bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of topoisomerase II expression and cancer-specific death in patients with surgically resected clear cell renal cell carcinoma.
Authors: Gardner Faithlore Patrice , Joseph Richard Wayne , Serie Daniel , Hilton Tracy W. , Parasramka Mansi , Eckel-Passow Jeanette , Cheville John , Leibovich Bradley C. , Parker Alexander S.
Published: February 2017

446

Background: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. Methods: We identified 947 patients who underwent nephrectomy to treat clinically localized ccRCC between January 16, 1990, and September 27, 2006. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features, we employed Kruskal-Wallis tests and for associations with cancer-specific survival, we generated Cox proportional hazard regression models. Results: HigherTOP2a expression is associated with later stage, higher grade and higher Mayo SSIGN score (all p < 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend < 0.0001). Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.31 95% CI 1.64-3.25; p < 0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ~95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.09 95% CI 1.29-7.40; p = 0.01). Conclusions: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients.
mTOR inhibitor therapy for metastatic sarcomatoid clear cell renal cell carcinoma (ccRCC).
Authors: Bastos Diogo Assed , Voss Martin Henner , Karlo Christoph , Ajeti Albulena , Patil Sujata , Feldman Darren Richard , Molina Ana M. , Motzer Robert John
Published: February 2017

450

Background: Sarcomatoid variant describes a histomorphologic pattern with presence of spindle-cell features that can be seen across all subtypes of RCC. It is associated with an aggressive phenotype and poor prognosis. Outcome to mTOR inhibitor therapy was accessed in patients (pts) with ccRCC with sarcomatoid features. Methods: Patients with metastatic sarcomatoid ccRCC treated with mTOR inhibitors at our center were retrospectively identified. Demographic characteristics and treatment outcome were assessed. Overall response rate (ORR) was determined by formal response criteria (RECIST 1.1). Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: 29 pts were treated with temsirolimus (18) or everolimus (11). Median age was 57 years (53 to 61) and there were 21 male pts (72%). Median number of metastatic sites was 3 (1 to 7) and 18 pts (62%) had ≥ 3 metastatic sites. Distribution between Memorial Sloan-Kettering Cancer Center risk groups was 14% favorable, 72% intermediate, and 14% poor-risk disease. Median number of prior therapies was 1 (0 to 5) and 79% of pts received mTOR inhibitor as ≥ 2nd-line of therapy. Three patients (10.3%) achieved a partial response (PR), 11 (38%) stable disease (SD), and 15 (51.7%) had progressive disease (PD). Tumor shrinkage was observed in 9 pts (31%) and the mean change in tumor burden was +24% (-45% to +100%). Median PFS and OS were 3.4 months (CI: 1.4-5.3) and 8.3 months (CI: 4.8- 17), respectively. Conclusions: OS was poor in this heterogeneous group of pts. Future studies to characterize this variant at a molecular level are warranted and might identify predictive markers for clinical outcome in patients treated with mTOR inhibitors. [Table: see text]
Predicting survival in renal cell carcinoma: The role of quality-of-life assessment.
Authors: Gupta Digant , Braun Donald Peter , Lis Christopher G. , Staren Edgar Donald
Published: February 2017

460

Background: Assessment of quality of life (QoL) with validated instruments has been increasing in the clinical oncology community, but to date few studies have examined its prognostic significance in renal cell carcinoma (RCC). We investigated the association between QoL at presentation and survival in RCC. Methods: A consecutive series of 138 RCC patients treated between January 2001 and December 2009. QoL was evaluated at baseline using EORTC-QLQ-C30 which incorporates 1 global, 5 functional and 8 symptom scales. Scores range from 0-100 with higher scores in the global/functional scales and lower scores in the symptom scales indicating better QoL. Patient survival was the primary endpoint. Cox regression was performed to evaluate the prognostic significance of QoL. Results: Mean age at diagnosis was 53.8 years. 51 patients were newly diagnosed at our hospital, while 87 were previously treated elsewhere. Stage at diagnosis was I, 32; II, 19; III, 32; and IV, 55. Median overall survival was 17.2 months (95% CI: 10.1-24.2 months). QoL scales predictive of survival upon univariate analysis were physical (p=0.003), role (p=0.02), social (p=0.03), fatigue (p=0.02), pain (p=0.03), and constipation (p=0.04). Upon multivariate analyses, after adjusting for age, gender, stage, and treatment history, physical (HR=0.89; 95% CI=0.78, 0.99; p=0.04), social (HR=0.91; 95% CI=0.83, 0.99; p=0.04), fatigue (HR=1.10; 95% CI=1.01, 1.19; p=0.03) and constipation (HR=1.11; 95% CI=1.02, 1.20; p=0.01) scales were significantly associated with survival, such that patients with higher (better) physical and social scores and lower (better) fatigue and constipation scores had better survival. For newly diagnosed patients, physical scale was significant, while for previously treated patients, physical, fatigue, and constipation scales were significant. Conclusions: Baseline QoL elements that reflect specific functional and symptomatic attributes provide useful prognostic information in RCC. Significantly, this held true for physical function for both newly diagnosed and previously treated patients. Such determinations should be considered when designing clinical trials with survival endpoints and may aid decision-making in clinical practice.
Treatment of adenocortical carcinoma: 11-year Birmingham experience.
Authors: Zvirinska Lenka , Tew Alice , Porfiri Emilio
Published: February 2017

