bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploration of risk factors for osteoporotic fracture following hematopoietic stem cell transplantation.
Authors: Lu Huifang , Murphy William A , Ebede Chidinma Chizoba , Karim Erfan , Rondon Gabriela , Leung Cheuk Hong , Liu Suyu , Champlin Richard E. , Pundole Xerxes
Published: September 2018

10080

Background: The incidence of fractures following hematopoietic stem cell transplantation (HSCT) ranges from 5% to 12% and the rates are up to 10 times greater than in the general population. The risk factors involved in osteoporotic fracture development following HSCT are incompletely understood. Methods: We conducted a retrospective cohort study of patients > 18 years that received a HSCT at MD Anderson Cancer Center, from January 1, 2001 to December 31, 2010. Patients were followed until December 31, 2013 for assessment of osteoporotic fracture occurrence using ICD-9 codes and confirmed by chart review. Cox regression model was used to identify independent risk factors for osteoporotic fractures. Factors included individual risk factors included in the World Health Organization Fracture Risk Assessment Tool FRAX and type of HSCT, type of preparatory regimen and underlying indication for HSCT. Results: A total of 5,170 patients received a HSCT during the 10-year study period, of which 527 (10%) patients developed an osteoporotic fracture. The median time of follow up was 3.2 years. A multivariate Cox regression model considering all clinical and malignancy specific risk factors was fitted. With the control of all other variables, the risk of developing fracture was 1.20 (95% confidence interval (CI):1.02-1.41) times higher for every 20 years increase in age at HSCT; female patients had a 1.24 (95% CI: 1.05-1.48) times higher risk compared to male patients; patients with a fracture prior to HSCT had a 2.01 (95% CI: 1.62-2.51) times higher risk compared to patients without a prior fracture; patients receiving an allogeneic HSCT had a 1.57 (95% CI: 1.20-2.05) times higher risk compared to patients receiving an autologous HSCT; and patients with multiple myeloma had a 2.62 (95% CI: 1.97-3.49) times higher risk compared to patients without multiple myeloma. Conclusions: Age at HSCT, gender, prior fracture status, type of HSCT, and underlying indication were identified to be statistically significantly associated with fracture. This is one of the first large scale studies assessing a comprehensive set of risk factors. To develop a risk model for fracture, we should consider these factors.
Cardiovascular disease and preventive care among cancer survivors: A population-based study.
Authors: Pearlstein Kevin A. , Basak Ramsankar , Chen Ronald C.
Published: September 2018

10081

Background: Cardiovascular disease (CVD) has been identified as a leading cause of mortality among cancer survivors, particularly long-term survivors. However, studies examining the prevalence of CVD risk factors and CVD-specific preventive care among US cancer survivors are lacking. We utilize the National Health Interview Survey (NHIS) data to address this knowledge gap. Methods: NHIS is an annual survey among roughly 88,000 individuals across the US, and its data are representative of US population-based estimates of health status, healthcare behavior, and healthcare utilization. 15,747 individuals surveyed from 2011 to 2015 who reported a history of cancer (except non-melanomatous skin cancer) were included in this study. Prevalence of CVD risk factors and preventive care received were calculated incorporating NHIS sample weights. A multivariable logistic regression model was used to evaluate factors associated with risk factor monitoring. Results: 55% of the cohort was ≥6 years out from cancer diagnosis and 53% were 65 years or older. CVD risk factors were prevalent across the entire cohort (Table). Among survivors < 50 years, 30% were active smokers, and 35% obese. Among survivors ≥65, 40% had known CVD. Among survivors with each risk factor, rates of monitoring and management of each is reported in Table. On multivariable analysis, seeing a generalist was strongly associated with monitoring of blood pressure (OR 18), cholesterol (OR 8), and fasting glucose (OR 3). Conclusions: This study provides the current status of preventive care among US cancer survivors, illustrating that CVD and its risk factors are common. Rates of monitoring of hypertension and hyperlipidemia are high, but there is room for improvement in interventions targeting obesity and smoking cessation. [Table: see text]
Effect of prophylactic fentanyl buccal tablet (FBT) on exertional dyspnea in patients with cancer: A pilot double-blind, placebo-controlled, randomized trial.
Authors: Hui David , Kilgore Kelly L. , Frisbee-Hume Susan , Park Minjeong , Liu Diane D , Bruera Eduardo
Published: September 2018

10085

Background: Exertional dyspnea is one of the most common, debilitating and difficult-to-treat symptoms in cancer patients. Few clinical trials have been conducted. We tested the hypothesis that FBT, a rapid onset opioid, given prophylactically prior to exertion can improve exertional dyspnea. Methods: In this double-blind parallel (1:1) RCT, we asked cancer patients who were opioid-tolerant and had exertional dyspnea to complete a 6 minute walk test (6MWT) at baseline, and then randomly assigned them to either FBT proportional to 20-50% of daily dose or placebo 30 minutes before a second 6MWT. The primary outcome was a validated 11-point dyspnea NRS assessing dyspnea “now” (where 0 = none and 10 = worst possible) every minute during each 6MWT. Secondary outcomes included walk distance, vital signs and neurocognitive testing, adverse effects, and global impression. Ten evaluable patients in the FBT provided 80% power to detect an effect size as small as 1.0 using a two-sided paired t-test with a significance level of 5% to compare the change of dyspnea between the first and second walk tests. We compared the outcomes between the first and second 6MWTs using paired t-test. Results: Among 22 patients enrolled, 20 (91%) completed the study (9 FBT, 11 placebo). FBT was associated with a significant within-arm reduction in dyspnea NRS between 0 and 6 minutes (mean change -2.4, 95% confidence interval [CI] -3.5, -1.3) and respiratory rate (mean change -2.6, 95% CI -4.7, -0.4). Placebo was also associated with a non-statistically significant decrease in dyspnea (mean change -1.1). Between arm comparison of dyspnea scores in the second 6MWT favored FBT, albeit not statistically significant (estimate -0.25, P = 0.068). Global impression revealed more patients in the FBT group than placebo group reporting their dyspnea was at least “somewhat better” in the second 6MWT (4/9 vs. 0/11, P = 0.03). The other secondary outcomes did not differ significantly between arms. Conclusions: These data support our hypothesis that proportionally dosed FBT was associated with improvement in exertional dyspnea, and highlights the need for larger confirmatory trials. Clinical trial information: NCT01856114.
The effect of pain self-management based on pain control diary on breakthrough pain.
Authors: Fan Zu-Yan , Lin Jin-Xiang , Li Xing , Chen Xiang-Wei , Huang Xiu-Yan
Published: September 2018

