Squamous Cell Carcinomas In Taiwan Research Articles

Abstract 1111: Poor radiation sensitivity and potential radiosensitizers for betel-nuts related head and neck squamous cell carcinoma in Taiwan

Abstract Background: Betel nut chewing might contribute to strong invasion & treatment refractoriness in HNSCC from Taiwan. Betel-nuts exposed HNSCC cell line, TW2.6, had high PDL1, defective p53 mutation, p16 loss, & BCL2 overexpression. In our studies, PI3K/AKT/mTOR inhibitors, anti-angiogenesis therapies, CDK4/6 inhibitors, DDR interventions, epigenetic modifications, and immunotherapy-containing regimens will be future combination options. The genomic signature of TW2.6 has been figured out in our study(AACR2020 & 2023), too, mainly with PIK3CA H1047R mutation, high TMB(8.42 muts/Mb)/MSS, VEGF-A amplification, p53/MYC/HRAS/DDR2/PDGFRbeta/EPHB1/ATM mutations, FAT1 loss, amplification of TERT/FGF10/CCND3/SOX9/IL-7R/SDHA/RICTOR/FLCN, CDK12/PTPRD loss of function, CDK8 mutation, & deletions of STK11/ARID1B/MITF/TNFAIP3 and molecularly-guided novel interventions will be designed. Purpose & Methods: Polo-like kinase 1 inhibitor(volasertib), gluconate(blocking citrate transport & glucose metabolism), IAP inhibitor(Debio1143), glutaminase 1 inhibitor(CB839) were tested on TW2.6 to evaluate synergistic effects with radiation. Results: TW2.6 was resistant to volasertib, gluconate, or radiation alone; but sensitive to Debio1143 and CB839. Volasertib significantly enhanced radiation. The flow cytometry revealed volasertib and radiation resulted in a significant G2/M arrest. Western blotting showed volasertib and radiation increased p-histone3, p-CDK1, & cyclin B levels and induced apoptosis. Gluconate, CB839, or Debio1143 each had significant synergistic effects with radiation. The radiosensitization efficacy would be volasertib>gluconate>CB839>Debio1143. Conclusions: In Taiwan, patients with R/M HNSCC progressing within 3 months after CCRT could be rescued by early ICIs. Recently, sequential CCRT followed by ICI or Debio-1143 with CCRT showed potential survival benefits. In our studies, novel agents such as PLK inhibitor, gluconate, and CB839 had even better radiosensitization compared with Debio1143. Sequential CCRT with novel agents followed by ICI will be the future trend, esp. in biology-aggressive betel-nuts related locally advanced HNSCC in Taiwan. Citation Format: Jo-Pai Chen, Jui-Ying Chang, Ruey-Long Hong. Poor radiation sensitivity and potential radiosensitizers for betel-nuts related head and neck squamous cell carcinoma in Taiwan [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 1111.

P37-6 Potential radiosensitizers for betel nuts-related head and neck squamous cell carcinoma in Taiwan

P37-6 Potential radiosensitizers for betel nuts-related head and neck squamous cell carcinoma in Taiwan

Incidence trends and spatial distributions of lung adenocarcinoma and squamous cell carcinoma in Taiwan

Lung cancer is the second most common cancer in Taiwan. After Taiwan implemented the Tobacco Hazards Prevention Act in 1997, smoking rates declined. However, the incidence rates of lung cancer for both sexes are still increasing, possibly due to risk factors other than smoking. We used age–period–cohort analysis to examine the secular trends of lung cancer incidence rates by histological type in Taiwan. A stabilized kriging method was employed to map these lung cancer incidence rates. Lung adenocarcinoma incidence rates increased, but lung squamous cell carcinoma incidence rates decreased, for both the sexes in recent birth cohorts, particularly in women. In Taiwan, the hotspots of lung adenocarcinoma incidence rates were in the northern, northeastern, and western coastal areas; the incidence rates increased rapidly in the western and southern coastal regions and southern mountainous regions. The high incidence rates of lung squamous cell carcinoma in men were in the southwestern and northeastern coastal areas. The incidence rates rapidly increased in the central and southern coastal and mountainous regions. For both sexes in Taiwan, lung squamous cell carcinoma incidence rates declined from 1997 to 2017, but lung adenocarcinoma increased. The increased incidence rates of lung adenocarcinoma may be related to indoor and outdoor air pollution. Some areas in Taiwan have increasing lung cancer incidence rates, including the northwestern and southern coasts and mountains, and warrant particular attention.

Secular-Trend Analysis of the Incidence Rate of Lung Squamous Cell Carcinoma in Taiwan.