462

Background: Due to the lack of prospective randomized phase III trial data, we have analysed patients with ACC treated between 2000 and 2011. Methods: All the patients given Mitotane (standard treatment of ACC in UHB, Birmingham) where extracted from pharmacy database. Results: 23 patients were identified, age 26-74 (median 53). Follow-up for whole group was 14–167m, median 60. Overall survival (OS) was 3-48m, medium 11.1 patient with slowly growing disease is still alive (167m) with 2nd dg of breast cancer. 19 patients were treated for metastatic disease, 4 in adjuvant setting. 7 patients were managed by endocrinologist only (3 adjuvant, 2 poor PS, 1 reluctant to treatment and 1 details unknown). 16 patients were under shared care. 4 these patients were never exposed to chemotherapy (2 poor PS, 1 returned to Africa, died within 5 months, 1 declined chemotherapy, still alive at 16 months post). 6/19 metastatic patients had chemotherapy as 1st treatment (4 patients etoposide/doxorubicin/cisplatin chemotherapy, 1 etoposide/carboplatin, 1 etoposide/cisplatin), 7 were treated with chemotherapy on PD(6 streptozocin, 1 etoposide/doxorubicin/cisplatin, 1 etoposide/cisplatin). There was no significant difference in OS when those approaches were compared (1st group 7-16 m, median 10, 2nd group 3-14, median 11) But TTP has been slightly worse for treatment on PD as expected (1st group 3-13m, median 6.5; 2nd group 3-14, median 3), although might be due to tendency to use Streptozocin, consistant with preliminary published results of FIRMACT trial.3 patients were treated with 2 lines of chemotherapy (age 30,31, 38), TTP 2- 5 m. Adjuvant patients within our sample has been followed up for limited perion only (11 – 71m, median 22.5), however no recurrence was diagnosed so far.In metastatic patient population 4 patients were treated for recurrence with time to relapse 3-43m, medium 23.5. Conclusions: ACC is heterogenic disease as confirmed by our survival data. In unselected population median OS is comparable to FIRMACT. Consistant with literature review, chemotherapy threatment can be delivered as 1st-line or delayed till PD. 2nd-line chemotherapy is of limited efficacy.
Involvement of miRNAs in the formation and maintenance of self-renewing kidney cancer spheres with stem cell properties.
Authors: Lichner Zsuzsanna , Saleh Carol , Subramaniam Venkateshwaran , Prud'homme Gerard , Yousef George M.
Published: February 2017

463

Background: Cancer cells may acquire stem cell (CSC) properties by activated TGFβ-epithelial-mesenchymal transition (EMT) axis resulting in formation of cancer stem cells. miRNAs are involved in CSC formation in solid tumors, but their role has not been investigated in renal cell carcinoma (RCC). Methods: RCC spheres were generated and propagated in serum-free defined medium (SFDM). mRNA expression was assessed by qRT-PCR. miRNA expression was screened on a qRT-PCR based panel. Tumorigenicity was assessed by subcutaneous injection of RCC sphere or parental cells into immunodeficient mice in different dilutions. TargetScan and miRPath was used for target prediction and clustering. Results: We isolated self-renewing cancer spheres from ACHN and CAKI-1 RCC cell lines in the stem cell supporting media, SFDM. Spheres were highly clonogenic and tumorigenic in xenograft tumor model and expressed high levels of stem cell-related markers and mesenchymal markers. These spheres were enriched in the mesenchymal marker CD44 and the kidney progenitor maker CD24 indicating that EMT contributed to their formation or maintenance. We compared miRNA expression between the spheres and the parental cells and identified differentially expressed miRNAs. Functional clustering of their predicted targets indicates that TGFβ signaling is a potential regulator of CSC self-renewal and is regulated by the candidate miRNAs. Further, we show that transfection of ACHN and CAKI-1 cells with the miR-17 inhibitor resulted in rapid and highly efficient formation of cancer spheres that were indistinguishable from the spheres formed in SFDM. These spheres were stable and could be propagated indefinitely. Histologic examination and immunohistochemistry of the sphere-derived xenografts confirmed the presence of clear cell RCC with large areas of sarcomatoid dedifferentiation. Finally, we prove that the TGFβ receptor II, and the co-Smad Smad4 are possible direct targets of miR-17. Conclusions: The TGFβ-EMT axis likely contributes to the self-renewing potential of RCC spheres. miRNAs are differentially expressed in RCC spheres and miR-17 inhibition transformed ccRCC cells to highly tumorigenic RCC spheres.
Fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (a-CGH) from percutaneous needle biopsy compared to renal mass histology.
Authors: Spaliviero Massimiliano , Stratton Kelly Lynn , Donahue Timothy F. , Gowrishankar Banumathy , Ma Charles , Durack Jeremy C. , Solomon Stephen Barnett , Houldsworth Jane , Coleman Jonathan A.
Published: February 2017

