bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of potential predictive markers of efficacy of dacomitinib in patients (pts) with recurrent/metastatic SCCHN from a phase II trial.
Authors: Audet Marie-Lise , Allo Ghassan , Weng Xiaoduan , Kim Lucia , Gologan Olguta , Kamel-Reid Suzanne , Siu Lillian , Coutlee Francois , Laurie Scott Andrew , Hotte Sebastien J. , Singh Simron , Winquist Eric , Chia Stephen K. L. , Chen Eric Xueyu , Chan Kelvin K. , English Patricia A , Taylor Ian , Quinn Susan , Mormont Christine , Soulieres Denis
Published: March 2020

6041

Background: Dacomitinib is an irreversible pan-HER TKI with preclinical (EGFRvIII+ cell lines, SCCHN xenografts) and clinical activity (phase II recurrent/metastatic SCCHN; Razak et al, Ann Oncol 2012). However, little is known about predictive markers of efficacy related to EGFR signalling in this setting. Methods: Of69 pts treated with 1st-line dacomitinib in a phase II trial for recurrent/metastatic SCCHN, 48 pts had archival tumor specimens obtained before treatment and 13 had paired biopsies (days 0 and 7 of therapy, FFPE and snap frozen). EGFRvIII and PTEN (IHC), HPV genotyping and human genomic mutations (Sequenom OncoCarta Panel – 19 genes, 238 mutations) were evaluated on archival tissue. IHC expression of AKT, CC3, EGFR, ERK, HER2, HER3, MET, Ki67, pAKT, pEGFR, pERK, pHER2 and pMET was evaluated in paired specimens. The presence/absence or expression level of these markers was correlated with response (RR)/clinical benefit (CB), PFS and OS. Results: In pts with archival tissue, no statistically significant difference was found in RR/CB or PFS based on HPV, EGFRvIII, PTEN or presence of mutation. There was a trend to increased OS in HPV+ pts (HR 0.47, 95% CI 0.21–1.07, P=0.068). In paired biopsies, some expression variation was seen for cytoplasm AKT, membrane EGFR, nuclear ERK and pAKT. There was no correlation between basal expression of these markers and RR/CB or PFS. Variations in ratio to baseline of EGFR, pAKT, pERK and MET were qualitatively associated with RR/CB. No statistically significant correlations could be established for PFS, but there were interesting qualitative variations in the levels of expression of some molecules, eg, EGFR, pAKT. Conclusions: No predictive efficacy marker was identified. It cannot be determined if increased OS in HPV+ cases is due to prognostic or predictive effects. Paired biopsies demonstrated that dacomitinib was associated with variation in expression of multiple elements in signalling pathways linked to EGFR. Given the small number of paired biopsies, and large amount of data generated, descriptive study of cases is required. Further data will be presented at the meeting. Clinical trial information: 00768664.
Health care-associated infections (HAIs) in head and neck carcinoma (HNC) patients treated with chemotherapy (CT) and/or radiotherapy (RT).
Authors: Mirabile Aurora , Vismara Chiara , Bossi Paolo , Locati Laura D. , Bergamini Cristiana , Granata Roberta , Resteghini Carlo , Morelli Daniele , Scarpellini Paolo , Licitra Lisa F.
Published: March 2020

6046

Background: HAIs are dangerous complications of HNC treatment. In lack of data we collected own data in a high volume HNCMOU, comparing them with those observed in other departments. Methods: HAIs recorded retrospectively among 2,288 hospital admissions at our HNCMOU observed from 2005 to 2009 were compared with 427 recent (2010-2012) hospital admissions. In the same period HAIs observed in ENT Surgical, Medical Oncology (MO) and Bone Marrow Transplantation (BMT) dept were recorded. Results: Between 2005 and 2009, 140 HAIs were observed in the HNCMOU: 49% Gram-, 35% Gram+, 16% fungi; 88% of P. Aeruginosa and all Enterobacteriaceae were sensible to meropenem and piperacillin/tazobactam, methicillin-resistant S. aurei (MRSA) were 42% (Table). In the last 3 years infections and resistances rates increased with a similar pattern of bacteria: among 212 HAIs (43% Gram-, 32% Gram+, 24% fungi) the majority (39%) involved respiratory tract, 89% of P. aeruginosa and 92% of Enterobacteriacae were sensible to carbapenem and 89% and 51% were sensible to piperacillin/tazobactam. MRSA were 29%. We compared these data with HAIs occurred from 2005 to 2012 into other dept: most of HAIs in ENT Surgical dept were at surgical site (41%) due to Gram+ (45%), in BMT were sepsis (56%) due to Gram+ (51%) and in MO were urinary tract infections (39%) due to Gram – (70%). Conclusions: Gram- continue to represent the first cause of HAIs in HNC cancer patients treated with CT and/or RT, suggesting a peculiar pattern. This is paralleled by a rise in carbapenem resistance, while MRSA still represent a significant fraction. [Table: see text]
Induction chemotherapy (IC) with docetaxel/cisplatin/5-fluorouracil (TPF) followed by cisplatin-containing concomitant chemoradiotherapy (CRT) in fit patients with locally advanced head and neck cancer (LAHNC): The CONDOR study—A study of the Dutch Head and Neck Society.
Authors: Driessen Chantal , De Boer J. P. , Gelderblom Hans , Rasch Coen R.N. , de Jong Martin , Verbist Berit M , Tesselaar Margot Et , Van Der Graaf Winette T.A. , Kaanders J. H. , Van Herpen Carla M.L.-
Published: March 2020

