Response Of Squamous Cell Carcinoma Research Articles

The efficacy of neoadjuvant immune checkpoint inhibitors in lung squamous cell carcinoma and adenocarcinoma: a systematic review and single-arm meta-analysis.

Neoadjuvant immunotherapy is effective in treating resectable non-small cell lung cancer (NSCLC) but shows different responses in lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Current studies are limited in size, necessitating further research to clarify these differences. This study aims to investigate whether there is a difference between the efficacy of neoadjuvant immune checkpoint inhibitors (ICIs) on lung SCC vs. ADC. Studies provided data of pathological or radiological response of ADC and SCC receiving neoadjuvant ICIs published before August 1, 2023, were retrieved. Pathological response included major pathological response (MPR), complete pathological response (cPR) and the sum of major pathological response and complete pathological response (McPR). Radiological response includes complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR). The protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO CRD42022328240). A total of 22 studies with 430 patients were included. Pathological response and radiological response were used to evaluate the efficacy of neoadjuvant immunotherapy on ADC and SCC. No significant difference was found in pathological response (MPR: P=0.15; cPR: P=0.61), while SCC had significantly higher ORR (P=0.02), lower SD (P<0.04) and PD (P=0.04) than ADC after neoadjuvant ICIs. Both SCC and ADC achieved significantly higher PR (P<0.01), ORR (P<0.01), and lower SD (P<0.01) when treated with chemo-immunotherapy compared to ICI monotherapy. Chemo-immunotherapy significantly improved the McPR in ADC (P<0.05). Toripalimab showed a higher ORR for both SCC and ADC (P<0.05) without a clear advantage in pathological remission across the ICIs. Pembrolizumab had significantly higher McPR (P<0.05) for treating SCC patients compare to ADC patients. In conclusion, our findings indicate that SCC patients exhibited higher ORR and lower SD and PD than those with ADC. No significant differences in pathological responses were seen between SCC and ADC, across ICI monotherapy or chemo-immunotherapy. Chemo-immunotherapy notably improved McPR in ADC. Toripalimab showed higher ORR in both cancers without distinct pathological remission advantage. Pembrolizumab, however, demonstrated superior McPR in SCC, indicating a preference in treating SCC.

Diffusion-weighted magnetic resonance imaging as an early prognostic marker of chemoradiotherapy response in squamous cell carcinoma of the anus: An individual patient data meta-analysis

Background and purposeSquamous cell carcinoma of the anus (SCCA) can recur after chemoradiotherapy (CRT). Early prediction of treatment response is crucial for individualising treatment. Existing data on radiological biomarkers is limited and contradictory. We performed an individual patient data meta-analysis (IPM) of four prospective trials investigating whether diffusion-weighted (DW) magnetic resonance imaging (MRI) in weeks two to three of CRT predicts treatment failure in SCCA. Material and methodsIndividual patient data from four trials, including paired DW-MRI at baseline and during CRT, were combined into one dataset. The association between ADC volume histogram parameters and treatment failure (locoregional and any failure) was assessed using logistic regression. Pre-defined analysis included categorising patients into a change in the mean ADC of the delineated tumour volume above and below 20%. ResultsThe study found that among all included 142 patients, 11.3 % (n = 16) had a locoregional treatment failure. An ADC mean change of <20 % and >20 % resulted in a locoregional failure rate of 16.7 % and 8.0 %, respectively. However, no other ADC-based histogram parameter was associated with locoregional or any treatment failure. ConclusionsDW-MRI standard parameters, as an isolated biomarker, were not found to be associated with increased odds of treatment failure in SCCA in this IPM. Radiological biomarker investigations involve multiple steps and can result in heterogeneous data. In future, it is crucial to include radiological biomarkers in large prospective trials to minimize heterogeneity and maximize learning.

HPV status and immunohistochemical analysis of p16, p53 and PD‑L1 expression as prognostic biomarkers in patients with squamous cell anal cancer receiving definitive radiotherapy/chemoradiotherapy.

