Interleukin-6/STAT3 Signaling is Prominent and Associated with Reduced Overall Survival in p16 Negative Oropharyngeal Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Lesinski GB
PROVIDER: S-EPMC6684688 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
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Interleukin-6/STAT3 Signaling is Prominent and Associated with Reduced Overall Survival in p16 Negative Oropharyngeal Squamous Cell Carcinoma.
Lesinski Gregory B GB Nannapaneni Sreenivas S Griffith Christopher C CC Patel Mihir M Chen Wanqi W Chen Zhengjia Z Ahmed Rafi R Wieland Andreas A Shin Dong M DM Chen Zhuo G ZG Saba Nabil F NF
Head and neck pathology 20180906 3
This study addresses the hypothesis that IL-6/STAT3 signaling is of clinical relevance in oropharyngeal squamous cell carcinoma (OPSCC). We evaluated relationships between key components of this pathway in tumors from a unique cohort of n = 59 fully annotated, treatment-naïve patients with OPSCC. The multiplex Opal platform was utilized for immunofluorescence (IF) analysis of tissues to detect IL-6 and phosphorylated STAT3 (pSTAT3), taking into consideration its nuclear versus cytoplasmic locali ...[more]
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Project description:BackgroundThe prescribed radiation dose to patients with oropharyngeal squamous cell carcinoma (OPSCC) is standardized, even if the prognosis for individual patients may differ. Easy-at-hand pre-treatment risk stratification methods are valuable to individualize therapy. In the current study we assessed the prognostic impact of primary tumor volume for p16-positive and p16-negative tumors and in relationship to other prognostic factors for outcome in patients with OPSCC treated with primary radiation therapy (RT).MethodsFive hundred twenty-three OPSCC patients with p16-status treated with primary RT (68.0 Gy to 73.1 Gy in 7 weeks, or 68.0 Gy in 4.5 weeks), with or without concurrent chemotherapy, within three prospective trials were included in the study. Local failure (LF), progression free survival (PFS) and overall survival (OS) in relationship to the size of the primary gross tumor volume (GTV-T) and other prognostic factors were investigated. Efficiency of intensified RT (RT with total dose 73.1 Gy or given within 4.5 weeks) was analyzed in relationship to tumor volume.ResultsThe volume of GTV-T and p16-status were found to be the strongest prognostic markers for LF, PFS and OS. For p16-positive tumors, an increase in tumor volume had a significantly higher negative prognostic impact compared with p16-negative tumors. Within a T-classification, patients with a smaller tumor, compared with a larger tumor, had a better prognosis. The importance of tumor volume remained after adjusting for nodal status, age, performance status, smoking status, sex, and hemoglobin-level. The adjusted hazard ratio for OS per cm3 increase in tumor volume was 2.3% (95% CI 0-4.9) for p16-positive and 1.3% (95% 0.3-2.2) for p16-negative. Exploratory analyses suggested that intensified RT could mitigate the negative impact of a large tumor volume.ConclusionsOutcome for patients with OPSCC treated with RT is largely determined by tumor volume, even when adjusting for other established prognostic factors. Tumor volume is significantly more influential for patients with p16-positive tumors. Patients with large tumor volumes might benefit by intensified RT to improve survival.
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Project description:Recently increasing high-risk HPV+ OSCC exhibits unique clinical and molecular characteristics compared to HPV-unrelated (HPV-) counterpart. Genomic copy number variations (CNVs), unique in HPV+ OSCCs, and their role for the prognosis prediction remains poorly studied. Here, we analyzed the distinct genomic copy number variations (CNVs) in human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinoma (OSCC) and their role as a prognosticator after curative resection. For 58 consecutive, Korean OSCC patients that underwent surgery-based treatment with median 10 years of follow-up, HPV-related markers, and genome-wide CNV analysis were analyzed. Clinical associations between the CNV profile and survival analyses were followed. p16 expression predicted the overall survival (OS) (hazard ratio [HR] = 0.27, confidence interval [CI]: 0.39-0.80, P = 0.0006) better than HPV L1 PCR (HR = 0.83, CI: 0.66-1.29, P = 0.64), smoking, or other variables. Although the overall number of CNVs was not significantly different, 30 loci showed unique CNV patterns between the p16+ and p16- groups. A region containing PRDM2 was amplified only in the p16+ group, whereas EGFR and 11q13.3 showed increased amplification in p16- counterpart. Loss of a locus containing FGF18 led to a worse, but gain of region including CDK10 and RAD18 led to better overall survival (OS) in all OSCC patients. Meanwhile, subgroup analysis of p16+ OSCC revealed that amplification of regions harboring HRAS and loss of locus bearing KDR led to better OS. p16+ OSCC exhibit distinct CNV patterns compared with p16- counterpart. Specific patterns of CNVs predict better survival, especially in p16+ OSCC. This might allow better insights of the outcome after curative resection for HPV+ and HPV- OSCC.