6057

Background: Standard treatment for patients (pts) with LAHNC is concomitant CRT containing cisplatin. In general 70% of the pts receive all planned cisplatin cycles. TPF IC is associated with survival benefit, but has never been studied in combination with standard CRT. We aimed to determine if TPF followed by cisplatin-containing CRT, in 2 different schedules, was feasible. Methods: In this multicenter randomized phase II trial LAHNC pts, PS 0-1, were treated with maximal 4 TPF courses (T 75 mg/m2, P 75mg/m2 and F 750 mg/m2 day 1-5) and thereafter randomized between P 100 mg/m2 on days 1, 22, 43 combined with conventional RT (arm A) or P 40 mg/m2weekly, maximally 6, combined with accelerated RT (arm B). Primary endpoint was feasibility, defined as receiving ≥ 90% of the planned total radiation dose. Based on power analysis 70 pts were needed. Results: Following an interim-analysis, the study was early terminated after inclusion of 65 pts because only 32% of pts could be treated with the full cisplatin dose during CRT after TPF. 81,5% of pts was male, median age was 56 yrs and PS was 0 in 79% and 1 in 21%, primary site: oral cavity (23%), oropharynx (57%), hypopharynx (12%), larynx (8%). 3 pts did not start TPF; 6/62 pts were not randomized after TPF, due to death (1), toxicity (3) or severe PD (2). RR after TPF was CR 4%, PR 64% and SD 28% in the randomized pts. 27 pts were randomized in arm A and 29 in arm B. 97% of the pts received at least 90% of the planned total radiation dose. However, in arm A only 6 of the 27 pts (22%) and in arm B 12 of the 29 pts (41%) received the total planned chemotherapy part of the CRT. Most common grade 3-4 toxicity during TPF was febrile neutropenia (18%),and during CRT arm A vs arm B dehydration (26% vs 14% ), dysphagia (26% vs 24%), mucositis (22% vs 57%) and creatinin increase (19% vs 3%). After a median follow-up of 21 (7-42) months 66% of the pts was still alive. Conclusions: After TPF IC cisplatin-containing concomitant CRT is not feasible in LAHNC, because the total planned dose of cisplatin could only be administered in 32% of the pts due to severe toxicity. Clinical trial information: NCT00774319.
Acupuncture for dysphagia after chemoradiation therapy in head and neck cancer: A randomized sham-controlled study.
Authors: Lu Weidong , Lorch Jochen H. , Wayne Peter M , Davis Roger B , Tishler Roy B. , Posner Marshall R. , Goguen Laura A , Li Hailun , Macklin Eric , Burke Elaine , Jaffa Zachary , Dreyer Nicholas J , Haddad Tyler C , Buring Julie E , Rosenthal David S. , Haddad Robert I.
Published: March 2020

6058

Background: Dysphagia is a common side effect following chemoradiation (CRT) in pts with head and neck cancer (HNC). The purpose of this pilot trial was to assess the feasibility of recruiting HNC pts and to collect preliminary data on the efficacy and safety of acupuncture on dysphagia-related QOL. Methods: Pts were eligible if diagnosed with stage III-IV HNC, without evidence of distance metastasis, receiving curative-intent CRT. Pts were randomized to 12 sessions of either active or sham acupuncture, once every two weeks, over 24 weeks from during CRT to 20-week post-CRT. All study personnel and the pts were blinded; the treating acupuncturists were not. MDADI and other questionnaires were measured at baseline (end of CRT), end of acupuncture, and at six months follow-up (12-month post-CRT). Data were analyzed by repeated-measures ANOVA adjusting for baseline. Results: Accrual was completed in December 2011. Among 42 pts enrolled, 35 (83%) received at least 8 sessions of acupuncture, and 28 (67%) received all 12. Six pts withdrew due to time constraints. No serious side effects were observed. The mean MDADI total scores improved from baseline in both treatment arms [64.5 (SE+2.4) vs. 71.4 (SE±3.1), p = 0.048; 64.5 (SE±2.4) vs. 77.8 (SE±3.0), p< 0.001]; the difference in improvement was not significant (p = 0.12). The median feeding tube duration did not differ between active and sham treatments (n = 39, median 125 days vs. 147 days, p = 0.93). Conclusions: Acupuncture is a safe and feasible treatment for HNC pts. There were improvements in QOL parameters from end of CRT to the time points examined that did not differ between the two arms. Efficacy of acupuncture to improve swallowing-related QOL in HNC pts may require more frequent or longer duration of treatment. Clinical trial information: NCT00797732.
Phase II trial of concomitant hyperfractionated-accelerated radiotherapy (HART) with cisplatin (Cis) plus cetuximab (Cet) for locoregionally advanced inoperable squamous cell carcinoma of the head and neck (LA SCCHN): Feasibility and 2-year OS.
Authors: Kuhnt Thomas , Schreiber Andreas , Pirnasch Anett , Hautmann Matthias , Hass Peter , Sieker Frank , Engenhart- Cabilic Rita , Richter Michael , Dellas Kathrin , Dunst Juergen
Published: March 2020

