bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic determinants of response to pembrolizumab in head and neck squamous cell carcinoma (HNSCC).
Authors: Haddad Robert I. , Seiwert Tanguy Y. , Chow Laura Quan Man , Gupta Shilpa , Weiss Jared , Gluck Iris , Eder Joseph Paul , Burtness Barbara , Tahara Makoto , Keam Bhumsuk , Kang Hyunseok , Muro Kei , Albright Andrew , Huang Lingkang , Ayers Mark , Mogg Robin , Cristescu Razvan , Cheng Jonathan D. , Mehra Ranee 
Published: September 2018

6009 Background: Somatic mutational load (ML) is associated with response to anti CTLA-4 and PD-1/-L1 immunotherapies in select tumors, due to formation of neoepitopes not subject to central immune tolerance. Neoepitopes specific to HPV, EBV virus infection are also present in some HNSCC. An IFNγ gene expression profile (GEP) characteristic of tumor inflammation is also related to response to anti PD-1/-L1 therapy. This study evaluated relationships between ML and clinical outcome and independent predictive values of ML and GEP in patients with HNSCC treated with pembrolizumab. Methods: Whole exome sequencing (WES) and GEP were assessed in FFPE tumor specimens of patients with HNSCC (KEYNOTE 012; subsets of B1 [PD-L1+, n = 34] and B2 [PD-L1+/‒, n = 73] cohorts). ML, neoantigen load (NL), HPV/EBV status and clonality were assessed by standard WES analytical methods. GEP score is a weighted sum of normalized expression values of 18 genes. Statistical testing of ML and response, and ML and GEP relationship by HPV/EBV status was prespecified. Results: There were 73 patients identified as HPV‒ and EBV‒ (n = 25 in B1; n = 48 in B2). In HPV‒ and EBV‒ patients in B1 and B2 cohorts, respectively, associations between ML and objective response (OR) (P = 0.029 and 0.055; AUROC 0.89 and 0.63), and GEP and OR (P = 0.064 and 0.01; AUROC 0.82 and 0.74) were statistically significant. In combined cohorts of HPV‒ and EBV‒ patients, ML and GEP were significantly associated with OR (P = 0.009 and 0.002; AUROC 0.70 and 0.76, respectively). ML and GEP were only weakly correlated (r = 0.173). In a joint model, ML was significantly associated with response (p = 0.020) after adjusting for GEP (also significant, p = 0.006). NL and clonality weighted ML were also significantly associated with response (P = 0.026 and 0.006, respectively). In HPV+ or EBV+subjects, OR association was not significant for ML, possibly due to a dominance of viral vs somatic neoepitopes; GEP was significant, likely due to tumor inflammation. Conclusions: ML and GEP are independently predictive of response to pembrolizumab in HPV‒/EBV‒ patients with HNSCC; GEP was predictive regardless of viral status. ML and GEP may have utility in characterizing responses to anti PD-1 therapies and novel cancer regimens in HNSCC. Clinical trial information: NCT01848834.
Epacadostat plus pembrolizumab in patients with SCCHN: Preliminary phase I/II results from ECHO-202/KEYNOTE-037.
Authors: Hamid Omid , Bauer Todd Michael , Spira Alexander I. , Olszanski Anthony J. , Patel Sandip Pravin , Wasser Jeffrey S. , Smith David C. , Balmanoukian Ani Sarkis , Aggarwal Charu , Schmidt Emmett V. , Zhao Yufan , Gowda Hema , Gangadhar Tara C. 
Published: September 2018

