bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, open-label, phase II study of afatinib versus cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Analysis of stage 2 (S2) following crossover.
Authors: Cupissol Didier , Seiwert Tanguy Y. , Fayette Jérôme , Ehrnrooth Eva , Blackman Alice Sarah , Cong Xiuyu Julie , Cohen Ezra E.W.
Published: March 2020

6001

Background: This open-label trial assessed the efficacy of the irreversible ErbB Family Blocker afatinib (A) vs cetuximab (C) in R/M HNSCC pts following failure of platinum-containing therapy. In Stage 1 (S1), A and C had confirmed objective response rates (RECIST 1.0) of 16.1% vs 6.5% by investigator review (8.1% vs 9.7% independent central review [ICR]; Seiwert TY, et al. MHNCS 2012. Abs 235). S2 data after crossover are presented. Methods: In S1, pts were randomized 1:1 to oral A 50 mg/day or IV C 250 mg/m2/wk (400 mg/m2 IV loading dose) until progressive disease (PD) or intolerable drug-related adverse events (DRAEs). Pts could then crossover to the other treatment arm (S2), with treatment given until further PD or intolerable DRAEs. Tumor response in S2 (RECIST 1.0) was evaluated at 4 wks after crossover and every 8 wks thereafter. Results: 56% of pts crossed over into S2: 32 from A to C and 36 from C to A. Of these, 88% crossed over after PD and 12% after intolerable DRAEs. Baseline characteristics of S2 pts were similar in the A and C groups and treatment duration in S1 prior to crossover was comparable (A: 3.7 [0.2–15.7] months; C: 3.5 [0.0–12.5] months). Median treatment duration in S2 was 2.1 (0.0–7.6) months for A and 1.2 (0.0–9.9) months for C. Tumor size decreases of ≥30% were observed in 1 pt in each treatment group (ICR). The disease control rate (DCR) for A was 33% vs 19% for C and the median progression-free survival time was 9.3 wks for A and 5.7 wks for C (ICR). The most frequently reported DRAEs (≥20%) for A were rash/acne (56%), diarrhea (53%) and stomatitis (22%), and for C was rash/acne (44%). DRAEs of ≥Grade 3 were seen in 47% of pts treated with A and 16% of pts treated with C. 12 A-treated patients had dose reductions to 40 mg and 1 pt had a further dose reduction to 30 mg; no C-treated pts had dose reductions. Conclusions: R/M HNSCC pts seem to benefit from sequential therapy with A/C or C/A, especially when using A treatment after C failure. Cross resistance is not universally present and further investigation of sequential treatment is warranted. Clinical trial information: NCT00514943.
Analysis of HPV and ERCC1 in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
Authors: Mehra Ranee , Egloff Ann Marie , Li Shuli , Yang Donghua , Wang Lin , Zhu Fang , Forastiere Arlene A. , Burtness Barbara , Argiris Athanassios ,   Eastern Cooperative Oncology Group
Published: March 2020

6006

Background: We studied the association of human papillomavirus (HPV) and excision repair cross-complementation group 1 (ERCC1) tumor expression with clinical outcomes in patients (pts) with R/M SCCHN. Methods: Archival baseline specimens were obtained from pts on ECOG trials: E1395, phase III trial of cisplatin/paclitaxel (CP) vs. cisplatin/5-FU (CF), and E3301, phase II trial of docetaxel/irinotecan. HPV DNA was detected by in situ hybridization (ISH) with a wide spectrum HPV probe. Tumor p16 status was defined as positive if immunohistochemical staining for p16 was strong and present in >80% of tumor cells. ERCC1 expression was measured (HistoRx PM-2000) and data analyzed using AQUA algorithms, after tissue was stained with ERCC1 ab (1:5000 HPA0297731, Sigma), and a wide-spectrum cytokeratin ab (Dako Z0622) for tumor mask. A prior determined cut point for nuclear staining was utilized. Fisher's exact test and log-rank test were used to compare categorical variables and survival. Stratified logistic regression and Cox regression model were used to estimate odds ratio (OR) and hazard ratio (HR), respectively, adjusting for potential confounding factors. p-values were two-sided. Results: Tissue was evaluable from 65 tumors (T) for HPV, 66 for p16 (E1395 and E3301), and 43 for ERCC1 expression (E1395). 11 T were HPV+ (12 p16+), and 54 were HPV-/p16-. HPV+ tumors were similarly represented in all treatment groups (p=0.58). Objective response rates (RR): 67% for HPV+, 22% for HPV- (p=0.013); 60% p16+, 22% p16- (p=0.05). RR rates were calculated excluding cases with unevaluable/unknown responses. HR for OS was 2.66 (HPV, p=0.02) and 2.27 (p16, p=0.04), favoring HPV+/p16+ pts. 18 T were ERCC1 high (H) and 25 ERCC1 low (L). HR for OS (H vs. L) was 1.96 (p=.11) RR: CF, 58% (L), 29% (H); CP, 33% (L), 56% (H). A test of ERCC1 by treatment interaction (p=0.12) suggested the effect of ERCC1 may be different for taxane vs. non-taxane regimens. Conclusions: This is the first study to show that HPV+/p16+ status is associated with a significant improvement in RR and OS among pts treated for R/M SCCHN. ERCC1 L was associated with a trend towards a better OS.
p16 expression as a human papillomavirus (HPV)-independent prognostic biomarker in non-oropharyngeal squamous cell carcinoma (non-OPSCC).
Authors: Chung Christine H. , Zhang Qiang , Kong Christina , Harris Jonathan , Ang K. Kian , Harari Paul M. , Wang Dian , Redmond Kevin P. , Shenouda George , Trotti Andy , Raben David , Gillison Maura L. , Jordan Richard , Le Quynh-Thu
Published: March 2020