6077

Background: To report the mature data of a prospective phase II-trial to investigate the feasibility, efficacy and safety of combination therapy with Cis, Cet and HART in LA SCCHN. Methods: Patients (pts) with stage III or IV, M0 SCCHN were enrolled and treated with an initial dose of Cet (400 mg/m2), followed by weekly dose of 250 mg/m² before HART, which started with a prescribed dosage of 2.0 Gy per day for three weeks followed by 1.4 Gy twice daily to a total dosage of 70.6 Gy to the gross tumor volume. Cis 40 mg/m² was administered weekly for 6 weeks. Results: From February 2007 through November 2010, 74 pts were enrolled, 68 pts with a median age of 56 years (range 37 to 69 years) were evaluable. 50% had oropharyngeal SCC. Of these, 65 pts (96%) received > 90% RT dosage, 50 pts (74%) > 90% Cet dosage and 56 pts (82%) > 4 cycles Cis 40 mg/m². 3D-CRT was used in 72% and 28 patients are currently still being followed up. The most common grade >3 toxicities were mucositis (59%) and dysphagia (52%). Cet-related grade >2- toxicities included dermatitis (15%) within the radiotherapy portals. Nine (14%) pts were missing for response evaluation (e.g. withdrawal of consent). Complete remission rate [(p)CR] was observed in 23/68 (34%) including with 16 pts (24%) who reached a CR of the primary tumor but a selective lymph node dissection was performed 6-8 weeks after end of radiation treatment for residual neck disease. Furthermore, partial remission (PR) was achieved in 29/68 (43%), so an overall response (OR) of 52/68 (77%) was reached. No change/stable disease occurred in 3/68 pts (4%), progressive disease (PD) occurred in 1 pt (1%) and 3 pts (4%) have died due to disease progression. The 2-year overall survival and disease-free survival were 64.2% and 45.3%, respectively. Conclusions: Combination therapy of LA SCCHN consisting of HART-Cis-Cet is an highly active regimen. The addition of Cet to weekly Cis and daily RT was well tolerated and resulted in encouraging local disease control and survival rates. Clinical trial information: 2005-000355-15.
Proton beam therapy combined with selective intra-arterial infusion chemotherapy for locally advanced tongue cancer.
Authors: Takayama Kanako , Nakamura Tatsuya , Takada Akinori , Makita Chiyoko , Suzuki Motohisa , Ishikawa Youjirou , Azami Yusuke , Kikuchi Yasuhiro , Tsukiyama Iwao , Kato Takahiro , Tohnai Iwai , Fuwa Nobukazu
Published: March 2020

6086

Background: The standard treatment for locally advanced tongue cancer is surgery. However, the patient’s quality of life is lost. As a newly non-operative treatment, we report the efficacy and toxicity of proton beam therapy combined with selective intra-arterial infusion chemotherapy (PBT-IACT) for locally advanced tongue cancer. Methods: Between February 2009 and August 2012, 45 cases of stage III-IV(M0) squamous cell carcinoma of the tongue (28 men and 17 women) were treated by PBT-IACT at Southern TOHOKU Proton Therapy Center. Median age was 58 years (range:24-83 years), and clinical stage III/IVA/IVB were 11/32/2 respectively. In case of surgery, the patients required subtotal or total resection of the tongue. Initially, 2 courses of systemic chemotherapy and prophyractic whole neck irradiation (36Gy/20fr.) were performed. Subsequently, for gross tumor targets, PBT (33Gy/15fr.) and IACT were administered via the superficial temporal artery by continuous infusion of cisplatin with sodium thiosulphate. For PBT, 1 or 2 portals of 210 MeV proton beam were arranged in optimal angles to avoid overdosing the risk organ. Systemic chemotherapy was performed only for age of 70 years or younger. Results: The median follow-up was 27 months (range:8-48 months). Over all survival (OS), disease-free survival (DFS), and local control (LC) rates at 2 years were 88%,78%, 80%, respectively. LC of cervical lymph node metastases at 2 years was 86%. As the early toxic event, grade 3 mucositis (32/45) and blood/bone marrow toxicity (22/45) were observed. Within 6 months after this therapy, mandibular osteomyelitis occurred in 1 case. Conclusions: PBT-IACT appeared to be safe and has a good LC rate for locally advanced tongue cancer. Furthermore, it is not inferior to surgery and can be one of the new effective treatment options for locally advanced tongue cancer.
Coexpression of HER3 as a predictor of survival in HER2-positve breast cancer patients.
Authors: Bartsch Rupert , Berghoff Anna Sophie , Bago-Horvath Zsuzsanna , Preusser Matthias , Steger Guenther G. , Rudas Margareta , Birner Peter , Zielinski Christoph
Published: March 2020

611

Background: Improved understanding of the pathobiology of the metastatic cascade as well as the identification of new prognostic markers may lead the path to the development of novel targeted agents in breast cancer patients (BC pts). Recently, HER3-expression was postulated as independent risk factor for metastatic spread. Methods: Pts of different BC subtypes (luminal, HER2-amplified, triple-negative) with metastatic disease were identified from a breast cancer data base. Tissue of the primary tumor was retrieved from the local pathology institute. Immunohistochemical staining of estrogen-receptor, progesterone-receptor, and HER2 and HER3 was performed. In HER2 equivocal cases, subsequent FISH analysis was performed. Results: Specimens of 110 pts (36/110 luminal, 35/110 HER2-amplified, 40/110 triple-negative) were available for this analysis. 23/110 (21%) specimens showed strong, complete, membranous staining for HER3 of at least 10% of all tumor cells. HER2/HER3 co-expression was observed in 12/110 (11%) specimens. HER3 showed a statistically significant association with HER2-expression (p=0.02; Chi square test). No correlation was observed for HER3-expression and overall survival (OS), incidence of brain metastases, or time to diagnosis of brain metastases in the entire patient cohort (p>0.05; log rank). In the HER2-amplified subgroup, however, HER3-expression was significantly associated with shorter OS (median 30 vs. 63 months; p=0.02; log rank test) and remained significant when entered into a multivariate model (p=0.02; Cox regression). Conclusions: HER2/HER3 co-expression is significantly associated with impaired OS in pts with HER2-positive metastatic breast cancer. Co-inhibition of HER2 and HER3 or inhibition of HER2/HER3 hetero-dimerization could improve prognosis of this patient population.
Association of MiR-1290 and its potential targets with characteristics of estrogen receptor α-positive breast cancer.
Authors: Endo Yumi , Toyama Tatsuya , Takahashi Satoru , Yoshimoto Nobuyasu , Iwasa Mai , Asano Tomoko , Fujii Yoshitaka , Yamashita Hiroko
Published: March 2020

