bluuebunny/crossref_metadata_2025 huggingface dataset:
Longitudinal assessment of cancer-related cognitive impairment (CRCI) up to six-months post-chemotherapy with multiple cognitive testing methods in 943 breast cancer (BC) patients and controls.
Authors: Janelsins Michelle Christine , Heckler Charles E. , Peppone Luke Joseph , Mohile Supriya Gupta , Mustian Karen Michelle , Ahles Tim , Palesh Oxana , O'Mara Ann M. , Minasian Lori M. , Williams AnnaLynn , Magnuson Allison , Schmidt Karen , Dakhil Shaker R. , Hopkins Judith O. , Morrow Gary R.
Published: September 2018

10014

Background: Large nationwide studies are needed to assess CRCI. Methods: NCORPs recruited BC patients and age-matched non-cancer controls. Computerized ((CANTAB Delayed Match to Sample (DMS), Rapid Visual Processing (RVP), Verbal Recognition Memory (VRM)), paper-based ((Controlled Oral Word Association (COWA), and Trail Making Test (TMT)) , and phone-based (category fluency, word recall, backward counting and digits backward) cognitive assessments of memory, attention, and executive function at pre-chemotherapy, post-chemotherapy, and 6 months follow-up (or time-equivalent for controls) were completed. Longitudinal mixed model (LMM)s included group, time, time*group, and adjusted for age, education, reading, anxiety, and depression. Results: 580 BC patients (mean age = 54) and 363 controls (mean age = 53) were assessed. In all LMMs, there was a significant group*time interaction depicting lower scores in patients compared to controls (p < 0.005) except for TMT (p = 0.09). For longitudinal change on the DMS memory test (primary aim), we observed no significant difference between groups from pre- to post-chemotherapy but did observe a significant difference from pre-chemotherapy to follow-up (p = 0.017) where patients significantly declined (p = 0.005) and controls did not change. We observed similar results for RVP. For VRM, there was a significant pre- to post-chemotherapy group difference (p = 0.003). For COWA, patients significantly declined and controls significantly improved reflecting a significant between group difference (p < 0.001) from pre- to post-chemotherapy. For TMT, both groups significantly improved with patients improving less than controls reflected by a significant between group difference (p = 0.04) that remained a trend at follow-up (p = 0.06). On all phone tests, there was a significant between group effect from both pre- to post-chemotherapy and at follow-up with patients doing less well than controls (all p < 0.001). Conclusions: This nationwide study shows CRCI in BC patients persists in multiple cognitive domains up to 6 months post-chemotherapy compared to controls. Clinical trial information: NCT01382082.
Effect of exercise on novel biomarkers of muscle damage and cancer-related fatigue: A nationwide URCC NCORP RCT in 350 patients with cancer.
Authors: Mustian Karen Michelle , Peoples Anita Roselyn , Peppone Luke Joseph , Lin Po-Ju , Janelsins Michelle Christine , Kleckner Ian , Cole Calvin , Esparaz Benjamin , Miller Jessica , Giguere Jeffrey K.
Published: September 2018

10020

Background: Chemotherapy may lead to systemic muscle damage. Up-regulation of developmental myosin light chain 5 (MYL5) and myosin heavy chain 8 (MYH8) genes is required for normal muscle regeneration in response to damage. However, secretion of MYL5 and MYH8 proteins into the serum suggest degradation of muscle, which, in turn, may lead to cancer-related-fatigue (CRF). In this study, we investigated (1) the effect of an exercise intervention, Exercise for Cancer Patients (EXCAP) on mRNA gene expression and serum protein levels of MYL5 and MYH8 and (2) the association of these novel biomarkers with CRF. Methods: Chemotherapy naïve cancer patients (N = 350; mean age = 55.7) from 39 community oncology practices throughout the U.S. affiliated with the URCC NCORP Research Base participated in this nationwide, multicenter, phase III RCT. Patients were randomized into 2 groups: (1) chemotherapy and (2) chemotherapy plus a 6-week aerobic and resistance exercise prescription-EXCAP. Gene expression and protein levels of MYL5 and MYH8, as well as CRF were assessed pre- and post-intervention from whole blood by qPCR, from serum by Luminex assays, and from patient-report by the Multidimensional Fatigue Symptom Inventory, respectively. Results: T-tests show MYL5, but not MYH8, mRNA levels were significantly up-regulated from pre- to post-intervention in exercisers and controls (all p < 0.01) with no significant group difference. Additionally, MYL5 and MYH8 serum protein levels significantly increased from pre to post in controls (all p < 0.05), but remained stable in exercisers. Significant group differences in these serum proteins (p < 0.01) suggest greater muscle degradation in non-exercisers. Pearson correlations revealed trends suggesting increases in MYL5 and MYH8 serum proteins are associated with increases in CRF (r = 0.09 and r = 0.11, respectively, all p < 0.10). Conclusions: Results suggest EXCAP exercise is protective from chemotherapy-induced muscle damage via its effects on MYL5 and MYH8, and changes in these novel biomarkers may mediate changes in CRF. Further research is needed to confirm these findings. NCI UGCA189961, R25 CA102618. Clinical trial information: NCT00924651.
Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE.
Authors: Gradishar William John , Hegg Roberto , Im Seock-Ah , Park In Hae , Tjulandin Sergei , Kenny Sarah , Sarp Severine , Williams Lisa , Izquierdo Miguel A. , Johnston Stephen R. D.
Published: September 2018

