المؤلفون: Vernon K. Sondak, Andrew Poklepovic, Nikhil I. Khushalani, Jason J. Luke, Sunil Babu, Sigrun Hallmeyer, Zeynep Eroglu, Mario R. Velasco, Emily F. Higgs, Bruce Brockstein, Daniel J Olson, Thomas Krausz, Madhuri Bajaj, Timothy Carll, Riyue Bao, Jose Lutzky, Theodore Karrison, Brian W. Labadie, Thomas F. Gajewski, Yuanyuan Zha

المصدر: J Clin Oncol

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Ipilimumab, Pembrolizumab, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, RAPID COMMUNICATIONS, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Melanoma, Language, Aged, Aged, 80 and over, biology, business.industry, Anti pd 1, Immunotherapy, Middle Aged, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Female, Antibody, business, medicine.drug

الوصف: PURPOSE Combination of antiprogrammed cell death protein-1 (PD-1) plus anti–cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non–anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody–based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1–negative, non-T-cell–inflamed, and intermediate tumor phenotypes. CONCLUSION To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f53f50387d5994f75ceeba750e8bc2f9Test
https://doi.org/10.1200/jco.21.00079Test

المؤلفون: Ye Chen, Lin Shen, Shujun Yang, Xiao-Li Wei, Sheng Yao, Xichun Hu, Xianglin Yuan, Yi Jiang, Haixin Huang, Qi Li, Yongqian Shu, Rui-Hua Xu, Xiaoyan Lin, Guanghai Dai, Fenghua Wang, Qingyuan Zhang, Weifeng Wang, Hai Wu, Hui Feng, Yunpeng Liu, Jifeng Feng, Wangjun Liao, Jianhua Shi, Nong Xu

المصدر: Journal of Clinical Oncology. 39:704-712

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, China, Herpesvirus 4, Human, Cancer Research, medicine.medical_specialty, Time Factors, Immune checkpoint inhibitors, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Prospective Studies, Progression-free survival, Prospective cohort study, Immune Checkpoint Inhibitors, Aged, Nasopharyngeal Carcinoma, Proto-Oncogene Proteins c-ets, business.industry, Chromosomes, Human, Pair 11, Nasopharyngeal Neoplasms, Middle Aged, Viral Load, medicine.disease, Progression-Free Survival, Repressor Proteins, Clinical trial, 030104 developmental biology, Nasopharyngeal carcinoma, 030220 oncology & carcinogenesis, DNA, Viral, Monoclonal, Disease Progression, Female, Neoplasm Recurrence, Local, Previously treated, business, Viral load

الوصف: PURPOSEAs yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy.PATIENTS AND METHODSIn this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).RESULTSAmong all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1− patients, respectively ( P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% ( P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab.CONCLUSIONThe POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6d5865b9a71fcd25db5548dea278cc7aTest
https://doi.org/10.1200/jco.20.02712Test

المؤلفون: Brian I. Rini, Ying Long, Charlene Mantia, Michael B. Atkins, Tyler F. Stewart, Moshe Chaim Ornstein, Neil J. Shah, Emily Stern Gatof, Hans J. Hammers, Michael E. Hurwitz, Anita Gul, David F. McDermott, Kimberly D Allman

المصدر: Journal of Clinical Oncology. 38:3088-3094

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Immune checkpoint inhibitors, Programmed Cell Death 1 Receptor, Salvage therapy, Ipilimumab, B7-H1 Antigen, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Renal cell carcinoma, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, medicine, Humans, In patient, Progression-free survival, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, Aged, Retrospective Studies, Aged, 80 and over, Salvage Therapy, business.industry, Middle Aged, medicine.disease, Kidney Neoplasms, Progression-Free Survival, Nivolumab, 030104 developmental biology, 030220 oncology & carcinogenesis, Retreatment, Disease Progression, Female, business, medicine.drug

الوصف: PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8edc31be2f2acfc6e054e39b50a66dfbTest
https://doi.org/10.1200/jco.19.03315Test

المؤلفون: Céleste Lebbé, Merrick I. Ross, Axel Hauschild, Theodore F. Logan, Robert H.I. Andtbacka, John A. Glaspy, Philip Friedlander, Claus Garbe, Jason Chesney, Omid Hamid, Howard L. Kaufman, Parminder Singh, Jenny J. Kim, Frances A. Collichio, Jennifer Gansert, Mohammed M. Milhem, Lisa Chen, Igor Puzanov