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Project description:PurposeTobacco smoking is associated with oropharynx cancer survival, but to what extent cancer progression or death increases with increasing tobacco exposure is unknown.Patients and methodsPatients with oropharynx cancer enrolled onto a phase III trial of radiotherapy from 1991 to 1997 (Radiation Therapy Oncology Group [RTOG] 9003) or of chemoradiotherapy from 2002 to 2005 (RTOG 0129) were evaluated for tumor human papillomavirus status by a surrogate, p16 immunohistochemistry, and for tobacco exposure by a standardized questionnaire. Associations between tobacco exposure and overall survival (OS) and progression-free survival (PFS) were estimated by Cox proportional hazards models.ResultsPrevalence of p16-positive cancer was 39.5% among patients in RTOG 9003 and 68.0% in RTOG 0129. Median pack-years of tobacco smoking were lower among p16-positive than p16-negative patients in both trials (RTOG 9003: 29 v 45.9 pack-years; P = .02; RTOG 0129: 10 v 40 pack-years; P < .001). After adjustment for p16 and other factors, risk of progression (PFS) or death (OS) increased by 1% per pack-year (for both, hazard ratio [HR], 1.01; 95% CI, 1.00 to 1.01; P = .002) or 2% per year of smoking (for both, HR, 1.02; 95% CI, 1.01 to 1.03; P < .001) in both trials. In RTOG 9003, risk of death doubled (HR, 2.19; 95% CI, 1.46 to 3.28) among those who smoked during radiotherapy after accounting for pack-years and other factors, and risk of second primary tumors increased by 1.5% per pack-year (HR, 1.015; 95% CI, 1.005 to 1.026).ConclusionRisk of oropharyngeal cancer progression and death increases directly as a function of tobacco exposure at diagnosis and during therapy and is independent of tumor p16 status and treatment.
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Project description:Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immuno-histochemistry. For HPV DNA-positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methylation-specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214; 95% confidence interval, 0.074-0.614; P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA-positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese.
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Project description:Human papillomavirus-related (p16-positive) oropharyngeal squamous cell carcinoma patients develop recurrent disease, mostly distant metastasis, in approximately 10% of cases, and the remaining patients, despite cure, can have major morbidity from treatment. Identifying patients with aggressive versus indolent tumors is critical. Hematoxylin and eosin-stained slides of a microarray cohort of p16-positive oropharyngeal squamous cell carcinoma cases were digitally scanned. A novel cluster cell graph was constructed using the nuclei as vertices to characterize and measure spatial distribution and cell clustering. A series of topological features defined on each node of the subgraph were analyzed, and a random forest decision tree classifier was developed. The classifier (QuHbIC) was validated over 25 runs of 3-fold cross-validation using case subsets for independent training and testing. Nineteen (11.9%) of the 160 patients on the array developed recurrence. QuHbIC correctly predicted outcomes in 140 patients (87.5% accuracy). There were 23 positive patients, of whom 11 developed recurrence (47.8% positive predictive value), and 137 negative patients, of whom only 8 developed recurrence (94.2% negative predictive value). The best other predictive features were stage T4 (18 patients; 83.1% accuracy) and N3 nodal disease (10 patients; 88.6% accuracy). QuHbIC-positive patients had poorer overall, disease-free, and disease-specific survival (P<0.001 for each). In multivariate analysis, QuHbIC-positive patients still showed significantly poorer disease-free and disease-specific survival, independent of all other variables. In summary, using just tiny hematoxylin and eosin punches, a computer-aided histomorphometric classifier (QuHbIC) can strongly predict recurrence risk. With prospective validation, this testing may be useful to stratify patients into different treatment groups.