614

Background: Recent analyses have identified heterogeneity in estrogen receptor (ER) α-positive breast cancer. Subtypes called luminal A and luminal B have been identified, and the tumor characteristics, such as response to endocrine therapy and prognosis are different in these subtypes. However, little is known about how the biological characteristics of ER-positive breast cancer are determined. Methods: In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissue were compared between ERhigh Ki67low tumors and ERlow Ki67hightumors by miRNA and mRNA microarrays. Results: Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs. We identified a down-regulation of miR-1290 and up-regulations of 6 miRNAs in ERhigh Ki67lowtumors. We picked up 11 genes that were potential target genes of the selected miRNAs. Protein expression patterns of the selected target genes were analyzed in ER-positive breast cancer samples by immunohistochemistry: miR-1290 and its 4 putative targets, BCL2, forkhead box A1 (FOXA1), microtubule associated protein tau (MAPT) and N-acetyltransferase-1 (NAT1) were identified. Transfection experiments revealed that introduction of miR-1290 into ER-positive breast cancer cells decreased mRNA and protein expression of NAT1 and FOXA1. Conclusions: Our results suggest that miR-1290 and its potential targets, NAT1 and FOXA1, might be associated with characteristics of ER-positive breast cancer.
Prognostic significance of the chemokine CXCL13 in node-negative breast cancer.
Authors: Schmidt Marcus , van de Sandt Leonie , Boehm Daniel , Sicking Isabel , Battista Marco Johannes , Lebrecht Antje , Solbach Christine , Naumann Gert , Rahnenfuehrer Joerg , Wirtz Ralph M , Hengstler Jan G
Published: March 2020

615

Background: The chemokine CXCL13 is chemotactic for B cells. We examined the prognostic significance of CXCL13 mRNA expression in node-negative breast cancer. Methods: Microarray based gene-expression data for CXCL13 (205242_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CXCL13 on metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes (ER+/HER2-, ER-/HER2-, HER2+). Independent prognostic relevance was analysed using multivariate Cox regression. Results: Higher RNA expression of CXCL13 was related to better MFS in a meta-analysis of the whole cohort (HR 0.88, 95% CI 0.83-0.94, P<0.0001). Prognostic significance was most pronounced in the HER2+ positive molecular subtype (HR 0.72, 95% CI 0.59-0.87, P=0.0009) as compared to ER+/HER2- (HR 0.86, 95% CI 0.76-0.98, P=0.0024) and ER-/HER2- (HR 0.85, 95% CI 0.75-0.98), P=0.02) carcinomas of the breast. CXCL13 showed independent prognostic significance (HR 0.81, 95% CI 0.7336 0.8982, P=0.0001) in multivariate analysis. In addition to CXCL13, only histological grade of differentiation (HR 2.20, 95% CI 1.41-3.42, P=0.0005) and tumor size (HR 1.72, 95% CI 1.13-2.61, P=0.012), but neither age nor HER2 status nor hormone receptor status retained an independent prognostic association with MFS. Conclusions: The chemokine CXCL13 has independent prognostic significance in node-negative breast cancer. Higher expression of CXCL13 is associated with improved outcome.
Phase II study of lapatinib in combination with vinorelbine, as first- or second-line therapy in women with HER2-overexpressing metastatic breast cancer.
Authors: Chew Helen K. , Schwartzberg Lee Steven , Badarinath Suprith , Rubin Peter , Shumaker Grace , Daugherty James P. , DeSilvio Michelle , Mahoney Janine M.
Published: March 2020

621

Background: Lapatinib (L), an inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) is approved in combination with capecitabine for second-line treatment of HER2+ metastatic breast cancer (MBC). Vinorelbine (V)is a semi-synthetic vinca alkaloid approved for use in patients (pts) with MBC. A previous phase I trial provided a maximum tolerated dose of L plus V. Methods: This was a multicenter, phase II study (LPT111110; NCT00709618) to evaluate the efficacy and safety of L plus V in women with histologically confirmed stage IV HER2+ MBC, ≤1 prior chemotherapeutic regimen (no prior L or V was allowed; prior trastuzumab was permitted) and a Zubrod performance status of 0-2. Pts received L (1500 mg daily) plus V (20 mg/m2IV on Days 1, 8, 15) in a 4-week treatment cycle until disease progression or study withdrawal. Primary endpoint: overall response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival, time to response (TTR), duration of response (DOR), time to progression, and safety assessments. Results: The study was terminated after three years due to slow enrollment; 60 pts were planned and 44 enrolled and were treated. The ORR was 41% (95% CI: 26.4%-55.4%; 4 complete responses, 14 partial responses). Investigator-assessed median (95% CI) PFS, TTR, and DOR were 24.1 (16.9-36.7), 7.5 (7.1–8.1), and 32.0 (18.0-42.3) weeks, respectively. Survival data are not available since data collection was terminated after discontinuation of study treatment. All pts experienced at least 1 adverse event (AE). Conclusions: The combination of L plus V resulted in a 41% ORR and was generally well tolerated. However, definitive conclusions could not be drawn as the study was terminated early and not powered for inference testing. Further exploration of L plus V is warranted to clearly define the role of this novel combination in the treatment of HER2+ MBC. Clinical trial information: NCT00709618. [Table: see text]
Prognostic and predictive value of a low estrogen receptor expression in breast cancer: A retrospective study from a reference center.
Authors: Diorio Caroline , Bouchard-Fortier Antoine , Blanchette Caty , Provencher Louise
Published: March 2020