6007

Background: p16 is an important tumor suppressor and cell cycle regulator that is commonly lost in HPV-negative (-) and upregulated in HPV-positive (+) OPSCC. While the role of p16 expression in OPSCC as a surrogate marker of HPV infection and its association with prognosis are well established, its significance has not been studied in non-OPSCC including oral cavity, hypopharynx and larynx, where HPV infection is rare. We hypothesize that p16 expression is a prognostic biomarker of favorable outcome (progression-free and overall survival) in non-OPSCC. Methods: p16 expression in non-OPSCC from RTOG 0129, 0234 and 0522 was determined by immunohistochemistry (p16 mouse monoclonal antibody, prediluted, MTM-CINtech, 9518) and considered positive if >70% of the tumor cells demonstrated diffuse staining. The high risk HPV status in non-OPSCC from RTOG 0129 and 0522 was determined by in situ hybridization using a cocktail probe including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66. Hazard ratios from Cox models were expressed as positive/negative, stratified by trial, and adjusted for age, gender, T, and N stage. Results: p16 expression was positive in 14.1% (12/85), 24.2% (23/95) and 19.0% (27/142) of non-OPSCC from RTOG 0129, RTOG 0234, and RTOG 0522, respectively. HPV ISH was positive in 6.5% (6/93) and 6.9% (7/101) of non-OPSCC from RTOG 0129 and RTOG 0522, respectively. There was moderate agreement between p16 and HPV status (kappa=0.53). The hazard ratios for p16 expression are 0.63 (p=0.03) and 0.56 (p=0.01) for PFS and OS, respectively. In 0522, there was no interaction between p16 status and two treatment arms (RT+cisplatin+/-cetuximab). In comparison of OPSCC and non-OPSCC, patients with p16(+) OPSCC have better PFS and OS than patients with p16(+) non-OPSCC, but patients with p16(-) OPSCC and non-OPSCC have similar outcomes. Conclusions: Similar to results in patients with OPSCC, patients with p16(+) non-OPSCC have better outcomes than patients with p16(-); however, the differential appears smaller than has been observed in HPV(+) OPSCC. Further studies are warranted to delineate the role of p16 expression as a prognostic biomarker in non-OPSCC and OPSCC. Clinical trial information: NCT00265941, NCT00047008, NCT00084318.
Multimodality determination of HPV status in head and neck cancers (HNC) and development of an HPV signature.
Authors: Zuo Zhixiang , Keck Michaela K. , Khattri Arun , Patel Rajesh D. , Walter Kim , Lingen Mark W. , White Kevin P. , Hammerman Peter S. , Cohen Ezra E.W. , Stenson Kerstin , Blair Elizabeth A. , Shames David S. , Vokes Everett E. , Seiwert Tanguy Y.
Published: March 2020

6008

Background: Determination of HPV status is prognostically important, and various testing modalities are commonly used. Discordant results are occasionally observed and a gold standard (for research purposes) is E6/E7 mRNA expression. We aimed to evaluate accuracy of multiple research HPV tests compared to p16 expression/anatomic site, and developed a new HPV signature that we hypothesize will capture HPV-related oncogenic processes independent for all HPV types. Methods: HNCsamples from 136 patients were evaluated by: 1) nested E6 PCR (DNA) (Sotlar 2004), 2) qPCR for E6, E7 (HPV16), E6, L1 (HPV18) (mRNA), 3) p16 expression by IHC and/or mRNA. Results were correlated with anatomic site. A gene expression (GE) signature was developed based on Agilent 4x44Kv2 data and validated in a second cohort. In equivocal cases mutational status of TP53 was evaluated. Results: p16/CDKN2A expression was unreliable outside the oropharynx (OP) (81% false-positives in non-OP tumors, compared to 12% for OP tumors). Anatomic site as described by clinical reports was unreliable. In our cohort, 52 out 77 OP (67.6%) were HPV positive by DNA and RNA based approaches, 3 only by DNA. DNA and RNA based approaches appeared to be similarly accurate and concordant in 97% of samples. The newly developed HPV-GE signature was highly accurate, and allowed to reconcile discrepant cases, suggesting that the DNA-based approach overcalled HPV(+) in 2 tumors while the RNA based approach underreported HPV status in two cases. Expression levels of E6/E7 mRNA showed extensive variability in HPV(+) samples. Interestingly the HPV-GE signature suggested continuous/overlapping biology for a minority of cases. Two tumors (1 supraglottis/HPV18, 1 oropharynx/HPV16) tested HPV(+) by DNA/RNA, p16/CDKN2A, and HPV-GE signature while at the same time having TP53 mutations. Conclusions: p16 should not be used outside the oropharynx and anatomic allocation may also be inaccurate. DNA and mRNA based approaches perform equally well and can be reconciled using the HPV-GE signature. The HPV-GE signature supports the hypothesis that HPV(+) and HPV(-) biology may overlap in a minority of cases.
An epithelial-mesenchymal transition (EMT) gene signature to predict resistance to EGFR inhibition and AXL identification as a therapeutic target in head and neck squamous cell carcinoma.
Authors: Cardnell Robert , Diao Lixia , Wang Jing , Bearss David , Warner Steven , Fan You Hong , Giri Uma , Story Michael D. , Weinstein John N. , Coombes Kevin R. , Williams Michelle D. , Genome Atlas Reseach Network The Cancer , Wistuba Ignacio Ivan , Mills Gordon B. , Myers Jeffrey , William William Nassib , Ang K. Kian , Heymach John , Byers Lauren Averett
Published: March 2020

