Squamous Cancer Research Articles

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.

Biological Potential and Therapeutic Effectiveness of Hinokiflavone in Medicine: The Effective Components of Herbal Medicines for Treatment of Cancers and Associated Complications

Background: Plants have been providing us medicines and food material for centuries. Traditional system of medicine, including Ayurveda, and Traditional Chinese medicines have been playing important role in health sectors for the treatment of human disorders since very early age. Plant secondary metabolites, including flavonoids, coumarins, saponins, and tannins have significant therapeutic potential in medicine. Biflavonoids are dimers of flavonoids, linked by a C–O–C or C–C bond. Hinokiflavone is an important class of biflavonoids found to be present in Toxicodendron succedaneum, Isophysis tasmanica, Juniperus rigida, Juniperus phoenicea, Platycladi cacumen, Rhus succedanea, Selaginella tamariscina, Platycladus orientalis, Selaginella bryopteris, and Metasequoia glyptostroboides. Methods: Biological potential of hinokiflavone in medicine have been analyzed in the present work through scientific data analysis of various literature work. Scientific database, including Google, Scopus, Science Direct, and PubMed were searched to collect all the scientific information of the present work using terms flavonoid, biflavonoid, herbal medicine, and hinokiflavone. Pharmacological activities of hinokiflavone were analyzed in the present work in very detailed manner. Analytical data of hinokiflavone were collected and analyzed in present work in order to know the biological source of hinokiflavone. Results: Present work signified the biological importance of hinokiflavone against various types of cancerous disorders, including breast cancer, colorectal cancer, esophageal squamous cancer, adenocarcinoma, hepatocellular carcinoma, myeloid leukemia, and melanoma. Further, its antiinflammatory, hepatoprotective, anti-viral, and anti-oxidant potential were also discussed in the present work. Moreover, its biological potential against COVID-19 and hair loss, and procoagulant activity were also summarized in this paper. Analytical data on hinokiflavone signified the importance of various analytical techniques in the extraction, separation, and identification of hinokiflavone with their pharmacokinetic parameters. Conclusion: Present work signified the biological importance and therapeutic potential of hinokiflavone in medicine.

Selenium May Be Involved in Esophageal Squamous Cancer Prevention by Affecting GPx3 and FABP1 Expression: A Case-Control Study Based on Bioinformatic Analysis

The role of selenium in the developmental process of esophageal cancer (EC) requires further investigation. To explore the relationship between selenium-related factors and EC through bioinformatic analysis, a case-control study was conducted to verify the results. Utilizing the GEPIA and TCGA databases, we delineated the differential expression of glutathione peroxidase 3 (GPx3) in EC and normal tissues, identified differentially expressed genes (DEGs), and a performed visualization analysis. Additionally, 100 pairs of dietary and plasma samples from esophageal precancerous lesions (EPLs) of esophageal squamous cancer (ESCC) cases and healthy controls from Huai’an district, Jiangsu, were screened. The levels of dietary selenium, plasma selenium, and related enzymes were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) or ELISA kits. The results showed lower GPx3 expression in tumor tissues compared to normal tissues. Further analysis revealed that DEGs were mainly involved in the fat digestion and absorption pathway, and the core protein fatty acid binding protein 1 (FABP1) was significantly upregulated and negatively correlated with GPx3 expression. Our case-control study found that selenium itself was not associated with EPLs risk. However, both the decreased concentration of GPx3 and the increase in FABP1 were positively correlated with the EPLs risk (p for trend = 0.035 and 0.046, respectively). The different expressions of GPx3 and FABP1 reflect the potential of selenium for preventing ESCC at the EPLs stage. GPx3 may affect myocardial infarction through FABP1, which remains to be further studied.

Differences in postoperative prognosis between early-stage lung adenocarcinoma and squamous cell carcinoma.

