bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term quality of life in high-risk prostate cancer: Results of a phase III randomized trial.
Authors: Nabid Abdenour , Carrier Nathalie , Martin André-Guy , Bahary Jean-Paul , Souhami Luis , Duclos Marie , Vincent François , Vass Sylvie , Bahoric Boris , Archambault Robert , Lemaire Céline
Published: February 2017

5

Background: To evaluate long-term quality of life (QOL) in 630 patients with high-risk prostate cancer (HRPC) treated in a prospective randomized phase III trial (PCS IV clinical trials, Gov. # NCT 00223171). Methods: Patients were randomized to radiotherapy (RT) plus 36 or 18 months of androgen deprivation therapy (ADT). QOL was assessed by two validated tools: EORTC30 (30 items) and PR25 (25 items). The 55 items were regrouped into 21 scales: 15 for EORTC30 and six for PR25. All items and scales scores were linearly transformed to a 0 to 100 points scale. A p value less than 0.01 was considered statistically significant and a difference between groups in mean scores of greater than or equal to 10 points as clinically relevant. Patient-reported outcomes were filled out before treatments, every six months during ADT, four months after and then once a year for five years. All items and scales scores were analysed with general linear model with repeated measures to evaluate changes between groups and over time periods. Results: Three hundred ten patients were randomized to 36 months and 320 to 18 months of ADT, with a median follow-up of 79 months, there was no difference in survival outcomes. The global adherence to QOL questionnaires was 72.4% (10,052 out of 13,880). When comparing the two groups, 6 out of 21 scales (physical, emotional, and social functioning, fatigue, hormonal treatment-related symptoms, and sexual active) and 14 out of 55 items (trouble with long walks, stay in bed during the day, weakness, tenseness, worry, irritable, depressed, close to a toilet, blood in stools, hot flushes, enlarged breasts, interested in sex, sexually active, enjoyable sex) were statistically significant (p< 0.01) in favor of the 18 months ADT group. None of the 21 scales reached clinical relevance (mean scores greater than or equal to 10 points) sexual active being the highest score with 9.0 points of difference. For the 14 statistically significant items, interest in sex with 9.9 points and sexually active with 8.1 points were close to clinical relevance and hot flushes with 24 points and enjoyable sex with 18 points had important clinical relevance at 42 months. Conclusions: In HRPC treated with RT and ADT, reducing the duration of ADT from 36 to 18 months improves QOL, without a negative impact on survival. Source of Funding: AstraZeneca Pharmaceuticals grant. Clinical trial information: PCS IV clinical trials, Gov. # NCT 00223171.
Acquired hypothyroidism as a predictive marker of outcome in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine-kinase inhibitors (TKIs): A literature-based meta-analysis.
Authors: Nearchou Andreas Demetrios , Valachis Antonis , Lind Pehr , Akre Olof , Sandstrom Per
Published: February 2017

500

Background: The development of hypothyroidism in patients with mRCC during treatment with the tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib is a well-established side effect. The potential role of hypothyroidism as predictive marker of outcome has been studied with conflicting results. The aim of the present meta-analysis was to assess the predictive value of hypothyroidism for both progression free (PFS) and overall survival (OS) in patients with mRCC treated with TKI. Methods: We searched PubMed as well as the electronic abstract databases of the major international congresses’ proceedings to identify all eligible studies which reported a correlation of the development of hypothyroidism during treatment with TKI and outcome in patients with mRCC. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were obtained from these publications and pooled in a meta-analysis by using random-effects or fixed-effects models based on the heterogeneity of the included studies. Results: Eleven studies with a total of 500 patients fulfilled the inclusion criteria. We found no statistical significant difference in PFS between patients who developed hypothyroidism and patients without hypothyroidism during sunitinib therapy (HR: 0.82, 95% CI: 0.59-1.13, p-value = 0.22) (6 studies; 250 patients). For studies that included patients treated with either sunitinib or sorafenib, the development of hypothyroidism was found to be predictive for longer progression free survival (HR: 0.59, 95% CI: 0.42-0.84, p-value = 0.003) (3 studies; 205 patients). The HR for OS was 0.52 (95% CI: 0.31-0.87, p-value = 0.01) for patients who developed hypothyroidism during sunitinib therapy compared to patients without hypothyroidism (4 studies; 147 patients). Conclusions: The development of hypothyroidism during TKIs therapy is not clearly shown to be predictive in patients with mRCC. The observed advantage in overall survival for patients with treatment related hypothyroidism should be interpreted with caution due to the potential imbalance of treatments received after first line treatment in each group.
Are regional funding decisions resticting pharmaceutical research and development in metastatic renal cell carcinoma (mRCC)?
Authors: Conter Henry Jacob
Published: February 2017

