Analysis of data from the PALOMA-3 trial confirms the efficacy of palbociclib and offers alternatives for novel assessment of clinical trials.

PURPOSE: There remains a need for novel therapies for patients with metastatic breast cancer (MBC). We explore the use of a novel biomarker of survival that could potentially expedite the testing of novel therapies. METHODS: We applied a tumor regression-growth model to radiographic measurement data from 393 women with MBC enrolled in PALOMA-3 examining efficacy of palbociclib in disease that had progressed on previous endocrine therapy. 261 and 132 women were randomized to fulvestrant plus palbociclib or placebo, respectively. We estimated rates of regression (d) and growth (g) of the sensitive and resistant fractions of tumors, respectively. We compared the median g of both arms. We examined the relationship between g and progression-free and overall survival (OS). RESULTS: As in other tumors, g is a biomarker of OS. In PALOMA-3, we found significant differences in g among patients with tumors sensitive to endocrine therapy but not amongst resistant tumors, emulating clinical trial results. Subgroup analysis found favorable g values in visceral metastases treated with palbociclib. Palbociclib efficacy demonstrated by slower g values was evident early in the trial, twelve weeks after the first 28 patients had been enrolled. CONCLUSION: Values of g, estimated using data collected while a patient is enrolled in a clinical trial is an excellent biomarker of OS. Our results correlate with the survival outcomes of PALOMA-3 and argue strongly for using g as a clinical trial endpoint to help inform go/no-go decisions, improve trial efficiency, and deliver novel therapies to patients sooner.

KRASG12D inhibition in pancreatic cancer: Fas expression facilitates immune clearance.

In an article in this issue of Developmental Cell and in a second paper in Cancer Cell, Mahadevan et al. demonstrate that KrasG12D suppression remodels the immunosuppressive microenvironment of KrasG12D pancreatic cancers, recruits activated CD8+ cytotoxic T cells, and epigenetically upregulates Fas expression in cancer cells, leading to tumor clearance via Fas/FasL-mediated apoptosis.

Tumor Growth Rate Informs Treatment Efficacy in Metastatic Pancreatic Adenocarcinoma: Application of a Growth and Regression Model to Pivotal Trial and Real-World Data.

BACKGROUND: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.

Gemcitabine plus nab-paclitaxel versus FOLFIRINOX for unresected pancreatic cancer: Comparative effectiveness and evaluation of tumor growth in Veterans.

PURPOSE: Advanced, unresectable pancreatic cancer is often treated with either gemcitabine plus nab-paclitaxel (Gem/NabP) or FOLFIRINOX, although these regimens have never been compared in a head-to-head trial. In this study, we compared these two regimens using Veterans Administration (VA) data and evaluated the use of a novel tumor growth formula to predict outcomes. METHODS: We identified 670 Veterans from national VA data with unresected stage II-IV pancreatic adenocarcinoma diagnosed between 2003 and 2016 who were treated with either first-line Gem/NabP or FOLFIRINOX. We compared overall survival (OS) and adverse events by treatment using propensity scores (PS) to account for allocation bias. Using longitudinal CA19-9 biomarker information we then fit the data to a novel tumor growth equation, comparing growth with OS. RESULTS: We found no difference in PS-adjusted (hazard ratio [HR] 1.00; 95% confidence interval [95% CI] 0.84-1.20) or PS-matched (HR: 0.93; 95% CI: 0.76-1.13) OS between the two treatment groups. Tumor growth analysis revealed similar growth parameter values for Gem/NabP and FOLFIRINOX (P = .074 for difference). CONCLUSIONS: Gem/NabP appeared noninferior to FOLFIRINOX for survival outcomes for advanced pancreatic adenocarcinoma based on national VA data. Biomarker-based growth equations may be useful for monitoring treatment response and predicting prognosis for pancreatic cancer.

Two decades of research toward the treatment of locally advanced and metastatic pancreatic cancer: Remarkable effort and limited gain.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is diagnosed at the locally advanced or metastatic stage in approximately 80% of cases. Relative to other tumor types, progress in the treatment of this disease has been painfully slow. While agents targeting DNA repair have proven successful in a subset of patients, the majority of PDACs do not exhibit validated molecular targets. Hence, conventional chemotherapy remains at the forefront of therapy for this disease. In this review, we study two decades of efforts to improve upon the gemcitabine backbone - 67 phase II and III trials enrolling 16,446 patients - that culminated in the approvals of gemcitabine/nab-paclitaxel (Gem/NabP) and FOLFIRINOX. Today, these remain gold standards for the first-line treatment of locally advanced unresectable and metastatic PDAC, while ongoing efforts focus on improving upon the Gem/NabP backbone. Because real world data often do not reflect the data of randomized controlled trials (RCTs), we also summarize the retrospective evidence comparing the efficacy of Gem/NabP and FOLFIRINOX in the first-line setting - 29 studies reporting a median overall survival of 10.7 and 9.1 months for FOLFIRINOX and Gem/NabP, respectively. These values are surprisingly comparable to those reported by the pivotal RCTs at 11.1 and 8.5 months. Finally, there is a paucity of RCT data regarding the efficacy of second-line therapy. Hence, we conclude this review by summarizing the data that ultimately demonstrate a small but significant survival benefit of second-line therapy with Gem/NabP or FOLFIRINOX. Collectively, these studies describe the long journey, the steady effort, and the myriad lessons to be learned from 20 years of PDAC trials to inform strategies for success in clinical trials moving forward.

A Prospective Study of Early Radiation Associated Cardiac Toxicity Following Neoadjuvant Chemoradiation for Distal Esophageal Cancer.

