bluuebunny/crossref_metadata_2025 huggingface dataset:
A gene signature of chemo-immunization to predict outcome in patients with triple negative breast cancer treated with neoadjuvant chemotherapy.
Authors: Bayar Mohamed-Amine , Criscitiello Carmen , Curigliano Giuseppe , Symmans William Fraser , Desmedt Christine , Bonnefoi Herve R. , Sinn Bruno Valentin , Pruneri Giancarlo , Vicier Cecile , Pierga Jean-Yves , Denkert Carsten , Loibl Sibylle , Sotiriou Christos , Michiels Stefan , Andre Fabrice
Published: September 2018

575

Background: In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after anthracycline-based neoadjuvant chemotherapy (NACT) is associated with a better prognosis. We aimed to develop a genomic signature from pre-treatment samples to predict the extent of TILs after NACT, and then to test its prognostic value on survival. Methods: Using 99 pre-treatment samples (training set), we generated a four-gene signature that predicts post-NACT TILs using the LASSO technique. Prognostic value of the signature on survival was assessed on the training set (n=99) and then evaluated on an independent validation set including 185 patients with TNBC treated with NACT. Results: A four-gene signature, assessed on pre-treatment samples and combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 predicted the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, a one-unit increase in the signature value was associated with distant-relapse free survival (DRFS) (HR: 0.28, 95%CI: 0.13-0.63, p=0.002). For the validation set, the four-gene signature was significantly associated with DRFS in the entire set (HR: 0.26, 95%CI: 0.11-0.59, p=0.001) and in the subset of patients with residual disease (HR: 0.23, 95%CI: 0.10-0.55, p< 0·001). Conclusions: We developed a four-gene signature of chemotherapy-induced immune-activation, which predicts outcome in patients with TNBC treated with NACT. [Table: see text]
Utilization, trend and impact of neoadjuvant endocrine therapy compared to neoadjuvant chemotherapy in postmenopausal breast cancer patients: Analysis of the National Cancer Data Base.
Authors: Basnet Alina , Wang Dongliang , Sivapiragasam Abirami
Published: September 2018

578

Background: Three small prospective trials that compared the efficacy of neoadjuvant endocrine therapy (NET) to neoadjuvant chemotherapy (NCT) showed no statistically significant difference. We report the differences in utilization of NET and NCT using National Cancer Data Base (NCDB) and their trend, response rates (RR) and breast conservation rates (BCR). Methods: A retrospective review of hormone receptor positive breast cancer patients ≥ 50 yrs without metastasis using NCDB was performed (2004-2014). Patients underwent NET or NCT prior to definitive surgery. Utilization pattern, practice trend, RR and BCR between NET and NCT was assessed using univariate and multivariate logistic analysis. Results: Out of 2,246,279 breast cancer patients reported in NCDB, 38,632 met our inclusion criteria. 9178 received NET and 29,454 received NCT. On multivariate analysis NET use was higher in academic vs community centers [Odds ratio (OR) 1.355, 95% CI 1.270-1.445], age >70 vs < 70 (OR 6.603, 95% CI 6.110-7.137) and high vs low Charlson Deyo comorbidity index (OR 1.817, 95% CI 1.548-2.133). NET use was lower in black vs white (OR 0.790, 95% CI 0.712- 0.875), tumors with higher vs lower grade (OR 0.153, 95% CI 0.138-0.169), higher vs lower T stage (OR 0.372, 95% CI 0.340-0.407), higher vs lower N stage (OR 0.274, 95% CI 0.243-0.310) and private vs no insurance (OR 0.600, 95% CI 0.509- 0.707), (all p<0.0001). A significant upward trend in utilization of NET was observed from year 2011 (25.9%) compared to before (22.2%), p<0.0001. RR was significantly higher for patients receiving NCT (90.5%) compared to NET (77.2%), with an [adjusted OR (aOR) 2.413; 95% CI 2.116-2.752], however the BCR was superior in the NET group (50.0%) compared to NCT group (31.1%) with (aOR 1.676; 95% CI 1.567-1.794). Conclusions: Our study is the first to compare NET and NCT utilization and their efficacy using NCDB database. Our results have shown striking differences in outcome among these two strategies as compared to other prospective trials. Despite high RR, more patients underwent mastectomy in the NCT group. We also see a steady upward trend in usage of NET from year 2011.
The impact of quality and quantity of visceral fat on survival outcome of early-stage breast cancer patients with prior chemotherapy.
Authors: Iwase Toshiaki , Sangai Takafumi , Sakakibara Masahiro , Nagashima Takeshi , Ohtsuka Masayuki
Published: September 2018

