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1.
J Thorac Oncol ; 15(7): 1232-1239, 2020 07.
Article in English | MEDLINE | ID: mdl-32179180

ABSTRACT

INTRODUCTION: Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown. METHODS: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants. RESULTS: Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation. CONCLUSIONS: Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.


Subject(s)
Li-Fraumeni Syndrome , Lung Neoplasms , Carcinogenesis , ErbB Receptors , Europe , Female , Germ-Line Mutation , Humans , Li-Fraumeni Syndrome/epidemiology , Li-Fraumeni Syndrome/genetics , Lung Neoplasms/epidemiology , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Prevalence , Protein Kinase Inhibitors , Protein-Tyrosine Kinases , Proto-Oncogene Proteins , Retrospective Studies , Tumor Suppressor Protein p53/genetics
2.
J Natl Cancer Inst ; 100(11): 805-14, 2008 Jun 04.
Article in English | MEDLINE | ID: mdl-18505968

ABSTRACT

BACKGROUND: Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS: After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS: Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS: Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Paclitaxel/therapeutic use , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/chemistry , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/secondary , Carcinoma, Lobular/drug therapy , Carcinoma, Lobular/secondary , Cyclophosphamide/administration & dosage , Disease-Free Survival , Drug Administration Schedule , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Infusions, Intravenous , Kaplan-Meier Estimate , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Treatment Outcome
3.
Clin Colorectal Cancer ; 5(6): 429-35, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16635282

ABSTRACT

PURPOSE: The purpose of this study was to evaluate the antitumor activity and toxicity of fixed sequences of capecitabine/oxaliplatin followed by capecitabine/irinotecan in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Adult patients with histologically confirmed, previously untreated, nonresectable, locally advanced or metastatic colorectal adenocarcinoma were enrolled in the study. Patients were treated as follows: capecitabine (1000 mg/m2 orally twice daily) on days 1-14 and oxaliplatin (130 mg/m2 2-hour intravenous infusion) on day 1, followed by capecitabine (1000 mg/m2 twice daily) on days 1-14 and irinotecan (240 mg/m2 1.5-hour intravenous infusion) on day 1. Each combination was administered every 21 days during 4 consecutive cycles followed by the alternating sequence to a maximum of 16 cycles. RESULTS: A total of 35 eligible patients have been included in this ongoing study. Response rate (complete responses plus partial responses) was 37.1%. With a median follow-up of 9.5 months, the median time to disease progression and overall survival were 7.4 months and 16.4 months, respectively. Treatment was well tolerated, with only 6% of the patients developing grade 3/4 neurotoxicity. However, the low number of patients treated beyond 4 cycles limits the interpretation of the data. CONCLUSION: The preliminary results from this ongoing study suggest the feasibility of this strategy, which resulted in promising antitumor activity with less neurotoxicity.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adenocarcinoma/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine , Colorectal Neoplasms/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug-Related Side Effects and Adverse Reactions , Female , Fluorouracil/analogs & derivatives , Humans , Irinotecan , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Survival Rate
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