10107

Background: Most patients suffer from cancer pain, especially breakthrough pain. The overall incidence of breakthrough pain is estimated to be 65%. Self-management makes patients actively participating in the use of drugs, transforming their roles and adjusting their moods in order to better cure their own diseases. Therefore, the aim of the study is to discuss the effect of reducing cancer pain patients' breakthrough pain through self-management based on pain control diary. Methods: From October, 2015 to October, 2016, a total of 200 patients treated with opioids for cancer pain were randomly divided into groups. Patients in the control group were given general management including the Standard "the three steps analgesic ladder treatment for cancer pain", the traditional form of health education and psychological care; While the intervention group in addition to conventional cancer pain management, self-management based on pain control diary was applied. Through repeated intensive training, patients learned how to do self-assessment, to master the feature of their own pain, problem-solving skills and formal report to their oncologists in charge. Results: After six weeks of intervention , 10% patients in the intervention group had suffer breakthrough pain compared with 54% patients in the control group (P < 0.05). The whole processing management model is a whole process, specialization and humanization Care model for patients with advanced cancer pain management, can effectively improve patient medication compliance, reduce the cancer breakthrough pain's incidence, improve the patients,s life quality with cancer pain. The medication compliance of the intervention group was significantly higher than that of the control group(X2= 46.606, P<0.001), and in intervention group the incidence of breakthrough pain was significantly lower than that of the control group (X2= 44.148, P<0.001) Conclusions: The self management based on pain control diary is a whole process, specialization and humanization Care model for patients with advanced cancer pain management, can effectively improve patient medication compliance, reduce the cancer breakthrough pain's incidence, improve the patients's life quality with cancer pain.
LCCC 1025: Phase II study of everolimus, trastuzumab, and vinorelbine for HER2+ breast cancer brain metastases (BCBM).
Authors: Anders Carey K. , Deal Allison Mary , Van Swearingen Amanda Elyse Day , Siegel Marni , Hayes David N. , Jo Heejoon , Little Paul , Dees Elizabeth Claire , Muss Hyman B. , Jolly Trevor Augustus , Zagar Timothy , Smith J Keith , Fisher Julie Gottlieb , Shah Nikita C. , Nabell Lisle , Nanda Rita , Dillon Patrick Michael , Puhalla Shannon , Abramson Vandana Gupta , Carey Lisa A.
Published: September 2018

1011

Background: HER2+ BC is an aggressive subset of BC with high rates of BM and poor survival. Two-thirds of BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy (Rx). This phase II study evaluated everolimus (E), a brain permeable mTOR inhibitor, added to trastuzumab (T) and vinorelbine (V) in patients (pts) with HER2+ BCBM. Methods: Eligible pts had progressing HER2+ BCBM. Pts received E (5mg PO QD), T (2mg/kg IV weekly) and V (25mg/m2 IV d1, 8 of 21d cycle). The primary endpoint was intracranial response rate (RR [CR+PR], modified RECIST); secondary objectives (CNS clinical benefit rate [CBR, CR+PR+SD], extracranial RR, time to progression (TTP), overall survival (OS), and correlative studies). Targeted DNA sequencing of 20 tissues from 18 pts was performed. We used a two-stage design to distinguish ORR of 5% vs 20%. Results: 32 pts were evaluable for toxicity; 26 for efficacy. Median age was 53 (28–70 yrs). 31/32 pts had prior radiation: 13 (42%) WBRT, 8 (26%) radiosurgery, 9 (29%) both. Median prior lines of metastatic Rx was 2 (0–7). 30 (94%) received anti-HER2 Rx: 91% T, 69% lapatinib, 38% pertuzumab, 25% TDM1. Intracranial RR was 4% (1 PR, 6 SD > 6 mos, 10 SD > 3 mos, 9 PD). CNS CBR (6 mos) was 27%; CNS CBR (3 mos) was 65%. Extracranial RR was 46%. Median TTP was 4 mos (95% CI, 2.2 –5). OS was 12.2 mos (95% CI, 0.6 – 20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). DNA sequencing showed heterogeneous HER2 copy number amplification (CN amp): only 11/20 show HER2 CN amp (median 40X v 0.7X; 5/11 BC, 4/4 BCBM, 1/2 liver mets, 1/3 LN). BCBM exhibited high-level HER2 CN amp (median 49X) vs other sites (16X). While 11/20 show both HER2 CN amp and PI3K pathway mutation, this was not associated TTP; RAD21 CN amp was associated with TTP < 3 mos. Lack of HER2 CN amp plus a HER2 Tyr-kinase domain mutation was seen in a pt with nonresponse and short OS. Conclusions: While intracranial RR to ETV was low in pts with HER2+ BCBM, a substantial proportion had CNS CBR; OS was 1 year for this pt population. No new toxicity signals were observed. Further evaluation of DNA heterogeneity, including degree of HER2 CN amp in HER2+ BCBM, and association with outcome is warranted. Clinical trial information: NCT01305941.
Efficacy of Gastroplegia Patch on treating postoperative gastroplegia: A multicenter, double-blind, randomized controlled trial.
Authors: Zhou Tian , Zhou Qin , Wang Yanbin , Ye Yingjiang , Tian Yantao , Hu Kaiwen
Published: September 2018