Anal squamous cell carcinoma (SCC) treated with definitive radiotherapy (RT)/chemoradiotherapy (CRT) has shown high success rates, yet challenges such as treatment resistance and recurrence persist. The present study aimed to investigate the associations between immunohistochemical (IHC) evaluation, treatment response and prognosis in anal SCC. A retrospective cohort analysis included 42 patients with anal SCC treated at a single institution between 2006 and 2022. Human papillomavirus (HPV) status was determined, and the IHC analysis of p16, p53 and PD-L1 expression was conducted using formalin-fixed, paraffin-embedded biopsies. A complete response to RT/CRT was observed in 71.4% of patients. Recurrence occurred in 38.1% of cases, of which 7.1% had local-regional recurrence (LRR), 14.3% had distant recurrence (DR), and 16.7% had both LRR and DR. HPV positivity (71.4%) was significantly associated with p16 positivity. Lack of complete response was associated with HPV-negative status, p16-negative status, increased recurrence and DR. In addition, recurrence was significantly associated with p53-positive status, and p53 positivity was significantly associated with increased LRR. PD-L1 positivity, defined as a combined positive score (CPS) ≥1% was found in 73.8% of the patients, and exhibited significant associations with HPV positivity and p16 positivity. PD-L1 CPS ≥ 1% was also associated with an increased LRR. Univariate analysis revealed that age <65 years, a complete response and HPV positivity were associated with increased 5-year overall survival (OS), while a complete response, HPV positivity and p53-negative status were associated with increased 5-year disease-free survival (DFS). Multivariate analysis identified that age <65 years and HPV positivity are independent prognostic factors for 5-year OS, and a complete response and p53-negative status are independent prognostic factors for 5-year DFS. In conclusion, these findings suggust that the identification of HPV status and poor prognostic biomarkers at diagnosis may be used to guide personalized treatment strategies, with the combination of immunotherapy with standard CRT potentially providing improved outcomes.

Prospective evaluation of body composition (BC) and nutritional status as predictors of treatment response in squamous cell carcinoma of head and neck (SCCHN) treated with immunotherapy (immuno-nutri study)

Prospective evaluation of body composition (BC) and nutritional status as predictors of treatment response in squamous cell carcinoma of head and neck (SCCHN) treated with immunotherapy (immuno-nutri study)

Corticotropin-releasing hormone receptor-1 is increased in mast cells in psoriasis and actinic keratosis, but not markedly in keratinocyte skin carcinomas.

Corticotropin-releasing hormone receptor-1 (CRH-R1) is expressed in human mast cells, but its role in skin diseases is unknown. By using a sequential double-staining technique, the mast cell expression of CRH-R1 was investigated in biopsies from lesional and non-lesional skin samples of patients with actinic keratosis (AK), basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and psoriasis. Dermal tryptase+ mast cells expressed CRH-R1 immunoreactivity in the non-lesional skin in all patient groups. The CRH-R1 expression was significantly increased in the lesional skin of AK (p = 0.03) and psoriasis (p = 0.02), non-significantly in BCC (p = 0.129), but not increased in SCC. To investigate the regulation of CRH-R1, the LAD2 mast cell line was irradiated with UVB or stimulated with CRH or 1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3 ]. Consequently, UVB at 90 mJ/cm2 (p = 0.041) and 120 mJ/cm2 (p = 0.039) decreased CRH-R1 expression. Instead, CRH at 100 and 1000 nM increased CRH-R1 immunostaining, but did not affect the proliferative response. The treatment with 10 and 100 nM 1,25-(OH)2 D3 led to a noticeable increase in CRH-R1 staining. After irradiating with UVB, the concentration of CRH increased in the conditioned medium, but not in sonicated LAD2 mast cells. In conclusion, the lack of sufficient levels of CRH-R1 in mast cells may be related to diminished antitumoural response in SCC and possibly in BCC.

Characterizing chromosome 3p/q genes as biomarkers of treatment response in squamous cell carcinoma of the lung and head and neck.