6011

Background: Epithelial-mesenchymal transition (EMT) has been associated with EGFR inhibitor resistance in preclinical studies of head and neck squamous cell carcinoma (HNSCC). Recently, we developed an EMT signature that predicts EGFR inhibitor resistance in lung cancer. Using this signature, we explored the association between EMT and drug response in HNSCC, focusing on the tyrosine kinase Axl as a potential therapeutic target. Methods: We conducted an integrated molecular and drug response analysis in HNSCC. A 76-gene EMT signature previously developed and validated in lung cancer was tested in HNSCC cell lines (n>50) and patient tumors from The Cancer Genome Atlas (TCGA) (n=113) and a MDACC cohort (n=105). Reverse phase protein array (RPPA) and proliferation assays were used to measure protein expression and sensitivity to erlotinib and the Axl inhibitors SGI-7079 and TP-0930. Results: The EMT signature identified distinct epithelial and mesenchymal subsets of HNSCC among cell lines and patient tumors. RPPA experiments revealed higher protein levels of the receptor tyrosine kinase Axl, vimentin, and N-cadherin and lower expression of E-cadherin and beta-catenin in mesenchymal HNSCC (p-values <0.02). Elevated Axl expression was also associated with significantly shorter overall survival in patients with locally advanced HNSCC (p<0.001 in TCGA cohort; p=0.003 MDACC). Consistent with previous studies, mesenchymal HNSCC cells exhibited resistance to erlotinib (IC50 >10μM); however, we discovered that mesenchymal HNSCC were highly sensitive to two Axl inhibitors, SGI-7079 and TP-0930 (IC50s ≤1.2μM and 0.2uM, respectively). Conclusions: Our EMT gene expression signature identified discrete epithelial and mesenchymal subgroups of HNSCC. Mesenchymal HNSCC cells expressed higher levels of Axl protein and exhibited sensitivity to Axl inhibition, but resistance to erlotinib. These results highlight differences in drug response between epithelial and mesenchymal cancers and support Axl as a potential therapeutic target and predictive marker of EGFR inhibitor resistance in HNSCC. (Funded in part by 5 P50 CA097007-10)
Efficacy of trastuzumab re-therapy in routine treatment of HER2-positive breast cancer patients who relapsed after completed (neo-)adjuvant anti-HER2 therapy.
Authors: Hanker Lars Christian , Hitschold Thomas , Hesse Tobias , Grafe Andrea , Foerster Frank Gerhard , Schroeder Jan Klaus , Janssen Jan , Reichert Dietmar Arno , Hielscher Carsten , Greinemann Jasmin , Borquez David Julian , Schmidt Marcus
Published: March 2020

602

Background: Addition of trastuzumab (Roche; T) to chemotherapy (CT) has improved outcomes in patients (pts) with HER2+ breast cancer at all stages, including locally advanced and metastatic disease. Anti-HER2 re-treatment with T is an increasingly used therapy option for the treatment of recurrent/metastatic breast cancer (MBC). However, limited data on T re-treatment is currently available. Methods: Patients with locally recurrent and/or MBC who received T re-therapy were included in this non-interventional study. Among 232 pts enrolled at 121 sites in Germany, 174 pts (33 locally recurrent disease, 141 MBC) were already sufficiently documented to be analyzed for efficacy of T re-therapy in this ongoing study. Progression-free survival (PFS) was assessed by the investigator. Results: The median disease-free interval (calculated from the time of resection of the primary tumor to diagnosis of local recurrence/MBC) was 3.1 years. Median duration of re-therapy with T was 9.3 months. The median PFS of all patients was 10.1 months (95% confidence interval (CI), 8.5 to 13.1). PFS for pts with only locally recurrent disease (n= 33) was 23.6 months. PFS for MBC pts (n=141) was 8.9 months (95% CI, 7.4 to 10.6). For pts with visceral metastases (n=96) a PFS of 8.0 months compared to 10.1 months in patients with only non-visceral (n=45) was recorded. 104 pts were re-treated with T + CT (>70% paclitaxel, vinorelbine, capecitabine or docetaxel alone; PFS= 9.3 months), 26 pts with T + hormonal therapy (HT) (mostly anastrozole, fulvestrant, exemestane, letrozole or tamoxifen; PFS=10.1 months), 24 pts with T+CT+HT (PFS= 19.9 months) and 20 pts with T monotherapy (PFS= 9.4 months). Conclusions: This study provides clinical evidence that re-application of T in combination with either CT, HT or alone is effective in the routine treatment of patients with MBC and/or locally recurrent disease. The benefit observed for pts receiving first-line treatment with T in combination with taxane in pivotal trials as well as recently published data seems comparable to the presented results of pts receiving T re-therapy.
Phase II study of dovitinib (TKI258) in patients with progressive metastatic adenoid cystic carcinoma.
Authors: Dillon Patrick Michael , Moskaluk Chris , Fracasso Paula M. , Petroni Gina R. , Thomas Christopher Y.
Published: March 2020

6021

Background: Adenoid cystic carcinoma (ACC) is an uncommon malignancy of secretory glands for which there is no standard systemic therapy. At least 90% of ACC tumors carry a t(6;9)(q22–23;p23–24) chromosome translocation that results in overexpression of the MYB oncogene that in turn upregulates FGF2 and other growth factors. Dovitinib is a multiple receptor kinase inhibitor that could potentially block autocrine activation of the FGFR and VEGFR-mediated angiogenesis. In a mouse model, dovitinib suppressed the growth of low passage ACC xenografts. Methods: In this open-label, single-arm trial, patients (n=21) with metastatic ACC that progressed in the last 6 months were treated with dovitinib 500 mg/d, 5-days on/2-days off. The primary endpoint was objective response rate using a two-stage design to test a null and alternative rate of 1% and 18%, respectively, with 90% power and type I error <5%. Secondary endpoints were progression-free survival, safety, quality of life, biomarker studies, and change in tumor growth rate. Results: All 21 patients (median age 54.3, range 29-74) had previous treatment with chemotherapy, radiotherapy or targeted agents. Median duration of treatment to date is 5.7 months (range 2-10 months) and is ongoing in 11 patients. Nine of 21 patients required dose reductions. Grade 3/4 drug-related adverse events included thromboembolism (4), hematuria (1), dehydration (1), pneumonia (2), hypertriglyceridemia (3), diarrhea (2), stomach pain (2), anxiety (1), transaminitis (3) and cytopenias (4). One death occurred unrelated to study drug. Among 19 evaluable patients, 2 had partial responses by RECIST criteria (1 with lung metastases and 1 with tracheal recurrence and stable bone metastases). Both experienced improvements in pain ratings and are free of disease progression at 8+ and 5+ months. Stable disease >6 months was observed in 9 patients while 6 others with shorter follow-up have not progressed. Four patients progressed early (<4 months) and two are too early to assess. Conclusions: Dovitinib produces objective partial responses and prolonged tumor stabilization with acceptable toxicity in patients with progressive ACC. Clinical trial information: NCT01524692.
A phase II study of everolimus in patients with aggressive RAI refractory (RAIR) thyroid cancer (TC).
Authors: Lorch Jochen H. , Busaidy Naifa , Ruan Daniel T , Janne Pasi A. , Limaye Sewanti Atul , Wirth Lori J. , Barletta Justine A. , Rabinowits Guilherme , Garraway Levi A. , Van Allen Eliezer Mendel , Wagle Nikhil , Hanna Glenn J. , Misiukiewicz Krzysztof , Suda Margaret , Haddad Tyler C , Devine Catherine E , Williams Amy , Warsi Ghulam , Posner Marshall R. , Haddad Robert I.
Published: March 2020

