bluuebunny/crossref_metadata_2025 huggingface dataset:
PIK3CA mutation as a prognostic factor in HPV-associated oropharynx cancer.
Authors: Beaty Brian T. , Gupta Gaorav , Shen Colette J. , Amdur Robert J , Weiss Jared , Grilley-Olson Juneko E. , Patel Shetal Arvind , Zanation Adam M. , Hackman Trevor , Thorp Brian , Blumberg Jeffrey , Patel Samip , Weissler Mark Christian , Yarbrough Wendell Gray , Sheets Nathan Christopher , Parker Joel S. , Hayes Neil , Mendenhall William M. , Dagan Roi , Chera Bhishamjit S.
Published: May 2019

6011

Background: PIK3CA is the most frequently mutated gene in HPV-associated oropharyngeal SCC (OPSCC), with a prevalence of 20-30%. While PIK3CA mutations have been associated with adverse outcomes in cervical cancer, their prognostic significance in HPV-associated OPSCC remains unknown. We sought to elucidate the significance of PIK3CA mutations in a prospective cohort of HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Methods: Seventy-eight patients with HPV-associated OPSCC were prospectively enrolled on three protocols: LCCC 1121 (NCT03161821) or two phase II clinical trials of de-intensified CRT (NCT02281955 / NCT03077243). De-intensified regimen was 60 Gy IMRT with concurrent cisplatin (30mg/m2). Next-generation sequencing of tumor samples was performed using a targeted panel-based assay (UNCSeq), including over 200 genes. We estimated disease-free survival (DFS) using the Kaplan-Meier method and compared treatment groups with two-sided log-rank test (Medcalc). Results: Sequencing was performed in 78 patients with a median follow-up of 24 months. Seventy-five patients received 60Gy; three patients received 70Gy. Ten patients had disease recurrence (2 regional only, 5 distant only, 3 regional and distant). Thirty-eight of 78 patients had at least one mutation identified (17 PIK3CA, 4 PTEN, 3 KRAS, 3 FBXW7, 3 FGFR3, 2 TP53, 2 prothrombin 20210, 1 NRAS, 1 BRCA1, 1 factor V Leiden, 1 FLT3, 1 RAD50, 1 PIK3R1). The most common site of PIK3CA mutation was the helical domain (E545K – 8/17, E542K – 2/17). Despite similar T/N staging and tobacco pack years, patients with WT-PIK3CA had significantly higher DFS (93%) compared with 65% for patients with PIK3CA mutations (p = 0.0009). Patients with mutations other than PIK3CA also had improved DFS relative to those with PIK3CA mutations (96% vs. 65%; p = 0.0147). Conclusions: PIK3CA mutation is associated with worse DFS in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with definitive CRT. These findings suggest that patients with PIK3CA mutations may not be suitable for de-intensified therapy and investigation of novel treatment strategies may be appropriate.
Anlotinib treatment in locally advanced or metastatic medullary thyroid carcinoma: A multicenter, randomized, double-blind, placebo-controlled phase IIB trial.
Authors: Li Dapeng , Tang Ping Zhang , Chen Xiaohong , Ge Minghua , Zhang Yuan , Guo Zhuming , Wang Jun , Shi Feng , Zhang Jiewu , Cheng Ying , Li Zhendong , Liu Hui , Qin Jianwu , Huang Rui , Cheng Ruochuan , Xu Zhengang , Chi Yihebali , Zheng Xiangqian , Gao Ming
Published: May 2019

6019

Background: Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferative signaling. Our previous single-arm phase 2 ALTN/MTC trial (NCT01874873) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in locally advanced or metastatic medullary thyroid carcinoma (MTC). Here we report results of the phase IIB trial (ALTER01031, NCT02586350) of anlotinib for locally advanced or metastatic MTC with a larger samples. Methods: Between September 2015 and September 2018, 91 patients were enrolled in China. Eligible patients have diagnosed as phase IV MTC with relapsed and measurable disease and without antiangiogenetic target therapy. The patients were randomly assigned in a 2:1 ratio to receive anlotinib or a matched placebo (12 mg QD from day 1 to 14 of a 21-day cycle). Patients who have been diagnosed with disease progression by the Independent Imaging Committee could be unblinded and crossed to the treatment group if the patient previous treated by placebo. The primary endpoint was progression-free survival (PFS). Results: 91 patients were randomized 62 to anlotinib arm and 29 to placebo arm. Until the data cutoff date (1 Feb 2019), median PFS was 20.67 months (95%CI, 14.03-34.63) in anlotinib arm vs 11.07 (95%CI, 5.82-14.32) months in placebo arm (HR 0.53, p = 0.0289). The OS data were not sufficiently mature for analysis. Considerable improvement in ORR was observed over the two arms (48.39% vs 3.45%, p < 0.0001). The adverse events (AEs) were 100% in anlotinib arm and 89.66% in placebo arm. The most common AEs in anlotinib arm were hand-foot syndrome, hypertension, hypertriglyceridemia and diarrhea. Conclusion: ALTER01031 met its primary endpoint of PFS shows that anlotinib treatment is effective and well tolerated. The safety profile was consistent and no new adverse events were identified. These data potentially extend the role of anlotinib monotherapy as a new therapy strategy for MTC patients. Clinical trial information: NCT02586350.
Induction chemotherapy with docetaxel, cisplatin and cetuximab versus docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced or inoperable squamous cell carcinoma of the head and neck: Promising results of a randomized phase II AGMT-trial.
Authors: Keil Felix , Hartl Maximilian , Altorjai Gabriela , Pecherstorfer Martin , Mayrbäurl Beate , de Vries Alexander , Berghold Andrea , Riedl Regina , Fridrik Michael A. , Fuereder Thorsten , Burian Martin , Greil Richard
Published: May 2019