471

Background: Image-guided percutaneous needle biopsies are increasingly utilized for the diagnosis of renal tumors. Histologic diagnosis of renal mass subtypes, including malignant clear cell (ccRCC), papillary (pRCC), chromophobe (chrRCC) renal cell carcinoma, and benign oncocytomas (OC) can be challenging due to the low cellularity and damaged architecture of needle biopsy specimens. However, each subtype exhibits unique genetic aberrations that can assist in histologic classification and potentially assist in guiding management decisions. We report our initial experience correlating renal mass histology to subtype-associated genomic alterations detected by FISH and a-CGH of percutaneous needle biopsy specimens. Methods: In an ongoing IRB-approved blinded study, 17 samples obtained from 15 patients with known renal masses were submitted to FISH (FReCaD) and targeted a-CGH (UroGenRA-Kidney). Specimens were classified using a subtype classification decision tree algorithm based on the presence/absence of genomic abnormalities. The results were compared to biopsy histology or surgical specimen when available. Results: Histology revealed ccRCC in 6 patients, pRCC in 4, OC in 2, Angiomyolipoma in 1, and unclassified type RCC in 2. In 6 of 9 cases FISH achieved a diagnosis, which correlated with histology in 4. FISH incorrectly classified as ccRCC two cases with pRCC on histology. A-CGH was diagnostic in 14 of 15 cases and correlated with histology in 13. In one case, a-CGH showed a genomic profile not consistent with ccRCC, pRCC, chrRCC, or OC according to the algorithm. Conclusions: The addition of genetic tumor tissue studies to complement histology from biopsy tissues may supplement or improve the accuracy of classification and biological characterization of renal tumor biopsies and influence treatment planning. In our initial experience, a-CGH showed better correlation with histology in subtype classification of malignant and benign renal masses than FISH. Prospective testing will be required to validate these results.
Use of preoperative C-reactive protein to improve predictive accuracy in clear cell renal cell carcinoma.
Authors: Kruck Stephan , Chun Felix K. , Merseburger Axel S. , Tezval Hossein , Scharpf Marcus , Kasprzyk Kathrin , Schilling David , Sievert Karl-Dietrich , Stenzl Arnulf , Bedke Jens
Published: February 2017

474

Background: White blood cell count (WBC) and C-reactive protein (CRP) are reliable biomarkers in clear cell renal cell carcinoma (ccRCC). Nevertheless, accepted cut-offs values for risk stratifications are missing. This study re-evaluated the prognostic and predictive significance of preoperatively WBC and CRP that independently predicts patient prognosis and to determine optimal cut-off values for CRP. Methods: 327 patients with surgery for ccRCC were retrospectively evaluated from 1996 to 2005. Cox-proportional hazard models were used, adjusted for the effects of tumor stage, tumor size, Fuhrman grade, and Karnofsky-Index; and to evaluate the prognostic significance of WBC and CRP; and to identify cut-off values. Identified cut-offs were correlated with clinico-pathological parameters and used to estimate cancer-speciﬁc survival (CSS). To prove any additional predictive accuracy of the identified cut-off it was compared to a clinico-pathological base model using Harrell c-index. Results: In univariable analyses WBC was a significant prognostic marker at a concentration of 9.5/µl (HR: 1.83) and 11.0/µl (HR: 2.09) and supported a CRP value of 0.25 mg/dL (HR: 6.47, p < 0.001) and 0.5mg/dL (HR: 7.15, p < 0.001) as potential cut-off values. If adjusted by the multivariable models WBC showed no clear breakpoint, but a CRP-value of 0.25mg/dL (HR: 2.80, p = 0.027) proved to be optimal. Reduced CSS was proven for CRP 0.25 mg/dL (median: 69.9 vs. 92.3 months). Median follow-up was 57.5 months with 72 (22%) tumor related deaths. The final model built by the addition of CRP 0.25mg/dL did not improve predictive accuracy (c-index = 0.877) than compared to the clinico-pathological base model (c-index =0.881) which included TNM-stage, grading and Karnofsky-Index. Conclusions: Multivariable analyses revealed an optimal breakpoint of CRP at a value of 0.25mg/dL best to stratify patients at risk of cancer-specific mortality, but CRP 0.25mg/dL added no additional information in the prediction model. Therefore we cannot recommend to measure CRP as the traditional parameters of TNM-stage, grading and Karnofsky-Index were already of high predictive accuracy.
Outcomes of patients with metastatic renal cell cancer treated with sunitinib in clinical practice at a reference cancer centre in Manchester, United Kingdom.
Authors: Galvis Victoria , Lawrence Dionne , Howell Matthew , Thistlethwaite Fiona , Hawkins Robert E.
Published: February 2017

477

Background: The development of anti-angiogenic therapy produced a change in the treatment of metastatic renal cancer (mRCC). There are now a range of drugs available with sunitinib being the most widely used first-line anti-angiogenic therapy. In the United Kingdom, until the advent of pazopanib it was the only such drug routinely funded by the NHS. The aim of this study was to audit the clinical outcomes of patients on routine treatment with sunitinib, to compare them with those obtained on trials and to analyze different subsets of patients. Methods: A database of mRCC patients treated at The Christie was set up to record clinical outcomes. Long-term follow-up data is available. Here we present a detailed analysis of 395 patients treated with sunitinib as a first-line anti-angiogenic therapy from 2005 to 2012. 397 patients treated out of a clinical trial. The outcomes were analysed according to various prognostic features. Results: The median OS of all patients audited was 18 months (m) with a PFS of 10.5m. This included clear cell RCC (n=305) and non-clear cell RCC (n=52). OS of clear cell RCC patients who received treatment second-line after cytokine therapy failure was 20.5m, longer than those treated first line 18.6m. This may be because we offer High-Dose IL2 to selected patients and these patients have a longer OS (24m) measured from the start of sunitinib. Baseline performance status was a predictor of outcome with OS being 23.5m for WHO PS 0/1 and 5.9m for WHO PS 2/3. Elderly age was not a predictor of poor outcome as the OS of patients <60, 60-70, and >70 was 15, 23, and 22m respectively. Time from nephrectomy to treatment with sunitinib had an influence on outcome with OS being 15, 24, and 48m for those <1, 1-5, and >5 years since nephrectomy. Further detailed analysis will be presented. Conclusions: Overall, the outcomes of patients treated in routine clinical practice were very similar to comparable groups treated on trials. Interestingly, the outcome post cytokine patients were particularly good but this may reflect particularly, careful choice of patients who receive cytokines since 2008.
Validation of a genomic classifier that predicts metastatic disease progression in men with biochemical recurrence post radical prostatectomy.
Authors: Ross Ashley E. , Ghadessi Mercedeh , Davicioni Elai , Crisan Anamaria , Buerki Christine , Erho Nicholas , Mitra Anirban Pradip , Thompson Darby J. S. , Triche Timothy J. , Schaeffer Edward M , Feng Felix Yi-Chung
Published: February 2017