e18048 Background: There is an urgent need to improve treatment options for lung squamous cell carcinoma (LUSC) and head and neck squamous cell carcinoma (HNSCC). Immunotherapy (IO) is used in both diseases, but response rates are ~20% to monotherapy. Chromosome alterations in 3p/3q are frequently found in both LUSC and HNSCC. Here we examined the association of expression of Chromosome 3p/3q genes with treatment outcomes and immune microenvironment. Methods: 3833 LUSC and 1386 HNSCC biopsies were analyzed by next-generation sequencing (592, NextSeq; WES, WTS NovaSeq). Selected Chr 3p ( DLEC1, FOXP1, LTF) and Chr 3q ( SOX2) genes were classified by above (-H, high) or below (-L, low) median RNA expression. HPV status inferred by staining of p16 by IHC. Real world median overall survival (mOS) was obtained from insurance claims and calculated from tissue collection or first IO treatment to last contact using Kaplan-Meier estimates. Immune cell infiltration was estimated based on RNA deconvolution method Quantiseq. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q &lt; 0.05). Results: High LTF ( LTF-H) was associated with improved OS in both LUSC (mOS: 559 vs 349 days; HR: 0.7, 95% CI (0.6-0.7)) and HNSCC (mOS: 567 vs 473 days; HR: 0.8, 95% CI (0.7-0.9)) (p &lt; 0.01). LTF-H was also associated with improved post-IO survival in both LUSC (Pembro, mOS: 532 vs 349 days; HR: 0.8, 95% CI (0.6-0.9)) and HNSCC (Nivo, mOS: 797 vs 604 days; HR: 0.5, 95% CI (0.2-0.9)) (p &lt; 0.05). Interestingly, this improved OS was specific to HPV+ HNSCC patients (Nivo, Pembro mOS: 1210 vs 473 days; HR: 0.39, 95% CI (0.22-0.69) (p &lt; 0.01)) and not HPV- HNSCC patients (Nivo, Pembro mOS: 313 vs 336 days; HR 0.98, 95% CI (0.664-1.47) (p = 0.95)). LTF-H LUSC and HNSCC had increased IFNy score (-0.24 vs -0.30; -0.16 vs -0.23, p &lt; 0.05) and immune cell infiltration of B cells (median cell fraction: 6.9% vs 5.8%; 6.9% vs 5.3%), M2 Mφ (5.7% vs 5.1%; 4.3% vs 3.8%), NK cells (3.1% vs 2.8%; 3.3% vs 2.7%), CD4 T cells (1.7% vs 1%; 1.7% vs 1%), CD8 T cells (1.5% vs 1%; 1.5% vs 1%) and Tregs (3.1% vs 2.4%; 4.1% vs 3.5%) compared to LTF-L tumors, respectively (all p &lt; 0.05). Additionally, high DLEC1 was associated with improved OS in LUSC (mOS: 484 vs 392 days; HR: 0.8, 95% CI (0.8-0.9)) and HNSCC (mOS: 594 vs 448 days; HR: 0.7, 95% CI (0.6-0.9) (p &lt; 0.01)). FOXP1 expression did not correlate with different survival in LUSC or HNSCC. High SOX2 expression was associated with an improved OS in LUSC (mOS: 526 vs 352 days; HR: 0.7, 95% CI (0.7-0.8)) and HNSCC (mOS: 634 vs 404 days; HR: 0.7, 95% CI (0.6-0.8)) (p &lt; 0.01). Conclusions: Our data suggest a strong association between LTF expression and differential immune cell infiltration and improved overall survival. Future studies interrogating additional Chr 3q/3p alterations may provide further information of the prognostic implications of LTF in LUSC and HNSCC.

288 Role of TGFβ1 in combination with NAC in the response of squamous cell carcinoma to photodynamic therapy

288 Role of TGFβ1 in combination with NAC in the response of squamous cell carcinoma to photodynamic therapy

Abstract 4597: TIMP1 is a major contributor of the angiogenic priming of tumor associated fibroblasts in lung adenocarcinoma