627

Background: Threshold of estrogen receptors positivity in breast cancer has been lowered to ≥1% of stained cells by immunohistochemistry testing. This change was based on experts’ recommendations from the 2009 St Gallen International Expert Consensus and from the 2010 guidelines of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP). However few studies support these guidelines and the benefit of treating weakly positive estrogen receptor tumors (1-9%) is unknown. Methods: We identified 2221 breast cancer patients with estrogen receptors tested by ligand-based assay, treated and followed in our institution between 1976 and 2008. Date and cause of death were identified through linkage to Quebec Mortality File. A multivariate Cox proportional-hazards model was used to assess the effect of estrogen receptor levels on breast cancer mortality in patients who received hormonal therapy (tamoxifen). Results: In patients with low estrogen receptors, 17% (383 patients) were within 0-3 fmol/mg of cytosol and 12% (266 patients) were within 4-9 fmol/mg of cytosol. Patients with estrogen receptor levels of 0-3, 4-9, 10-19, 20-49, and ≥50 fmol/mg of cytosol had a 20-year breast cancer survival rate of 56%, 56%, 63%, 71% and 60% respectively. From the 2221 patients, 661 (29.8%) received hormonal therapy. In these patients, estrogen receptor levels of 0-3, 4-9, 10-19, 20-49 and ≥50 fmol/mg of cytosol were associated with lower breast cancer mortality (HR (p-value) of 1.00 (reference), 0.59 (0.09), 0.19 (<0.0001), 0.26 (<0.0001) and 0.31 (<0.0001) respectively); with significant mortality reduction only for estrogen receptor levels ≥10 fmol/mg of cytosol. Conclusions: A weak expression of estrogen receptors (<10 fmol/mg) in breast cancer is associated with increase breast cancer mortality. Our results did not show a significant benefit to treat these patients with hormonal therapy as oppose to those with estrogen receptor levels ≥10 fmol/mg of cytosol. To further support these findings, a similar study should be repeated in patients with estrogen receptors tested by immunohistochemistry.
Lack of efficacy of adjuvant lapatinib in HER2-negative breast cancer (HER2–ve BC): Analysis of patients in the TEACH trial.
Authors: Chavarri Guerra Yanin , Chan Arlene , Finkelstein Dianne M. , Chan Valorie F. , Harvey Vernon J. , Lee Keun Seok , Jain Minish Mahendra , Petrakova Katarina , Raina Vinod , Xu Binghe , Gomez Henry , Rappold Erica , Kaneko Tomomi , Huang Yingjie , Goss Paul E.
Published: March 2020

628

Background: Benefit from trastuzumab (T) in patients (pts) with HER2–ve tumors by central laboratory FISH testing was shown in an exploratory analysis of the NSABP B-31trial and confirmed by levels of expression of HER2 mRNA. DNA sequencing studies demonstrate that undetected HER2 mutations may drive tumor growth. It is hypothesized that pts with BC deemed as HER2–ve based on amplification may still benefit from anti-HER2 therapy. We undertook an exploratory analysis of disease free survival (DFS) in pts in TEACH whose tumors were HER2–ve or borderline by central FISH testing. Methods: TEACH, a randomized, double-blind, placebo (P)-controlled trial in 33 countries, evaluated lapatinib (L) in reducing relapse risk in T-naive pts pretreated with chemotherapy for HER2+ BC. L showed a hazard ratio (HR) for DFS compared with P of 0.83 (95% confidence interval [CI] 0.70-1.00); P=.053 in the ITT population (n=3147) and in pts with HER2+ BC by central FISH [HR: 0.82 (0.67-1.00); P=.04]. We conducted an exploratory analysis of DFS in pts with borderline or HER2–ve tumors by central FISH. Estimated DFS times were calculated using a stratified log-rank test. HR was estimated by a stratified Cox regression model. Results: 657 pts (21%) did not have centrally confirmed HER2+ BC (L: 341 and P: 316) in the ITT population: 425 had negative (HER2:CEP-17 ratio <1.8) or borderline (≥1.8–<2.0) FISH testing (L: 218 and P: 207), 216 were unevaluable due to insufficient tissue or sample failed to hybridize (L: 114 and P: 102) and 16 were not centrally tested. In the 425 pts with centrally confirmed HER2–ve or borderline FISH results with 27 events in L and 34 in P, the HR for DFS in L compared with P was 0.94 (0.56-1.57). The percentage of pts with DFS at 4 yrs was 85.0% (79.5%-90.4%) in L and 81% (75.1%-87.1%) in P. Conclusions: Although L showed efficacy in pts with centrally confirmed HER2+ BC in the TEACH trial, our analysis did not show benefit in pts whose tumors were HER2–ve or borderline by central FISH. The TEACH trial shows once again that quality control of HER2 testing is crucial and central laboratory testing should be considered for non-specialized centers worldwide. Clinical trial information: NCT00374322.
Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) patients who received taxane plus trastuzumab treatment.
Authors: Park Yeon Hee , Jung Hyun Ae , Chang Won Jin , Choi Moon Ki , Hong Jung Yong , Ok Oh-Nam , Seo Jeong Ju , Choi Yoon-La , Do Ingu , Ahn Jin Seok , Im Young-Hyuck
Published: March 2020

637

Background: The HER3 receptor is a key member of ErbB family and preferentially signals through the PI3K pathway. Formation of dimers between HER3 and HER2 seems to be crucial for HER2-driven signals in HER2 overexpressing tumors. Given the fact that HER2-HER3 is considered the most active signalling dimer of the ErbB system, HER3 activity may contribute to the resistance of trastuzumab. PTEN plays a well-established role in the negative regulation of the PI3K pathway. Our aim of this study was to investigate the role of HER3 and PTEN expression in patients with HER2 overexpressed MBC. Methods: One-hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as the first line therapy were included in this analysis. Immunohistochemical stainings (IHC) with HER3 and PTEN antibody were conducted retrospectively. Results: Median age was 48 years. HER3 IHC was graded from 0 to 3. PTEN IHC was scored as multiplication of intensity and proportion from 0 to 300. The patients who had negative HER3 stain showed better progression free survival (PFS) to taxane plus trastuzumab chemotherapy than those positive HER3 stain (p=0.001, median PFS 21 vs. 11 mo.). The patients who had PTEN score of more than 20 showed longer PFS than those PTEN score of 20 or less than 20 (p=0.006, median PFS 13 vs. 9 mo.). The patients who had PTEN score of more than 20 showed longer overall survival (OS) than those PTEN score of 20 or less than 20 (p=0.005, median OS 48 vs. 25 mo.). HER3 negativity and PTEN loss were identified as independent risk factors for PFS [Hazard Ratio (HR) 0.4 (95% CI 0.3-0.8 for HER3 negativity; HR 2.1 (95% CI 1.2-3.7) for PTEN loss]. However, PTEN loss (HR 3.1 [95% CI 1.6-6.3]) was identified as an independent risk factor for OS. Conclusions: HER3 and PTEN expression may be predictive markers for trastuzumab treatment in HER2-positive MBCs. PTEN expression may have a potential predictive and prognostic biomarker for trastuzumab treatment.
Use of high-intensity surveillance in patients following a diagnosis of stage I-II non-small cell lung cancer.
Authors: Wright Jason Dennis , Neugut Alfred I. , Siddiq Zainab , Glied Sherry A. , Hershman Dawn L.
Published: March 2020