Lung cancer is the leading cause of cancer deaths worldwide, and squamous cell carcinoma (SQC) is Taiwan's second most common lung carcinoma histotype. This study aimed to investigate changes in the long-term trend of the SQC incidence rate in Taiwan. SQC cases between 1985 and 2019 were adopted from Taiwan's Cancer Registry System; the age-adjusted incidence rate was calculated using the World Standard Population in 2000. The long-term trends of the age, period, and birth cohort effect of SQC incidence rates were estimated using the SEER Age-Period-Cohort Web Tool. The results revealed that the incidence of lung carcinoma in Taiwan increased, while the incidence of SQC exhibited a slight decrease during this study period. The age rate ratio (ARR) of the incidence rate in men declined gradually, and the period effect changed more slowly for women than men. The cohort effect formed a bimodal curve. The annual percentage change results for women indicated that the ARR decreased from 1.652 (95% confidence interval (CI): 1.422, 1.9192) at 30 to 34 years to 0.559 (95% CI: 0.4988, 0.6265) at 75 to 79 years; the period effect decreased from 1.2204 (95% CI: 1.1148, 1.336) in 1995 to 1999 to 0.608 (95% CI: 0.5515, 0.6704) in 2015 to 2019, with a greater decline in the later period. The cohort effect was unimodal, with the SQC risk value peaking in the 1915 birth cohort and exhibiting a steady decline thereafter. The results of this study suggest that a decrease in the smoking rate may be the reason for the decline in the incidence of SQC, and we observed a similar trend between SQC and the smoking rate in men.

Long-term outcomes of endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma in Taiwan

BackgroundEndoscopic submucosal dissection (ESD) is gradually turning into the standard treatment for superficial esophageal squamous cell carcinoma (SESCC), however, the long-term outcomes have hardly ever been reported outside Japan.MethodWe consecutively recruited patients with SESCC who had received ESD treatment at E-Da Hospital. The demographics, pathological characteristics, and Lugol staining background pattern (type A or B: none or < 10 small Lugol-voiding lesions [LVLs]; type C or D: > 10 small or multiform LVLs) were collected, and then correlated to outcomes and survival.ResultsTotal of 229 lesions were enrolled and the mean lesion size was 3.28 ± 1.69 (range 1–10) cm. 72% of the lesions had a type C-D Lugol staining background pattern. After ESD, the en bloc and R0 resection rates were 93.9% and 83.5%, respectively. Forty-nine subjects developed complications, including six (2.6%) with major bleeding, two (0.9%) with perforation, and 41 (17.9%) with strictures. Pathological staging showed that 19 cases had deep submucosal cancer invasion and subsequently received adjuvant therapies. During a mean follow-up period of 52.6 (range 3–146) months, 41 patients developed metachronous recurrence. The patients with a type C-D Lugol staining background pattern were associated with a higher risk of recurrence than those with few LVLs (log-rank P = 0.019). The 10-year survival rate was more than 90%, and only eight patients died of ESCC.ConclusionESD has excellent long-term outcomes but a high risk of metachronous recurrence. The Lugol staining pattern over the background mucosa could offer the risk stratification of metachronous recurrence.

Understanding the impact of high-risk human papillomavirus on oropharyngeal squamous cell carcinomas in Taiwan: A retrospective cohort study.

Background and objectivesHuman papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally. In Taiwan, HPV-positive OPSCC is obscured by tobacco, alcohol, and betel quid use. We investigated the role of high-risk HPV (hrHPV) in a large retrospective Taiwan OPSCC cohort.Methods and resultsThe cohort of 541 OPSCCs treated at Chang Gung Memorial Hospital from 1998–2016 consisted of 507 men (94%) and 34 women (6%). Most used tobacco (81%), alcohol (51%), and betel quid (65%). Formalin-fixed, paraffin-embedded tissue was used for p16 staining (a surrogate marker for HPV) and testing for HPV DNA presence and type by Multiplex HPV PCR-MassArray. HPV DNA and/or p16 staining (HPV-positive) was found in 28.4% (150/528) tumors. p16 and HPV DNA were strongly correlated (F < 0.0001). HPV16 was present in 82.8%, and HPV58 in 7.5% of HPV-positive tumors. HPV was associated with higher age (55.5 vs. 52.7 years, p = 0.004), lower T-stage (p = 0.008) better overall survival (OS) (hazard ratio [HR] 0.58 [95% CI 0.42–0.81], p = 0.001), and disease-free survival (DFS) (HR 0.54 [95% CI 0.40–0.73], p < 0.0001). Alcohol was strongly associated with recurrence and death (OS: HR 2.06 [95% CI 1.54–2.74], p < 0.0001; DFS: HR 1.72 [95% CI 1.33–2.24], p < 0.0001). OS and DFS in HPV-positive cases decreased for alcohol users (p < 0.0001). Obscured by the strong alcohol effect, predictive associations were not found for tobacco or betel quid.ConclusionsAs with HPV-positive OPSCC globally, HPV is an increasingly important etiological factor in Taiwanese OPSCC. HPV-positive OPSCC has considerable survival benefit, but this is reduced by alcohol, tobacco, and betel quid use. hrHPV is a cancer risk factor in males and females. Vaccinating both sexes with a multivalent vaccine including HPV58, combined with alcohol and tobacco cessation policies will be effective cancer-prevention public health strategies in Taiwan.