6010 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. IDO1 overexpression has been associated with poor survival in SCCHN. Epacadostat (E) is a potent, selective oral IDO1 inhibitor. ECHO-202/KEYNOTE-037 is an open-label, phase I/II (P1/2) study evaluating E plus PD-1 inhibitor pembrolizumab (P) in multiple tumor types. We report preliminary P1/2 efficacy, safety, and tolerability findings in the SCCHN cohort as of a 29OCT2016 data cutoff. Methods: Eligible adult patients (pts) had metastatic SCCHN and received ≥1 prior chemotherapy regimen that included a platinum agent. Prior checkpoint inhibitor therapy (tx) was not permitted, and pts with carcinoma of the nasopharynx or salivary gland were excluded. In P1 dose escalation (3+3+3), pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for P2 cohort expansion. Response was assessed in RECIST 1.1 evaluable pts. Results: A total of38 pts (P1, n = 2; P2, n = 36) were evaluated. Median age was 63 years, 87% of pts were men, 95% were white, and 66% received prior cetuximab. Of 36 efficacy-evaluable pts, 81% (n = 29) received 1–2 prior lines of tx and 19% (n = 7) received ≥3 prior lines of tx. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 1–2 prior tx were 34% (2 CR, 8 PR) and 62% (8 SD), respectively; for pts with ≥3 prior tx, ORR and DCR were 14% (1 PR) and 43% (2 SD). Response was observed regardless of HPV status. At data cutoff, 9/11 responses were ongoing (range, 1+ to 563+ days). PFS and biomarker analyses are ongoing. The most common TRAEs in all 38 pts were fatigue (24%), nausea (11%), and decreased weight (11%). Grade ≥3 TRAEs occurred in 11% of pts; only increased amylase and lipase (both asymptomatic) were grade ≥3 TRAEs that occurred in > 1 pt. TRAEs led to discontinuation in 1 pt (increased amylase and lipase). Conclusions: In pts with advanced SCCHN, E + P was generally well tolerated and associated with encouraging response rates, particularly in pts with 1–2 prior lines of tx. A phase III SCCHN study is planned. Clinical trial information: NCT02178722.
Safety of pembrolizumab with chemoradiation (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).
Authors: Powell Steven Francis , Gitau Mark Mutuota , Sumey Christopher Joseph , Reynolds John T. , Lohr Michele , McGraw Steven , Nowak Ryan Kenneth , Terrell Andrew M , Jensen Ashley Wayne , Blanchard Miran Joel , Ellison Christie , Black Lora Jane , Thompson Paul A. , Gold Kathryn A. , Cohen Ezra E.W. , Lee John H. , Spanos William Charles 
Published: September 2018

6011 Background: Pembrolizumab (pembro) is a humanized monoclonal antibody that blocks the programmed death receptor-1 (PD-1) interaction with its ligands (PD-L1, PD-L2). While pembro is approved for platinum-refractory, recurrent/metastatic SCCHN, its role in definitive therapy for LA-SCCHN is not yet defined. Here we present the safety results of pembro with cisplatin-based CRT for patients (pts) with LA-SCCHN (NCT02586207). Methods: 27 pts with oropharyngeal (OP), hypopharyngeal (HP), and laryngeal (L) stage III-IVB SCCHN (any HPV status) eligible for cisplatin-based, definitive CRT were enrolled from November 2015 to August 2016 as part of a safety cohort. Pembro was given at a fixed dose of 200 mg IV 4-7 days prior to initiation of CRT and then every 3 weeks during CRT (2 concomitant doses) and then following CRT for 5 additional doses. CRT consisted of weekly cisplatin 40 mg/m2 IV x 6 doses (240 mg/m2 maximum) given concurrently with radiation at a dose of 2 Gy once daily for 35 fractions (total 70 Gy). Safety was determined by the occurrence of CRT or pembro dose-limiting adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on imaging or with salvage surgery at 100 days post-CRT completion. Results: 20 (74%) pts with OP HPV+ and 7 (26%) pts with HPV- (4 L, 2 OP, 1 HP) tumors were enrolled. 21 (78%) completed all planned doses of pembro. 3 discontinued due to irAEs (G2 peripheral motor neuropathy, G3 AST elevation, G1 Lhermitte-like syndrome). 3 discontinued due to protocol reasons (early neck dissection -2 pts, prolonged hospitalization-1 pt). All pts completed the full radiation dose (70 Gy) without significant delay (defined as > 5 days). 23 (85%) received the goal target dose of cisplatin (≥200 mg/m2). There was one pt death due to concurrent illness, unrelated to treatment. The study has been reopened with expansion cohorts of 34 HPV+ pts and 23 HPV- pts to evaluate efficacy. Conclusions: Pembro in combination with weekly cisplatin-based CRT is safe and does not significantly impair radiation or chemotherapy dosing. Efficacy of this combination is being explored further in this study and through larger phase III clinical trials. Clinical trial information: NCT02586207.
An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC).
Authors: Delord Jean-Pierre , Hollebecque Antoine , De Boer J. P. , De Greve Jacques , Machiels Jean-Pascal H. , Leidner Rom S. , Ferris Robert L. , Rao Shangbang , Soumaoro Ibrahima , Cao Z. Alexander , Kang Hyunseok , Topalian Suzanne Louise 
Published: September 2018

