous process: isolated BCH→stopping at the stage of hyperplasia, BCH+SM→progression of hyperplasia into metaplasia, SM+dysplasia→progression of metaplasia into dysplasia. In this study, DNA methylome of various forms of precancerous changes in the bronchial epithelium of SCLC patients was analyzed using the genome-wide bisulfite sequencing. In BCH combined with SM, in contrast to isolated BCH, differentially methylated regions were identified in genes of the pathogenetically significant MET signaling pathway (RNMT, HPN). Differentially methylated regions affecting genes involved in inflammation regulation (IL-23, IL-23R, IL12B, IL12RB1, and FIS1) were detected in SM combined with dysplasia in comparison with SM combined with BCH. The revealed changes in DNA methylation may underlie various "scenarios" of the precancerous process in the bronchial epithelium.

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.

Advances of Molecular Targeted Therapy in EGFR-mutated Squamous Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is a prevalent tumour type in our country, with lung squamous carcinoma being a commonly observed NSCLC subtype besides lung adenocarcinoma. Epidermal growth factor receptor (EGFR) is a significant driver gene in lung cancer, and EGFR mutation frequency is considerably lower in lung squamous carcinoma in comparison to lung adenocarcinoma. Although targeted therapy against EGFR has demonstrated significant advancements in lung adenocarcinoma, while progress in lung squamous carcinoma has been relatively sluggish. This paper reviews recent studies on molecular targeted therapy for EGFR-mutated lung squamous carcinoma and summarises the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in treating squamous carcinoma of the lung, in order to provide a reference for treating patients with EGFR-mutated squamous carcinoma of the lung. .

Implications of ZNF334 gene in lymph node metastasis of lung SCC: potential bypassing of cellular senescence

BackgroundThe primary goal of this work is to identify biomarkers associated with lung squamous cell carcinoma and assess their potential for early detection of lymph node metastasis.MethodsThis study investigated gene expression in lymph node metastasis of lung squamous cell carcinoma using data from the Cancer Genome Atlas and R software. Protein-protein interaction networks, hub genes, and enriched pathways were analyzed. ZNF334 and TINAGL1, two less explored genes, were further examined through in vitro, ex vivo, and in vivo experiments to validate the findings from bioinformatics analyses. The role of ZNF334 and TINAGL1 in senescence induction was assessed after H2O2 and UV induced senescence phenotype determined using β-galactosidase activity and cell cycle status assay.ResultsWe identified a total of 611 up- and 339 down-regulated lung squamous cell carcinoma lymph node metastasis-associated genes (FDR < 0.05). Pathway enrichment analysis highlighted the central respiratory pathway within mitochondria for the subnet genes and the nuclear DNA-directed RNA polymerases for the hub genes. Significantly down regulation of ZNF334 gene was associated with malignancy lymph node progression and senescence induction has significantly altered ZNF334 expression (with consistency in bioinformatics, in vitro, ex vivo, and in vivo results). Deregulation of TINAGL1 expression with inconsistency in bioinformatics, in vitro (different types of lung squamous cancer cell lines), ex vivo, and in vivo results, was also associated with malignancy lymph node progression and altered in senescence phenotype.ConclusionsZNF334 is a highly generalizable gene to lymph node metastasis of lung squamous cell carcinoma and its expression alter certainly under senescence conditions.

Abstract CT114: Phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously untreated advanced head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC)

