Phase I study of continuous and intermittent schedules of lapatinib in combination with vinorelbine in solid tumors.

BACKGROUND: Chemotherapy in combination with small-molecule epidermal growth factor receptor inhibitors has yielded inconsistent results. Based on preclinical models, we conducted a phase I trial of two schedules of lapatinib and vinorelbine. PATIENT AND METHODS: Patients had advanced solid tumors and up to two prior chemotherapeutic regimens. Patients were enrolled on two dose-escalating schedules of lapatinib, continuous (arm A) or intermittent (arm B), with vinorelbine on days 1, 8, and 15 of a 28-day cycle. Tumors from a subset of patients were evaluated for gene mutations and expression of targets of interest. RESULTS: Fifty-one patients were treated. The most common grade 3/4 toxic effects included leukopenia, neutropenia, and fatigue. Dose-limiting toxic effects were grade 3 infection, febrile neutropenia, and diarrhea (arm A) and bone pain and fatigue (arm B). The maximum tolerated dose was vinorelbine 20 mg/m(2) weekly and lapatinib 1500 mg daily (arm A) and vinorelbine 25 mg/m(2) weekly and lapatinib 1500 mg intermittently (arm B). One patient on each arm had a complete response; both had human epidermal growth factor receptor 2-positive breast cancer. In a subset of patients, lack of tumor PTEN expression correlated with a shorter time to progression. CONCLUSION: In an unselected population, two schedules of lapatinib and vinorelbine were feasible and well tolerated.

The incidence of venous thromboembolism among patients with primary lung cancer.

BACKGROUND: The incidence of venous thromboembolism (VTE) by lung cancer histology and stage is unknown. OBJECTIVES: To determine the incidence of VTE and the risk factors associated with development of VTE in a large population-based study of patients with non-small cell and small cell lung cancer. METHODS: The California Cancer Registry was merged with the Patient Discharge Data Set to determine the incidence of VTE among lung cancer cases diagnosed between 1993 and 1999. RESULTS: Among 91 933 patients with newly diagnosed lung cancer, the 1-year and 2-year cumulative VTE incidences were 3.0% and 3.4%, respectively, with a person-time rate of 7.2 events/100 patient-years during the first 6 months. The 1-year incidence of VTE was significantly increased in comparison to the general population [standardized incidence ratio = 21.2, 95% confidence interval (CI) = 20.4-22.0]. In a multivariate model, significant predictors of developing VTE within 1 year of non-small cell lung cancer (NSCLC) diagnosis were: younger age, the number of chronic medical comorbidities [hazard ratio (HR) = 2.8 if 3 vs. 0, 95% CI = 2.5-3.1], advancing cancer stage (HR = 4.0 for metastatic vs. local disease, 95% CI = 3.4-4.6) and adenocarcinoma histology (HR = 1.9 vs. squamous cell, 95% CI = 1.7-2.1). In multivariate models, VTE was a significant predictor of death within 2 years for both NSCLC and small cell lung cancer (SCLC), HR = 2.3, 95% CI = 2.2-2.4, and HR = 1.5, 95% CI = 1.3-1.7, respectively. CONCLUSIONS: Approximately 3% of lung cancer patients developed VTE within 2 years. The diagnosis of VTE was associated with a higher risk of death within 2 years for NSCLC and SCLC.

Genetic evaluation of cancer: the importance of family history.

Although the etiology of most cancers is thought to be sporadic and multifactorial, 5% to 10% of breast, ovarian, and colon cancers result from defects or mutations in specific genes inherited by a person through the germline. Distinctions may be made between hereditary and sporadic cancers. Because the risk of developing cancer is greater for persons from a hereditary cancer family than for the general public, these people should be considered for early detection and prevention options. Testing for selected cancer genes is available commercially, and physicians must determine which patients are appropriate candidates for these tests. Risk-reduction strategies and options for high-risk patients as well as legal and ethical issues pertaining to genetic counseling and testing will be considered.

Emerging roles of BRCA1 in transcriptional regulation and DNA repair.

BRCA1 was the first breast cancer susceptibility gene to be identified and cloned. In individuals from high-risk families, mutations in BRCA1 increase the lifetime risk of developing breast cancer eight to tenfold, compared to the general population. How the BRCA1 protein product normally functions to suppress tumor formation and how defects in the gene can ultimately lead to breast cancer have been the focus of intense scrutiny by the scientific and medical communities. BRCA1 has intrinsic transactivation activity and is able to activate the p21 promoter. In addition, BRCA1 is linked to a number of genes involved in transcriptional regulation, including CtIP, c-Myc, the RNA holoenzyme complex, and the histone deacetylase complex. Moreover, BRCA1 is essential for cellular response to DNA damage repair. Inactivation of Brca1 in mouse embryonic stem and fibroblast cells results in increased cell sensitivity to DNA-damaging agents. In human cells, BRCA1 binds to both Rad50 and Rad51 and colocalizes with these proteins at repair foci. Part of BRCA1's response to DNA damage may in fact be corroborated through transcriptional regulation. The expression of GADD45, a DNA damage-responsive gene, is increased immediately after induction of BRCA1. Recently, BRCA1 was shown to repress estradiol (E2)-responsive ER-alpha-mediated transcriptional activity, potentially linking the multiple functions of BRCA1 to specific tissue targets. These recent developments in BRCA1 function are an encouraging step toward understanding the role of BRCA1 in breast cancer formation.