Abstract Background: Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most common histologic subtypes in lung cancer. Intriguingly, ADC and SCC exhibit distinct responses to the multi-tyrosine kinase inhibitor nintedanib and other antiangiogenic drugs, suggesting that angiogenesis may depend on the histologic subtype in lung cancer. In addition, tumor-associated fibroblasts (TAFs) are known regulators of angiogenesis, and we have recently reported that TAFs exhibit enhanced fibrosis and response to nintedanib in ADC compared to SCC, owing to the stronger epigenetic repression of SMAD3 in SCC-TAFs caused by excessive exposure to cigarette smoke particles. However, how the histotype-dependent fibrotic phenotype in TAFs impacts their pro-angiogenic functions remains unknown. Methods: A panel of angiogenesis markers was assessed in patient samples using publicly available databases. The pro-angiogenic function of the conditioned medium of TAFs from ADC and SCC patients pre-activated with TGF-β1 was analyzed in vitro using migration and network formation assays of endothelial cells. The secretion of pro-angiogenic factors in TGF-β1-activated TAFs was analyzed using an angiogenesis antibody blot array. Selected factors were functionally validated in vitro and in vivo using genetic models. Results: All angiogenesis markers were consistently upregulated in ADC compared to SCC concomitantly with a lower necrosis in ADC, unveiling a larger angiogenesis in ADC. We also observed that the conditioned medium of TGF-β1-activated TAFs elicited a larger endothelial cell network formation and migration in ADC than SCC, revealing that ADC-TAFs exhibit enhanced angiogenesis. Our immunoblot array analysis identified a subset of pro-angiogenic factors that were selectively overexpressed in ADC-TAFs compared to SCC-TAFs, including TIMP-1. Notably, TIMP-1 overexpression in ADC-TAFs was SMAD3-dependent and knocking down TIMP-1 by siRNA in ADC-TAFs impaired angiogenesis in vitro and in tumor xenografts in vivo. Conclusions: Our results reveal a larger angiogenesis in ADC compared to SCC, and implicate the TGF-β1/SMAD3/TIMP-1 pathway in the enhanced angiogenesis of ADC-TAFs. Our findings identify a biological process underlying the poor response of SCC to antiangiogenic therapies like nintedanib, and provide a rationale for the earlier metastasis of ADC patients compared to SCC patients based on the enhanced pro-angiogenic role of ADC-TAFs. Citation Format: Natalia Isabel Diaz Valdivia, Paula Duch, Rafael Ikemori, Eduard Monso, Noemi Reguart, Jordi Alcaraz. TIMP1 is a major contributor of the angiogenic priming of tumor associated fibroblasts in lung adenocarcinoma. [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 4597.

Canine squamous cell carcinoma: Electrochemotherapy association with surgery and correlation with overall survival.

Squamous cell carcinoma (SCC) is an important malignancy in dogs, due to its incidence and clinical presentation, which can be of locally aggressive single or multiple lesions with a metastatic potential. The objective of this investigation was to evaluate SCC response to treatment, anatomopathological and immunohistochemical characteristics, disease-free interval and overall survival time. 54 dogs with histopathologically diagnosed SCC were included in this study. Their mean age was 9.16 years with a range of 1-14 years. Of the 54 animals in the study, 34 (65.4%) had white skin and white fur coats. There was a significant correlation between fur coat colour and the development of tumours in areas of sun exposure (p=.001). Animals with tumours in areas of the body exposed to the sun had longer overall survival time than animals with tumours in areas not associated with sun exposure (p=.001). Surgery combined with electrochemotherapy (ECT) yielded a survival rate 32% higher than using a surgical approach alone (HR=0.32, p=.038, IC=0.11-0.94). ECT, with or without surgery, had an objective response rate of 90.9%. Local lymph node and/or distant site metastasis at diagnosis, or at some point during follow-up, occurred in 34.6% (18/52) of animals. Animals with tumours in sun exposed locations had more aggressive histopathological characteristics but had longer overall survival time. This is probably due to individualised therapeutic treatment with both surgery and ECT.

A pilot study using immunohistochemical staining to characterize dihydropyrimidine dehydrogenase expression in keratinocyte neoplasms

