Patterns of colorectal cancer screening and adherence rates among an average-risk population enrolled in a national health insurance provider during 2009-2018 in the United States.

While colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States (US), outcomes can be improved through timely screening. Despite the benefits and widespread availability of screening tests, adherence to recommended screening strategies is low. The study aimed to provide recent evidence regarding screening rates and adherence to screening recommendations among adults at average risk for CRC in a commercially insured and Medicare Advantage population. De-identified administrative data from a large US research database were examined to determine screening rates for the years 2009 through 2018. The study population included adults aged 50-75 years and annual study population counts ranged from 1,390,594 in 2009 to 1,654,544 in 2018. Incident screening rates were found to be relatively stable across the study years (approximately 15 %) with adherence lowest in the youngest age group (ages 50-54 years). Colonoscopies accounted for approximately 50 % of all screening tests performed, while there was a substantial increase in the use of home-based screening tests over the study timeframe. The use of the fecal immunochemical test increased from 17.2 % in 2009 to 28.9 % in 2018 and the multi-target stool DNA test increased from 0.4 % in 2015 to 9.0 % in 2018. Overall though, CRC screening and adherence rates remain relatively low among adults at average risk for CRC in the US. Improving adherence rates with CRC screening recommendations among individuals at average risk for CRC is required to improve health outcomes.

Patterns of initial colorectal cancer screenings after turning 50 years old and follow-up rates of colonoscopy after positive stool-based testing among the average-risk population.

OBJECTIVES: Effective colorectal cancer (CRC) screening requires proper adherence beginning at the recommended screening age. For those with positive results on stool-based tests (SBTs), a follow-up colonoscopy is warranted. The objectives of this study were to 1) examine initial screening rates after turning 50 years old; and 2) assess rates of follow-up colonoscopy after a positive SBT. METHODS: This retrospective study used de-identified administrative claims data from 01/01/2006 to 06/30/2020 for commercially insured and Medicare Advantage enrollees. For objective 1, the index year was the year enrollees turned 50. Rates of CRC screening during and after the index year were captured. For objective 2, the index date was the claim date of a fecal immunochemical test (FIT) or multitarget stool DNA test (mt-sDNA) where linked lab data indicated a positive test result. Rates and time to follow-up colonoscopy after a positive SBT were assessed. RESULTS: Approximately 53% of enrollees initiated CRC screening within five years after turning 50 (50+ cohort N = 718,562). Among enrollees with an available lab result indicating a positive SBT (N = 7329; 2110 FIT and 5219 mt-sDNA), overall follow-up colonoscopy within 6 months of the positive result was less than optimal (65%) and varied by modality; 72% vs 46% (p < .001) among enrollees with a positive mt-sDNA test compared to FIT test, respectively. CONCLUSION: There is potential for improving CRC screening among the eligible average-risk population, both to start screening once they reach the screening-eligible age, and to complete the CRC screening paradigm after a positive stool-based screen.

Real-World Outcomes and Value of First-Line Therapy for Metastatic Non-Small Cell Lung Cancer†.

Although physicians rely on clinical trial data to guide cancer treatment decisions, patient characteristics and outcomes often differ between real-world and clinical trial populations. We analyzed retrospective clinical data collected from a prior authorization (PA) tool linked with payer claims data to describe outcomes of first-line treatment for metastatic non-small cell lung cancer among 2,108 patients. Duration of therapy was shorter than observed in clinical trials. Healthcare costs and hospitalizations varied substantially by regimen. PA clinical data linked with administrative claims enable head-to-head comparisons of contemporary cancer treatments used in routine clinical practice, which are not available from clinical trials.

Real-World Treatment Patterns Among Patients Initiating Small Molecule Kinase Inhibitor Therapies for Thyroid Cancer in the United States.