المصدر: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol 36, iss 17

مصطلحات موضوعية: Male, 0301 basic medicine, Cancer Research, Skin Neoplasms, Phases of clinical research, Herpesvirus 1, Human, Gastroenterology, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Clinical endpoint, Medicine, Melanoma, 6.2 Cellular and gene therapies, Cancer, Aged, 80 and over, Middle Aged, Progression-Free Survival, Oncology, Rapid Communications, 030220 oncology & carcinogenesis, Female, Chills, medicine.symptom, Talimogene laherparepvec, Human, medicine.drug, Proto-Oncogene Proteins B-raf, Adult, medicine.medical_specialty, Clinical Trials and Supportive Activities, Clinical Sciences, Oncology and Carcinogenesis, Ipilimumab, Young Adult, 03 medical and health sciences, Clinical Research, Internal medicine, Genetics, Humans, Oncology & Carcinogenesis, Progression-free survival, Neoplasm Staging, Aged, Biological Products, Herpesvirus 1, business.industry, Evaluation of treatments and therapeutic interventions, medicine.disease, Surgery, 030104 developmental biology, business

الوصف: Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f8badceef0af92ffd8b3a736c40a1376Test
https://doi.org/10.1200/jco.2017.73.7379Test

المؤلفون: Phillip Gray, Beth Souders, Swati Shah, Chia Ling Gau, Carla Mason, Megan L. Landsverk, Negar Ghahramani, Brittany Dougall, Brigette Tippin-Davis, Kory Jasperson, Stephanie Gutierrez, Melissa R.F. Truelson, Kelly Fulk, Elizabeth C. Chao, Jessica Profato, Daniel Chen, Melissa Pronold, Hsiao Mei Lu, Mary Helen Black, Holly LaDuca, Monalyn Umali Salvador

المصدر: Journal of Clinical Oncology

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Genetic Testing for Cancer, DNA Mutational Analysis, Germline, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Germ-Line Mutation, Aged, Retrospective Studies, business.industry, Reproducibility of Results, Diagnostic test, ORIGINAL REPORTS, DNA Methylation, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, Endometrial Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, MutL Protein Homolog 1, business

الوصف: PURPOSE The current diagnostic testing algorithm for Lynch syndrome (LS) is complex and often involves multiple follow-up germline and somatic tests. We aimed to describe the results of paired tumor/germline testing performed on a large cohort of patients with colorectal cancer (CRC) and endometrial cancer (EC) to better determine the utility of this novel testing methodology. MATERIALS AND METHODS We retrospectively reviewed a consecutive series of patients with CRC and EC undergoing paired tumor/germline analysis of the LS genes at a clinical diagnostic laboratory (N = 702). Microsatellite instability, MLH1 promoter hypermethylation, and germline testing of additional genes were performed if ordered. Patients were assigned to one of five groups on the basis of prior tumor screening and germline testing outcomes. Results for each group are described. RESULTS Overall results were informative regarding an LS diagnosis for 76.1% and 60.8% of patients with mismatch-repair–deficient (MMRd) CRC and EC without and with prior germline testing, respectively. LS germline mutations were identified in 24.8% of patients in the group without prior germline testing, and interestingly, in 9.5% of patients with previous germline testing; four of these were discordant with prior tumor screening. Upon excluding patients with MLH1 promoter hypermethylation and germline mutations, biallelic somatic inactivation was seen in approximately 50% of patients with MMRd tumors across groups. CONCLUSION Paired testing identified a cause for MMRd tumors in 76% and 61% of patients without and with prior LS germline testing, respectively. Findings support inclusion of tumor sequencing as well as comprehensive LS germline testing in the LS testing algorithm. Paired testing offers a complete, convenient evaluation for LS with high diagnostic resolution.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd3843d83c1490e469a734034178320bTest
https://doi.org/10.1200/jco.18.00696Test

المؤلفون: Joseph P. Neglia, Melissa M. Hudson, Xuexia Wang, Wendy Landier, Kandice Smith, Kevin C. Oeffinger, Doojduen Villaluna, Leo Mascarenhas, Douglas S. Hawkins, Can-Lan Sun, Leslie L. Robison, Lindsey Hageman, A. Kim Ritchey, Smita Bhatia, Purnima Singh, Sunil Desai

المصدر: Journal of Clinical Oncology. 35:3688-3696

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Neoplasms, Radiation-Induced, Adolescent, Genes, BRCA2, Childhood cancer, Single-nucleotide polymorphism, LIG4, Polymorphism, Single Nucleotide, Risk Assessment, Central Nervous System Neoplasms, DNA Ligase ATP, 03 medical and health sciences, XRCC1, 0302 clinical medicine, Cog, Risk Factors, Neoplasms, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, DNA Polymerase III, POLD1, business.industry, Age Factors, ORIGINAL REPORTS, Endonucleases, DNA-Binding Proteins, X-ray Repair Cross Complementing Protein 1, 030104 developmental biology, Adult Survivors of Child Adverse Events, Case-Control Studies, 030220 oncology & carcinogenesis, Immunology, Female, Tumor Suppressor Protein p53, ERCC1, business

الوصف: Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::42c5e826488e9418b202d6febf36af25Test
https://doi.org/10.1200/jco.2017.74.7444Test