6505

Background: The incidence of stage I and II lung cancer has been increasing due to the reported benefits of CT screening in high risk individuals. Guidelines suggest continued surveillance following diagnosis, however the extent to which this is done is unclear. We examined the patterns and predictors of surveillance imaging in patients following a diagnosis of stage I-II non-small cell lung cancer (NSCLC). Methods: The SEER-Medicare database was used to identify patients with stage I-II, NSCLC who underwent curative intent surgical resection from 2000-2006.Three surveillance periods (6-18, 18-30, 30-42 months) after diagnosis were identified. Use of imaging was quantified for each period and logistic regression models developed to examine predictors of thoracic imaging during all 3 surveillance periods. Results: Between 2000-2006 5269 patients were identified. During the first year of surveillance use of chest CT (48% in 2000 to 78% in 2006) and PET (2% to 23%) increased while use of bone scan (12% to 6%) and chest radiography (87% to 71%) decreased over time. Similar trends were noted for surveillance periods 2 and 3. During the study, surveillance imaging was performed in all 3 surveillance periods in 38% of the cohort. Yearly surveillance imaging increased with time; 21% of patients diagnosed in 2000 vs. 78% diagnosed in 2006 underwent testing in the first 3 years of follow-up (P<0.0001). In a multivariable model, in addition to year of diagnosis, patients with high socioeconomic status (OR=1.96; 95% CI, 1.51-2.55 compared to low SES) were more likely to undergo yearly surveillance imaging, while Hispanics (OR=0.42; 95% CI, 0.21-0.85) and older patients (OR=0.52; 95% CI, 0.43-0.63) were less likely to undergo testing. Conclusions: The use of costly diagnostic imaging of uncertain value is increasing rapidly for patients with localized NSCLC. Non-clinical factors including high socioeconomic status and white race are among the strongest predictors of use of high intensity surveillance.
Choosing mastectomy over lumpectomy: Factors associated with surgical decisions in young women with breast cancer.
Authors: Rosenberg Shoshana M. , Sepucha Karen , Ruddy Kathryn Jean , Tamimi Rulla M. , Gelber Shari I. , Meyer Meghan E , Schapira Lidia , Come Steven E. , Borges Virginia F. , Winer Eric P. , Partridge Ann H.
Published: March 2020

6507

Background: Few studies have comprehensively evaluated surgical decisions in young women with breast cancer. Young women have unique medical and psychosocial concerns, and identifying factors associated with surgical choices in this population can inform their decision-making process. Methods: As part of an ongoing multi-center cohort study enrolling women diagnosed with breast cancer at age 40 or younger, we evaluated 277 women with stage I-III disease who indicated they had a choice between mastectomy and breast conserving surgery (BCS). Logistic regression was used to identify predictors of choosing mastectomy vs. BCS. Independent variables with a p-value ≤ 0.15 in bi-variate analyses were included in the final multivariable model. Results: 172/277 women (62%) had either a single or bilateral mastectomy as their definitive surgery. Median age at diagnosis was 37 (range: 17-40). Most women were married (75%), had stage I or II disease (90%), and estrogen receptor (ER) positive tumors (65%); approximately 14% were carriers of a BRCA 1 or 2 mutation. In the multivariable analysis (Table), having a mutation, nodal involvement, HER2-positivity, tumor grade, lower BMI, having 2 or more children, anxiety, and decisional involvement by the patient were all associated with mastectomy. Age, race, marital status, tumor size, having a first degree relative with breast or ovarian cancer, ER status, fear of recurrence, and depression were not significantly associated with having a mastectomy. Conclusions: Despite being candidates for BCS, many young women choose to have a mastectomy. Our results suggest potential targets for interventions such as anxiety reduction and fostering fully informed shared decision-making. [Table: see text]
For-profit hospital ownership status and use of brachytherapy after breast-conserving surgery.
Authors: Sen Sounok , Soulos Pamela R. , Herrin Jeph , Roberts Kenneth B , Yu James B. , Lesnikoski Beth-Ann , Ross Joseph S. , Krumholz Harlan , Gross Cary Philip
Published: March 2020