INTRODUCTION: Little is known about real-world use of small molecule kinase inhibitors (SMKI) for advanced thyroid cancer in the United States. This study examined prescribing patterns of SMKI agents recommended by the National Comprehensive Cancer Center (NCCN). METHODS: This retrospective study used a national health insurance database to identify patients diagnosed with thyroid cancer during 1/1/2006-6/30/2016 and with prescription claims for NCCN-recommended SMKI during 1/1/2010-5/31/2016 whose first claim date was the index date. Inclusion also required continuous enrollment in a health plan for 3 months pre-index (baseline) and ≥ 1 month post-index (follow-up) with no claims for SMKI during baseline. Lines of therapy (LOT) were defined by the date of SMKI claims and days of drug supply. Median time to SMKI discontinuation in each LOT was estimated by Kaplan-Meier method. RESULTS: The study included 217 patients. During follow-up (mean duration 499.0 days), 35.5% of patients (n = 77) received a second or later LOT; among patients with ≥ 12 months follow-up after first LOT (LOT1) initiation, 53.1% (n = 60) received a second or later LOT. Median treatment duration was 5.0 months for LOT1 and 5.1 months for LOT2. Over the entire follow-up period (2010-2016), sorafenib was the most common regimen in LOT1 (36.9% of patients) and LOT2 (24.7%) followed by sunitinib and levantinib (13.4% each) in LOT1 and sunitinib (19.5%) in LOT2. Starting in 2015, the year lenvatinib was approved for differentiated thyroid cancer, lenvatinib was the most common first-line regimen among patients initiating LOT1 in 2015 (43.4%) and 2016 (66.7%). CONCLUSION: Sorafenib was the most common first-line agent during 2010-2014 but was supplanted by lenvatinib starting in 2015. Approximately 36-53% of patients received a second-line treatment. Median treatment duration results suggested potential benefit of SMKI in second-line therapy. SMKI treatment after first-line failure may be considered for appropriately selected patients. FUNDING: Eisai, Inc. (Woodcliff Lake, NJ).

Cost of Disease Progression in Patients with Metastatic Breast, Lung, and Colorectal Cancer.

INTRODUCTION: To reduce health care costs and improve care, payers and physician groups are piloting value-based and episodic or bundled-care payment models in oncology. Disease progression and associated costs may affect these models, particularly if such programs do not account for disease severity and progression risk across patient populations. This study estimated the incremental cost of disease progression in patients diagnosed with metastatic breast cancer (mBC), colorectal cancer (mCRC) and lung cancer (mLC) and compared costs among patients with and without progression. METHODS: This was a retrospective study using U.S. administrative claims data from commercial and Medicare Advantage health care enrollees with evidence of mBC, mCRC, and mLC and systemic antineoplastic agent use from July 1, 2006, to August 31, 2014. Outcome measures included disease progression, 12-month health care costs, and 3-year cumulative predictive health care costs. RESULTS: Of 5,709 patients with mBC, 3,707 patients with mCRC, and 5,201 patients with mLC, 56.8% of patients with mBC, 58.1% of those with mCRC, and 80.3% of those with mLC patients had evidence of disease progression over 12 months. Among patients with mBC and mCRC, adjusted and unadjusted health care costs were significantly higher among progressors versus nonprogressors. Per-patient-per-month costs, which accounted for variable follow-up time, were almost twice as high among progressors versus nonprogressors in patients with mBC, mCRC, and mLC. In each of the three cancer types, delays in progression were associated with lower health care costs. CONCLUSION: Progression of mLC, mBC, and mCRC was associated with higher health care costs over a 12-month period. Delayed cancer progression was associated with substantial cost reductions in patients with each of the three cancer types. IMPLICATIONS FOR PRACTICE: Data on the rates and incremental health care costs of disease progression in patients with solid tumor cancers are lacking. This study estimated the incremental costs of disease progression in patients diagnosed with lung cancer, breast cancer, and colorectal cancer and compared health care costs in patients with and without evidence of disease progression in a real-world population. The data obtained in our study quantify the economic value of delaying or preventing disease progression and may inform payers and physician groups about value-based payment programs.

Cost of Disease Progression in Patients with Chronic Lymphocytic Leukemia, Acute Myeloid Leukemia, and Non-Hodgkin's Lymphoma.