6025 Background: Treatment options for patients (pts) with R/M NPC are limited to palliative chemotherapy. NPC is often associated with the Epstein–Barr virus (EBV), a potential antigen for immune recognition, and high expression levels of the immune checkpoint receptor programmed death-1 (PD-1) and its major ligand PD-L1. Nivolumab disrupts PD-1–mediated signaling, restoring T-cell antitumor function. Methods: In CheckMate 358 (NCT02488759), PD-L1–unselected adults with R/M NPC, ECOG PS of 0–1, and ≤2 prior systemic therapies in the R/M setting were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity, as part of an ongoing multicohort study of 5 virus-associated cancers. Human papillomavirus-associated NPC and keratinizing squamous cell carcinoma (WHO Type 1) were excluded. Primary endpoints were objective response rate (ORR) and safety; secondary endpoints were duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Of 24 treated pts with R/M NPC, median age was 51 years, 88% were male, 62% were white, 88% were European, and 88% had EBV+ tumors. At a median follow-up of 26 weeks (range: 4–40), ORR was 20.8% and appeared to be higher in pts with no prior R/M therapy (Table). The disease control rate (ORR + SD) was 45.8%. Responses were observed regardless of PD-L1 or EBV status. Median PFS was 2.4 mo (95% CI: 1.5, NR); median OS was NR. Conclusions: Nivolumab demonstrated clinical activity and a manageable safety profile in R/M NPC, supporting ongoing research with nivolumab in this disease. Updated efficacy and biomarker data will be presented. Clinical trial information: NCT02488759. [Table: see text]
The impact of HPV infection on survival of patients with non-oropharyngeal head and neck cancer.
Authors: Alsidawi Samer , Westin Gustavo Figueiredo Marcondes , Chintakuntlawar Ashish V. , Okuno Scott H. , Price Katharine Andress Rowe 
Published: September 2018

6048 Background: The role of Human Papilloma Virus (HPV) infection in non-oropharyngeal squamous cell carcinoma (non-OPSCC) of the head and neck is unknown. Current available studies have yielded conflicting results due to limited number of patients. We present a large analysis from the National Cancer Database (NCDB) evaluating HPV-positive non-OPSCC. Methods: Using the NCDB registry, we included adults diagnosed with non-OPSCC from 2004-2012 with available HPV status. A cohort of patients with OPSCC was analyzed for HPV prevalence comparison. Survival analysis was performed using Kaplan-Meier method and stratified using HPV-status. The prognostic effect of variables was studied using Cox proportional hazards models. The JMP software was used for statistical analysis. Results: A total of 8726 non-OPSCC patients were identified and primary sites included the oral cavity (50%), larynx (41%) and hypopharynx (9%). 11% of non-OPSCC patients had evidence of infection with high-risk HPV strains compared to 61% of OPSCC patients. HPV-positive non-OPSCC patients presented at slightly younger age, had more advanced stage and higher tumor grade compared to HPV-negative patients (P < 0.01). HPV-positive non-OPSCC patients had better survival than HPV-negative patients (HR 0.82, 95% CI 0.72-0.93, P < 0.01) and this was most pronounced in patients with locally advanced disease (5-year survival 50% versus 40%, HR 0.69, 95% CI 0.6-0.8, P < 0.01). A univariate and multivariate analysis were performed adjusting for age, sex, race, stage, primary site, Charlson/Deyo comorbidity score, financial income, tumor grade, surgery, radiation and chemotherapy administration. Smoking history was unavailable. HPV positivity was an independent predictor of better survival in non-OPSCC in multivariate analysis (HR 0.69, 95% CI 0.59-0.8, P < 0.01). Conclusions: HPV infection is seen in a subset of patients with non-OPSCC head and neck cancer and these present with more advanced tumors. The survival of patients with HPV-positive non-OPSCC is significantly better than HPV-negative tumors. Routine HPV testing and enrollment in treatment de-intensification clinical trials similar to OPSCC might be appropriate for this patient population.
Cell-free DNA for treatment monitoring and outcome predictor in head and neck cancer.
Authors: Beck Julia , Schirmer Markus , Rave-Fraenk Margret , Urnovitz Howard , Bornemann-Kolatzki Kirsten , Mitchell William Marvin , Oellerich Michael , SchÃ¼tz Ekkehard , Canis Martin 
Published: September 2018