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Project description:Importance:Clinical trials that deintensify treatment for patients with suspected human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) use p16 expression to identify HPV-mediated tumors and guide treatment. While p16 staining has a strong correlation with good outcomes, approximately 12% of p16-positive patients have recurrent disease. Biomarkers that reveal tumor-specific characteristics, such as nodal involvement, may change therapy decisions. Objective:To assess whether if a tumor-specific genetic signature exists for node-negative vs node-positive HPV 16-positive/p16-positive OPSCCs. Design, Setting, and Participants:This was a retrospective cohort study with randomized case selection for p16 OPSCCs undertaken at a university-based, tertiary care cancer center. Samples were collected from patients with p16-positive OPSCC. A total of 21 HPV 16/p16-positive tumors were used in this study. Main Outcomes and Measures:Gene expression profiles of node-negative vs node-positive tumor samples were evaluated using a differential expression analysis approach and the sensitivity and specificity of a molecular signature was determined. Results:Among the 21 patients in the study (3 women, 18 men; mean [SD] age, 54.6 [9.6] years), 6 had node-negative disease and 15 had node-positive disease. Using differential expression analysis, we found 146 genes that were significantly different in patients with node-negative disease vs those with node-positive disease, of which 15 genes were used to create a genetic signature that could distinguish node-negative-like from node-positive-like disease. The resultant molecular signature has a sensitivity of 88.2% (95% CI, 63.6%-98.5%) and specificity of 85.7% (95% CI, 42.1%-99.6%). The positive likelihood ratio of this signature was 6.1 (95% CI, 1.0-38.2) and the negative likelihood ratio was 0.1 (95% CI, 0.04-0.5). Given this population's prevalence of node-positive disease of 70.8%, the positive- and negative-predicative values for this gene signature were 93.7% (95% CI, 70.8%-98.9%) and 75.0% (95% CI, 44.1%-92.0%), respectively. In addition, we developed a gene signature using agnostic, machine learning software that identified a 40-gene profile that predicts node-negative disease from node-positive disease (area under the curve, 0.93; 95% CI, 0.63-1.00). Conclusions and Relevance:Many HPV-16 and p16-positive tumors are treated as "lower-risk," but they do not have similar genetic compositions at the biological level. The identification of subgroups with unique expression patterns, such as those with nodal metastases, may guide physicians toward alternative or more aggressive therapies. In our study, unguided clustering suggested that that the larger biological characteristics of a tumor could be a better prognostic biomarker.
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Project description:PurposeMultimodality treatment of squamous cell carcinoma of the head and neck (SCCHN) often involves radiotherapy and cisplatin-based therapy. Elevated activity of DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway, of which ERCC1 is a rate-limiting element, are associated with cisplatin and possibly RT resistance. We have determined excision repair cross-complementing group 1 (ERCC1) expression in human papillomavirus (HPV)-negative SCCHN treated with surgery [± adjuvant radiotherapy/chemoradiation (CRT)].Experimental designWe assessed ERCC1 protein expression in archival tumors using immunofluorescence staining and automatic quantitative analysis (AQUA) with three antibodies to ERCC1 (8F1, FL297, and HPA029773). Analysis with Classification and Regression Tree (CART) methods ascertained the cutoff points between high/low ERCC1 expression. Multivariable analysis adjusted for age, T, and N stage. Kaplan-Meier curves determined median survival. ERCC1 expression at initial tumor presentation and in recurrent disease were compared. Performance characteristics of antibodies were assessed.ResultsERCC1 low/high groups were defined on the basis of AQUA analysis with 8F1/2009, FL297, and HPA029773. Among patients treated with surgery plus adjuvant radiotherapy/CRT, longer median survival was observed in ERCC1-low versus ERCC1-high tumors (64 vs. 29 months; P = 0.02; HPA029773). Data obtained with HPA029773 indicated no survival difference among patients treated only with surgery. Recurrent cancers had lower ERCC1 AQUA scores than tumors from initial presentation. Extensive characterization indicated optimal specificity and performance by the HPA029773 antibody.ConclusionsUsing AQUA, with the specific ERCC1 antibody HPA029773, we found a statistical difference in survival among high/low-ERCC1 tumors from patients treated with surgery and adjuvant radiotherapy.
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