INTRODUCTION: To reduce health care costs and improve care, payers and physician groups are switching to quality-based and episodic or bundled-care models. Disease progression and associated costs may affect these models, particularly if such programs do not account for differences in disease severity and progression risk within the cohort. This study estimated the incremental cost of disease progression in patients diagnosed with chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), and non-Hodgkin's lymphoma (NHL) and compared costs among patients with and without progression. METHODS: This was a retrospective study using U.S. administrative claims data from commercial and Medicare Advantage health care enrollees with evidence of CLL, AML, and NHL and systemic antineoplastic agent use from July 1, 2006 to August 31, 2014. Outcome measures included disease progression, 12-month health care costs, and 3-year cumulative predictive health care costs. RESULTS: Of 1,056 patients with CLL, 514 patients with AML, and 7,601 patients with NHL, 31.1% of patients with CLL, 63.8% of those with AML, and 36.9% of those with NHL had evidence of disease progression. Among patients with CLL and NHL, adjusted and unadjusted health care costs were significantly higher among progressors versus nonprogressors. Per-patient-per-month costs, accounting for variable follow-up time, were almost twice as high among progressors versus nonprogressors in patients with CLL, AML, and NHL. In each of the three cancer types, the longer disease progression was delayed, the lower the health care costs. CONCLUSION: Progression of CLL, AML, and NHL was associated with higher health care costs over a 12-month period. Delaying cancer progression resulted in a substantial cost reduction in patients with all three cancer types. IMPLICATIONS FOR PRACTICE: Data on the rates and incremental health care costs of disease progression in patients with hematologic malignancies are lacking. This study estimated the incremental costs of disease progression in patients diagnosed with chronic lymphocytic leukemia, acute myeloid leukemia, and non-Hodgkin's lymphoma and compared health care costs in patients with and without evidence of disease progression in a real-world population. The data obtained in this study will assist future studies in quantifying the cost impact of decreased progression rates and will inform payers and physician groups about setting rates for episode and bundled payment programs.

A retrospective analysis of delays in the diagnosis of lung cancer and associated costs.

PURPOSE: Diagnosis of lung cancer at advanced stages can result in missed treatment opportunities, worse outcomes, and higher health care costs. This study evaluated the wait time to diagnose non-small-cell lung cancer (NSCLC) and the cost of diagnosis and treatment based on the stage at diagnosis. PATIENTS AND METHODS: Adult patients diagnosed with NSCLC between January 2007 and September 2011 were identified from a proprietary oncology registry and linked to health insurance claims from a large US health insurance company. Continuous enrollment in the health plan was required for at least 12 months prediagnosis (baseline) and at least 3 months postdiagnosis (follow-up). Use of diagnostic tests and time to diagnosis were examined. The rates of health care utilization and per-patient per-month (PPPM) health care costs were calculated. RESULTS: A total of 1,210 patients with NSCLC were included in the analysis. Most patients (93.6%) had evidence of diagnostic tests beginning 5 to 6 months prior to diagnosis, and most were diagnosed at an advanced stage (23% Stage IIIb and 46% Stage IV). The PPPM total health care costs in USD pre- and postdiagnosis were $2,407±$3,364 (mean±standard deviation) and $16,577±$33,550, respectively. PPPM total health care costs and utilization after lung cancer diagnosis were significantly higher among patients diagnosed at Stage IV disease and lowest among patients diagnosed at Stage I disease ($7,239 Stage I, $9,484 Stage II, $11,193 Stage IIIa, $17,415 Stage IIIb, and $21,441 Stage IV). CONCLUSION: This study showed that most patients experienced long periods of delay between their first diagnostic test for lung cancer and a definitive diagnosis, and the majority were diagnosed at advanced stages of disease. Costs associated with the management of lung cancer increased substantially with higher stages at diagnosis. Procedures that diagnose lung cancer at earlier stages may allow for less resource use and costs among patients with lung cancer.

ReCAP: Treatment Patterns and Cost of Care Associated With Initial Therapy Among Patients Diagnosed With Operable Early-Stage Human Epidermal Growth Factor Receptor 2-Overexpressed Breast Cancer in the United States: A Real-World Retrospective Study.

PURPOSE: Overexpression of the human epidermal growth factor receptor 2 (HER2) protein negatively affects survival in breast cancer. This study aimed to assess real-world treatment patterns and costs associated with resected nonmetastatic HER2-positive breast cancer in the United States. PATIENTS AND METHODS: Commercially insured patients with HER2-positive breast cancer were identified from oncology registry data linked to a large US commercial administrative claims database. Treatment patterns and health care use and costs in the initial phase of care were examined. RESULTS: Among the 915 patients who met the study criteria, 662 (72%) were hormone receptor (HR) positive, and 253 (28%) were HR negative. Overall, 72% (n = 662) of patients received HER2-targeted therapy (HR positive, 69% v HR negative, 80%; P < .01), specifically trastuzumab. The most common treatment regimens, regardless of HR status, were carboplatin, docetaxel, and trastuzumab (47% of patients) during neoadjuvant therapy and carboplatin, docetaxel, and trastuzumab ± hormone therapy (30% of patients) during adjuvant therapy. Overall unadjusted cost of treatment per patient per month (HR positive, $11,906 v HR negative, $14,367; P < .001) was mainly cancer related (HR positive, $10,513 v HR negative, $13,073; P < .001). Adjusted 12-month cost was $176,779 (HR positive, $167,088 v HR negative, $180,226; P > .05). CONCLUSION: Although trastuzumab-based therapy is considered standard of care among patients with HER2-positive early-stage breast cancer, approximately 28% of these patients did not receive HER2-targeted therapy. Additional studies are warranted to examine whether patients who have not received targeted therapy are eligible for and would benefit from an HER2-targeted approach.

