bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II randomized study of cixutumumab (IMC-A12: CIX) or ramucirumab (IMC‐1121B: RAM) plus mitoxantrone (M) and prednisone (P) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following disease progression (PD) on docetaxel (DCT) therapy.
Authors: Hussain Maha , Rathkopf Dana E. , Liu Glenn , Armstrong Andrew J. , Kelly William Kevin , Ferrari Anna C. , Hainsworth John D. , Yang Ling , Schwartz Jonathan D. , Higano Celestia S.
Published: February 2017

97

Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis and insulin-like growth factor (IGF-IR)-mediated signaling contribute to mCRPC growth. CIX and RAM are fully human IgG1 human monoclonal antibodies targeting IGF‐IR and VEGF receptor-2 (VEGFR-2) respectively. We investigated the safety and efficacy of CIX or RAM in combination with M + P in mCRPC pts with PD on DCT.

Methods: Eligible pts had mCRPC and PD during/within 120 days of DCT, ECOG PS 0-2, PSA ≥ 2 ng/mL, and adequate organ function. All pts received M 12 mg/m2 IV every 3 weeks (w) + P 5 mg PO BID for up to 12 cycles and were randomized to either CIX 6 mg/kg or RAM 6 mg/kg IV q w. Tumor assessments were after the first 3 cycles and then q6w. Primary endpoint was composite progression-free survival (cPFS: either RECIST PD, bone scan PD or new skeletal events). Other endpoints included safety, response and overall survival (OS). Sample size was based on a targeted 50% increase in median (mdn) cPFS from 2.6 months (m) to 3.9 m.

Results: 132 pts were treated; 66 each to CIX or RAM. Mdn age and baseline PSA was 65 yr and 129 ng/mL for pts treated with CIX and 68 yr and 111 ng/mL for RAM. Involvement of sites other than bone was CIX: 79% and RAM: 70%. The most frequent Grade ≥3 related adverse events for CIX/M/P: fatigue 17%, leukopenia 12%, and neutropenia 8%, and for RAM/M/P: leukopenia 8%, neutropenia 8% and hypertension 8%. Left ventricular dysfunction/CHF: 12% for CIX (0% G3) and 23% for RAM (8% G3). Mdn number of Rx cycles were 5 for CIX and 6 for RAM. Mdn follow-up was 22.7 m for CIX and 21.8 m for RAM. PSA response was 18.4% (8.8-32% 95% CI) on CIX and 22.0% (11.5-36% 95% CI) on RAM. Mdn cPFS and OS were 4.1 m (3.0-5.6 m 95% CI) and 10.8 m (6.5-13.0 m 95% CI) for CIX and 6.7 m (4.5-8.3 m 95% CI) and 13.0 m (9.5-16.0 m 95% CI) for RAM.

Conclusions: CIX/M/P and RAM/M/P were reasonably tolerated and achieved the primary endpoint. Preliminary cPFS and OS of RAM/M/P appear encouraging; sustained disease control was observed in pts on both rx arms. Correlation of serum markers of IGF and VEGF activity with clinical endpoints is planned.
Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: Results from the phase III AFFIRM study.
Authors: Scher Howard I. , Fizazi Karim , Saad Fred , Taplin Mary-Ellen , Sternberg Cora N. , Miller Kurt , De Wit Ronald , Mulders Peter , Hirmand Mohammad , Selby Bryan , De Bono Johann Sebastian ,   for the AFFIRM Investigators
Published: February 2017

LBA1

Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), competitively inhibits binding of androgens to the androgen receptor (AR), inhibits AR nuclear translocation, and inhibits association of the AR with DNA (Tran et al, Science. 2009;324:787). MDV3100 was selected for development based on activity in prostate cancer model systems with overexpressed AR, and was active in a phase I-II trial enrolling pre- and post-chemotherapy treated patients with progressive castration resistant disease (CRPC) (Scher et al, Lancet. 2010;375:1437). The AFFIRM trial evaluated whether MDV3100 could prolong overall survival (OS) in men with CRPC who progressed following docetaxel-based chemotherapy.

Methods: In this randomized, double-blind, placebo-controlled, multinational phase III study ( NCT00974311 ), patients who had received ≤ 2 regimens of docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids was allowed but not required. Patients were stratified by baseline ECOG performance status and mean brief pain inventory score. The primary endpoint was OS. Other efficacy endpoints included radiographic progression-free survival (PFS), time to first skeletal-related event, time to prostate-specific antigen (PSA) progression, and circulating tumor cell count conversion rate.