52

Background: The majority of the 29,000 men who die annually from prostate cancer present initially with localized disease and develop biochemical recurrence (BCR) following radical prostatectomy (RP). While the post-RP recurrence group of patients is highly enriched for those who will develop lethal disease, many of these patients will experience BCR without subsequent metastases. Thus, there is a clear need to improve patient risk stratification in this context. Here, we evaluate Decipher, a genomic classifier (GC) in men with BCR for its ability to predict metastasis. Methods: The 22-feature GC model was validated in a prospectively designed case-cohort study of a clinically high-risk population of 1,010 RP patients treated at Mayo Clinic between 2000-06. A random sample of 20% of this population was subjected to microarray analysis and GC scores were generated for 219 patients, including 110 who developed BCR post RP. The c-index for predicting metastatic disease progression (i.e., positive bone or CT scans), Cox modeling, decision curves and multivariable analyses were used to compare the performance of GC to Gleason score (GS), PSA doubling time (PSAdT) and time to BCR (ttBCR). Results: The c-index for predicting metastatic disease progression 3 years after BCR was 0.82 (95% CI, 0.80-0.90) for GC, which compared favorably to GS 0.65 (0.54-0.69), PSAdT 0.60 (0.62-0.78) and ttBCR 0.54 (0.64-0.81). Decision curve analysis showed that GC had a higher overall ‘net benefit’ compared to GS, PSAdT and ttBCR for risk of metastasis. Cumulative incidence of metastasis 3 years after BCR was 9% versus 43% (p<0.001) for patients with low and high GC scores, respectively. In multivariable modeling with clinicopathologic variables, GC (p<0.001) and GS (p=0.02) scores remained the only significant predictors of metastasis. Conclusions: When compared to clinicopathologic variables, GC better predicted metastatic progression among our cohort of men with BCR following RP. While confirmatory studies in additional patient populations are required, these results suggest that use of GC can allow for better selection of men requiring additional treatment at the time of BCR.
Image guidance for post-prostatectomy radiotherapy: Are we missing the mark?
Authors: Kalman Noah S. , Banez Lionel L. , Gerber Leah , Moul Judd W. , Anscher Mitchell Steven , Lee W. Robert , Koontz Bridget F.
Published: February 2017

56

Background: Image-guided radiation therapy (IGRT) has been widely adopted for both definitive and post-operative prostate radiotherapy. In the postoperative setting, numerous studies of prostate bed motion have recommended tight planning margins (<10mm) if IGRT is used daily. The purpose of this analysis is to determine the effect of IGRT on the efficacy and toxicity of post-operative prostate radiotherapy. Methods: Between 1998 and 2010, 286 patients received radiation therapy after prostatectomy at Duke. Recurrent disease following radiation therapy was defined as PSA >0.2 ng/ml and rising or initiation of salvage ADT. CTCAE v 4.0 and the RTOG/LENT late morbidity scores were used to grade acute and late toxicities. Risk for biochemical failure and late Grade 2+ GI toxicity were compared between IGRT (N = 113) and non-IGRT (N = 173) patients using multivariable adjusted Cox regression controlling for age, treatment technique (3D vs IMRT), radiation dose, androgen suppression, pathologic Gleason Score, margin status, pathologic stage, and pre-radiotherapy PSA level. Results: The median margin size for patients with IGRT was 7mm (IQR 6-10mm) and 15mm (IQR 7-15mm) for those without IGRT (p < 0.001). Median follow up was 21 months (IQR 15-33 mo) for patients with IGRT and 49 months (IQR 30-73 mo) for those without IGRT (p < 0.001). On multivariate analysis, patients treated with IGRT had a greater risk of progression versus non-daily imaging (HR = 2.51, p < 0.001), as did patients who received salvage versus adjuvant radiotherapy (HR = 2.41, p = 0.005). Higher pathologic Gleason Score (HR = 1.96, p = 0.026) and pathologic stage (HR = 1.93, p = 0.003) conferred increased risk of progression, while positive margin status was protective (HR = 0.53, p = 0.002). Age, radiation dose, androgen suppression, and treatment technique did not affect biochemical outcome (p > 0.1). There were no differences in acute or late GI toxicity according to treatment technique or use of IGRT (both p > 0.1). Conclusions: The use of IGRT was associated with increased biochemical recurrence for patients receiving post-operative prostate radiotherapy. For these patients, we recommend using treatment margins of at least 10mm to address subclinical disease and organ motion.
Prior cancer diagnosis in men with nonmetastatic prostate cancer and the risk of prostate cancer specific and all-cause mortality.
Authors: Mirabeau-Beale Kristina , Chen Ming-Hui , D'Amico Anthony Victor
Published: February 2017