6027

Background: Induction chemotherapy (ICT) with Cisplatin (P), 5-FU (F) and Taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial and toxicity and/or delay of radiotherapy may reduce the potential benefit of this treatment regimen. Here we report promising results of a randomized phase II trial comparing TPF with TP and Cetuximab (C) replacing F. Methods: In our trial, N= 100 patients with locally advanced or unresectable stage III or IV SCCHN were randomly assigned to either Arm A ( N= 49), receiving TPF, or Arm B ( N= 51), receiving TPC, both followed by radiotherapy (RT) + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished. Results: We observed a remarkable response rate (CR + PR) of 86.4% in the TPC-arm that compared favorably with 77.5% responding patients in the TPF-arm three months after RT + C was completed. OS and PFS were similar in both arms. After 400 days we observed an OS rate of 79% in the TPF and 86% in the TPC arm, and a PFS rate of 67% in the TPF and 70% in the TPC arm. TPC containing ICT led to less serious adverse events (SAEs), including blood and lymphatic disorders (40.8% in TPF arm, 27.5% in TPC arm) and metabolism and nutrition disorders (22.4% in TPF arm, 9.8% in TPC arm) during ICT. Interestingly, in HPVp16 positive patients, 88.24% in the TPF-arm and 93.33% in the TPC-arm showed CR or PR three months after RT + C, whereas only 69.57% in the TPF-arm and 82.76% in the TPC-arm showed CR or PR. We only lost one patient because of treatment-related mortality (TRM) and no delay from the end of ICT to local radiotherapy was observed in any patient. All patients received RT + C within three weeks after ICT was completed. Conclusions: In conclusion, TPC is a feasible and tolerable therapy regimen and can be applied within one day with less hematological toxicities. In contrast, more local reactions were observed after TPC. TPC containing ICT leads to improved response rates, while OS and PFS were similar in both arms. TRM was extremely low with 1%. Therefore, we conclude, that TPC containing ICT could be a considerable therapeutical alternative for patients with locally advanced or unresectable stage III or IV SCCHN, who are eligible for ICT. Clinical trial information: 2011-005540-99.
An open label, nonrandomized, multi-arm, phase II trial evaluating pembrolizumab combined with cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Results of cohort 1 interim analysis.
Authors: Sacco Assuntina Gesualda , Chen Ruifeng , Ghosh Debanjali , Wong Deborah J.L. , Worden Francis P. , Adkins Douglas , Pittman Emily , Messer Karen , Gold Kathryn A. , Daniels Gregory A. , Swiecicki Paul , Sutton Brian , Natsuhara Amanda , Cohen Ezra E.W.
Published: May 2019

6033

Background: Pembrolizumab (a humanized monoclonal antibody blocking programmed death receptor-1[PD-1]), and cetuximab (a chimeric monoclonal antibody inhibiting epidermal growth factor receptor) are both FDA-approved, second-line monotherapies for R/M HNSCC. This is the first trial to evaluate anti-tumor efficacy of dual therapy with pembrolizumab and cetuximab. Previously reported safety data demonstrated favorable toxicity. An interim futility analysis of cohort 1 (anti-PD-1/PD-L1 and cetuximab naïve) was completed per protocol. Methods: Patients (pts) with platinum-refractory/ineligible, R/M HNSCC were treated with pembrolizumab 200mg IV on day 1 and cetuximab 400mg/m2 loading dose followed by 250mg/m2 weekly (21-day cycle). Primary endpoint: overall response rate (complete and partial responses) by 6 months (mo). Secondary endpoints: 12-mo progression-free survival (PFS) probability, overall survival, response duration, safety, correlative analyses. Results: 14 evaluable pts were enrolled March 2017-October 2018. Median age 60y (range 47-86y), M:F 6:8, ECOG (0:1) 2:12, 14 mucosal primaries (9 oral cavity, 2 HPV-mediated oropharynx, 2 non-EBV-associated nasopharynx, 1 larynx). 11 pts (79%) had no prior lines of systemic therapy for R/M HNSCC (range 0-1). 6 pts (42.8%) had a partial response by 6 months, meeting pre-planned criteria for trial continuation. 4 pts (28.6%) had stable disease and 4 (28.6%) had progressive disease. Median PFS was 128 days (4.3 mo). Median duration of response was 160.5 days (5.4 mo) for partial responders and 133 days (4.4 mo) for pts with stable disease. Disease control rate (partial + stable) was 71.4%. There were 7 grade 3 treatment-related toxicities. 2 pts discontinued cetuximab due to toxicity, however, both continued pembrolizumab. Conclusions: Interim analysis indicates that pembrolizumab plus cetuximab is potentially active for platinum-refractory/ineligible pts with R/M HNSCC. These results meet protocol specifications for trial continuation. Final results will include PD-L1 expression data. Clinical trial information: NCT03082534.
COX-2 expression and mesenchymal-transition status on circulating tumor cells to predict survival in patients with nasopharyngeal carcinoma: A prospective analysis.
Authors: Li Yongjiang , Xie Xiaoqi , Zhang Hong , Lv Chen , Miao Dongyan , Guo Zhigui , Zhang Yumei , Li Changhu , Ge Wei , Wang Feng
Published: May 2019

6042

Background: The prognostic significance of circulating tumor cells (CTCs) in head and neck cancer is still under active investigation. It remains unclear whether just CTC count alone is sufficient to predict outcomes or whether the functional status of the CTCs is also needed. We investigated the clinical significance of determining epithelial-to-mesenchymal transition status and geno-/pheno-typic biomarkers of aggressiveness of CTCs in predicting outcomes in nasopharyngeal carcinoma (NPC). Methods: The prospective study enrolled 131 patients with NPC. CTCs were isolated at baseline and at the end of concurrent chemoradiotherapy using the CanPatrol system. Subsequently, the epithelial-mesenchymal transition (EMT) biomarkers and cyclooxygenase-2 (COX-2) expression status of the CTCs were identified by RNA-in situ hybridization (ISH) method. Results: COX-2 expression was found in 87/131 (66.4%) patients at baseline and 53/115 (46.1%) patients post-treatment. Independent of initial COX-2 expression status, the patients with post-treatment COX-2 expression on CTCs had significantly poorer treatment response (P = 0.011), and higher risk of tumor relapse (P = 0.026) and metastasis (P = 0.007). Similarly, post-treatment mesenchymal transition was also associated with higher risk of tumor relapse and metastasis. In multivariate analysis, post-treatment COX-2 expression on CTCs remained an independent prognostic indicator of poorer overall survival (HR 2.41, 95% CI 1.12-5.19; P = 0.024). Post-treatment COX-2 expression and mesenchymal transition in CTCs was the strongest prognostic indicator of overall survival on multivariate analysis (HR 2.73, 95% CI 1.28-5.83; P = 0.009). Conclusions: Post-treatment COX-2 expression on CTCs, especially on the mesenchymal subtype, is a novel and promising prognostic indicator for NPC patients treated with chemoradiation therapy. Future studies are needed to validate our findings and further clarify the value of integrating the indicators with current clinical strategies in improving survival of NPC patients.
Development of a clinicomolecular risk stratification system for nonmetastatic nasopharyngeal carcinoma using Epstein–Barr virus DNA and TNM stage: A “Big data” analysis of 9,160 endemic cases.
Authors: Chen Fo-Ping , Zhou Guan-Qun , Luo Ying-Shan , Tan Kuan Rui Lloyd , Tan Sze Huey , Zheng Yu , Lin Li , Guo Ying , Ma Jun , Chua Melvin L.K. , Sun Ying
Published: May 2019