Results: 1,199 patients were randomized between Sep 2009 and Nov 2010. Based on a planned interim analysis at 520 death events, the Independent Data Monitoring Committee (IDMC) recommended the study be unblinded and placebo patients offered MDV3100 due to a significant OS benefit (p<0.0001; hazard ratio 0.631). The estimated median OS was 18.4 months for MDV3100 treated compared to 13.6 months for placebo treated men, a median OS difference of 4.8 months. Data to be available include PFS, time to PSA progression, and safety.

Conclusions: MDV3100, a novel ARSI, significantly improves OS in men with postdocetaxel-treated CRPC reducing the risk of death by 37% relative to placebo. The IDMC determined the risk:benefit of MDV3100 was favorable and recommended the phase III AFFIRM trial be unblinded.
Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study
Authors: Visvanathan Kala , Fackler MaryJo S. , Zhang Zhe , Lopez-Bujanda Zoila A. , Jeter Stacie C. , Sokoll Lori J. , Garrett-Mayer Elizabeth , Cope Leslie M. , Umbricht Christopher B. , Euhus David M. , Forero Andres , Storniolo Anna M. , Nanda Rita , Lin Nancy U. , Carey Lisa A. , Ingle James N. , Sukumar Saraswati , Wolff Antonio C.
Published: February 2017

Purpose

Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA).

Patients and Methods

Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch).

Results

Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS ( P < .001) and progressive disease at first restaging ( P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells ( P = .004).

Conclusion

Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring.
Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2–Positive Metastatic Bladder Cancer
Authors: Powles Thomas , Huddart Robert A. , Elliott Tony , Sarker Shah-Jalal , Ackerman Charlotte , Jones Robert , Hussain Syed , Crabb Simon , Jagdev Satinder , Chester John , Hilman Serena , Beresford Mark , Macdonald Graham , Santhanam Sundar , Frew John A. , Stockdale Andrew , Hughes Simon , Berney Daniel , Chowdhury Simon
Published: February 2017

Purpose

To establish whether maintenance lapatinib after first-line chemotherapy is beneficial in human epidermal growth factor receptor (HER) 1/HER2–positive metastatic urothelial bladder cancer (UBC).

Methods

Patients with metastatic UBC were screened centrally for HER1/HER2 overexpression. Patients who screened positive for HER1/2 and who did not have progressive disease during chemotherapy (four to eight cycles) were randomly assigned one to one to lapatinib or placebo after completion of first-line/initial chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS).

Results

Between 2007 and 2013, 446 patients with UBC were screened, and 232 with HER1- or HER2-positive disease were randomly assigned. The median PFS for lapatinib and placebo was 4.5 (95% CI, 2.8 to 5.4) and 5.1 (95% CI, 3.0 to 5.8) months, respectively (hazard ratio, 1.07; 95% CI, 0.81 to 1.43; P = .63). The overall survival for lapatinib and placebo was 12.6 (95% CI, 9.0 to 16.2) and 12.0 (95% CI, 10.5 to 14.9) months, respectively (hazard ratio, 0.96; 95% CI, 0.70 to 1.31; P = .80). Discontinuation due to adverse events were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3 to 4 adverse events for lapatinib and placebo was 8.6% versus 8.1% ( P = .82). Preplanned subset analysis of patients strongly positive for HER1/HER2 (3+ on immunohistochemistry; n = 111), patients positive for only HER1 (n = 102), and patients positive for only HER2 (n = 42) showed no significant benefit with lapatinib in terms of PFS and overall survival ( P > .05 for each).

Conclusion

This trial did not find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.
Tissue Factor As a Predictor of Recurrent Venous Thromboembolism in Malignancy: Biomarker Analyses of the CATCH Trial
Authors: Khorana Alok A. , Kamphuisen Pieter W. , Meyer Guy , Bauersachs Rupert , Janas Mette S. , Jarner Mikala F. , Lee Agnes Y.Y.
Published: February 2017

Purpose

Circulating tissue factor (TF) has been studied as a biomarker for predicting initial, but not recurrent, venous thromboembolism (VTE) in cancer, a setting in which predictors are incompletely understood. We evaluated the association of TF, clinical risk factors, and other biomarkers measured at the time of initial VTE with recurrent VTE in a prespecified analysis of the CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trial.

Methods

CATCH was a randomized, multicenter trial that investigated tinzaparin 175 IU/kg once daily or dose-adjusted warfarin for 6 months in patients with cancer and acute, symptomatic VTE. TF ELISA, soluble P-selectin, d-dimer, FVIII, and C-reactive protein were assayed. Fisher’s exact test was used to screen for association with VTE; competing risk regression analysis of time to recurrent VTE was conducted, accounting for multiple variables.

