bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide association analysis in host characteristics of progression to high-grade cervical intraepithelial neoplasia for women with human papilloma virus infection and normal cytology.
Authors: Lai Chyong-Huey , Chao Angel , Lin Chiao-Yun , Huang Chu-Chun , Su Wen-Hui
Published: March 2020

5109

Background: Although it is well accepted that persistent human papillomavirus (HPV) is necessary for carcinogenesis of cervical neoplasms, the molecular mechanism for progression is unclear. HPV testing is widely used for cervical cancer screening. The hazard ratio of developing cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) in baseline HPV-positive/normal cytology women is 30-50 fold as compared with HPV-negative/normal cytoloy women. HPV positivity would cause substantial anxiety. It is important to identify a prognostic profile for predicting progression. Methods: We collected blood samples from women aged ≥ 30 years in a population-based nested cohort study enrolling women with HPV infection (n = 871) or HPV-negative (n = 902) with normal cytology in 2004-2009 for prospective follow-up. To identify the host genetic characteristics associated with cervical carcinogenesis, a genome-wide association study (analyzing 530,194 SNPs) was conducted in 23 cases who developed CIN2+ and 62 viral type- and age-matched controls who were HPV-positive at baseline without developing CIN throughout the follow-up period. Results: One SNP with significant P values (rs16969682; P=4.58 x 10-5, OR=5.9, 95% CI=2.52-13.96) located in SEC14-like 1 (SEC14L1) gene localized to chromosome 17 was identified with association between progression to CIN2+ and controls without CIN throughout follow-up. SEC14L1 belongs to the widely-expressed SEC14-superfamily. This superfamily consists of > 500 members that are involved in biological functions including membrane trafficking and phospolipid metabolism. Furthermore, using T-cell based cDNA screening, SEC14L-1a is identified as a regulator of HIV-1 replication. Conclusions: The potential role of SEC14L1 in host-viral interaction will be further elucidated. Additional statistically significant SNPs including rs16969682 will be validated on cases with CIN2+ (n = 250) and normal controls (normal cytology/HPV-negative at baseline without acquisition of HPV or abnormal cytology/histology during follow-up, n = 500).
Nomogram prediction for overall survival of patients diagnosed with cervical cancer.
Authors: Grimm Christoph , Reinthaller Alexander , Hofstetter Gerda , Concin Nicole , Marth Christian , Polterauer Stephan
Published: March 2020

5111

Background: Cervical cancer is clinically staged based upon the International Federation of Gynecologists and Obstetricians (FIGO) system. FIGO stage is well established as prognostic parameter. It is well known that other additional parameters are useful to estimate overall survival (OS) in patients with cervical cancer. The aim of this multi-center was to create a nomogram to predict OS in patients diagnosed with cervical cancer. Methods: Cervical cancer databases of two large Austrian institutions were analysed. Characteristics known to predict OS were collected. For each patient association between each prognostic parameter and OS was assessed by multivariable modeling. The corresponding 3-year and 5-year OS probabilities were then determined using the nomogram. The constructed nomogram was then validated using the bootstrap correction technique. Results: Mean 5-year OS rates for patients with FIGO stage IA, IB, II, III, and IV were 99.0% (1.0), 88.6% (3.0), 65.8% (5.2), 58.7% (11.0), and 41.5% (14.7), respectively (p<0.001). Mean five-year OS time was 44.2 (30.9) months. Based on the multivariable model FIGO stage, tumor size, age, histologic subtype, lymph node ratio, and parametrial involvement were identified as nomogram parameters. The bootstrap sample corrections provided an estimated concordance probability (interquartile range) of 0.794 (0.779-0.805). Conclusions: Based on 6 easily available parameters a novel nomogram to predict 3-year and 5-year OS of patients diagnosed with cervical cancer was constructed and internally validated. Application of this nomogram allows more accurate and individual prediction of patients’ prognosis.
Progression of genomic signatures in local and metastatic estrogen receptor-positive (ER+) breast cancer: Relevance to palliative treatment.
Authors: Symmans William Fraser , Andreopoulou Eleni , Booser Daniel J. , Hatzis Christos , Wallace Michael J. , Zhang Ya , Gong Yun , Ignatiadis Michail , Sotiriou Christos , Andre Fabrice , Peintinger Florentina , Regitnig Peter , Marth Christian , Desmedt Christine , Loi Sherene , Moulder Stacy L. , Hortobagyi Gabriel N. , Pusztai Lajos , Valero Vicente
Published: March 2020

515

Background: Biological progression of ER+ breast cancer accelerates clinical progression and resistance to treatments. Methods: One laboratory used Affymetrix U133A gene expression microarrays to profile 588 biopsy samples from patients with ER+ breast cancer: 74 AJCC Stage I, 155 Stage IIA, 105 Stage IIB, 127 Stage III, 127 Stage IV (27 at presentation, 100 relapsed). We evaluated stage dependence of ER [ESR1, PGR, sensitivity to endocrine therapy (SET) index], proliferation [MKI67, AURKA, genomic grade index (GGI)], invasion [PLAU (uPA)], PI3-kinase (PIK3CA-GS), VEGF, genomic subtype [PAM50, 3-gene classifier (ESR1, ERBB2, AURKA)], and housekeeper control genes. Significance was evaluated through ordinal median regression (P < 0.002, for multiple testing) after adjusting for staging method (clinical or pathologic). Exploratory Cox regression analyses of progression-free survival (PFS) and overall survival (OS) were performed when treatment was hormonal therapy (HT, N=58) or chemotherapy (CT, N=27) after biopsy of metastatic ER+ breast cancer (MBC). Results: Stage progression was associated with reduced SET index and increased proliferation (GGI, MKI67, AURKA) and metabolism (GAPDH). These changes occurred between Stages IIB and III, and Stages III and IV. Luminal B and proliferation subtypes were more prevalent in Stage IV and less in Stage I. Interestingly, invasion (PLAU) genes were lower in MBC. Only SET index demonstrated a significant interaction with treatment (HT or CT) for MBC (PFS: p=0.018). SET was predictive of PFS and OS following HT, as a continuous score (PFS: HR=0.69, 95%CI 0.49 to 0.97, p=0.035; OS: HR=0.61, 95%CI 0.40 to 0.94, p=0.025) or dichotomized at median value (PFS: HR=0.43, 95%CI 0.24 to 0.76, p=0.003; OS: HR=0.37, 95%CI 0.18 to 0.77, p=0.006). Genomic subtype was prognostic for PFS irrespective of treatment type. High PIK3CA-GS expression predicted OS in the HT subset. Conclusions: Stage progression was associated with decreased ER-related transcription (SET) and increased proliferation, grade, higher risk subtype, and metabolism. In MBC samples, only SET index was predictive of PFS and OS with palliative hormonal therapy.
Dual effects of metformin on breast cancer proliferation in a randomized trial.
Authors: De Censi Andrea , Pollak Michael N. , Puntoni Matteo , Gandini Sara , Cazzaniga Massimiliano , Pruneri Giancarlo , Serrano Davide , Guerrieri-Gonzaga Aliana , Mora Serena , Gennari Alessandra , Johansson Harriet Ann , Aristarco Valentina , Macis Debora , Bassi Fabio , Luini Alberto , Lazzeroni Matteo , Bonanni Bernardo
Published: March 2020