10110

Background: Postoperative gastroplegia is common in digestive cancer patients and there were no effective treatments. Gastroplegia Patch is an external-used Chinese Herbal Medicine recipe. It has been applied clinically for more than ten years, which showed good effect. We conducted this study to verify its safety and efficacy on the symptoms of postoperative gastroplegia. Methods: This clinical trial was designed as a multi-center, double-blind, superior effect, randomized controlled trial. It has been registered in ISRCTN (No.18291857) before initiation and was monitored by the third party. Patient inclusion criteria: 1. Gastroenterological cancer patient who was diagnosed as post-surgery gastroplegia, could not eat and need tube feeding (parenteral nutrition or with Jejunum nutrient canal); 2. The local identification of abdomen is cold pattern, which means this kind of patient prefers heat to cold, likes hot food and hates cold ones. Eligible participants were randomized into two arms, placebo arm and Patch arm, respectively. Beside the basic treatments (nutrition support, gastrointestinal decompression, promoting gastric dynamics medicine), placebo or Gastroplegia Patch was applied in control group or Patch group, respectively. Placebos or the patches were allocated at two acupuncture points ( Zhongwan and Shenque). The intervention course was 14 days or reached primary endpoint. The primary endpoint was able to eat without tube feeding. Results: All the 120 eligible participants (60 per arm) were recruited from four AAA hospitals in Beijing, China. Analysis was conducted based on intent-to-treat strategy. After the intervention, 68.33% of the participants in the Patch group were able to eat without tube feeding, which significantly higher than that of 41.67% in the control group (p = 0.003). It took 8 days on average in the Patch group to show effect, which significantly faster than that of 10 days in the control group (p = 0.017). The incidences of adverse events were compatible between the two arms (p = 0.244). Conclusions: Gastroplegia Patch is safe and effective in treating postoperative gastroplegia in gastroenterological cancer patients with cold syndrome. Clinical trial information: 18291857.
Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim for the prevention of severe neutropenia, in patients with breast cancer receiving myelosuppressive chemotherapy.
Authors: Krendyukov Andriy , Harbeck Nadia , Gascon Pedro , Gattu Sreekanth , Li Yuhan , Blackwell Kimberly L.
Published: September 2018

10116

Background: In 2015, filgrastim EP2006 (Zarxio) became the first biosimilar approved by the FDA for commercial use in the US. This phase III randomized, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC) compares US-licensed filgrastim, Neupogen (reference), with two groups who received alternating treatment with reference and biosimilar every other treatment cycle. Methods: A total of 218 patients receiving 5µg/kg/day filgrastim over 6 chemotherapy cycles were randomized 1:1:1:1 into 4 arms. Two arms received only 1 product, biosimilar or reference (unswitched), and 2 arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over cycles 1─6). Since the switch occurred from Cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during Cycles 2─6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for Cycles 2─6 was shown if 95% confidence intervals (CIs) were within a pre-defined margin of -15%. Results: A total of107 patients switched treatment, and 51 patients received reference in all cycles. Baseline characteristics were similar between groups. Incidence of FN was 3.4% (switched) vs. 0% (reference) (95% CI: -9.65; 4.96), which is within the predefined non-inferiority margins. Infections occurred in 9.3% (switched) vs. 9.9% (reference). Hospitalization due to FN was low with 1 patient in Cycle 6 (switched). TEAEs related to filgrastim were reported in 42.1% (switched) vs. 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) vs. 39.2% (reference) (all cycles), including bone pain (30.8% vs. 33.3%). No anti-drug antibodies were identified. Conclusions: There was no evidence of clinically meaningful differences when patients with breast cancer were switched from reference to biosimilar filgrastim, or from biosimilar to reference filgrastim. Clinical trial information: NCT01519700.
Frequency and factors predictive of aberrant drug behavior in patients presenting to outpatient supportive care center at a comprehensive cancer center.
Authors: Yennu Sriram , Edwards Tonya , Arthur Joseph Anthony , Williams Janet L. , Lu Zhanni , Reddy Suresh , Bruera Eduardo
Published: September 2018