271P Cost-effectiveness of pembrolizumab as monotherapy or in combination with chemotherapy versus EXTREME regimen for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma in Taiwan

271P Cost-effectiveness of pembrolizumab as monotherapy or in combination with chemotherapy versus EXTREME regimen for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma in Taiwan

Abstract B07: High-risk human papillomavirus association with oropharyngeal squamous cell carcinoma in Taiwan

Abstract Introduction: Taiwan has a high rate of oropharyngeal squamous cell carcinoma (OPSCC). The etiologic factors are primarily tobacco and alcohol abuse. High-risk human papillomaviruses (hrHPV) have been reported in oral cancers in Taiwan, but their role in oropharyngeal cancer has not been studied. We investigated the possible role of hrHPV in OPSCC Taiwanese patients. Materials and Methods: We identified 546 OPSCC tumors from patients undergoing standard care and informed consent, between 1998 and 2016, at the Chang Gung Memorial Hospital (CGMH) in Taiwan. Formalin-fixed, paraffin-embedded (FFPE) tissue sections from 504 patients were screened by p16 immunostaining, a surrogate marker for active HPV (Ventana antibody, Cat. No. 725-4713, prediluted), and scored for intensity and proportion of positive tumor cells according to the 2018 College of American Pathologists recommendations. Genomic DNA was extracted from FFPE sections (AllPrep Kit, Qiagen) and HPV was detected and genotyped by Multiplex PCR-Mass Array (PCR-MA) analysis designed to detect 15 high-risk, 1 intermediate-risk, and 2 low-risk HPV types. Results: Of the 504 OPSCC tumors tested for p16, 104 (20.6%) were positive, 380 (75.4%) negative, and 20 (4.0%) could not be scored. Spearman nonparametric correlation analysis demonstrated a linear increase in p16 positivity with time from 1998 to 2015 in this Taiwanese population (r= 0.6320, p= 0.003; R2= 0.4901, p= 0.0012). To date, HPV genotyping in 179 Taiwan tumors showed that 38 (21.2%) were hrHPV positive, 120 (67.0%) negative, and 21 (11.7%) had insufficient DNA. Of the 38 HPV-positive tumors, HPV16 alone was found in 31 (81.6%), HPV39 and HPV59 were each found once in separate tumors, and several tumors had two HPV types present: HPV16 and HPV18 were present together in 2 tumors, and each of the following pairs were found in one tumor each: HPV16 with HPV35, HPV16 with HPV59, and HPV16 with HPV6. Of the tumors tested by both p16 and PCR-MA, there was 97% concordance between the results (130/134). Conclusion: Our preliminary findings indicate that the proportion of hrHPV positive OPSCC tumors in this Taiwanese population is increasing over the period from 1998 to 2015 in Taiwan. The concordance of p16 and HPV DNA is very high (p&amp;lt;0.0001), demonstrating that the hrHPV in the tumors is transcriptionally active and likely is an etiologic factor in the majority of OPSCC patients treated at CGMH in the past 18 years. This is consistent with the increasing role of hrHPV in OPSCC in Western countries and may reflect changing socioeconomic trends in Taiwan. Citation Format: Guadalupe Lorenzatti Hiles, Chun-I Wang, Lisa M. Pinatti, Christine M. Goudsmit, Lila Peters, Hannah L. Briggs, Trey B. Thomas, Mohammed Charara, Reem A. Khatib, Macy A. Afsari, Anna C. Morris, Nadine Jawad, Devraj Som, Kai-Ping Chang, Thomas E. Carey, Heather M. Walline. High-risk human papillomavirus association with oropharyngeal squamous cell carcinoma in Taiwan [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B07.