Purpose: This study aimed to prospectively evaluate the early effects of radiation on cardiac structure and function following neoadjuvant chemoradiation for distal esophageal cancer. Methods and Materials: Patients with non-metastatic esophageal cancer who were suitable for tri-modality therapy with concurrent chemoradiotherapy followed by esophagectomy were enrolled. Cardiac magnetic resonance imaging (CMR) was obtained at baseline and 3-5 months following completion of chemoradiation. Standardized myocardial segmentation was used to identify regions on post-treatment CMR with new T2 signal or late gadolinium enhancement (LGE). Pre and post-treatment cardiac function was assessed with quantitative end points including left ventricle end-systolic volume (LSESV). Serum biomarkers of cardiac damage including troponin I, CRP, and BNP were collected at baseline and time of follow-up CMR. Results: A total of 11 patients were enrolled from 2016 to 2018. Patients had clinical stage T2 (18%) and T3 (82%) disease with clinical N0 (27%) and N1 (73%) nodal stage. All patients completed baseline CMR and completed chemoradiotherapy. One patient did not complete follow-up CMR or serum biomarkers and was excluded from the analysis. The median time from completion of chemoradiation to follow-up CMR was 3.9 months. Three out of 10 patients (30%) developed new structural findings of myocardial fibrosis and/or reversible ischemia involving the basal and mid-inferior and inferoseptal walls. In these three patients, the LVESV was significantly increased from baseline following radiation. There were no differences in other quantitative end points or serum biomarkers between the patients with myocardial damage and those without. Conclusions: Our study is the first to our knowledge to prospectively demonstrate radiation associated structural and functional heart damage as early as 3 months following neoadjuvant chemoradiation for distal esophageal cancer. Given the early onset of this subclinical heart damage, strategies should be developed to identify patients at risk for future clinically significant heart toxicity.

Plasma metabolite biomarkers predictive of radiation induced cardiotoxicity.

PURPOSE: Although advancements in cancer treatments using radiation therapy (RT) have led to improved outcomes, radiation-induced heart disease (RIHD) remains a significant source of morbidity and mortality in survivors of cancers in the chest. Currently, there are no diagnostic tests in clinical use due to a lack of understanding of the natural history and mechanisms of RIHD development. Few studies have examined the utility of using metabolomics to prospectively identify cancer survivors who are at risk of developing cardiotoxicity. METHODS: We analyzed plasma and left ventricle heart tissue samples collected from a cohort of male Sprague Dawley (SD) rats that were either sham irradiated or received fractionated doses (9 Gy per day × 5 days) of targeted X-ray radiation to the heart. Metabolomic and lipidomic analyses were utilized as a correlative approach for delineation of novel biomarkers associated with radiation-induced cardiac toxicity. Additionally, we used high-resolution mass spectrometry to examine the metabolomic profiles of plasma samples obtained from patients receiving high dose thoracic RT for esophageal cancer. RESULTS: Metabolic alterations in the rat model and patient plasma profiles, showed commonalities of radiation response that included steroid hormone biosynthesis and vitamin E metabolism. Alterations in patient plasma profiles were used to develop classification algorithms predictive of patients at risk of developing RIHD. CONCLUSION: Herein, we report the feasibility of developing a metabolomics-based biomarker panel that is associated with adverse outcomes of cardiac function in patients who received RT for the treatment of esophageal cancer.

CLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer- and actin-mediated endocytic trafficking.

Chloride intracellular channel 4 (CLIC4) is a mammalian homologue of EXC-4 whose mutation is associated with cystic excretory canals in nematodes. Here we show that CLIC4-null mouse embryos exhibit impaired renal tubulogenesis. In both developing and developed kidneys, CLIC4 is specifically enriched in the proximal tubule epithelial cells, in which CLIC4 is important for luminal delivery, microvillus morphogenesis, and endolysosomal biogenesis. Adult CLIC4-null proximal tubules display aberrant dilation. In MDCK 3D cultures, CLIC4 is expressed on early endosome, recycling endosome and apical transport carriers before reaching its steady-state apical membrane localization in mature lumen. CLIC4 suppression causes impaired apical vesicle coalescence and central lumen formation, a phenotype that can be rescued by Rab8 and Cdc42. Furthermore, we show that retromer- and branched actin-mediated trafficking on early endosome regulates apical delivery during early luminogenesis. CLIC4 selectively modulates retromer-mediated apical transport by negatively regulating the formation of branched actin on early endosomes.

IGF-1 activates a cilium-localized noncanonical Gßγ signaling pathway that regulates cell-cycle progression.

Primary cilia undergo cell-cycle-dependent assembly and disassembly. Emerging data suggest that ciliary resorption is a checkpoint for S phase reentry and that the activation of phospho(T94)Tctex-1 couples these two events. However, the environmental cues and molecular mechanisms that trigger these processes remain unknown. Here, we show that insulin-like growth-1 (IGF-1) accelerates G1-S progression by causing cilia to resorb. The mitogenic signals of IGF-1 are predominantly transduced through IGF-1 receptor (IGF-1R) on the cilia of fibroblasts and epithelial cells. At the base of the cilium, phosphorylated IGF-1R activates an AGS3-regulated Gßγ signaling pathway that subsequently recruits phospho(T94)Tctex-1 to the transition zone. Perturbing any component of this pathway in cortical progenitors induces premature neuronal differentiation at the expense of proliferation. These data suggest that during corticogenesis, a cilium-transduced, noncanonical IGF-1R-Gßγ-phospho(T94)Tctex-1 signaling pathway promotes the proliferation of neural progenitors through modulation of ciliary resorption and G1 length.