1004

Background: Combination ofHER2-targeted therapy+AI improved clinical benefit in patients (pts) with HER2+, HR+ MBC vs AI alone in two previous trials, median progression free survival (mPFS) 4.8 vs 2.4 mo (TAnDEM), and 8.2 vs 3.0 mo (EGF30008). Dual HER2 blockade enhances clinical benefit vs single HER2 blockade. This study evaluated the safety and efficacy of dual vs single HER2 blockade (L+T vs T/L)+AI in HER2+, HR+ MBC progressing on (neo)adjuvant/first-line T+chemotherapy (CT). HER2 and HR status were assessed for eligibility at local lab. Methods: PMW were randomized 1:1:1 to receive T (8mg/kg followed by 6mg/kg IV Q3W)+L (1000mg/d)+AI or T+AI or L (1500mg/d)+AI. AI was per investigator’s choice. Pts were excluded if they were intended for CT. The primary endpoint was to assess superiority of PFS with L+T vs T. Secondary endpoints included PFS (L vs T), overall survival (OS), overall response rate (ORR), and safety. Results: 369 pts were enrolled; current analysis included 355 pts (data cutoff, March 11, 2016); L+T (n = 120), T (n = 117) or L (n = 118). Final PFS data were analyzed after 137 events. Baseline characteristics were balanced across all treatment (tx) arms. The primary endpoint was met; superior PFS was observed with L+T vs T (mPFS, 11 vs 5.7 mo; HR = 0.62, 95% CI [0.45, 0.88], P= 0.0064). This benefit of L+T was consistent in key subgroups. mPFS with L vs T was 8.3 vs 5.7 mo (HR = 0.71, 95% CI [0.51, 0.98], P= 0.0361). ORR with L+T, T, and L was 32%, 14%, and 19% respectively. OS data are immature. Most common adverse events (AEs) with L+T, T and L (≥15%, any arm) were diarrhea (69%, 9%, 51%), rash (36%, 2%, 28%), nausea (22%, 9%, 22%), and paronychia (30%, 0, 15%). Hepatic abnormalities of > 3 ULN ALT/AST levels were noted in 4%, 6%, and 16% respectively. Incidence of tx-related SAEs was 5%, 2%, and 4% and on-tx deaths was 3%, 4%, and 5%, respectively. Conclusions: Dual HER2 blockade with L+T+AI showed superior PFS benefit vs T+AI, in pts with HER2+, HR+ MBC. Incidence of AEs was increased with L+T. This combination can potentially offer an effective CT-sparing tx option in subgroup of HER2+, HR+ pts without aggressive disease and who are not candidates for CT. Clinical trial information: 2010-019577-16.
Serum frailty biomarkers to predict overall survival in older patients with metastatic solid tumors: A substudy of prospective multi-center cohort study (KCSG PC13-09).
Authors: Kim Se Hyun , Kim Jin Won , Hwang In Gyu , Jang Joung Soon , Hong Soojung , Kim Tae Yong , Baek Ji Yeon , Shin SeongHoon , Sun Der Sheng , Hong Dae Sik , Kim Hyo Jung , Hong Yong Sang , Lee Ju-Hyun , Woo In Sook , Kim Jee Hyun ,   Korean Cancer Study Group Geriatric Oncology Working Party
Published: September 2018