Upregulated NPM1 is an independent biomarker to predict progression and prognosis of oral squamous cell carcinomas in Taiwan.

Nucleophosmin/nucleoplasmin family 1 (NPM1) has broad physiological functions, such as DNA replication, transcription, ribosome biogenesis, and centrosome replication. This study explored the clinicopathological importance of NPM1 as a prognostic marker for oral squamous cell carcinoma (OSCC). We collected specimens from 96 OSCC, 45 oral epithelial dysplasia (OED), and 29 normal oral mucosa (NOM). NPM1 expression was analyzed via immunohistochemistry. Correlations between NPM1and clinical parameters were analyzed using Student t test, chi-squared test, and Kaplan-Meier product-limit method. The NPM1 labeling indices (LIs) were significantly higher in OSCCs than in NOM and oral OED. Higher NPM1 expression was significantly correlated with larger tumor size, nodal metastasis, and advanced clinical stage. Multivariate analysis revealed that higher NPM1 LIs were an unfavorable independent factor for survival. Upregulated NPM1 is an independent biomarker of poor prognosis and NPM1 inhibitors may be promising in molecular targeted therapy against OSCC.

Human papillomavirus infection is not associated with laryngeal squamous cell carcinoma in Taiwan.

To examine whether the prevalence rate of human papillomavirus (HPV) infection in Taiwanese patients with primary laryngeal squamous cell carcinoma (LSCC) is different from that in those with a vocal polyp (VP) or vocal fold leukoplakia (VFL). This prospective cohort study recruited 41 consecutive patients with primary LSCC and 27 and 20 patients with VP and VFL, respectively. The HPV L1 gene in surgical specimens was detected using polymerase chain reaction. High-risk HPV DNA in tissue microarray specimens was detected using in situ hybridization. Expression of p16INK4a in tissue microarray specimens was determined through immunohistochemistry. The prevalence of HPV L1 DNA in the LSCC group was equivalent to that in the VP and VFL groups (7.3% vs. 7.4% vs. 10.0%; P=0.929; effect size=0.20). High-risk HPV DNA detected using in situ hybridization was relatively rare in all groups (2.6% vs. 5.3% vs. 0.0%; P=0.636; effect size=0.81). The prevalence of p16INK4a positivity was significantly lower in the LSCC group than in the VP and VFL groups (5.1% vs. 58.8% vs. 14.3%; P<0.001). Multivariate analysis results revealed that age ≥65 years (adjusted odds ratio, 4.09; 95% confidence interval, 1.21-13.91; P=0.024) and p16INK4a positivity (adjusted odds ratio, 0.10; 95% confidence interval, 0.02-0.53; P=0.006) were LSCC risk factors. HPV infection is uncommon in Taiwanese patients with LSCC and seems not to be associated with an increased LSCC risk. Larger sample size is warranted for further study.

Abstract IA10: Integrated omics analyses identify prognostic biomarkers of oral cavity squamous cell carcinoma in Taiwan

Abstract To uncover genomic alterations that can be used as molecular markers for oral cavity squamous cell carcinoma (OSCC) in Taiwan, we recruited patients who were ethnically Taiwanese and admitted to Chang Gung Memorial Hospital at Taipei. We performed whole-exome sequencing (WES) of matched tumor/PBMC DNAs from 50 OSCC patients (75-Mbp target region, mean depth = 244 ± 54), and RNA sequencing of matched tumor/adjacent normal tissues from 39 of the 50 patients (mean read count = 38.7 ± 15.2 million). A subset of the identified somatic mutations was validated in 49 tumor tissues using an IonAmpliSeqTM Comprehensive Cancer Panel (CCP; 409 cancer-related genes). In total, our exome sequencing analyses uncovered 33,160 somatic single nucleotide variants (SNVs) and InDels. The targeted approach of CCP enabled us to independently validate 84.91% of the SNVs identified by our whole-exome sequencing. We cross-referenced our data with that of 172 oral cavity cancer samples (OSCC-TCGA) from the Head-Neck Squamous Cell Carcinoma (HNSC) project of TCGA (HNSC-TCGA) and 106 from India (OSCC-India), as annotated in the International Cancer Genome Consortium (ICGC). We found that our patient cohort was characteristic of OSCC with regard to frequently mutated genes, such as CDKN2A, TP53, and NOTCH1. Interestingly, however, our analysis further identified mutations in seven other genes that turned out to be unique, locally prevalent (&amp;gt;10% of patients) alterations. We further used our exome sequencing data to examine copy number alterations in our samples and our findings largely recapitulated the profile found in OSCC-TCGA, which included significantly amplified/deleted regions encompassing genes such as EGFR, FGFR1, FADD, FAT1 and CDKN2A. Comparative analysis of the transcriptomes of tumor and normal tissues allowed us to identify 3,548 genes as being differentially expressed in OSCC-Taiwan; these included 1,220 up-regulated and 2,328 down-regulated genes. Notably, 91.3% of these differentially expressed genes were similarly identified in the OSCC-TCGA data, indicating that the overall expression profile of OSCC is highly similar across ethnic groups. In the meeting, I will report the unique genomic alterations with the potential biomarkers in OSCC, and these findings might introduce a hitherto unknown genetic component of this disease. Citation Format: Kai-Ping Chang, Ting-Wen Chen, Curtis R. Pickering, Jeffrey N. Myers, Yu-Sun Chang. Integrated omics analyses identify prognostic biomarkers of oral cavity squamous cell carcinoma in Taiwan [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr IA10.