Results

The study population comprised 900 patients (recurrent VTE, n = 76; 8.4%). Of these patients, 805 had samples available for TF assay. Mean and median TF levels were 72.5 pg/mL and 50.3 pg/mL, respectively (range, 15.6 pg/mL to 4,798 pg/mL). Patients in the highest quartile of TF experienced the greatest VTE recurrence (> 64.6 pg/mL; 38 [19%] of 203 patients v 34 [6%] of 602 patients; relative risk, 3.3; 95% CI, 2.1 to 5.1; P < .001). In competing risk regression analysis of time to recurrent VTE, TF remained strongly associated with recurrent VTE (subdistribution hazard ratio [SHR], 3.3; 95% CI, 1.7 to 6.4). Other significant variables included venous compression from mass (SHR, 3.1; 95% CI, 1.4 to 6.5) and hepatobiliary cancer (SHR, 5.5; 95% CI, 2.3 to 13.6).

Conclusion

This is the first report, to our knowledge, to describe TF as a potential biomarker of recurrent VTE in patients with cancer who are on anticoagulation treatment. A risk-adapted strategy could help identify high-risk patients who may benefit from more intensive anticoagulation approaches.
Impact of Examined Lymph Node Count on Precise Staging and Long-Term Survival of Resected Non–Small-Cell Lung Cancer: A Population Study of the US SEER Database and a Chinese Multi-Institutional Registry
Authors: Liang Wenhua , He Jiaxi , Shen Yaxing , Shen Jianfei , He Qihua , Zhang Jianrong , Jiang Gening , Wang Qun , Liu Lunxu , Gao Shugeng , Liu Deruo , Wang Zheng , Zhu Zhihua , Ng Calvin S.H. , Liu Chia-chuan , Horsleben Petersen René , Rocco Gaetano , D’Amico Thomas , Brunelli Alessandro , Chen Haiquan , Zhi Xiuyi , Liu Bo , Yang Yixin , Chen Wensen , Zhou Qian , He Jianxing
Published: February 2017

Purpose

We investigated the correlation between the number of examined lymph nodes (ELNs) and correct staging and long-term survival in non–small-cell lung cancer (NSCLC) by using large databases and determined the minimal threshold for the ELN count.

Methods

Data from a Chinese multi-institutional registry and the US SEER database on stage I to IIIA resected NSCLC (2001 to 2008) were analyzed for the relationship between the ELN count and stage migration and overall survival (OS) by using multivariable models. The series of the mean positive LNs, odds ratios (ORs), and hazard ratios (HRs) were fitted with a LOWESS smoother, and the structural break points were determined by Chow test. The selected cut point was validated with the SEER 2009 cohort.

Results

Although the distribution of ELN count differed between the Chinese registry (n = 5,706) and the SEER database (n = 38,806; median, 15 versus seven, respectively), both cohorts exhibited significantly proportional increases from N0 to N1 and N2 disease (SEER OR, 1.038; China OR, 1.012; both P < .001) and serial improvements in OS (N0 disease: SEER HR, 0.986; China HR, 0.981; both P < .001; N1 and N2 disease: SEER HR, 0.989; China HR, 0.984; both P < .001) as the ELN count increased after controlling for confounders. Cut point analysis showed a threshold ELN count of 16 in patients with declared node-negative disease, which were examined in the derivation cohorts (SEER 2001 to 2008 HR, 0.830; China HR, 0.738) and validated in the SEER 2009 cohort (HR, 0.837).

Conclusion

A greater number of ELNs is associated with more-accurate node staging and better long-term survival of resected NSCLC. We recommend 16 ELNs as the cut point for evaluating the quality of LN examination or prognostic stratification postoperatively for patients with declared node-negative disease.
Promoting End-of-Life Discussions in Advanced Cancer: Effects of Patient Coaching and Question Prompt Lists
Authors: Rodenbach Rachel A. , Brandes Kim , Fiscella Kevin , Kravitz Richard L. , Butow Phyllis N. , Walczak Adam , Duberstein Paul R. , Sullivan Peter , Hoh Beth , Xing Guibo , Plumb Sandy , Epstein Ronald M.
Published: February 2017

Purpose

To build on results of a cluster randomized controlled trial (RCT) of a combined patient-oncologist intervention to improve communication in advanced cancer, we conducted a post hoc analysis of the patient intervention component, a previsit patient coaching session that used a question prompt list (QPL). We hypothesized that intervention-group participants would bring up more QPL-related topics, particularly prognosis-related topics, during the subsequent oncologist visit.