10041

Background: To determine individualized cancer treatment for older patients, easily measurable markers that predict functional decline and mortality are needed. The purpose of this study was to confirm prognostic value of potential biomarkers of frailty in older patients with metastatic solid tumors. Methods: Serum samples were prospectively collected before first line chemotherapy at 11 academic centers in Korea. All patients were participants in a prospective cohort study of older patients with metastatic solid tumors (KCSG PC13-09, WHO ICTRP number: KCT0001071). Serum levels of C-reactive protein (CRP), CXCL10, SIRT1, VEGF-A, Activin A, C-terminal telopeptide of type I collagen (CTx), total 25-hydroxyvitamin D (vitD) were measured by ELISA and IL-6, Myostatin, Irisin, FGF-19, FGF-21, FGF-23 by luminex mutiplex assay. Overall survival (OS) was studied by means of Kaplan-Meier, Log Rank and Cox methods. Results: Serum samples from 138 patients (median age: 75, range: 70-92) were collected from Feb 2014 to Dec 2016. During a median follow up time of 13.8 months, 72 (52.6%) patients had died. Among 13 serum markers, CRP (log-rank, P=0.006), Activin A (P=0.003), and Myostatin (P=0.043) were significantly correlated with OS in univariate analyses. In a Cox regression analysis, Activin A (HR 2.36, 95% CI 1.41-3.96; P=0.001) and Myostatin (HR 2.70, 95% CI 1.24-5.84; P=0.012) were significantly associated with OS after adjustment of other clinical factors (Age, Gender, ECOG PS, BMI, Geriatric assessment, Chemotherapy response, WBC, Albumin). Conclusions: In older cancer patients, high serum concentration of Activin A and Myostatin are predictive of poor OS. [Table: see text]
Psychosocial effects of the relaxation response resiliency program (SMART-3RP) in patients with MGUS and smoldering multiple myeloma: A waitlist controlled randomized clinical trial.
Authors: Denninger John W. , Laubach Jacob P. , Yee Andrew Jenho , O'Donnell Elizabeth , Macklin Eric A. , Perez Giselle Katiria , Traeger Lara N. , Chad-Friedman Emma , Proszynski Jacqueline , Jacquart Jolene , Goldman Roberta , Riklin Eric , Niles Halsey , Nehrt Emily M. , Chaukos Deanna C. , Richardson Paul G. , Raje Noopur S. , Fricchione Gregory L. , Park Elyse R. , Benson Herbert
Published: September 2018

10051

Background: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic clonal precursors to multiple myeloma, a hematological malignancy. Because observation is currently the standard of care, a diagnosis of MGUS or SMM can be associated with stress and worry about progression. We evaluated the efficacy of the evidence-based mind-body intervention, the Stress Management and Resiliency Training: Relaxation Response Resiliency Program (SMART-3RP) in reducing distress and stress reactivity in patients with MGUS and SMM. Methods: In participants diagnosed with intermediate or high risk MGUS or SMM, this randomized, waitlist controlled trial (Oct 2013 – Sep 2016) assessed distress (10-point scale) as the primary outcome and perceived stress (PSS-10), stress reactivity (MOCS-A), and mindfulness (FFMQ) as secondary outcomes and hypothesized mediators of distress reduction. We collected self-report measures at enrollment (T1), 3 months (T2), and 6 months (T3). The immediate treatment arm received the 8-session, 1.5 hour/week SMART-3RP group intervention from T1 to T2 and continued practicing skills from T2 to T3; the waitlist arm received the intervention from T2 to T3. Results: 93 participants (59% women) diagnosed with MGUS (n = 49) or SMM (n = 44) were randomized to immediate treatment (n = 45) or waitlist (n = 48). In an ITT analysis of immediate SMART-3RP vs. waitlist (T1-T2), we found significantly greater improvement in distress (-1.4 vs. -0.3, p = .04) and stress reactivity (0.39 vs. 0.02, p < .001), but not perceived stress (-3.9 vs. -2.2, p = .12) or mindfulness (2.4 vs. -0.1, p = .17). Improvements in stress reactivity were maintained for the immediate treatment group (T2-T3), but only partially for distress. Conclusions: The SMART-3RP, compared to waitlist, reduced distress in participants with intermediate or high-risk MGUS and SMM, with improvements in stress reactivity as a primary mediator of distress reduction. Participants strongly endorsed the intervention’s ability to enhance coping and reduce distress. Clinical trial information: NCT01955395.
Can exercise influence survival following breast cancer: Results from a randomised, controlled trial.
Authors: Hayes Sandra Christine , Steele Megan , Spence Rosa , Pyke Christopher , Saunders Christobel , Bashford John , Eakin Elizabeth
Published: September 2018