Abstract Background: ILT4 is an immunosuppressive receptor commonly expressed on myeloid cells. Antagonism of ILT4 may induce a proinflammatory state and stimulate antitumor T-cell response, especially with PD-(L)1 blockade. In the dose escalation phase of a first-in-human phase 1 study (NCT03564691), the anti-ILT4 IgG4 monoclonal antibody, MK-4830, in combination with pembrolizumab (pembro) was well tolerated and demonstrated antitumor activity in advanced solid tumors. Here, we present safety, efficacy, and biomarker analyses for MK-4830 + pembro from the multi-cohort expansion phase of patients (pts) with previously untreated advanced HNSCC or NSCLC. Methods: Pts aged ≥18 y with previously untreated advanced HNSCC and PD-L1 combined positive score (CPS) ≥1 (cohort D) or NSCLC regardless of PD-L1 status (cohorts E and F) were enrolled. Pts in all cohorts received either MK-4830 800 mg (cohorts D and E) or 1600 mg (cohort F) + pembro 200 mg Q3W for ≤35 cycles. Primary end points were safety and ORR per RECIST v1.1 by investigator assessment. Exploratory end points included DOR and PFS per RECIST v1.1 by investigator assessment and evaluating possible biomarkers of response to MK-4830 + pembro. Results: At data cut-off (September 27, 2023), 35, 47, and 11 pts were enrolled and received treatment in cohorts D, E, and F, respectively. Median study follow-up was 34.4 mo (range, 26.5-42.4) in cohort D, 35.9 mo (22.4-39.8) in cohort E, and 38.7 mo (37.6-39.6) in cohort F. Adverse events (AEs) occurred in 33 pts (94%) in cohort D, 43 pts (91%) in cohort E, and 10 pts (91%) in cohort F. Treatment-related AEs (TRAEs) occurred in 20 pts (57%) in cohort D, 26 pts (55%) in cohort E, and 6 pts (55%) in cohort F; grade 3-5 TRAEs occurred in 5 pts (14%), 4 pts (9%), and 1 pt (9%), respectively. One pt in cohort E and 1 pt in cohort F died due to a TRAE (pneumonitis and pneumonia, respectively). ORR was 24% (95% CI, 11-41) in cohort D, 30% (17-45) in cohort E, and 27% (6-61) in cohort F. Median DOR was 16.4 mo (range, 2.2+ to 24.4+) in cohort D, 14.8 mo (4.2+ to 32.9+) in cohort E, and 8.4 mo (3.0-21.5) in cohort F. Median PFS was 5.2 mo (95% CI, 2.0-8.0) in cohort D, 4.3 mo (1.8-8.1) in cohort E, and 3.3 (1.2-7.6) in cohort F. In cohort D, T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) did not enrich for response to MK-4830 + pembro. In cohorts E and F, PD-L1 tumor proportion score (TPS) and TcellinfGEP trended higher in pts with response to MK-4830 + pembro than pts with no response; TMB did not trend with response. Conclusions: In pts with advanced HNSCC or NSCLC, first-line MK-4830 + pembro had a manageable AE profile with modest antitumor activity. Consistent with what was previously observed for pembro alone, a trend was observed between PD-L1 TPS and response to MK-4830 + pembro in pts with NSCLC. Citation Format: Byoung Chul Cho, John Hilton, Cristina P. Rodriguez, Marcelo Bonomi, Lillian L. Siu, Marta Gil-Martin, Shabana Siddiqi, Nicole M. Myer, Leah Suttner, Douglas Wilson, Omobolaji Akala, Rafal Dziadziuszko. Phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously untreated advanced head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT114.

CLO24-066: Cemiplimab Use in Advanced Cutaneous Squamous Cell Carcinoma and Non-Small Cell Lung Cancer: Risk Factors Associated With Mortality.

CLO24-066: Cemiplimab Use in Advanced Cutaneous Squamous Cell Carcinoma and Non-Small Cell Lung Cancer: Risk Factors Associated With Mortality.