6043

Background: To construct a clinicomolecular index integrating circulating Epstein-barr virus (cfEBV) DNA with T- and N- categories for better prognostication in nasopharyngeal carcinoma (NPC). Methods: Clinical and treatment records of 9,160 biopsy-proven, non-metastatic NPC cases were identified from an institutional “Big-data” platform. Decision tree modeling (DTM), recursive partitioning analysis (RPA) and adjusted hazard ratio (AHR) methods were used to generate clinicomolecular risk models. Outcome prediction of the models were compared against 8th edition TNM stage and two RPA-original models. Results: We observed linearity between cfEBV DNA and DFS; cfEBV DNA of > 2,000 copies was consistent for risk discretisation (HR > 1.0) for DFS, OS and DMFS in our cohort of 9,160 patients. DTM, RPA-new and AHR modelling using a two-tiered stratification by cfEBV DNA (≤2,000 and > 2,000 copies) and T- and N- categories yielded five risk groups with significantly disparate DFS (P < 0.001 for all subgroup comparisons). AHR model outperformed all other models and the TNM stage classification with better hazard consistency, hazard discrimination, explained variation, sample size balance and likelihood difference. Importantly, our clinicomolecular AHR groupings were significantly associated with the efficacy of different therapeutic regimes. Outcomes were comparable between concurrent chemoradiotherapy and intensity-modulated radiotherapy (IMRT) and IMRT alone for AHR1-2 (3-y DFS [AHR1] = 96.2% [IMRT] vs 95.3% [chemo-IMRT]; 3-y DFS [AHR2] = 91.1% vs 90.4%). Neoadjuvant chemotherapy and chemo-IMRT was superior to chemo-IMRT alone for AHR4-5 (AHRDFS 0.77[0.65-0.93], P = 0.005; 0.77[0.61-0.97], P = 0.027), but not for AHR3 (AHRDFS 1.07[0.86-1.34]). Conclusions: Here, we present a robust clinicomolecular risk stratification system that outperforms the TNM stage classification in non-metastatic NPC. Our clinicomolecular model is associated with the efficacy of different therapeutic regimes.
Correlation of angiogenic and immunomodulatory proteins with clinical outcomes of durvalumab (anti-PDL1) in recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Guo Xiang , Higgs Brandon W. , Baverel Paul , Fan Jean , Morsli Nassim , Wrona Magdalena , Yovine Alejandro Javier , Chang Shao-Chun , Arends Rosalin , Roskos Lorin
Published: May 2019

6048

Background: The potential for durvalumab, a PD-L1 blocking monoclonal antibody, to treat head and neck squamous cell carcinoma (HNSCC) is being evaluated in multiple clinical trials. We assessed circulating protein biomarkers in HNSCC patients prior to treatment to better understand pathways related to clinical outcomes and potentially relevant for targeting in combination with durvalumab. Methods: Sixty-six selected serum proteins were measured by multiplex immunoassay at baseline in HNSCC patients receiving durvalumab treatment: 106 patients with high PD-L1 (≥25% tumor cells; SP263 assay) in phase II HAWK trial and 52 patients with low/no PD-L1 in phase II CONDOR trial. Results: Multivariate Cox modeling demonstrated that higher baseline concentrations of angiogenic, pro-inflammatory, and myeloid-associated proteins (ANGPT2, CRP, IL6, S100A12) were associated with shorter overall survival (OS), while higher concentration of a bone formation marker and immunostimulatory hormone (BGLAP) correlated with longer OS in 158 durvalumab-treated HNSCC patients ( P< 0.05). These 4 proteins also showed higher baseline levels in patients with progressive disease (PD) compared to stable disease (SD) and partial or complete responses (PR/CR), while BGLAP had lower levels in PD compared to SD or PR/CR (Mann-Whitney P< 0.05). The 5 proteins remained significantly associated with OS in a multivariate model including PD-L1, ECOG, tumor size, and neutrophil count. Bone metastasis status had no impact on the association of BGLAP with OS, which has not been reported before in HNSCC. Interestingly, ANGPT2 level above median showed the highest hazard ratio (HR = 2.2, P <0.001) among all evaluated variables. Furthermore, higher levels of VWF, an angiogenesis-related protein, correlated with shorter OS by univariate survival analysis ( P < 0.001). Conclusions: Our results suggested an important role of angiogenesis in the resistance of HNSCC patients to durvalumab treatment, and ANGPT2 may have predictive utility for durvalumab combination with an anti-angiogenic agent. The predictive value of BGLAP remains to be evaluated in a randomized clinical study. Clinical trial information: NCT02207530; NCT02319044.
Phase 1b study of chemoprevention with green tea polyphenon E (PPE) and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (Erlotinib) in patients (pts) with advanced premalignant (AP) lesions of the head and neck.
Authors: Shin Dong Moon , Beitler Jonathan Jay , El-Deiry Mark , Steuer Conor Ernst , Chen Amy Y. , Baddour Harry Micael , Chen Zhuo Georgia , Roser Steve , Magliocca Kelly R. , Patel Mihir , Griffith Christopher C , Klein Adam , Owonikoko Taofeek Kunle , Khuri Fadlo , Nannapaneni Sreenivas , Saba Nabil F.
Published: May 2019