506

Background: Targeted therapy has revolutionized the treatment of mRCC. However, cost has lead to variable regional approval and funding. Can such variation in funding of established drugs impede approval of newer agents? Methods: Regulatory agency decisions regarding axitinib, the most recently approved mRCC therapy in the U.S., were reviewed. Reports from the US Food and Drug administration (FDA), the European Medicines Agency (EMA), the pan-Canadian Oncology Drug Review (pCODR), UK's National Institute for Health and Care Excellence (NICE), and the Therapeutic Goods Administration (TGA) of Australia were included. Data abstracted included the date of report publication, basis for determination of clinical efficacy, determination of cost-effectiveness, theme of stakeholder submissions prior to and after the regulatory decision, final decision, and rational for approval/rejection. Results: At the time of analysis, all agency decisions had been finalized. All of the agencies based their assessment of clinical efficacy of primarily on the same phase III clinical trial: the AXIS trial, demonstrating a progression-free survival benefit of axitinib compared to sorafenib (6.7 versus 4.7 months, p<0.001). Cost-effectiveness data was considered by NICE and pCODR, but not the FDA, the EMA, or the TGA. Axitinib was recommended received approval by the FDA, the EMA, and the TGA for use in patients with mRCC who have failed prior treatment with sunitinib or cytokines. pCODR recommended axitinib for funding in the 2nd line setting only in patients unable to tolerate everolimus. And NICE recommended against the funding of axitinib. Both dissenting organizations cited concerns with the pivotal trial’s control arm, sorafenib, not representing their regional standards of care as primary reasons for restricted access and rejection. Cost considerations were also cited as factors in the rejections. Conclusions: Differing regulatory approvals and funding worldwide are creating regional standards of care that impeding the research, development, and approval of newer agents. Divergent standards of care before and after clinical trials may restrict their external validity and applicability.
Retrospective evaluation of tyrosine kinase inhibitor (TKI)-everolimus (eve) and/or TKI-eve-TKI sequences in metastatic renal cell carcinoma (mRCC): A French survey—The sector study.
Authors: Oudard Stephane , Joly Florence , Geoffrois Lionnel , Laguerre Brigitte , Houede Nadine , Barthelemy Philippe , Gross-Goupil Marine , Yann-Alexandre Vano , Lucidarme Olivier , Bidault François , Kelkouli Nadia , Escudier Bernard
Published: February 2017

509

Background: In the RECORD-1 study, only 22% of the mRCC patients (pts) received eve in pure 2nd line. Thus more data in real world are needed. A retrospective French survey, on a large patient population, was designed to evaluate efficacy for the sequence TKI-eve and/or TKI-eve-TKI in mRCC. Methods: Between 10/08 and 10/12, 164 mRCC pts from 26 french centers, who progressed on initial TKI and received eve as 2nd line were recorded. In these pts, 3rd line TKI was recorded. Primary endpoint was Duration of Treatment (DT) of each sequence. Secondary endpoints were best radiological response for eve evaluated by 2 independent radiologists, tolerability, dose reduction, overall survival from the start of first TKI (OS). Patients characteristics: Amongst 164 pts, 144 pts with follow-up > 4 months since initiation of eve were evaluated, 59/144 pts received TKI-eve-TKI. Before eve initiation: median age was 65 yrs, most pts were male (70.3%), had clear cell histology (92.3%), had received sunitinib as first TKI (94.4%). Main comorbidities were: hypertension (43.8%), diabetes (15.3%), and hypercholesterolemia (19.4%). At the time of eve initiation, MSKCC classification was good (24.4%), intermediate (61.5%) or poor (14.1%). Results: median DT of eve was 4 months and 21% pts were treated >9 months with 2.9% PR and 67.6% SD by central review. Correlation between response to first TKI and eve was observed. Dose reduction of eve for toxicity was 23.2%. The most common toxicities (all grades) were: stomatitis (25.3%), PNI (13%), fatigue (40.7%), hyperglycemia (9.3%), hypercholesterolemia (17.3%) and hypertriglyceridemia (22.8%). Median duration of TKI-eve sequence was 18 months (IC95%: 15-20), and OS was 36 months (IC95%: 27-56). For TKI-eve-TKI sequence (59 pts), sorafenib was mostly used (76.3%) with dose reduction and clinical benefit rate of 26.7% and 42.2% respectively. Median DT and OS were 24 and 41 months (IC95%: 19-29; 25-57) respectively. Conclusions: In real world experience, for mRCC pts receiving TKI-eve sequence, median DT of eve is 4 months with OS of 36 months which compares favorably with RECORD1 and RECORD 3 trials respectively.
Reliability of the CT-SCAN percutaneous biopsy for small renal masses.
Authors: Ingels Alexandre , Barret Eric , Audenet Francois , Lunelli Luca , Prada Costa Guilherme , Rozet Francois , Galiano Marc , Sanchez-Salas Rafael , Lenoir Stephane , Validire Pierre , Cathelineau Xavier
Published: February 2017

514

Background: The aim of this study was to assess the veracity of the outcomes from renal biopsy performed under CT-scan control for patients harboring cT1a stage tumors. Methods: In a retrospective study, we analyzed the outcomes of renal biopsies performed under CT-scan control for patients harboring tumors under 4 cm. Pathology has been compared between biopsy sample and nephrectomy specimen. Every patient included had a small renal mass (cT1a) and had to undergo a CT-scan guided renal biopsy before nephron sparing or enlarged nephrectomy (that had to be done within 6 months after the biopsy). Results: From January 2007 to December 2012, we performed 79 CT-scan guided renal biopsies. Among these patients, biopsy lead to the diagnosis of the renal lesion for 70 cases. For 9 cases, biopsy was not contributive. Following the biopsy, 19 patients underwent a nephron sparing surgery and 10 a radical nephrectomy. Comparison of the pathological outcomes between biopsy and surgical specimen showed an agreement for the diagnosis of carcinoma in 28 cases (97%): one case of chromophobe carcinoma on biopsy sample analyze happened to be an oncocytoma on the surgical specimen. Sensitivity was 100% and Specificity 67%. Conclusions: Renal biopsy under CT-scan control yield to a trustful diagnosis of small renal mass in most of the cases. It seems relevant to systematically offer this strategy to the patients in order to adapt their following treatment.
Association of baseline health and gender with small renal mass pathology.
Authors: Bazzi Wassim , Dejbakhsh Sheila , Bernstein Melanie , Coleman Jonathan A. , Russo Paul
Published: February 2017