Abstract CT054: Amivantamab in wild-type advanced non-small cell lung cancer after disease progression on checkpoint inhibition and chemotherapy: Results from the phase 1b CHRYSALIS study

Abstract Background: Overexpression of EGFR and MET has been observed in wild-type (WT) adenocarcinoma and squamous non-small cell lung cancer (NSCLC; Huang L. J Thorac Oncol. 2014). Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, demonstrated pre-clinical activity against WT tumors overexpressing EGFR and MET. We examined ami monotherapy activity in WT-NSCLC after disease progression on platinum-based chemotherapy and anti-PD-1 or PD-L1 therapy. Methods: The WT-Ad and WT-Sq cohorts of the CHRYSALIS study enrolled pateints (pts) with adenocarcinoma or squamous cell carcinoma histology, respectively, without evidence of EGFR, ALK, and MET Exon 14 skipping activating mutations. Pts received ami monotherapy at the approved dose (1050 mg; 1400 mg if ≥80 kg) weekly for the first 4 weeks and biweekly thereafter. Response was assessed by the investigator per RECIST v1.1. Plasma samples were collected pre-treatment, with ctDNA analyzed by Guardant Health (Redwood City, CA). Results: In the WT-Ad cohort, 41 pts received ami (30 with ≥1 post-baseline disease assessment; 11 discontinued due to adverse events [AEs], disease progression, or physician decision), with a median follow-up of 6.2 mo. The median age was 62 years, 63% were men, and 37% were Asian. The objective response rate (ORR) was 7% (3/41), the clinical benefit rate (CBR) was 29%, and the median duration of response (DoR) was 4.2 mo (95% CI, 4.1-not estimable [NE]). Among pts with detectable ctDNA (n=24), 9 pts had KRAS/HER2 mutations. The ORR for pts with and without KRAS/HER2 mutations was 0% (0/9) and 20% (3/15), respectively. The corresponding median PFS for pts with and without KRAS/HER2 mutations was 1.4 mo (95% CI, 1.4-NE) and 4.2 mo (95% CI, 1.6-NE), respectively. In the WT-Sq cohort, 14 pts received ami (12 with ≥1 post-baseline disease assessment; 2 discontinued), with a median follow-up of 6.3 mo. Median age in the WT-Sq cohort was 71 years, 57% were men, and 43% were Asian. ORR was 21% (3/14) with a median DoR that was NE and 2 pts with a DoR ≥6 mo. The overall CBR was 43% (6/14), median PFS was 4.0 mo (95% CI, 2.2-7.3), and median OS was NE. Most common treatment-emergent AEs in both cohorts were rash (grouped term; 66% for WT-Ad, 57% for WT-Sq) and infusion-related reactions (63% WT-Ad and 57% WT-Sq). Grade ≥3 treatment-related AEs (TRAEs) were reported in 17% of pts in the WT-Ad cohort and 21% the WT-Sq cohort. One (2%) pt in the WT-Ad cohort experienced grade 2 interstitial lung disease. Four pts in WT-Ad and 2 pts in WT-Sq cohort discontinued due to TRAEs. Conclusions: Ami demonstrated preliminary antitumor activity in pts with refractory WT squamous and adenocarcinoma NSCLC, particularly in those lacking KRAS/HER2 activating mutations. Safety profile was consistent with the previously reported monotherapy experience, and no new signals were identified. Citation Format: Byoung Chul Cho, Jonathan Goldman, Natasha Leighl, Filippo De Braud, Ki Hyeong Lee, François Ghiringhelli, Pilar Garrido, Julio Peguero, Benjamin Besse, Philippe Cassier, Nicolas Girard, Maria de Miguel, Rosa Alvarez, Alastair Greystroke, Yuichiro Ohe, Te-Chun Hsia, Joshua C. Curtin, Sanjib Chowdhury, Xuesong Lyu, Grace Gao, Siyang Qu, Patricia Lorenzini, Aastha Kapoor, Priya Kim, Mahadi Baig, Meena Thayu, Roland E. Knoblauch, Sandrine Hiret, Pascale Tomasini. Amivantamab in wild-type advanced non-small cell lung cancer after disease progression on checkpoint inhibition and chemotherapy: Results from the phase 1b CHRYSALIS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT054.

Immunotherapy as first-line treatment in locally advanced/metastatic and previously untreated squamous cell lung cancer: which advances?