6023

Background: We present results of an open label phase II study of the mTOR inhibitor Everolimus in patients (pts) with RAIR TC. Methods: Pts with metastatic, incurable RAIR TC who had shown radiographic progression within 6 months prior to enrollment received Everolimus 10mg orally once daily. Responses were monitored by CT's every two months. The primary endpoint was progression free survival. Sequential biopsies were obtained in selected pts. Results: Enrollment to the differentiated TC (DTC) cohort finished in Jan 2013 and included 33 pts, among them 11 with Hurthle cell TC. Exploratory cohorts enrolled 10 pts with medullary [MTC] and 5 with anaplastic [ATC] with 2 added openings remaining for ATC. For the DTC cohort, median time on study to date is 10 months (mo) (<1-23+). 31 pts are evaluable at this time. PFS in the DTC cohort by Kaplan-Meier (K-M) analysis is 16.0 mo (95%CI 10-NR). Currently, disease stability for 6 and 12 mo or more was achieved in 18 and 10/31 pts, respectively, 11 pts remain on study. Median OS was not reached but 1 year survival by K-M analysis was 76%. One pt achieved a PR. 3 pts with DTC underwent sequential biopsies which revealed activation of autophagy while markers for apoptosis were not detected. Among 10 MTC pts, one achieved a PR and 9 pts had stable disease for 6 mo or more (6-33+). Among 5 ATC pts, 3 progressed, one has ongoing disease stability for 5 mo. One patient achieved a complete response that lasted for 18 mo and whole exome sequencing revealed somatic loss of function mutation affecting the Tuberous Sclerosis 2 (TSC2) protein, a negative regulator of mTOR activity [TSC2 (Q1178*) and FLCN (R17fs)]. Most common treatment-related adverse events were as anticipated and included fatigue, stomatitis and infections. Grade (gr) 3 events included infection 5, weight loss 3, leukopenia 3, thrombocytopenia 3, fatigue 3, hypophosphatemia 2, stomatitis 2, pneumonitis 1 and thrombosis 1pts. One pt had gr 4 hypercholesterinemia and one pt had gr 4 leukopenia. Conclusions: Everolimus has significant anti-tumor activity in pts with advanced TC. Activation of autophagy could account for high rate of disease stability. Sequencing may identify mechanistic basis and predictive markers for treatment response. Clinical trial information: NCT00936858.
HPV prevalence in the different subsites of the oropharynx.
Authors: Attner Per
Published: March 2020

6037

Background: Oropharyngeal cancer patients are often reported as one group in articles and studies regardless that within the subsites of the oropharynx, there are differences regarding clinical features, treatment and HPV prevalence. To investigate these differences, we wanted to further analyze HPV prevalence in the different subsites of the oropharynx. Methods: We identified all patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden, between 2000 and 2007, using the Swedish Cancer Registry, a registry unique in its reliability. Using the ICD 10 codes C01.9 (base of tongue cancer), C09.0-C09.9 (tonsillar cancer) and C10.0-C10.9 (oropharyngeal cancer) and C50.1-C50.8 (cancer of the soft palate). The two last subsites were grouped together into the group Other Oropharyngeal Cancer (OOC). We retrieved pre-treatment biopsies and tested for HPV-DNA using PCR, both with general primers and HPV16 specific primers. Results: We identified 474 patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden between 2000 and 2007; 290 diagnosed with tonsillar cancer, 109 diagnosed with base of tongue cancer and 75 diagnosed with other oropharyngeal cancer. Of these 474 patients, pre-treatment biopsies for HPV-testing were available for 400 patients (236, 95 and 69, respectively). In the tonsillar cancer group, 185 biopsies were HPV-DNA-positive (79%), in the base of tongue cancer group 71 (75%) and in the other oropharyngeal cancer group 17 were positive (25%) Conclusions: Tonsillar and base of tongue cancer share some similarities and HPV prevalence is similarly high in both groups. Other oropharyngeal cancer (OOC) does not share the high HPV-prevalence and it would then be preferred that the sub-sites of the oropharynx are reported separately.
Phase II randomized trial of radiotherapy (RT), cetuximab (E), and pemetrexed (Pem) with or without bevacizumab (B) in locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Argiris Athanassios , Ohr James , Kubicek Greg J. , Duvvuri Uma , Heron Dwight Earl , Kotsakis Athanasios Panayotis , Spencer Christina , Kim Seungwon , Grandis Jennifer R. , Johnson Jonas Talmadge , Bauman Julie E. , Gibson Michael K. , Ferris Robert L.
Published: March 2020