المؤلفون: Heather Hampel, Chia-Ling Gau, Holly LaDuca, Shuwei Li, Rachel McFarland, Carin R. Espenschied

المصدر: J Clin Oncol

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Cancer Research, DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, DNA Mismatch Repair, 0302 clinical medicine, Child, Mismatch Repair Endonuclease PMS2, Aged, 80 and over, Genetics, education.field_of_study, DNA, Neoplasm, ORIGINAL REPORTS, Middle Aged, Epithelial Cell Adhesion Molecule, Lynch syndrome, DNA-Binding Proteins, MutS Homolog 2 Protein, Phenotype, 030220 oncology & carcinogenesis, Female, MutL Protein Homolog 1, Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Adolescent, Population, Breast Neoplasms, MLH1, Risk Assessment, Young Adult, 03 medical and health sciences, Breast cancer, Internal medicine, medicine, Humans, Genetic Testing, education, neoplasms, Aged, Retrospective Studies, business.industry, Endometrial cancer, nutritional and metabolic diseases, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, MSH6, 030104 developmental biology, MSH2, Mutation, business

الوصف: Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10−5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10−7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3cdd3ad78774f5e9984812354f3c7c0Test
https://doi.org/10.1200/jco.2016.71.9260Test

المؤلفون: Hajime Uno, Jeffrey A. Meyerhardt, Jason L. Hornick, Matthew B. Yurgelun, Nanda Singh, Brian Allen, Matthew H. Kulke, Richard J. Wenstrup, Philip G. McNamara, Anne-Renee Hartman, Robert J. Mayer, Deborah Schrag, Lauren K. Brais, John Kidd, Sapna Syngal, Kimmie Ng, Chinedu Ukaegbu, Charles S. Fuchs

المصدر: Journal of Clinical Oncology. 35:1086-1095

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Cancer Research, Colorectal cancer, DNA Mutational Analysis, Genes, BRCA2, Genes, BRCA1, Penetrance, Germline, DNA Glycosylases, 0302 clinical medicine, Family history, Mismatch Repair Endonuclease PMS2, Aged, 80 and over, Genetics, Nuclear Proteins, ORIGINAL REPORTS, Middle Aged, Epithelial Cell Adhesion Molecule, Lynch syndrome, DNA-Binding Proteins, MutS Homolog 2 Protein, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, Fanconi Anemia Complementation Group N Protein, MutL Protein Homolog 1, Adult, medicine.medical_specialty, Adenomatous Polyposis Coli Protein, Young Adult, 03 medical and health sciences, Germline mutation, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Aged, business.industry, Genes, p16, Tumor Suppressor Proteins, Microsatellite instability, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Checkpoint Kinase 2, 030104 developmental biology, Tumor Suppressor Protein p53, business

الوصف: Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results. All participants underwent germline testing for mutations in 25 genes associated with inherited cancer risk. Each gene was categorized as high penetrance or moderate penetrance on the basis of published estimates of the lifetime cancer risks conferred by pathogenic germline mutations in that gene. Results One hundred five (9.9%; 95% CI, 8.2% to 11.9%) of 1,058 participants carried one or more pathogenic mutations, including 33 (3.1%) with Lynch syndrome (LS). Twenty-eight (96.6%) of 29 available LS CRCs demonstrated abnormal MSI/MMR results. Seventy-four (7.0%) of 1,058 participants carried non-LS gene mutations, including 23 (2.2%) with mutations in high-penetrance genes (five APC, three biallelic MUTYH, 11 BRCA1/2, two PALB2, one CDKN2A, and one TP53), 15 of whom lacked clinical histories suggestive of their underlying mutation. Thirty-eight (3.6%) participants had moderate-penetrance CRC risk gene mutations (19 monoallelic MUTYH, 17 APC*I1307K, two CHEK2). Neither proband age at CRC diagnosis, family history of CRC, nor personal history of other cancers significantly predicted the presence of pathogenic mutations in non-LS genes. Conclusion Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC. MSI/MMR testing reliably identifies LS probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5185111baac1b51ca8d1fa882da0b09eTest
https://doi.org/10.1200/jco.2016.71.0012Test

المؤلفون: Nogova, Lucia, Sequist, Lecia V, Perez Garcia, Jose Manuel, Andre, Fabrice, Delord, Jean-Pierre, Hidalgo, Manuel, Schellens, Jan H M, Cassier, Philippe A, Camidge, D Ross, Schuler, Martin, Vaishampayan, Ulka, Burris, Howard, Tian, G Gary, Campone, Mario, Wainberg, Zev A, Lim, Wan-Teck, LoRusso, Patricia, Shapiro, Geoffrey I, Parker, Katie, Chen, Xueying, Choudhury, Somesh, Ringeisen, Francois, Graus-Porta, Diana, Porter, Dale, Isaacs, Randi, Buettner, Reinhard, Wolf, Jürgen, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology

المساهمون: Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology

المصدر: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol 35, iss 2
Journal of Clinical Oncology, 35(2), 157. American Society of Clinical Oncology

مصطلحات موضوعية: Male, 0301 basic medicine, Cancer Research, Fibroblast Growth Factor, Medizin, Pharmacology, Gastroenterology, Tyrosine-kinase inhibitor, Hyperphosphatemia, 0302 clinical medicine, Receptors, 80 and over, 6.2 Cellular and gene therapies, Cancer, Middle Aged, Oncology, Fibroblast growth factor receptor, 6.1 Pharmaceuticals, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, Maximum Tolerated Dose, medicine.drug_class, Clinical Trials and Supportive Activities, Clinical Sciences, Oncology and Carcinogenesis, Antineoplastic Agents, Article, 03 medical and health sciences, Pharmacokinetics, Clinical Research, Internal medicine, Genetics, medicine, Humans, Oncology & Carcinogenesis, Lung cancer, Adverse effect, Aged, business.industry, Phenylurea Compounds, Fibroblast growth factor receptor 1, Evaluation of treatments and therapeutic interventions, medicine.disease, Pyrimidines, 030104 developmental biology, Pharmacodynamics, business

الوصف: Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non–small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event–related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e36e04910ffeb41a502b62a818879994Test
https://doi.org/10.1200/jco.2016.67.2048Test

المؤلفون: Stéphane Oudard, Christy Ralph, Janet E. Brown, Yulei Wang, Joseph A. Ware, Ling Huw, Mark R. Lackner, Rui Zhu, Jill M. Spoerke, Wei Lin, Michelle Byrtek, Bridget O'Keeffe, Thomas Powles, Shan Lu, Michael Staehler, Robert J. Motzer, Brian I. Rini, Daniel Castellano, Bernard Escudier, Alain Ravaud, Robert E. Hawkins

المصدر: Journal of Clinical Oncology. 34:1660-1668

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, mTORC1, Mechanistic Target of Rapamycin Complex 1, Bioinformatics, Disease-Free Survival, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Renal cell carcinoma, Internal medicine, Biomarkers, Tumor, medicine, Carcinoma, Humans, Everolimus, Carcinoma, Renal Cell, Aged, Phosphoinositide-3 Kinase Inhibitors, Aged, 80 and over, business.industry, TOR Serine-Threonine Kinases, Hazard ratio, ORIGINAL REPORTS, Middle Aged, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, Kidney Neoplasms, Clinical trial, Pyrimidines, 030104 developmental biology, Multiprotein Complexes, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, business, medicine.drug

الوصف: Purpose To the best of our knowledge, this study is the first to compare dual inhibition of PI3K/mammalian target of rapamycin (mTOR) by apitolisib (GDC-0980) against single inhibition of mTORC1 by everolimus in metastatic renal cell carcinoma (mRCC). Patients and Methods Patients with clear-cell mRCC who progressed on or after vascular endothelial growth factor–targeted therapy were randomly assigned to apitolisib 40 mg once per day or to everolimus 10 mg once per day. End points included progression-free survival, safety, overall survival, and objective response rate. Biomarker assessments were conducted. Results Eighty-five patients were randomly assigned. After 67 events, stratified analysis revealed that median progression-free survival was significantly shorter for apitolisib than for everolimus (3.7 v 6.1 months; hazard ratio, 2.12 [95% CI, 1.23 to 3.63; P < .01]); apitolisib was not favored in any stratification subgroup. Median overall survival was not significantly different but trended in favor of everolimus (16.5 v 22.8 months; hazard ratio, 1.77 [95% CI, 0.97 to 3.24; P = .06]). The objective response rate was 7.1% for apitolisib and 11.6% for everolimus. Patients administered apitolisib with a greater incidence of grade 3 to 4 adverse events were more likely to discontinue treatment (31% v 12% for everolimus). No drug-related deaths were observed. Apitolisib in comparison with everolimus was associated with substantially more high-grade hyperglycemia (40% v 9%) and rash (24% v 2%). Apitolisib pharmacokinetics suggested a relationship between exposure, and rash and hyperglycemia. Retrospective biomarker analyses revealed a relationship between VHL mutation status and outcome with everolimus but not with apitolisib. High hypoxia-inducible factor 1α protein expression was associated with better outcome in both arms. Conclusion This study demonstrated that dual PI3K/mTOR inhibition by apitolisib was less effective than was everolimus in mRCC, likely because full blockade of PI3K/mTOR signaling resulted in multiple on-target adverse events. VHL mutation and hypoxia-inducible factor 1α expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required.

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الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7708f770be181acc7ac771d90800748cTest
https://doi.org/10.1200/jco.2015.64.8808Test