6049

Background: Based on the strong synergistic effects between green tea polyphenon E (PPE) and EGFR-TKI in our preclinical studies (Int J Cancer, 2008; Cancer Prev Res, 2009; JCO, 2009), we conducted a phase 1b study with PPE and erlotinib combination for APL (mild-, moderate-, severe-dysplasia or carcinoma in situ [CIS]) of the oral cavity and larynx from 2/2011 to 11/2017 at Emory Winship Cancer Institute. Methods: All pts were enrolled after signing the IRB approved Informed Consent Form. Tissue biopsy before and at 6-months (6-M) treatment was mandatory, and cytobrushed samples of the APL and normal buccal mucosa at 3-, 6-, and 12-M were obtained for biomarker studies. Treatment included fixed dose of PPE (200 mg, P.O.,TID) and dose escalation of erlotinib P.O., (50mg [level 1], 75mg [level 2] and 100mg [level 3]) for 6-M. The primary endpoint was safety and toxicity, and secondary endpoints were evaluation of pathologic responses, cancer free survival (CFS) and biomarker modulation. Results: Out of 27 enrolled pts, 6 control subjects for biomarker studies, 2 ineligible, and 19 were treated with PPE and erlotinib for 6-M. Clinical characteristics of treated patients included median age, 63 yrs. (range,33-78); 9 M/10 F; 10 former or current smokers/9 never smokers; 15 severe dysplasia or CIS, 2 moderate dysplasia, 2 mild dysplasia; 13 had surgical resection; 17 oral cavity primary; and 2 at larynx. 3 pts were treated at dose level 1, 4 at level 2, and 12 at level 3. Toxicity (G0 or G1 excluded) were: skin rash (1 G3, 1 G2), pruritus/dry skin (1 G2), fatigue (1 G2), diarrhea (1 G2), epistaxis (1 G2), and hypertension (2 G3, 1 G2). Skin rash (associated with erlotinib) may be DLT and MTD has not been reached. The recommend doses for phase 2 or 3 studies will be PPE 200mg TID plus erlotinib 100mg QD. 17 pts were assessed for pathologic responses at 6-M: pCR 7/17 (41%), pPR 2/17 (12%), pSD 5/17 (29%) and pPD (3/17 (18%). The median follow up was 32 months. Median CFS has not been reached. 16 pts are alive at the time of data analyses and 1 pt died (by noncancerous reason). Biomarker studies are ongoing for tissues and/or cytobrushed samples. Conclusions: The treatment of the combination of green tea PPE plus erlotinib for 6-M was well tolerated in pts with APL of the head and neck, and showed significant pathologic response rates (pCR and pPR, 53%). This combination therefore deserves further investigation for efficacy testing. Clinical trial information: NCT01116336.
Connective tissue growth factor (CTGF) methylation status is associated with prognosis of patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy (RCHT): A multicenter study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
Authors: Tawk Bouchra , Schwager Christian , Zaoui Karim , Hess Jochen , Linge Annett , Budach Volker , Stuschke Martin , Balermpas Panagiotis , Grosu Anca , Zips Daniel , Combs Stephanie E. , Krause Mechthild , Kouchakji Elias , Lipson Kenneth , Herpel Esther , Belka Claus , Baumann Michael , Herold-Mende Christel , Debus Juergen , Abdollahi Amir
Published: May 2019

6050

Background: CTGF plays a central role in tissue remodeling and has emerged as an attractive novel therapeutic target. We sought to investigate the impact of CTGF methylation status (CTGF-M) in predicting outcome of HNSCC patients undergoing RCHT. Methods: CTGF-M was discovered by applying Illumina 450K/850K arrays to DNA extracted from FFPE material of patients homogeneously treated with surgery followed by adjuvant cisplatin-based RCHT in frame of the DKTK-ROG multicenter retrospective trial (n = 194, training cohort). Methylation probes correlating with overall survival (OS) and progression were identified using random forest. Validation was done in 4 cohorts including DKTK-ROG definitive RCHT (n = 110) and 3 RCHT cohorts from Heidelberg, Dresden and Munich (n = 222). CTGF-M and RNAseq data from The Cancer Genome Atlas (TCGA) (n = 206) were analyzed to identify differentially expressed genes (DEG) as a function of CTGF-M. Results: Increased methylation of 2 probes (mapping to CTGF 3’UTR and gene body) was associated with significantly improved OS in the training cohort (HR = 0.51, p = 0.044) and the validation cohort (HR = 0.67, p = 0.016), in multivariate cox regressions adjusting for HPV status, age, T and N stages, location and treatment (adjuvant vs definitive RCHT). In the TCGA, probes’ methylation was significantly inversely correlated with CTGF gene expression (r = -0.18 and -0.51, p < 0.05). 1843 DEGs were found at FDR < 0.05 as a function of CTGF-M. Pathways mapping to tissue remodeling were significantly enriched for among downregulated genes in CTGF hypermethylated tumors. Increased CTGF methylation was inversely correlated with the mesenchymal subtype mRNA gene signature (r = -0.21, p = 0.0026) and correlated with the atypical subtype (r = 0.32, p = 0.000002). Conclusions: Implementation of CTGF-M in routine diagnostic is feasible and correlates well with CTGF gene-expression levels and activation of tissue remodeling pathways. Therefore, CTGF-M might be instructive for stratifying HNSCC patients for CTGF targeting therapies. CTGF emerges as a promising prognostic marker independently of HPV status.
Identifying adverse molecular features of HPV+ head and neck cancers using patient-derived models.
Authors: Basu Devraj , Facompre Nicole D , Gimotty Phyllis A. , Rajagopalan Pavithra , Sahu Varun , Pearson Alexander T. , Califano Joseph A. , Netto Frederico , Pickering Curtis R.
Published: May 2019