To the Editor: Topical 5-fluorouracil (5-FU) is a chemotherapeutic agent used to treat actinic keratoses (AK), superficial basal cell carcinoma, and squamous cell carcinoma in situ (SCCis). 5-FU is metabolized and inactivated by the enzyme dihydropyrimidine dehydrogenase (DPD), which is highly active in the liver but can be expressed in tumors as well. In several visceral malignancies, tumor DPD expression predicts response to systemic 5-FU: tumors with lower DPD expression correlate with higher 5-FU reactivity and better clinical response.1Horiguchi J. Yoshida T. Koibuchi Y. et al.DPD activity and immunohistochemical DPD expression in human breast cancer.Oncol Rep. 2004; 11: 65-72PubMed Google Scholar, 2Oi K. Makino M. Ozaki M. et al.Immunohistochemical dihydropyrimidine dehydrogenase expression is a good prognostic indicator for patients with Dukes' C colorectal cancer.Anticancer Res. 2004; 24: 273-279PubMed Google Scholar, 3Fukuda H. Takiguchi N. Koda K. Oda K. Seike K. Miyazaki M. Thymidylate synthase and dihydropyrimidine dehydrogenase are related to histological effects of 5-fluorouracil and cisplatin neoadjuvant chemotherapy for primary gastric cancer patients.Cancer Invest. 2006; 24: 235-241https://doi.org/10.1080/07357900600632082Crossref PubMed Scopus (18) Google Scholar Although this association has been studied in visceral tumors, the expression of DPD in keratinocyte neoplasms is not known. In this pilot study, we assessed DPD expression in benign, premalignant, and malignant keratinocyte neoplasms to assess the range and level of DPD activity. We performed DPD immunohistochemistry (IHC) staining of 26 superficial and nodular basal cell carcinomas (BCCs), 10 SCCis, 16 AKs, and 8 seborrheic keratoses from formalin-fixed paraffin-embedded specimens collected within the past 3 years. Diagnoses were confirmed by dermatopathologists (B.H., B.D.). DPD IHC was performed with anti-DPD antibody (Abcam #134922, 1:500 dilution). DPD expression was scored by intensity ranging from 0 to 3 by 2 authors (O.I. and B.D.), with hepatic staining as a positive control (Table I). Fisher’s exact test was used to compare DPD scores between classes of keratinocyte neoplasms (R software, version 4.0.3, https://www.r-project.org).Table IDihydropyrimidine dehydrogenase immunohistochemistry intensity score in patient samples (n = 60)DPD IHC intensity score0123Seborrheic keratosis0422Actinic keratosis1960SCC in situ0442Basal cell carcinoma21410Basal cell carcinoma includes both superficial and nodular subtypes. DPD IHC intensity was scored from 0 to 3 (0: no expression, 1: weak expression, 2: moderate expression, 3: strong expression). Fisher’s exact test P value = 3.95 × 10−9.DPD, Dihydropyrimidine dehydrogenase; IHC, immunohistochemistry; SCC, squamous cell carcinoma. Open table in a new tab Basal cell carcinoma includes both superficial and nodular subtypes. DPD IHC intensity was scored from 0 to 3 (0: no expression, 1: weak expression, 2: moderate expression, 3: strong expression). Fisher’s exact test P value = 3.95 × 10−9. DPD, Dihydropyrimidine dehydrogenase; IHC, immunohistochemistry; SCC, squamous cell carcinoma. The results showed a significantly enriched proportion of BCCs (81%, 21/26) displaying no DPD expression (DPD IHC intensity score of 0), compared to 0% (0/10) of SCCis and 6% (1/16) of AKs (P = 3.95 × 10−9, Table I). By contrast, 15% of BCC, 40% of SCCis, and 56% of AK had an intensity score of 1; 3% of BCC, 40% of SCCis, and 37.5% of AK had an intensity score of 2; and 0% of BCC, 20% of SCCis, and 0% of AK had an intensity score of 3 (Table I). The DPD intensity scores of seborrheic keratoses, a noncancerous keratinocyte neoplasm control, were distributed between 1 and 3. Our results suggest that DPD expression varies both within and across different keratinocyte neoplasms, and that a substantial fraction of BCC may have lower DPD expression compared to AK, squamous cell carcinoma (SCC), and seborrheic keratoses. Clinical studies have reported a wide range of efficacy in the use of topical 5-FU treatment for early-stage BCC and SCC, with success rates in SCC ranging from 27% to 93%.4Love W.E. Bernhard J.D. Bordeaux J. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma.Arch Dermatol. 2009; 145: 1431-1438Crossref PubMed Scopus (191) Google Scholar,5Neale H. Michelon M. Jacob S. et al.Topical 5% 5-fluorouracil versus procedural modalities for squamous cell carcinoma in situ and superficial basal cell carcinoma: a retrospective cohort analysis.J Am Acad Dermatol. 2022; 87: 423-425https://doi.org/10.1016/j.jaad.2021.08.045Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar While differences in treatment regimens and study design are likely to contribute to this variability, our results raise the possibility that differences in keratinocyte tumor DPD expression could also play a role in topical 5-FU treatment efficacy. The results of this pilot study support the value of a larger prospective study to investigate if DPD expression predicts clinical response of low-grade BCC and SCC to topical 5-FU. If true, then DPD IHC staining could be performed by pathology services to identify keratinocyte neoplasms that are more likely to respond favorably to topical 5-FU, reducing the uncertainty of treatment efficacy to this useful therapeutic option. None disclosed.