515

Background: Previous reports describe that 20% of small renal masses (SRM) are benign and women are twice as likely to have benign pathology. In this study we further explore the association of baseline health and gender with SRM pathology. Methods: After IRB approval, retrospective chart review of patients who have undergone nephrectomy at Memorial Sloan-Kettering Cancer Center from 05/1998 to 10/2012 with final path ≤ 4cm and staged as pT1a if malignant. Tumor size ≤ 4cm was chosen to limit the tumor mass effect on renal function. Patients with solitary kidney, multiple and bilateral tumors, and history of prior renal surgeries were excluded. Collected data included age, gender, race, ASA class for medical co−morbidities which were divided into low (I−II) and high (III−IV), procedure, preoperative serum creatinine, eGFR, and final pathology. eGFR was calculated using the CKD−Epi formula. Preoperative Chronic kidney disease (pCKD) was defined as eGFR < 60 mL/min per 1.73 m2. Malignant pathologies were clear cell renal cell carcinoma (RCC), papillary RCC and chromophobe RCC whereas benign were oncocytoma, angiomyolipoma and other. Logistic regression analysis was performed to determine clinical factors associated with malignant SRM. Results: Our cohort consisted of 1726 patients with mean age 59.7 yrs. 61% (n=1045) were men, 90% (n=1,553) were white, 43% (n=736) had high ASA, 89% (1,540) underwent partial nephrectomy, 30% (n=525) had pCKD, 83% (n=1426) with malignant pathology and mean tumor size 2.5cm. On bivariable analysis patients with malignant SRM had a higher proportion of men (64.3 vs. 42.7%, p<0.001), high ASA class (43.8 vs. 37.3%, p=0.041) and larger tumors (2.6 vs. 2.3, p<0.001). There were no differences in age, race, mean eGFR or proportion with pCKD. On logistic regression analysis by gender factors associated with malignant pathology in women were high ASA class (OR 1.57, 95% CI 1.07−2.32) and tumor size (OR 1.48, 95% CI 1.20−1.81), and in men tumor size only (OR 1.33, 95% CI 1.06−1.67). Conclusions: Our results are in line with previous reports on the association of male gender and larger tumor size with malignant SRM. In addition we do show that among women those with poor health have a higher likelihood for having a malignant SRM.
Diabetes mellitus and risk of cancer-specific mortality among patients with clear cell renal cell carcinoma undergoing nephrectomy.
Authors: Psutka Sarah P. , Stewart Suzanne B. , Lohse Christine M. , Tollefson Matthew K. , Boorjian Stephen A. , Cheville John C. , Leibovich Bradley C. , Thompson R. Houston
Published: February 2017

516

Background: The impact of diabetes mellitus (DM) on outcomes in patients with renal cell carcinoma (RCC) is controversial. Herein, we evaluated the association of DM with survival among patients with RCC. Methods: We reviewed 2,589 patients treated with nephrectomy for sporadic, unilateral, M0 RCC between 1990 and 2008 and compared demographic and tumor characteristics in patients with and without DM (nonDM). Patients with DM (n=313) were matched 1:2 to nonDM patients according to date of surgery, age, smoking status, obesity, ECOG performance status (PS), CKD stage, histological subtype, and nuclear grade. Cancer-specific (CSS) and overall survival (OS) were compared by Kaplan-Meier analysis. The association of DM with outcomes was evaluated with Cox proportional hazards regression models. Results: A total of 313 (12%) patients had DM. DM patients were significantly older at RCC diagnosis, more likely to be obese, and had higher Charlson scores, CKD class, rates of smoking, and worse PS at surgery (p<0.001). Patients with DM were also more likely to have ccRCC (83% vs. 76%, p=0.02) and to undergo nephron-sparing surgery (42% vs. 35%, p=0.01), while other pathologic features were similar in DM and nonDM. Among the 939 matched cases and controls, 463 patients died within a median of 5.5 years after nephrectomy. Median follow-up for survivors was 8.6 years. Five-year CSS was not significantly different among DM patients 84% vs. nonDM patients 87% (p=0.11), although 5-year OS was significantly worse among DM patients (66% vs. 75%; p<0.001). Indeed, even after adjusting for Charlson score, DM patients were noted to have a significantly increased risk of all-cause mortality (HR 1.33; p=0.004). In a subanalysis of patients with clear cell RCC, DM patients were more likely to die from RCC compared with nonDM patients after adjusting for the SSIGN (Stage, Size, Grade, Necrosis) score (HR 1.44; p=0.034). Conclusions: In this surgical cohort, DM was independently associated with decreased CSS among patients with ccRCC and with decreased OS in all RCC subtypes. Further studies to determine the potential biologic mechanism for this interaction are warranted.
Evaluating 18F-16β-fluoro-5α-dihydrotestosterone (FDHT) and FDG PET as prognostic biomarkers for patients (pts) treated with abiraterone acetate (AA).
Authors: Feldman Jarett Lawrence , Fox Josef J. , Autio Karen A. , Gavane Somali C. , Heller Glenn , Schöder Heiko , Humm John , Martinez Danny F. , Slovin Susan F. , Scher Howard I. , Larson Steven M. , Morris Michael J.
Published: February 2017