6057

Background: Advancing therapy for human papilloma virus-related (HPV+) head and neck squamous cell carcinoma (HNSCC) is hindered by inadequate preclinical models and risk stratification tools. This study addresses both barriers by characterizing a panel of patient-derived xenografts (PDXs) that includes nine new models of HPV+ disease. Methods: Exome-sequenced genetic features of the PDXs were compared to their growth properties and the outcomes of their patients of origin. Genetic traits with potential prognostic utility were validated in multiple retrospective patient cohorts. Results: The HPV+ PDXs avoided known artifacts in HPV+ cell lines, including 3q amplifications and loss of PIK3CA mutants, while enriching for alterations in H3K4 methyltransferases and Notch pathway genes. A positive association emerged between PDX tumor mutational burden (TMB) and their growth efficiency both in vivo and as organoids. This finding led to identification in The Cancer Genome Atlas (TCGA) of an association between high TMB and worse survival of early-stage HPV-negative cancers but not HPV+ ones. Insight into aggressive HPV+ disease came from a PDX established from a patient before lethal relapse. The reduced levels of viral E7 and p16INK4A present in this model were also detected in early lethal HPV+ cases in TCGA as well as the recurrences in a second HPV+ HNSCC cohort (JHU). This observation suggested a diminished contribution of viral oncogenes to cell cycle dysregulation in aggressive cases. To evaluate this possibility, hierarchical clustering of both cohorts was performed based on expression of E2F target genes. This analysis discovered a distinct cell cycle-related transcriptional pattern in the clusters of cases containing the recurrences and early lethal events. Furthermore, a subset of these transcripts proved to be stage-independent predictors of survival for the HPV+ HNSCCs in both TCGA and JHU cohorts. Conclusions: Characterizing the most HPV+ patient-derived models described to date revealed novel prognostic utility for E2F target expression in HPV+ HNSCCs and TMB in HPV-negative HNSCCs. These features have potential for application to risk stratification, biomarker development, and trial design.
Depth of invasion in early oral cancers: Is it an independent prognostic factor?
Authors: Dhar Harsh , D'Cruz Anil , Vaish Richa , Hawaldar Rohini W , Gupta Sudeep , Pantvaidya Gouri , Chaukar Devendra , Chaturvedi Pankaj , Pai P. S. , Deshmukh Anuja , Kane Shubhada , Nair Deepa , Nair Sudhir Vasudevan , Laskar Sarbani , Agarwal Jaiprakash
Published: May 2019

6058

Background: Depth of invasion (DOI) has been incorporated in the new AJCC TNM staging (8th edition) for oral cancers. We hypothesized that the negative effect of increasing DOI on outcomes was a result of an increased propensity to node metastasis and appropriate neck treatment would negate its detrimental effect on outcomes. Methods: Patients with T1/ T2 oral squamous cell carcinoma, clinically node negative, from a previously reported Randomized Controlled Trial (NCT 00193765) formed the cohort for this study. Patients were restaged according to the new staging system . Overall survival(OS) was estimated by the revised T stage for the entire cohort and separately for those who underwent END and those who did not (TND arm) using Kaplan Meier and log rank test . Multivariate analysis was performed using Cox proportional hazard model making adjustment for neck treatment, T stage, site, prognostic factors and the interaction between revised T stage and neck treatment. Results: Of the 596 patients 577 were evaluable, with a median follow up of 77.57 months. Initial pT staging was pT1, 389(67.4%); pT2, 181(31.4%); pT3, 7(1.2%) and was modified to pT1, 195(33.8%); pT2, 280(48.5%); pT3, 102(17.7%) on restaging . 288 patients underwent END and 289 did not (TND arm). For the entire cohort 5-year OS rates were 79.0% [95 %CI, 73.12-84.88] for pT1, 69.4% [95% CI, 63.91-74.89] for pT2 and 53.0% [95% CI, 43.2 -62.8] for pT3 with significant difference between the 3 groups (p < 0.001). In those without upfront neck treatment( TND ), OS difference was maintained between the pT1 and pT2 groups [81.1% (95%CI, 73.26-88.94) vs 65.0% (95%CI, 56.77-73.23)], p = 0.004. This difference was not apparent in the END arm ,pT1 -76.9% (95 %CI, 68.47-85.33) vs pT2 -73.7% (95%CI, 66.25-81.15), p = 0.73. T3 tumours had uniformly poor survival irrespective of neck treatment. On multivariate analysis of the revised pT1/T2 cohort (n = 475), pT stage, neck treatment and grade were independent prognostic factors impacting OS. There was a significant interaction between the T stage and neck treatment (p = 0.03). Conclusions: When DOI < 10 mm, END supplants the prognostic implication of depth with similar outcomes for T1 and T2 tumours (new AJCC staging). The exact role of DOI on outcomes warrants further research. Clinical trial information: NCT00193765.
Predictive biomarkers for response to nivolumab in head and neck squamous cell carcinoma (HNSCC) (NCT#03652142).
Authors: Psyrri Amanda , Gavrielatou Niki , Spathis Aris , Anastasiou Maria , Fortis Ekaterina , Gkotzamanidou Maria , Kladi-Skandali Athina , Kousidou Evgenia , Economopoulou Panagiota , Kotsantis Ioannis , Rusakiewicz Sylvie , Vagia Elena Mihal , Panayiotides Ioannis , Coukos George , Foukas Periklis
Published: May 2019