297 Role of TGFβ1 in combination with N-acetyl cysteine in the response of squamous cell carcinoma to photodynamic therapy

In the present study, we aim to understand the implications of transforming growth factor β1 secreted by cancer-associated fibroblasts (CAFs) in the resistance of cutaneous squamous cell carcinoma (cSCC) cells to photodynamic therapy (PDT), as well as the effects of the combination of PDT with N-acetyl cysteine (NAC). PDT is widely used for the treatment of cSCC, and it involves the combination of visible light, molecular oxygen and a photoactive compound (photosensitizer), leading to cell death owing to the generation of reactive oxygen species.

P-178 Diffusion-weighted magnetic resonance imaging as an early predictive marker of chemoradiotherapy response in squamous cell carcinoma of the anus: An individual patient data meta-analysis

Patients with squamous cell carcinoma of the anus (SCCA) are at risk of locoregional recurrence after chemoradiotherapy (CRT). An early prognostic marker of treatment response would enable timely individualisation of treatment for patients with SCCA. Diffusion-weighted (DW) magnetic resonance imaging (MRI) features, such as apparent diffusion coefficient (ADC), may be prognostic; however, few trials with small patient numbers exist for SCCA. Using an individual patient data meta-analysis, we aimed to investigate in a larger cohort whether ADC based histogram parameters from paired DW-MRI at baseline and during CRT correlate with local or any relapse in patients with SCCA.

Strontium 90 plesiotherapy for the treatment of eyelid squamous cell carcinoma in eight cats.

Squamous cell carcinoma (SCC) is the most common eyelid tumour in cats. The main treatment is extensive surgery and the cosmetic outcome can be worrisome for some owners. Strontium 90 (ST-90) plesiotherapy is a therapeutic modality used for superficial tumours, including SCC. The aim of this study was to describe the use and response of feline eyelid SCC to ST-90 plesiotherapy either as single treatment or as adjuvant therapy following surgery. A referral centre clinical database was searched for all cats diagnosed with SCC located on an eyelid. Cats treated with ST-90 plesiotherapy were included. The response to treatment was evaluated visually every 4-6 weeks until complete healing and based on response evaluation criteria in solid tumours (RECIST). Descriptive statistics of the survival were applied to the data collected. Eight cats treated between 2014 and 2017 met the inclusion criteria. The median age was 10.8 years. In six cases, ST-90 was used as the only treatment modality, while in two cats it was used as an adjuvant to surgery. Four cats received a single protocol and four a hypofractionated protocol. In the six cats in which ST-90 was used as the primary treatment, the response was 100%. Four cats died at a median time of 9 months (3-17 months) after ST-90 due to causes unrelated to SCC. Of the remaining four cats, three had no signs of recurrence at a median time of 34 months and one was lost to follow-up at 17 months with no signs of recurrence. This small study showed that ST-90 can be used for treatment of eyelid SCC with good therapeutic and cosmetic outcomes.

Ex vivo functional assay for predicting radiation treatment response in squamous cell carcinoma of the head and neck

Ex vivo functional assay for predicting radiation treatment response in squamous cell carcinoma of the head and neck

Cutaneous squamous cell carcinomas in domestic rabbits (Oryctolagus cuniculus): 39 cases (1998-2019)

Domestic rabbits ( Oryctolagus cuniculi ) can develop a variety of cutaneous neoplasms, including squamous cell carcinoma (SCC). A detailed review of gross and microscopic pathology and response to treatment of spontaneously arising SCCs in domestic rabbits has not been published. A retrospective survey study of the clinical characteristics and response to treatment in 39 cases of spontaneous SCC in pet rabbits was performed in an attempt to better characterize the typical presentation, prognosis, and therapeutic response of SCCs in domestic rabbits. Sixteen of these cases were also selected for papillomavirus testing using a generic polymerase chain reaction. SCC was identified in rabbits between 2 and 10 years of age, with a median age of 7 years. The neoplasm has a predilection for ears and feet and the conventional subtype is most commonly diagnosed microscopically. Lighter colored rabbits may be predisposed to developing SCC. The majority of cases examined were found in rabbits housed primarily indoors. Only one SCC tested positive for papillomavirus and was located in the oral cavity. Sequencing of the detected PCR product detected 98.75% similarity to human papillomavirus type 120. The significance of this virus for tumorigenesis is unknown. Aggressive surgical resection provided the most successful therapeutic option and proved curative in 12 of 23 rabbits. Papillomavirus likely does not play a major role in the development of spontaneous SCCs in pet rabbits. More research is needed to investigate the use of adjunctive therapies in treatment of this neoplasm in pet rabbits.