519

Background: Metformin lowers breast cancer risk in observational studies in diabetics, but evidence for its clinical activity is scanty. We studied the metformin antiproliferative effect in a pre-surgical study. Since the antidiabetic effect of metformin is heterogeneous according to obesity and insulin resistance (IR), we also determined whether its antiproliferative effect was modified by risk biomarkers. Methods: After tumor biopsy, we randomly allocated 200 non-diabetic women with breast cancer to either metformin, 850 mg/bid (n=100) or placebo (n=100) for 4 wks. The primary endpoint was the post-pretreatment change in Ki-67 between arms. We explored effect modifications by STEPP and tested biomarker thresholds that showed an interaction with treatment on Ki-67. Results: Overall, median (IQR) Ki-67 was 19 (14-31) at baseline and 21 (14-32) after 4 wks and 18 (12-29) at baseline and 20 (13-31) after 4 wks in the metformin and placebo arm, respectively with mean increase of 4.0% (95%CI, -5.6 to 14.4) on metformin versus placebo. Multivariate analyses showed an increase of Ki-67 after 4 wks placebo in the following subgroups: HOMA> IR threshold, IGFBP3> highest quartile, IGFBP1< lowest quintile, IGFratio (IGF1/IGFBP3)< median, CRP> inflection point at STEPP analysis, HER2+ve tumors (versus –ve). Metformin blunted the increase of Ki-67 noted on placebo in these subgroups. Conclusions: Overall, metformin did not affect Ki-67 in most subjects with breast cancer. However, in exploratory analysis we identified subgroups of patients where metformin showed antiproliferative effect. Further studies to a personalized approach are warranted with selection of study populations. [Table: see text]
Impact of expression levels of mRNA HER2 and ESR1 on the pathologic complete remission (pCR) rate after neoadjuvant treatment with anthracycline-taxane containing chemotherapy in combination with trastuzumab in the GeparQuattro trial.
Authors: Huober Jens Bodo , Denkert Carsten , Von Minckwitz Gunter , Prinzler Judith , Kronenwett Ralf , Darb-Esfahani Silvia , Mehta Keyur , Sinn Bruno Valentin , Untch Michael , Loibl Sibylle
Published: March 2020

523

Background: Recent data suggest that benefit from (neo)adjuvant trastuzumab might be related to expression of HER2 and estrogen receptor (ESR1). We investigated mRNA levels of HER2 and ESR1 in core biopsies in HER2 positive tumors of the GeparQuattro trial and compared it to response to neoadjuvant treatment. Methods: In the GeparQuattro trial 445 HER2+ pts were included based on local testing and received neoadjuvant trastuzumab and chemotherapy (either 4 x EC →4 x docetaxel (D) or 4 x EC → 4 x D/capecitabine (C) or 4 x EC →4x D →4 X C). In 217 available pretherapeutic core biopsies HER2 levels were analysed by IHC, SISH and quantitative RT-PCR using predefined cutoffs; pCR was defined as ypT0is;ypN0. Results: Only 73% of the tumors (158 of 217) were centrally HER2 positive (cHER2+) by IHC/SISH, while 59 tumors (27%) were centrally HER2 negative (cHER2-). As all pts had received neoadjuvant trastuzumab, this gave us the possibility to evaluate response of HER2- tumors to trastuzumab. The pCR rate of cHER2+ tumors was significantly increased (46.8%, p<0.0005) compared to cHER2-, who had a pCR rate of only 20.3%. Similar results were obtained if HER2 positivity was determined by RT-PCR (pCR rate 50% vs. 17.4%, p<0.0005). Assessment of HER2 status by RT-PCR showed a concordance of 86.2% with the IHC/SISH status. In uni- and multivariate logistic regression analysis of cHER2+ cases including continuous HER2 and ESR1 mRNA levels the HER2 mRNA expression was significantly associated with prediction for a pCR in (univ.: OR 1.43, 95% CI 1.11-1.83, p=0.005; multiv.: OR 1.42, 95% CI 1.11-1.83, p=0.006). In the cHER2+ tumors, the pCR rate was similar for ESR1 mRNA positive (47.4%) and ESR1 negative tumors (46.3%). Conclusions: Only pts with cHER2+ tumors independently of the method used have an additional benefit in terms of a pCR from adding trastuzumab to chemotherapy. In cHER2-negative patients the pCR rate is comparable to the pCR rate in the non trastuzumab treated population. Increasing HER2 mRNA levels were associated with a better response to trastuzumab based treatment in cHER2 + tumors.
Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in the CLEOPATRA study.
Authors: Ewer Michael , Baselga José , Clark Emma , Benyunes Mark , Ross Graham , Swain Sandra M.
Published: March 2020