Health care utilization and risk of infection and bleeding among patients with myelodysplastic syndromes with/without transfusions, and with/without active therapy.

This study utilized claims data from a national US commercial health insurer to examine rates of cytopenia-related complications (significant bleeding, infection) and health care utilization (emergency room visits, inpatient hospitalizations) among patients with myelodysplastic syndromes (MDS) within predefined periods of transfusion activity and active therapy. Periods with no transfusions, regardless of relationship to treatment intervention, were associated with lower rates of cytopenia-related complications. These data suggest that eliminating or reducing the need for transfusions may help to reduce MDS-related medical problems, and treatment toward that goal should be considered in patients with MDS needing transfusions.

Healthcare costs, treatment patterns, and resource utilization among pancreatic cancer patients in a managed care population.

BACKGROUND: Pancreatic adenocarcinoma has few effective treatment options and poor survival. The objective of this study was to characterize treatment patterns and estimate the costs and resource use associated with its treatment in a commercially-insured US population. METHODS: In this retrospective claims-based analysis, individuals ≥18 years old with evidence of pancreatic adenocarcinoma between January 1, 2001 and December 31, 2010 were selected from a managed care database. Treatment phase (either initial non-metastatic or metastatic) was determined using a claims-based algorithm. Patients in the pancreatic cancer population were matched 1:3 to a control population. Resource use (events/person-years), treatment patterns, and healthcare costs (per-patient per-month, PPPM) were determined during a variable length follow-up period (from first pancreatic cancer diagnosis to earliest of death, disenrollment, or study end). RESULTS: In this study, 5262 pancreatic cancer patients were matched to 15,786 controls. Rates of office visits, inpatient visits, ER visits, and inpatient stays, and mean total all-cause healthcare costs PPPM ($15,480 vs $1001) were significantly higher among cancer patients than controls (all p < 0.001). Mean inpatient costs were the single largest cost driver ($9917 PPPM). Also, mean total all-cause healthcare costs were significantly higher during the metastatic treatment phase vs the initial treatment phase of non-metastatic disease ($21,637 vs $10,358, p < 0.001). CONCLUSIONS: These results indicate that pancreatic cancer imposes a substantial burden on the US healthcare system, and that treatment of more advanced disease is significantly more costly than initial treatment of non-metastatic disease. LIMITATIONS: Additional research is needed to validate the accuracy of the claims-based algorithms used to identify the treatment phase.

Corroboration of claims algorithm for second-line costs of metastatic colorectal cancer treatment with targeted agents.

OBJECTIVE: To refine a claims algorithm for identifying second-line systemic regimens for metastatic colorectal cancer (mCRC) based on clinical evidence and to compare costs during second-line treatment by targeted therapy administered. METHODS: This retrospective analysis of a large US managed care database identified patients diagnosed with mCRC during 1 July 2007-30 June 2011. A claims-based algorithm was developed to identify patients with at least two lines of therapy (LOT) and the second LOT contained one targeted agent: bevacizumab or any anti-epidermal growth factor receptor (EGFR). Medical chart data from 92 patients were used to corroborate and refine the LOT algorithm. The positive predictive value (PPV) of the initial algorithm and refined algorithm for identification of second LOT are presented. The final algorithm was applied to claims data and two mutually exclusive second-line cohorts were examined: patients with bevacizumab- or cetuximab-containing regimens. Second-line healthcare costs were analyzed with generalized linear models adjusted for demographic and clinical characteristics. RESULTS: The PPV increased from 50.0% (95% CI = 39.4-60.6) for the initial algorithm to 72.1% (95% CI = 59.2-82.9) for the final algorithm. Mean age in the cohorts (n = 569) was 61 years; 58% were men. Days of therapy were similar for the bevacizumab (n = 450) vs cetuximab (n = 119) cohorts, respectively: 131 vs 148 in first LOT and 123 (both cohorts) in second LOT (p ≥ 0.27). Total costs during second-line treatment in the bevacizumab cohort were lower by $12,318 (p = 0.02) and medical costs were lower by $13,809 (p = 0.01). Monthly total and medical costs were lower by $2728 (p = 0.03) and $3133 (p = 0.01), respectively. Results are based on commercially or Medicare-insured patients and may not be generalizable to Medicaid or uninsured patients. CONCLUSIONS: Corroboration of claim-based algorithms with medical chart data improved algorithm performance. Second-line total and medical costs were lower for mCRC patients treated with bevacizumab compared with cetuximab.