10067

Background: Exercise for Health was a randomised, controlled trial designed to evaluate an 8-month translational exercise intervention, commencing 6-weeks post-surgery for newly diagnosed breast cancer. Outcomes for this follow-up exploratory analysis were overall- and disease-free survival. Methods: Consenting urban-based women (n = 194) were randomized to one of two exercise groups (intervention delivered either face-to-face or over the telephone) or a usual care group, while consenting rural/regional women (n = 143) were randomised to either the telephone-delivered exercise group or usual care group. For the purposes of these analyses, exercise groups and usual care groups were combined (exercise group, n = 207; usual care group, n = 130). Analyses were done on an intention-to-treat basis and trials were registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000233527; 12609000809235). Results: Participant disease and treatment characteristics were similar to the wider breast cancer population in Queensland, Australia, and 42% of the sample resided in rural or regional areas. After a median follow-up of 101 months, there were 15/130 (11.5%) survival events in the usual care group, compared with 11/207 (5.3%) events in the exercise group. Disease-free events for the usual care versus exercise group were 23/130 (17.7%) and 25/207 (12.1%), respectively. The corresponding unadjusted hazard ratio for the exercise group for overall survival was 0.45 (95% CI = 0.21-0.97; p = 0.037), and for disease-free survival was 0.66 (95% CI = 0.38-1.17; p = 0.155). Conclusions: Epidemiological evidence consistently shows a positive relationship between physical activity and survival post-breast cancer, but is unable to establish causality. These exploratory findings suggest that an exercise intervention delivered during and beyond conventional treatment for breast cancer and that was designed to cater for all women, irrespective of place of residence and access to medical services, has clear potential to influence survival. Clinical trial information: ACTRN12606000233527; 12609000809235.
Clinical, sociodemographic, and behavioral factors associated with cumulative burden of morbidity (CBM) among testicular cancer survivors (TCS) in the Platinum study.
Authors: Kerns Sarah L. , Fung Chunkit , Williams AnnaLynn , Abu Zaid Mohammad Issam , Sesso Howard D. , Monahan Patrick , Ardeshirrouhanifard Shirin , Feldman Darren R. , Hamilton Robert James , Vaughn David J. , Beard Clair , Huddart Robert Anthony , Kim Jeri , Kollmannsberger Christian K. , Sahasrabudhe Deepak M. , Morlang Ashley Amidon , Cook Ryan , Fossa Sophie D. , Einhorn Lawrence H. , Travis Lois B. ,   The Platinum Study Group
Published: September 2018

10075

Background: TCS are an important group in which to characterize late effects of cancer and its therapy given their young age at diagnosis and high cure rate. We comprehensively evaluated CBM and identified associated clinical, sociodemographic, and behavioral risk factors among TCS given cisplatin based chemotherapy in a multicenter study. Methods: TCS completed a comprehensive health questionnaire. Responses were grouped into 22 adverse health outcomes (AHO) and graded by severity. A CBM score was calculated based on AHO number and severity, following Geenen et al (JAMA 2007). Multivariable ordinal logistic regression examined the association of clinical, sociodemographic, and behavioral factors with CBM. Variable-based hierarchical clustering identified individual AHOs that co-occurred. Results: Among 1,215 TCS (median age at evaluation 38 y, range 19-68 y; time since chemotherapy 4.6 y), over 20% had a CBM score of high (17%), very high (4%) or severe (0.4%). Most TCS, however, had CBM scores of low (37%), medium (28%), very low (9%) or none (5%). In a multivariable model controlling for time since chemotherapy, older attained age (OR 1.2; 95% CI 1.1 - 1.3), being widowed/divorced/separated (OR 1.8; 95% CI 1.1 - 3.1), having less than college-level education (OR 1.7; 95% CI 1.3 - 2.2), being retired/on disability (OR 2.5; 95% CI 1.2 - 5.3), and receipt of 4 cycles of BEP vs. 4 cycles of EP or 3 cycles of BEP (OR 1.3; 95% CI 1.01 - 1.8) were associated with increased odds of a worse CBM score; vigorous exercise (OR 0.7; 95% CI 0.5 - 0.9) and non-white race (OR 0.6; 95% CI 0.4 - 0.9) were associated with decreased odds. A separate cluster analysis revealed five groups of AHOs: those known to be cisplatin-related (e.g. neuropathy, ototoxicity); metabolic abnormalities (e.g. hypercholesterolemia, diabetes); vascular damage (e.g. stroke); testicular cancer-related (e.g. hypogonadism); and other (e.g. thyroid disease). Conclusions: TCS with factors associated with worse CBM may be candidates for closer monitoring. If confirmed, our cluster analysis showing that groups of conditions tend to co-occur in TCS could provide guidance for survivorship care plans.
Scalp Cooling Alopecia Prevention trial (SCALP) for patients with early stage breast cancer.
Authors: Nangia Julie R. , Wang Tao , Osborne Cynthia R. C. , Niravath Polly Ann , Otte Kristen , Papish Steven W. , Holmes Frankie Ann , Abraham Jame , Goldfarb Shari Beth , Courtright Jay G. , Paxman Richard , Rude Mari , Hilsenbeck Susan G. , Osborne C. Kent , Rimawi Mothaffar F.
Published: September 2018