6043

Background: We previously developed a novel regimen by the addition of Pem to RT and E (Ann Oncol 2011;22:2482). The current study evaluated PemE in the phase II setting and assessed the addition of B, an anti-VEGF monoclonal antibody, to PemE based on promising data with Pem/B (JCO 2011;29:1140) and E/B (Ann Oncol 2013;24:200) in recurrent/metastatic SCCHN. Methods: Patients (pts) with previously untreated stage III/IV SCCHN of the oropharynx, larynx or hypopharynx, performance status (PS) 0-1, no history of bleeding, and adequate laboratory parameters were randomized after stratification for PS, stage and site to: RT 2 Gy/day to 70Gy, E 250mg/m2 weekly, after a loading dose of 400 mg/m2 1 week prior starting RT, and Pem 500mg/m2 every 21 days x 3 cycles (arm A, PemE), or the same regimen plus B 15mg/kg every 21 days x 3 cycles during RT followed by B maintenance x 8 cycles (arm B, B-PemE), with antibiotic prophylaxis. The primary endpoint was progression-free survival (PFS) with a target of 64% at 2 years; planned sample size was 80. Results: 79 pts were randomized of whom 77 were eligible and analyzable (arm A/B:36/41); oropharynx 65/larynx 12; HPV+ 38/HPV- 15/HPV unknown 24; stage IV 54/stage III 23. 31 pts were enrolled in community centers. Treatment delivery of E and Pem was similar between arms: E, median number of doses 8 (range, 5-11); Pem 3 (2-3); and B 3 (1-3). 5 deaths occurred: 3 due to progression; 1 from unknown cause; 1 pt died from hemoptysis after bronchoscopy within 4 weeks of the 8th cycle of B leading to elimination of B maintenance after the 6th pt was enrolled. 9 pts (2 HPV+) progressed. With a median follow-up of 18 months, the 2-year PFS was 81% vs 87% and the 2-year overall survival (OS) was 96% vs 86% for arm A vs B. Grade 3/4 acute toxicities for arm A vs B (N=59) : dermatitis 3/1 vs 4/1; mucositis 13/2 vs 13/0; neutropenia 7/4 vs 7/3; rash 6/1 vs 8/1; fatigue 1/0 vs 3/0; weight loss 2/0 vs 5/0. Conclusions: Both regimens are feasible in academic and community practice settings with expected toxicities. Preliminary efficacy results are very promising and better than projected, however, the addition of B does not appear to improve outcomes. Clinical trial information: NCT00703976.
Predictive values of (18)f-FDG PET standardized uptake value for adjuvant chemotherapy in patients with nasopharyngeal carcinoma.
Authors: Lin Ching Chan , Hsieh Te-Chun , Chen Tzu-Ting , Hsieh Ching-Yun , Lin Chen-Yuan , Huang Hsin-Hui , Bai Li-Yuan , Lin Po-Han , Chiu Chang-Fang , Yeh Su-Peng , Liao Yu-Min , Lo Woei-Chung
Published: March 2020

6052

Background: Concurrent chemoradiotherapy (CCRT) with or without adjuvant chemotherapy is the mainstay of treatment for locally advanced nasopharyngeal carcinoma (NPC). However the benefit of adjuvant chemotherapy has been controversial and search for adequate predictive factors is warranted. We conduct this study to evaluate the predictive values of mean standardized uptake value (SUV) measured in [(18)F]-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) for adjuvant chemotherapy in patients with locally advanced NPC. Methods: From January 2004 and July 2010, Data collection were performed in 108 NPC patients who underwent (18)F-FDG-PET before CCRT and adjuvant chemotherapy. The SUV was recorded for the primary tumor. All patients received intensity modulated radiotherapy. Concurrent chemotherapy was composed of cisplatin 100mg/m2 triweekly. Adjuvant chemotherapy was consisted of 3 cycles of cisplatin 75 milligrams/m2 and fluorouracil 1000 milligrams/m2for 4 days. Results: The median follow-up was 41months. The optimal cutoff value was 8.35 for SUV. 63.8% of patients had lower SUV (n=69), and 36.2% had higher SUV (n=39). Patients with a lower SUV had a significantly better 3-year overall survival (OS), disease-specific survival (DDS), and distant relapse-free survival (DRFS), but showed no difference in local relapse-free survival. Multivariate analysis showed only stage, SUV and adjuvant chemotherapy were significant in terms of overall survival. In patients with higher SUV, those receiving adjuvant chemotherapy had significantly higher 3-year OS, DDS, and DRFS compared with those without adjuvant chemotherapy. However, in those with lower SUV, there was no difference of OS, DDS and DRFS between patients with and without adjuvant chemotherapy. Conclusions: SUV of (18)F-FDG-PET for primary tumor could identify NPC patients who benefit from adjuvant chemotherapy. [Table: see text]
Use of gene expression signature to discriminate oropharyngeal cancers according to HPV16 status.
Authors: Mirghani Haitham , Ory Catherine , Ugolin Nicolas , Amen Furrat , Guigay Joel , Lacau Saint Guily Jean , Chevillard Sylvie , Lacave Roger
Published: March 2020

