Barriers to Clinical Trial Implementation Among Community Care Centers.

Importance: While an overwhelming majority of patients diagnosed with cancer express willingness to participate in clinical trials, only a fraction will enroll onto a research protocol. Objective: To identify critical barriers to trial enrollment to translate findings into actionable practice changes that increase cancer clinical trial enrollment. Design, Setting, and Participants: This survey study included designated site contacts at oncology practices with teams who were highly involved with the Association of Community Cancer Centers (ACCC) Community Oncology Research Institute (ACORI) clinical trials activities, all American Society of Clinical Oncology (ASCO)-ACCC collaboration pilot sites, and/or sites providing care to at least 25% African American and Hispanic residents. To determine participation trends among health care practices in oncology-focused research, identify barriers to clinical trial implementation and operation, and establish unmet needs for cancer clinics interested in trial participation, a 34-question survey was designed. Survey questions were defined within 3 categories: cancer center demographic characteristics, clinical trial characteristics, and referral practices. The survey was distributed through email and was open from June 20 through October 5, 2022. Main Outcomes and Measures: Participation in and barriers to conducting oncology trials in different community oncology settings. Results: The survey was distributed to 100 cancer centers, with completion by 58 centers (58%) across 25 states. Fifty-two centers (88%) reported that they conduct therapeutic clinical trials, of which 33 (63%) were from urban settings, 11 (21%) were from suburban settings, and 8 (15%) were from rural settings. Only 25% of rural practices (2 of 8) offered phase 1 trials, compared with 67% of urban practices (22 of 33) (P = .01). Respondents noted challenges in conducting research, including patient recruitment (27 respondents [52%]), limited staffing (27 [52%]), and nonrelevant trials for their patient population (25 [48%]). Among sites not offering therapeutic trials, barriers to research conduct included limited infrastructure, funding, and staffing. Most centers (46 of 58 [79%]) referred patients to outside centers for clinical trial enrollment, particularly in the context of late-stage disease and/or disease progression. Only 17 of these sites (37%) had established protocols for patient follow-up subsequent to outside referral. Conclusions and Relevance: In this national survey study of barriers to clinical trial implementation, most sites offered therapeutic trials, but there were significant disparities in trial availability across care settings. Furthermore, fundamental deficiencies in trial support infrastructure limited research activity, including within programs currently conducting research as well as at sites interested in future clinical research opportunities. These results identify crucial unmet needs for oncology clinics to effectively offer clinical trials to patients seeking care.

Resource and Reimbursement Barriers to Comprehensive Cancer Care Delivery: An Analysis of Association of Community Cancer Centers Survey Data.

PURPOSE: Comprehensive cancer care (CCC) delivery is recommended in guidelines and considered essential for high-quality cancer management. Barriers, such as insufficient reimbursement, prevent consistent access to and delivery of CCC. Association of Community Cancer Centers conducted a national survey to elucidate capacity and barriers to CCC delivery to inform policy and value-based payment reform. METHODS: Survey methodology included item generation with expert review, iterative piloting, and cognitive validity testing. In the final instrument, 27 supportive oncology services were assessed for availability, reasons not offered, and coverage/reimbursement. RESULTS: 204 of 704 member programs completed survey questions. Despite most services being reported as offered, a minority were funded through insurance reimbursement. The services least likely to obtain reimbursement were those that address practical and family/childcare needs (0.7%), caregiver support (1.5%), advanced care directives (1.7%), spiritual services (1.8%), and navigation (2.7%). These findings did not vary by region or practice type. CONCLUSION: There is a lack of sufficient reimbursement, staffing, and budget to provide CCC across the United States. Care models and reimbursement policies must include CCC services to optimize delivery of cancer care.

The RASSF1A tumor suppressor restrains anaphase-promoting complex/cyclosome activity during the G1/S phase transition to promote cell cycle progression in human epithelial cells.

Multiple molecular lesions in human cancers directly collaborate to deregulate proliferation and suppress apoptosis to promote tumorigenesis. The candidate tumor suppressor RASSF1A is commonly inactivated in a broad spectrum of human tumors and has been implicated as a pivotal gatekeeper of cell cycle progression. However, a mechanistic account of the role of RASSF1A gene inactivation in tumor initiation is lacking. Here we have employed loss-of-function analysis in human epithelial cells for a detailed investigation of the contribution of RASSF1 to cell cycle progression. We found that RASSF1A has dual opposing regulatory connections to G(1)/S phase cell cycle transit. RASSF1A associates with the Ewing sarcoma breakpoint protein, EWS, to limit accumulation of cyclin D1 and restrict exit from G(1). Surprisingly, we found that RASSF1A is also required to restrict SCF(betaTrCP) activity to allow G/S phase transition. This restriction is required for accumulation of the anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 and the concomitant block of APC/C-dependent cyclin A turnover. The consequence of this relationship is inhibition of cell cycle progression in normal epithelial cells upon RASSF1A depletion despite elevated cyclin D1 concentrations. Progression to tumorigenicity upon RASSF1A gene inactivation should therefore require collaborating genetic aberrations that bypass the consequences of impaired APC/C regulation at the G(1)/S phase cell cycle transition.

Targeting B-lymphocyte stimulator/B-cell activating factor and a proliferation-inducing ligand in hematologic malignancies.