584

Background: Obesity not only increases morbidity, but also chemo-resistance of breast cancer (BC). Several studies focusing on body mass index (BMI) of BC patients have been performed; however, a recent report suggested that the quality of visceral adipose tissue (VAT) plays a crucial role in fat cell function. We set out to clarify the effect of quality and quantity of VAT on survival outcome of BC patients who underwent chemotherapy. Methods: From 2,230 patients who underwent treatment for BC at our institution from January 2004 to December 2015, we included 271 patients who received chemotherapy in neo-adjuvant (NAC) or adjuvant setting. Quantification was performed using computed tomography (CT) 3-dimensional volumetric software and quality of VAT was assessed based on the CT Hounsfield Unit of VAT (VAT-HU) using electrically stocked CT images. The correlation between BMI, amount of VAT (aVAT), and VAT-HU were analyzed using Pearson’s correlation test. The effect of these factors on pathologic complete response (pCR) was evaluated using Logistic regression model with the following covariates: menopausal status, size, nodal status, and subtype. Furthermore, survival analysis for distant disease-free survival (DDFS) was performed using Kaplan Meier method and Cox proportional hazard model. Results: aVAT and VAT-HU were significantly correlated with patient BMI (p<0.05). Forty-six patients achieved pCR (24%). Logistic regression model for pCR showed that aVAT and VAT-HU did not affect pCR (p=0.60 and 0.36). After a median follow-up of 112 months, tertile stratification revealed that the third tertile of aVAT had significantly shorter DDFS in the NAC setting (p<0.05). When adjusted by covariates in the Cox proportional regression model, aVAT and VAT-HU demonstrated significant contribution to worse DDFS ([p<0.05, hazard ratio {HR} 1.39; 95% confidence interval {CI} 1.11 to 1.75] and [p<0.05, HR 1.20, 95% CI 1.01 to 1.43], respectively). Conclusions: The quantity and quality of VAT was significantly related to the survival outcome especially in the NAC setting. This new insight would enable prediction of recurrence risk in obese BC patients with prior chemotherapy.
LUX-head and neck 2: Randomized, double-blind, placebo-controlled, phase III trial of afatinib as adjuvant therapy after chemoradiation (CRT) in primary unresected, high/intermediate-risk, squamous cell cancer of the head and neck (HNSCC) patients (pts).
Authors: Burtness Barbara , Haddad Robert I. , Dinis José , Trigo Perez Jose Manuel , Yokota Tomoya , Viana Luciano De Souza , Romanov Ilya , Vermorken Jan Baptist , Bourhis Jean , Tahara Makoto , Segalla J.G.M. , Psyrri Amanda , Vasilevskaya Irina , Nangia Chaitali Singh , Chaves-Conde Manuel , Wang Bushi , Gibson Neil , Ehrnrooth Eva , Harrington Kevin , Cohen Ezra E.W. ,   On Behalf of the LUX-Head and Neck 2 Investigators
Published: September 2018

6001

Background: Locally advanced HNSCC is treated curatively, but recurrence is common. In HNSCC, EGFR is richly expressed and EGFR inhibition is validated treatment (tx); the ErbB family blocker afatinib (A) showed efficacy in recurrent/metastatic disease. This Phase III trial assessed if A after definitive CRT improves disease-free survival (DFS). Methods: Eligible pts had complete response after CRT ≥66 Gy (or equivalent) with concurrent cisplatin or carboplatin but not prior EGFR inhibition, for HNSCC of oral cavity, hypopharynx, larynx, or oropharynx with >10 pack years (pk yrs) tobacco use. Pts were stratified by ECOG PS (0/1) and nodal stage (N0–2a/N2b–3), and randomized 2:1 to A 40 mg/d or placebo (P); tx continued for 18 m if tolerated, or until disease recurrence. The primary endpoint was DFS. Results: Of 669 pts planned, 617 were randomized; A 411, P 206. Median age was 58 yrs; 86% were male; 65% ECOG PS 0; most had smoked (A/P ex-smoker: 66/72%; current: 28/22%). Subsites (A/P) were: oropharynx 53/54%; hypopharynx 21/23%; larynx 18/12%; oral cavity 9/10%. The majority had T3 or 4 (A/P 70/68%) and N2 disease (67/63%). Accrual was halted for futility on independent DMC recommendation: at a pre-planned interim analysis (40% of DFS events), median DFS was A 43.4 m vs P not reached (NR; HR 1.13 [95% CI 0.81–1.57], p=0.48); the Table shows key subgroups. Median treatment duration was A 300.0 d, P 455.5 d. Recurrence was A 23%, P 23%. Dose reduction of A was required in 53% (mostly due to diarrhea, stomatitis). Tx was discontinued due to AEs in A 15%, P 4%. Conclusions: A after CRT did not improve DFS vs P. Subgroup analyses were underpowered to provide definitive conclusions. Harrington and Cohen contributed equally. Clinical trial information: NCT01345669. [Table: see text]
Induction gemcitabine cisplatin followed by chemoradiation in locally advanced nasopharyngeal cancer.
Authors: Usman Sadaf , Rasheed Sara , Raza Ali , Hussain Raza , Jamshed Arif
Published: September 2018

6027

Background: The current standard of treatment in locally advanced nasopharyngeal cancer is concurrent chemoradiation, however recent addition of induction chemotherapy in the already established regimen has presented an attractive alternative approach. We report on survival with induction Gemcitabine and Cisplatin (GC) followed by chemoradiation (CRT) in the treatment of advanced nasopharyngeal carcinoma. Methods: Between 2005 and 2015, 300 patients (M 70%: F 30%) with histologically confirmed nasopharyngeal carcinoma. Histological subtypes WHO I 4% (13) and WHO III 96% (287). AJCC (7th edition) stage was Stage III 28% (85) and Stage IV 72% (215) patients. IC included a 2 drug combination; intravenous gemcitabine 1000 mg/m2 on day 1 and 8 and cisplatin 75 mg/m2 on day 1 only. Radiotherapy was given as a phase treatment to a total dose of 70 Gy in 35 fractions. Concurrent three weekly cisplatin (75 mg/m2) was administered to all patients. Results: Median follow up time was 30 months. The 5-year overall survival (OS), loco regional control (LRC) and relapse free survival (RFS) rates were 70% (95% CI 6.43 – 7.52), 69% (95% CI 6.52 – 7.64) and 52% (95% CI 5.25 – 6.34) respectively. One hundred and seven patients failed treatment; local or loco-regional 39% (42), regional 16% (17) and distant 45% (48). Conclusions: We conclude that induction gemcitabine and cisplatin followed by chemo-radiation is an effective regimen in management of nasopharyngeal carcinoma, meriting further investigation in randomized clinical trials.
Premilinary survival results and potential beneficiaries for locally advanced nasopharyngeal carcinoma treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy.
Authors: Feng Mei , Lang Jinyi , Li Lu , Huang Yecai , Xu Peng , Qi Yunxiang , Li Fang , Wang Weidong
Published: September 2018