Abstract 59: Novel mechanisms-guided treatments for betel nuts-related head and neck squamous cell carcinoma in Taiwan

Abstract Background: Betel nuts-related HNSCCs in Taiwan will cause (1) strong inflammation, invasion, and angiogenesis; (2) poor response to chemotherapy, radiation, and epidermal growth factor receptor inhibitors. Methods: HNSCC cell lines (SCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, and TW2.6, betel nuts-related) were used to evaluate (1) the in vitro drug sensitivity; (2) synergistic effects of different treatment combinations with MTT assay, colony formation, flow cytometry, and Western blotting; (3) invasion capacity by wound healing. TW2.6 had already been proved to possess defective p53, p16 loss, and increased Bcl2. Results: TW2.6 was resistant to chemotherapies, radiation, and EGFR inhibition, but sensitive to PI3K/mTOR dual inhibition (BEZ235), CDK4/6 inhibitor (palbociclib), Bcl2 inhibitor (ABT-199), WEE1 inhibitor(AZD1775), FGFR inhibitor(BGJ398), ALK/IGF-1R inhibitor (ceritinib), and eribulin. Polo-like kinase inhibitor (volasertib) with radiation, resulting in G2/M arrest in flow-cytometry and increased cyclin B levels in Western blotting, caused TW2.6 apoptosis. Nintedanib and regorafenib (VEGFR/PDGFR/FGFR inhibitor) and foretinib (VEGFR/c-MET/Axl inhibitor) would suppress HUVEC, block invasion capacity of TW2.6, inhibit TW2.6 growth, and resensitize TW2.6 to docetaxel, afatinib, and volasertib. Western blotting showed (1) mesenchymal markers (Slug, Snail, Axl, Twist, Vimentin, Claudin-1), PI3K/Akt/mTOR signaling (p-Akt and p70S6K), and BMI-1 dropped after nintedanib, regorafenib, and foretinib; (2) PDL1 drop after foretinib use. BYL719, ABT-199, and ceritinib also sensitize TW2,6 to docetaxel. Astragalus polysaccharides, minimally cytotoxic on TW2.6, could inhibit tumor migration, suppress epithelial-mesenchymal transformation and PI3K/AKT/mTOR pathway, and induce PDL1 drop. APS re-sensitizes TW2.6 to afatinib and volasertib. Olaparib (PARP inhibitor) also had poor effect on TW2.6, but volasertib, AZD1775, and foretinib could reverse olaparib resistance. Conclusions: TW2.6 might reflect treatment refractoriness of betel nuts-related HNSCC in Taiwan. Several novel mechanisms-guided treatment combinations should be tried in the future. Citation Format: Jo-Pai Chen, Jui-Ying Chang, Ruey-Long Hong. Novel mechanisms-guided treatments for betel nuts-related head and neck squamous cell carcinoma in Taiwan [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 59.

Novel mechanisms-guided treatments for betel-nuts related head and neck squamous cell carcinoma in Taiwan.

