tbuckley/cabot-search huggingface dataset:
Clinical impact of gastric acid suppressing medication use on the efficacy of elrotinib and gefitinib in patients with advanced non-small cell lung cancer harboring EGFR mutations.
Authors: Yoshitaka Zenke, Kiyotaka Yoh, Shingo Matsumoto, Shigeki Umemura, Seiji Niho, Koichi Goto, Hironobu Ohmatsu, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2014)

8108 Background: Gastric acid suppressing medications (AS), namely, proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RA), increase the gastric pH, which may reduce the absorption of the EGFR tyrosine kinase inhibitors (EGFR-TKIs) erlotinib and gefitinib. The aim of this study was to evaluate the clinical impact of the use of AS on the efficacy of erlotinib and gefitinib in NSCLC patients harboring EGFR mutations. Methods: From 2008 to 2011, 130 consecutive patients with advanced NSCLC harboring EGFR mutations were treated with the EGFR-TKIs erlotinib or gefitinib at our institution. The clinical characteristics of the patients were reviewed, and the efficacy and toxicity of erlotinib and gefitinib were compared between patients receiving and not receiving AS. Results: Among the 130 patients treated with erlotinib or gefitinib, 47 were receiving AS (AS group), while the remaining 83 patients were not receiving AS (non-AS group). The overall response rate (ORR) and median progression-free survival (PFS) in the subject population were 60.9% and 10.0 months, respectively. In the sub-analysis carried out in the AS and non-AS groups, the ORR was 61.7% in the AS group and 60.5% in the non-AS group (p = 0.89), and the median PFS was 8.7 in the AS group and 10.7 months in the non-AS group (p = 0.13). Thus, no significant difference in the ORR or PFS was observed between the AS and non-AS groups. The median overall survival in the subject population was 31.2 months. In regard to the toxicity, the frequencies of rash (83% vs. 86%, p = 0.60) and diarrhea (34% vs. 29%, p = 0.55) were similar in the AS and non-AS groups. There were no deaths that were deemed to be treatment-related in either group. Conclusions: Concurrent use of AS did not affect the efficacy or toxicity of the EGFR-TKIs erlotinib and gefitinib in patients with NSCLC harboring EGFR mutations.
Phase II study of the MEK inhibitor refametinib (BAY 86-9766) in combination with gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer: Biomarker results.
Authors: Hanno Riess, Jean-Luc Van Laethem, Uwe Marc Martens, Volker Heinemann, Patrick Michl, Marc Peeters, David Van Brummelen, Colin D. Weekes, Svein Dueland, Wolff H. Schmiegel, Marius Giurescu, Vittorio Luigi Garosi, Anke Schulz, Henrik Seidel, Barrett H. Childs, Michael Teufel
Journal: Journal of Clinical Oncology (2014)

4129 Background: Refametinib is a potent oral allosteric MEK 1/2 inhibitor with both single-agent and synergistic activity in combination with gemcitabine in preclinical models of pancreas cancer (PC). A synergistic effect between refametinib and erlotinib was also reported in KRAS wild-type human PC in vitro (Diep et al, Clin Cance Res 2011). We report the biomarker results of a single-arm, open label, phase 2a study combining refametinib and gemcitabine in advanced PC. Methods: Refametinib was administered 50 mg bid in combination with gemcitabine. The primary objective was overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS) and biomarker assessment. KRAS mutational analysis was performed from plasma collected at baseline on circulating tumor DNA (ctDNA) by BEAMing. Circulating miRNA were obtained from plasma collected at baseline and post-dose and analyzed by qPCR. Targeted tumor gene next-generation sequencing, gene expression analysis by RNA sequencing and the proliferation index were conducted. Results: Of the 60 patients treated, 39 (65%) had KRAS mutations. In the KRAS subgroups (mut/WT, respectively), the ORR, mPFS and OS were 28%/48% (p=0.136), 4.6/9.0 mo (HR 0.26) and 6.6/18.2 mo (HR 0.27). There was a trend correlating allele frequency with response. KRAS G12D, G12V and G12R were the most frequent mutations. Mutations of codon 38 or 436 were not observed. Tumor exome sequencing was performed from 16 patients, 15 of which had a KRAS mutation (G12D or G12V). The most frequent co-occurring somatic mutations or amplifications were TP53, CDKN2A, and cMYC. Tumor proliferation index and miRNA signatures were not correlated with response. Gene expression data were tested for correlation with response or the presence of published KRAS pathway signatures. Additional subgroup analyses were performed. Conclusions: The high prevalence of KRAS mutations in patients with PC has been confirmed using BEAMing. There was a trend towards improved response, mPFS and OS in the wild-type KRAS subset and for KRAS allele frequency to correlate with response. Clinical trial information: NCT01251640.
Prevalence of germline BAP1 mutations in patients with malignant mesothelioma (MM).
Authors: Matthew David Hellmann, Laetitia Borsu, Ahmet Zehir, Donavan T Cheng, Zheng Zha, Beth Siegel, Rebecca W Rohrer, Mark E. Robson, Angela G. Arnold, Megan Harlan Fleischut, Magali Cavatore, Alice A. Gaskell, Craig Gawel, Alexander Robertson, Agnes Viale, Valerie W. Rusch, Lee M. Krug, Marc Ladanyi, Marjorie Glass Zauderer
Journal: Journal of Clinical Oncology (2014)