56

Background: There are no available imaging biomarkers that can prognosticate for clinical outcomes for patients treated with AA. FDG and FDHT PET demonstrate glucose metabolism and androgen receptor expression, respectively. This is the first study of FDG and FDHT PET as a prognostic biomarker for pts treated with AA. Methods: Pts with progressive metastatic castration resistant prostate cancer (mCRPC) starting AA underwent FDG and FDHT PET scans on an imaging clinical trial. PSA, SUVmax (hottest slice of hottest lesion), and SUVmaxavg (average SUVmax of 5 index lesions) were collected. An SUV value of 1 was imputed for calculating SUVmaxavg in the absence of 5 index lesions. Imaging characteristics were compared to PFS, defined as time to radiographic progression, biochemical relapse or death. The Cox proportional hazards model was used to determine the association between the PET measurements and PFS. The statistics used to measure the association was the concordance probability estimate (CPE). Results: 24 scans sets were obtained. Median pt characteristics were: age 70 (48-85), Gleason score 8 (range 6-10), PSA 85 (2-459). Radiographic and PSA progression occurred in 15/24 (63%), radiographic only 4/24 (17%), and biochemical only 2/24 (9%). 1 pt died on study, 1 elected to discontinue tx, and 1 remains on AA. 16/24 (67%) and 18/24 (75%) of FDG and FDHT PET scans respectively had ≥ 5 hypermetabolic lesions. Median FDG SUVmax was 8 (2-15), FDG SUVmaxavg 5 (1-11), FDHT SUVmax 11 (3-28) and FDHT SUVmaxavg 7 (1-16). The correlation between PET measurements and PFS is described (Table). Conclusions: Preliminarily, baseline FDG SUVmax and SUVmaxavg appear to be prognostic for PFS in pts treated with AA. Higher SUV values prognosticate for a shorter time to progression. Further evaluations of FDG/FDHT PET in mCRPC are underway to better define the role each modality has as a prognostic and response biomarker for AA. Clinical trial information: NCT00588185. [Table: see text]
Pattern of occult nodal relapse diagnosed with 18F fluoro-choline PET/CT in prostate cancer patients with biochemical failure after prostate-only radiotherapy.
Authors: Lepinoy Alexis , Cochet Alexandre , Cueff Adele , Cormier Luc , Martin Etienne , Maingon Philippe , Bosset Jean Francois , Brunotte Francois , Crehange Gilles
Published: February 2017

77

Background: 11C or 18F-labeled choline PET/CT has led to better understanding of the lymph drainage pattern of prostate cancer. It can provide radiation oncologists with maps to guide the delivery of prophylactic pelvic radiotherapy while minimizing radiation toxicity to non-target normal tissue with intensity modulated radiation therapy (IMRT). The purpose of this study was twofold: (1) to describe the pattern of nodal relapse in prostate cancer patients with biochemical failure after prostate-only radiotherapy; and (2) to determine whether patients with 18F-fluoro-choline (FCH) PET/CT positive nodes experienced treatment failure within the clinical target volume (CTV) defined by the RTOG guidelines (CTVRTOG). Methods: Between July 2008 and December 2012, 83 patients with a prostate cancer had a FCH PET/CT for biochemical failure after radiotherapy. Of 65 patients with FCH-positive findings, 33 had positive nodes. This analysis included 31 patients who had undergone prior prostate-only radiotherapy or radical prostatectomy followed by local radiotherapy. Each choline FCH positive node was assigned to a lymph node station and situated with regard to the CTVRTOG. Results: Fourteen patients (45.2%) had a relapse outside the CTVRTOG. Of the 17 patients with a positive node inside the CTVRTOG, 15 had a single node (88.2%) while seven patients out of the 13 evaluable patients (53.9%) who had a relapse outside the CTVRTOG had two or more positive nodes on FCH PET/CT. Patients with FCH+ nodes outside the CTVRTOG were more likely than patients with FCH+ nodes inside the CTVRTOG to have two or more involved nodes (OR= 8.75, [95% CI: 1.38-54.80], p= 0.020). The ventral part of the external iliac station (29.0%) was the main site of relapse inside the CTVRTOG whereas relapses that occurred outside the CTVRTOGinvolved the proximal common iliac (19.3%) and lower periaortic nodes (19.3%) up to L2-L3. Conclusions: Nearly half of the patients had FCH+ nodes outside the CTVRTOG with a significantly higher number of nodes involved outside the CTVRTOG. Three-dimensional mapping of nodal relapses evaluated with FCH PET/CT suggests that with IMRT the upper field limit of pelvic radiotherapy could be extended to L2-L3 safely to cover 95% of nodal stations at risk of an occult relapse.
Degarelix monotherapy versus luteinizing hormone-releasing hormone (LHRH) agonists plus antiandrogen flare protection in the treatment of men with advanced prostate cancer.
Authors: Tombal Bertrand , Damber Jan-Erik , Malmberg Anders , Persson Bo-Eric , Klotz Laurence , Iversen Peter
Published: February 2017

86

Background: Short-term antiandrogen (AA) flare protection is used to counter the testosterone surge associated with luteinising-hormone-releasing hormone (LHRH) agonist therapy. Degarelix, a gonadotrophin-releasing hormone antagonist, does not cause testosterone surge. Data from two phase III trials have been used to compare the one year efficacy of degarelix monotherapy versus combined agonist plus AA flare protection. Data has reported testosterone surge in agonist patients despite AA therapy, as well as improved prostate-specific antigen (PSA) progression-free survival (PFS) and lower mortality in degarelix patients. Here we focus on PSA PFS outcomes and serum alkaline phosphatase (S-ALP) in high risk patients (metastatic disease or PSA more than 50 ng/mL). Methods: Data were pooled from two randomised, one-year studies; CS21 compared monthly degarelix with leuprolide and CS35 compared 3 month formulations of degarelix and goserelin. AA was administered in the agonist groups at the investigator’s discretion. Analyses were performed by the Kaplan-Meier method and Log-rank test (probability of PSA PFS), Cox regression (adjusted hazard ratios [HR] for PSA PFS failure) and repeated measures ANCOVA (S-ALP). Results: Nine hundred seventy four patients received degarelix and 69 patients agonist plus AA. The agonist plus AA group contained a higher proportion of patients with Gleason score 7 to 10, metastatic disease, or baseline PSA more than 50 ng/mL compared with the degarelix group. Cox regression was used to account for these baseline differences. PSA PFS failure rate for metastatic patients and those with baseline PSA more than 50 ng/mL was significantly lower with degarelix than with agonist plus AA (HR=0.516, p=0.0198 and HR=0.490, p=0.0077, respectively). S-ALP levels in metastatic patients and those with baseline PSA more than 50 ng/mL during the year of treatment were significantly lower with degarelix (p=0.0025 and 0.0005, respectively). S-ALP fell below baseline by 2 months or less with degarelix and 7 months or less with agonist plus AA. Conclusions: This pooled analysis indicates LHRH agonist plus AA therapy flare protection may not achieve similar disease control as degarelix monotherapy during the first year of therapy in patients at high risk of symptomatic disease progression.
Multidisciplinary clinic evaluation changes prostate cancer stage and risk stratification.
Authors: Sundi Debasish , Cohen Jason , Cole Alexander , Neuman Brian , Cooper Jack , Faisal Farzana , Raben Marian , Song Danny Y. , Drake Charles G. , Netto George J. , Macura Katarzyna , DeWeese Theodore L. , Partin Alan Wayne , Ross Ashley E. , Schaeffer Edward M.
Published: February 2017