6060

Background: Tumor immune cell compositions determine response to immunotherapy. For a better understanding of the mechanisms of resistance to nivolumab in HNSCC, we sought to investigate a prospective cohort of longitudinal HNSCC samples from recurrent/metastatic HNSCC pts treated with nivolumab and identify biomarkers of response and resistance. We will specifically focus on modulation of immune markers following two cycles of nivolumab. Methods: Patients with platinum-refractory HNSCC with no contraindication to nivolumab therapy are included in this study. Tumor biopsies are performed at baseline, 24-72 hours after the second cycle and at progression with appropriate written informed consent. Samples were assessed for the presence of Tertiary Lymphoid Structures (TLS), PD-L1 expression (TPS and CPS) and CD8 T cell infiltrates combined with Ki67 (CD8/Ki67 double IHC stain). The primary outcome measure of the study is change in the percentage of immune cells in post treatment compared to baseline biopsies. Secondary endpoints include safety of performing a second biopsy, best overall response rate, biomarker expression in association with response and survival. Evaluation of other biomarkers including tumor mutational burden, HLA class I and II expression and adaptive immunity cell populations using multiplex IF is ongoing. Results: Of 20 patients evaluable for response, 14 had PD (8 of whom showed hyper-progression) and 6 attained disease control (1 with PR). PD-L1 status (CPS or TPS) was not altered by treatment (p = 0.905) and CPS > 20 pre-treatment showed a favorable trend towards response (p = 0.117). Absence of tertiary lymphoid structures was associated with disease progression (p = 0.0374). Infiltrating plasma cell count remained unchanged pre- and post-treatment and was unrelated to response (p = 0.458). The percentage of proliferating CD8+ T cells (CD8+/Ki67+) increased in post-treatment biopsies in the entire population (p = 0.022) and especially in progressors (p = 0.039). Pre-treatment CD8+ T cell density was higher in patients with hyper-progression compared to progressors (p = 0.029). Conclusions: Increased percentage of proliferating CD8+ T cells in progressors might represent dysfunctional T cells as has been recently shown in melanoma pts (Li H et al Cell 2019) and clinical efforts to reactivate intratumoral T cells may augment the efficacy of PD1 checkpoint inhibitors. Clinical trial information: NCT03652142.
Safety and efficacy of docetaxel combined with cisplatin as induction chemotherapy followed by cisplatin concurrent chemoradiotherapy plus gemcitabine as adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma: A prospective and multicenter phase II trial.
Authors: Wang Zhi Hui , Peng Peijian , Wang Siyang , Liu Yumeng , Lin Zhong
Published: May 2019

6064

Background: Radiation therapy is the only curative treatment modality for nonmetastatic nasopharyngeal cancer (NPC). Concurrent chemoradiation (CCRT) is the standard treatment strategy for NPC in locally advanced stages. However, the results after such treatment are suboptimal. Clearly, novel treatment strategies are needed to further improve patients’ survival rates. This trial aimed to determine the safety and efficacy of a new treatment strategy. Methods: Patients with stage III – IVa-b NPC received TP (docetaxel 75 mg/m2, cisplatin 75 mg/m2 every 3 weeks for 2-3 cycles) followed by cisplatin chemotherapy concurrently with either 3-dimentional conformal radiation therapy or intensity-modulated radiation therapy plus gemcitabine (1000mg/m2 every 2 weeks for 2 cycles) as adjuvant chemotherapy. Objective response rates and acute toxicity were assessed based on RECIST (1.1) and CTCAE v.4.0, respectively. Kaplan-Meier analysis was used to calculate survival rates. This trial is registered with the Chinese Clinical Trials Registry, number ChiCTR-OIC-17011464. Results: From July 2010 to July 2017, 20 eligible patients with nonmetastatic stage III-IVb NPC were enrolled. The objective response rates were 90% (3 complete responses [CRs] and 15 partial responses [PRs]) after two or three cycles of induction chemotherapy (ICT) and 100% (17 CRs and three PRs) after CCRT plus gemcitabine adjuvant chemotherapy, respectively. With a median follow-up time of 41 months, the 3-year overall survival rates were 90% (18/20,95% confidence interval [CI], 76.9%-100%).The 3-year progression-free survival, distant metastasis-free survival, and local progression-free survival rates were 80% (16/20,95% CI, 62.5%-97.5%), 85% (17/20,95% CI, 69.4%-100%),95% (19/20,95% CI, 85,4%-100%), respectively. The most frequent grade 3–4 toxicities were neutropenia (3/20,15%) and nausea (2/20,10%) after ICT and thrombocytopenia (6/20,30%) and leukopenia (6/20,30%) after CCRT plus gemcitabine adjuvant chemotherapy. Conclusions: Neoadjuvant TP followed by concurrent chemoradiation plus gemcitabine as adjuvant chemotherapy was well tolerated and produced promising outcomes in patients with LA-NPC in this hypothesis-generating study. The authors concluded that randomized controlled trials are warranted to definitively confirm this aggressive and potentially efficacious strategy. Clinical trial information: ChiCTR-OIC-17011464.
A randomized trial of laryngeal organ preservation evaluating two cycles of induction chemotherapy with platinum, docetaxel, and a novel Bcl-xL inhibitor.
Authors: Swiecicki Paul , Bellile Emily , Casper Keith , Malloy Kelly M , Kupfer Robbi , Spector Matthew E , Shuman Andrew , Chinn Steven Bennett , Stucken Chaz , Srinivasan Ashok , Owen Dawn , Dragovic Aleksandar Filip , Mierzwa Michelle , Jolly Shruti , Bradford Carol Rossier , Eisbruch Avraham , Carey Thomas E. , Prince Mark E , Wolf Gregory T. , Worden Francis P.
Published: May 2019