70

Background: We evaluated the impact of a prior diagnosis of cancer on the risk of prostate cancer specific mortality (PCSM) and all cause mortality (ACM) in men with a diagnosis of non-metastatic prostate cancer (PC). Methods: Using the SEER population data registry, 166,104 men (median age: 66 [Interquartile range (IQR): 60 to 73 years]) diagnosed with prostate cancer (PC) between 2004 and 2007 comprised the study cohort. We used a Fine and Grays competing risks and Cox regression to evaluate the impact a prior cancer diagnosis (excluding non-melanoma skin cancer) had on the risk of PCSM and ACM adjusting for PSA level, Gleason score (GS), tumor (T) category, age at and year of diagnosis, race and whether initial treatment received was curative, non-curative or patients underwent active surveillance (AS) or watchful waiting (WW). Prior to the diagnosis of PC, 1,457 malignancies occurred at a median of 4.8 years. Results: After a median follow up of 2.75 years, 12,453 men died: 3,809 (30.6%) from PC. On multivariable analysis, advancing age in years was associated with an increased risk of PCSM as was Gleason score 8 to 10 PC and the use of WW/AS or non-curative therapy (all p values < 0.001). However, men with a prior cancer were significantly older (median age: 72 vs 66 years, p=0.001) and followed longer (median follow up: 3.0 vs 2.75 years, p < 0.001) and were more likely to have high-risk PC (30.1% vs 26.8%, p=0.01) based on the occurrence of Gleason 8 to 10 PC (19.2% vs 15.1%, P < 0.001) and underwent WW or AS more frequently (30.5% vs 22.5%, p<0.001). Despite these findings which would tend toward an increased risk of PCSM in these men, the adjusted risk of PCSM was significantly decreased in these men (Adjusted Hazard Ratio (AHR): 0.66 [95% Confidence Interval (CI): [0.45, 0.97]; p =0.033) while the risk of ACM was increased (AHR: 2.92 [95% CI: 2.64, 3.23]; p < 0.001) suggesting that competing risks and not curative PC treatment may be accounting for the reduction in the risk of PCSM. Conclusions: In men with a malignancy prior to the diagnosis of PC, a careful assessment of life expectancy is needed to decide on whether curative treatment for PC versus WW or AS is appropriate.
Relationship of sipuleucel-T with time to first use of opioid analgesics (TFOA) in patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) on the IMPACT trial.
Authors: Small Eric Jay , Higano Celestia S. , Kantoff Philip W. , Whitmore James Boyd , Frohlich Mark Walter , Petrylak Daniel Peter
Published: February 2017

74

Background: Sipuleucel-T (sip-T) is an autologous cellular immunotherapy which was shown to prolong survival in pts with mCRPC in the pivotal IMPACT trial (NCT00065442) (Kantoff PW et al. N Engl J Med 2010;363:411-22). TFOA was a prespecified secondary end point but was subsequently removed as an end point following a protocol amendment to expand enrollment to include minimally symptomatic pts in addition to asymptomatic pts. TFOA data were nevertheless collected in the 512 pts enrolled in the trial. Methods: At baseline, pts were required to have an average pain score <4 on a 10-point visual analog scale and no ongoing opioid analgesic use (OAU). Concomitant medications were collected until confirmed objective disease progression. OAU was identified by medical review of preferred drug names in the coded concomitant medication information on case report forms (CRFs). OAU unrelated to cancer pain (e.g. meperidine used for infusion reactions) was excluded by medical review of CRFs. Pts not reporting OAU were censored at the time of protocol amendment. TFOA was analyzed using a Cox regression model with adjustment for baseline PSA and LDH. Results: 341 sip-T- and 171 placebo-treated patients were evaluated. Median TFOA was 11.9 months (mo) with sip-T vs 8.3 mo for placebo (hazard ratio=0.727; 95% confidence interval 0.536, 0.987; p=0.041). Censoring rate was high (sip-T, 66.9%; placebo, 61.4%). Median follow-up for OAU was 5.2 mo (sip-T, 5.3 mo; placebo, 5.0 mo). Kaplan-Meier estimates of being opioid free at 12 mo were 48.7% for sip-T vs 39.7% for placebo; curve separation began at 6 mo. Significant independent baseline predictors of shorter TFOA were: higher PSA, alkaline phosphatase; younger age; higher number of bone metastases; Gleason score ≥8; ECOG performance status 1; higher weight; and prior primary radiotherapy. Conclusions: Relative to placebo, sip-T delays the TFOA in patients with asymptomatic or minimally symptomatic mCRPC. Clinical trial information: NCT00065442.
Safety profile of poxviral vaccines: NCI experience.
Authors: Kim Joseph W. , Marte Jennifer L. , Bilusic Marijo , Singh Nishith K. , Heery Christopher Ryan , Madan Ravi Amrit , Pazdur Mary , McMahon Sheri , Rauckhorst Myrna , Schlom Jeffrey , Gulley James L.
Published: February 2017