Although prognosis and treatments differ between small-cell- and nonsmall-cell carcinoma, comparisons of the histological types of NSCLC are uncommon. Thus, we investigated the oncological factors associated with the prognosis of early-stage adenocarcinoma and squamous cell carcinoma. We retrospectively compared the clinicopathological backgrounds and postoperative outcomes of patients diagnosed with pathological stage I-IIA adenocarcinoma and squamous cell carcinoma primary lung cancer completely resected at our department from January 2007 to December 2017. Multivariable Cox regression analysis for overall survival and recurrence-free survival was performed. The median follow-up duration was 55.2months. The cohort consisted of 532 adenocarcinoma and 96 squamous cell carcinoma patients. A significant difference in survival was observed between the two groups, with a 5-year overall survival rate of 90% (95% confidence interval 86-92%) for adenocarcinoma and 77% (95% CI 66-85%) for squamous cell carcinoma (P<0.01) patients. Squamous cell carcinoma patients had worse outcomes compared to adenocarcinoma patients in stage IA disease, but there were no significant differences between the two groups in stage IB or IIA disease. In multivariate analysis, invasion diameter was associated with overall survival in adenocarcinoma (hazard ratio 1.76, 95% confidence interval 1.36-2.28), but there was no such association in squamous cell carcinoma (hazard ratio 0.73, 95% confidence interval 0.45-1.14). The importance of tumor invasion diameter in postoperative outcomes was different between adenocarcinoma and squamous cell carcinoma. Thus, it is important to consider that nonsmall-cell carcinoma may have different prognoses depending on the histological type, even for the same stage.

First-line immunotherapy efficacy in advanced squamous non-small cell lung cancer with PD-L1 expression ≥50%: a network meta-analysis of randomized controlled trials

ObjectiveThe optimal first-line immunotherapy regimen for patients with PD-L1 expression ≥50% in squamous non-small cell lung cancer (Sq-NSCLC) remains uncertain. This study utilized net-work meta-analysis (NMA) to indirectly compare the efficacy of various first-line immuno-therapy regimens in this patient subset.MethodsSystematic searches were conducted across PubMed, the Cochrane Library, Web of Science, and Embase databases for randomized controlled trials reporting overall survival (OS) and progression-free survival (PFS) outcomes. The search spanned from database inception to November 3, 2023. Bayesian network meta-analysis was employed for a comprehen-sive analysis. To ensure scientific rigor and transparency, this study is registered in the Interna-tional Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022349712.ResultsThe NMA encompassed 9 randomized controlled trials (RCTs), involving 2170 patients and investigating 9 distinct immunotherapy regimens. For OS, the combination of camrelizumab and chemotherapy demonstrated the highest probability (36.68%) of efficacy, fol-lowed by cemiplimab (33.86%) and atezolizumab plus chemotherapy (23.87%). Regarding PFS, the camrelizumab and chemotherapy combination had the highest probability (39.70%) of efficacy, followed by pembrolizumab (22.88%) and pembrolizumab plus chemotherapy (17.69%). Compared to chemotherapy, first-line treatment with immune checkpoint inhibitors (ICIs) in Sq-NSCLC pa-tients exhibited significant improvements in OS (HR 0.59, 95% CI 0.47-0.75) and PFS (HR 0.44, 95% CI 0.37-0.52).ConclusionThis study suggests that, for Sq-NSCLC patients with PD-L1 expression ≥50%, the first-line immunotherapy regimen of camrelizumab plus chemotherapy provides superior OS and PFS outcomes. Furthermore, ICIs demonstrate enhanced efficacy compared to chemotherapy in this patient population.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD 42022349712.