e18542 Background: Somatic BAP1 mutations are found in nearly a quarter of MM tumors and germline BAP1 mutations define a new cancer syndrome characterized by familial mesothelioma, uveal melanoma, and other cancers. The prevalence of germline BAP1 mutations in unselected patients with MM remains uncertain. Methods: Unselected patients with MM were enrolled prospectively to collect germline DNA, detailed family history, exposure questionnaires, and tumor tissue if available. De-identified germline DNA sequencing was performed using a custom AmpliSeq panel including BAP1, sequenced on an IonTorrent PGM using Hi-Q chemistry. The sequence data were analyzed for point mutations and small indels using a custom pipeline. Patients with prespecified high-risk criteria (age <50 yrs, no asbestos exposure, personal/family history of choroidal nevus, uveal melanoma, melanoma, or mesothelioma, or cancer in ≥ two 1st degree relatives) were offered genetic counseling and clinical BAP1 testing in a CLIA laboratory. Results: 23 of the 100 planned pts with MM have been tested. In this cohort, 15 (65%) were male, the median age was 69 yrs, 17 (74%) had occupational exposure to asbestos, and 10 had a personal history of another malignancy (including 2 with prior melanoma). 20 pts had pleural MM, 3 pts had peritoneal MM. 20 pts had epithelioid histology, 3 had other histologies. 9 pts qualified as high-risk. One patient was found to be heterozygous for a novel missense variant (E306K) of uncertain functional significance. This pt had asbestos exposure and 5 first-degree relatives with cancer (1 stomach, 4 lung). Studies are ongoing to assess the functional significance of this rare sequence variant. If this variant is shown to be pathogenic, germ line BAP1mutations will account for 1 in 23 unselected pts with MM (4%, 95% CI 0-22%) and 1 in 9 in high-risk pts (11%, 95% 0-48%). Conclusions: Germline BAP1 mutations are uncommon in unselected patients with MM. Further studies are needed to evaluate the role of BAP1 in the oncogenesis of MM and to identify subsets of patients with significant BAP1 mutation prevelance. Clinical trial information: NCT01773655.
The expression pattern of members of the EGFR signaling pathway and its relation with the duration of response in metastatic breast cancer (BC) patients (pts) treated with endocrine therapy (ET)
Authors: G. Atalay, V. Durbecq, D. Larsimont, G. Rouas, A. Di Leo, J.-Y. Leroy, M. J. Piccart
Journal: Journal of Clinical Oncology (2004)

3170 Background: Several lines of evidence suggest that EGFR, Her-2 and their downstream effectors Akt and MAPK are associated with endocrine resistance in BC. We investigated the expression pattern of these molecules and its relation with duration of response in metastatic BC pts treated with ET. Methods: The expression of EGFR, Her-2, pAkt, pMAPK were evaluated in tumor(tm) specimens from 44 BC pts who were treated with tamoxifen(T) or aromatase inhibitors (AIs) as first-line metastatic therapy. Her-3 and Her-4 were evaluated only in those cases with pAkt or pMAPK expression. The pts were stratified into 2 groups; A:those who progressed early (best response is PD ≤6mo of treatment), B:those who progressed late (PR or SD lasting ≥12 mo). Results: The median age of pts who received T/AIs was 45/55. The median duration of response to T-AIs was 2–3 mo/20–32 mo for pt groups A/B respectively. 22 pts progressed early on T/AIs(n=10/12), while 22 pts progressed late on T/AIs (n=9/13). EGFR,Her-2,pMAPK,pAkt were expressed in 4.5%,9%,37% and11% of tms. All tms with EGFR(n=2) and 4/5 tms with Her-2(n=5) expression were in the pt group A. In those cases with pMAPK(n=16) or pAkt(n=5) expression, Her-4 was the most frequently expressed EGF receptor. In 8/16 tms with pMAPK staining, none of the EGF receptors were expressed, 6/8 pts in this group had late progression on ET. 6/8 pts with tms expressing pMAPK and any of the EGF receptors were in the pt group A. 4/5 pts with pAkt positive tms progressed early on ET. At least one of the EGF receptors was expressed in tms with pAkt expression. Conclusion: Despite being a retrospective analysis with small number of pts, our findings suggest that pAkt expression alone or concurrent expression of both pMAPK and one of the EGF receptors might have some predictive value for sensitivity/duration of response to ET.Our findings need prospective validation in the setting of clinical trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pfizer Novartis
Tailored chemotherapy (CT) information (info) faxed to general practitioners (GP) improves knowledge and confidence in managing side effects (SFX): Results from a randomized controlled trial (RCT)
Authors: M. H. Jefford, C. Baravelli, A. Dabscheck, M. Evans, M. Moloney, P. Schofield
Journal: Journal of Clinical Oncology (2007)