91

Background: The use of multidisciplinary clinics (MDCs) for outpatient cancer evaluation is increasing. Data on whether MDCs improve prostate cancer (PCa) care are limited. We studied the frequency of changes in PCa grade and stage upon MDC evaluation. Methods: Between May 2008 and December 2012, 887 consecutive patients underwent consultation for newly diagnosed prostate cancer at the Johns Hopkins Hospital (JHH) MDC, which features real-time collaboration among urologists, radiation oncologists, and medical oncologists. Retrospective chart review identified presenting tumor characteristics, based on outside assessment (medical records sent upon referral to MDC), as compared with disease stage and grade as determined at MDC evaluation. All outside biopsy slides were reviewed by JHH pathologists, and all outside imaging (CT, MRI, bone scan) was reviewed by JHH radiologists. Results: The three most chosen treatments after MDC evaluation were external beam radiotherapy +/- androgen deprivation (39.3%), radical prostatectomy (32.0%) and active surveillance/expectant management (12.9%). Using the NCCN guidelines as a benchmark, many men were found to have undergone non-indicated imaging (bone scan 23.9%, CT/MRI 47.4%). Overall, 186/647 (28.7%) had a change in their NCCN risk classification or N or M stage. For example, 2.9% of men were down-classified as very-low-risk, rendering them eligible for active surveillance. 5.7% of men thought to have localized cancer were up-classified as metastatic, thus prompting systemic management approaches. Conclusions: Comprehensive evaluation of prostate cancer patients in a MDC is associated with critical changes in presenting disease classification from baseline in over one in four men. While questions about the long term costs and benefits of MDCs remain, these results lend credence to the growing belief that MDCs may dramatically impact management for a large number of men with prostate cancer. [Table: see text]
The initial report of RTOG 0524: Phase I/II trial of a combination of paclitaxel and trastuzumab with daily irradiation or paclitaxel alone with daily irradiation following transurethral surgery for noncystectomy candidates with muscle-invasive bladder cancer.
Authors: Michaelson M. Dror , Hu Chen , Pham Huong T. , Dahl Douglas M. , Wu Chin-Lee , Whittington Richard M. , Swanson Gregory P. , Vuky Jacqueline , Lee R. Jeffrey , Souhami Luis , Chang Brian K. , George Asha , Sandler Howard Mark , Shipley William U.
Published: February 2017

LBA287

Background: Most patients (pts) with muscle-invasive bladder urothelial carcinoma (UC) undergo definitive local treatment with radical cystectomy. Up to 50% of pts with UC overexpress HER2/neu, which may be associated with reduced responsiveness to chemoradiation and reduced survival. Many pts with UC have comorbidities that preclude surgery, creating a traditionally underserved population with worse outcomes. RTOG 0524 evaluated the safety and efficacy of trimodality, organ-preserving therapy in pts not suitable for cystectomy. Methods: Pts with invasive bladder UC (stages T2-T4a, N0-1, M0) underwent cystoscopic tumor resection. Tumors were analyzed by HER2/neu immunohistochemistry (IHC) and assigned to chemotherapy group I (IHC 2+ or 3+; paclitaxel and trastuzumab) or II (IHC negative or 1+; paclitaxel alone). Concurrent weekly paclitaxel (50 mg/m2), weekly trastuzumab (group I only) and daily radiation (64.8 Gy total in 36 fractions) were given for seven consecutive weeks. Results: 21 eligible patients were entered in group I and 47 in group 2, with median ages of 80 and 73, respectively. The primary endpoint was acute protocol-defined toxicity related to treatment. Acute toxicity was observed in 7/21 pts (33%) in group I and 14/47 pts (30%) in group II. Most common grade > 3 adverse events in groups I and II were marrow suppression (43% and 17%), diarrhea (33% and 30%), and hyponatremia (14% and 4%). Three deaths on study were attributed to colonic perforation, pneumonia, and sudden death. Radiation completion rates were 72% and 85% in the two groups, and full-dose chemotherapy completion rates were 52% and 51%. Evaluation by cystoscopy and/or tumor biopsy at 12 weeks noted complete response in 9/13 pts (69%) in group I, in 19/33 pts (58%) in group II, and was not performed in the remaining pts. Conclusions: Trimodality bladder-preserving therapy is an appropriate treatment in noncystectomy candidates with invasive UC. The response rate for HER2/neu-targeted therapy is encouraging but may increase certain adverse events in this challenging population. Clinical trial information: NCT00238420.
ASET study: Long-term follow-up data of patients with metastatic renal cell carcinoma treated with MGN1601.
Authors: Gruenwald Viktor , Weikert Steffen , Schmidt-Wolf Ingo G. H. , Hauser Stefan , Magheli Ahmed , Schroff Matthias , Schmidt Manuel , Wittig Burghardt
Published: February 2017