6055

Background: Strong evidence supports the hypothesis that high-risk human papillomavirus (HPV), particularly HPV16, is a causative agent for an increasing subset of oropharyngeal squamous cell carcinomas (OPSCC). These tumors have distinct oncogenic mechanisms and a more favorable prognosis than tobacco induced OPSCC. Although these differences emphasize the need for a specific therapeutic approach, HPV status is still not used to guide treatment. A better understanding of the molecular profile related to HPV16 induced OPSCC may help to develop personalized treatments. Methods: To identify an HPV16-related molecular signature, we compared the gene expression profile of 15 transcriptionally active HPV16-positive and 15 HPV16-negative OPSCC. The study was conducted in two steps. First, a learning set of 16 OPSCC comprising 8 HPV16-positives and 8 HPV16-negatives OPSCC was analyzed in order to identify the signature. Potentially confounding factors of stage, sex and tobacco consumption were equally distributed in both groups. Secondarily, the robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 14 OPSCC. Results: We identified a signature composed of 224 genes which discriminates HPV16-induced OPSCC from their tobacco induced counterparts. After the viral status was revealed, 13 out of 14 tumors were correctly classified according to tumor etiology, 1/14 was undetermined and none were misclassified. Interestingly, deregulated genes in HPV16-positive tumors are principally involved in innate immunity, in cell cycle regulation through the TP53/RB/E2F pathway, and autophagy through mTOR regulation. Well known targets of E6 and E7 proteins are also found to be deregulated. Conclusions: Our results demonstrate that a set of selected genes can distinguish OPSCC according to etiology. These genes shed light on HPV16 induced carcinogenesis since specific molecular pathways are deregulated. Further investigations are required for a better understanding of the differing natural histories and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HPV-related OPSCC.
Radiotherapy (RT) potentiation with weekly (q1w) or standard every 3 weeks (q3w) cisplatin chemotherapy (CT) for locally advanced head and neck squamous cell carcinoma (HNSCC).
Authors: Molin Yann , Lavergne Emilie , Pommier Pascal , Racadot Severine , Montbarbon Xavier , Poupart Marc , Zrounba Philippe , Ceruse Philippe , Fayette Jerome
Published: March 2020

6056

Background: Q3w CT is standard RT potentiation for HNSCC but its toxicity requires to look for new treatment’s modalities. The aim was to explore if q1w CT could be a safe and effective alternative. Methods: Patients (pts) treated by chemoradiation (CT-RT) for a HNSCC were retrospectively included. Study population was first described. Then overall (OS) and progression-free survival since the RT onset were performed. Survival distributions were estimated by Kaplan-Meier method and compared between CT groups using the Log-Rank test. Prognostic effect of CT group was explored using Cox model. Results: 266 pts treated between January 2004 and December 2008 were included: 170 and 96 pts respectively received q1w and q3w CT. At diagnosis, 46% had oropharynx lesions, 20% larynx, 17% hypopharynx and 14% oral cavity. 70% pts experienced surgery, 39% CT induction and a median dose of radiation of 64 Gy without any significant difference between CT groups. However, median age at diagnosis was significantly different between q1w and q3w CT (58 vs 54, p<0.001) as well as alcohol consumption (79% vs 68, p=0.047), stage at diagnosis (30%-60% stage III-IV vs 13% -80%, p=0.003), IMRT use (4% vs 13%, p=0.011) and median weight before RT (66 kg vs71kg, p=0.014). Q3w CT was more toxic than q1w in terms of weight loss (87% vs 75%, p=0.012), renal failure (50% vs 35%, p=0.022), worse CT plan completion (42% vs 66%, p<0.001). Moreover, grade 3/4 toxicities, such as mucositis (34% vs 13%, p<0.001) and dermatitis (7% vs 1%, p=0.012), were more frequent. More pts needed parenteral nutrition (10% vs 2%, p=0.008), analgesics (91% vs 70%, p<0.001), secondary hospitalization (31% vs 8%, p<0.001), RT interruption >= 3 days (8% vs 2%, p=0.037) and had long-term toxicities (24% vs 12%, p=0.014). With a median follow-up of 42 months 95% CI [36.8-48.8], a trend in favour of q3w CT was found:2-years OS of 83% (95% CI [73-90]) vs 74% (95% CI [66-80]), p=0.089. However, after adjustment on prognostic factors CT group was not significantly associated with OS nor with PFS. Conclusions: Q1w RT-CT is safer than q3w and may be as efficient. Follow-up data will be updated to reinforce efficacy results.
Treatment-associated mortality in head and neck cancer: Analysis of phase III trials.
Authors: Shcherba Marina , Viswanathan Shankar , Blakaj Dukagjin , Garg Madhur , Haigentz Missak
Published: March 2020

6064

Background: Chemoradiotherapy is an accepted standard for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Although acute and long-term toxicities of this approach are known, little is known about early mortality associated with curative-intent treatment. Methods: We reviewed 45 phase III trials of curative-intent radiotherapy in SCCHN published from 2000-2012 for adequate reporting of early mortality defined as deaths during and within 3 months of therapy, regardless of attribution. We estimated pooled proportions of deaths during prescribed therapy using a random effects model of radiotherapy alone (RT), concurrent chemoradiotherapy (CCRT) and induction chemotherapy (IC) regimens. The relative risk of death during CCRT vs. RT and CCRT/IC vs. RT were estimated. Results: Although all trials reported early mortality statistics, definitions had wide variability, and only 34 trials (75%) met adequate reporting characteristics. Ten trials excluded enrolled patients who died prior to initiating therapy. Of studies reporting early mortality statistics, crude frequency of death during prescribed therapy was 2.7% (308/11362). The pooled estimated rates of death observed during RT alone was 1.7% (SE: 0.3, I2=89.2%) from 29 studies, while 2.8% (SE: 0.4, I2=64.9%, 19 studies) and 3.1% (SE: 0.5, I2=53.5%, 9 studies) for CCRT and IC regimens, respectively. The pooled relative risk for death in CCRT compared to RT treatment was 1.08 (95%CI: 0.78, 1.48, p=0.63, I2=0, 15 studies). The relative risk for death in CCRT or IC therapy compared to RT was 1.06 (95%CI: 0.77, 1.45, p=0.72, I2=0, 15 studies). When reported, most early deaths were attributed to infectious complications or cardiovascular events. Conclusions: Early death remains an uncommon but important complication of curative-intent radiotherapy in SCCHN that necessitates consistent reporting. Despite strict eligibility criteria and protocol-defined care, treatment-associated death occurs with all regimens, though no clear increase was observed with CCRT/IC regimens over RT alone. Early mortality should be considered during treatment planning, particularly for patients with considerable comorbidities.
Significance of myeloid-derived suppressor cells in squamous cell carcinoma of the head and neck.
Authors: Kim Grace G , Zanation Adam M , Taylor Nicholas A , Shores Carol G. , McKinnon Karen P , Serody Jonathan Stuart
Published: March 2020

