Elizabeth A. Guancial

FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder

While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle‐invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle‐invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin‐fixed paraffin‐embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild‐type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle‐invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon.

Estrogen receptor α in cancer-associated fibroblasts suppresses prostate cancer invasion via modulation of thrombospondin 2 and matrix metalloproteinase 3

The prostate cancer (PCa) microenvironment contains active stromal cells known as cancer-associated fibroblasts (CAF) that may play important roles in influencing tumor progression. Here we studied the role of CAF estrogen receptor alpha (ERα) and found that it could protect against PCa invasion. Immunohistochemistry on prostatectomy specimens showed that PCa patients with ERα-positive stroma had a significantly lower risk for biochemical recurrence. In vitro invasion assays further confirmed that the stromal ERα was able to reduce PCa cell invasion. Dissection of the molecular mechanism revealed that the CAF ERα could function through a CAF-epithelial interaction via selectively upregulating thrombospondin 2 (Thbs2) and downregulating matrix metalloproteinase 3 (MMP3) at the protein and messenger RNA levels. Chromatin immunoprecipitation assays further showed that ERα could bind to an estrogen response element on the promoter of Thbs2. Importantly, knockdown of Thbs2 led to increased MMP3 expression and interruption of the ERα mediated invasion suppression, providing further evidence of an ERα-Thbs2-MMP3 axis in CAF. In vivo studies using athymic nude mice injected with CWR22Rv1 (22Rv1) PCa epithelial cells and CAF cells ± ERα also confirmed that mice coimplanted with PCa cells and CAF ERα+ cells had less tumor foci in the pelvic lymph nodes, less metastases, and tumors showed less angiogenesis, MMP3, and MMP9 (an MMP3 downstream target) positive staining. Together, these data suggest that CAF ERα could play protective roles in suppressing PCa metastasis. Our results may lead to developing new and alternative therapeutic approaches to battle PCa via controlling ERα signaling in CAF.

Bladder cancer in the elderly patient: challenges and solutions

Bladder cancer (BC) is an age-associated malignancy with increased prevalence in the elderly population. Elderly patients are a vulnerable population at increased risk for treatment-related toxicity secondary to medical comorbidities and geriatric syndromes. As a result, this population has been historically undertreated and suffers worse disease-specific outcomes than younger patients with BC. Recognition of this disparity has led to efforts to individualize treatment decisions based on functional status rather than chronologic age in an effort to optimize the use of curative therapies for the fit elderly and modify treatments to reduce the risk of toxicity and disease-related morbidity in vulnerable or frail patients. The comprehensive geriatric assessment is a decision framework that helps to balance underlying health considerations and risks of therapy with aggressiveness of the cancer. Development of systemic therapies with increased efficacy against BC and reduced toxicity are eagerly awaited, as are techniques and interventions to reduce the morbidity from surgery and radiation for patients with BC.

HER2 as a target in invasive urothelial carcinoma.

We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum‐based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH‐3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2‐positive tumors expressed higher levels of HER2 mRNA than HER2‐negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH‐3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2‐targeted therapies in UC.

Integrative analysis of 1q23.3 copy-number gain in metastatic urothelial carcinoma

Purpose: Metastatic urothelial carcinoma of the bladder is associated with multiple somatic copy-number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy. Experimental Design: We obtained overall survival (OS) and array DNA copy-number data from patients with metastatic urothelial carcinoma in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by NanoString nCounter to identify transcripts from the region that are associated with copy-number gain. In addition, expression data from an independent cohort were used to identify candidate genes. Results: Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in both cohorts [adjusted HR, 2.96; 95% confidence interval (CI), 1.35–6.48; P = 0.01 and adjusted HR, 5.03; 95% CI, 1.43–17.73; P < 0.001]. The F11R, PFDN2, PPOX, USP21, and DEDD genes, all located on 1q23.3, were closely associated with poor outcome. Conclusions: 1q23.3 copy-number gain displayed association with poor survival in two cohorts of metastatic urothelial carcinoma. The identification of the target of this copy-number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of patients with poor-risk urothelial carcinoma. Prospective validation of the survival association is necessary to demonstrate clinical relevance. Clin Cancer Res; 20(7); 1873–83. ©2014 AACR.

Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study

To describe the management strategies and outcomes of patients with renal medullary carcinoma (RMC) and characterise predictors of overall survival (OS).

Role of copper transporters in platinum resistance.

Platinum (Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1 (CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7A and ATP7B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.

Critical analysis of contemporary clinical research in muscle-invasive and metastatic urothelial cancer: A report from the Bladder Cancer Advocacy Network Clinical Trials Working Group

There have been no improvements in the treatment of metastatic urothelial cancer in the past several decades. A census of contemporary clinical research in this disease was performed to identify potential barriers and opportunities.

Infiltrating T cells promote renal cell carcinoma (RCC) progression via altering the estrogen receptor β-DAB2IP signals

Previous studies indicated the T cells, one of the most common types of immune cells existing in the microenvironment of renal cell carcinoma (RCC), may influence the progression of RCC. The potential linkage of T cells and the estrogen receptor beta (ERβ), a key player to impact RCC progression, however, remains unclear. Our results demonstrate that RCC cells can recruit more T cells than non-malignant kidney cells. Using an in vitro matrigel invasion system, we found infiltrating T cells could promote RCC cells invasion via increasing ERβ expression and transcriptional activity. Mechanism dissection suggested that co-culturing T cells with RCC cells released more T cell attraction factors, including IFN-γ, CCL3 and CCL5, suggesting a positive regulatory feed-back mechanism. Meanwhile, infiltrating T cells may also promote RCC cell invasion via increased ERβ and decreased DAB2IP expressions, and knocking down DAB2IP can then reverse the T cells-promoted RCC cell invasion. Together, our results suggest that infiltrating T cells may promote RCC cell invasion via increasing the RCC cell ERβ expression to inhibit the tumor suppressor DAB2IP signals. Further mechanism dissection showed that co-culturing T cells with RCC cells could produce more IGF-1 and FGF-7, which may enhance the ERβ transcriptional activity. The newly identified relationship between infiltrating T cells/ERβ/DAB2IP signals may provide a novel therapeutic target in the development of agents against RCC.

Fatalism and educational disparities in beliefs about the curability of advanced cancer

OBJECTIVE Understanding socioeconomic disparities in the care of patients with incurable cancer is a high priority. We hypothesized that patients without a high school education are more likely to believe that they could be cured and we explored the role of fatalism. METHODS We studied 977 patients with advanced, incurable cancer. Two logistic regression analyses were conducted. Model One examined the effect of education on beliefs about curability. Model Two added fatalism. RESULTS The significant association between having less than a high school education and the belief that advanced cancer can be cured (OR=2.55; 95% CI: 1.09-5.96) in Model One was attenuated by 39% and rendered nonsignificant in Model Two. Fatalism was associated with the belief that advanced cancer can be cured. Whites were less likely to believe they could be cured than Blacks and Asians/Pacific Islanders. Beliefs about curability were not associated with income or insurance status. CONCLUSIONS People who do not complete high school are more likely to believe that their advanced cancer is curable, in part because they are more likely to hold fatalistic worldviews. PRACTICE IMPLICATIONS Interventions to help oncologists care for patients with fatalistic beliefs could mitigate socioeconomic disparities in end-of-life care.