10118

Background: Opioid misuse is a growing crisis in cancer patients. Cancer patients at risk of aberrant drug behaviors (ADB) are frequently underdiagnosed in routine cancer care. The aim of this study was to determine the frequency and factors associated with ADB using the “Screener and Opioid Assessment for Patients tool” (SOAPP-14) in cancer patients seen at the outpatient supportive care center. We also examined the screening performance of Cut Down, Annoyed, Guilty, and Eye Opener (CAGE-AID) as compared to The SOAPP-14 as a gold standard. Methods: In this retrospective study, 1108 consecutive patients referred to supportive care clinic were reviewed. Patients were eligible if they were ≥18 yrs, have a diagnosis of cancer, and were on opioids for pain for atleast a week. Patients’ demographics, the Edmonton Symptom Assessment Scale (ESAS), SOAPP-14, and CAGE-AID scores were analyzed. ADB+ was defined as SOAPP-14 score ≥7. Descriptive statistics, spearman correlation coefficient, multivariate, and ROC analysis were performed. Results: 703/1108 consults were eligible. A total of 153/703 (22%) were ADB +ve. SOAPP-14 scores were positively correlated with CAGE-AID r = .38, p < 0.001; male gender r = 0.11, p = 0.003; ESAS pain r = 0.11, p = 0.005; ESAS depression r = 0.22, p < 0.001; ESAS anxiety r = 0.22, p < 0.001, and ESAS financial distress r = 0.23, p < 0.001. Multivariate analysis indicated that the odds ratio for ADB +ve was 6.18 in patients with CAGE-AID+ (p < 0.001), 1.8 for male gender (p = 0.007), 1.1/pt. for ESAS anxiety (p = 0.044), and 1.1/pt. for ESAS financial distress (p = 0.007). A CAGE-AID score of 1/4 has a sensitivity of 47%, specificity of 89% positive predictive value 63.6% and negative predictive value 69.2%. Conclusions: Our study suggests that 22% of cancer patients on opioids presenting to supportive care center are at risk of aberrant drug behavior (ADB). Male patients with anxiety, financial distress, and prior alcoholism/illicit drug use are significant predictors of ADB’s. A cut off score of ≥1 out 4 on CAGE-AID questionnaire allows better screening of ADB in outpatient advanced cancer patients. Further research to effectively manage these patients is needed.
Radiation for bone metastases: Reconsidering the optimal timing.
Authors: Yang Joanna C. , Hsu Brittany , Wu Abraham Jing-Ching , Kohutek Zachary , Yang T. Jonathan
Published: September 2018

10122

Background: Bone metastases impair function and decrease quality of life due to acute or chronic pain. The standard approach for patients with multiple bone metastases is systemic therapy and palliative radiation therapy (RT) when the metastases become symptomatic. This study aims to understand the characteristics and outcomes for inpatients admitted for painful bone metastases. Methods: An inpatient radiation oncology consult registry was created in 2015 to evaluate patterns of care for patients receiving RT in the inpatient setting. Of the 1151 consults requested between 7/2015 and 6/2016, 28% (n = 323) were for evaluation of symptomatic bone metastases in patients who were hospitalized for acute or chronic pain. Among this cohort, 64% (n = 208) went on to receive RT for 225 bone metastases. Sixty percent of RT courses were initiated while the patient was hospitalized. Clinical characteristics correlated with overall survival (OS) were evaluated through Cox regression analysis. Results: The median follow up for the 208 patients who received RT was 4 months (0.1-9 months). Patient median age was 61 (10-92 years), and the median KPS was 70 (20-90). The most common sites treated were spine (50%), joints such as hip and shoulder (11%), long bones including femur and humerus (11%), and pelvis (10%). Sixty-one percent (n = 138) of the treated metastases were diagnosed ≥4 months prior to RT. The median survival after receiving palliative RT was 4 months (0-19 months). Among the 141 patients who had died at the time of analysis, 92 (65%) died within 2 months, and 128 (91%) within 6 months. Eighteen patients (9%) discontinued RT to transition to hospice care. OS after RT is significantly correlated with KPS (p < 0.0001) at the time of consult but not with patient age or site of treated disease. Conclusions: In this select group of inpatients who were evaluated for palliation of symptomatic bone metastases, we found a short OS after RT. The majority of metastases were present for ≥4 months prior to RT. This study suggests that earlier RT for high-risk metastases should be considered to prevent development of symptomatic disease that requires hospitalization. Risk factors for development of painful bone metastases are being studied prospectively at our institution.
Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA (ctDNA) in metastatic breast cancer.
Authors: Fribbens Charlotte Victoria , Garcia-Murillas Isaac , Beaney Matthew , Hrebien Sarah , Howarth Karen , Epstein Michael , Rosenfeld Nitzan , Ring Alistair E. , Johnston Stephen R. D. , Turner Nicholas C.
Published: September 2018

1015

Background: Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have a high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to first line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Methods: Seventy-one patients on first line AI therapy for metastatic breast cancer were enrolled in a prospective study to collect plasma samples for ctDNA analysis every three months on therapy, and at disease progression. All plasma samples were analysed with ESR1 multiplex digital PCR assays, and samples at disease progression were analysed by InVision (enhanced tagged-amplicon sequencing). Mutations were tracked back through samples prior to disease progression to study the evolution of mutations on therapy. Results: Of the 34 patients who progressed on first line AI, 53% (18/34) had ESR1 mutations detectable at progression. Sequencing of progression plasma ctDNA identified polyclonal RAS mutations in 10.7% (3/28) progressing patients (2 polyclonal KRAS, 1 monoclonal HRAS), all of whom also had ESR1 mutations, and a patient with an activating p.R248C FGFR3 mutation. ESR1 mutations were subclonal in 78.6% (11/14) patients, with all RAS mutations being rare subclones. In serial tracking prior to progression, ESR1 mutations were detectable in plasma with a median of 5.3 months (95% CI 2.9-NA) prior to clinical progression. Conclusions: ESR1 mutations are found at high frequency in patients progressing on AI, but are frequently sub-clonal and may not be the sole driver of AI resistance in these patients. Poly-clonal KRAS mutations are identified as a novel mechanism of resistance to AI, associated with detection of ESR1 mutations.
Efficacy of trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (MBC) previously treated with pertuzumab (P).
Authors: Urruticoechea Ander , Im Seock-Ah , Munoz Montserrat , Baselga Jose , Yardley Denise A. , Heeson Sarah , Jones Sarah , Knott Adam , Douthwaite Hannah , Badovinac Crnjevic Tanja , Swain Sandra M.
Published: September 2018