6055 Background: Copy number instability (CNI) signatures of cancers can be readily detected by Next Generation Sequencing of plasma cell-free DNA (cfDNA). HPV detected in oropharyngeal carcinomas is currently the only prognostic biomarker available. We report here CNI scores for disease monitoring of Head and Neck Cancers (HNC) with potential predictive value for personalized therapeutic options. Methods: A total of 132 plasma samples were collected from 54 HNC patients under informed consent and IRB approval. cfDNA was extracted from plasma, ~20M paired-end NGS mappable reads (reference: HG19) per sample were generated and CNI scores were calculated by read counting statistics. After unblinding CNI scores were evaluated as diagnostic parameter for association with disease characteristics and progression. Survival analysis was conducted after dichotomization of baseline CNI scores at a value of 31 corresponding to the 97.5thpercentile of a normal reference group (RG, n = 141). Results: CNI scores above the 97.5th RG percentile were detected in 40 out of 54 (74%) treatment naïve baseline samples. 29 patients with tumors ≤ T3 (62%, n = 42) and 11 out of 12 (92%) with T4 tumors had CNI scores > 31, with significantly higher CNI scores (p = 0.04) seen for T4 tumors. Higher CNI scores were also found in patients with tumor lymph node invasion (n = 37; median: 381, Q25-Q75: 57-1573) compared to negative lymph nodes (pN0, n = 17; 27, 19-64, p= 0.0004). A steep decline of CNI scores was detected after surgical resection, with increasing CNI scores in later disease progression. The pre-operative CNI scores were a stronger predictor of time to recurrence (p = 7*10-5) than the pN status (p = 0.05) (Cox regression). High baseline CNIs ( > 31) strongly correlated with time to recurrence (Kaplan-Meier log-rank p = 0.018) with a median of 20 months and median overall survival of 30 months in the high CNI group, neither reached in the low CNI-score group (60 m follow-up). Conclusions: Chromosomal instability within HNC was quantified from plasma cfDNA as CNI score. The CNI score may serve as better predictor for the time to recurrence interval than pN status. The data suggests that cfDNA analysis as CNI score may serve as real-time marker of treatment efficacy and outcome.
FGFR3 correlation with mutant p53 and its prognostic value in oropharyngeal squamous cell carcinoma (OPSCC).
Authors: Chen Zhuo Georgia , Nannapaneni Sreevinas , Griffith Christopher C , Wang Dongsheng , Zhang Chao , Magliocca Kelly R. , Wang Xu , Chen Zhengjia , Patel Mihir , Steuer Conor Ernst , Shin Dong Moon , Saba Nabil F. 
Published: September 2018

6057 Background: Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. Information on its prognostic value and its correlation with other relevant cancer related proteins is limited. Methods: We performed immunohistochemistry (IHC) analyses of p16, mutant p53 (mp53), and FGFR3 on 221 retrospectively collected OPSCC tissue samples. mp53, and FGFR3 were semi-quantified as weighted index [WI = % positive x intensity (0. 1+, 2+, and 3+)]. Correlations of FGFR3 WI with p16 status, and mp53 WI were analyzed. Association of FGFR3 with disease-free survival (DFS) or overall survival (OS) was assessed. Results: A total of 144/221 (65%) were p16 +, 93/172 (54%) had mp53, and 140/221 (63%) expressed FGFR3. FGFR3 was highly correlated with mp53 (p < 0.001), which was true in both p16 + and – OPSCC (p < 0.0001 and p = 0.0006, respectively).mp53 level was significantly lower in p16 positive versus p16 negative group (p < 0.0001). Univariate analysis revealed an association of p16 negative and high mp53 with worse OS (p < 0.001 and p < 0.001, respectively) and DFS (p < 0.001 and p = 0.004, respectively). FGFR3 was associated with worse OS and DFS (p = 0.014 and p = 0.047, respectively). On multivariable analysis FGFR3 was associated with worse DFS (p = 0.005), but not OS. Kaplan-Meier plot using medians of both FGFR3 and mp53 as the cut-off values showed that higher FGFR3 and mp53 correlated to worst DFS (p = 0.025) and OS (p = 0.009). Conclusions: Our results suggest that FGFR3 is associated with mp53 and p16 – OPSCC and correlates with worse clinical outcome. The biologic relation of FGFR3 and mp53 in OPSCC deserves further investigation. (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).
Resource utilization in patients with head and neck cancer: Analysis of CCTG HN6 (NCT00820248).
Authors: Ghate Ketan , Parulekar Wendy R. , Chen Bingshu E. , Montenegro Alexander , Khaouam Nader , McCarthy Joy S. , Walker John , Waldron John , Siu Lillian L. , Johnson Ana 
Published: September 2018