Patients and Methods

This cluster RCT with 170 patients who had advanced nonhematologic cancer (and their caregivers) recruited from practices of 24 participating oncologists in western New York. Intervention-group oncologists (n = 12) received individualized communication training; up to 10 of their patients (n = 84) received a previsit individualized communication coaching session that incorporated a QPL. Control-group oncologists (n = 12) and patients (n = 86) received no interventions. Topics of interest identified by patients during the coaching session were summarized from coaching notes; one office visit after the coaching session was audio recorded, transcribed, and analyzed by using linear regression modeling for group differences.

Results

Compared with controls, more than twice as many intervention-group participants brought up QPL-related topics during their office visits (70.2% v 32.6%; P < .001). Patients in the intervention group were nearly three times more likely to ask about prognosis (16.7% v 5.8%; P =.03). Of 262 topics of interest identified during coaching, 158 (60.3%) were QPL related; 20 (12.7%) addressed prognosis. Overall, patients in the intervention group brought up 82.4% of topics of interest during the office visit.

Conclusion

A combined coaching and QPL intervention was effective to help patients with advanced cancer and their caregivers identify and bring up topics of concern, including prognosis, during their subsequent oncologist visits. Considering that most patients are misinformed about prognosis, more intensive steps are needed to better promote such discussions.
Validation and Modification of a Prediction Model for Acute Cardiac Events in Patients With Breast Cancer Treated With Radiotherapy Based on Three-Dimensional Dose Distributions to Cardiac Substructures
Authors: van den Bogaard Veerle A.B. , Ta Bastiaan D.P. , van der Schaaf Arjen , Bouma Angelique B. , Middag Astrid M.H. , Bantema-Joppe Enja J. , van Dijk Lisanne V. , van Dijk-Peters Femke B.J. , Marteijn Laurens A.W. , de Bock Gertruida H. , Burgerhof Johannes G.M. , Gietema Jourik A. , Langendijk Johannes A. , Maduro John H. , Crijns Anne P.G
Published: February 2017

Purpose

A relationship between mean heart dose (MHD) and acute coronary event (ACE) rate was reported in a study of patients with breast cancer (BC). The main objective of our cohort study was to validate this relationship and investigate if other dose-distribution parameters are better predictors for ACEs than MHD.

Patients and Methods

The cohort consisted of 910 consecutive female patients with BC treated with radiotherapy (RT) after breast-conserving surgery. The primary end point was cumulative incidence of ACEs within 9 years of follow-up. Both MHD and various dose-distribution parameters of the cardiac substructures were collected from three-dimensional computed tomography planning data.

Results

The median MHD was 2.37 Gy (range, 0.51 to 15.25 Gy). The median follow-up time was 7.6 years (range, 0.1 to 10.1 years), during which 30 patients experienced an ACE. The cumulative incidence of ACE increased by 16.5% per Gy (95% CI, 0.6 to 35.0; P = .042). Analysis showed that the volume of the left ventricle receiving 5 Gy (LV-V5) was the most important prognostic dose-volume parameter. The most optimal multivariable normal tissue complication probability model for ACEs consisted of LV-V5, age, and weighted ACE risk score per patient (c-statistic, 0.83; 95% CI, 0.75 to 0.91).

Conclusion

A significant dose-effect relationship was found for ACEs within 9 years after RT. Using MHD, the relative increase per Gy was similar to that reported in the previous study. In addition, LV-V5 seemed to be a better predictor for ACEs than MHD. This study confirms the importance of reducing exposure of the heart to radiation to avoid excess risk of ACEs after radiotherapy for BC.
Fentanyl Sublingual Tablets Versus Subcutaneous Morphine for the Management of Severe Cancer Pain Episodes in Patients Receiving Opioid Treatment: A Double-Blind, Randomized, Noninferiority Trial
Authors: Zecca Ernesto , Brunelli Cinzia , Centurioni Fabio , Manzoni Andrea , Pigni Alessandra , Caraceni Augusto
Published: February 2017

Purpose

Fentanyl sublingual tablets (FST) are a potentially useful alternative to parenteral opioids such as subcutaneous morphine (SCM) to treat severe cancer pain episodes. No direct comparison between FST and SCM is available. The aim of this study was to test noninferiority of FST versus SCM during the first 30 min postadministration.

Methods

Patients receiving stable opioid therapy and experiencing a severe pain episode were randomly assigned to either 100 µg FST or 5 mg SCM in a double-blind, double-dummy trial. Average pain intensity (PI) assessed on a 0 to 10 numerical rating scale at 10, 20, and 30 min postadministration was the main end point. Analysis of covariance, adjusted by baseline PI, was the main analysis. The noninferiority margin (NIm) for the between-group difference was set at −0.6, that is, equal to one third of the minimum clinically important PI difference of two points.