Immunotherapy as first-line treatment in locally advanced/metastatic and previously untreated squamous cell lung cancer: which advances?

Characterization of cell cycle, inflammation, and oxidative stress signaling role in non-communicable diseases: Insights into genetic variants, microRNAs and pathways

Non-Communicable Diseases (NCDs) significantly impact global health, contributing to over 70% of premature deaths, as reported by the World Health Organization (WHO). These diseases have complex and multifactorial origins, involving genetic, epigenetic, environmental and lifestyle factors. While Genome-Wide Association Study (GWAS) is widely recognized as a valuable tool for identifying variants associated with complex phenotypes; the multifactorial nature of NCDs necessitates a more comprehensive exploration, encompassing not only the genetic but also the epigenetic aspect. For this purpose, we employed a bioinformatics-multiomics approach to examine the genetic and epigenetic characteristics of NCDs (i.e. colorectal cancer, coronary atherosclerosis, squamous cell lung cancer, psoriasis, type 2 diabetes, and multiple sclerosis), aiming to identify novel biomarkers for diagnosis and prognosis. Leveraging GWAS summary statistics, we pinpointed Single Nucleotide Polymorphisms (SNPs) independently associated with each NCD. Subsequently, we identified genes linked to cell cycle, inflammation and oxidative stress mechanisms, revealing shared genes across multiple diseases, suggesting common functional pathways. From an epigenetic perspective, we identified microRNAs (miRNAs) with regulatory functions targeting these genes of interest. Our findings underscore critical genetic pathways implicated in these diseases. In colorectal cancer, the dysregulation of the “Cytokine Signaling in Immune System” pathway, involving LAMA5 and SMAD7, regulated by Hsa-miR-21-5p, Hsa-miR-103a-3p, and Hsa-miR-195-5p, emerged as pivotal. In coronary atherosclerosis, the pathway associated with “binding of TCF/LEF:CTNNB1 to target gene promoters” displayed noteworthy implications, with the MYC factor controlled by Hsa-miR-16-5p as a potential regulatory factor. Squamous cell lung carcinoma analysis revealed significant pathways such as “PTK6 promotes HIF1A stabilization,” regulated by Hsa-let-7b-5p. In psoriasis, the “Endosomal/Vacuolar pathway,” involving HLA-C and Hsa-miR-148a-3p and Hsa-miR-148b-3p, was identified as crucial. Type 2 Diabetes implicated the “Regulation of TP53 Expression” pathway, controlled by Hsa-miR-106a-5p and Hsa-miR-106b-5p. In conclusion, our study elucidates the genetic framework and molecular mechanisms underlying NCDs, offering crucial insights into potential genetic/epigenetic biomarkers for diagnosis and prognosis. The specificity of pathways and related miRNAs in different pathologies highlights promising candidates for further clinical validation, with the potential to advance personalized treatments and alleviate the global burden of NCDs.

Abstract 1793: Transmembrane serine protease TMPRSS11B promotes tumorigenesis in lung squamous cell carcinoma through enhanced lactate export and modulation of the tumor microenvironment