B-lymphocyte stimulator/B-cell activating factor (BLyS/BAFF) and a proliferation-inducing ligand (APRIL), members of the tumor necrosis family of ligands, are expressed by monocytes, macrophages, and dendritic cells, and increased expression of these ligands is noted in lymphomas and plasma cell malignancies. BLyS and APRIL are essential for the survival of normal and malignant B lymphocytes, and altered expression of BLyS or APRIL or the receptors B-cell maturation, transmembrane activator and calcium-modulating cyclophilin ligand interactor, or BAFF-R have been reported in various B-cell malignancies, including B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, Hodgkin's lymphoma, multiple myeloma, and Waldenstrom's macroglobulinemia. Levels of BLyS (in the tumor and in the serum) increased with the transformation of the tumors to a more aggressive phenotype. A high BLyS level inversely correlated with a poor median overall survival, presence of constitutional symptoms, and increased levels of lactate dehydrogenase in patients with non-Hodgkin's lymphoma. Additionally, patients who responded to therapy had a lower BLyS level than those with progressive disease. Several agents targeting BLyS and APRIL are currently being pursued in phase I clinical studies in patients with B-cell malignancies.

Selective blockade of vascular endothelial growth factor receptor 2 with an antibody against tumor-derived vascular endothelial growth factor controls the growth of human pancreatic adenocarcinoma xenografts.

BACKGROUND: Vascular endothelial growth factor (VEGF), a key regulator of angiogenesis, is critical for growth of human pancreatic adenocarcinoma. Preclinical studies demonstrate that blockade of VEGF activity can control the growth of pancreatic tumors in mice. In this study, we evaluated the efficacy of 2C3, an antibody that inhibits VEGF receptor 2 activation by human VEGF, to inhibit the growth of human pancreatic adenocarcinoma in mice. METHODS: Human pancreatic cancer cell lines (MiaPaca-2, Panc-1, and Capan-1) were used to establish xenografts in nu/nu mice. The expression of VEGF and its receptors was determined in each cell line. Proliferation of tumor cells in vitro and tumor growth in vivo in the presence of 2C3 or a control antibody was evaluated. The effect of 2C3 on tumor weight, total vessel density, number of pericyte-associated vessels, and tumor perfusion was determined, and the level of 2C3 in the serum of animals was measured by enzyme-linked immunosorbent assay. RESULTS: 2C3 did not affect the proliferation of cells in culture. 2C3 was present and active in the serum of tumor-bearing animals treated with 2C3, and these animals showed a decrease in tumor burden compared with control-treated mice. Therapy with 2C3 resulted in reduced vascular function, measured by a decrease in vessel density and in the percentage of vessels associated with pericytes. Furthermore, tumors derived from Capan-1 cells demonstrated decreased perfusion after treatment with 2C3. CONCLUSIONS: Blockade of VEGF receptor 2 activation by tumor-derived VEGF decreases tumor vessel function and growth of some human pancreatic adenocarcinoma cell lines in mice.

Bcl-2 gene expression as a predictor of outcome in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with a 5-year survival rate of 35%-60%. Various clinical factors included in the International Prognostic Index have failed to identify the patients with DLBCL who will not benefit from the standard R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab) treatment regimen. Bcl-2 has been implicated in conferring resistance to chemotherapy in non-Hodgkin's lymphoma and is therefore a candidate prognostic marker in DLBCL. To identify the correlation between Bcl-2 expression and response to rituximab-containing treatment regimens, histologic materials were analyzed from 292 elderly patients with confirmed DLBCL. Of these, 155 patients had received R-CHOP (53%) and 137 had received CHOP (47%). One hundred ninety-three patients (66%) were found to express high levels of Bcl-2 protein in > 50% of the tumor cells. Of the 193 Bcl-2-positive patients, the patients who received R-CHOP had a better 5-year overall rate than patients treated with CHOP (56% vs. 42%; P = 0.01), whereas in the patients with Bcl-2-negative disease, there was no statistically significant difference in the 5-year overall survival rates between the R-CHOP and CHOP regimens (58% vs. 52%; P = 0.6). Therefore, the addition of rituximab to the standard chemotherapy regimen seems to have overcome the Bcl-2-associated resistance to chemotherapy.

The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation.

The RASSF1A locus at 3p21.3 is epigenetically inactivated at high frequency in a variety of solid tumors. Expression of RASSF1A is sufficient to revert the tumorigenicity of human cancer cell lines. We show here that RASSF1A can induce cell cycle arrest by engaging the Rb family cell cycle checkpoint. RASSF1A inhibits accumulation of native cyclin D1, and the RASSF1A-induced cell cycle arrest can be relieved by ectopic expression of cyclin D1 or of other downstream activators of the G(1)/S-phase transition (cyclin A and E7). Regulation of cyclin D1 is responsive to native RASSF1A activity, because RNA interference-mediated downregulation of endogenous RASSF1A expression in human epithelial cells results in abnormal accumulation of cyclin D1 protein. Inhibition of cyclin D1 by RASSF1A occurs posttranscriptionally and is likely at the level of translational control. Rare alleles of RASSF1A, isolated from tumor cell lines, encode proteins that fail to block cyclin D1 accumulation and cell cycle progression. These results strongly suggest that RASSF1A is an important human tumor suppressor protein acting at the level of G(1)/S-phase cell cycle progression.