10088

Background: Adjuvant chemotherapy decreases the risk of recurrence. However, it has distressing side effects, including alopecia. There are no randomized trials assessing modern scalp cooling to prevent alopecia, and success rates in non-randomized trials have varied. Methods: We conducted a multi-center randomized trial to evaluate the safety and efficacy of the Orbis Paxman Hair Loss Prevention System (OPHLPS) in reducing chemotherapy-induced alopecia. Women with stage I-II breast cancer planned to receive anthracycline- or taxane- based chemotherapy for at least four cycles were eligible and randomized in a 2:1 ratio to scalp-cooling or control. Scalp-cooling was done with the OPHLPS 30 minutes prior to, during and 90 minutes after each chemotherapy. The primary efficacy endpoints were hair preservation and device safety. We planned to enroll 235 subjects to provide 85% power to detect a 20% difference in hair preservation. Secondary endpoints included wig/scarf use and quality of life assessed by the EORTC QLQ-30, HADS and BIS. Subjects will be followed for 5 years for recurrence, overall survival, and site of recurrence. One interim analysis was planned to allow the study to stop early for efficacy after 142 subjects were enrolled and evaluable for the primary endpoint. To maintain the overall type 1 error rate, an O’Brien-Fleming spending function was used (interim boundary p = 0.0061). Results: This is the first randomized trial with modern scalp cooling in the world. For the interim analysis, 142 subjects were evaluable. Among them, 48 (50.5%) out of 95 in the cooling group and 0 (0%) out of 47 in the control group had hair preservation. The one-tailed p-value from the Fisher’s exact test is < 0.0001, which crosses the superiority boundary (p = 0.0061). Thus on 9/26/2016 the DSMB stopped the study early. The interim analysis was presented at SABCS 2016. There are 195 subjects enrolled on this clinical trial, and the final subject will be evaluable for the primary outcome February 2017. The final analysis will be presented. Conclusions: Our trial showed that scalp cooling using OPHLPS is highly effective in hair retention. Paxman Coolers has applied for FDA clearance for the OPHLPS based on the results of the interim analysis. Clinical trial information: NCT01986140.
Morphological correlates of oxaliplatin induced peripheral neuropathy assessed by magnetic resonance neurography.
Authors: Apostolidis Leonidas , Schwarz Daniel , Xia Annie , Weiler Markus , Heiland Sabine , Schlemmer Heinz-Peter , Jaeger Dirk , Bendszus Martin , Baumer Philipp
Published: September 2018