Results

A total of 114 patients were randomly assigned to either FST (n = 58) or SCM (n = 56). One patient (in the FST group) withdrew consent before drug administration and was excluded from analysis. Baseline mean PIs were 7.5 in both groups; mean average PIs assessed at 10, 20, and 30 min postadministration were 5.0 and 4.5 for FST and SCM, respectively, with the 95% CI of the between-group difference including the NIm (−0.49; 95% CI, −1.10 to 0.09). Patients taking FST received a second drug dose after 30 min more frequently than did patients taking SCM (51% v 37%, respectively; risk difference, −13%; 95% CI, −30% to 3%). Both treatments were well tolerated, with average follow-up adverse event scores below the response of “A Little.” Ninety-three percent of patients preferred the sublingual administration.

Conclusion

This trial did not show noninferiority of FST versus SCM within the chosen NIm. Both treatments were safe, and patients preferred the sublingual route of administration. FST provides analgesia with modest to moderate increased risk of lower efficacy compared with SCM.
Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody–Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study
Authors: Moore Kathleen N. , Martin Lainie P. , O’Malley David M. , Matulonis Ursula A. , Konner Jason A. , Perez Raymond P. , Bauer Todd M. , Ruiz-Soto Rodrigo , Birrer Michael J.
Published: February 2017

Purpose

This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody–drug conjugate consisting of a humanized anti–folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer.

Patients and Methods

Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined.

Results

Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed.

Conclusion

IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.
Intentional Weight Loss and Endometrial Cancer Risk
Authors: Luo Juhua , Chlebowski Rowan T. , Hendryx Michael , Rohan Thomas , Wactawski-Wende Jean , Thomson Cynthia A. , Felix Ashley S. , Chen Chu , Barrington Wendy , Coday Mace , Stefanick Marcia , LeBlanc Erin , Margolis Karen L.
Published: February 2017

Purpose

Although obesity is an established endometrial cancer risk factor, information about the influence of weight loss on endometrial cancer risk in postmenopausal women is limited. Therefore, we evaluated associations among weight change by intentionality with endometrial cancer in the Women’s Health Initiative (WHI) observational study.

Patients and Methods

Postmenopausal women (N = 36,794) ages 50 to 79 years at WHI enrollment had their body weights measured and body mass indices calculated at baseline and at year 3. Weight change during that period was categorized as follows: stable (change within ± 5%), loss (change ≥ 5%), and gain (change ≥ 5%). Weight loss intentionality was assessed via self-report at year 3; change was characterized as intentional or unintentional. During the subsequent 11.4 years (mean) of follow-up, 566 incident endometrial cancer occurrences were confirmed by medical record review. Multivariable Cox proportional hazards regression models were used to evaluate relationships (hazard ratios [HRs] and 95% CIs) between weight change and endometrial cancer incidence.

Results

In multivariable analyses, compared with women who had stable weight (± 5%), women with weight loss had a significantly lower endometrial cancer risk (HR, 0.71; 95% CI, 0.54 to 0.95). The association was strongest among obese women with intentional weight loss (HR, 0.44; 95% CI, 0.25 to 0.78). Weight gain (≥ 10 pounds) was associated with a higher endometrial cancer risk than was stable weight, especially among women who had never used hormones.

Conclusion

Intentional weight loss in postmenopausal women is associated with a lower endometrial cancer risk, especially among women with obesity. These findings should motivate programs for weight loss in obese postmenopausal women.
Role of High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Men With Previously Treated Germ Cell Tumors
Authors: Pagliaro Lance C.
Published: February 2017

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

A 39-year-old, previously healthy man presented with a left testicular mass, confirmed on ultrasound. He underwent left inguinal orchiectomy, which disclosed testicular carcinoma composed of 90% choriocarcinoma, 9% seminoma, and 1% teratoma. Imaging revealed numerous metastases in the lungs, liver, and brain. Prechemotherapy levels of serum tumor markers were alpha-fetoprotein (AFP) 2.0 ng/mL, human chorionic gonadotropin (hCG) 151,111 IU/L, and lactate dehydrogenase 588 U/L. He received four courses of etoposide, ifosfamide, and cisplatin chemotherapy, given without bleomycin because of the anticipated need for postchemotherapy thoracic surgery. He had an incomplete response to induction chemotherapy. The serum hCG level was 8.1 IU/L, and there were residual lesions in the liver and lungs whereas the brain metastases had nearly resolved. His Eastern Cooperative Oncology Group performance status was zero. He had no symptoms of ototoxicity or peripheral neurotoxicity. Repeat serum hCG levels after chemotherapy were 12.3 IU/L at 2 weeks and 325 IU/L at 4 weeks. He was referred to discuss optimal ongoing treatment.
Clinical and Technical Aspects of Genomic Diagnostics for Precision Oncology
Authors: Sheikine Yuri , Kuo Frank C. , Lindeman Neal I.
Published: February 2017