e23217 Background: Betel-nuts related HNSCCs in Taiwan will cause (1)strong inflammation, invasion, and angiogenesis; (2)poor response to chemotherapy, radiation, and epidermal growth factor receptor inhibitors. Methods: HNSCC cell lines(SCC4, SCC9, SCC15, SCC25, FaDu, KB, Cal27, SAS, and TW2.6, betel-nuts related) were used to evaluate (1)the in vitro drug sensitivity; (2)synergistic effects of different treatment combinations with MTT assay, colony formation, flow cytometry, and western blotting; (3)invasion capacity by wound healing. TW2.6 had already been proved to possess defective p53, p16 loss, and increased Bcl2. Results: TW2.6 was resistant to chemotherapies, radiation, &amp; EGFR inhibition; but sensitive to PI3K/mTOR dual inhibition(BEZ235), CDK4/6 inhibitor(palbociclib), Bcl2 inhibitor(ABT-199), WEE1 inhibitor(AZD1775), FGFR inhibitor(BGJ398), ALK/IGF-1R inhibitor(ceritinib), &amp; eribulin. Polo-like kinase inhibitor(volasertib) with radiation, resulting in G2/M arrest in flow-cytometry and increased cyclin B levels in western blotting, caused TW2.6 apoptosis. Nintedanib &amp; regorafenib(VEGFR/PDGFR/FGFR inhibitor) and foretinib (VEGFR/c-MET/Axl inhibitor) would suppress HUVEC, block invasion capacity of TW2.6, inhibit TW2.6 growth, and resensitize TW2.6 to docetaxel, afatinib, and volasertib. Western blotting showed (1)mesenchymal markers(Slug, Snail, Axl, Twist, Vimentin, Claudin-1), PI3K/Akt/mTOR signaling(p-Akt &amp; p70S6K), and BMI-1 dropped after nintedanib, regorafenib, and foretinib; (2)PDL1 drop after foretinib use. BYL719, ABT-199, and ceritinib also sensitize TW2,6 to docetaxel. Astragalus polysaccharides, minimally cytotoxic on TW2.6, could inhibit tumor migration, suppress epithelial-mesenchymal transformation &amp; PI3K/AKT/mTOR pathway, and induce PDL1 drop. APS re-sensitizes TW2.6 to afatinib &amp; volasertib. Olaparib(PARP inhibitor) also had poor effect on TW2.6; but volasertib, AZD1775, and foretinib could reverse olaparib resistance. Conclusions: TW2.6 might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan. Several novel-mechanisms-guided treatment combinations could be developed in the future.

Abstract 3260: Differential effects of antiangiogenesis treatments on betel-nuts-related head and neck squamous cell carcinoma in Taiwan

Abstract Background: The treatment of head and neck squamous cell carcinoma(HNSCC) in Taiwan is very challenging and might be related to betel-nuts use. Betel-nuts chewing might contribute to (1)strong inflammation, invasion, and angiogenesis; (2)easy recurrence or metastasis; (3) poor response to chemotherapy, radiation, and epidermal growth factor receptor(EGFR) inhibitors. Purpose: We try to prove different kinds of anti-angiogenesis treatments will lead to different response on betel-nuts related HNSCC in Taiwan. Methods: Different anti-angiogenesis treatments, such as axitinib(VEGFR2 inhibitor), nintedanib(VEGFR2/FGFR inhibitor), and regorafenib(VEGFR2/FGFR/ more other signals inhibitor) were first used to treat (1)HUVEC; (2)HNSCC cell lines(SCC4, SCC9, SCC15, SCC25, FaDu, SAS, KB, Cal27, and TW2.6, betel-nuts related) to evaluate (a) invasion capacity by wound healing; (b) drug sensitivity by MTT assay; (c)synergistic effect with chemotherapy, EGFR inhibitor, and polo-like kinase inhibitor. Western blotting was also used to test signal change by treatments. TW2.6 had already been proved to possess defective p53, p16 loss, and increased Bcl2. Results: In our previous study, TW2.6 was resistant to chemotherapy, radiation, EGFR inhibitors, and ani-angiogenesis treamtents, such as axitinib and sunitinib. Axitinib, pure VEGFR2 inhibitor, was found to suppress HUVEC more prominently than nintedanib or regorafenib did. Invasion capacity of all HNSCC cell lines were all blocked by the three drugs but regorafenib did mostly well. However, axitinib had no effect on TW2.6; but nintedanb and regorafenib had moderate response on TW2.6. Besides, nintedanib and regorafenib both would resensitize TW2.6 to respond to chemotherapy, EGFR inhibitor, and polo-like kinase inhibitor again. Western blotting showed mesenchaml differentiation markers(slug, Twist, snail, Axl, c-MET, Vimentin) decreased after nintedanib and regorafenib use, too. Conclusion: TW2.6 might reflect treatment refractoriness of betel-nuts related HNSCC in Taiwan. In addition to PI3K/mTOR dual inhibition and polo-like kinase inhibitor with radiation(our studies shown in AACR and ESMO2015), VEGFR2/FGFR dual blockage might be effective on TW2,6 and resensitize TW2.6 to EGFR inhibitor, polo-like kinase inhibitor, &amp; chemotherapy, maybe through the inhibition of mesenchymal transformation. VEGFR2/FGFR dual blockage will be one future combination backbone of betel-nuts related HNSCC. Citation Format: Jo-Pai Chen, Jui-Ying Chang, Sung-Hsin Kuo, Ruey-Long Hong. Differential effects of antiangiogenesis treatments on betel-nuts-related head and neck squamous cell carcinoma in Taiwan. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3260.