6531 Background: The literature indicates discontinuity in patient (pt) care and poor communication between hospitals and community practice. GPs would like more info about CT, SFX and how to manage these. We aimed to develop standardized info for GPs about CT and to assess the impact of this in an RCT. Primary endpoints were: confidence managing pts having CT, knowledge of CT SFX, and satisfaction with both info and shared care of pts. Secondary endpoints included how useful and instructive GPs found the info. Methods: Peter Mac IRB approved the study. Initial focus group work with GPs informed the development of info about 23 CT regimens. GPs of pts due to commence a CT regimen for the first time were randomized to receive usual correspondence (UC) or UC plus info. Prior to randomization GPs were telephoned and verbal consent obtained. Telephone questionnaire (qstnre) assessed GPs confidence in managing pts and knowledge of CT SFX, as well as satisfaction with info and shared care of pts. GPs in the intervention group were then faxed the relevant info. One week later all GPs were phoned and completed a similar standardized qstnre. Measures used a 5 point scale/range. Results: 97 GPs managed 97 pts receiving 21 types of CT. GPs on average had 27.1 yrs clinical experience (SD=9.8) and were managing 5.5 pts receiving CT (SD=6.8). Of 97 GPs randomized, 81 (83.5%) completed the follow up qstnre. GPs confidence in managing CT SFX was fair at baseline (M=3.34, SD=0.69). GPs in the intervention group demonstrated a significantly greater increase in confidence (difference 0.36; p&lt;0.01) and knowledge of CT SFX - eg febrile neutropenia (diff 0.55; p&lt;0.01) - and close to significant effect for satisfaction with info / shared care (diff 0.35; p=0.051) compared with UC. GPs receiving info + UC also considered it significantly more useful (diff 1.48; p&lt;0.001) and instructive (diff 1.88; p&lt;0.001) than GPs who only received UC. Conclusions: Info about CT faxed to GPs is a simple, inexpensive intervention that increases GPs knowledge of CT SFX and confidence in managing pts. Further, GPs find this info more useful and instructive than UC alone. This intervention could have widespread application. No significant financial relationships to disclose.
Contribution of mouse adrenal glands to intratumor androgens and growth of castration-resistant prostate cancer xenografts.
Authors: Elahe A. Mostaghel, Heather Biehl, Susanna Hernandez, Ailin Zhang, Jon Bartlett, Eva Corey, Trevor M. Penning, Riikka Oksala, Lawrence D. True, Peter Nelson
Journal: Journal of Clinical Oncology (2017)