The emergence of precision medicine has been predicated on significant recent advances in diagnostic technology, particularly the advent of next-generation sequencing (NGS). Although the chemical technology underlying NGS is complex, and the computational biology expertise required to build systems to facilely interpret the results is highly specialized, the variables involved in designing and deploying a genomic testing program for cancer can be readily understood and applied by understanding several basic considerations. In this review, we present key strategic decisions required to optimize a genomic testing program and summarize the technical aspects of different technologies that render those methods more or less suitable for different types of programs.
Genomics of Myeloproliferative Neoplasms
Authors: Zoi Katerina , Cross Nicholas C.P.
Published: February 2017

Myeloproliferative neoplasms (MPNs) are a group of related clonal hematologic disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR -ABL1–negative MPNs and a unifying therapeutic target. In addition, MPNs show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continue to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy, and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but there is a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems as well as the need to standardize the laboratory methodologies that are used.
Genomics, Signaling, and Treatment of Waldenström Macroglobulinemia
Authors: Hunter Zachary R. , Yang Guang , Xu Lian , Liu Xia , Castillo Jorge J. , Treon Steven P.
Published: February 2017

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88. Deletions involving chromosome 6q are common and include genes that modulate nuclear factor–κB, BCL2, BTK, apoptosis, differentiation, and ARID1B. Non–chromosome 6q genes are also frequently deleted and include LYN, a regulator of B-cell receptor signaling. MYD88 and CXCR4 mutations affect WM disease presentation and treatment outcome. Patients with wild-type MYD88 show lower bone marrow disease burden and serum immunoglobulin M levels but show an increased risk of death. Patients with CXCR4 mutations have higher bone marrow disease burden, and those with nonsense CXCR4 mutations have higher serum immunoglobulin M levels and incidence of symptomatic hyperviscosity. Mutated MYD88 triggers BTK, IRAK1/IRAK4, and HCK growth and survival signaling, whereas CXCR4 mutations promote AKT and extracellular regulated kinase-1/2 signaling and drug resistance in the presence of its ligand CXCL12. Ibrutinib is active in patients with WM and is affected by MYD88 and CXCR4 mutation status. Patients with mutated MYD88 and wild-type CXCR4 mutation status exhibit best responses to ibrutinib. Lower response rates and delayed responses to ibrutinib are associated with mutated CXCR4 in patients with WM. MYD88 and CXCR4 mutation status may be helpful in treatment selection for symptomatic patients. Novel therapeutic approaches under investigation include therapeutics targeting MYD88, CXCR4, and BCL2 signaling.
A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma
Authors: Ornstein Moshe C. , Wood Laura S. , Elson Paul , Allman Kimberly D. , Beach Jennifer , Martin Allison , Zanick Beth R. , Grivas Petros , Gilligan Tim , Garcia Jorge A. , Rini Brian I.
Published: February 2017

Purpose

Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored.

Patients and Methods

Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy.

Results

Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, −2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable).

Conclusion

Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.
Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology
Authors: Sepulveda Antonia R. , Hamilton Stanley R. , Allegra Carmen J. , Grody Wayne , Cushman-Vokoun Allison M. , Funkhouser William K. , Kopetz Scott E. , Lieu Christopher , Lindor Noralane M. , Minsky Bruce D. , Monzon Federico A. , Sargent Daniel J. , Singh Veena M. , Willis Joseph , Clark Jennifer , Colasacco Carol , Rumble R. Bryan , Temple-Smolkin Robyn , Ventura Christina B. , Nowak Jan A.
Published: February 2017

Purpose

Molecular testing of colorectal cancers (CRCs) to improve patient care and outcomes of targeted and conventional therapies has been the center of many recent studies, including clinical trials. Evidence-based recommendations for the molecular testing of CRC tissues to guide epidermal growth factor receptor (EGFR) –targeted therapies and conventional chemotherapy regimens are warranted in clinical practice. The purpose of this guideline is to develop evidence-based recommendations to help establish standard molecular biomarker testing for CRC through a systematic review of the literature.

Methods

The American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for patients with CRC. A comprehensive literature search that included over 4,000 articles was conducted to gather data to inform this guideline.

Results

Twenty-one guideline statements (eight recommendations, 10 expert consensus opinions and three no recommendations) were established.