A case of nutritional management and challenges after esophageal cancer surgery

Malnutrition and cachexia are common in cancer patients. Malnutrition rates of cancer patients vary according to the location of the tumor. In esophageal cancer, severe cachexia and sarcopenia are seen at the time of diagnosis. The defense of nutritional therapy (NT) against cancer, especially gastrointestinal cancer, is very difficult. NT should start with the diagnosis of the disease. The aim of NT should be to prevent cancer cachexia, related complications, and mortality. In Türkiye, squamous cell esophageal cancer is often seen, especially due to dietary habits (hot drinks, meat-based diet low in vegetables). This is a case report of a 55-year-old male patient who had lots of challenges during the nutritional management after esophageal cancer surgery. The patient’s complaints did not improve after neoadjuvant therapies and minimally invasive esophagectomy (MIE) was performed. Inflammation and fistula were seen after major abdominal surgery. As long as the fistula and drainage were continued, parenteral nutrition (PN) remained the only option for NT allowing the bowel to rest in the presence of a fistula. In case of contraindication to oral or enteral nutrition (EN), PN was started on day 6 of MIE. Since it was thought that oral or EN could not be started for more than 10 days, a central catheter was placed, and the patient was fed with CPN (central parenteral nutrition). After the insertion of a stent and a nasojejunal (NJ) tube, EN combined with CPN could be applied. Because of anastomotic leakage, oral nutrition couldn’t be continued. Short-term peripheral parenteral nutrition (PPN) therapy was continued until the leakage stopped. The patient was discharged with oral and oral nutritional supplements. Two years after the MIE, no significant difference from previous radiological reports was found and there were no problems with oral nutrition.

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.

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.

HRU-Net: A high-resolution convolutional neural network for esophageal cancer radiotherapy target segmentation

Background and objectiveThe effective segmentation of esophageal squamous carcinoma lesions in CT scans is significant for auxiliary diagnosis and treatment. However, accurate lesion segmentation is still a challenging task due to the irregular form of the esophagus and small size, the inconsistency of spatio-temporal structure, and low contrast of esophagus and its peripheral tissues in medical images. The objective of this study is to improve the segmentation effect of esophageal squamous cell carcinoma lesions. MethodsIt is critical for a segmentation network to effectively extract 3D discriminative features to distinguish esophageal cancers from some visually closed adjacent esophageal tissues and organs. In this work, an efficient HRU-Net architecture (High-Resolution U-Net) was exploited for esophageal cancer and esophageal carcinoma segmentation in CT slices. Based on the idea of localization first and segmentation later, the HRU-Net locates the esophageal region before segmentation. In addition, an Resolution Fusion Module (RFM) was designed to integrate the information of adjacent resolution feature maps to obtain strong semantic information, as well as preserve the high-resolution features. ResultsCompared with the other five typical methods, the devised HRU-Net is capable of generating superior segmentation results. ConclusionsOur proposed HRU-NET improves the accuracy of segmentation for squamous esophageal cancer. Compared to other models, our model performs the best. The designed method may improve the efficiency of clinical diagnosis of esophageal squamous cell carcinoma lesions.

Synthesis of substituted terpyridine nickel nitrate complexes and their inhibitory selectivity against cancer cell lines

Six terpyridine‑nickel complexes 1–6 were formed by the coordination of 4′-(4-R-phenyl)-2,2′:6′,2″-terpyridine (R = hydroxyl (L1), methoxyl (L2), methylsulfonyl (L3), fluoro (L4), bromo (L5), iodo (L6)) derivatives to nickel nitrate. The compositions and structures of these complexes were analyzed by Fourier Transform infrared spectroscopy (FT-IR), elemental analyses, electrospray ionization mass spectra (ESI-MS), solid-state ultraviolet-visible (UV–Vis) spectroscopy, and single crystal X-ray diffraction (1, 2 and 4) studies. In vitro anticancer cell proliferation experiments against SiHa (human cervical squamous cancer cell line) cells, Bel-7402 (human hepatoma cancer cell line), Eca-109 (human esophageal cancer cell line) and HL-7702 (human normal hepatocyte cell line) indicate that they have more excellent anti-proliferation effects than the cis-platin against Siha cells, Bel-7402 cells and Eca-109 cells. Especially, complex 5 showed a rather outstanding inhibitory effect against the SiHa cell line and was less toxic than the other compounds to the HL-7702 cell line, implying an obvious specific inhibitory effect. Therefore, complex 5 has the potential value to be developed as an anticancer cell-specific drug against human cervical squamous carcinoma. Molecular docking simulation, UV–vis absorption spectroscopy and circular dichroism experiments show that they prefer to bind to DNA part in an embedded binding manner.