10092

Background: Oxaliplatin induced peripheral neuropathy (OXA-PNP) is a frequent side effect of oxaliplatin containing chemotherapy protocols. It is commonly assessed clinically via physical examination and patient reported symptoms. Research has been impeded by the lack of objective tests to quantify OXA-PNP. Neurophysiological examination is time-consuming and can only cover a selected part of the examined nerve. The aim of this study was to investigate in-vivo morphological correlates of OXA-PNP by magnetic resonance neurography (MRN). Methods: 20 patients with mild to moderate OXA-PNP and 20 matched controls were prospectively enrolled. All patients underwent a detailed neurophysiology examination prior to neuroimaging. A standardized MRN imaging protocol at 3.0 Tesla with large-coverage included the lumbosacral plexus, as well as both sciatic nerves and their branches using T2-weighted fat-saturated sequences at high resolution. Qualitative evaluation of sciatic, tibial, and peroneal nerves were performed by two readers regarding the presence, degree, and distribution of nerve lesions. Quantitative assessment included volumetry of the dorsal root ganglia (DRG) and sciatic nerve normalized T2 (nT2) signal and caliber. Results: Significant DRG hypertrophy in OXA-PNP patients (207.3±47.7mm3 vs. 153.0±47.1mm3 in controls, p = 0.001) was found as morphological correlate of the sensory neuronopathy. Peripheral nerves only exhibited slight morphological alterations qualitatively. Quantitatively, sciatic nerve caliber was unchanged (26.0±5.1mm2 vs. 27.4±7.4mm2, p = 0.19) while sciatic nerve nT2 signal was slightly and non-significantly elevated in patients (1.32±0.22 vs. 1.22±0.26, p = 0.19). Conclusions: OXA-PNP leads to morphological correlates that can be detected in-vivo by MRN. Significant hypertrophy of the DRG was observed, a phenomenon which has not been described in OXA-PNP previously. DRG volume should be investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies as well as in studies evaluating neuroprotective strategies for OXA-PNP.
Use of heart rate variability (HRV) biofeedback for symptom management among cancer survivors.
Authors: O'Rourke Mark Allen , Franco Regina A. , Sofge Jameson , Ginsberg Jay , Susko Kerri , Crowley Elizabeth , Anderson Annie , Christ Alex , Hanna John , Hendry William , Burch James
Published: September 2018

10099

Background: Late effects of cancer and its treatment include pain, fatigue, stress, and depression all mediated by autonomic dysfunction. Heart Rate Variability (HRV) coherence is an established measure of autonomic dysfunction. Cancer survivors have lower HRV coherence than normal controls. HRV biofeedback (HRV-B) training improves HRV coherence, restores autonomic health, and reduces the above symptoms. This report describes a feasibility study of HRV-B in symptomatic cancer survivors. Methods: In a randomized, waitlist controlled, clinical trial, 179 were screened, 34 enrolled and 31 completed the protocol. Participants in the intervention arm received weekly HRV-B training up to six weeks. Outcome measures assessed at baseline (pre) and after week six (post) included HRV coherence plus Insomnia Symptom Questionnaire (ISQ), Suscro Distress Inventory (SDI), Brief Pain Inventory (BPI), Multi-Dimensional Fatigue Inventory (MFI), Perceived Stress Scale (PSS) and Beck Depression Inventory II (BDI-II). Results: See table below. Conclusions: Delivering HRV Biofeedback training to cancer survivors is feasible at our Cancer Institute. This pilot study provides preliminary evidence that HRV-B for cancer survivors improves HRV coherence and reduces insomnia, pain, fatigue, depression, and stress. The intervention has great potential and further research is indicated. [Table: see text]
Everolimus (EVE) plus endocrine therapy in patients with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (BC): First- and second-line data from the BOLERO-4 study.
Authors: Cardoso Fatima , Villanueva Cristian , Royce Melanie , Cruz Felipe , Debled Marc , Hegg Roberto , Toyama Tatsuya , Falkson Carla Isadora , Jeong Joon , Srimuninnimit Vichien , Ozguroglu Mustafa , Gradishar William John , Azevedo Sergio J , Arce Christina H. , Ridolfi Antonia , Lin Chinjune , Bachelot Thomas Denis
Published: September 2018