LBA399

Background: The cell-based therapeutic cancer vaccine MGN1601 is a fixed combination of allogeneic tumor cells modified via MIDGE vectors to express IL-7, GM-CSF, CD80, and CD154 plus the immunomodulator dSLIM. In the ASET trial heavily pretreated patients with metastatic renal cell carcinoma (mRCC) were enrolled to assess safety, immunological effects, and clinical efficacy of MGN1601. Methods: The ASET study was a multicenter, single-arm phase 1/2 study. The treatment phase consisted of 8 intradermal vaccinations over 12 weeks. Following evaluation, patients with at least disease stabilization entered an extension phase (EP, 5 vaccinations over 120 weeks). Overall, 19 patients were included and received at least one MGN1601 injection (ITT); the majority (N=17) had ≥3 lines of previous therapy. Results: Of 19 patients, 10 (55%) completed the treatment phase per-protocol (PP); 9 patients discontinued the study due to disease progression (PD) or rapid deterioration. Overall, 110 adverse events were documented (grade 1-2: 80.9%) of which only 10 (9.1%) were drug-related. No drug-related serious adverse event was reported. PBMCs from patients increased cytokine secretion after re-stimulation with standard antigens, confirming an improved cellular immune function. Two patients achieved disease control (PR, SD) after 12 treatment weeks and continued in the extension phase: One patient had PD after 60 weeks, the other remains in sustained partial remission after completion of the EP. Median overall survival (OS) was 24.8 weeks in the ITT population and 115.3 weeks in the PP population. Univariate analysis of pre-treatment characteristics revealed absolute lymphocyte counts, neutrophil to lymphocyte ratios, platelets, MSKCC score, and liver metastasis as putative predictive factors of longer overall survival. Conclusions: MGN1601 administration was safe and showed promising OS in a population of heavily pretreated RCC patients who could receive therapy over 12 weeks (PP population). These results warrant further evaluation in a larger, controlled clinical trial. Baseline biomarkers and factors may allow identifying patients more likely to benefit from this innovative vaccination approach. Clinical trial information: NCT01265368.
Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067).
Authors: Wolchok Jedd D. , Chiarion-Sileni Vanna , Gonzalez Rene , Rutkowski Piotr , Grob Jean Jacques , Cowey Charles Lance , Lao Christopher D. , Schadendorf Dirk , Ferrucci Pier Francesco , Smylie Michael , Dummer Reinhard , Hill Andrew Graham , Haanen John B. A. G. , Maio Michele , McArthur Grant A. , Yang Arvin , Rollin Linda , Horak Christine E. , Larkin James M. G. , Hodi F. Stephen
Published: February 2017

LBA1

Background: The results of a phase I study in MEL suggested complementary clinical activity with NIVO (a PD-1 checkpoint inhibitor) plus IPI (a CTLA-4 checkpoint inhibitor). Here, we report the results of a randomized, double-blind, phase III trial designed to evaluate NIVO combined with IPI or NIVO alone vs IPI alone in MEL. Methods: Treatment-naïve pts (N = 945) were randomized 1:1:1 to NIVO 1 mg/kg Q2W + IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W, NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status, BRAF mutation status, and M-stage. Co-primary endpoints are progression-free survival (PFS) (reported here) and overall survival (pts continue to be followed). Secondary endpoints include objective response rate (ORR) by RECIST v1.1 and safety. Results: At a minimum follow-up of 9 months, NIVO + IPI and NIVO alone significantly improved PFS and ORR vs IPI (Table). Grade 3-4 drug-related adverse events (AEs) occurred in 55.0%, 16.3%, and 27.3% of pts in the NIVO + IPI, NIVO, and IPI arms, respectively (most commonly diarrhea [9.3%, 2.2%, 6.1%], increased lipase [8.6%, 3.5%, 3.9%], increased alanine aminotransferase [8.3%, 1.3%, 1.6%], and colitis [7.7%, 0.6%, 8.7%]). Drug-related AEs led to discontinuation in 36.4%, 7.7%, and 14.8% of pts in the NIVO + IPI, NIVO, and IPI arms, with 0, 1, and 1 drug-related deaths, respectively. Efficacy outcomes by PD-L1 status will also be presented. Conclusions: NIVO + IPI and NIVO alone had superior clinical activity vs IPI alone. The results with NIVO + IPI and NIVO alone further suggest complementary activity of the two agents. There were no new safety signals or drug-related deaths observed with the combination. Clinical trial information: NCT01844505. [Table: see text]
Primary results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy.
Authors: Margolese Richard G. , Cecchini Reena S. , Julian Thomas B. , Ganz Patricia A. , Costantino Joseph P. , Vallow Laura , Albain Kathy S. , Whitworth Pat W. , Cianfrocca Mary E. , Brufsky Adam , Gross Howard M. , Soori Gamini S. , Hopkins Judith O. , Fehrenbacher Louis , Sturtz Keren , Wozniak Timothy F. , Seay Thomas E. , Mamounas Eleftherios P. , Wolmark Norman
Published: February 2017