533^

Background: Addition of trastuzumab (T) to chemotherapy has transformed outcomes in pts with HER2-positive breast cancer. In pts who had received anthracyclines (A), T has been associated with cardiac dysfunction. Monitoring cardiac tolerability of anticancer drugs is important, including that of a new regimen combining T with a second anti-HER2 antibody that inhibits HER2 dimerization, pertuzumab (P). In CLEOPATRA, efficacy and safety of P+T+docetaxel (D) were studied in HER2-positive 1st-line MBC (Baselga 2012). Methods: CLEOPATRA, a randomized, double-blind, placebo-controlled, ph III trial, enrolled 808 pts; 804 were included in the safety population. A baseline (BL) LVEF ≥50%, no history of congestive heart failure, and no LVEF decline to <50% during/after prior T were required. Treatment was administered q3w until disease progression or unmanageable toxicity (P/placebo [Pla]: 840 mg, followed by 420 mg; T: 8 mg/kg, followed by 6 mg/kg; D [≥6 cycles recommended]: 75 mg/m2, escalating to 100 mg/m2 if tolerated). LVEF was assessed by ECHO or MUGA at BL, every 9 wks during treatment, at discontinuation, and up to 3 yrs thereafter. Adverse events (AE) were monitored continuously and graded according to NCI-CTCAE v3.0. Results: The incidence of any cardiac disorder (grade ≥1) as assessed by the investigators was similar with Pla+T+D (16.4%) and P+T+D (14.5%). LVSD (grade ≥1) was the most frequent cardiac AE and more common with Pla+T+D. At the time of data cutoff for this analysis, 8/11 symptomatic LVSD events had resolved; none fatal. All pts who developed symptomatic LVSD had ≥1 potential cardiac risk factor (prior A, prior T, radiation, smoking, diabetes, hypertension, other). Compared to the overall pt population, only prior A and radiation were higher in pts who developed symptomatic LVSD. Conclusions: CLEOPATRA provides evidence that P+T+D does not increase overall cardiac disorders, specifically symptomatic LVSD, compared to Pla+T+D. [Table: see text]
BOLERO-2: Health-related quality-of-life in metastatic breast cancer patients treated with everolimus and exemestane versus exemestane.
Authors: Beck J. Thaddeus , Rugo Hope S. , Burris Howard A. , Baselga José , Noguchi Shinzaburo , Gnant Michael , Pritchard Kathleen I. , Bennett Lee , Ricci Jean-Francois , Hortobagyi Gabriel N.
Published: March 2020

539

Background: BOLERO-2, a phase III study, randomized 724 patients with hormone-receptor–positive metastatic breast cancer, who had recurrence or progression on/after prior nonsteroidal aromatase inhibitor therapy, to everolimus (EVE) plus exemestane (EXE) or EXE and placebo. A preplanned 12-month median time interim analysis demonstrated that EVE+EXE significantly improved progression-free survival (PFS) vs EXE+placebo but that EVE+EXE resulted in a higher rate of grade 3/4 toxicity. Per-protocol patient reported health-related quality-of-life (HRQoL) data are limited; here we report on additional post-hoc analyses of these outcomes. Methods: Using the EORTC–QLQ‑C30 questionnaire, HRQoL was assessed at baseline and every 6 weeks thereafter until progression. The QLQ‑C30 consists of 30 items combined into 15 subscales, including a Global Health Status (GHS) where higher scores (range 0 to 100) indicate better HRQoL. This analysis included a protocol-specified time to definitive deterioration (TTD) analysis at a 5% decrease in QoL relative to baseline, with no subsequent increase above this threshold. We report additional sensitivity analyses using 10-point minimally important difference (MID) decreases in QLQ‑C30 score relative to baseline. Treatment arms were compared using a stratified logrank test and a Cox proportional hazards model adjusted for trial stratum (visceral metastases and previous hormone sensitivity), age, sex, race, baseline score and ECOG performance status, prognostic factors, and treatment history. Results: Baseline QLQ‑C30 GHS scores were not statistically significantly different across treatment groups (64.7 vs 65.3; difference -0.7 [95% CI; -4.3, 3.0]). The median TTD in HRQoL was 7.0 months (95% CI; 5.6, 8.3) for EVE+EXE vs 5.6 (95% CI; 4.2, 7.0) for EXE (P = .0792). Adjusted HR (0.80) approached significance (95% CI; 0.63, 1.02). At the 10-point MID, median TTD for EVE+EXE was 9.7 months (95% CI; 8.3, 11.2) vs 8.4 months (95% CI; 6.3, 12.5) for EXE. Adjusted HR was 0.90 (95% CI; 0.69, 1.18). Conclusions: These additional analyses demonstrate that in addition to significantly improving PFS, EVE+EXE does not compromise HRQoL.
BOLERO-2: Everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone receptor-positive breast cancer.
Authors: Noguchi Shinzaburo , Masuda Norikazu , Ito Yoshinori , Iwata Hiroji , Mukai Hirofumi , Horiguchi Jun , Tokuda Yutaka , Kuroi Katsumasa , Iwase Hirotaka , Inaji Hideo , Ohsumi Shozo , Piccart-Gebhart Martine J. , Hortobagyi Gabriel N. , Rugo Hope S. , Gnant Michael , Campone Mario , Sahmoud Tarek , Pritchard Kathleen I. , Burris Howard A. , Baselga José
Published: March 2020