6067 Background: As new treatments for head and neck cancer arise, further information is required regarding resource utilization. The Canadian Cancer Trials Group HN.6 study included collected resource utilization data prospectively on patients with locally advanced squamous cell carcinoma of the head and neck treated with cisplatin or panitumumab plus radiotherapy (RT). Methods: The HN.6 phase III trial enrolled 320 patients across Canada between 2008-2011. The economic analysis was conducted from the societal perspective. Resource utilization was collected prospectively for 3 categories: outpatient, hospitalization and institutionalization (end of life care) at baseline, 8 weeks, every 3 months(mo) for 2 years and every 4 mo until 3 years. Lost productivity questionnaires were collected in the last week of RT. Descriptive statistics were used to summarize the outcomes. Categorical variables were reported by percentage and continuous variables were reported by mean and standard deviation. Results: Of 320 pts randomized, resource utilization and lost productivity data were available for 317 (99%) and 285 (89%) pts, respectively. Eighty nine pts required 130 emergency room visits (mean 1.46±0.85). There were 696 (mean 3.74±3.22) office visits among 186 pts and 367 (mean 3.95±6.43) outpatient visits among 93 pts. Surgeons, radiation oncologists and emergency room physicians were the top three providers of outpatient care with 234 (mean 2.05±1.54), 137 (mean 1.67±1.19) and 118 (mean 1.4±0.78) visits for 114, 82 and 84 pts, respectively. CT scans (286), lab tests (418), x-rays (182) and other tests (400) were conducted in 136, 180, 120 and 194 pts, respectively. Three pts were institutionalized for end of life care (mean 28 days±26.06), and 214 pts were hospitalized (mean 14.5 days±28.8). One hundred and thirteen (41%) pts reported a change in work status at the end of RT. Conclusions: Radical treatment for locally advanced SCCHN is resource intensive. Tracking resources utilized prospectively in clinical trial settings and reporting this information consists of an efficient way to inform health resource allocation decisions. Clinical trial information: NCT00820248.
A personalized approach using hypoxia resolution to guide curative-intent radiation dose-reduction to 30 Gy: A novel de-escalation paradigm for HPV-associated oropharynx cancers (OPC).
Authors: Riaz Nadeem , Sherman Eric Jeffrey , Katabi Nora , Leeman Jonathan Eric , Higginson Daniel S. , Boyle Jay , Singh Bhuvanesh , Morris Luc G. , Wong Richard J. , Tsai C. Jillian , Schupak Karen , Gelblum Daphna Y. , McBride Sean Matthew , Hatzoglou Vaios , Baxi Shrujal S. , Pfister David G. , Dave Amita , Humm John , Schöder Heiko , Lee Nancy Y. 
Published: September 2018

6076 Background: We conducted a pilot study using functional imaging to guide reduction in radiation (RT) to 30Gy with concurrent chemotherapy in patients with HPV+ OPC. Methods: 19 patients were enrolled prospectively from 7/2015-10/2016. Primary tumors were excised and analyzed for DNA repair foci ex-vivo. A pre-RT dynamic 18F-FMISO (fluoromisonidazole) PET was then used to assess tumor hypoxia (defined as > 1.2 tumor to muscle SUV ratio) in cervical lymph nodes. Patients without hypoxia on baseline or repeat scan done 5-10 days after initiation of chemoRT received 30Gy (57% reduction) over 3 weeks to the tumor bed and neck with 2 cycles of concurrent chemotherapy (high-dose cisplatin or carboplatin/5-FU). Patients with persistent hypoxia received the standard dose of 70Gy over 7 weeks with chemo. Neck dissection (ND) was done 4-months post chemoRT. Weekly DWI MRI, ctDNA, whole exome & RNA sequencing were performed. Results: 19 patients (11 tonsil, 5 BoT, 3 unknown primaries) were enrolled. Staging: 11 T1, 5 T2, 3 Tx; 5 N1, 3 N2a, 11 N2b; all M0. On pre-RT 18F-FMISO scans, 13 were positive and 6 were negative for hypoxia. Of the 12 intra-treatment 18F-FMISO scans (1 not done due to intermittent illness, this patient received 70Gy), 3 were positive and these patients received 70Gy chemoRT. 15 patients were de-escalated to 30Gy. To date, analysis showed complete pathologic response in 8 of 9 patients (all 15 expected to have ND by April 2017. The one positive case received only 1 cycle of cisplatin. To date, 18 of 19 patients (95%-6 pending ND) remain disease free. Correlative analysis with sequencing, DNA repair foci, ctDNA, and results from pathologic and intra-treatment imaging response will be presented. Conclusions: This is the first report of apersonalized approach to a major decrease in RT dosing for definitive treatment of HPV+ oropharyngeal carcinoma guided by patient-specific imaging-based treatment response. De-escalation to 30Gy informed by intra-treatment imaging for hypoxia appears feasible, safe and efficacious. A multi-center trial to validate these pilot results is planned. Clinical trial information: NCT00606294.