85

Background: Recombinant poxviruses have been developed as therapeutic cancer vaccines. Here, we report the safety data from NCI clinical trials with poxviral vaccines. Methods: We evaluated all vaccine injections from 215 patients in 8 clinical trials involving poxviral viral vaccines. The Office of Biotechnology Activities, National Cancer Institute (NCI) Institutional Review Board, and NCI Scientific Review Committee approved all of these trials. Vaccines were consisted of recombinant vaccinia and recombinant fowlpox encoded with 3 human costimulatory molecules (TRICOM), and prostate specific antigen (PSA), or carcinoembryonic antigen, and/or mucin-1. Vaccines were administered at doses between 1.2x108 to 2x109 pfu, subcutaneously, in all patients. Twenty-one patients were also vaccinated intra-tumorally. 84 patients also received other concurrent treatment modalities, such as radiation, celecoxib, ipilimumab, samarium-153, or flutamide on 4 of these trials. All 8 clinical trials involved granulocyte-macrophage colony-stimulating factor (GM-CSF) 100mcg, or recombinant fowlpox encoding GM-CSF at 1x 108pfu as an immune adjuvant. Here, we report here the grade 2 or higher adverse events given at least a possible attribution to vaccine. Results: A total of 1,348 poxviral injections were given in 215 patients. No contact transmission, inadvertent inoculation, or any serious adverse events (AEs) related to vaccinia was observed. Below is the summary of proportion of vaccine administrations associated with specific AEs. Conclusions: These data demonstrate a favorable safety profile of the poxviral vaccines at a broad range of doses, routes of administration, in combination with other treatments, and in various tumor types. Clinical trial information: NCT00060528, NCT00096551, NCT00088413, NCT00081848, NCT00113984, NCT00450619, NCT00450463. [Table: see text]
Association of declining PSA values with a lower risk of progression in the Canary Prostate Cancer Active Surveillance Study (PASS).
Authors: Brooks James D. , Brown Elissa C. , Cooperberg Matthew R. , Newcomb Lisa F. , Carroll Peter , Feng Ziding , Gleave Martin Edwin , Lance Raymond , Sanda Martin G. , Thompson Ian Murchie , Wei John Thomas , Nelson Peter , Lin Daniel W.
Published: February 2017

88

Background: Active Surveillance of men with low risk prostate cancer entails uncertainty for the patient and physician in determining risk of progression. While PSA determinations are frequently measured in men on active surveillance, no study thus far has found PSA velocity (PSAV) or PSA doubling times that identify patients at risk for clinical progression. However, based on observations in PASS, we hypothesized that men with negative PSAV might be at decreased risk for progression. Methods: From 723 PASS participants, we identified 396 who had at least 5 PSA values over 12-24 months after their diagnosis and prior to progression or last follow-up. Of the 396 patients, 56 progressed as defined by increase in Gleason score or increase in tumor involvement of the core biopsies to ≥ 34%, or increase in clinical stage while 340 men had no progression. PSAV is the slope of the log(PSA) values over time. ROC analysis was used with PSAV as the predictor of biopsy/clinical progression. Results: PSAV was mildly associated with clinical/biopsy progression with an AUC of 0.62 (95% CI: 0.54-0.70). Interestingly, by thresholding PSAV at 0, 150 of 396 men had negative a PSAV. Subjects with with a negative PSAV had a much lower rate of progression while on active surveillance. PSAV<0 had a negative predictive value for progression of 0.93 (95% CI: 0.88-0.97). The progression rate for those with negative PSA velocity was 11/150 ≈ 0.07, or 7% and 18% (45/246) for those with positive PSA velocity. Viewed another way, men with PSAV<0 had a 0.4 fold relative risk of progression compared to men with a positive PSAV or were 60% less likely to have clinical/grade progression than those with positive PSA velocity (95% CI: 0.21-0.75). Conclusions: Declining PSAV in men on active surveillance for clinically localized prostate cancer is associated with a lower risk of clinical progression. Clinical trial information: NCT00756665.
Long-term health-related quality of life in patients treated for localized prostate cancer.
Authors: Punnen Sanoj , Cowan Janet E. , Carroll Peter , Cooperberg Matthew R.
Published: February 2017

93

Background: Few studies have reported long term quality of life after primary treatment for localized prostate cancer. The objective of this study was report 10 year sexual and urinary quality of life data for men undergoing various treatments in the Cancer of the Prostate Strategy and Research Endeavor database. Methods: Men who have been treated for localized prostate cancer and have baseline and follow up quality of life date made up the study cohort. Primary treatment modalities included radical prostatectomy (RP), external beam radiotherapy (EBRT), brachytherapy (BT), cryotherapy (CT), primary androgen deprivation therapy (ADT), and active surveillance/ watchful waiting (AS/WW). Sexual and urinary quality of life were assessed by the validated UCLA Prostate Cancer Index and measured on a scale from 0-100. Mixed model repeated measures analysis was used to assess the association between primary treatment modality and long term urinary and sexual quality of life. Results: 3, 772 men made up the study cohort. Among all men being treated for prostate cancer the mean urinary function score was 92 at baseline, 76 at 1 year, 81 at 5 years and 77 at 10 years. Urinary bother scores were 84 at baseline, 71 at 1 year, 82 at 5 years, and 78 at 10 years. With respect to sexual function the mean score was 49 at baseline, 23 at 1 year, 29 at 5 years, and 24 at 10 years. Finally, the mean sexual bother score was 59 at baseline, 37 at 1 year, 46 at 5 years, and 47 at 10 years. With respect to quality of life by primary treatment modality most treatments showed a similar pattern of decreased scores in the first year followed by an increased in the following two years and a plateau up to the 10 year mark. EBRT and BT showed a longer decline in sexual and urinary function post treatment while RP scores plateau after 3 years. Conclusions: Men undergoing primary treatment for localized prostate cancer experience declines in sexual and urinary function and bother in the first year which improves after 3 years and plateaus up to 10 years.
Prediction of risk for prostate cancer in histopathologically negative biopsies by multigene epigenetic assay.
Authors: Van Neste Leander , Van Criekinge Wim , Thas Olivier , Bigley Joseph , Stewart Grant Duncan , Harrison David James
Published: February 2017