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. Existing therapeutic options have limited efficacy, underscoring the critical need for the identification of new actionable therapeutic targets. We previously identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes the transformation of human bronchial epithelial cells in vitro and induces tumorigenesis in vivo. TMPRSS11B promotes extracellular release of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1/4, enhancing lactate export and glycolytic metabolism, and thereby promoting tumorigenesis. Importantly, TMPRSS11B is frequently overexpressed in human lung squamous cell cancers (LSCC) and high expression is associated with poor patient survival. Moreover, as a cell surface protein and enzyme, TMPRSS11B represents a tractable target for therapeutic intervention. To investigate whether TMPRSS11B activity impacts the host immune system and the tumor microenvironment (TME), we evaluated the effect of Tmprss11b depletion in a syngeneic LSCC mouse model, KLN205. Tmprss11b loss of function in KLN205 LSCC cells significantly reduced tumor burden in immunocompetent mice and triggered an accumulation of CD4+ T cells. We are currently extending these studies by investigating the effect of Tmprss11b loss of function using CRISPR/Cas9 editing in the Rosa26LSL-Sox2-IRES-GFP; Nkx2-1 fl/fl; Lkb1fl/fl (SNL) mouse model of LSCC. Tumor burden analysis and pH-sensitive fluorescent imaging are ongoing to assess changes in lactate accumulation. Moreover, RNA FISH analysis and spatial transcriptomics revealed that Tmprss11b expression is highly enriched in lung squamous tumors compared to lung adenocarcinomas and normal lung in SNL mice. Spatial analysis of the transcriptome is currently ongoing to assess the effects of Tmprss11b expression on the TME. Collectively, these studies will elucidate the molecular mechanisms through which TMPRSS11B promotes tumor growth and alters the tumor microenvironment in LSCC. Citation Format: Hari Shankar Sunil, Barrett L. Updegraff, Jingfei Zhu, Lisa Thomas, Bret M. Evers, Jean R. Clemenceau, Isabel Barnfather, John D. Minna, Ralph J. Deberardinis, Trudy G. Oliver, Tae Hyun Hwang, Kathryn A. O'Donnell. Transmembrane serine protease TMPRSS11B promotes tumorigenesis in lung squamous cell carcinoma through enhanced lactate export and modulation of the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1793.

Abstract 3365: Reliable detection of potentially therapeutically actionable ecDNA using clinical-grade NGS in a large pan-cancer cohort

Abstract Background Focal high-level oncogene amplifications (FH-amp) (e.g., MYC, EGFR) frequently occur on extrachromosomal DNA (ecDNA), highly transcribed units of circular non-chromosomal DNA. FH-amp on ecDNA promote intra-tumoral heterogeneity, resistance to therapies, and poor prognosis. Recently, a Phase 1 clinical trial exploring ecDNA-directed treatments has begun. However, to date, bioinformatic detection of ecDNA has relied on whole-genome sequencing data, and no standard method exists to detect ecDNA on targeted NGS. We thus sought to explore the feasibility of detecting ecDNA in a large cohort of patients with solid tumors sequenced with the targeted NGS panel, MSK-IMPACT, and describe the pan-cancer prevalence of oncogenes amplified on ecDNA. Methods We utilized a novel bioinformatic ecDNA-diagnostic algorithm, ECHO, to determine the presence of oncogene FH-amp on ecDNA (including HSR) vs. chromosomal in clinical-grade NGS data. 72,651 tumor samples profiled by MSK-IMPACT were queried for high level oncogene FH-amp (AR, CCNE1, CDK4/6, EGFR, FGFR1-4, KRAS, MDM2, MDM4, MET, MYC, MYCL, and MYCN) above a fold-change of three, and subsequently annotated with ECHO. Patients with concomitant oncogenic driver mutations or fusions (e.g., EGFR L858R, EML4-ALK) were excluded based on the hypothesis that they might be mutually exclusive with oncogene FH-amp. Results FH-amp of any above listed oncogene were found in 3065 (4.2%) samples. Cancer types with frequent FH-amp without concomitant driver alterations were liposarcoma (LPS) (61% FH-amp; 43% were ecDNA+), glioblastoma (GBM) (22%; 72%), gastroesophageal adenocarcinoma (GE AD) (10%; 57%) squamous cell lung cancer (7%; 18%), and breast cancer (BRCA) (7%; 23%). Among tumors with oncogene FH-amp, GBM and GE AD had high frequencies of ecDNA+ FH-amp of EGFR (39% and 15% of all EGFR ecDNA+). LPS had the highest frequency of ecDNA+ FH-amp of CDK4 (64%), followed by GBM (15%). The majority of ecDNA+ FGFR1 and FGFR2 FH-amp were in BRCA (75% and 47%). EGFR in GBM and EGFR or FGFR2 in GE AD were ecDNA+ in more than 90% of patients, while CDK4 in LPS and FGFR1 in BRCA were ecDNA+ in 45% and 39% respectively.Evaluation the relationship between ecDNA+ by ECHO and amp FC range showed higher ecDNA+ in samples with higher level amp (FC &amp;gt; 5; 58% ecDNA+) compared to lower level amp (FC 4~5; 12%, FC 3~4; 6% ecDNA+). Conclusions A novel ecDNA clinical diagnostic tool, ECHO, was successfully applied to a large clinical cohort of patients enriched for actionable oncogene amplifications sequenced with MSK-IMPACT. The results demonstrate that detection of ecDNA using clinical-grade NGS assays is feasible and that key oncogene FH-amp on ecDNA (e.g., EGFR, FGFR2) are common in select tumor types. ECHO may be developed as a clinical trial device to prospectively identify patients with oncogene ecDNA+ FH-amp for clinical testing of ecDNA-directed therapies. Citation Format: Matteo Repetto, Klaus Wagner, Shalabh Suman, Peter Krein, Pavitra Rao, Maria Arcila, Christian Hassig, Mark Donoghue, Alexander Drilon, Michael Berger. Reliable detection of potentially therapeutically actionable ecDNA using clinical-grade NGS in a large pan-cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3365.