Recommendations

Evidence supports mutational testing for genes in the EGFR signaling pathway, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize molecular testing for predictive and prognostic molecular biomarkers involve selection of assays, type of specimens to be tested, timing of ordering of tests and turnaround time for testing results. Additional information is available at: www.asco.org/CRC-markers-guideline and www.asco.org/guidelineswiki
Evidence on Effectiveness of Upper Neck Irradiation Versus Whole Neck Irradiation as Elective Neck Irradiation in Node-Negative Nasopharyngeal Cancer: A Meta-Analysis
Authors: Co Jayson L. , Mejia Michael Benedict A. , Dizon Janine Margarita R.
Published: February 2017

Purpose

Nasopharyngeal carcinoma (NPC) is a central tumor with a rich lymphatic network and a propensity for bilateral cervical lymph node metastasis. There is an orderly pattern of lymph node involvement in NPC. There is no current standard for prophylactic neck irradiation in node-negative or limited retropharyngeal (RP) node–positive NPC. This study aims to synthesize the current evidence on upper neck irradiation (UNI) versus whole neck irradiation (WNI) as prophylactic neck irradiation in node-negative or limited RP node–positive NPC.

Materials and Methods

A search of relevant articles was done from 2000 to October 2015. Critical appraisal and meta-analysis of the eligible studies were undertaken to assess the effectiveness of UNI versus WNI as prophylactic neck irradiation in node-negative or limited involved RP node NPC.

Results

Only one randomized controlled trial investigated the use of prophylactic UNI versus WNI and showed no confirmed nodal relapse in both arms. Pooled analysis of four retrospective studies showed no significant difference in nodal recurrence, whether in-field or out-of-field recurrence. There was also no significant difference in terms of 5-year distant metastasis–free and overall survival.

Conclusion

In node-negative or limited RP node–positive NPC, the current evidence shows the possibility of treating only the upper neck (levels II, III, and VA) without compromising nodal control, distant metastasis, and overall survival. As a result of the scarcity of data, more randomized clinical trials are warranted in this subset of patients.
Clinical and Epidemiological Profile of Breast Cancer in Mexico: Results of the Seguro Popular
Authors: Reynoso-Noverón Nancy , Villarreal-Garza Cynthia , Soto-Perez-de-Celis Enrique , Arce-Salinas Claudia , Matus-Santos Juan , Ramírez-Ugalde María Teresa , Alvarado-Miranda Alberto , Cabrera-Galeana Paula , Meneses-García Abelardo , Lara-Medina Fernando , Bargalló-Rocha Enrique , Mohar Alejandro
Published: February 2017

Purpose

One half of the Mexican population lacks comprehensive health care coverage. In 2003, a reform to the General Health Law was approved that led to the creation of the System of Social Protection in Health and made universal health coverage mandatory. The main innovation of this reform was Seguro Popular, which provided coverage for breast cancer. Here we report the outcomes of women with breast cancer treated at a cancer center in Mexico under Seguro Popular.

Materials and Methods

This was a retrospective cohort study that included all patients with breast cancer treated in the Instituto Nacional de Cancerología in Mexico City between January 2007 and December 2013 with Seguro Popular coverage. Demographic and clinical information were collected and survival outcomes were analyzed.

Results

A total of 4,300 women with breast cancer were included in this analysis. Most patients had locally advanced disease at diagnosis (53%, n = 2,293), and 13% (n = 558) presented with stage IV disease. Neoadjuvant chemotherapy was administered to 1,834 patients (52%), with a pathologic complete response in 25.1% (n = 460). Median follow-up was 40.5 months. Five-year survival for the entire cohort was 82% (95% CI, 81% to 84%). Five-year survival was 97% for early-stage disease (95% CI, 95% to 98%), 82% for locally advanced disease (95% CI, 80% to 84%), and 36% for metastatic disease (95% CI, 30% to 42%).

Conclusion

This represents the first description of a cohort of patients with breast cancer treated in Mexico under Seguro Popular. Seguro Popular has allowed our institution, and other Mexican centers, to establish efficient standardized mechanisms to treat patients with breast cancer.
Impact of Payer Constraints on Access to Genetic Testing
Authors: Whitworth Pat , Beitsch Peter , Arnell Christopher , Cox Hannah C. , Brown Krystal , Kidd John , Lancaster Johnathan M.
Published: February 2017

Background:

With increased demand for hereditary cancer genetic testing, some large national health-care insurance payers (LNHPs) have implemented policies to minimize inappropriate testing by mandating consultation with a geneticist or genetic counselor (GC). We hypothesized such a restriction would reduce access and appropriate testing.