1023

Background: T-DM1 was approved for pts with HER2+ MBC previously treated with trastuzumab (H) and a taxane based on the phase III EMILIA study. P in combination with H + docetaxel (T) later became the first-line standard of care for HER2+ MBC, but there are limited data on T-DM1 efficacy in pts who previously received P. We present exploratory efficacy results from pts treated with T-DM1 any time after P from 2 phase III studies: CLEOPATRA and PHEREXA. Methods: CLEOPATRA (NCT00567190) and PHEREXA (NCT01026142) are randomized, 2-arm trials evaluating P-based regimens for HER2+ MBC. CLEOPATRA studies H + T + P vs HT + placebo in pts with no prior anti-HER2 treatment (tx) or chemotherapy for MBC, while PHEREXA studies H + capecitabine (C) +/− P in pts who progressed during/after previous H tx for MBC. We assessed overall survival (OS) in an exploratory analysis of pts who either received or did not receive T-DM1 at any time after discontinuing study-assigned tx in CLEOPATRA or PHEREXA. Results: Of 408 pts who received HTP in CLEOPATRA and 228 pts who received HCP in PHEREXA, 32 and 43 pts received subsequent T-DM1, respectively (Table). Median duration of T-DM1 tx was 7.1 mo (range 0−44) and 4.2 mo (range 0−22), respectively, and median time from discontinuation of P to start of T-DM1 was 3.5 mo (range 1−47) and 10.6 mo (range 1−28). Conclusions: Although data are limited in these exploratory analyses, our results provide additional evidence of T-DM1 clinical activity in pts with HER2+ MBC who progressed on prior P + H, a finding with real-world implications. Clinical trial information: NCT00567190, NCT01026142. [Table: see text]
Eribulin in combination with pertuzumab plus trastuzumab for HER2-positive advanced or recurrent breast cancer (JBCRG-M03).
Authors: Narui Kazutaka , Yamashita Toshinari , Kitada Masahiro , Kawaguchi Hidetoshi , Hattori Masaya , Yoshinami Tetsuhiro , Matsunami Nobuki , Yanagihara Kazuhiro , Kawasoe Teru , Nagashima Takeshi , Bando Hiroko , Yano Hiroshi , Hasegawa Yoshie , Nakamura Rikiya , Kashiwaba Masahiro , Masuda Norikazu , Morita Satoshi , Ohno Shinji , Toi Masakazu ,   Japan Breast Cancer Research Group (JBCRG)
Published: September 2018

1025

Background: Pertuzumab (P) provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer (MBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of intravenous docetaxel at a dose of 75 mg/m2 every 3 weeks in MBC patients is difficult. Eribulin (E) is a well-tolerated cytotoxic agent. We report the efficacy and safety of E in combination with trastuzumab (T) plus P as first- and second-line therapy for metastatic or advanced BC in a multicenter, open-label phase II study (UMIN000012232). Methods: HER2-positive advanced or recurrent BC patients with no or a single prior therapy as advanced or recurrent chemotherapy were enrolled. All patients were administered T and taxane as adjuvant or first-line chemotherapy. Treatment consisted of E 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and T (8 mg/kg loading dose > 6 mg/kg) plus P (840 mg loading dose > 420 mg) once every 3 weeks, all given intravenously. The primary end point was PFS. Results: From November 2013 to April 2016, 50 patients were enrolled. Forty-nine patients were eligible for safety analysis; full analysis set (FAS) includes 46 patients. The median patient age was 56 years (range 23–70), and 8 (16%) and 41 (84%) patients were treated in first- and second-line settings, respectively. Twenty-eight patients out of 49 patients (57%) continued the protocol therapy at the end of 8 cycles and median PFS was not yet reached. The response rate by RECIST ver.1.1 was 56.5% in FAS. The relative dose intensity of E, T, and P were 93.3% (range 77.0%–100%), 100% (range 96.0%–100%) and 100% (range 89.7%–100%), respectively in FAS. The grade 3/4 adverse effects (AE) were neutropenia in 5 patients (10.2%) including 2 patients (4.1%) with febrile neutropenia, hypertension in 3 patients (6.1%), and other AEs in only one patient. Average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusions: E in combination with T plus P was well-tolerated and could be an alternative to docetaxel-based combination therapy for HER2-positive MBC. Clinical trial information: 000012232.
Palbociclib (PAL) + letrozole (L) as first-line (1L) therapy (tx) in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC): Efficacy and safety across patient (pt) subgroups.
Authors: Finn Richard S. , Dieras Veronique , Rugo Hope S. , Joy Anil A. , Moulder Stacy L. , Walshe Janice Maria , Mukai Hirofumi , Shparyk Yaroslav V. , Park In Hae , Mori Ave , Lu Dongrui (Ray) , Gauthier Eric Roland , Gelmon Karen A.
Published: September 2018