6030

Background: Neoadjuvant is a promising chemotherapy modality for recurrent nasopharyngeal carcinoma (NPC). However, there is still controversy for locally advanced NPC. We study the survival results of locally advanced NPC treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NACT) retrospectively, and to explore the potential beneficiaries. Methods: 147 stage III-IVa+b NPC treated with IMRT were included and divided into two groups. NACT group (76) received 2-3 cycles of neoadjuvant chemotherapy with TP or TPF, and then 2-3 cycles of platinum-based chemoradiotherapy (CCRT). CCRT group (71) received 3 cycles of platinum-based chemoradiotherapy. TNM stage, age and whole blood count before treatment were all collected. The stratified analysis was used for distinguishing the potential beneficiaries. Results: median follow-up time was 30 months. For all patients, the 3-year LRRFS, DMFS and OS in NACT and CCRT were 94.5%, 96.8%; 85.8%, 82.8% and 81.6%, 83.4% respectively ( p> 0.05). For stage III patients, the 3-year LRRFS, DMFS and OS were 95.2%, 97.3%; 91.4%, 84.6% and 86.3%, 82.1% respectively ( p= 0.38, p= 0.15, p= 0.58). Though there was no statistical significance, DMFS in NACT was better than it in CCRT. However, for stage IV, the survival rate had no significant difference. The incidence of grade 3-4 bone marrow suppression was higher in NACT ( p= 0.007), and the other toxicities were similar. Univariate analysis showed the percentages of neutrophil and neutrophil-to-lymphocyte ratio (NLR) were significantly correlated with OS ( p= 0.031, p= 0.049). N and clinical stage were the adverse prognostic factors for OS ( p= 0.025, p= 0.007) and DMFS ( p= 0.018, p= 0.001). Clinical stage was the prognostic factors for OS and DMFS in multivariate analyses ( p= 0.019, p= 0.01). Conclusions: NACT had a comparable survival results and tolerable toxicity with CCRT for locally advanced NPC. Stage III might be the potential beneficiaries from NACT, especially for DMFS. Percentages of neutrophil and NLR might be the new adverse prognostic factor for OS. Clinical stage was still the prognostic factor for OS and DMFS.
Aspirin use and survival in head and neck squamous cell cancer (HNC) patients.
Authors: Rafei Hind , Lumley Catherine , Han Jim , Kaffenberger Thomas M. , Maxwell Jessica H.
Published: September 2018

6042

Background: The phosphatidylinositol-3-kinase (PI3K) signaling pathway is the most common genetic alteration in HNC, particularly in oropharynx cancers (OPC). Up-regulation of the PI3K pathway enhances the production of prostaglandins inhibiting apoptosis in cancer cells. We hypothesized that aspirin (ASA) improves survival in HNC patients (pts) by counteracting the effects of prostaglandins. Methods: This is an IRB-approved retrospective cohort study of 584 veterans with HNC treated at the Washington DC Veterans Affairs Medical Center between 1995 and 2015. Charts were reviewed for clinical-pathologic and treatment data; recurrence/distant metastases; cause of death; and for the number, date and dose of ASA prescriptions. Pts who filled more than one prescription, excluding refills, after diagnosis of HNC were considered ASA users. All others were considered non-ASA users. The Kaplan-Meier method and log-rank test were used to compare disease-free survival (DFS) and disease-specific survival (DSS) between users and non-users. Results: 332 pts met inclusion criteria. Primary subsites included oropharynx (n = 146), larynx (n = 105), oral cavity (n = 62), and hypopharynx (n = 19). 86 pts were ASA users after diagnosis (25.9%) and more likely to be older (p = 0.002), African American (p = 0.03), never-alcohol users (p = 0.044), and have early stage cancer (I/II; p < 0.0005) compared to non-ASA users. Among all HNC pts, ASA users demonstrated significantly better 5-year (y) DSS (82%) compared to non users (43%; p = 0.009). 5-y DFS was also significantly higher among users (72%) vs non users (39%; p < 0.001). Among the OPC pts, 5-y DSS was higher for ASA users (74%) vs non users (41%; p = 0.024). 5-y DFS was also better for users (72%) vs non users (39%; p = 0.004). For stages III and IV, 5-y DFS was significantly higher among ASA users (64%) vs non users (44%; p = 0.035). 5-y DSS was higher as well in users (69%) vs non users (44%) but p = 0.098. On multivariate analysis, aspirin use remained an independent prognostic factor associated with improved DSS and DFS when accounting for age, race, gender, subsite, stage, tobacco and alcohol use. Conclusions: Aspirin use following diagnosis and curative treatment of HNC is associated with improved DSS and DFS.
Predicting response to radical (chemo)radiotherapy (R-CRT) with circulating HPV DNA and tumor DNA (ctDNA) analysis in locally-advanced head and neck squamous cell carcinoma (LAHNC).
Authors: Bhide Shreerang , Lee Jen , Garcia-Murillas Isaac , Cutts Ros , Hurley Tara , Grove Lorna , Nutting Christopher , Newbold Kate , Turner Nicholas C. , Harrington Kevin
Published: September 2018