LBA500

Background: The primary endpoint of NSABP B-35, a phase III trial comparing 1 mg/day anastrozole to 20 mg/day tamoxifen, each given for 5 years, was breast cancer-free interval (BCFI), defined as the time from randomization to any breast cancer (BC) event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS. Methods: Postmenopausal women with ER-receptor or PgR-receptor positive (by IHC analysis) DCIS and no invasive BC who had undergone a lumpectomy with clear resection margins were randomly assigned to receive either 20 mg/day tam or 1 mg/day A (blinded) for 5 years. Stratification was by age (<60 v ≥60). Results: From 1/6/2003 to 6/15/2006, 3,104 pts were entered and randomized (1552 in groups tam and A each). As of 2/28/15, follow-up information was available on 3,083 pts for OS and on 3,077 pts for all other disease-free endpoints, with mean time of follow-up of 8.6 years. There were 198 BCFI events, 114 in the tam group and 84 in the A group (HR, 0.73; p=0.03). 10-year point estimates for BCFI were 89.2% for tam and 93.5% for A. A significant time-by-treatment interaction (p=0.02) indicated that the effect was not evident until later in the study. There was a significant interaction between treatment and age group (p=0.04); benefit of A is only in women <60 years old. As to secondary endpoints, there were 495 DFS events, 260 in the tam group and 235 in the A group (HR, 0.89; p=0.21). 10-year point estimates for DFS were 77.9% for tam and 82.7% for A. There were 186 deaths, 88 in the tam group and 98 in the A group (HR, 1.11; p=0.48). 10-year point estimates for OS were 92.1% for tam, 92.5% for A. There were 8 deaths due to breast cancer in the tam group and 5 in the A group. There were 63 cases of invasive breast cancer in the tam group and 39 in the A group (HR, 0.61; p=0.02). There was a non-significant trend for a reduction in breast second primary cancers with A (HR, 0.68; p=0.07). Conclusions: Anastrozole provided a significant improvement compared to tamoxifen for BCFI, which was seen later in the study, primarily in women <60 years. Support: CA12027, 37377, 69651, 69974; 180868, 180822, 189867 196067, 114732; AstraZeneca Pharmaceuticals LP. Clinical trial information: NCT00053898.
Trends in BRCA1/2 mutation testing rates among young women and men with breast cancer, 2005-2012.
Authors: Kehl Kenneth L , Shen Chan , Litton Jennifer Keating , Arun Banu , Giordano Sharon Hermes
Published: February 2017

103

Background: Guidelines recommend consideration of testing for germline mutations in the BRCA1/2 genes for certain patients with breast cancer, including women diagnosed under age 45 and male patients. However, there are limited data regarding rates of genetic testing in these patients on a population basis. Methods: Using insurance claims from the national MarketScan database of privately insured patients, we identified incident breast cancer cases among women age ≤ 40, women age 41-45, and men of all ages, diagnosed from 2005-2012. We assessed claims for BRCA1/2 testing using Kaplan-Meier analysis and a Cox proportional hazards model, compared across patient cohorts and years of diagnosis. Results: We identified 28,495 patients (11,198 women age ≤ 40, 15,929 women age 41-45, and 1,368 men) for analysis. BRCA1/2 testing rates increased with later years at diagnosis (log-rank P < 0.001 for women age ≤ 40 and women age 41-45; P = 0.01 for men). Men had lower testing rates than women age 41-45, who in turn had lower rates than women age ≤ 40. Furthermore, among women diagnosed in earlier years, testing rates never approached those of patients diagnosed in later years, even after extended follow-up. For example, women age ≤ 40 diagnosed in 2005 had a testing rate by one year after surgery of 19.6% (95% confidence interval, CI, 17.0%-22.5%), and a rate by five years after surgery of 35.3% (95% confidence interval, CI, 31.1%-39.9%). However, for women age ≤ 40 diagnosed in 2009, the testing rate at one year was 57.1% (95% CI, 54.8%-59.5%; hazard ratio for testing, 3.40, 95% CI 2.95-3.92, compared to women age ≤ 40 diagnosed in 2005). Conclusions: Genetic testing rates among men and young women with breast cancer increased with time, but uptake of testing was uneven. Among young women, testing rates for survivors diagnosed in earlier years and followed over time never approached those of patients diagnosed later. These results demonstrate a need to better incorporate genetic counseling into survivorship care, and to promote awareness among providers that long-term breast cancer survivors may be eligible for genetic testing that was not offered or available when they were diagnosed.
Functional subtyping with BluePrint 80-gene profile to identify distinct triple-positive subtypes with and without trastuzumab/chemosensitivity.
Authors: Whitworth Pat W. , Beitsch Peter D. , Rotkis Michael C. , Pellicane James V. , Murray Mary , Baron Paul , Dul Carrie L. , Mislowsky Angela Marie , Nash Charles H. , Richards Paul D. , Lee Laura A. , Stork Lisette , De Snoo Femke , Untch Sarah , Gittleman Mark , Akbari Stephanie , Beatty Jennifer
Published: February 2017

114

Background: Classification by molecular subtype can aid in the selection of therapy for patients with breast cancer. However at present, the methodology for molecular subtyping is not standardized. The aim of the prospective NBRST study is to compare chemosensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint (BP) functional subtype profile vs. conventional IHC/FISH subtyping. Methods: The study includes women aged 18–90 with histologically proven breast cancer, written informed consent, no excision biopsy or axillary dissection, and no prior therapy for breast cancer. Neo-adjuvant Chemotherapy (NCT) was at the discretion of the physician adhering to NCCN approved or other peer-reviewed regimens. BP in combination with MammaPrint classifies patients into 4 molecular subgroups: Luminal A, Luminal B, HER2 and Basal. Results: 721 patients had definitive surgery. 58/335 (17%) IHC/FISH HR+/HER2- patients were re-classified by BP as Basal (57) or HER2 (1). 92/222 (41%) IHC/FISH HER2+ patients were re-classified as BP Luminal (67) or BP Basal (25). 7/164 (4%) IHC/FISH triple negative (TN) patients were re-classified as BP Luminal (5) or BP HER2 (2). NCT pCR rates were 3% in Luminal A and 9% in Luminal B patients versus 10% pCR in IHC/FISH luminal patients. The NCT pCR rate was 54% in BP HER2 patients. This is significantly superior (p = 0.02) to the pCR rate in IHC/FISH HER2+ patients (40%). BP Basal and IHC/FISH TN had a pCR rate of 35%. Functional BP subtyping divided the 137 IHC/FISH triple positive patients into two major subgroups: BP Luminal (n = 66, pCR = 11%) and BP HER2 (n = 60, pCR = 45%).11 patients were re-classified as BP Basal with pCR = 45%. Conclusions: Molecular subtyping using BP leads to a reclassification of 23% of tumors. The re-classification is most prominent in classically assessed triple positive patients where 48% of patients are re-assigned to the less responsive BP Luminal-type group vs. 44% of patients assigned to the responsive BP HER2-type group. These findings confirm the more accurate identification of molecular subgroups for treatment decision by BluePrint functional subtype classifier. Clinical trial information: NCT01479101.
Tumor profiling of 1189 geriatric breast tumors.
Authors: Xiu Joanne , Reddy Sandeep K. , Pohlmann Paula Raffin
Published: February 2017