6070

Background: Patients with advanced stage squamous cell carcinoma of the head and neck (SCCHN) have less than 50% 5-year survival rate Human papillomavirus (HPV)-associated SCCHN in oropharyngeal sites have shown better prognosis. Little is known about the role of myeloid-derived suppressor cells (MDSCs) in immune suppression or tumor progression in the setting of SCCHN. Our objective is to evaluate the clinical significance of MDSCs in subjects with SCCHN, HPV-positivity, and advanced cancer staging. Methods: Thirty-three subjects with SCCHN and 10 healthy donors were enrolled in this prospective cohort study. Fresh blood was collected at the time of surgical resection of SCCHN in a tertiary academic center between August 2011 and January 2013. Peripheral blood mononuclear cells (PBMCs) were obtained using Ficoll Hypaque. MDSCs were immunophenotyped as CD14-CD33+CD11b+by flow cytometry. HPV status was determined by in situ hybridization Frequencies of MDSCs in blood of different cohorts were evaluated. Results: Thirty-three subjects (ages 34-83 years, 25 males) with SCCHN were enrolled. Increased numbers of CD14-CD33+CD11b+ cells of total leukocytes were found in HPV-associated SCCHN (median 26.6%, n=11) compared to HPV-negative SCCHN (16.3%, n=19). Interestingly, 3 subjects who previously had HPV-positive SCCHN but with no evidence of disease had 6.24% (n=3) CD14-CD33+CD11b+cells of leukocytes which was higher than healthy donors (3.55%, n=10). Subjects with advanced cancer stages (III-IV) had higher levels of MDSCs (26%, n=19) compared to those with a lower grade (I-II, 15.5%, n=11) regardless of HPV status. Three subjects were lost to follow up. Of the remaining subjects, the overall median follow time was 3 months and subjects who were found to have recurrence, regional or local metastasis had higher frequencies of MDSCs in the blood (26.35%, n=4) compared to those with no evidence of disease (18.5%, n=26) at the time of surgery. Conclusions: This study suggests there is an accumulation of MDSCs in peripheral blood of patients with SCCHN, particularly in HPV-associated SCCHN. Further, increased levels of MDSCs in the peripheral blood are related to more advance cancer stage and poor clinical outcomes.
Induction chemotherapy (CT) with docetaxel, cisplatin, and fluorouracil (TPF) followed by concomitant cisplatin plus radiotherapy in locally advanced nasopharyngeal cancer (NPC): Results after 06 years.
Authors: Kerboua Esma , Bouzid Kamel
Published: March 2020

6075

Background: In squamous cell carcinoma of head and neck cancer, TPF induction CT improved survival over cisplatin plus fluorouracil (Posner MR: NEJM, vol357, Oct 2007). The main objective of this study is to evaluate the activity and safety of TPF in patients (pts) with locally advanced NPC followed by concomitant cisplatin plus radiotherapy (cCTRT). Methods: Pts with undifferentiated NPC were enrolled from December 2006–December 2012 and received 3 cycles of TPF (docetaxel 75 mg/m2 and cisplatin 75/m2 day 1, plus fluorouracil 750 mg/m2 days 1–5, every 4 wks) with G-CSF days 1–5 post CT. CT was followed by cCTRT with cisplatin 40 mg/m2/wk and radiotherapy (65–70 Gy) starting 4–6 wks after the third cycle of CT. The primary endpoint was overall response rate (ORR) after induction CT and after cCTRT. Secondary end points were safety, disease free survival (DFS), and overall survival (OS). Results: 42 pts have been enrolled (26 M/16 F). UICC 1997 classification: n=9 stage II, n=10 stage III, n=23 stage IV. Median age is 37 yrs (range 18–64). Evocative clinical signs are cervical nodes n=20, rhinologic n=13, otologic n=5, and neurologic n=4. All pts were evaluated for safety and 38 for response.TPF well tolerated with main toxicities grade 3–4 (WHO) were neutropenia 36%, thrombocytopenia 32%, anemia 18%, diarrhea 6%, and mucositis 18%. Four pt died from sepsis that was probably treatment-related. ORR was 90% with an 71.4% (n=27) complete response (CR) rate, 23.6% (n=9) partial response (PR), and 5.2% (n=2) stable disease. No pts progressed after induction CT. Main toxicity during cCTRT was neutropenia grade 3–4 in 9%, mucositis grade 3 in 45% and grade 4 in 4%. Late toxicities were xerostomia grade 3 in 50%. At treatment completion, CR and PR rates were 79% and 20%; 2 pts had stable disease. At a median follow up of 72 months (range 7–72), 8% of pts have shown recurrence or progressive disease. DFS and OS rates at 72 months were 65% and 70%, respectively. Conclusions: TPF followed by cCTRT appears to be an active and feasible regimen with a manageable safety profile and may be a promising therapeutic option for pts with high stage NPC.
Specific detection of Epstein-Barr virus microRNAs in plasma samples from nasopharyngeal carcinoma patients: Correlation with tumor mass assessed by MRI.
Authors: Ferrand francois-Regis , Gatolliat charles-Henry , Bidault Francois , Verillaud Benjamin , Gelin Aurore , Jimenez-Pailhes anne-Sophie , Amiel Corinne , Guigay Joel , Busson Pierre
Published: March 2020