6043

Background: Following R-CRT for human papilloma virus positive (HPV+) and negative (HPV-) LAHNC, patients frequently undergo unnecessary neck dissection (ND) and/or repeated biopsies for abnormal PET-CT findings even in the presence of a complete pathological response (pCR), which causes significant morbidity. We assessed the role of circulating tumor DNA analysis in identifying patients with true residual disease. Methods: We prospectively recruited development (DC, n=55) and test (TC, n=33) cohorts of LAHNC patients having R-CRT. For HPV+ tumors we developed a novel amplicon based next generation sequencing assay (HPV-detect) to detect circulating HPV DNA and for HPV- tumors we used personalised droplet digital PCR assays of somatic mutations. Circulating tumor DNA levels at 12 weeks post-R-CRT were correlated to residual disease assessed by PET-CT and surgery. Results: In the DC (27 HPV+), baseline HPV-detect demonstrated 100% sensitivity and 93% specificity, confirmed in the TC (20 HPV+). 37 HPV+ patients (DC&TC) had complete samples-set. 36 had a negative HPV-detect at end of treatment, including 6 patients who underwent ND (3) and repeat primary site biopsies (3) for positive PET-CT but had pCR on surgical/biopsy specimen. 1 patient had positive HPV-detect and positive biopsy, indicating 100% agreement for HPV-detect and residual cancer. In a 10 HPV- patients with complete sample-set, there was 90% agreement between ctDNA and residual disease in HPV- tumors (3 ctDNA positive and tumor present, 1 ctDNA negative but tumor present, and 6 negative ctDNA negative tumor) with 80% sensitivity for residual disease and 100% specificity. Combined agreement between ctDNA testing (HPV+ and -) & residual disease was 98% (Table). Conclusions: Circulating HPV DNA quantified using HPV-detect and ctDNA identifies patients with residual disease post-R-CRT in LAHNC. Further studies are required to validate these findings. [Table: see text]
HPV status and survival in non-oropharyngeal squamous cell carcinoma of the head and neck.
Authors: Wookey Vanessa , Kusi Appiah Adams , Kallam Avyakta , Ernani Vinicius , Smith Lynette , Ganti Apar Kishor
Published: September 2018

6046

Background: HPV positive squamous cell carcinoma of the oropharynx and tonsil has been associated with increased survival. However, the prognostic value of HPV status for other primary sites is unclear. We assessed the effect of HPV status on survival in patients with non-oropharyngeal head and neck squamous cell carcinoma at all stages. Methods: Data was obtained from the National Cancer Database (NCDB) to determine the effect of HPV status on overall survival (OS) in adults with non-oropharyngeal head and neck squamous cell carcinoma (gum, lip, floor of mouth, tongue (excluding base), hypopharynx and nasopharynx) using SAS software. Pearson’s Chi square test was used for comparisons by HPV status. The Kaplan-Meier method was used to estimate OS and differences were compared using a log-rank test. A multivariate Cox proportional hazards regression model analysis was performed to determine effects of individual variables on outcomes. Results: Patients with all stages of squamous cell carcinoma of the gum, lip, floor of mouth, tongue (excluding base), hypopharynx and nasopharynx diagnosed from 2010 to 2013 with complete HPV data were included (n = 13,908). In univariate analysis, HPV positivity, female gender, Asian race, primary site (lip, tongue, nasopharynx and hypopharynx), private insurance and any treatment (except for chemotherapy alone) were associated with increased OS, whereas increased age, Black race, higher Charlson-Deyo comorbidity score, hypopharynx primary, and higher AJCC stage were associated with worse OS. After adjustment for covariates, HPV positivity was associated with improved OS (HR 0.83, 95% CI 0.74-0.93; p < 0.001). Female gender, gum, lip, nasopharynx primaries, and private insurance on multivariate analysis predicted for improved OS, while age > 70, higher Charlson-Deyo score and higher AJCC stage were associated with worse OS. Conclusions: HPV positivity and female gender are good prognostic factors in squamous cell carcinoma of the head and neck, independent of primary site. Trials evaluating de-escalation of treatment should be considered for HPV positive tumors from non-oropharyngeal sites in the head and neck region.
Association of mannitol (MAN) with cisplatin (CIS)-induced nephrotoxicity (NTX) and cumulative CIS dose (CCD).
Authors: Ramalingam Sri , Szabo Aniko , Kilari Deepak , Bhosekar Chitra , Wong Stuart J.
Published: September 2018

6051

Background: CIS is widely used in cancer therapy with CCD linked to survival outcome. CCD, however, is constrained by side effects—particularly NTX (incidence 20-30%). MAN is widely used to prevent CIS NTX despite low level of evidence. Herein, we took advantage of a national shortage of MAN to examine renoprotective effects of MAN in CIS treated patients. Methods: Between 2006-2012, 704 consecutive pts undergoing CIS therapy, with or without MAN, were analyzed. Pt characteristics, oncologic diagnosis, treatment, and renal function data were collected. The primary objective was to compare clinically significant NTX, as defined by > 25% reduction in glomerular filtration rate (GFR) from baseline, between the treatment groups. Cox proportional hazards regression was used to model the hazard of NTX as a function of CIS dose. Results: Of 704 pts, 442 were treated with MAN and 262 without. The median age was 58.9 years. Age (p = 0.83), gender (p = 0.77), and race (p = 0.056) were similar between groups whereas baseline GFR (MAN 91.2 ± 22; CIS 86.3 ± 24; p = 0.005) and diagnoses (p < 0.001) differed. The distribution of diagnoses was: head and neck (25.9%), genitourinary (26.0%), lung (14.3%), gastrointestinal (10.4%), lymphoma (4.5%), and other (18.9%). The mean CIS dose (mg) per cycle in MAN versus CIS only group was 126.1 ± 58 and 109.3 ± 58 respectively (p < 0.001). The CCD (mg) was higher in the MAN compared to the CIS only group (469.8 ± 295 versus 299.0 ± 241; p < 0.001). After adjusting for baseline GFR, age, gender, race, and diagnoses, the MAN group experienced lower risk of > 25% decrease in GFR at any given CCD (HR: 0.68, CI: 0.51-0.91, p = 0.01). Females (HR: 1.72, CI: 1.28-2.32; p = 0.0003), older pts (HR: 1.24, CI: 1.10-1.40; p = 0.0003), and Hispanic pts (HR: 2.39, 1.04-5.50; p = 0.04) were more likely to sustain > 25% reduction in GFR. Conclusions: MAN enhances CCD by protecting against CIS-induced NTX. Pts with MAN experienced a lower risk of clinically significant acute kidney injury (AKI) and received a higher average CIS dose per cycle and CCD. Women, older pts, and Hispanic pts had a higher risk of AKI. Future investigation is warranted to examine whether MAN-associated CCD effects translate into survival advantages.
Molecular signatures of class II HLA and p-16 status as an immune-based classification of OPSCC relying on known predictors of sensitivity to PD-1 blockade.
Authors: Saba Nabil F. , Seby Sandra , Rossi Michael R. , Magliocca Kelly R. , Griffith Christopher C , Wang Xu , Wang Dongsheng , Dwivedi Bhakti , Patel Mihir , El-Deiry Mark , Steuer Conor Ernst , Shin Dong Moon , Kowalski Jeanne , Chen Zhuo Georgia
Published: September 2018

