Sima Porten

Identification of Distinct Basal and Luminal Subtypes of Muscle-Invasive Bladder Cancer with Different Sensitivities to Frontline Chemotherapy

Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.

Outcomes of Active Surveillance for Men With Intermediate-Risk Prostate Cancer

PURPOSE Active surveillance (AS) is an option for the initial management of early-stage prostate cancer. Current risk stratification schema identify patients with low-risk disease who are presumed to be most suitable for AS. However, some men with higher risk disease also elect AS; outcomes for such men have not been widely reported. PATIENTS AND METHODS Men managed with AS at University of California, San Francisco, were classified as low- or intermediate-risk based on serum prostate-specific antigen (PSA), Gleason grade, extent of biopsy involvement, and T stage. Clinical and demographic characteristics, and progression in terms of Gleason score, PSA kinetics, and active treatment were compared between men with low- and intermediate-risk tumors. RESULTS Compared to men with low-risk tumors, those with intermediate-risk tumors were older (mean, 64.9 v 62.3 years) with higher mean PSA values (10.9 v 5.1 ng/mL), and more tumor involvement (mean, 20.4% v 15.3% positive biopsy cores; all P < .01). Within 4 years of the first positive biopsy, the clinical risk group did not differ in terms of the proportions experiencing progression-free survival, (low [54%] v intermediate [61%]; log-rank P = .22) or the proportions who underwent active treatment (low [30%] v intermediate [35%]; log-rank P = .88). Among men undergoing surgery, none were node positive and none had biochemical recurrence within 3 years. CONCLUSION Selected men with intermediate-risk features be appropriate candidates for AS, and are not necessarily more likely to progress. AS for these men may provide an opportunity to further reduce overtreatment of disease that is unlikely to progress to advanced cancer.

Changes in Prostate Cancer Grade on Serial Biopsy in Men Undergoing Active Surveillance

PURPOSE Active surveillance is now considered a viable treatment option for men with low-risk prostate cancer. However, little is known regarding changes in Gleason grade on serial biopsies over an extended period of time. PATIENTS AND METHODS Men diagnosed with prostate cancer between 1998 and 2009 who elected active surveillance as initial treatment, with 6 or more months of follow-up and a minimum of six cores at biopsy, were included in analysis. Upgrading and downgrading were defined as an increase or decrease in primary or secondary Gleason score. Means and frequency tables were used to describe patient characteristics, and treatment-free survival rates were determined by life-table product limit estimates. RESULTS Three hundred seventy-seven men met inclusion criteria. Mean age at diagnosis was 61.9 years. Fifty-three percent of men had prostate-specific antigen of 6 ng/mL or less, and 94% had Gleason score of 6 or less. A majority of men were cT1 (62%), had less than 33% of biopsy cores involved (80%), and were low risk (77%) at diagnosis. Median number of cores taken at diagnostic biopsy was 13, mean time to follow-up was 18.5 months, and 29% of men had three or more repeat biopsies. Overall, 34% (129 men) were found to have an increase in Gleason grade. The majority of men who experienced an upgrade (81%) did so by their second repeat biopsy. CONCLUSION A proportion of men experience an upgrade in Gleason score while undergoing active surveillance. Men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation.

Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy

PURPOSE We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy. MATERIALS AND METHODS We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings. RESULTS We identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p <0.001). Survival outcomes were confirmed in the validation subset. On final pathology 49.2% of low risk patients had disease up staged. CONCLUSIONS The 5-year disease specific survival of low risk patients was greater than 80%, supporting the distinction of high risk and low risk muscle invasive bladder cancer. The presence of high risk features identifies patients with a poor prognosis who are most likely to benefit from neoadjuvant chemotherapy, while many of those with low risk disease can undergo surgery up front with good expectations and avoid chemotherapy associated toxicity.

The Relationship Between Prostate Specific Antigen Change and Biopsy Progression in Patients on Active Surveillance for Prostate Cancer

PURPOSE We assessed whether an association exists between a change in prostate specific antigen and biopsy progression in men on active surveillance. MATERIALS AND METHODS A cohort of patients undergoing active surveillance for prostate cancer was identified from the urological oncology database at our institution. Multivariate logistic regression was performed to determine whether prostate specific antigen velocity, defined as the change in ln(prostate specific antigen) per year, is associated with biopsy progression, defined as a Gleason upgrade or volume progression on repeat biopsy within 24 months of diagnosis. RESULTS A total of 241 men with a mean ± SD age of 61 ± 7 years and mean prostate specific antigen 4.9 ± 2.2 ng/ml met study inclusion criteria. Median time to repeat biopsy was 10 months (IQR 6-13). Biopsy progression developed in 55 men (23%), including a Gleason score upgrade in 46 (19%), greater than 33% positive cores in 11 (5%) and greater than 50% maximum single core positive in 12 (5%). The median prostate specific antigen ratio per year was 1.0 (IQR 0.95-1.03), although 1 man had a ratio of greater than 1.26 (doubled over 3 years) and 7 had a ratio of less than 1/1.26 (halved over 3 years). On multivariate analysis prostate specific antigen doubling within 3 years was associated with a 1.4-fold increase in the odds of biopsy progression (OR 1.4, 95% CI 0.6-3.4, p = 0.46). CONCLUSIONS There is little change in prostate specific antigen during the first 24 months of surveillance in men with well staged, low risk prostate cancer. We believe that these findings highlight the importance of repeat biopsy during surveillance.

Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma

High‐grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. The authors compared the survival rates of patients with UTUC who received neoadjuvant chemotherapy before surgery with the rates among patients who did not.

A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naïve Urothelial Cancer is Predictive of Clinical Outcomes from Neoadjuvant Chemotherapy: A Phase 2 Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin with Bevacizumab in Urothelial Cancer

BACKGROUND Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. OBJECTIVE To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. DESIGN, SETTING, AND PARTICIPANTS Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. RESULTS AND LIMITATIONS Chemotherapy was active, with pT0N0 and ≤pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p=0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ≤ 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p=0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP. CONCLUSION GEP was predictive of clinical UC outcomes. The basal subtype was associated with better survival, and the p53-like subtype was associated with bone metastases and chemoresistant disease. PATIENT SUMMARY We can no longer think of urothelial cancer as a single disease. Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy.

Diabetic Kidney Stone Formers Excrete More Oxalate and Have Lower Urine pH Than Nondiabetic Stone Formers

PURPOSE The epidemiological relationship between nephrolithiasis and type 2 diabetes mellitus is well-known. Patients with diabetes mellitus are at increased risk for nephrolithiasis and those with nephrolithiasis are at risk for diabetes mellitus. We examined 24-hour urine composition in stone formers with and without diabetes mellitus. MATERIALS AND METHODS We retrospectively reviewed a database of 462 stone forming patients to examine the relationship between hypertension and 24-hour urine composition. Multivariate linear regression models were adjusted for age, race, gender, body mass index, hypertension, relevant medications and 24-hour urine constituents. RESULTS On univariate analysis diabetic patients had significantly greater urine volume than nondiabetic patients (2.5 vs 2.1 l daily, p = 0.004). Those with diabetes mellitus also excreted less daily potassium (61.1 vs 68.8 mEq, p = 0.04), phosphate (0.84 vs 1.0 gm, p = 0.002) and creatinine (1405.5 vs 1562.8 mg, p = 0.03), and had significantly lower daily urine pH (5.78 vs 6.09, p <0.001) and CaP supersaturation (0.49 vs 1.20, p <0.001) than nondiabetic patients. On multivariate analysis compared to patients without diabetes mellitus those with type II diabetes mellitus had significantly lower urine pH (-0.34, 95% CI -0.48 to -0.21) and significantly greater urine oxalate (6.43 mg daily, 95% CI 1.26 to 11.60) and volume (0.38 l daily, 95% CI 0.13 to 0.64). CONCLUSIONS Results show that of stone formers patients with type II diabetes mellitus excrete significantly greater urinary oxalate and significantly lower urine pH than those without diabetes mellitus. These findings are important for treating nephrolithiasis since they may influence dietary counseling, medical management and stone prevention.

Prevalence and severity of undiagnosed urinary incontinence in women.

BACKGROUND Urinary incontinence is a highly prevalent condition in aging women that results in significant morbidity. Less than half of women who suffer from urinary incontinence seek treatment, resulting in a significant proportion of clinically relevant urinary incontinence remaining undiagnosed. Therefore, the purpose of this study was to quantify the prevalence of urinary incontinence in undiagnosed women in a managed care population. METHODS There were 136,457 women aged 25-80 years enrolled in Kaiser Permanente Northwest who were free of genitourinary diagnoses, including urinary incontinence, who were included in this study. Of the 2118 women who were mailed questionnaires ascertaining information on demographic and urinary incontinence characteristics, 875 completed the survey. A chart review of the 234 women who reported moderate to severe urinary incontinence was performed. RESULTS The prevalence of undiagnosed urinary incontinence was 53% in the preceding year, and 39% in the preceding week. The prevalence of undiagnosed stress, mixed, and urge incontinence was found to be 18.7%, 12.0%, and 6.8%, respectively. Quality of life was found to significantly decrease with increasing urinary incontinence severity. Of the 234 chart-reviewed women, 5% were found to have physician-documented urinary incontinence. CONCLUSIONS These results suggest that a significant proportion of women in this managed care population are suffering from urinary incontinence that remains undiagnosed. Efforts should be made to encourage women and physicians to initiate conversations about urinary incontinence symptoms in order to decrease the unnecessary burden of this disease.

The independent value of tumour volume in a contemporary cohort of men treated with radical prostatectomy for clinically localized disease

Study Type – Prognosis (case series)
 Level of Evidence 4