6066

Background: Laryngeal bio-selection with induction chemotherapy (platinum + 5-FU infusion: PF) has been demonstrated to result in impressive rates of survival and organ preservation with moderate toxicities. We sought to reduce the toxicity of PF by substituting docetaxel (T) for 5-FU and improve the tumor response rate with the addition of the Bcl-xL inhibitor AT-101. Methods: Pts with advanced stage laryngeal cancer were treated with 1 cycle of T 75 mg/m2 + platinum (P) (cisplatin 100 mg/m2 or carboplatin AUC 6) and were randomized 2:1 to the addition of AT-101. Patients with a CR proceeded to chemoradiation (CRT) with concurrent weekly P. All pts with PR or NR underwent a second cycle of induction with TP + AT-101. Pts with a > 50% response (CR or PR) after the second cycle of induction chemotherapy underwent CRT. Pts with a ≤ 50% response (NR) underwent laryngectomy. PET-CT was performed 12 weeks after CRT. Pts with residual disease underwent salvage laryngectomy (SL). Results: 54 eligible pts were enrolled; 46 M, 8 F; median age 59; 26 T4; stage III 16, stage IV 38; site: 2 hypopharyngeal, 39 supraglottic, 11 glottic, 2 subglottic. After cycle 1 of induction, 2/54 (4%) died prior to assessment by DL and 2 were removed from protocol due to adverse events (AEs). 29/50 pts (58%) had ≥ 50% response, 3 of which had CR; 2 proceeded to CRT & 1 received a 2nd cycle of IC. 21/50 pts (42%) had < 50% response. A total of 48 pts received cycle 2 of IC. After the 2nd cycle, a total of 39/50 pts (78%) had ≥ 50% response & received CRT. No difference in response was seen with addition of AT-101. 11/50 pts (22%) had < 50% response- 8 had laryngectomy & 3 refused. Following CRT, 10 pts underwent SL, 2 for residual disease & 8 late SL. The organ preservation rate was 31/50 (62%). The most common grade 3/4 toxicities associated with IC were nausea 9%, neutropenia 9%, & infection 7%. 1 pt died of CNS hemorrhage unrelated to therapy & 1 from sepsis. The median follow-up time is 28 months. The 2 yr laryngectomy-free survival is 54% (95% CI:38-68) & 2 yr overall survival is 81% (95% CI: 64-90). Conclusions: AT-101 did not improve responses to P. Treatment with 2 cycles of IC with PT produced similar response rates to our institutional controls, but organ preservation was somewhat less following treatment with weekly P + RT. Toxicities were overall improved with this treatment strategy. Clinical trial information: NCT01633541.
Hafnium oxide nanoparticles NBTXR3 activated by radiotherapy as a new therapeutic option for elderly/frail HNSCC patients.
Authors: Le Tourneau Christophe , Moreno Victor , Salas Sebastien , Mirabel Xavier , Calvo Emiliano , Doger Bernard , Florescu Carmen , Thariat Juliette , Fijuth Jacek , Rutkowski Tomasz , Magné Nicolas , Liem Xavier , Fakhry Nicolas , Wong-Hee-Kam Stéphanie , Calugaru Valentin , Hoffmann Caroline
Published: May 2019

6069

Background: New therapeutic approaches are needed for elderly or frail head and neck squamous cell carcinoma (HNSCC) patients (pts) ineligible for standard of care treatment. NBTXR3, a crystalline solution of hafnium oxide nanoparticles may represent such an option. Injected intratumorally, NBTXR3 enters tumor cells and yields an increased cell-localized energy deposit upon exposure to radiotherapy (RT), leading to increased tumor cell death compared to the same dose of RT alone. Methods: Phase I study of NBTXR3 activated by RT in pts ≥70 years old or ≥65 years old and unable to receive cisplatin, eligible for exclusive RT with stage III or IV HNSCC of the oral cavity or oropharynx [NCT01946867]. A 3+3 dose escalation design was implemented with dose levels corresponding to 5%, 10%, 15% and 22% of baseline tumor volume, followed by an expansion phase. Pts received an intratumoral (IT) injection of NBTXR3 and intensity modulated RT (IMRT; 70 Gy/35 fractions/7 weeks). Determination of Recommended Phase 2 Dose (RP2D) and Dose Limiting Toxicities (DLT) were primary endpoints of phase I. Absence of NBTXR3 leakage and preliminary efficacy using RECIST 1.1 principles were also evaluated. Results: The dose-escalation is complete. Nineteen pts were enrolled: 3 at 5%, 3 at 10%; 5 at 15% and 8 at 22% with no observed DLT or SAE related to NBTXR3 or IT injection. One grade 1 NBTXR3-related AE (asthenia at 22%) and four IT injection-related AE (grade 2 oral pain; grade 1 tumor hemorrhage; grade 1 asthenia, and grade 1 injection site hemorrhage) were reported. RT-related toxicity was as expected with IMRT. RP2D has been determined to be 22%. CT-scan assessment between 24h and 7 weeks post-IT injection demonstrated absence of NBTXR3 leakage in the surrounding tissues. Among 13 evaluable pts treated at doses ≥10%, 9 achieved a complete response of the injected lesion. Conclusions: These results show that NBTXR3 activated by RT is safe and well tolerated at all doses with preliminary encouraging efficacy results. It thus represents a promising future treatment for frail and elderly pts with locally advanced HNSCC with limited therapeutic options. Expansion phase has started at the RP2D. Clinical trial information: NCT01946867.
Long-term survival of adjuvant high-dose (HDC) vs weekly cisplatin (WC) for human papilloma-virus (HPV) and non-HPV head and neck squamous cell carcinoma (HNSCC).
Authors: Price Katharine Andress Rowe , Chintakuntlawar Ashish V. , Foote Robert Leonard , Garces Yolanda I. , Ma Daniel , Neben-Wittich Michelle A. , Moore Eric J. , Kasperbauer Jan C. , Price Daniel L. , Janus Jeffrey R. , Van Abel Kathryn M. , Geiger Jessica Lyn
Published: May 2019