6052

Background: PD-1 inhibitors are known to have significant clinical activity in head and neck squamous cell cancer (SCCHN); there is, however, no selection criterion for SCCHN patients who may benefit from PD-1 inhibition. Utilizing RNA-seq analysis we explored a set of human genes encoding leukocyte antigens (HLAs) as part of a 37-gene panel predictive of response in melanoma patients to PD-1 inhibitors (Chen et al, Cancer Discov. 2016 Aug;6(8):827-37).We investigated whether this panel could define an immune-based classification of oropharyngeal squamous cell carcinoma (OPSCC). Methods: We have applied a minimal mutation and copy number content (151 genes) using an Agilent Clearseq DNA and an extensive Illumina Truseq RNA panel providing key information on gene fusions, differential gene expression, coding mutation and metagenomics on 47 SCCHN FFPE samples including 27 OPSCC. We performed an unsupervised hierarchical clustering of the samples. Two clusters with high and low expression were noted. Fisher’s exact test was performed to determine if the samples in each clusters were associated with p16 as a surrogate marker for HPV status. The same procedure was repeated on Level 3 transcriptome data from the TCGA via GDC data portal. Results: A set of fourteen immune related HLA antigen genes were identified within the 37-gene panel predictive to response to PD-1 inhibitors in p16+ versus - OPSCC (p = 0.015).We applied the same set of immune related HLA genes on the 103 patient samples from TCGA with known p16 status. When applied on all samples, there was no correlation between the HLA gene expression and p16 status (p = 0.1366); however, when restricted to OPSCC patients there was a high correlation with p16 status (p = 0.0047). Conclusions: We have identified a set of immune related HLA type II genes that are over-expressed in p16 positive OPSCC. This opens the door for further evaluation of these genes to better understand the immune related factors affecting the biology of HPV-associated OPSCC and its response to PD-1 inhibitors. (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).
IDO1 as a mechanism of adaptive immune resistance to anti-PD1 monotherapy in HNSCC.
Authors: Wirth Lori J , Burtness Barbara , Mehra Ranee , Bauman Jessica Ruth , Lee Jina , Smith Nicole Marie Stauffer , Lefranc-Torres Armida , Westra William H. , Bishop Justin A. , Faquin William C , Lin Derrick T. , Pai Sara I.
Published: September 2018

6053

Background: Patients with recurrent/metastatic human papillomavirus-associated head and neck squamous cell carcinoma (HPV-HNSCC) demonstrate improved response rates to anti-PD-1 blockade, which may be attributed to the inherent inflammation associated with the local expression of foreign, highly immunogenic viral antigens. However, these response rates are at best 25%, suggesting there may be immune resistance networks that are limiting clinical responses to anti-PD-1 therapy. To address this question, we investigated other potential immune checkpoint pathways that may be upregulated in PD-L1 expressing HPV-HNSCCs. Methods: Using a custom microarray of 59 immune-related genes, we compared the gene expression profile of laser-captured micro-dissected PD-L1 (+) and (-) immune fronts in HPV-HNSCCs. Gene expression was validated using quantitative PCR (qPCR) and protein expression geographically localized using quantitative multiplex biomarker imaging in a separate cohort of HPV-HNSCCs. Furthermore, we assayed pre- and post-treatment biopsies from anti-PD-1 treated patients and correlated gene expression with clinical responses. Results: Of the immune-related genes, IDO1 was increased 65-fold in 10 PD-L1(+) as compared to 5 PD-L1(-) HPV-HNSCCs (p = 0.004). qPCR confirmed upregulated expression of IDO1 and quantitative immunofluorescence demonstrated that PD-L1 and IDO1 geographically co-localized within the tumor microenvironment in a validation cohort of 25 HPV-HNSCC patients. In anti-PD1 treated patients, IDO1 expression increased up to two-fold and correlated with disease progression in HNSCC patients. Conclusions: IDO1 is an immune checkpoint molecule that modulates T cell activity through the depletion of L-tryptophan. We propose that IDO1 is an adaptive immune resistance pathway to anti-PD-1 monotherapy. The results provide rationale for combinatorial therapies targeting the IDO1 and PD-1:PD-L1 networks in HNSCC patients.
Poor-prognosis nasopharyngeal carcinoma as defined by a molecularly distinct subgroup and prediction by a miRNA expression signature.
Authors: Zhao Lan , Gao Feng , Wei Wang , Duan Xin , Zhang Yuchen , Zhu Lina , Wang Xin
Published: September 2018