6511

Background: Because the benefits of adjuvant radiation therapy (RT) for breast cancer decrease with increasing age, the use of newer and more expensive RT modalities such as brachytherapy in the treatment of older women has been questioned. In particular, patients and policy makers may be concerned that for-profit hospitals might be more likely to use therapies with higher reimbursements. Among both younger and older Medicare beneficiaries with breast cancer, we examined whether hospital ownership status is associated with use of adjuvant brachytherapy. Methods: Using the Centers for Medicare and Medicaid Services Chronic Condition Warehouse database, we conducted a retrospective study of female Medicare beneficiaries aged 66-94 years old receiving breast-conserving surgery for invasive breast cancer in 2008 and 2009. We assessed the relationship between hospital ownership and receipt of brachytherapy, as well as overall RT (i.e. brachytherapy or whole breast irradiation) using hierarchical generalized linear models. Results: The sample consisted of 35,118 women, 8.0% of whom had undergone surgery at for-profit hospitals.Among patients who received RT, those who underwent surgery at for-profit hospitals were significantly more likely to receive brachytherapy (20.2%) than patients treated at not-for-profit hospitals (15.2%; OR for profit vs. not-for profit: 1.50; 95% CI: 1.23-1.84; p<0.001). Among women 66-79 years old, there was no relation between hospital profit status and overall RT use. However, among women age 80-94 years old, receipt of surgery at a for-profit hospital was significantly associated with higher overall RT use (OR: 1.22; 95% CI: 1.03-1.45, p=0.03) and brachytherapy use (OR: 1.66; 95% CI: 1.18-2.34, p=0.003), but not whole breast irradiation use (OR: 1.14; 95% CI: 0.96-1.36, p=0.13) Conclusions: Medicare beneficiaries undergoing breast-conserving surgery at for-profit hospitals were more likely to receive brachytherapy, a newer, less proven, and more expensive technology. Among the oldest women, who are least likely to benefit from RT, care at a for-profit hospital was associated with higher overall RT use, with this difference largely driven by the use of brachytherapy.
Multitrial evaluation of longitudinal tumor measurement (TM)-based metrics for predicting overall survival (OS) using the RECIST 1.1 data warehouse.
Authors: Mandrekar Sumithra J. , An Ming-Wen , Dong XinXin , Grothey Axel , Bogaerts Jan , Sargent Daniel J.
Published: March 2020

6520

Background: We previously reported that alternative cutpoints and alternate categorical metrics to RECIST standards provided no meaningful improvement in OS prediction. Here, we sought to identify and validate continuous, longitudinal TM-based metrics for predicting OS. Methods: Data from 13 trials (1739 patients with sufficient imaging-based measurements from breast, lung or colon cancer) were randomly split (60:40) into training and validation datasets and landmarked at 12-weeks (w). Multiple candidate metrics that capture tumor curve trajectory were considered: first slope (or % change) from baseline to 6 w, last slope (or % change) from 6 w to 12 w, and indicator of increase (<5% (includes no increase or a decrease) vs. ≥5%) from the prior assessment (baseline to 6 w, 6 w to 12 w). Multivariable Cox models stratified by study and number of baseline target lesions (<3 vs. >3) and adjusted for baseline tumor burden (ratio of the sum of lesions/number of lesions) were fit for each tumor type. Predictive ability was assessed via concordance (c)-index (0.5: no association to 1.0: perfect association), and hazard ratios/p-values (HR/p). Results: Patients whose tumor size increased by at least 5% from the prior assessment, as well as whose tumors showed a positive slope (or % change) from 6 to 12 w (indicating tumor growth) had worse OS. The first slope (or % change) metric was less consistent, with an initial decrease in slope suggesting worse OS in some cases. Predictive ability of these metrics varied across tumor type with poorest prediction in Breast (Table). Conclusions: Continuous TM-based metrics performed no better than categorical RECIST metrics for OS prediction. [Table: see text]
Association of survival with chemotherapy intensity, myelosuppression, and supportive care in patients with advanced solid tumors.
Authors: Lyman Gary H. , Poniewierski Marek S. , Wogu Adane Fekadu , Culakova Eva , Kuderer Nicole Maria , Crawford Jeffrey , Dale David C.
Published: March 2020

6534

Background: The value of chemotherapy and supportive care for advanced cancer has been questioned. Two systematic reviews were conducted to study the impact of chemotherapy-induced myelosuppression and supportive care on subsequent survival. Methods: Phase 1 identified trials evaluating the relationship of chemotherapy associated with myelosuppression and subsequent survival in patients with cancer. Phase 2 evaluated randomized controlled trials (RCTs) chemotherapy with or without G-CSF support for advanced cancer. Outcomes included hazard ratios (HR), relative risk (RR) and absolute risk (AR) ±95% CI. Results: In Phase 1, 11 of 25 identified studies were conducted in patients with advanced/metastatic disease with 10 in patients with solid tumors. Among the 7 studies in patients with solid tumors reporting survival outcomes, a consistent association between chemotherapy-associated myelosuppression and reduced mortality was observed (HR=0.69; 0.61-0.77; P<.0001). A significant interaction between myelosuppression and cancer type for mortality was observed (P=.046) with significant effects observed for all tumor types. In Phase 2, 22 of 61 RCTs identified were in patients with stage IV solid tumors. Mortality was reduced with chemotherapy with G-CSF support overall (RR=0.95; 0.92-0.98; P=.003) and in patients with non-small cell lung cancer (RR=0.90; P=.037; AR=-6.6%; P=.014), sarcomas (RR=0.73; P=.007; AR=-22.1%; P=.004) or urothelial cancers (RR=0.87; P=.019; AR=-11.4%; P=.016). Reductions in mortality were seen with dose dense chemotherapy (RR=0.88; P=.021; AR=-10.0%; P=.019) and when survival was the primary outcome (n=11;RR=0.92; P=.022; AR=-5.2%; P=.001) with a trend toward greater benefit with longer duration of follow-up (P=.071). Conclusions: Studies of patients with advanced solid tumors demonstrate favorable effects of chemotherapy effect on survival. Chemotherapy treatment resulting in myelosuppression is associated with reduced mortality. RCTs of patients with advanced/metastatic solid tumors confirm that greater chemotherapy dose intensity with G-CSF support is associated with greater reductions in mortality.
Trial prospector: An automated clinical trials eligibility matching program.
Authors: Parchman Andrew J. , Zhang Guo-Qiang , Mergler Patrick , Barnholtz-Sloan Jill , Lanese Robert , Miller Dawn M. , Opper Chris , Sahoo Satya , Tao Shiqiang , Teagno Joseph , Warfe James , Meropol Neal J.
Published: March 2020