Comparative analysis of survival, treatment, cost and resource use among patients newly diagnosed with brain metastasis by initial primary cancer.

Brain metastases are a frequent complication of many systemic cancers and portend a poor prognosis. This retrospective analysis of health claims data compared survival, treatment and health care utilization and costs in patients with brain metastasis by primary tumor site. Adult commercial and Medicare Advantage enrollees newly diagnosed with brain metastasis in 01 Jan 2004 through 30 Apr 2010 were identified. Inclusion required at least 2 claims that identified the same primary cancer site prior to diagnosis of brain metastasis and no evidence of primary brain tumors. Health care utilization rates and costs were calculated at the patient level for each month of follow-up. Differences among primary cancer site cohorts were assessed by ANOVA (continuous variables), Chi square test (proportions) and the Poisson distribution (utilization rates). The primary cancer cohorts comprised 1,031 lung cancer, 93 melanoma and 395 female breast cancer patients. During the 6 months prior to brain metastasis diagnosis, 59 % of lung cancer patients had no evidence of lymph node involvement or other metastatic disease compared to 55 and 42 % of melanoma and breast cancer patients (P < 0.001). Survival after brain metastasis diagnosis was less than 3 months for 52, 43 and 39 % for lung cancer, breast cancer and melanoma, respectively (P < 0.001). Melanoma patients had the highest rate of inpatient stays and outpatient visits (P ≤ 0.003). Total monthly all-cause costs were: melanoma, $23,426; breast cancer $19,708; lung cancer, $17,007 (P = 0.003). Health care utilization and costs after brain metastasis diagnosis were substantial and differed by primary tumor site.

Age distribution of patients with advanced non-melanoma skin cancer in the United States.

The epidemiology of non-melanoma skin cancer (NMSC) is not well understood due to exclusion from most US cancer registries. Patients with at least two claims with a NMSC diagnosis (ICD-9-CM 173.xx) at least 60 days apart, or at least one claim for a NMSC-specific treatment from 1/2010 to 12/2010, were identified from a large US commercial insurance claims database and grouped into one of three cohorts: metastatic (MET), locally advanced (LA), or "all other". MET patients had at least two claims with a metastasis code at least 30 days apart. LA patients had at least two visits to a medical oncologist, one diagnostic imaging service, two radiation therapy services, or one visit to two or more physician specialties. Remaining patients were "all other". Incidence and prevalence of NMSC were calculated from among the total number of persons continuously enrolled in the plan during the study period and standardized to the 2010 US population. From among 6,610,256 patients, there were 47,451 incident cases of NMSC (MET n=16, LA n=387, all other n=47,048). The age-adjusted incidence rate of 693 per 100,000 persons (2010 population) approximates to 2,139,535 total NMSC cases in the US (0.7% of population). 671 prevalent cases had advanced disease (MET n=43, LA n=628); an age-adjusted rate of 0.6 and 10 per 100,000 US persons equivalent to 1,993 and 29,841 MET and LA cases, respectively. Although NMSCs rarely progress, the number of patients with advanced disease is significant. Further studies to determine proportions of advanced NMSC by subtype are needed.

The burden of metastatic melanoma: treatment patterns, healthcare use (utilization), and costs.