116

Background: Breast cancer (BC) is a disease of aging and the number of geriatric patients is rising in the US. However, this group of patients is often excluded from clinical trials and under-represented in biomarker literature, complicating treatment selection strategies. Methods: BC tumors referred to Caris Life Sciences (Phoenix, AZ) between 2009 and 2015 were tested with a combination of immunohistochemistry (IHC), fluorescent/chromogenic in-situ hybridization (ISH) and sequencing (Next-generation and Sanger). De-identified biomarker data were analyzed. Results: A total of 1189 tumors collected from BC patients (M = 21/F = 1168) aged ≥ 70 (range: 70-97, average 75.6) were analyzed (breast biopsy n = 512; metastatic site n = 677). Of the 1088 tumors with available IHCs of ER, PR and IHC and/or ISH of HER2, 613 (56%) were HR+/HER2-, 72 (7%) were HR+/HER2+, 346 (32%) were TNBC and 57 (5%) were HR-/HER2+. Overall, 39 of 47 genes sequenced carried mutations with frequencies ranging from 0.2% to 37%. Highest mutation rates were seen in PIK3CA (37%), TP53 (37%), BRCA2 (12%), PTEN (5.8%), AKT1 (4.2%), cMET (3.9%), ERBB2 (3.5%), BRCA1 (3.3%) and ATM (3.2%). Among 13 patients with ERBB2 mutation, 3 had it amplified. PD-L1 expression on tumor cells was seen in 13% and PD-1 expression on tumor-infiltrating lymphocytes in 46%, with TNBC subtype showing the highest expression: 20% and 60%, respectively. In addition, TOPO1, TLE3, AR, TOP2A, SPARC were overexpressed in 61%, 58%, 55%, 51%, 37% of tumors, respectively, suggesting potential sensitivity to irinotecan, taxanes, anthracyclines and nab-paclitaxel. TS, RRM1 and ERCC1 were under-expressed in 69%, 69% and 53%, respectively, suggesting potential sensitivity to fluoropyrimidines, gemcitabine and platinums. A comparison with 7531 tumors from patients younger than 70, as well as description of abnormalities per molecular subtype of BC will be presented. Conclusions: Using multiple testing technologies, potentially targetable biomarker aberrations were identified in a large cohort of geriatric tumors. Our study provides key elements for the design of clinical trials focusing on geriatric patient population.
Invasive disease-free survival benefit following neratinib as extended adjuvant therapy in centrally-confirmed HER2+ early-stage breast cancer: The ExteNET phase III randomized placebo-controlled trial.
Authors: Chan Arlene , Martin Miguel , Von Minckwitz Gunter , Ejlertsen Bent , Chia Stephen K. L. , Buyse Marc E. , Mansi Janine , Gnant Michael , Holmes Frankie Ann , Moy Beverly , Iwata Hiroji , Wong Alvin , Lalani Alshad S. , Bryce Richard , Bebchuk Judith D , Delaloge Suzette
Published: February 2017

117

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor with clinical efficacy in trastuzumab pre-treated HER2-positive (HER2+) metastatic breast cancer (BC). ExteNET is an ongoing multicenter randomized placebo-controlled phase III trial evaluating the efficacy and safety of a 1-year course of neratinib in patients with early-stage HER2+ BC after trastuzumab-based adjuvant therapy (clinicaltrials.gov: NCT00878709). Methods: Women with locally-confirmed early-stage HER2+ BC were randomly assigned to oral neratinib 240mg/day or matching placebo for 1 year. Archived diagnostic tumor samples were submitted for HER2 gene amplification testing at a central laboratory. Primary endpoint: invasive disease-free survival (iDFS). Secondary endpoints: DFS including ductal carcinoma in situ (DFS+DCIS); distant disease-free survival (DDFS); time to distant recurrence (TDR). Stratified Cox proportional-hazards models were used to estimate hazard ratios (HR) for the ITT and amended ITT (aITT) populations; unstratified models were used for the centrally confirmed HER2 population. Treatment groups were compared using 2-sided log-rank tests. Results: The ITT population included 2840 patients (neratinib, N=1420; placebo, N=1420). The higher-risk aITT population (i.e. node-positive disease and randomized ≤1 year of completing prior trastuzumab) included 1873 patients (neratinib, N=938; placebo, N=935). Of the tumor samples analyzed, 1463 (86%) were centrally confirmed (neratinib, N=741; placebo, N=722). Conclusions: Neratinib significantly improves iDFS in trastuzumab-treated early-stage HER2+ BC patients. An enhanced treatment effect is observed with neratinib in women with centrally confirmed HER2+ tumors. Clinical trial information: NCT00878709. [Table: see text]