Abstract NG03: Functional and computational approaches to uncover selection advantages of cancer aneuploidy

Abstract Aneuploidy, including the gain or loss of whole chromosomes or chromosome arms, is a near-universal feature of cancer. We previously applied methods that define chromosome arm aneuploidy to over 10,000 tumors in the Cancer Genome Atlas (TCGA). Cancer subtypes are often characterized by tumor specific patterns of chromosome arm copy number alterations and breakpoints; for example, squamous cell carcinomas (SCCs) from different tissues of origin are characterized by chromosome 3p (chr3p) loss and chromosome 3q (chr3q) gain. From the TCGA aneuploidy data, we developed an algorithm called BISCUT to distinguish peak regions of aneuploidy breakpoints on each chromosome arm. BISCUT identified loci affected by broad copy number alterations that provide fitness advantages or disadvantages both within individual cancer types and across cancers. Our analyses are consistent with selection being the primary driver of aneuploidy events in cancer. We next wanted to validate some BISCUT peaks without a known driver, to identify potential gene deletions that are beneficial in cancer cells. We focused on chromosome 8p (chr8p), as this arm is frequently deleted across cancer types, but no strong tumor suppressors have been identified. Recent advances in genome engineering allow generation of large chromosomal alterations and validation of findings from patient genomic data. For this study, we used our CRISPR-Cas9 arm-deletion system to delete chr8p in human immortalized epithelial cells. Cells with chr8p deletion showed lower amounts of cell death in culture. Knockdown of WRN, one of the two genes in the smallest chr8p BISCUT peak, was sufficient to reproduce this phenotype, suggesting that WRN haploinsufficiency may be beneficial to tumor development. As aneuploidy occurs in tissue-specific patterns, we also wanted to explore the role of chr3 arm aneuploidies in squamous cancers. We again used the CRISPR-Cas9 system to delete one copy of chr3p in a human immortalized lung epithelial cell line similar to the putative cell-of-origin in lung SCC. Consistent with patient data, expression of chr3p genes was decreased upon deletion, as well as increased expression of interferon response genes. Cells with chr3p deletion initially proliferated more slowly than their siblings. Interestingly, after several passages in culture, this proliferation defect was rescued in chr3p deleted cells. Genome sequencing and karyotype analyses suggested that this was partially the result of chr3 duplication, with cells transitioning to a state of chr3q gain. Culturing these cells as organoids also demonstrated that chr3p deletion and chr3q gain can affect basal cell differentiation, consistent with their high frequency in squamous cancers. Our genome engineering approach to model chromosome arm aneuploidies provides a robust model to validate drivers from aneuploidy events, which will be critical to address the gap in our understanding of aneuploidy in cancer. In addition, our methods have identified consequences of individual aneuploidy events, which will lead to new precision oncology targets for patients. Citation Format: Alison M. Taylor. Functional and computational approaches to uncover selection advantages of cancer aneuploidy [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 NG03.

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?

MRNA vaccines in cancer clinical trials: HPV16 tumor-derived antigens (e6 and e7 oncoproteins) associated with head and neck squamous cell carcinoma (HNSCC), oropharyngeal and cervical cancers

Human papillomavirus (HPV) induces the most common sexually transmitted disease and has been classified in the Alphapapillomavirus genus, Papillomaviridae family. They are non‒enveloped viruses presenting a closed circular double‒stranded non‒segmented DNA genome of approximately 8 kb that infect the anogenital epithelium causing cervical cancer, anal and penis cancer. There are viral groups based on their oncogenic activity as high‒risk types, low‒risk types and types of undetermined‒risk. mRNA vaccines are being evaluated in people with HPV-related cancers. This study described how mRNA cancer vaccines work and their applications recruiting several strategies for HPV cancer immunotherapy. Several biopharmaceuticals are developing mRNA vaccines encoding neoepitopes that can induce immune responses against target tumors. One trial is testing a personalized mRNA vaccine in combination with an immune checkpoint inhibitor in patients with advanced head and neck cancer. The production of therapeutic mRNA proteins for development of vaccine cancer have been manufactured by upstream and downstream methods. Several stages are processed in bioreactors using input and output parameters to measure the quality control of purified substance. Thus, novel technologies using different mRNA delivery system can be able to be integrated in clinical trials of HPV16 tumor-derived antigens associated cervical intraepithelial lesions of different stages until head and neck squamous cell carcinoma, oropharyngeal and cervical cancers.