Using a large national claims database, this study investigates the differences in survival and healthcare costs of metastatic melanoma patients by the number of metastatic sites. An analysis was carried out using data obtained from January 2007 to March 2010. Patients included had at least two claims for metastatic disease at least 30 days apart, at least two claims for melanoma at least 30 days apart, or at least one claim for cancer-related treatment with a diagnosis of melanoma and evidence of anticancer systemic therapy. The index date was the first metastatic diagnosis date. Patients were characterized as having evidence of lymph node (LN) involvement only, 1-3 distant metastatic sites, or 4+ distant metastatic sites. Average per-patient per-month (PPPM) costs and mortality were examined. There were 431 metastatic melanoma patients: most were male (65%) with mean baseline Charlson's comorbidity index of 3.52. The mean (SD) total unadjusted costs PPPM in the follow-up period were lower for patients with metastases to LN only ($6773 [$5521]) than for those who had 1-3 ($10 999 [$11 319]) or 4+ ($15 762 [$12 377]) distant metastases (P<0.001). When compared with patients with LN metastases only, patients having 1-3 [cost ratio (CR): 1.739, P<0.001] or 4+ (CR: 2.375, P<0.001) distant metastatic sites had higher all-cause healthcare costs. Among the entire study cohort, 42% died with a median survival time of 270 days. Mortality varied by cohort: 3% in LN only; 37% in 1-3 non-LN, and 64% in >3 non-LN (P<0.001). In conclusion, patients with metastatic melanoma with a greater number of metastatic sites have increased healthcare costs and significantly worse survival times.

Evaluation of medication compliance in patients on antidepressants at an outpatient tertiary cancer center setting.

OBJECTIVE: The purpose is to evaluate antidepressant compliance in a cancer population at a tertiary cancer center and to determine if there are covariates of importance in predicting the level of compliance in the study population. METHODS: Patients who received at least three prescriptions covering parts of each month for a continuous 6-month period with at least one of the months being in 2006 from a tertiary cancer center were identified as the prevalent population of interest for this retrospective study. Data collected included demographics, cancer and co-morbid diagnoses, and compliance to antidepressant medication using medication possession ratio (MPR) by patient, medication class, and individual agents. Analysis was conducted using descriptive statistics, analysis of variance, and logistic regression (using MPR ≥ 80 as cutoff). RESULTS: The study population included 297 patients with demographics showing 69% female, 71% Caucasian, a mean age of 52.94 (SD: 12.42), and an average 403 days of follow-up. The MPR for the total study population was 0.87 with 78% of the population having an MPR of ≥ 80% and 22% having an MPR of less than 80%. While there was no significant difference in MPR by different pharmaceutical classes, there were significant differences in the MPR by specific agents (p = 0.02), with nortriptyline having the lowest MPR of 0.79 and doxepin, fluoxetine, mirtazapine, and venlafaxine all having MPR over 0.90. There was also a trend toward a difference in MPR between Caucasians versus non-Caucasians, p = 0.055. CONCLUSION: There appears to be relatively good compliance to antidepressant medications in the study population.

Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-beta.

We used 2D-cocultures employing fibroblasts of different genetic backgrounds and MCF10A-derived human breast epithelial cells of increasingly malignant potential to investigate tumor-stroma interactions in breast cancer and to identify possible signaling pathways involved. Tumor cells induced expression of matrix-metalloproteinase 9 (MMP-9) in fibroblasts in a pattern dependent on the degree of their malignancy. In-situ zymography localized the main gelatinolytic activity around stromal cells in cocultures and xenografted tumors. Use of Smad3 knockout fibroblasts, small molecule inhibitors, and neutralizing antibodies showed that MMP-9 expression was induced by tumor cell-derived TNF-alpha and TGF-beta, dependent on Smad-, Ras-, and PI3-kinase-signaling, and likewise modulated by subsequent HGF- and EGF-signaling. Together, our results indicate that MMP-9 levels in tumor fibroblasts are regulated by a complex tumor-stroma cross-talk, involving multiple ligands and cellular signaling pathways.

SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7.

Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.

Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines.

The role of transforming growth factor beta in breast cancer is controversial with tumor suppressor and pro-oncogenic activities having been demonstrated. To address whether the same or different signal transduction pathways mediate these opposing activities, we manipulated the Smad2/3 signaling pathway in cells of common origin but differing degrees of malignancy derived from MCF10A human breast cells. We show that interference with endogenous Smad2/3 signaling enhances the malignancy of xenografted tumors of premalignant and well-differentiated tumor cells but strongly suppresses lung metastases of more aggressive carcinoma cells after tail vein injection. Overexpression of Smad3 in the same cells has opposite effects. The data demonstrate that the Smad2/3 signaling pathway mediates tumor suppressor and prometastatic signals, depending on the cellular context.