1039

Background: Hormone tx (HT) is the primary 1L tx for ER+ ABC. In the PALOMA-2 study (NCT01740427), PAL+L as 1L ABC tx prolonged progression-free survival (PFS; hazard ratio [HR] 0.58; P<.001) (Finn et al, NEJM. 2016). Methods: Postmenopausal pts with ER+/HER2– ABC and no prior systemic treatment in the advanced setting were randomized 2:1 to PAL (125 mg/d oral [3 wk on, 1 wk off]) + L (2.5 mg QD) or placebo (P) + L. Key endpoints were investigator-assessed PFS and safety. Results: 666pts (444, PAL+L; 222, P+L) were enrolled. Pts were similarly distributed between arms for visceral (48%) and nonvisceral (52%) disease and prior HT (56%) and no prior HT (44%); more pts had disease-free interval (DFI) >12 mo (40%) than ≤12 mo (22%). Median PFS (mPFS) was improved in all subgroups by adding PAL to L (Table). Adverse events were consistent across subgroups, as described for the full study population. Conclusions: PAL+L improved mPFS vs P+L with manageable toxicity across all subgroups including those with visceral disease. PAL+L provides a 1L option that should be considered for all pts with ER+/HER2- ABC. Sponsor: Pfizer Clinical trial information: NCT01740427. [Table: see text]
Preliminary results of a phase I/IIa study of BMS-986156 (glucocorticoid-induced tumor necrosis factor receptor–related gene [GITR] agonist), alone and in combination with nivolumab in pts with advanced solid tumors.
Authors: Siu Lillian L. , Steeghs Neeltje , Meniawy Tarek , Joerger Markus , Spratlin Jennifer L. , Rottey Sylvie , Nagrial Adnan , Cooper Adam , Meier Roland , Guan Xiaowei , Phillips Penny , Bajaj Gaurav , Gokemeijer Jochem , Korman Alan J. , Aung Kyaw Lwin , Carlino Matteo S.
Published: September 2018

104

Background: BMS-986156 is a fully human IgG1 agonist mAb that binds GITR and promotes T effector cell activation and possible reduction/inactivation of T regulatory cells. Preclinical data show enhanced antitumor T-cell activity with anti-GITR + anti–programmed death-1 (PD-1). Here we describe preliminary dose escalation data from a phase I/IIa study of BMS-986156 ± nivolumab (anti–PD-1 mAb) in pts with advanced solid tumors (NCT02598960). Methods: During dose escalation, pts received BMS-986156 (10–800 mg) or BMS-986156 (30–800 mg) + nivolumab (240 mg) every 2 weeks. Objectives included safety (primary), immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of Dec 12, 2016, 66 pts were treated with BMS-986156 (n = 29) or BMS-986156 + nivolumab (n = 37).No dose-limiting toxicities (DLTs) were reported during dose escalation. The most common treatment-related adverse events reported with BMS-986156/BMS-986156 + nivolumab included pyrexia (21%/30%), chills (10%/16%), and fatigue (14%/14%); events were G1/2 in all pts except for 4 pts (6%) treated with the combination (G3 lipase [n = 1], G3 lung infection [n = 1], G3 fatigue [n = 1], and G3 aspartate aminotransferase with G4 creatine phosphokinase [n = 1; leading to discontinuation of treatment]). Preliminary data indicate that the incidence of immunogenicity to BMS-986156 was low when BMS-986156 ± nivolumab was administered. Preliminary data also indicate that BMS-986156 ± nivolumab exhibits linear PK with dose proportionality after a single dose, and BMS-986156 ± nivolumab is biologically active in PD analyses in peripheral blood. Initial antitumor activity has been observed in several pts treated with the combination; these data will be reported. Conclusions: This is the first report of clinical data with an anti-GITR mAb ± a PD-1 inhibitor.BMS-986156 ± nivolumab was well tolerated, with no DLTs and low immunogenicity. Antitumor activity was observed with BMS-986156 + nivolumab at doses predicted to be biologically active. Further evaluation of this combination in pts with advanced solid tumors is ongoing. Clinical trial information: NCT02598960.
Evaluation of tumor and circulating cell free (cf) DNA mutations in women with hormone refractory metastatic breast cancer (MBC) enrolled in a phase I study of Z-endoxifen (MC093C).
Authors: Goetz Matthew P. , Suman Vera J. , Reid Joel M. , Northfelt Donald W. , Burhow Sarah A , Safgren Stephanie L. , McGovern Renee M. , Dockter Travis J. , Haddad Tufia C. , Erlichman Charles , Adjei Alex A. , Visscher Daniel W. , Kipp Benjamin , Hawse John , Doroshow James H. , Collins Jerry M. , Streicher Howard , Ames Matthew M. , Ingle James N. , Liu Minetta C.
Published: September 2018

1043

Background: In estrogen receptor (ER) positive MBC, mutations (e.g. ESR1), identified from tumor biopsies or cfDNA, confer resistance. The concordance between mutations observed in tumor and cfDNA and the implications for response to Z-endoxifen, a potent anti-estrogen, are unknown. Methods: We previously conducted a phase I trial of Z-endoxifen in endocrine refractory, ER positive MBC. Seven dose levels were considered ranging from 20 to 160 mg/day followed by expansion cohorts (EC) of 40, 80, and 100 mg/day. Pretreatment blood samples (all pts) and fresh tumor biopsies (EC) were collected prospectively. Tumor and cfDNA were evaluated by targeted NGS. Results: 41 pts (38 evaluable) were enrolled. Prior endocrine therapy included aromatase inhibitors (37/38, 97%), fulvestrant (22/38, 58%) and tamoxifen (26/38, 68%). Substantial endoxifen exposure without DLTs at doses above 80 mg/day led to a halt in dose escalation and opening of the EC. Overall clinical benefit (stable > 6 months [7 pts.] or partial response by RECIST criteria [3 pts.]) rate was 26.3% (95%CI: 13.4-43.1%). cfDNA was obtained from 36 pts and mutations were identified in 13 (36%) including ESR1 [ Y537N or D538G] (5), PIK3CA [ H1047R or E542K] (8), TP53 [ K132R, R248Q, R267Q, or H179Y] (4), AKT ( Q79K) (1), and KRAS ( G12D) (1). In 5 pts with cf ESR1 mutations, 4 had additional cfDNA mutations including PIK3CA (3), and TP53 (1). PFS was shorter in pts with cfDNA mutations relative to those without (median: 61 vs.132 days; log-rank p = 0.021). Discordance was observed between tumor and cfDNA mutations where 3/7 PIK3CA tumor mutations were detected by cfDNA, 1/2 TP53 tumor mutations were detected by cfDNA, and 0/1 AKT tumor mutations were detected by cfDNA. Conversely, 2 pts had cfDNA mutations (either ESR1, TP53 or AKT) undetected in tumor. Conclusions: The absence of cfDNA mutations in patients with endocrine resistant, MBC treated with Z-Endoxifen was associated with significantly longer PFS. Given the discordance between tumor and cfDNA sequence data, future studies must determine which approach maximizes prognosis and prediction of benefit for estrogen-targeted therapy. Clinical trial information: NCT01327781.
Tumor genomics and response to CDK 4/6 inhibitors for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Spring Laura , Niemierko Andrzej , Juric Dejan , Zangardi Mark , Abraham Elizabeth , Dias-Santagata Dora , Ellisen Leif W. , Isakoff Steven J. , Iafrate A. John , Moy Beverly , Bardia Aditya
Published: September 2018