224 Background: Historical studies using radioimmunoassay did not detect adrenal androgens in serum from castrate mice, and it is widely held that rodent adrenal glands do not make adrenal androgens due to lack of CYP17A expression. This contrasts with the clinical setting in which circulating adrenal androgens are significant and inhibition of adrenal CYP17A markedly decreases tissue androgens. Methods: We evaluated CYP17A (by methylation, transcript and protein) and androgens (by mass spectrometry) in adrenal glands of CB17-NOD/SCID mice. We determined the impact of adrenalectomy (ADX) on suppressing tumor androgens and growth in two patient derived xenografts (PDX) models of castration resistant prostate cancer (CRPC). Results: CYP17A is unmethylated, and transcript and protein are present in adrenals from intact and castrate mice. In castrate mice adrenal levels of DHEA (0.75 pg/mg), androstenedione (AED; 44pg/mg), T (12.5pg/mg) and DHT (4.7 pg/mg) are detectable and nearly 2 orders of magnitude higher than in kidney, liver or muscle (p &lt; 0.05 for all). In castrate mice bearing LuCaP35 and LuCaP96 tumors, ADX suppressed tumor steroids at 21-30 days after ADX vs castration alone (LuCaP35: AED 0.05 vs 0.02 pg/mg, p = 0.005; T 0.64 vs 0.03 pg/mg p &lt; 0.001; DHT 2.3 vs 0.23 pg/mg, p = 0.0003; LuCaP96: AED 0.06 vs 0.02 pg/mg p = 0.08; T 0.81 vs 0.03 pg/mg, p &lt; 0.0001; DHT 1.3 vs 0.04 pg/mg, p = 0.002), and delayed time to tumor re-growth (median survival: LuCaP35 33 vs 179 days, p = 0.006; LuCaP96 25 vs 301 days, p = 0.0012). Whereas tumor recurrence in LuCaP96 was uniformly delayed, a subset of tumors in LuCaP35 showed more rapid regrowth after ADX (66 days vs undefined, p = 0.008), with a trend toward increased levels of tumor steroids (progesterone 0.25 vs 0.02 pg/mg, p = 0.07; T 0.14 vs 0.02, p = 0.04; DHT 0.36 vs 0.21, p = 0.17). Recurrent tumors variably showed induction of full length and truncated AR variants and/or induction of steroidogenic enzymes as potential mechanisms of resistance. Conclusions: Adrenally-derived steroids are produced in mice and contribute to tumor androgen levels and growth in PDX models. Mice are an appropriate model for evaluation of steroidogenesis inhibitors in CRPC xenograft studies
Influence of gender on treatment outcome and toxicity in small cell lung cancer (SCLC)
Authors: S. Singh, W. Parulekar, N. Murray, R. Feld, B. Evans, D. Tu, J. Pater, F. A. Shepherd
Journal: Journal of Clinical Oncology (2004)

7041 Background: Female gender has been shown consistently to be a favourable prognostic factor in SCLC. Studies have shown that women with other tumor types experience greater treatment toxicity, but there have been few studies of gender related toxicity in SCLC. Methods: This was a gender-based retrospective analysis of 4 SCLC trials, which were conducted by the NCIC CTG between 1981 and 1996. All 1006 patients (648 male, 358 female) received similar chemotherapy consisting of cyclophosphamide/ doxorubicin/vincristine and etoposide/ cisplatin . Toxicities examined included myelosuppression, stomatitis, vomiting and infection. Other endpoints included number of dose reductions required, number of omitted cycles, response rates and overall survival. Toxicities between the genders were compared using chi-square test in univariate analyses and logistic regression adjusting for age, BSA, performance status, LDH and individual trial in multivariate analyses. Results: Women experienced significantly more toxicity in both univariate and multivariate analyses (see Table). However, toxic death rates were similar for men and women (1.5% vs 1.1%, p=0.58). Despite increased toxicity, 76% of females vs 73.4% of males received all 6 treatment cycles (p=0.38), but 52% of females vs 43.4% of males had treatment delayed for ≥ 2 weeks (p=0.022). The ORR was 80.3% for females and 66.9% for males (p<0.0001) and the median survival was 1.31 years for females and 0.91 for males (p<0.0001) Conclusions: Women clearly experience more chemotherapy related toxicity in the treatment of SCLC, but this does not result in more toxic deaths or omitted treatment cycles, nor does it compromise outcome. No significant financial relationships to disclose.
Upregulation of RAS pathway to predict the risk of distant metastases in HPV + oropharynx cancer.
Authors: Laura D. Locati, Loris De Cecco, Federica Perrone, Barbara Cortelazzi, Annunziata Gloghini, Chiara Volpi, Silvana Pilotti, Roberta Granata, Paolo Bossi, Ester Orlandi, Carlo Resteghini, Salvatore Alfieri, Cristiana Bergamini, Maria Chiara Cau, Martina Imbimbo, Pasquale Quattrone, Silvana Canevari, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2015)