Abstract 6882: Exploring aryl hydrocarbon receptor expression and distribution in the tumor microenvironment, with a focus on immune cells, in various solid cancer types

Abstract Background: The aryl hydrocarbon receptor (AhR) is a transcription factor that performs various biological functions upon ligand activation. While there have been extensive studies and development of AhR-targeting anticancer therapies, including active clinical trials, research on the expression of AhR, a key biomarker, in the TME remain limited. Herein, we evaluated the nuclear and cytosolic AhR expression across five solid cancer types: head and neck squamous cell carcinoma (HNSCC), bladder cancer, colorectal cancer, esophageal cancer, and non-small cell lung cancer (NSCLC). Methods: Multiplexed immunohistochemistry (mIHC) and image cytometry were employed to investigate the AhR expression and distribution in 513 patient samples, of which 292 were from patients with one of five solid cancer types. For quantification of AhR expression levels, FCS files were generated, and the resulting data was analyzed using the R program. Results: AhR expression was predominantly high in cancer cells, followed by T cells and macrophages across all cancer types. All 513 patient samples were categorized into three clusters based on distinct expression and localization patterns of AhR. Cluster 1 exhibited high AhR expression in the cancer cell nucleus, whereas cluster 3 showed the lowest. AhR expression in the stromal macrophage nucleus was the most pronounced in cluster 2. In cluster 1, NSCLC was entirely absent, with esophageal cancer representing the largest proportion. In contrast, cluster 2 was notably different from cluster 1, with a 5% prevalence of NSCLC and a relatively higher proportion of HNSCC and colorectal cancer. The AhR expression in macrophages within cluster 2 was noticeably higher than in cluster 1. Cluster 3, which had the highest NSCLC proportion, generally displayed low AhR expression compared to other clusters, but also exhibited AhR expression in regulatory T cells (Tregs), a pattern which was not observed in other cancer types. Notably, a positive correlation was observed between the nuclear and cytosolic expressions of AhR, suggesting that AhR expression as a biomarker is independent of its subcellular localization. Furthermore, there was no clear correlation between AhR expression levels and cancer stage, grade, and metastatic status. Conclusion: We elucidated the expression profile of AhR within the TME across five cancer types, then classified the patient samples into three clusters based on their distinct AhR expression patterns. By demonstrating different expression patterns of AhR in cancer cells and immune cells, our findings are anticipated to provide a fundamental basis for clinical and immunological research on AhR-targeting therapies. Citation Format: Dong Kwon Kim, Chai Young Lee, Yu Jin Han, So Young Park, Heekyung Han, Kwangmin Na, Mi Hyun Kim, Seung Min Yang, Sujeong Baek, Youngtaek Kim, Joon Yeon Hwang, Seul Lee, Seong-san Kang, Taedong Han, Hyounmie Doh, Jongho Cho, Dajeong Kim, Daewon Cha, Min Hee Hong, Sun Min Lim, Jii Bum Lee, Jae Hwan Kim, Kyoung-Ho Pyo, Byoung Chul Cho. Exploring aryl hydrocarbon receptor expression and distribution in the tumor microenvironment, with a focus on immune cells, in various solid cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6882.