26P Analysis of prognostic and predictive factors of response in squamous cell carcinoma using NGS techniques

Background: In recent years, the diagnosis and treatment of different neoplasms has undergone a great change due to the development of immunotherapy and targeted therapies. Furthermore, the incorporation of massive sequencing techniques (NGS) has made it possible to better understand the molecular profile of tumors and thus, the identification of possible biomarkers related to prognosis and response.

Epigenetic Alterations in Keratinocyte Carcinoma

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are both derived from epidermal keratinocytes but are phenotypically diverse. To improve the understanding of keratinocyte carcinogenesis, it is critical to understand epigenetic alterations, especially those that govern gene expression. We examined changes to the enhancer-associated histone acetylation mark H3K27ac by mapping matched tumor-normal pairs from 11 patients (five with BCC and six with SCC) undergoing Mohs surgery. Our analysis uncovered cancer-specific enhancers on the basis of differential H3K27ac peaks between matched tumor-normal pairs. We also uncovered biological pathways potentially altered in keratinocyte carcinoma, including enriched epidermal development and Wnt signaling pathways enriched in BCCs and enriched immune response and cell activation pathways in SCCs. We also observed enrichment of transcription factors that implicated SMAD and JDP2 in BCC pathogenesis and FOXP1 in SCC pathogenesis. On the basis of these findings, we prioritized three loci with putative regulation events (FGFR2 enhancer in BCC, intragenic regulation of FOXP1 in SCC, and WNT5A promoter in both subtypes) and validated our findings with published gene expression data. Our findings highlight unique and shared epigenetic alterations in histone modifications and potential regulators for BCCs and SCCs that likely impact the divergent oncogenic pathways, paving the way for targeted drug discoveries.

Avasopasem Manganese Protects Against Radiation Induced Oral Mucositis and Enhances the Response of Squamous Cell Carcinoma of the Head and Neck to Ionizing Radiation and Radioimmune Therapy

Locoregional recurrence (LRR) is the major cause of morbidity and mortality in patients with squamous cell carcinoma of the head and neck (HNSCC). For those patients that experience surgically unresectable LRR, median overall survival (OS) is less than one year. Approaches utilizing stereotactic ablative radiotherapy (SabR) and immuno-oncology agents such as Nivolumab (α-PD-1 inhibitor) in the salvage setting have become alternatives to conventional chemoradiation therapy. Despite improvements in OS, rates of acute oral mucositis (OM) and late toxicities (skin fibrosis) remain concerns with SabR in the context of re-irradiation. Here we present pre-clinical evidence that avasopasem manganese (GC4419), a highly selective superoxide dismutase mimetic that has received FDA Breakthrough Therapy Designation and is currently in a Phase III trial for reducing severe OM in patients undergoing chemoradiotherapy for locally advanced HNSCC (NCT03689712) also enhances the anti-tumor radiation response of HNSCC tumors. We demonstrate in pre-clinical animal models that avasopasem protects the normal mucosa of the mouse tongue from primary irradiation toxicity. We will also report the results of ongoing studies examining whether avasopasem protects murine mucosa from reirradiation as with SabR as a salvage therapy. Utilizing clonogenic survival assays, we demonstrate that avasopasem at physiologically achievable concentrations exhibits single agent anti-cancer activity and also enhances the response of HNSCC lines to irradiation. In tumor growth delay (TGD) experiments utilizing the syngeneic HNSCC tumor model, AT-84, when avasopasem is delivered in combination with biologically equivalent fractionation schedules of 17 Gy x 1 fxn, 10.24 Gy x 2 fxn, or 5 Gy x 5 fxn, an enhancement of the radiation response is achieved. This potentiation of the anti-tumor response with GC4419 is more pronounced at fraction doses exceeding the threshold considered for intensity modulated radiation therapy. In addition, when avasopasem is combined with radiation and an α-PD-1 inhibitor, a further enhancement of the radiation response is observed, indicating that it compliments radiotherapy combined with immunotherapy. The pre-clinical data strongly suggest that avasopasem should be combined with radio-immune therapy to not only enhance local tumor control, but also to provide normal tissue protection with SabR which may allow dose escalation and further improve treatment outcomes. Whether radiation combined with avasopasem and checkpoint inhibitor has an effect on metastasis is under examination.