e17073 Background: Locally advanced HPV+ oropharynx cancer (OPC) patients have a remarkable good outcome. However, the frequency of distant metastases (DM) is similar to HPV – cases. Some clinical characteristics (i.e. bulky nodes; T4) correlate with a higher risk of DM. To date no biological predictors has been found. We wondered whether we could predict DM by gene profiling of the primary tumor. Methods: We revised HPV+ OPC cases treated at our Institution since 2004 (No. 107)to find out patients with DM. Low-risk and intermediate risk was defined according to Ang et al. (NEJM 2010). HR-HPV DNA by means of HR-HPV DNA in situ hybridisation (ISH) and p16 expression by IHC were performed in each case. After RNA extraction, a gene expression analysis was done by DASLwg Illumina BeadChips. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA) through GSEA v2.0.14. Results: Seven patients with DM were identified. Paired matched tissues from primary tumor and DM were available in 5 out 7 cases. All patients were stage III-IV, 3 low-risk and 2 intermediate-risk, with a median PFS and FU of 44 months (range, 43-93) and of 73 months (range, 65-138), respectively. As control group (CG), 12 cases were identified. All patients were stage III-IV, 6 low-risk and 6 intermediate-risk with a median follow up of 65 months (range, 55-88). Gene expression profile resulted in a data matrix containing about 24,000 detected genes. By class comparison analysis, differentially expressed genes between paired primary/DM and low-/intermediate risk cases of the CG were identified. Our analysis showed that i) pathways related to RAS activity were enriched in primary tumor with DM; cell-to-cell signaling transduction and growth factor activity were enriched as well; ii) enrichment of gene-sets involving the regulation of metabolic RNA process and DNA repair pathway (i.e. EGFR, ERB2, MEK) was present in intermediate risk cases of CG, in line with the smoking addition; iii) no significant gene-sets deregulation was observed in low-risk cases of CG. Conclusions: Primary HPV+ OPC gene profile seems to harbor the information of the disease history. Further confirmation is needed in larger series.
Phase I trial of pegylated liposomal doxorubicin in combination with BIBF 1120 (nintedanib) in platinum-resistant ovarian cancer: Hoosier Oncology Group GYN10-149.
Authors: Maria Creselda deLeon, Alesha Arnold, Emma Caroline Rossi, Jamie Case, Cynthia Johnson, Yan Zeng, Daniela Matei
Journal: Journal of Clinical Oncology (2014)

5541^ Background: The triple PDGFRα/β, VEGFR1-3, FGFR1-3 angiokinase inhibitor BIBF 1120 (B) is active in ovarian cancer (OC). This phase I/II trial evaluates tolerability and efficacy of B combined with pegylated liposomal doxorubicin hydrochloride (D) in platinum-resistant OC. Methods: The primary endpoints (EPs) are to determine the maximum-tolerated dose (MTD, phase I) and response rate (RR, phase II) to D+B. Secondary EPs were PFS, toxicities and rate of clinical benefit. Translational EPs were treatment effects on circulating hematopoietic stem and progenitor cells (CHSPCs), containing 2 phenotypically distinct populations; pro-angiogenic (p) CHSPCs (ViViD-CD14-glyA-CD34+AC133+CD45dimCD31+ cells) and non-angiogenic (n) CHSPCs (ViViD-CD14-glyA-CD34+AC133-CD45dimCD31+ cells). Eligible pts had measurable OC, primary peritoneal (PP), fallopian tube and uterine (phase I only) cancer, up to 3 prior regimens, ECOG PS of 0-1 and normal end-organ function. B was given orally BID and D was given IV at 40mg/m2every 28 days. 3+3 dose escalation was used, starting with B at 150mg BID. Results: Eleven pts were enrolled in phase I. Median age was 59 (range 26-82); 8 pts had OC, 2 uterine and 1 PP cancer. Histologic types: serous (73%), endometrioid (18%) and mucinous (9%) carcinoma. Dose level+1 (B at 150mg BID) was not tolerated due to grade 3 fatigue, and grade 2 diarrhea, causing treatment interruption (DLT). Among 6 pts at dose level-1 (B at 100mg BID), 1 pt with history of chemotherapy induced myelosupression had grade 4 neutropenia (DLT). Other toxicities were diarrhea (36.4%), fatigue (36.4%), vomiting (27.3%), headache (27.3%), allergic reaction (9.1%) and oral pain (9.1%). Three pts had PRs, 3 SD and 4 disease progression; 1 was not evaluable. A decrease in the pCHSPC/nCHSPC ratio was observed after 1 cycle (1.58, n=8) compared to baseline (1.68, n=10, p=0.4). At treatment discontinuation, the pCHSPC/nCHSPC ratio was 1.97 (n=4). Analyses are ongoing. Conclusions: In summary, D+B is tolerated at 40mg/m2 and 100mg BID. An expanded cohort using generic liposomal doxorubicin and B at level -1 is planned before initiation of the phase II cohort. Clinical trial information: NCT01485874.