95

Background: Many men are biopsied for suspicion of prostate cancer (PCa), often based on a serum PSA test, while cancer is missed in up to 30% of the cases due to sampling errors, leading to uncertainty of diagnosis. The diagnostic process is further complicated due to the fear of overtreatment of insignificant PCa. The multi-center MATLOC (Methylation Analysis To Locate Occult Cancer) study confirmed that epigenetic silencing of key genes is a significant predictor of those men with a histologically negative biopsy whose tumor is missed by the biopsy procedure. The epigenetic profile of GSTP1, APC and RASSF1,determined on collected prostatic tissue, resulted in a negative predictive value (NPV) of 90%, identifying a large proportion of men that could forgo repeat biopsy. In current clinical practice, risk factors are intuitively combined to determine the risk that cancer is missed and the need for rebiopsy. Methods: PCa risk factors age, PSA (> 10 ng/mL), DRE (suspicious) and histopathology (HGPIN or atypical cells) were combined with an epigenetic profile to construct a comprehensive metric that improves PCa risk assessment after a negative biopsy. Logistic regression models were fit on a subset of MATLOC with a complete panel of risk factors (n = 391, ncases = 71, prevalence = 18%). These models were subjected to 10-fold cross validation to assess clinical performance. Results: DNA methylation was the strongest predictor (Youden’s J = 0.303) that PCa was missed by biopsy, while PSA was the lowest performing individual marker (J = 0.083). Combinations of risk factors were evaluated, however, only a model including epigenetic profiling and histology of the initial biopsy could improve upon the results of epigenetics alone (J = 0.361). Cross validation resulted in a sensitivity of 74%, a specificity of 63% and a NPV of 91%. Conclusions: Epigenetic profiling is a significant predictor for PCa risk, especially to identify those men who should (not) undergo a repeat biopsy following a negative initial biopsy. An integrated risk management approach that combines epigenetics with other risk factors, most notably histopathology of the cancer-negative initial biopsy, resulted in an improved prediction for the presence of PCa.
Racial differences in survival outcomes among men with localized prostate cancer.
Authors: Lu-Yao Grace L. , Moore Dirk , Lin Yong , Demissie Kitaw , Shih Weichung , Albertsen Peter C. , DiPaola Robert S. , Yao Siu-Long
Published: February 2017

98

Background: This study addresses whether the recent favorable survival trends observed among contemporary prostate cancer patients can be extended to African American men who have historically suffered excess prostate cancer mortality. Methods: The study cohort consisted of men over age 65, who resided in the SEER catchment area and were diagnosed with T1-T2 prostate cancer (ICD-O-3 code C61.9) during the period 1992-2005. In order to quantify race-specific prostate cancer mortality, separate competing risk models were fit separately for Whites and Blacks. Results: This study includes 35,509 white men and 5,256 black men who received conservative management for localized prostate cancer. The median age of the patients is 76 years at diagnosis and the median follow-up is 106 months. Overall, African Americans have slightly higher adjusted prostate cancer mortality than Whites (hazard ratio [HR] =1.16; 95% confidence interval [C.I.] 1.03 – 1.29). The racial difference was more pronounced in men with moderately differentiated cancer (HR=1.24, 95% CI 1.05 – 1.45), compared to poorly differentiated cancer (HR=1.00, 95% C.I. 0.85 – 1.18). Further analyses by comorbidity status and income level revealed that African Americans and Whites have similar excellent prostate cancer survival if they lived in areas with incomes above the median. Conclusions: African Americans diagnosed in the contemporary PSA era have similarly excellent survival outcomes as their white counterparts if they lived in areas with incomes above the median. Further studies should be conducted to confirm these findings and assess care and health habits that may improve cancer control and outcomes among African Americans.
First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC).
Authors: Piccart-Gebhart Martine J. , Holmes Andrew Peter , Baselga Jose , De Azambuja Evandro , Dueck Amylou C. , Viale Giuseppe , Zujewski Jo Anne , Goldhirsch Aron , Santillana Sergio , Pritchard Kathleen I. , Wolff Antonio C. , Jackisch Christian , Lang Istvan , Untch Michael , Smith Ian E. , Boyle Frances , Xu Binghe , Gomez Henry Leonidas , Gelber Richard D. , Perez Edith A.
Published: February 2017

