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Background: Delays in time to treatment initiation (TTI) for new cancer diagnoses cause patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of increased TTI and association with overall survival. Methods and findings: We utilized prospective data from the National Cancer Database for newly diagnosed United States patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004–13. TTI was defined as days from diagnosis to first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (N = 363,863), renal (N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 to 29 days (P<0.001). Aside from year of diagnosis, determinants of increased TTI included care at academic center, race, education, prior history of cancer, transfer of facility, comorbidities and age. Increased TTI was associated with worsened survival for stages I and II breast, lung, renal and pancreas cancers, and stage I colorectal cancers, with hazard ratios ranging from 1.005 (95% confidence intervals [CI] 1.002–1.008) to 1.030 (95% CI 1.025–1.035) per week of increased TTI. Conclusions: TTI has lengthened significantly and is associated with absolute increased risk of mortality ranging from 1.2–3.2% per week in curative settings such as early-stage breast, lung, renal and pancreas cancers. Studies of interventions to ease navigation and reduce barriers are warranted to diminish potential harm to patients. [ABSTRACT FROM AUTHOR]

The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with “surrogate” anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development. Therefore, mouse models that allow concomitant evaluation of drug efficacy and safety are highly desirable. The C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for tumor-targeted and immuno-oncology therapeutics, with multiple mouse immunization-derived antibodies undergoing clinical trials. Given the pleiotropic role of CXCR4 in cancer biology, we anticipate continuous interest in this target, particularly in the testing of therapeutic combinations for immuno-oncology. Here, we describe the generation and validation of the first mouse knock-in of the whole coding region of human CXCR4. Homozygous human CXCR4 knock-in (hereafter designated as HuCXCR4KI) mice were viable and outwardly healthy, reproduced normally and nursed their young. The expression pattern of human CXCR4 in this model was similar to that of CXCR4 expression in normal human tissues. The human CXCR4 knock-in gene was expressed as a biologically active protein, thereby allowing normal animal development and adequate”homing” of leukocytes to the bone marrow. To further validate our model, we used an in vivo functional assay of leukocyte mobilization from bone marrow to peripheral blood by blocking CXCR4 signaling. Both an anti-human CXCR4 -specific blocking antibody and the small molecule CXCR4 inhibitor AMD3100 induced increased leukocyte counts in peripheral blood, whereas an anti-mouse CXCR4 –specific blocking antibody had no effect. This new mouse model is useful to evaluate efficacy and safety of anti-human CXCR4 -specific drugs as single agents or in combination therapies, particularly in the oncology, immuno-oncology, wound healing and chronic inflammation therapeutic areas. [ABSTRACT FROM AUTHOR]