540

Background: Estrogen-receptor–positive (ER+) breast tumors can become refractory to aromatase inhibitor (AI) therapy. The mTOR pathway plays a critical role in hormone-resistant advanced breast cancer (ABC). Accordingly, the addition of everolimus (EVE) to exemestane (EXE) was evaluated in an international, phase III study (BOLERO-2) in patients with ER+ aBC refractory to letrozole or anastrozole. This report presents updated analyses from the population of Asian patients enrolled in this study. Methods: Eligible patients were randomized (2:1) to EXE (25 mg/day) with EVE (10 mg/day) or with matching placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, quality of life, and safety. Results: EVE + EXE significantly improved PFS versus EXE alone (HR = 0.44; 95% CI, 0.36-0.53; P < .0001) in the overall study population at median follow-up of 12.5 months. Of 143 patients of Asian origin (n = 106; 74% Japanese) enrolled in this study, 98 received EVE + EXE and 45 received EXE + placebo. At the time of database lock, 55 Asian patients (56%) in the combination arm had experienced disease progression compared with 34 patients (76%) in the EVE + placebo arm. Combination therapy reduced the risk of disease progression versus EXE alone by 44% among Asian patients (HR = 0.56; 95% CI, 0.37-0.87; P < .05). Commonly reported adverse events in the combination arm were consistent with previous clinical studies of mTOR inhibitors and included stomatitis (80%), rash (49%), dysgeusia (31%). Adverse events that occurred more frequently in the Asian subset versus Caucasians included stomatitis (80% vs 54%) and rash (49% vs 37%), whereas dyspnea (8% vs 24%) and asthenia (1% vs 17%) occurred less frequently in the Asian subset versus Caucasians. Conclusions: The addition of EVE to EXE significantly prolonged PFS in Asian patients versus EXE alone. Adverse events were higher in the combination arm but generally manageable. Combining EVE with an AI is a safe and effective treatment option for Asian women with non-steroidal AI resistant/refractory ER+ ABC.
Response pattern in 844 patients with infiltrating lobular carcinoma (ILC) of the breast after neoadjuvant chemotherapy.
Authors: Pirvulescu Cristina , Loibl Sibylle , Von Minckwitz Gunter , Mau Christine , Blohmer Jens U. , Costa Serban Dan , Eidtmann Holger , Fasching Peter A. , Gerber Bernd , Untch Michael
Published: March 2020

541

Background: Patients (pts) with infiltrating lobular carcinoma (ILC) have a different response to neoadjuvant chemotherapy compared to patients with non-lobular carcinoma (NLC). The aim of our analysis was to characterize correlates of the outcome impact of neoadjuvant chemotherapy in ILC and to compare those with NLC. Methods: Between 1998 and 2006; 6377 breast cancer patients were enrolled to 7 randomized neoadjuvant chemotherapy trials in Germany. For 6205 (98.3%) pts the histological type was available. 844 (13.6%) were classified as ILC, 5361 (86.4%) were classified as NLC. Endpoints of the analyses were: pathological complete response (pCR) defined as no invasive and no in-situ residuals in the breast and the lymph nodes, type of surgery, disease-free (DFS), local recurrence (LRFS) and overall survival (OS). Results: ILC was associated with older age, larger tumor size, negative nodes, lower grading, and hormone receptor (HR) positivity (all p<0.0001). The majority of pts with ILC were HR positive (717 pts, 86.9%) and had G1-G2 tumors (603 pts, 78.6%). Patients with ILC had a significant lower pCR rate than pts with NLC (pCR 6.04% vs. 16.4%, p<0.001). In the ILC group, pts with HR positive, triple-negative and HER2-positive tumors had a pCR rate of 5%, 18.3% and 9.2%, respectively. One of 35 pts with G1 and HR positive ILC had a pCR. Breast conservation therapy (BCT) in pts with pCR was 72.5% in the ILC group and 85.5% in the NLC group (p<0.0001). Predictors for pCR in the multivariate analysis were for ILC: patient age, grading and HR status. ILC pts had a significantly longer LRFS compared to NLC pts (with or without pCR after neoadjuvant chemotherapy, mean 112 months 95%CI [109.7-115.7] vs. 106 months 95%CI [104.4-107.4], p=0.002). Conclusions: In patients with ILC age, grading and HR status were predictive for pCR. Pts with ILC have a more favourable outcome after neoadjuvant chemotherapy despite a significantly lower pCR rate compared to pts with NLC.
A prospective clinical utility study of the impact of the 21-gene recurrence score assay (Oncotype DX) in estrogen receptor positive (ER+) node negative (pN0) breast cancer in academic Canadian centers.
Authors: Davidson James Ashley , Cromwell Ian , Ellard Susan , Lohrisch Caroline A. , Gelmon Karen A. , Shenkier Tamara Nina , Villa Diego , Lim Howard John , Sun Sophie , Taylor Sara Kristina , Taylor Marianne , Czerkawski Barbara , Hayes Malcolm , Ionescu Diana , Pope Janice , Berube Jayne , Yoshizawa Carl N. , Chao Calvin , Peacock Stuart , Chia Stephen K. L.
Published: March 2020

549^

Background: The Oncotype DX 21-gene Recurrence Score assay (RS) can potentially predict the magnitude of chemotherapy benefit in patients with stage I-II, node-negative, ER+ disease who will be treated with tamoxifen for 5 years. While use in the United States has grown significantly since its introduction, it is not yet routinely ordered by oncologists in most parts of Canada. The primary purpose of this study was to measure the impact of the Oncotype DX test on the physician’s treatment recommendation in ER+ pN0 breast cancer in British Columbia. Methods: After providing informed consent, patients and medical oncologists completed respective pre-RS questionnaires indicating their treatment preferences and level of confidence and a decisional conflict scale (patients only). At a subsequent visit, after the RS result was known and discussed, the patient and oncologist completed a second set of questionnaires. The proportion of physician treatment recommendations that changed from baseline to follow-up (post RS) were calculated with 95% confidence interval (CI). A prospective health economic (HE) analysis was also performed. Results: From May 2010 to July 2011, two participating BCCA centres enrolled 156 patients. Of the 150 for whom successful RS assay results were obtained, physicians changed their chemotherapy recommendation in 45 cases (30%; 95% CI 22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95% CI 13.9-27.3%) adjuvant chemotherapy. As a secondary end-point, in 84 cases (56%; 95% CI 47.7-64.1%) there was a change in either the planned chemo and/or endocrine therapy recommendation. There was an overall significant improvement in physician confidence post RS (p < 0.001). Patient decisional conflict also significantly decreased following the RS assay (p < 0.001). The HE analysis is ongoing and will be presented separately. Conclusions: Within the context of a publicly funded health care system, the RS assay significantly affects adjuvant treatment recommendations in ER+ node negative breast cancer, in addition to reducing patient decisional conflict.
Cilengitide with cetuximab, cisplatin, and 5-FU in recurrent and/or metastatic squamous cell cancer of the head and neck: The ADVANTAGE phase II trial.
Authors: Vermorken Jan Baptist , Peyrade Frederic , Krauss Juergen , Mesia Ricard , Remenar Eva , Gauler Thomas C. , Keilholz Ulrich , Delord Jean-Pierre , Schafhausen Philippe , Erfán Jozsef , Brummendorf Tim H. , Iglesias Lara , Bethe Ullrich , de La Bourdonnaye Guillaume , Clement Paul M.
Published: March 2020