6056

Background: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. Our aim in this study is to dissect the molecular heterogeneity of NPC, followed by construction of a prognostic model for prediction of distant metastasis. Methods: For molecular subtyping of NPC using miRNA expression data, we selected 86 stage II (AJCC 7th Edition) NPC patients from GSE32960 as training cohort. The remaining 226 NPC patients from GSE32960 and 246 NPC patients from GSE70970 were used as two validation cohorts. Consensus clustering was employed for unsupervised classification of the training cohort. Classifier was built using support vector machine (SVM), and was validated in the two validation cohorts. Univariate and multivariate Cox regression analyses were employed for feature selection and constructing a prognostic model for predicting high-risk distant metastasis, respectively. Results: We identified three NPC subtypes (NPC1, 2, and 3) that are molecularly distinct and clinically relevant. NPC1 (~45%) is enriched for cell cycle related pathways, and patients classified to NPC1 have an intermediate survival; NPC3 (~19%) is enriched for immune related pathways, and has good clinical outcomes. More importantly, NPC2 (~36%) is associated with poor prognosis, and is characterized by upregulation of epithelial-mesenchymal transition (EMT). Out of the total 25 differentially expressed miRNAs in NPC2, miR-142, miR-26a, miR-141 and let-7i have significant prognostic power (p < 0.05), as determined by univariate Cox regression analysis. For identification of high-risk distant metastasis, we built a multivariate Cox regression model using the selected 4 miRNAs. Our model can robustly stratify NPC patients into high- and low- risk groups both in GSE32960 (HR 3.1, 95% CI 1.8-5.4, p = 1.2e-05) and GSE70970 (HR 2.2, 95% CI 1.1-4.5, p = 0.022) cohorts. Conclusions: We proposed for the first time that NPC can be stratified into three subtypes. Using a panel of 4 miRNAs, we established a prognostic model that can robustly stratify NPC patients into high- and low- risk groups of distant metastasis.
CDKN2A copy number loss in HPV- and HPV+ head and neck cancer to indicate poor prognosis: An integrated genomic and clinical TCGA analysis.
Authors: Chen William S. , Bindra Ranjit , Mo Allen , Hayman Thomas , Husain Zain , Contessa Joseph N. , Gaffney Stephen G. , Townsend Jeffrey P. , Yu James B.
Published: September 2018

6060

Background: HPV infection is associated with high p16 expression and relatively good prognosis in head and neck cancers. Analysis of CDKN2A, the gene that encodes the p16 tumor suppressor protein, may further elucidate the association between HPV status and prognosis in head and neck squamous cell carcinomas (HNSCCs). We aimed to identify whether CDKN2A copy number loss was associated with poor survival in HNSCCs stratified by HPV status. Methods: We analyzed The Cancer Genome Atlas (TCGA) head and neck cancer data, integrating genomic measurements with clinical metadata. Patients 85 years old or younger with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Defining CDKN2A copy number loss as a relative log2 copy number ratio < −0.6, CDKN2A mRNA and p16 protein expression levels were compared to confirm significant differences in gene transcription and translation between the copy number loss and non-copy number loss patient groups. Overall survival (OS) and disease-free survival (DFS) were evaluated to characterize prognostic differences between genomic groups. Results: 397 patients negative for HPV (HPV−) and 91 patients positive for HPV (HPV+) HNSCC were identified. 139 HPV− patients and 9 HPV+ patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group in both HPV+ and HPV− disease. Median OS for HPV− patients with and without CDKN2A copy number loss was 21.8 months and 46.0 months (P = 0.02). Median DFS was 12.0 and 19.4 months respectively (P < 0.05). Median OS for HPV+ patients with and without CDKN2A copy number loss was 12.7 months and 57.4 months (P = 0.004) and median DFS was 7.0 and 36.6 months respectively (P = 0.02). Conclusions: CDKN2A copy number loss was associated with low CDKN2A mRNA and p16 protein expression, with poor prognosis in terms of disease-free and overall survival.
Multimodality risk adapted therapy with induction carboplatin/paclitaxel/lapatinib for SCCHN amenable to transoral surgery.
Authors: Weiss Jared , Hayes David N. , Deal Allison Mary , Zevallos Jose , Chera Bhishamjit S. , Paul Jennifer , Knowles Mary , Usenko Dmitriy , Weissler Mark Christian , Patel Samip , Grilley-Olson Juneko E. , Hackman Trevor
Published: September 2018

6064

Background: Induction chemotherapy in SCCHN has mostly been studied prior to XRT where proof of improved survival is lacking. Regimens using weekly platinum, taxane and targeted therapy have resulted in high RR. Attempts are frequently made to intensify or de-intensify, but few have adapted therapy by response. Methods: Patients with transorally resectable, treatment naïve SCCHN and node positivity or T > 3 were treated weekly 6 times with Carboplatin AUC 2, paclitaxel 135mg/m2 and daily lapatinib 1000mg followed by transoral resection. Subjects with pN0/1 received no radiation; those with close margins, ECE, pN2a-b, PNI/LVSI were treated with weekly cisplatin 30mg/m2 and XRT with involved-field XRT allowed while those with pN2c/3 were treated with cisplatin 100mg/m2 Q3W and standard XRT. Primary endpoint was clinical RR (cRR) following induction chemotherapy. Results: Primary sites: oropharynx (OP) (30), supraglottic larynx (5), oral cavity (4) and hypophyarnx (1). Of OP patients, 17 were HPV low risk. Grade 3/4 toxicity during induction: decreased WBC (7), fatigue (3), diarrhea (2), febrile neutropenia (2), neuropathy (2), rash (2) and 1 each of ALT and AST increased, hyperglycemia, hypotension, nausea, PPDE. 39/40 proceeded to surgical resection (1 patient refused for non-study reasons). 29/39 subjects who were projected to require XRT were able to avoid it. 8/10 subjects with study-defined indication for adjuvant XRT received it. cRR 37/40, pRR 14/40. Clinical and pathologic responses correlated poorly (see table). With median FU of 1.7 years, there has been no recurrence or death. Mean VRQOL was 91.7 before induction, 92.3 before surgery and 92.3 1 year post surgery. Mean MDADI was 82.8 before induction, 85.9 before surgery and 84.5 1 year post surgery. Conclusions: The regimen led to excellent feasibility of surgical resection, high cRR and a real pCR. cR predicted poorly for pR. Most patients were able to avoid XRT. Speech and swallowing function were preserved. NCT01612351. Clinical trial information: NCT01612351. [Table: see text]
Interim baseline characteristics from RIFTOS MKI, a global non-interventional study assessing the use of multikinase inhibitors (MKIs) in the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC).
Authors: Brose Marcia S. , Pitoia Fabian , Smit Johannes WA , Lin Chia-Chi , Fellous Marc Mardoche , De Sanctis Yoriko , Sugitani Iwao , Schlumberger Martin
Published: September 2018