LBA4

Background: Lapatinib (L) is a HER1-HER2 tyrosine kinase inhibitor. The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial is a randomised, phase III trial comparing 3 oral L-containing regimens with T, each given for 1 year. Methods: From June 2007 to July 2011, 8381 patients (pts) were randomised from 946 sites in 44 countries to receive either L+T, T→L, L, or T. Anti-HER2 therapy was initiated after completing all chemotherapy (N=4613), concurrently with a taxane following anthracycline (N=3337), or concurrently with a non-anthracycline, platinum-containing regimen (N=431). The L arm was closed in Aug 2011 for futility and is not presented. The primary endpoint is invasive disease-free survival (DFS). L+T vs. T is tested for superiority and T→L vs. T is tested for non-inferiority at 1.11 margin. P≤0.025 is required for statistical significance. 850 DFS events in the L+T vs. T comparison would provide 80% power to detect a true hazard ratio (HR) of 0.80 with experiment-wide alpha=0.05. The current analysis was planned to occur either after observing these 850 events or at 4.5 yrs median follow up (MFU). Results: Pt and disease characteristics were well balanced. 40% were node-negative and 57% were hormone receptor positive. Only 555 DFS events for the L+T vs. T comparison were observed at 4.5 years MFU. HR for DFS was 0.84 (97.5% CI, 0.70-1.02; P=0.048; 4-yr DFS%=88% vs. 86%) for L+T vs. T and 0.93 (97.5% CI, 0.76-1.13; non-inferiority P=0.044; 4-yr DFS%=87% vs. 86%) for T→L vs. T. Diarrhoea (75% vs. 20%), rash (55% vs. 20%) and hepatobiliary (23% vs. 16%) adverse events were more frequent in L+T vs. T. Primary cardiac endpoints were infrequent (<1%) in all arms. Conclusions: L+T has lower risk of a DFS event compared with T, and T→L appeared non-inferior to T, but neither finding was statistically significant. The first DFS results of dual HER2 blockade in the adjuvant ALTTO at 4.5 years MFU are unexpected considering the effect shown by doubling the pCR rate with L+T vs. T in the NeoALLTO trial. Follow up continues. Clinical trial information: NCT00490139.
Is axillary lymph node dissection necessary after sentinel lymph node biopsy in patients with mastectomy and pathological N1 breast cancer?
Authors: Fu Yun , Chung Debra , Cao Minh-An D. , Apple Sophia , Chang Helena R.
Published: February 2017

101

Background: Recently, axillary lymph node dissection (ALND) was shown to be unnecessary in patients with lumpectomy and 1-2 positive nodes detected by sentinel lymph node biopsy (SLNB). The aim of this study was to determine whether patients with mastectomy and pathological N1 disease found by SLNB could forego ALND. Methods: 214 patients with primary invasive breast cancer who were treated by mastectomy and lymph node staging surgery (SLNB or ALND) at UCLA were identified between Jan. 2002 and Dec. 2010. Patients were grouped by their first nodal surgery into SLNB (subgroups: observation, radiation and additional ALND with or without radiation) and ALND groups (subgroups: ALND with or without radiation). Results: After a median follow up of 43.6 months, in the SLNB group, the 5-year OS rate was worse in the observation group (71%) when compared to 94% in the additional ALND group and 100% in the radiation group (p=0.031). Systemic recurrence rate in patients with positive SLNs was also significantly higher in the observation group (17.4%) when compared with 7.8% in the additional ALND and no recurrence in the radiation group (p=0.046). Her-2 expression (p=0.006, HR 7.493, 95%CI 1.781~31.520) was found to predict OS. Young age (p=0.024, HR 0.921, 95%CI 0.857~0.989), higher histological grades (p=0.021, HR 5.571, 95%CI 1.295~23.954), and positive Her-2 status (p=0.013, HR 8.916, 95%CI 1.590~49.995) were significant in predicting systemic recurrence in the multivariate analysis with type of nodal surgery and radiation controlled. Compared to the SLNB group, pain (p=0.021) and lymphedema (p=0.043) occurred more frequently in the ALND group. Conclusions: Radiation was as effective as complete ALND in patients with mastectomy and N1 disease detected by SLNB for OS and relapse free survival rates, yet radiation after SLNB had fewer side effects than ALND. SLNB followed by radiation could replace ALND in patients with mastectomy and pathological N1 breast cancer identified by SLNB.
Disparities in utilization of breast-conserving therapy among breast cancer patients.
Authors: Lautner Meeghan Ann , Lin Heather Y. , Shen Yu , Parker Catherine , Kuerer Henry Mark , Shaitelman Simona Flora , Babiera Gildy , Bedrosian Isabelle
Published: February 2017

104

Background: Since 1990 breast conserving therapy (BCT) has become a widely accepted modality in the treatment of breast cancer. However, many women continue to undergo mastectomy over BCT. The objective of this study was to provide a comprehensive population based review of the factors that influence utilization of BCT. Methods: Using the National Cancer Database (NCDB), we evaluated women who underwent a mastectomy or BCT for T1/T2, any N breast cancer between 1998 and 2011. We conducted a retrospective review of patient and facility variables associated with undergoing BCT and the trends over time. Logistic regression analysis was used to assess the multivariate relationship between these variables and the probability of undergoing BCT. Results: Among the 727,927 patients who met study criteria, BCT rates increased from 54% in 1998 to 59% in 2006 and then stabilized. After adjusting for demographic and clinical characteristics, BCT utilization was more likely in patients aged 52-61 compared to younger patients (odds ratio (OR) 1.14 {95% CI 1.12-1.15}) and in those with the highest education level (OR 1.16 {95% CI 1.14-1.19}). BCT rates were higher in patients with private insurance compared to the uninsured (OR 1.33 {95% CI 1.28-1.38}) and in those with the highest median income (OR 1.09 {95% CI 1.06-1.11}) (all p < 0.0001). Academic Cancer Programs, facilities in the Northeast and patients who lived within 17 miles of a treatment facility had higher utilization of BCT than Community Cancer Programs (OR 1.13 {95% CI 1.11-1.15}), facilities located in the South (OR 1.50 {95% CI 1.48-1.52}) and those who lived further from a treatment facility (OR 1.25 {95% CI 1.23-1.27}) (all p<0.0001). When comparing BCT utilization in 1998 and 2011, increases were seen across age groups, in community cancer programs and in facilities located in the South; however, disparities by insurance status, income level and travel greater than 17 miles to a treatment facility persist. Conclusions: BCT rates have increased during the last two decades. Disparities based on age, geographic location and type of cancer program have improved. However, socio-economic status and travel distance to treatment facilities persist as key barriers to BCT utilization.