5516^

Background: Prognosis for patients with recurrent and/or metastatic squamous cell cancer of the head and neck (R/M-SCCHN) is very poor. αvβ5 integrin is overexpressed in SCCHN and selective integrin blockade is being investigated as a treatment strategy. Methods: ADVANTAGE was a phase I/II study evaluating cilengitide with cetuximab and platinum-based chemotherapy. Eligible patients were ≥18 years with ≥1 measurable lesion, Karnofski performance status ≥70%, and confirmed R/M-SCCHN. The phase II part reported herein was an open-label, randomized, controlled trial investigating progression-free survival (PFS) in patients treated with 2 cilengitide 2000 mg regimens: once weekly (CIL1W) and twice weekly (CIL2W) administration combined with cisplatin, 5-FU, and cetuximab (PFE) as compared with PFE alone (control). Secondary objectives included overall survival (OS) and objective response (OR). Treatment-emergent adverse events (TEAEs) were monitored. Results: 184 eligible patients were enrolled. Overall, patient characteristics were similar across arms. Median duration of treatments was shorter in the CIL2W arm compared with the CIL1W arm (cilengitide: 16.1 vs 23.4 wk, cetuximab: 16.0 vs 22.6 wk, platinum: 16.0 vs 18.0 wk, and 5-FU: 14.6 vs 18.0 wk). Median PFS was 6.4 months in the CIL1W group, 5.6 months in the CIL2W group and 5.7 months in the control group, with CIL1W and CIL2W having HRs of 1.03 (95% CI: 0.67–1.59) and 1.55 (95% CI: 0.99–2.43) vs control. The latter HR was possibly due to less compliance in the CIL2W arm. Median OS was 12.4, 10.6, and 11.6 months in the CIL1W, CIL2W, and control groups, respectively. ORs were observed in 46.8%, 26.7%, and 35.5% of patients in the CIL1W, CIL2W, and control arms, respectively. Most common (≥15%) grade 3/4 TEAEs were neutropenia, hypokalemia, leukopenia, stomatitis, and fatigue. No safety differences were noted between treatment arms. Overall, there were 7 drug-related TEAEs (2 in CIL1W, 2 in CIL2W, and 3 in control) leading to death. Conclusions: In this population, neither of the cilengitide-containing regimens was able to demonstrate a PFS benefit over PFE alone.
Differential expression of EGFR, HER2, P16, and high-risk (hr) HPV status in oropharyngeal (Or) and oral cavity (OC) squamous cell carcinoma (SCC).
Authors: Sudaka Anne , Saada Esma , Natale Romain , Poissonnet Gilles , Benezery Karen , Bozec Alexandre , Hebert Christophe , Dassonville Olivier , Peyrade Frederic
Published: March 2020

5521

Background: We aimed to better characterize the expression of epidermal growth factor receptors family in Or and OC SCC and correlate it to hr HPV status and anatomoclinical features. Methods: In formalin fixed paraffin embedded tumor tissues, chromogenic in situ hybridization (CISH) was performed to detect hr HPV and immunohistochemistry to evaluate EGFR (positive score: 4 to 6), HER2 (0=negative, 1=positive) and P16 (positive score:≥70% labeled cells) expression. Baseline data were collected and analyze will be used. Results: Among 128 pts, 69 were tobacco users and 58 male. Median age at diagnosis was 61 y [23-95]. EGFR, Her2, P16 expression and hrHPV positivity were seen in 84 (65%), 12 (9%), 47 (37%) and 47 (37%) respectively. P16 signal was linked with absence of tobacco (31% vs. 72%, Pearson chi2 test: p<10-3), absence of alcohol (48% vs. 83%, p<10-3), Or site (53% vs. 76%, p=0.005), T1 (34% vs. 19%, p=0.06), N0 (52% vs. 23%, p=0.003), absence of nodal capsular rupture (85% vs. 68%, p=0.02), WHO grade 3 (37% vs. 68%, p=0.001), hr HPV detection (17% vs. 70%, p<10-3). Multivariate analysis confirmed the link between P16 expression and hr HPV CISH positivity (OR=0.05, CI 95% [0.01-0.21], p<10-3) , absence of tobacco (OR=9.2, CI 95% [2.1-40.7], p=0.03) and N0 (OR=0.2, CI 95% [0.04- 0.75], p=0.02). EGFR signal was linked with tobacco (31% vs 78%,p=10-3), alcohol (57% vs 81%, p=0.02), OC localization (77% vs 58%, p=0.03), well differentiated SCC (73% WHO grade 1-2 vs 56% grade 3, p=0.04), absence of hr HPV detection (74% vs 52%, p=0.01) and absence of P16 labeling (78% vs 44%, p<10-3). Multivariate analysis confirmed the link between EGFR positivity and tobacco (OR=0.32, CI 95% [0.1-0.9], p=0.03), alcohol (OR=9.5, CI 95% [1.2- 72.8], p=0.03) and OC localization (OR=0.3, CI 95% [0.1-1], p=0.05). HER2 signal was linked with alcohol (5% vs 18%, p=0.04), history of tobacco associated neoplasia (10% vs 0%, p=0.02), Or site (14% vs 2%, p=0.03) and who grade 3 (5% vs 14%, p=0.06). Her2 labeling was not associated with tobacco, sex, hr HPV detection, P16 positivity or EGFR one. Conclusions: Hr HPV associated SCC have a low expression of EGFR and are not associated with HER2 labeling.
ARIX: A randomized trial of acupuncture versus oral care sessions in patients with chronic radiation-induced xerostomia following treatment for head and neck cancer.
Authors: Simcock Richard , Fallowfield Lesley , Monson Kathryn , Solis-Trapala Ivonne , Parlour Louise , Langridge Carolyn I , Jenkins Valerie A
Published: March 2020