6079

Background: Epstein-Barr virus (EBV) microRNAs of the BART family can be detected in the plasma of at least a fraction of nasopharyngeal carcinoma (NPC) patients. Our aim was to investigate the specificity of plasma BART detection in NPC patients and the correlation with viral DNA load and/or clinical characteristics. Methods: Hsa miR484 and 4 miR-BARTs (ebv-miR BART 2-5p, 5, 9 and 18) were assessed by RT-PCR following RNA extraction in 37 plasma samples including 20 NPC, 8 non-NPC head and neck squamous cell carcinoma (SCC) patients and 9 healthy EBV carriers. EBV DNA copy numbers (viral load) were measured in the same samples. To explore correlations of BART concentrations with tumor mass, MRI-based volume analysis was designed and performed on a subset of 13 patients with non metastatic NPC. In addition, longitudinal variations of BART concentrations were studied in 9 NPC patients for whom we had sequential plasma samples. Results: The cellular hsa miR-484 was detected in all plasma samples with a slightly higher average concentration in plasma samples from NPC and SCC patients. On the other hand, the miR-BARTs were undetectable or at a very low level in samples from SCC patients and healthy carriers contrasting with a high level in most NPC patients. There was an overall positive correlation between EBVDNA copy numbers and plasma concentrations of each miR-BART. However substantial amounts of plasmatic miR-BARTs were observed in several patients for whom no plasma EBV DNA was detected.Their concentration was apparently not correlated to the initial tumor volume but their longitudinal variations were parallel with clinical evolution in all but one case. Conclusions: To a large extent, detection of plasma miR-BART-2-5p, 5, 9, and 18 is specific of NPC patients. Their concentration does not seem to correlate with tumor mass, at least in localized NPC patients. In a fraction of patients without initial detection of plasma EBV DNA, the kinetics of plasma BARTs may provide informations on early tumor response under treatment and may have prognostic value.
The Long-HER study: Clinical and molecular analysis of advanced HER2+ breast cancer treated with trastuzumab and associated to long-term survival.
Authors: Espinosa Enrique , Gámez-Pozo Angelo , Perez Carrion Ramon Maria , Manso Luis , Crespo Carmen , Mendiola Cesar , Alvarez Isabel , Margeli Mireia , Bayo Juan L. , Gonzalez Xavier , Santaballa Ana , Ciruelos Eva , Cabrera Miguel Angel , Anton Antonio , Catalan Gustavo , Álvarez Gallego José Valero , Miramon Jose , Lopez Vacas Rocio , Zamora Pilar
Published: March 2020

608

Background: Some patients with advanced HER2+ breast cancer survive in the long-term after receiving trastuzumab-based therapy. Long-HER study was an observational, multicenter study that compared long-term survivors and a control group from the clinical and molecular point of view. Methods: Patients with metastatic HER2+ breast cancer that had been treated with trastuzumab-based therapy and had an objective response or stable disease for at least 3 years were included. A control group having a progression in the first year of therapy was selected for comparison (similar first-line therapy). A microarray platform was used to assess whole genome expression analysis in paraffin-embedded samples. Differential expression, ontology and analysis of metabolic pathways were performed. Results: 103 patients were registered, 71 of who had a long-term complete remission. Only 5 of these patients had received trastuzumab in the adjuvant setting: this was the only clinical factor associated to long-term survival. The molecular study included 35 Long-HER and 18 control samples. Gene expression ontology revealed alterations in HIF, apoptosis, and EGF, PI3K and p53 pathways. The PI3K pathway was mostly related with a poor response to therapy. Conclusions: trastuzumab-based therapy achieves long-term survival in a selected group of women with advanced HER2-positive breast cancer. Whole genome analysis comparing such a group with a control group found some alterations that may predict early progression to trastuzumab.
Long-term disease control of ≥2 years achieved with cabozantinib in subjects with metastatic medullary thyroid carcinoma on a phase I study.
Authors: Cohen Ezra E.W. , Hong David S. , Pfister David G. , Salgia Ravi , Burtness Barbara , Cohen Roger B. , Ball Douglas Wilmot , Mehra Ranee , Mangeshkar Milan , Yaron Yifah , Bentzien Frauke , Kurzrock Razelle
Published: March 2020

6090

Background: Metastatic medullary thyroid cancer (MTC) carries a median survival of about two years (Modigliani et al. 1998; Roman et al. 2006). Cabozantinib inhibits three primary pathways implicated in MTC pathogenesis and progression: MET, vascular endothelial growth factor receptor-2 (VEGFR2), and RET. A phase I study was initiated in September 2005 in patients (pts) with advanced solid tumors. Methods: 85 pts, including 37 with MTC were enrolled to evaluate safety, pharmacokinetics, and to determine maximum-tolerated dose (MTD). Once the MTD of 140 mg freebase (equivalent to 175 mg malate salt) was determined, 20 metastatic or locally advanced MTC pts were enrolled in an MTD expansion cohort. 10/37 MTC pts achieved a confirmed partial response (cPR) (Kurzock et al. 2011). We report here on long-term disease control (DC), defined as cPR or progression-free at ≥ 24 months (m), in the MTC cohort. Results: After a minimum follow-up period of 52 m, 11 of 37 pts (30%) experienced DC, and have remained progression-free for > 24 m. Time from diagnosis and time since development of metastatic disease was similar in patients with (11) or without (26) long term DC. As of 04 Dec 2012, 5 of these 11 pts remain on treatment for a median time of 55 m (53-73m). A best response of cPR was associated with long-term benefit: 4/5 pts continuing on treatment achieved cPR, one achieved SD. The adverse event profile of cabozantinib was generally predictable and adverse events were managed with symptomatic treatment and dose modifications. The median final dose for pts with long-term DC was 60 mg (range 20-140), with a median number of dose reductions of 2 (range 0E4). Reasons for dose reductions in two or more pts experiencing long-term DC included diarrhea (7), palmar-plantar erythrodysaesthesia syndrome/rash (6), mucositis/stomatitis (3), anorexia (3), nausea (2), and vomiting (2). Conclusions: Treatment with cabozantinib demonstrates long-term DC in a cohort of pts with metastatic MTC. Cabozantinib offers an important new treatment option for patients with progressive, metastatic MTC. Clinical trial information: NCT00215605.