Methods:

Test cancellation rates (ie, tests ordered that did not result in a reported test result), mutation-positive rates, and turnaround times for comprehensive BRCA1/2 testing for a study LNHP that implemented a GC-mandate policy were determined over the 12 months before and after policy implementation (excluding a 4-month transition period). Cancellation rates were evaluated based on the reason for cancellation, National Comprehensive Cancer Network testing criteria, and self-identified ancestry. A control LNHP was evaluated over the same period for comparison.

Results:

The study LNHP cancellation rate increased from 13.3% to 42.1% ( P < .001) after policy implementation. This increase was also observed when only individuals who met National Comprehensive Cancer Network criteria for hereditary breast and ovarian cancer testing were considered (9.5% to 37.7%; P < .001). Cancellation rates increased after policy introduction for all ancestries; however, this was more pronounced among individuals of African or Latin American ancestry, for whom cancellation rates rose to 48.9% and 49.6%, respectively, compared with 33.9% for individuals of European ancestry. Over this same time period, control LNHP cancellation rates decreased or stayed the same for all subgroups.

Conclusion:

These findings demonstrate that a GC-mandate policy implemented by a LNHP substantially decreased access to appropriate genetic testing, disproportionately impacting minority populations without any evidence that inappropriate testing was decreased.
Characterizing the Nature of Scan Results Discussions: Insights Into Why Patients Misunderstand Their Prognosis
Authors: Singh Sarguni , Cortez Dagoberto , Maynard Douglas , Cleary James F. , DuBenske Lori , Campbell Toby C.
Published: February 2017

Introduction:

Patients with incurable cancer have poor prognostic awareness. We present a detailed analysis of the dialogue between oncologists and patients in conversations with prognostic implications.

Methods:

A total of 128 audio-recorded encounters from a large multisite trial were obtained, and 64 involved scan results. We used conversation analysis, a qualitative method for studying human interaction, to analyze typical patterns and conversational devices.

Results:

Four components consistently occurred in sequential order: symptom-talk, scan-talk, treatment-talk, and logistic-talk. Six of the encounters (19%) were identified as good news, 15 (45%) as stable news, and 12 (36%) as bad news. The visit duration varied by the type of news: good, 15 minutes (07:00-29:00); stable, 17 minutes (07:00-41:00); and bad, 20 minutes (07:00-28:00). Conversational devices were common, appearing in half of recordings. Treatment-talk occupied 50% of bad-news encounters, 31% of good-news encounters, and 19% of stable-news encounters. Scan-talk occupied less than 10% of all conversations. There were only four instances of frank prognosis discussion.

Conclusion:

Oncologists and patients are complicit in constructing the typical encounter. Oncologists spend little time discussing scan results and the prognostic implications in favor of treatment-related talk. Conversational devices routinely help transition from scan-talk to detailed discussions about treatment options. We observed an opportunity to create prognosis-talk after scan-talk with a new conversational device, the question “Would you like to talk about what this means?” as the oncologist seeks permission to disclose prognostic information while ceding control to the patient.
Choosing Wisely: Opportunities for Improving Value in Cancer Care Delivery?
Authors: Rocque Gabrielle B. , Williams Courtney P. , Jackson Bradford E. , Wallace Audrey S. , Halilova Karina I. , Kenzik Kelly M. , Partridge Edward E. , Pisu Maria
Published: February 2017

Introduction:

Patients, providers, and payers are striving to identify where value in cancer care can be increased. As part of the Choosing Wisely (CW) campaign, ASCO and the American Society for Therapeutic Radiology and Oncology have recommended against specific, yet commonly performed, treatments and procedures.

Methods:

We conducted a retrospective analysis of Medicare claims data to examine concordance with CW recommendations across 12 cancer centers in the southeastern United States. Variability for each measure was evaluated on the basis of patient characteristics and site of care. Hierarchical linear modeling was used to examine differences in average costs per patient by concordance status. Potential cost savings were estimated on the basis of a potential 95% adherence rate and average cost difference.

Results:

The analysis included 37,686 patients with cancer with Fee-for-Service Medicare insurance. Concordance varied by CW recommendation from 39% to 94%. Patient characteristics were similar for patients receiving concordant and nonconcordant care. Significant variability was noted across centers for all recommendations, with as much as an 89% difference. Nonconcordance was associated with higher costs for every measure. If concordance were to increase to 95% for all measures, we would estimate a $19 million difference in total cost of care per quarter.

Conclusion:

These results demonstrate ample room for reduction of low-value care and corresponding costs associated with the CW recommendations. Because variability in concordance was driven primarily by site of care, rather than by patient factors, continued education about these low-value services is needed to improve the value of cancer care.