Cervical Squamous Intraepithelial Lesions: A Comparison of Diagnostic Approaches

Aim. To compare the effectiveness of Papanicolaou test, screening for oncogenic human papillomavirus (HPV) strains, and colposcopy in diagnosis of cervical squamous intraepithelial lesions and cervical cancer.Materials and Methods. We conducted a retrospective study which included 101 patients aged 21-65 years (mean age 36.9 ± 8.2 years). All patients underwent cytological examination, screening for 14 high-risk HPV types, and colposcopy. The prognostic value of the methods was calculated using standard formulas for determining the sensitivity, specificity, and prognostic value of positive and negative results. Cervical biopsy was accepted as the gold standard.Results. Among the examined women (n = 101), high-risk HPV types were detected in 78 women (77.2%). According to the results of cytological examination, cervical intraepithelial neoplasia (CIN) I, CIN II, CIN III, and cancer were detected in 24 (23.8%), 24 (23.8%), 22 (21.7%), and 2 (2%) cases, respectively. Abnormal colposcopy results of the 1st and 2nd degree were found in 33 (32.7%) and 51 (50.5%) women, respectively. The highest sensitivity in the diagnosis of low-grade squamous intraepithelial lesion was demonstrated by colposcopy (81.3%), whilst HPV testing and cytological examination had lower sensitivity values (75.0% and 58.3%, respectively). However, HPV testing had the highest sensitivity (85.7%) in diagnosis of high-grade squamous intraepithelial lesion and cervical cancer, whereas colposcopy and Papanicolaou test were behind (82.9% and 63.6%, respectively).Conclusion. Detection of high-risk HPV types has a high sensitivity in detecting both low- and highgrade squamous intraepithelial lesions and cervical cancer.

Metachronous Multiple Primary Inoperable Squamous Cancer of the Esophagus: Case Report

The incidence of primary multiple malignant neoplasms (PMMN) in Russia is steadily increasing due to the increasing frequency of detection of metachronous tumors. A similar trend is observed in esophageal cancer (EC). Advances in the diagnosis and treatment of cancer have led to an increase in the life expectancy of patients after a cured primary tumor and, in turn, to an increase in the detection rate of a second tumor. The longer life expectancy of patients with cancer, the higher the likelihood of developing a second tumor. PMMN of the esophagus is one of the least studied problems in modern oncology, which complicates the choice of treatment tactics, since there are no standards for the management of such patients. This article reflects a multidisciplinary and individual approach to the treatment of a patient with primary multiple metachronous inoperable squamous cell carcinoma of the middle and lower thoracic esophagus. The patient underwent chemoradiotherapy (CRT) with full effect, with no post-radiation damage and improved quality of life.

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.

Human Papillomavirus-Induced Chromosomal Instability and Aneuploidy in Squamous Cell Cancers

Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. CIN is defined as a continuous rate of chromosome missegregation events over the course of multiple cell divisions. CIN causes aneuploidy, a state of abnormal chromosome content differing from a multiple of the haploid. Human papillomavirus (HPV) is a well-known cause of squamous cancers of the oropharynx, cervix, and anus. The HPV E6 and E7 oncogenes have well-known roles in carcinogenesis, but additional genomic events, such as CIN and aneuploidy, are often required for tumor formation. HPV+ squamous cancers have an increased frequency of specific types of CIN, including polar chromosomes. CIN leads to chromosome gains and losses (aneuploidies) specific to HPV+ cancers, which are distinct from HPV− cancers. HPV-specific CIN and aneuploidy may have implications for prognosis and therapeutic response and may provide insight into novel therapeutic vulnerabilities. Here, we review HPV-specific types of CIN and patterns of aneuploidy in squamous cancers, as well as how this impacts patient prognosis and treatment.