6538

Background: Clinical trials are the evidence base for improving cancer treatment. Unfortunately, only approximately 5% of cancer patients (pts) take part in clinical research studies. Even in settings where clinical trials (CTs) are available, pt participation remains low. We hypothesize that the time required to identify appropriate studies for individual pts is a significant barrier to clinical trial accrual. Methods: Our multidisciplinary team developed Trial Prospector (TP), an innovative and flexible computer-based system that utilizes artificial intelligence and natural language processing to automatically extract information (e.g. demographics, pathologic diagnosis, stage, labs) from multiple clinical data systems and then match it to CT eligibility criteria. A user-friendly interface allows physician perusal of relevant CTs and eligibility checklists at the point of care without requiring manual data entry. We pilot tested TP in our cancer center GI oncology subspecialty clinics. TP was deployed for consecutive new pts, and oncologists (oncs) completed surveys after each visit to assess the usability and impact of TP. Results: Eleven medical oncologists (6 attendings and 5 fellows) participated in the pilot study. TP was deployed during 60 new pt visits. Of the 15 relevant GI/phase I CTs, TP identified a mean of 7 ± 2.7 eligible trials per patient. The most common reasons for ineligibility were pathologic diagnosis and labs. CTs were considered by the treating onc for 66.7% of the pts. 95% of participating oncs reviewed the TP output at the point of care with 70% spending 0-5 minutes assessing eligibility. Of the pts considered for CTs, a TP report was reviewed 72.5% of the time. Oncs reported that TP saved time identifying potential CTs during 57.1% of the visits. The reports were manually reviewed, and the TP matching algorithm was 100% accurate. 90.9% of the oncs recommended TP for CT screening. Conclusions: These results indicate that Trial Prospector is a feasible, accurate, and effective means to identify CTs for individual pts during a busy outpatient oncology clinic. Ongoing refinements will expand clinical data extraction and CT warehouse to improve precision and applicability across diseases.
Cancer clinical trial accessibility in the United States: An analysis of travel distance.
Authors: Latif Asma , Stensland Kristian D , Hendricks Ryan , Moshier Erin L. , Godbold James H. , Oh William K. , Galsky Matt D.
Published: March 2020

6540

Background: Accessibility of cancer clinical trials has been cited as a barrier to participation. While there are several dimensions to accessibility, travel distance may represent an important measure with potential socio-demographic implications. We sought to identify the driving distance from each ZIP-code in the United States to the nearest clinical trial site for four common solid tumors, and correlate ZIP-code level demographics with travel distance. Methods: The ClinicalTrials.gov database was queried on September 12, 2012 to identify all open, actively recruiting phase II and phase III therapeutic interventional trials in first-line metastatic disease for the four most common solid tumor types in the United States (prostate, breast, lung, and colorectal). Driving distance from each ZIP-code in the continental United States to the nearest trial site for each tumor type was calculated. Trial sites located within the ZIP-code were set at a travel distance of 0 miles. ZIP-code level demographics, derived from the 2010 Census, were correlated with driving distance. Results: We identified 42 prostate cancer trials with 958 sites, 81 breast cancer trials with 1,345 sites, 83 lung cancer trials with 2,249 sites, and 32 colorectal cancer trials with 566 sites which met inclusion criteria. The travel distances for each tumor type are shown in the Table. Analyses correlating driving distance with ZIP-code level demographics are ongoing. Conclusions: Substantial heterogeneity exists regarding accessibility of cancer trials in the United States as measured by driving distance. The optimal geographic distribution of trials, the burden imposed by travel, and the degree to which travel distance contributes to poor cancer clinical trial enrollment all warrant further investigation. [Table: see text]
Willingness of patients to provide biologic samples for pharmacogenomic testing.
Authors: Loo Tenneille T. , Cuffe Sinead , Hon Henrique , Martin Petra , Brown M Catherine , Alibhai Shabbir M.H. , Leighl Natasha B. , Mascaux Celine , Tsao Ming-Sound , Shepherd Frances A. , Qiu Xin , Xu Wei , Liu Geoffrey
Published: March 2020

6543

Background: Additional biopsies and/or blood sampling (i.e.: germline and plasma markers, circulating DNA or tumour cells) may be necessary to complete pharmacogenomic testing (PGT) in some patients. Cancer patients’ perspectives on providing additional biospecimens are important in addressing potential knowledge translation barriers. Methods: 790 clinic patients from the Princess Margaret Cancer Centre (Toronto, Canada) were interviewed with a standardized questionnaire, representing a wide distribution of adult solid and hematological disease sites. Study endpoints included patient preferences and willingness to provide biological samples (new blood, new biopsy, or pre-existing tumor samples) on a 5-point Likert scale. Univariate and multivariate models were created using SAS 9.3. Results: Patients were 49% female; 77% Caucasian/12% Asian; median age 58 years; and 67% had completed high school. Median household income was evenly trichotomized at $50K and $100K. Despite 33% of the patients being uncomfortable with the level of their knowledge about PGT, 75% agreed that additional tests would be beneficial to their health. Patient willingness to provide new samples was 88% for blood and 53% for biopsy, and 27% preferred existing tumor samples to be used in lieu of additional sampling. Caucasians and those with the highest incomes were more agreeable to providing blood and/or biopsy samples, whereas non-Caucasians and low-income earners preferred utilization of existing tumor samples over additional blood sampling (p<0.05). Conclusions: Patients were more willing to provide a new blood sample than a biopsy sample for PGT. Despite the vast majority agreeing to the potential benefit of additional sampling, only half were willing to provide a new biopsy sample. Level of willingness was related to sociocultural and economic factors. Improved patient education and increased efforts to design blood-based markers may improve uptake of PGT.