5527

Background: Radiation induced xerostomia impairs quality of life of in head and neck cancer survivors. Prior small non-randomised studies suggest that acupuncture may alleviate symptoms. We report the first large randomised trial comparing 8 weeks of group acupuncture with oral care sessions as a control. Methods: 145 patients with radiation induced xerostomia>18 months were recruited from 7 UK Cancer centres. Subjects received standardised group sessions of oral care (OC) education and 8 sessions of weekly group acupuncture (A) in a randomised crossover design with a 4 week washout (Group One OC/A and Group Two A/OC). Acupuncture was standardised to a technique previously piloted (3 auricular points and two distal points bilaterally). Patients completed the EORTC QLQ H&N questionnaire at baseline and weeks 5, 9, 13, 17 and 21 in addition to rating 4 key dry mouth symptoms. The primary outcome was patient reported improvement in dry mouth symptoms. The statistical analysis was longitudinal based on logistic regression models and adjustment for potential carry over. Stimulated and unstimulated saliva was measured. Results: An improvement for 5/7 symptoms was noted following acupuncture. In Group One 24% showed improvement 8 weeks following A (19% after OC). In Group Two 26% reported improvement in severe dry mouth after A (14% after OC). The estimated OR of improved dry mouth 5 weeks after A compared to OC was 2.0 (p=0.031), after adjusting for effects of time, potential carry-over, centre and patient characteristics. The estimated odds ratios of improvement in severity of symptoms for A compared to OC were (OR=1.67, p=0.048) for sticky saliva, (OR=2.08, p=0.011) for needing to sip to swallow food and (OR=1.71, p=0.013) for waking up at night needing to drink. Mean attendance rate for A was 89% and 80% for OC. There was no significant change in saliva production over time or by intervention. Mean global QoL score did not change significantly over time either within or between groups. No adverse events were seen. Conclusions: Eight sessions of weekly group acupuncture provides significantly better relief of radiation induced xerostomia than group oral care education.
Cost-effectiveness of zoledronic acid (ZOL) in postmenopausal women with early breast cancer receiving adjuvant letrozole.
Authors: Xue Mei , Fishman Peter , Botteman Marc
Published: March 2020

553

Background: In the ZO-FAST trial, postmenopausal women with early breast cancer and a bone mineral density (BMD) T-score ≥ –2 and receiving adjuvant letrozole (2.5 mg/day) were randomized to either immediate ZOL (4 mg/6 months) treatment (upfront ZOL) or to the same therapy but only when BMD T-score decreased to < –2 or fracture occurrence (delayed ZOL). After 60 months, upfront ZOL increased both BMD and disease-free survival (P < .05) relative to delayed ZOL. The present analysis assessed, from a US payer perspective, the cost effectiveness of upfront ZOL vs delayed ZOL in this population. Methods: A Markov state-transition model was developed to estimate the lifetime costs and quality-adjusted life-years (QALYs) for a hypothetical cohort of postmenopausal women with early breast cancer receiving letrozole with upfront or delayed ZOL. Consistent with ZO-FAST, patients were 57 years of age and breast cancer recurrence-free at baseline. Patients could progress over time to Local Recurrence, Contra-lateral Tumor, Distant Recurrence, or Death. Transition probabilities were derived from ZO-FAST, supplemented with literature. Costs and utilities were literature based. All outcomes were discounted 3% per year. Results: Compared to delayed ZOL, upfront ZOL resulted in better overall survival, disease-free survival, and QALYs, but at a higher cost (Table). In the base case, the incremental cost/QALY gained with upfront vs delayed ZOL was $7,967. In > 95% of 1,000 probabilistic sensitivity analysis runs, upfront ZOL costs less than $38,376/QALY gained. Conclusions: Upfront ZOL may increase survival and QALY and, at a cost per QALY well under the $50,000/QALY threshold, is very cost-effective in this population. [Table: see text]
A phase I study of everolimus (E) plus weekly cisplatin (CDDP) plus intensity-modulated radiation therapy (IMRT) in head and neck (HN) cancer.
Authors: Fury Matthew G. , Sherman Eric Jeffrey , Ho Alan Loh , Rao Shyam S. , Shen Ronglai , Korte Susan H. , Lisa Donna M. , Ganly Ian , Katabi Nora , Patel Snehal G. , Wong Richard J. , Kraus Dennis , Shaha Ashok R. , Shah Jatin P. , Haque Sofia , Lee Nancy Y. , Pfister David G.
Published: March 2020