1046

Background: The combination of endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor, such as palbociclib, has changed the treatment paradigm of HR+ MBC, particularly as 1stline therapy. However, there are no predictive biomarkers at present, and little is known about the impact of tumor genomics on outcomes. For example, mutations in TP53 could impact the ability of p53 to negatively regulate p21, thereby promoting cell cycle progression despite CDK 4/6 inhibition. The aim of this study was to evaluate the association between tumor genomics, particularly PIK3CA and TP53 mutations, and response to CDK 4/6 inhibitors in HR+ MBC. Methods: All HR+/HER2- MBC patients at our institution receiving a CDK 4/6 inhibitor in the second line or beyond were identified. Tumor genomics were analyzed utilizing the institutional tumor genotyping next generation sequencing (NGS) assay known as “Snapshot-NGS assay” on DNA isolated from the tumor, covering key oncogenic driver mutations and tumor suppressor genes. The log-rank test was used for statistical analysis. Results: A total of 83 patients with HR+/HER2- MBC were identified, of which 61 had available tumor genotyping results available (52 metastatic specimens). The median line of therapy was three. Median progression-free survival (PFS) on CDK 4/6 inhibitor-based therapy, as second line or beyond, was 9.2 months (mo) overall. No significant difference in PFS was seen among patients with PIK3CA (n = 31) mutations (7.1 vs. 9.7 mo; p = 0.28) or with any alteration in the PI3K/Akt/mTOR (n = 36) pathway (8.2 vs. 9.3 mo; p = 0.40). The presence of a p53 mutation (n = 9) or complex tumor genomics (n = 14) demonstrated a trend towards shorter PFS (5.5 vs. 9.2 mo; 5.5 vs. 9.5 mo, respectively), although statistical significance was not reached due to small numbers (p = 0.76; p = 0.31). In a multivariable analysis adjusting for age and prior lines of therapy, similar results were observed. Conclusions: This study suggests patients with HR+ MBC harboring p53 mutations or complex tumor genomics may experience shorter PFS on CDK 4/6 inhibitor-based therapy in the second line and beyond, and these novel findings require validation in additional studies.
Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma.
Authors: Hegde Meenakshi , DeRenzo Christopher C. , Zhang Huimin , Mata Melinda , Gerken Claudia , Shree Ankita , Yi Zhongzhen , Brawley Vita , Dakhova Olga , Wu Meng-Fen , Liu Hao , Hicks John , Grilley Bambi , Gee Adrian P. , Rooney Cliona M. , Brenner Malcolm K. , Heslop Helen E. , Wels Winfried , Gottschalk Stephen , Ahmed Nabil M.
Published: September 2018

10508

Background: Outcome for patients with advanced sarcoma is extremely poor and treatment options are limited. Encouragingly, in our phase 1 dose-escalation trial (Ahmed et al, JCO 2015), systemic administration of up to 1x108/m2 autologous HER2-CAR T cells in patient with HER2+ sarcoma was safe. While T cells did not expand, 4/19 evaluable patients are alive 37-61 months post infusion without evidence of disease. The goal of this study was to evaluate if lympohodepleting chemotherapy can safely induce the expansion of HER2-CAR T cells. Methods: In a phase 1 clinical study, NCT00902044, we administered 1x108/m2 autologous HER2-CAR (with a CD28.zeta signaling domain) T cells to patients with refractory/metastatic HER2+ sarcoma after lymphodepletion. Results: Six patients with refractory/metastatic HER2+ sarcoma (4 osteosarcoma, 1 rhabdomyosarcoma, 1 synovial sarcoma) with a median age of 16 (range: 4 to 55) received up to 3 infusions of 1x108 cells/m2 CAR T cells after lymphodepletion with either fludarabine (Flu; n = 3) or Flu and cyclophosphamide (Flu/Cy; n = 3). Flu and Flu/Cy induced lymphopenia with an absolute lymphocyte count (ALC) of < 100/ml at the day of the T-cell infusion. Only Flu/Cy induced neutropenia (absolute neutrophil count [ANC] < 500/ml) for up to 14 days. 4/6 patients developed grade 1-2 cytokine release syndrome (CRS) within 24 hours of CAR T-cell infusion that resolved completely with supportive care within 3 days of onset. T cells expanded in 5/6 patients (median 89-fold (range: 41 to 2,893) with a median peak expansion on day 7 (range: 5 to 28). CAR T cells could be detected by qPCR in 6/6 patients at 6 weeks post infusion. One patient with rhabdomyosarcoma metastatic to the bone marrow had a complete responses (CR), 2 had stable disease (SD), and 3 had progressive disease (PD). Two patients are alive with a median overall survival of 14.2 months. Conclusions: Infusion of autologous HER2-CAR T cells after lymphodepletion is safe, and can be associated with objective clinical benefit in patients with advanced HER2+ sarcoma. These findings warrant further evaluation in a phase 2b study as a single agent or in combination with other approaches. Clinical trial information: NCT00902044.
Type, intensity, and duration of chemotherapy (CHT) and their correlation with prognosis of localized soft tissue Ewing tumors (STET): Experience of the Cooperative Weichteilsarkomstudiengruppe (CWS).
Authors: Koscielniak Ewa , Scheer Monika , Sparber-Sauer Monika , Hallmen Erika , Leuschner Ivo , Kazanowska Bernarda , Ljungman Gustaf , Niggli Felix , Ladenstein Ruth , Bielack Stefan S. , Muenter Marc W. , von Kalle Thekla , Feuchtgruber Simone , Klingebiel Thomas
Published: September 2018