6084

Background: RIFTOS MKI was designed to compare the time to symptomatic progression from study entry in patients with RAI-R DTC for whom there was a decision to treat or not to treat with an MKI in the real-life setting. Here, we report interim baseline characteristics for the first 274 patients enrolled in the study. Methods: RIFTOS MKI is a non-interventional study enrolling patients with asymptomatic RAI-R DTC. The decision to initiate MKIs at study entry was at the discretion of the treating physician. Final analysis will be performed once 700 patients have been enrolled and the last enrolled patient has been followed for 24 months. Results: Of 274 patients, the median duration of observation was 169.5 days. Patients have been enrolled from USA (n = 74), Japan (n = 55), Europe (n = 80), and rest of the world (n = 65); 54% were female and the median age was 68 years. Most patients had an ECOG performance status of 0 or 1 (97%) and distant metastases (81%). The most frequent histology was papillary (73%). The median time from initial diagnosis of DTC to study entry was 7 years. RAI refractoriness was mainly due to lack of RAI uptake (60%), primarily in Japan (80%). Japan also had the shortest median time from RAI classification to initial visit (2 months) vs other regions, and the average dose per RAI treatment and median cumulative activity of RAI were lower in Japanese patients (3.4 and 3.7 GBq, respectively) (Table). Conclusions: The RIFTOS MKI study is the largest non-interventional study in RAI-R DTC. The regional differences in treatment history observed in the RIFTOS MKI study reflect differences in accessibility and treatment practice. The study is ongoing. Clinical trial information: NCT02303444. [Table: see text]
Combination of dabrafenib (DAB).
Authors: Sherman Eric Jeffrey , Ho Alan Loh , Baxi Shrujal S. , Dunn Lara , Korte Susan H. , Haque Sofia , Ghossein Ronald A. , Chen Helen X. , Pfister David G.
Published: September 2018

6085

Background: BRAFV600E mutations (BRAFm) are the most common mutations in thyroid cancer. BRAF inhibitors are active in BRAFm melanoma, but there is less activity noted in BRAFm thyroid cancer. Preclinically, BRAF inhibitors inhibit BRAFm thyroid cancers only transiently due to activation of HER2/HER3, driven by a neuregulin-dependent autocrine loop. The addition of LAP, a HER2/HER3 kinase inhibitor, sensitizes the cell to growth suppression by BRAF inhibitors (Cancer Discov 5(3):520, 2013). A phase I study evaluating the combination of DAB, a BRAF inhibitor, and LAP was initiated to evaluate the safety and pharmacodynamic changes the combination. Methods: Eligibility included thyroid cancers with the presence of a BRAFV600E mutation. Any prior treatment was allowed. All patients received DAB 150 mg bid starting 2 weeks prior to LAP. Doses of daily lapatinib were escalated in a standard 3+3 design at (1) 750 mg; (2) 1250 mg; (3) 1500 mg. Toxicities, including Dose Limiting Toxicities (DLT), were noted only after both drugs were started. Patients (pts) removed before the start of LAP were not included in the analysis. Biopsies were done at baseline, after the start of DAB, and after the start of both DAB and LAP. Responses were defined using RECIST 1.1. Results: 15 evaluable pts were enrolled on the phase I portion of the study. Gender – 10/15 (67%) male; median age – 63 years; histology – differentiated thyroid cancer (DTC) 13 (87%), anaplastic thyroid cancer (ATC) 2 (13%); brain metastases – 4/15 (27%); prior tyrosine kinase inhibitor – 9/15 (54%). There was one DLT - Grade 5 event unlikely related to drugs in a pt with ATC. Grade 4 toxicities – 0. Grade 3 toxicities –lymphocytes (1). The partial response rate is 60%. The response rate in the DTC group is 69% (0% in ATC). One other pt came off treatment due to withdrawal of consent. Median progression-free survival is 15 months (range, 2-34+ months). Median follow up is 15 months. Translational studies are pending. Conclusions: The combination of DAB 150 mg bid and LAP 1500 mg daily was safe and well-tolerated. Furthermore, significant activity was noted, especially at the top dose level. Further investigation with this regimen is warranted. Clinical trial information: NCT01947023. [Table: see text]
Global impact of a clinical informatics system: Scalable delivery of on-time access to evidence-based multidisciplinary expert treatment decisions for all cancers.
Authors: Badwe Rajendra A. , CS Pramesh , Gupta Sudeep , Nair Nita S. , Feldman Nancy Renee , D'Cruz Anil
Published: September 2018