6071

Background: Phase III data suggests a benefit of HDC in the adjuvant setting, but the effect of HDC and WC on long term survival and for HPV+ HNSCC is unknown. Methods: Data from a published retrospective study (Geiger Oral Onc 2013) of HDC vs WC in resected HNSCC was updated. Overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier method for all pts and by HPV status. Multivariate analyses were performed to assess impact of HPV status, smoking, age, HDC vs WC, and cumulative cisplatin dose ( < 200mg/m2 vs ≥200 mg/m2). Results: 51 patients (pts) received HDC and 53 WC. Median follow-up was 8.7 yrs (0.8-13.7). For the whole cohort, HDC had significantly improved OS over WC (p = 0.0095; 5- and 10-yr OS 84% and 80% vs 72% and 60%). No OS benefit for HDC was seen in pts with HPV+HNSCC (5- and 10-yr OS 90% and 87% for HDC and 81% and 81% for WC; p = 0.51). For HPV-negative HNSCC, OS had borderline significance with HDC vs WC (5- and 10-yr OS 73% and 68% vs 65% and 44%; p = 0.06). For the whole cohort, there was no difference in 5- and 10-yr RFS (78% and 74% for HDC vs 72% and 62% for WC; p = 0.32). When analyzed by HPV status, there was no difference in RFS with HDC or WC for either HPV+ (p = 0.43) or HPV-negative HNSCC (p = 0.97). On multivariate analyses of OS for all pts, only HPV status was significant (p = 0.0011; HR 0.27, CI 0.12-0.62). For HPV+ HNSCC, there was no significant predictor of OS. For non-HPV HNSCC, the benefit of HDC approached significance with a decreased risk of death (HR 0.38; p = 0.07). For all pts, those who received ≥200mg/m2 had significantly improved OS (5-yr 90% vs 72% and 10-yr 86% vs 61%; p = 0.004). By HPV status, cumulative dose had no significant effect on OS. Conclusions: OS is better with HDC and with cumulative dose > 200 mg/m2 in unselected patients. The benefit of cisplatin is likely higher for non-HPV HNSCC. A difference in OS with no difference in RFS suggests non cancer-related causes of death in the WC cohort. Ability to receive HDC could be a surrogate marker of comorbidity. [Table: see text]
Is there a benefit of adding surveillance imaging to frequent history and physical exams in patients treated definitively for head and neck squamous cell carcinoma?
Authors: Chi Jeffrey , Sugarman Ryan , Lee Matthew C. , Kamdar Dev , Frank Douglas K. , Pereira Lucio , Gabalski Edward Z. , Goncalves Priscila Hermont , Parashar Bhupesh , Teckie Sewit , Ghaly Maged , Seetharamu Nagashree
Published: May 2019

6074

Background: In head and neck squamous cell carcinoma (HNSCC) patients (pts) who completed curative-intent definitive treatment (tx), close surveillance is important. Across all centers, pts are closely monitored for symptoms and undergo frequent dedicated head and neck evaluation. Role of surveillance imaging after the initial 12 week post-treatment PET/CT however is less clear. Our institutional practice is to follow pts with regular interval imaging for two years after treatment. However this carries a financial cost, and risk for false positives and unnecessary biopsies. Methods: This is a retrospective chart review of pts treated definitively for HNSCC at our institution from 2012 to 2016. Pts who had a biopsy (bx) post-tx due to suspicion for recurrence were included. Pts belonged to 3 groups: In the first group (A), biopsy was prompted by findings on surveillance imaging (SI); in the second (B), biopsy was prompted by symptom triggered imaging (STI) and in the third (C), biopsy was based on physical exam (PE). We recorded the aggregate results of bx in each group and calculated the positive predictive value (PPV) for each. Results: Of 353 HNSCC pts, 66 underwent post-tx bx for suspected recurrence of which 46 were positive. Of the 30 pts in group A, 21 had positive bx (PPV = 70%). Within this group, PPV was highest with PET/CT (81.82%) followed by magnetic resonance imaging (66.67%) and CT (62.5%). 20 out of 20 pts in group B had bx-proven recurrence (PPV = 100%). 27 out of 36 pts in group C had positive bx (PPV = 75%). While there was no overlap between groups A and B, there was some overlap between groups A and C; and B and C. 45.45% of all recurrences were captured because of SI. When both imaging and PE conducted were positive simultaneously, 54.35% of recurrences were detected first by PE and 45.65% by imaging. Conclusions: Bx triggered by STI has the highest PPV. SI has the lowest PPV, but 45.65% of recurrences were diagnosed because of SI alone. Our study suggests that routine SI for at least two years post treatment for HNSCC patients may add to the surveillance value of frequent PE but larger studies are needed to determine the optimal frequency and type of SI modality.
A retrospective analysis of cisplatin dosing strategies when used with radiation on outcomes in head and neck squamous cell carcinoma of the oropharynx.
Authors: Tchekmedyian Vatche , Ho Alan Loh , Dunn Lara , Fetten James Vincent , Pfister David G. , Lobaugh Stephanie , Zhang Zhigang , Kang Jung , Chen Linda , Riaz Nadeem , McBride Sean Matthew , Yu Yao , Tsai C. Jillian , Lee Nancy Y. , Sherman Eric Jeffrey
Published: May 2019

6079

Background: Cis is the gold standard radiosensitizer for CRT to treat head and neck cancer. Prospective trials have required that cis be administered early in the week (Mon/Tues) to optimize radiosensitization without evidence to support this practice. This retrospective analysis considers the impact of cis day of week (DOW) administration and other variables on OPSCC pt outcomes. Methods: We reviewed OPSCC cases treated with primary CRT at our center. Pts treated with non-cis or induction chemotherapy were excluded. Data collected includes age, DOW (Mon/Tues vs Wed/Thurs/Fri), smoking status, total dose (TD) of cis (≤200mg/m2 vs > 200mg/m2), single dose (SiD) [100mg/m2 x1 day] vs split dose (SpD) [50mg/m2 x2 days] administration, T stage (0-2b vs 2c-3), N stage (0-2b vs 2c-3), overall survival (OS) (from start of RT), local/regional/distant failure, KPS and HPV/p16 status. Univariate Cox proportional hazards regression was used to analyze OS and multivariate Cox proportional hazard model investigated the relationships between OS and cis dosing variables while controlling for other factors. Results: 745 pts with OPSCC were treated with CRT from 7/31/2001-2/7/2014. 459 used cis based regimens and were included. Median age at start of RT was 55. 311 pts (67.8%) received SpD, 124 (27%) received SiD, 8 (1.7%) received weekly cis and 16 (3.5) received mixed cycles. 269 (58.6%) received ≤200mg/m2. 232 (50.5%) were HPV/p16 positive, 40 (8.7%) were negative and 187 (40.7%) were unknown. Median f/u was 7.9yrs (1.8m -18.9yrs). There were 92 (20%) deaths, and 75 (16.4%) recurrences (local/regional and distant) with 44 (9.6%) competing events. In univariate analysis, age, N stage, T stage, KPS and HPV/p16 status were significantly associated with OS, while DOW, TD, and SiD/SpD were not. In multivariate analysis (MVA), none of the associations between cis dosing and OS were significant (although MVA was limited by low number of events and total variables included). Conclusions: This retrospective analysis suggests that the DOW cis is given has no impact upon CRT outcomes for OPSCC pts. SpD cis represents an alternative administration approach.