Bladder cancer remains a leading cause of cancer death worldwide and is associated with substantial impacts on patient quality of life, morbidity, mortality, and cost to the healthcare system. Gross hematuria frequently precedes the diagnosis of bladder cancer. Non-muscle-invasive bladder cancer (NMIBC) is managed initially with transurethral resection of a bladder tumor (TURBT), followed by a risk stratified approach to adjuvant intravesical therapy (IVe), and is associated with an overall survival of 90%. However, cure rates remain lower for muscle invasive bladder cancer (MIBC) owing to a variety of factors. NMIBC and MIBC groupings are heterogeneous and have unique pathological and molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers and luminal and basal molecular subtypes of MIBC with distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) is the gold standard treatment for high grade and high risk NMIBC to reduce or prevent both recurrence and progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. IVe gene therapy and combination IVe chemotherapy have recently been completed, with promising results. For localized MIBC, essential goals are improving care and reducing morbidity following cystectomy or bladder preserving strategies. In metastatic disease, advances in understanding of the genomic landscape and tumor microenvironment have led to the implementation of immune checkpoint inhibitors, targeted treatments, and antibody-drug conjugates. Defining better selection criteria to identify the patients most likely to benefit from a specific treatment is an urgent need.

Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms ‘BRAF,’ ‘mutation,’ and ‘cancer/tumor.’ These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression.

BACKGROUND The presence of lymph node metastasis is a poor prognostic sign for patients with prostate carcinoma. Results of published reports on survival among patients with lymph node metastasis are difficult to assess because of treatment selections. The extent to which lymph node status will have an impact on a patient's survival is uncertain. METHODS The authors analyzed 3463 consecutive Mayo Clinic patients who underwent radical prostatectomy and bilateral pelvic lymphadenectomy for prostate carcinoma between 1987 and 1993. Of these patients, 322 had lymph node metastasis at the time of surgery, and 297 lymph node positive patients also received adjuvant hormonal therapy within 90 days of surgery. The progression free rate and the cancer specific survival rate were used as outcome endpoints in univariate and multivariate Cox proportional hazards models. The median follow‐up was 6.3 years. Progression was defined by elevation of serum prostate specific antigen (PSA) ≥ 0.4 ng/mL after surgery, development of local recurrence, or distant metastasis documented by biopsy or radiographic examination. RESULTS The 5‐year and 10‐year progression free survival rates (± standard error [SE]) for patients with lymph node metastasis were 74% ± 2% and 64% ± 3%, respectively, compared with 77% ± 1% and 59% ± 2%, respectively, for patients without lymph node metastasis. The 5‐year and 10‐year cancer specific survival rates were 94% ± 1% and 83% ± 4%, respectively, compared with 99% ± 0.1% and 97% ± 0.5%, respectively, for patients without lymph node metastasis. Among patients with a single lymph node metastasis, the 5‐year and 10‐year cancer specific survival rates were 99% ± 1% and 94% ± 3%, respectively. After adjustment for extraprostatic extension, seminal vesicle invasion, Gleason grade, surgical margins, DNA ploidy, preoperative serum PSA concentration, and adjuvant therapy, the hazard ratio for death from prostate carcinoma among patients with a single lymph node metastasis compared with patients who were without lymph node metastasis was 1.5 (95% confidence interval, 0.5–5.0; P = 0.478), whereas the hazard ratio for death from prostate carcinoma was 6.1 (95% confidence interval, 1.9–19.6; P = 0.002) for those with two positive lymph nodes and 4.3 (95% confidence interval, 1.4–13.0; P = 0.009) for those with three or more positive lymph nodes. There was no significant difference in the progression free survival rate among patients with or without lymph node metastasis in multivariate analysis after controlling for all relevant variables, including treatments (hazard ratio,1.0; 95% CI, 0.7–1.3; P = 0.90). CONCLUSIONS Patients with prostate carcinoma who have multiple regional lymph node metastases had increased risk of death from disease, whereas patients with single lymph node involvement appeared to have a more favorable prognosis after radical prostatectomy and immediate adjuvant hormonal therapy. Excellent local disease control was achieved by using combined surgery and adjuvant hormonal therapy in patients with positive lymph nodes. Cancer 2001;91:66–73. © 2001 American Cancer Society.

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

Around 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.