6502

Background: There is a scarcity of expert oncologists in the world. Patients in nonurban areas have poor access to evidence-based treatment decisions and worse outcomes. In India, there are ~1600 experts for 1.8 Million patients. Created in May 2014, “TMC NCG Navya Online” is an expert opinion service based on an informatics system. We prospectively study its real-world impact. Methods: Navya exhaustively searches and outputs evidence and experience based treatment options for an individual patient. Its accuracy was validated in trials at TMC (one of the world’s largest tertiary care centers) and UCLA-OVMC. Navya’s patient data summary and treatment options are rapidly reviewed and vetted (1-2 minutes) on mobile by experts from TMC and NCG, (consortium of 104 cancer centers in India). Expert decisions are converted into a simple language report for patients. System generated evidence based information on diagnostics, regimens, side effects etc are also provided. To prospectively assess impact, from July to December 2016, all patients were asked via phone follow-up: 1. If report was shared with treating provider, 2. Final treatments delivered. Results: 9361patients from 22 developing countries registered with TMC NCG Navya Online. 3402 expert decisions were provided and converted into 2614 simple language reports. 5229 patients received system generated evidence based information. Median time to deliver a report was 24 hours. The prospective sample was 582 decisions with a 75% (n = 436) follow-up rate. 74% of reports were shared with treating providers. 73% of TMC NCG Navya’s decisions, (n = 306), were the final treatments delivered. Common reasons for non-implementation included decline in ECOG status and not testing biomarkers (ER/PR etc). Conclusions: Expert oncologists use Navya to provide rapid online opinions to patients across 22 developing countries. Patients shared the expert opinions with their providers and received evidence-based treatments. Expanding the reach and impact of such a service to nonurban USA and the world, can maximize outcomes for patients without ready access to expertise.
Impact of the timing of hepatitis B virus (HBV) identification and anti-HBV therapy initiation on the risk of adverse liver outcomes in patients receiving cancer therapy.
Authors: Hwang Jessica , Suarez-Almazor Maria E. , Cantor Scott B. , Barbo Andrea G. , Lin Heather Y. , Ahmed Sairah , Chavez-Mac Gregor Mariana , Donato-Santana Christian , Eng Cathy , Ferrajoli Alessandra , Fisch Michael , McLaughlin Peter , Simon George R. , Rondon Gabriela , Shpall Elizabeth J. , Lok Anna S. F.
Published: September 2018

6503

Background: Patients with cancer and hepatitis B virus (HBV) infection receiving cancer therapy are at risk for HBV reactivation. We aimed to determine the impact of early vs. late HBV identification and early vs. late/no anti-HBV therapy on adverse liver outcomes of patients with cancer with chronic (HBsAg+/anti-HBc+) or past (HBsAg-/anti-HBc+) HBV infection. Methods: We retrospectively studied adult patients with solid or hematologic malignancies who received chemotherapy during 2004-2011. Adverse liver-related events included hepatitis flares, liver failure, and death. Time-to-event analysis was used to determine incidence, and multivariable hazard models to determine predictors of outcomes. Early was defined as at the initiation of cancer therapy and late as after therapy initiation. Results: There were 18,688 study patients (80.4% had solid tumors). Among patients with hematologic malignancies, 89.6% had HBV testing of which 90.4% was early. Among patients with solid tumors, 10.8% had HBV testing of which 46.4% was early. Prevalence of chronic HBV was 1.1% (52/4905) and past HBV was 7.1% (350/4905). Among patients with chronic HBV with hematologic or solid malignancy, those identified late had 2.95 times (1.45-6.01) higher risk of liver failure than those identified early. Among chronic HBV patients, 59% (23/39) with early testing had early initiation of anti-HBV therapy, while all of those tested late had late/no initiation of anti-HBV therapy. Predictors of liver failure were male sex, chronic HBV, and late HBV identification for patients with solid tumors, and allogeneic SCT for patients with hematologic malignancies. Conclusions: Early HBV identification correlated with early anti-HBV therapy initiation and reduced risk of liver failure after chemotherapy in chronic HBV patients with solid tumors or hematologic malignancies as well as patients with past HBV and solid tumors.
The role of chronic disease in the costs of potentially preventable emergency department use during treatment: A regional study.
Authors: Panattoni Laura Elizabeth , Fedorenko Catherine R. , Kreizenbeck Karma L. , Greenlee Stuart , Walker Julia Rose , Greenwood-Hickman Mikael Anne , Barger Sarah , Rieke John Whitelaw , Conklin Ted , Brown Thomas D. , Chance Sharon , Eaton Keith D. , Guerrero Rose , Gunkel Mary , Martins Renato G. , Moorhouse Marilyn , Smith Bruce , Lyman Gary H. , Ramsey Scott David
Published: September 2018

6505

Background: The Centers for Medicare and Medicaid Services (CMS) released a quality metric for potentially preventable chemotherapy-associated emergency department (ED) use, effective in 2020. This metric excludes diagnoses with emerging evidence for outpatient management, such as proactive symptom management (PSM) and those for ambulatory care sensitive chronic conditions. Little is known about the intersection between potentially preventable ED visits due to cancer vs. other chronic disease. This study characterized the number and costs of ED visits during treatment. Methods: Western Washington cancer registry records from 2011- 2015 were linked with claims from two commercial insurers. Patients with newly diagnosed solid tumors undergoing initial treatment with chemotherapy or radiation were eligible. ED use was tracked one year post treatment initiation. ED diagnosis codes for fields 1-10 from the CMS metric and the PSM literature were labeled “Potentially Preventable” (Pp). Codes from the Agency for Healthcare Research and Quality’s Prevention Quality Indicators (PQI) for Chronic Conditions were labeled “Potentially Preventable-Chronic Disease” (PpChronic). Costs were adjusted to $2016. Results: Of the 7,053 eligible patients, 2,543 (36.1%) visited the ED (median # visits [IQR]: 1 [1-2]). The most commonly listed codes included Pain (1,054 visits) and Dyspnea (279 visits) for Pp, Hypertension-PQI (652 visits) and COPD-PQI (206 visits) for PpChronic, and Diabetes (247 visits) and Hyperlipidemia (181 visits) for the other codes. Spending on ED visits including both potentially preventable cancer and chronic disease diagnoses totalled $706,552 (20% of ED costs). Conclusions: One fifth of ED costs potentially resulted from simultaneous poor cancer symptom and chronic disease management. Future research should explore the role of chronic illness in categorizing which ED visits are potentially preventable during cancer treatment. [Table: see text]