5545^

Background: The PI3K/mTOR/eIF4E pathway is upregulated in many HN cancers, and expression of eIF4E in surgical margins has been associated with increased risk of recurrence (Cancer Res 2007; 67:2160. Clin Cancer Res 2004; 10:5820. JCO 1999; 17:2909). Daily E + weekly CDDP was well tolerated in a phase I study for patients with advanced solid tumors (Cancer Chemother Pharmacol 2011 Sep 13; Epub ahead of print]. E achieves radiosensitization in pre-clinical models. This study evaluated weekly CDDP + daily E given concurrently with IMRT in HN cancer. Methods: This was a single institution phase I study with a standard 3 + 3 dose escalation plan. Patients (pts) received standard definitive IMRT (66 Gy resected tumors, 70 Gy unresected tumors) concurrent with CDDP 30 mg/m2 weekly X 6 and daily oral E according to the dose escalation plan. Four dose levels (DLs) of daily oral E were planned: 2.5 mg, 5 mg, 7.5 mg, and 10 mg. Toxicities were recorded according to NCI CTCAE v.3. Results: Thirteen (9M, 4F) pts enrolled, with median age 52y (range, 37 – 65y) and median KPS 90 (range, 80-100). Primary sites: oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), unknown primary (1). Stage: IVA (11), IVB (1), II (1). Prior treatment: surgery (10), chemotherapy (2). The most common ≥ G.3 treatment related AEs were mucositis (functional 62%, clinical 31%), oral pain (31%), and lymphopenia (31%). There were no DLTs among 3 patients at DL1 or the first 3 patients at DL2. Among 4 pts at DL3, there were 2 DLTs: grade 3 mucositis with failure to thrive, and grade 3 mucositis with hypoxia. Among 3 additional patients enrolled at DL2, there was one 1 DLT: grade 3 mucositis with inability to tolerate E. There were no treatment-related deaths. With a median follow-up of 8.9 months, 3 patients have experienced recurrent disease, one of whom has died of disease. Median PFS has not been reached. Tissue correlates in process. Conclusions: When administered with weekly CDDP (30 mg/m2) and definitive IMRT for HN cancer, the phase II recommended dose of E is 5 mg/day.
Association of smoking status with p16 and cyclin D1 (CCND1) expression with clinical characteristics and overall survival (OS) in oropharyngeal squamous cell carcinoma (OSC).
Authors: Ang Mei-Kim , Ang Siok Hoon , Krishna Sai Sakktee , Chen Wallace Jian Jun , Thu Minn Minn Myint , Tai Wai Meng David , Tan Daniel S. W. , Tan Eng-Huat , Tan Puay Hoon , Hwang Siok Gek Jacqueline , Lim Wan-Teck
Published: March 2020

5551

Background: Smoking-related head and neck cancer (HNC) is genetically different, with higher mutation rates compared with non-smokers (NS). Human papillomavirus (HPV)-positive (+) OSC has a superior prognosis independent of treatment. Among HPV+ patients (pt), current or prior smokers (CS) have poor OS compared with NS. Expression of p16, a known HPV surrogate, and CYD1, a cell cycle marker often dysregulated in HNC, was evaluated with respect to smoking status and OS. Methods: Expression of p16 and CYD1 was assessed by immunohistochemistry in 108 OSC pt treated between 1999-2009, using cutoffs of ≥70% (p16+) and ≥10% (CYD1+) stained tumor cells. Associations between expression, clinical characteristics and OS were evaluated by Kaplan-Meier method and compared by log rank test. Hazard ratio (HR) for death was estimated using Cox models. Results: 31 pt (28.7%) were p16+ and 80 pt (75.5%) were CYD1 negative(-). p16+ pt were younger (median age 57 v 66 yrs, p=0.002), more likely female (35.5% v 15.2%, p=0.035), NS (51.6% v 13.9%, p<0.001) with lower combined age-comorbidity score (ageCS) (p=0.003). CYD1+ pt were older (median 66 v 57 yrs, p=0.015), more likely CS (81.5% v 48.1%, p=0.002) with higher ageCS (p=0.018). At a median f/u of 65.7 months, median OS was 57.3 months. p16+ pt had better OS than p16- pt (median OS not reached (NR) v 22.3 mths, p<0.001). CYD1+ pt had poorer OS than CYD1- pt (median OS NR v 17.7 mths, p<0.001). On multivariable analysis p16 and CYD1 status were independently associated with OS (HR 0.412, p=0.045 and HR 4.06, p=0.011 respectively), independent of smoking status (HR 5.01, p=0.008), ageCS (HR 1.32 per 1 point increase, p<0.001) and stage. Strikingly, among NS, 5-year OS in p16+ compared with p16- pt was 100% vs 67% (p<0.001). In contrast, among CS, p16 status had no association with OS (HR 0.97, p=0.943), while CYD1 status and ageCS were independent predictors of death (HR 4.70, p=0.025 and HR 1.28, p<0.001 respectively). Conclusions: In OSC, NS with high p16 expression have excellent prognosis. Among CS, pt with fewer comorbidities and low CYD1 expression have better OS. p16 status was not prognostic in the latter group of patients.
Expression and prognostic significance of directed therapy targets and mutational analysis of the EGFR pathway in malignant salivary gland tumors.
Authors: Cros Jerome F , Blons Helene , Sbidian Emilie , Tartour Eric , Hans Stephane , Brasnu Daniel , Laurent-Puig Pierre , Bruneval Patrick , Badoual Cecile
Published: March 2020