Abstract 6284: GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy

Abstract Locoregional recurrence (LRR) is the major cause of morbidity and mortality in patients with squamous cell carcinoma of the head and neck (HNSCC). For those patients that experience surgically unresectable LRR, median overall survival (OS) is less than one year. Approaches utilizing stereotactic ablative radiotherapy (SAbR) and immune oncology agents such as Nivolumab (α-PD-1 agonist) in the salvage setting have become alternatives to conventional chemoradiation therapy. Despite improvements in OS, rates of acute oral mucositis (OM) and late toxicities (skin fibrosis) remain a concern with SAbR, particularly in the context of re-irradiation. Here we present pre-clinical evidence that GC4419 (Galera Therapeutics), a highly selective superoxide dismutase mimetic that recently received FDA Breakthrough therapy status following a Phase II, randomized, placebo controlled trial for reducing the duration and incidence of severe OM in patients undergoing chemoradiation therapy for locally advanced HNSCC (NCT02508389) also enhances the anti-tumor radiation response of HNSCC tumors to irradiation. We demonstrate in pre-clinical animal models that GC4419 protects the normal mucosa of the mouse tongue from radiation exposure. Utilizing clonogenic survival assays, GC4419 demonstrates single agent anti-cancer activity at physiologically achievable concentrations, while also enhancing the response of HNSCC lines to irradiation. In tumor growth delay (TGD) experiments utilizing the syngeneic HNSCC tumor model, AT-84, when GC4419 is delivered 30-60 minutes pre-irradiation with biologically equivalent fractionation schedules of 17 Gy x 1 fxn, 10.24 Gy x 2 fxn, or 5 Gy x 5 fxn, an enhancement of the radiation response is achieved. In tumor cure rate (TCD50) studies, GC4419 enhanced radiation exposure with a DEF of 1.25. Furthermore, when GC4419 is combined with radiation and an α-PD-1 inhibitor, a further enhancement of the radiation response is observed, indicating that GC4419 compliments radiotherapy combined with immune oncology. We will also report the results of ongoing studies examining the potency of GC4419 in protecting normal murine mucosa in the setting of reirradiation relevant to SAbR as a salvage therapy. This potentiation of the anti-tumor response with GC4419 is more pronounced at doses exceeding the threshold to be considered for intensity modulated radiation therapy (IMRT). The accompanying pre-clinical data strongly suggest that GC4419 should be combined with radio-immune therapy to not only enhance local tumor control, but that the potential for normal tissue protection with SAbR also creates the opportunity for dose escalation and may further improvement in treatment outcome. Citation Format: Brock James Sishc, Elizabeth Polsdofer, Debabrata Saha, Michael Story. GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6284.

Next-generation sequencing identifies novel single nucleotide polymorphisms in high-risk cutaneous squamous cell carcinoma: A pilot study.

Cutaneous squamous cell carcinoma (SCC) causes 1 million cases in the United States annually. There are germline single nucleotide polymorphisms (SNPs) that result in an increased risk of SCC and altered response to therapy. There may be biologically relevant SNPs not detected using traditional GWAS studies. There are clinically and biologically relevant SNPs in high-risk SCC that may only be appreciated with next-generation sequencing. We performed next-generation sequencing (NGS) on primary SCCs using a targeted mutation panel with 76 cancer-associated genes. We analysed the presence of SNPs in a cohort of 20 high-risk SCCs compared to the American population (AP) (dbSNP). Missense rs3822214 was present in significantly more SCC cases versus the AP. While the remainder is synonymous SNPs, there is growing evidence suggesting clinical relevance of these variants. A larger cohort to validate these findings would be useful.