Management of prostate cancer patients following radiation therapy after radical surgery referred from urology to radiation oncology departments in Spain

Abstract

Purpose

To define usual clinical management of prostate cancer (PCa) patients following postoperative radiation therapy (RT) (adjuvant or salvage) and its evolution over time in radiation oncology (RO) departments in Spain.

Methods

An epidemiological, cross-sectional, multicentre study was conducted. 567 PCa patients that had undergone radical prostatectomy (RP) and received postoperative RT between February and December of both 2006 and 2011 participated in the study. In patients from 2006, health-related quality of life (HRQoL) was assessed using the EPIC questionnaire. Investigators completed a specific survey on two clinical cases of adjuvant and salvage RT.

Results

70.6 % of patients received salvage RT versus 29.4 % who received adjuvant RT; no significant differences were found in terms of frequency for each procedure between both the years. Regarding the survey, a positive surgical margin was the main criteria used in adjuvant RT decision making. In terms of salvage RT scenario, 85.7 % of the investigators stated that adjuvant RT should have been offered instead, 81.4 % of the investigators agreed on a PSA score >0.2 ng/mL as the main criteria for identifying biochemical recurrence after RP, and 67.4 % of investigators did not consider any PSA score for ruling out salvage RT treatment.

Conclusions

Most patients are referred to RO departments to receive salvage RT. Despite the publication of three IA evidence level randomized clinical trials, the patterns for using adjuvant and salvage RT did not change from 2006 to 2011, although patients’ profile did. A consensus regarding postoperative RT indications should be reached in order to correct this controversial situation.

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Immunomodulatory effects of radiation: what is next for cancer therapy?

Future Oncology Ahead of Print.


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Role of ATDC in Bladder Cancer

Bladder cancer is a common and deadly malignancy but its treatment has advanced little due to poor understanding of the factors and pathways that promote disease. ATDC/TRIM29 is a highly expressed gene in several lethal tumor types, including bladder tumors, but its role as a pathogenic driver has not been established. Here we show that overexpression of ATDC in vivo is sufficient to drive both noninvasive and invasive bladder carcinoma development in transgenic mice. ATDC-driven bladder tumors were indistinguishable from human bladder cancers, which displayed similar gene expression signatures. Clinically, ATDC was highly expressed in bladder tumors in a manner associated with invasive growth behaviors. Mechanistically, ATDC exerted its oncogenic effects by suppressing miR-29 and subsequent upregulation of DNMT3A, leading to DNA methylation and silencing of the tumor suppressor PTEN. Taken together, our findings established a role for ATDC as a robust pathogenic driver of bladder cancer development, identified downstream effector pathways, and implicated ATDC as a candidate biomarker and therapeutic target. Cancer Res; 75(23); 5155–66. ©2015 AACR.

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New Roles for p53 in Breast Cancer

The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor-derived factor prostaglandin E2, inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer. Cancer Res; 75(23); 5001–7. ©2015 AACR.

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Selective Inhibitor for CBP/p300 Bromodomains

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein–protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. Cancer Res; 75(23); 5106–19. ©2015 AACR.

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Macrophages as Effector Cells in mAb Therapy

Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as mAbs, that bind to tumor-associated antigens. Subsequently, mAbs can use a wide range of effector functions that mostly engage the immune system. mAbs can bridge immune effector cells with tumor cells, which can result in antibody-dependent cytotoxicity. Increasing evidence, however, identified macrophages as prominent effector cells and induction of antibody-dependent cell phagocytosis as one of the primary mechanisms of action mediated by mAbs. Macrophages are extremely effective in eliminating tumor cells from the circulation. Several immunosuppressive mechanisms may, however, hamper their function, particularly in solid malignancies. In this review, we discuss the evolving insight of macrophages as effector cells in mAb therapy and address novel (co)therapeutic strategies that may be used to fully unleash their cytotoxic capacity for the treatment of cancer. Cancer Res; 75(23); 5008–13. ©2015 AACR.

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Immunoregulatory Proteins Predict Outcome of Ipilimumab Treatment

Treatment with ipilimumab improves overall survival (OS) in patients with metastatic melanoma. Because ipilimumab targets T lymphocytes and not the tumor itself, efficacy may be uniquely sensitive to immunomodulatory factors present at the time of treatment. We analyzed serum from patients with metastatic melanoma (247 of 273, 90.4%) randomly assigned to receive ipilimumab or gp100 peptide vaccine. We quantified candidate biomarkers at baseline and assessed the association of each using multivariate analyses. Results were confirmed in an independent cohort of similar patients (48 of 52, 92.3%) treated with ipilimumab. After controlling for baseline covariates, elevated chemokine (C-X-C motif) ligand 11 (CXCL11) and soluble MHC class I polypeptide–related chain A (sMICA) were associated with poor OS in ipilimumab-treated patients [log10 CXCL11: HR, 1.88; 95% confidence interval (CI), 1.14–3.12; P = 0.014; and log10 sMICA quadratic effect P = 0.066; sMICA (≥ 247 vs. 247): HR, 1.75; 95% CI, 1.02–3.01]. Multivariate analysis of an independent ipilimumab-treated cohort confirmed the association between log10 CXCL11 and OS (HR, 3.18; 95% CI, 1.13–8.95; P = 0.029), whereas sMICA was less strongly associated with OS [log10 sMICA quadratic effect P = 0.16; sMICA (≥247 vs. 247): HR, 1.48; 95% CI, 0.67–3.27]. High baseline CXCL11 and sMICA were associated with poor OS in patients with metastatic melanoma after ipilimumab treatment but not vaccine treatment. Thus, pretreatment CXCL11 and sMICA may represent predictors of survival benefit after ipilimumab treatment as well as therapeutic targets. Cancer Res; 75(23); 5084–92. ©2015 AACR.

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