1010

Background: Initial first-line (1L) data from the phase 2 BOLERO-4 (NCT01698918) study of EVE + letrozole (LET) in postmenopausal patients (pts) with ER+, HER2− metastatic BC (MBC) or locally advanced BC (LABC) have been previously reported. Here, we present updated 1L progression-free survival (PFS) data, plus new data describing second-line (2L) EVE + exemestane (EXE) in pts with disease progression after EVE + LET. Methods: Postmenopausal pts with ER+, HER2− MBC or LABC with no prior therapy for advanced disease received EVE 10 mg/day + LET 2.5 mg/day. After disease progression, pts could receive EVE + EXE 25 mg/day until further disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint: 1L PFS. Secondary endpoints: overall response rate (ORR), clinical benefit rate (CBR), 2L PFS, overall survival (OS), and safety (1L and 2L). Results: Among 202 pts (median age, 64 years) with 1L MBC (96%) or LABC (4%), median PFS (95% CI) was 21.7 (18.123.9) months, ORR was 43.6%, and CBR was 74.3%. 42 pts (median age, 62 years) with MBC (88%) or LABC (12%) who progressed on 1L EVE + LET received optional 2L EVE + EXE. 2L median PFS (95% CI) was 3.7 (1.89.1) months, ORR was 4.8%, and CBR was 21.4%. Common 1L adverse events (all grades, regardless of drug relationship) were stomatitis (69%), weight loss (44%), diarrhea (40%), nausea (37%), and anemia (35%); 2L adverse events included stomatitis (19%) and weight loss (19%). Median duration of follow-up from start of 1L to the data cutoff for these new analyses (17 June 2016) was 23.5 months. OS will be analyzed at a later data cut. Conclusions: EVE + LET is an effective regimen in 1L ER+, HER2− advanced BC. Thesedata support previously reported BOLERO-2 data demonstrating a PFS improvement from addition of EVE to an aromatase inhibitor. 2L data, although limited by the small number of pts, show preliminary evidence of EVE activity when continued beyond disease progression. No new safety signals were seen. Lower rates of stomatitis in 2L were noted. Clinical trial information: NCT01698918.
Effect of exercise on muscle immune response and mitochondrial damage and their relationship with cancer-related fatigue: A URCC NCORP study.
Authors: Peoples Anita Roselyn , Peppone Luke Joseph , Lin Po-Ju , Cole Calvin , Heckler Charles E. , Janelsins Michelle Christine , Rousey Steven , Onitilo Adedayo A. , Melnik Marianne , Mustian Karen Michelle
Published: September 2018

10119

Background: Chemotherapy (CT) via inflammation and oxidative stress can cause muscle inflammatory injury, mitochondrial damage, and cancer-related fatigue (CRF). Following muscle and mitochondrial damage, various cytoplasmic and mitochondrial components are released into circulation. HLA-DQB1 gene encodes a protein involved in the activation of immune response, and is not expressed in normal muscle cells but is up-regulated under highly inflammatory states. Mitochondrial gene MT-CO2 encodes subunit 2 of complex IV, which plays a critical role in energy metabolism and mitochondrial function. We investigated the (i) influence of an exercise intervention, Exercise for Cancer Patients (EXCAP), on gene expression levels of muscle immune response and mitochondrial damage and (ii) the relationships of these genes with CRF. Methods: In this nationwide, multicenter, phase III RCT conducted through the URCC NCORP Research Base, cancer patients (N = 350; mean age = 55.7) were randomized to 2 groups: (i) CT and (ii) CT plus a 6-week individualized, home-based, aerobic and resistance exercise program (EXCAP). Gene expression and CRF were assessed pre- and post-intervention from whole blood by qPCR and from patient-report by MFSI, respectively. Results: T-tests revealed significant upregulation of peripheral HLA-DQB1 and MT-CO2 mRNA following CT in controls (both p < 0.00001) while there was less up-regulation in exercisers (both p≤0.005). ANCOVA showed a trend for significant differences between controls and exercisers for HLA-DQB1 (9.2% vs 5.4%; p = 0.059) and MT-CO2 (16.3% vs 12.7%; p = 0.061). Pearson correlations revealed that increases in HLA-DQB1 (r = 0.21; p = 0.051) and MT-CO2 (r = 0.19; p = 0.025) were significantly associated with concurrent increase in CRF in controls, but not in exercisers. Conclusions: CT alters muscle immune response and mitochondrial gene expression causing muscle and mitochondrial damage, which may be mediators for CRF. EXCAP is a promising intervention that may reduce both muscle and mitochondrial damage via its positive effects on HLA-DQB1 and MT-CO2. Funding: NCI UGCA189961, R25 CA102618. Clinical trial information: NCT00924651.
Phase 1 dose escalation of ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-expressing cancers.
Authors: Meric-Bernstam Funda , Beeram Muralidhar , Blum Mariela A. , Hausman Diana Felice , Infante Jeffrey R. , Patnaik Amita , Piha-Paul Sarina Anne , Rasco Drew W. , Rowse Gerry , Thimmarayappa Jamuna , Tolcher Anthony W. , Hamilton Erika Paige
Published: September 2018