Impact of Treatment Modalities on Survival of Patients With Locoregional Esophageal Squamous-Cell Carcinoma in Taiwan.

The optimal treatment modality for locoregional esophageal squamous-cell carcinoma (ESCC) is still undetermined. This study investigated the treatment modalities affecting survival of patients with ESCC in Taiwan.Data on 6202 patients who underwent treatment for locoregional esophageal squamous-cell carcinoma during 2008 to 2012 in Taiwan were collected from the Taiwan Cancer Registry. Patients were stratified by clinical stage. The major treatment approaches included definitive chemoradiotherapy, preoperative chemoradiation followed by esophagectomy, esophagectomy followed by adjuvant therapy, and esophagectomy alone. The impact of different treatment modalities on overall survival was analyzed.The majority of patients had stage III disease (n = 4091; 65.96%), followed by stage II (n = 1582, 25.51%) and stage I cancer (n = 529, 8.53%). The 3-year overall survival rates were 60.65% for patients with stage I disease, 36.21% for those with stage II cancer, and 21.39% for patients with stage III carcinoma. Surgery alone was associated with significantly better overall survival than the other treatment modalities for patients with stage I disease (P = 0.029) and was associated with significantly worse overall survival for patients with stage III cancer (P < 0.001). There was no survival risk difference among the different treatment methods for patients with clinical stage II disease.Multimodality treatment is recommended for patients with stage II–III esophageal squamous-cell carcinoma. Patients with clinical stage I disease can be treated with esophagectomy without preoperative therapy.

Prognostic factors in Taiwanese patients with penile-invasive squamous cell carcinoma

In Taiwanese patients, carcinoma of the penis is an uncommon disease. We retrospectively reviewed potential prognostic factors in Taiwanese patients with invasive-penile squamous cell carcinoma (SCC). From 1997 to 2009, 52 patients were enrolled. The median patient age at diagnosis was 66.5 years and the peak incident occurred during the 6th and 7th decades of life. Thirteen patients (25%) died of penile cancer, with a mean follow-up time of 45 months (interquartile range: 15–64 months). The 5-year cumulative cancer-specific survival rate was 81%, with 100% for those with Stage I, 90% for those with Stage II, 60% for those with Stage III, and 14% for those with Stage IV. Eleven variables, including grade, tumor, node, metastasis (TNM) stage, involvement of corpus spongiosum or corpora cavernosa, lymphovascular or perineural invasion, lymphadenectomy, and palpable lymph node, with p < 0.05 using univariate analysis were chosen for multivariate regression analysis. Three of these potential prognostic factors, including histological grade, distant metastasis, and lymphovascular invasion, remained statistically significant. Our study is the first report using the latest TNM classification (2009) to determine these potential predictors with penile SCC in Taiwan.

Detection of synchronous cancers by fluorodeoxyglucose positron emission tomography/computed tomography during primary staging workup for esophageal squamous cell carcinoma in Taiwan.

AimThe aim of this retrospective study was to investigate the ability of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the detection of synchronous cancers during staging workup for esophageal squamous cell carcinoma.Materials and MethodsWe performed a retrospective chart review of 426 Taiwanese patients with esophageal cancer who received FDG-PET/CT during their primary staging workup between December 2006 and December 2011. We defined synchronous cancers as those occurring within 6 months of the FDG-PET/CT scan. All of the synchronous lesions were confirmed by histology or imaging follow-up. The study patients were followed for at least 18 months or were censored on the date of last follow-up.ResultsFifty patients were excluded from analysis because of the presence of distant metastases. Of the remaining 376 patients, 359 were diagnosed with squamous cell carcinoma (SCC). We identified 17 patients with synchronous cancers, and all of them had a diagnosis of SCC. Synchronous head and neck cancers were the most frequent (n=13, 76.4%), followed by gastrointestinal cancers (colon cancer, n=2; hepatocellular carcinoma, n=1), and renal cell carcinoma (n=1). FDG-PET/CT successfully detected 15 synchronous cancers (12 head and neck cancers, 2 colon cancers, and 1 renal cell carcinoma). In contrast, conventional workup detected only 9 synchronous cancers (7 head and neck cancers, 1 hepatocellular carcinoma and 1 renal cell carcinoma). The sensitivity of FDG-PET/CT and conventional workup in detecting synchronous cancers were 88.2% and 52.9% respectively.ConclusionThe most frequent synchronous lesions in patients with esophageal SCC were head and neck cancers in Taiwan. Our data indicate that FDG-PET/CT is superior to conventional workup in the detection of synchronous tumors during primary staging for esophageal squamous cell carcinoma.