Abstract 6182: Artificial intelligence (AI)-powered quantification of glypican-3 (GPC3) expression facilitates patient selection for GPC3-targeted therapy in solid tumors

Abstract Introduction: GPC3 is a glycosyl-phosphatidylinositol-anchored cell surface glycoprotein that functions to control cell growth and differentiation in early development. Membrane GPC3 is highly expressed in hepatocellular carcinoma (HCC) and moderately in squamous non-small cell lung cancer (SQ-NSCLC) with limited expression in normal tissues which makes it an attractive target for immune cell engagers. This study aims to develop an AI-powered algorithm to evaluate GPC3 expression and compare it with manual immunohistochemistry (IHC) scoring in HCC, adeno-NSCLC and SQ-NSCLC. Methods: 147 NSCLC (94 SQ-NSCLC and 53 adeno-NSCLC) and 113 HCC FFPE tumor blocks were obtained from commercial sources. GPC3 protein level was quantified by a qualified IHC assay for tumor cell membrane and cytoplasm individually. PD-L1 expression is reported as tumor cell proportion score (TPS), combined positive score (CPS) and immune cell proportion score (IPS/IC) TPS, regardless of staining pattern and intensity. FFPE slides were stained for GPC3+ (GC33, Ventana), PD-L1+ (22C3, Dako) cells and then scanned at 20x using the Aperio Versa8 scanner. Machine learning (ML) models were developed using the digitized whole slide images to identify GPC3+ tumor area. Data-driven cutoffs were applied to model-generated human-interpretable features of GPC3+ percentage of tumor area to classify samples as positive and negative. As an orthogonal approach to the GPC3+ percentage cutoff method, tissue and cell annotations were used to train a convolutional neural network (CNN) to classify GPC3 positivity. Results: The epidemiology profiling results revealed that GPC3 protein is highly expressed in HCC (57.5% cases with &amp;gt; 1% positive cells), followed by SQ-NSCLC (52.1%) and adeno-NSCLC (5.7%). GPC3 expression was only detected in tumor cells with two staining patterns observed: membrane + cytoplasm and cytoplasm-only. There was no significant correlation between GPC3 and PD-L1 expression across tumor types, although a trend of lower level of PD-L1 was observed in the samples with GPC3 ≥50%. ML model quantification of GPC3+ and GPC3- showed high concordance with the consensus score of 2 independent pathologists on a test set of held-out samples not used in training. This concordance was comparable to that of individual annotators to consensus. Instead, GPC3 positivity results using both cutoff and CNN methods showed moderate concordance with 2-way pathologist consensus. Conclusions: Here we profiled GPC3 expression across tumor types and showed high level of expression in HCC followed by SQ-NSCLC. We have established an AI-powered digital pathology platform that can provide a standardized, scalable, and reproducible method of characterizing GPC3 positivity to support further patient selection in clinical study. Citation Format: Ellen Meng, Robin Meng, Ying Tong, Yuchen Li, Hong Wang, Paola Fiorentini, Elham Attieh, Qi Tang, Asma Kefsi, Serena Masciari, Giovanni Abbadessa, Cecile Combeau, Lei Tang, Benoit Pasquier, Rui Wang. Artificial intelligence (AI)-powered quantification of glypican-3 (GPC3) expression facilitates patient selection for GPC3-targeted therapy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6182.