10527

Background: The optimal type and intensity of CHT in the treatment of STET is still a matter of debate. The CWS group has treated STET similar to rhabdomyosarcoma. We have analyzed the prognosis of STET in relation to the CHT regimens used in three consecutive CWS studies CWS-91, -96 and CWS- 2002P. Methods: 243 pts with localized STET were included. Their median age was 12 (range 0.1-29) yrs. In the CWS-91 pts with primary tumor resection (IRSG I and II) were treated with VACA (vincristine (VCR), actinomycin D (Act D), cyclophosphamide (CYC), doxorubicin (DOX), for 10 or 20 weeks. All other CWS-91 pts (high risk group, HRG) received EVAIA (ifosfamide (IFO) instead of CYC plus VP16) for 37 weeks. In the CWS-96 and CWS-2002P all STET pts were allocated to the HRG. In CWS-96 therapy was randomized: VAIA (IFO, DOX, Act D, VCR) vs. CEVAIE (Epi-DOX instead of DOX, plus carboplatin and VP16), for 25 weeks. In CWS-2002P VAIA (25 weeks) plus maintenance CHT with CYC and vinblastine (VBL) for 26 weeks were used. The cumulative doses varied: IFO 24-72 g/m², CYC 4.8-7.35 g/m², DOX 120-360 mg/m², Act D 3-9 mg/m², VP16 1.8-5.4 g/m². Irradiation was stratified depending on results of the primary or secondary resection and response. Results: 5 yr event free (EFS) and overall survival (OS) were 64% and 73%. The median observation time of survivors was 9 yrs. 5yr EFS and OS by study were: CWS-91 64 % and 72 %, CWS-96 57% and 70 %, CWS-2002P 78 % and 86 % respectively (n.s.). 5 yr EFS and OS for VACA arm were 79% and 90%. 5 yr EFS and OS by CHT for HRG were: EVAIA 57% and 65%, VAIA 64% and 80%, CEVAIE 45% and 54%, VAIA with CYC/VBL 84% and 87%, respectively (p = 0 .003). 5yr EFS and OS for irradiated (n = 181) vs. not irradiated (n = 48) patients were 63 % and 72% vs. 63% and 79%, respectively. Conclusions: The outcomes between CHT arms differed significantly: CEVAIA correlated with the worst outcome while VAIA with CYC/VBL showed the best results. A small group of low risk patients have an excellent prognosis with substantially reduced CHT. Ewing tumors are biologically heterogeneous and more diversification in therapy stratification is warranted to avoid overtreatment.
Mortality in young adults with Ewing sarcoma treated at specialized cancer centers in California.
Authors: Alvarez Elysia Marie , Malogolowkin Marcio H. , Pollock Brad , Li Qian , Marina Neyssa , Wun Theodore , Keegan Theresa
Published: September 2018

10538

Background: Ewing sarcoma is a rare malignancy of the soft tissue or bone that is most frequently seen in children and adolescents. One study suggested that care at specialized cancer centers (SCC) may mitigate survival disparities associated with public insurance in patients with sarcoma, but no large population-based studies have considered how location of care affects survival outcomes. Methods: We performed a retrospective, population-based cohort analysis of patients hospitalized within one year of diagnosis with primary Ewing sarcoma between 2000–2013 using the California Cancer Registry linked with state hospitalization data. Patients were divided into two groups based on whether they received inpatient treatment at a SCC [Children’s Oncology Group (if age ≤25) and/or National Cancer Institute-designated center] or not. We excluded 12 patients whose location of cancer treatment could not be determined. Multivariable Cox proportional hazards regression identified factors associated with mortality. Results are presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: Of the 470 patients with newly diagnosed Ewing sarcoma, 40% were female, 52% were non-Hispanic white, and 53% had private health insurance. Sixty-one percent received their inpatient care at a SCC. Multivariable analysis across all ages demonstrated that higher mortality was associated with increasing age, metastatic disease, and large tumors, but mortality was not impacted by treatment at an SCC (HR 0.77, CI: 0.55-1.08; p = 0.134). However, when analyses were stratified by age, treatment at a SCC was associated with lower mortality among patients ages 19–39 years, but not among younger or older patients, and this association was only apparent within 2 years of diagnosis (HR = 0.43, CI: 0.23-0.79; p = 0.007). Conclusions: Our results suggest that treatment for Ewing sarcoma at a SCC significantly improves survival in young adults adjusted for other factors known to be associated with poor prognosis (metastatic disease, larger tumor size and older age). The lower mortality in this age group may be due to access to clinical trials and other specialized services specific to young adults available at SCCs.