Analysis of p16INK4A expression of oral squamous cell carcinomas in Taiwan: Prognostic correlation without relevance to betel quid consumption

In this study, we examined the role of p16(INK4A) , a surrogate biomarker of HPV-related head and neck cancers with better prognosis, in an endemic area of betel quid (BQ)-related oral squamous cell carcinoma (OSCC). p16(INK4A) immunohistochemistry was examined in 165 OSCCs, statistical analyses were performed to elucidate the correlation between p16(INK4A) expression and BQ habits/pathologic features, and the prognostic impact of p16(INK4A) and different parameters were analyzed. The incidence of p16(INK4A) expression was similar between BQ chewers and non-chewers. p16(INK4A) expression was significantly associated with nodal metastasis (P = 0.005). There was a trend suggesting that the loss of p16(INK4A) expression was more frequent in higher T stages, however, this was found only in patients without lymph node metastasis (P = 0.059). A poorer prognosis and a higher risk of tumor recurrence were found in OSCCs without p16(INK4A) expression. (The HR for cancer-specific mortality and cancer recurrence was 3.55 and 1.89, respectively.) Although it has been suggested that BQ chewers had a greater tendency toward tumor recurrence and poor outcome, our data demonstrated that p16(INK4A) expression is unrelated to BQ habit and that p16(INK4A) downregulation is a strong predictor for OSCC progression, recurrence and survival in Taiwan.

Significant association of SRC protein expression with the progression, recurrence, and prognosis of oral squamous cell carcinoma in Taiwan

Src protein overexpression correlates with progression and prognosis of a variety of human cancers. This study used immunohistochemistry to examine the expression of Src protein in 93 specimens of oral squamous cell carcinoma (OSCC). We found a significant association of high expression of Src protein (labeling indices >50%) with larger tumor size (p = .017), positive lymph node metastasis (p = .030), more advanced clinical stages (p = .007), and recurrence (p < .001) of OSCC. High expression of Src protein was identified as an independent unfavorable prognosis factor by multivariate Cox regression analysis. The Kaplan-Meier curve showed that patients with OSCC with high expression of Src protein had a significantly poorer cumulative survival than those with low expression of Src protein (log-rank test, p = .00267). The expression of Src protein is significantly associated with the progression, recurrence, and prognosis of OSCCs in Taiwan.

Interaction between tumour necrosis factor-α gene polymorphisms and substance use on risk of betel quid-related oral and pharyngeal squamous cell carcinoma in Taiwan

ObjectiveBetel quid (BQ) components induce the secretion of tumour necrosis factor-alpha (TNF-α) in oral keratinocytes, which promotes oral mucosal inflammation and oral cancer. This study was carried out to evaluate the association of TNFA genetic variants (−308G>A and −238G>A) with the risk and prognosis of BQ-related oral and pharyngeal squamous cell carcinoma (OPSCC). DesignA total of 403 subjects (205 cancer cases and 198 healthy controls) who habitually chewed BQ were recruited. The genotypes were determined by TaqMan real-time assays. ResultsG allele and G/G genotype at TNFA −308 were associated with a 1.95-fold (95%CI: 1.16–3.28, pcorrected=0.024) and 2.28-fold (95%CI: 1.30–4.00, pcorrected=0.008) increased risk of cancer as compared to those with A allele or A/A+A/G genotypes, respectively. In addition, G allele (p=0.080) and G/G genotype (p=0.076) at TNFA −238 were associated with a borderline but statistically significant increased risk of OPSCC. The combined G/G+G/G genotype at both loci had a 2.37-fold increased risk of OPSCC as compared to those with other combined genotypes (95%CI: 1.41–4.00, p=0.001). Interactions between combined genotypes and smoking status were also found to contribute to risk of BQ-related OPSCC. There was no association of TNFA genotypes with clinicopathologic findings or the survival of OPSCC patients. ConclusionsBQ-chewers who carry the G allele or G/G genotype in TNFA −308 may have an increased risk of OPSCC. The intensity of cigarette smoking modulates the effect of the combined TNFA genotypes on risk of BQ-related OPSCC.