5554

Background: Malignant salivary gland tumors are rare and pleomorphic entities (24 sub types, WHO 2005). Curative treatment relies on surgery sometimes completed by radiotherapy. Management of non-surgical, locally advanced or metastatic tumors is difficult as conventional chemotherapies are ineffective. Directed therapies may provide important benefits for these patients. The aim of this work was to assess the expression and prognostic value of directed therapy targets on salivary gland tumors and search for mutations within the key players of the EGFR pathway. Methods: Immunochemistry on formalin fixed paraffin embedded (FFPE) samples from 124 patients for c-KIT, EGFR, c-ERBB2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was performed and related to progression free interval and survival. DNA was extracted from FFPE samples and conditional for treatment mutations of EGFR/KRAS/BRAF were assessed. An additional high throughput screening for mutations of key oncogenic genes was performed. Results: EGFR was the most expressed marker, found across almost all histotypes. Expression of the other markers was heterogeneous but some potential therapy leads were suggested by high levels of C-ERBB2 and androgen receptors in salivary duct carcinomas or C-KIT over expression in myoepithetial carcinomas. Tumor grade and a high proliferation index (Ki67>20%) were associated with progression free interval and survival. None of the other marker was. No mutation was found in EGFR/KRAS/BRAF. 7% (7/104) of the tumors harbored a mutation at the codon 61 of HRAS. In epithelial and epithelial-myoépithélial carcinoma, the mutation rate reached 33%. Mutations of PI3K and p53 were the most frequently found in the broader screen. Conclusions: Several tumor subtypes expressed frequently some targets of directed therapies suggesting potential therapy leads. The EGFR/MAPK pathway seems intact suggesting a low efficacy of small kinase inhibitors such as erlotinib or gefitinib. The mutation of H-RAS, known to be important but not sufficient to trigger urothelial carcinoma, could be a key oncogenic event in tumors with a myoepithelial component.
Association between salivary cytokine levels and chemoradiotherapy-induced toxicities in head and neck cancer patients.
Authors: Bossi Paolo , Filipazzi Paola , Resteghini Carlo , Miceli Rosalba , Orlandi Ester , Locati Laura , Fallai Carlo , Tana Silvia , Cova Agata , Squarcina Paola , Rodolfo Monica , Bergamini Cristiana , Granata Roberta , Mirabile Aurora , Rivoltini Licia , Licitra Lisa F.
Published: March 2020

5555

Background: Mucositis is a common complication of chemoradiotherapy (CTRT) for head and neck cancer (HNC), linked to a balance between pro- and anti-inflammation serum cytokines. No study has yet addressed the role of salivary cytokines in influencing toxicity severity. Methods: Twenty consecutive stage III (15%) and IV (85%) HNC patients (pts) were treated with radiotherapy (64-70 Gy) plus cisplatin (n=15), carboplatin (n=4) or cetuximab (n=1). Primary tumor site was oral cavity (15%), oropharynx (55%), nasopharynx (15%), larynx or hypopharynx (15%). Unstimulated saliva samples were collected according to standardized protocols before CTRT, during (3rd, 5th and 7th weeks) and two weeks after; concomitantly, mucositis grade (WHO classification), weight loss and need for feeding tube were evaluated. The salivary levels of 11 different cytokines (IFNγ, IL1β, IL2, IL4, IL5, IL6, IL8, IL10, IL12p70, TNFα and TNFβ) were analysed both in pts and in healthy donors (HD, n=10) by optimized bead-based multiplex immunoassay. The cytokine change during treatment was calculated as the difference between the mean of individual values and the baseline value. The Wilcoxon rank sum test was used for between-groups comparisons. Results: At baseline, no difference in cytokine levels was observed in pts as compared with HD, except IL8. A significant and progressive increase of IL1β, IL6, IL8, TNFα and IL10 levels was observed during treatment, with high levels persisting two weeks after treatment for all cytokines but IL1β. Significant association was shown between IL6 increase and G3/4 mucositis (p=0.009) or feeding tube need (p=0.04). The same trend was observed for TNFα. Interestingly, IL8 increase appeared to be specifically linked to weight loss (>10%, p=0.003). In contrast, baseline cytokine salivary levels were not predictive of treatment-induced toxicities. Conclusions: The increase of IL6, IL8 and TNFα salivary levels occurring in HNC patients with CTRT seems to be directly associated with mucositis severity, feeding tube prevalence and weight loss. Cytokines may represent a potential new target for preventive and/or therapeutic intervention.
Outcomes of occult primary (OP) of the head and neck squamous cell carcinoma (HNSCC) treated with oropharynx (OPX)-targeted radiotherapy (RT) and concurrent chemotherapy (CCRT).
Authors: Hu Kenneth , Harrison Louis Benjamin , Shourbaji Rania Ayman , Culliney Bruce , Li Zujun , Mourad Waleed Fouad
Published: March 2020

5559

Background: OP of HNSCC is commonly treated with comprehensive mucosal RT including nasopharynx, OPX, hypopharynx and larynx and bilateral neck. We are reporting the long term outcomes of a conservative mucosal sparing technique consisting of targeting only the OPX mucosa and bilateral necks. Methods: This is a single-institution retrospective study. From January 1998-2010, a total of 68 patients with OP of HNSCC were treated with CCRT (90%) or RT alone (10%), 40% with IMRT. RT fields comprehended OPX mucosa only and bilateral necks. Gross disease in the neck received 70Gy, involved neck 63 Gy, OPX 60 Gy, uninvolved neck and ipsilateral retropharyngeal nodes 54 Gy. All fractions were given at the rate of 1.8-2 Gy/fraction. The median age was 58 (21-87), 80% Caucasian, and 75% males. Stage IVa (N2) was 75% of the population, while stages III (N1), and IVb (N3) were 9, and 16% respectively. 16 patients (9N3+7 bulky N2) underwent neck dissection (ND). The median time interval from diagnosis to RT and RT duration were 60 (13-70) and 50 days (49-63) respectively. The Median number of Chemotherapy cycles was 2 (1-3). Cisplatin was given to 70% of pts, while Carboplatin and Cetuximab were 10 and 20% respectively. Results: With a median follow-up of 5.3 years (1– 13.6), the loco-regional control, (LRC) for all stages is 95.6 %. The median time to LRF is 18 months (12 - 63). Chronic CCRT toxicity was; grade (1) xerostomia (67%), dysphagia (35%), altered taste (28%), neck stiffness (15%), skin toxicity (12%), dysphonia (9%), and trismus (6%). One HIV patient developed grade 4 dysphagia. No patients experienced distant metastases. The emergence of primary was (1.5%) 1 patient developed subglottic SCC 2 years after CCRT, 2 patients failed in the neck (originally N3) all the 3 patients were salvaged successfully by surgery. Kaplan-Meier curve shows the 5-year cause-specific survival to be 100. Conclusions: Our data show that CCRT or definitive RT alone to the OPX and bilateral neck provides excellent oncologic and functional outcomes. Sparing the mucosal surfaces of the nasopharynx, hypopharynx, and larynx seems reasonable and likely reduces toxicity.