1035

Background: The HER2 receptor is expressed across a range of cancers (ca) although expression and heterogeneity vary greatly within and between tumors. FDA approved HER2-targeted therapies (tx) have shown clinical benefit only in HER2 high (IHC3+ or IHC2+/FISH+) breast and gastric ca. ZW25, built on the Azymetric™ platform which utilizes unique Fc mutations to create IgG1-like bispecific antibodies, binds to the same extracellular domains of HER2 as trastuzumab (T) and pertuzumab (P) with increased binding and internalization compared to T alone. In preclinical studies ZW25 was well tolerated and active in models of HER2 low to high ca. Methods: Eligible pts (HER2 IHC 1-3+, progression after standard of care (SOC) tx, normal LVEF) were enrolled in a 3+3 dose escalation study of ZW25 (5, 10 or 15 mg/kg) IV weekly in 4 week cycles. Assessments included adverse events (AEs), LVEF, tumor response and PK. Results: 9 pts have received ZW25 at 5 (n = 3) or 10 mg/kg (n = 6); 15 mg/kg is ongoing. All pts were HER2 high (breast = 4; gastric/GEJ = 4; adnexal = 1). Prior tx included T in all pts; P and T-DM1 in 4 and lapatinib (L) in 3 of 4 breast pts. The most common AEs (all Gr 1/2) were infusion reaction (IR) (5/9), diarrhea (4/9), and fatigue (3/9), with no DLTs and one related Gr 3 AE of hypophosphatemia. The IRs occurred only with 1st dose and did not recur with prophylactic tx (primarily acetaminophen and diphenhydramine; steroids included for 2 pts). At 5 mg/kg, peak drug levels after C1D1 = ~100 ug/ml, accumulating ~50% higher by dose 4. Best response in 8 pts (1 too early): 2 PR (both breast ca with prior T, P, T-DM1, and L; 10 mg/kg, 55% and 33% target lesion decrease, respectively, after 2 cycles), 1 SD (breast ca, 5 mg/kg, ongoing after 4 cycles), and 5 PD. 5 pts currently active; includes 1 gastric pt (10 mg/kg) with PD (new nodal lesions) and clinical benefit with decrease in target lesions and CEA (33 to 1.5 ng/ml). Conclusions: ZW25 has been well tolerated with promising anti-tumor activity in pts with HER2-expressing ca progressing after SOC therapy. These early signs of activity support the therapeutic potential for bispecific antibodies using the Azymetric platform. Development of ZW25 is ongoing, including in lower HER2-expressing ca. Clinical trial information: NCT02892123.
Phase II study of gemcitabine (G), trastuzumab (H), and pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) after prior pertuzumab-based therapy.
Authors: Iyengar Neil M. , Smyth Lillian Mary , Lake Diana , Gucalp Ayca , Singh Jasmeet Chadha , Traina Tiffany A. , DeFusco Patricia Anne , Dickler Maura N. , Fornier Monica N. , Goldfarb Shari Beth , Jhaveri Komal L. , Modi Shanu , Troso-Sandoval Tiffany A. , Jack Kellie , Ulaner Gary , Jochelson Maxine S. , Baselga Jose , Norton Larry , Hudis Clifford A. , Dang Chau T.
Published: September 2018

1037

Background: The combination of taxanes with HP for first line treatment of HER2-positive MBC is associated with improved progression-free (PFS) and overall survival (OS). Treatment per physician’s choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is standard, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown. Methods: This is a single arm phase II trial of G with HP. Eligible patients (pts) had HER2-positive (IHC 3+ or FISH > 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Pts received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months. Results: As of 1-27-17, 41 of 45 pts are enrolled; 34 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 26/34 (76%) are progression free (1 CR, 8 PR, 17 SD); 8 pts progressed. There are no cardiac or febrile neutropenic events to date. 4 pts required G dose reduction (3 grade 3 neutropenia and 1 grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2. Conclusions: The preliminary 3 month-PFS is 76% in evaluable pts (95% CI 60% to 88%). The updated 3 month-PFS results will be presented. Continuation of P beyond progression is associated with apparent clinical benefit. A randomized trial is justified to confirm this clinically important observation. Clinical trial information: NCT02252887.
Safety and efficacy of the BCL2 inhibitor venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: The mBEP study.
Authors: Lindeman Geoffrey John , Lok Sheau Wen , Bergin Alice Ruth , Whittle James Richard , Shackleton Kylie , Sherman Peter , Dawson Sarah-Jane , Desai Jayesh , Liew Danny , Mann Bruce , Murugasu Anand , Roberts Andrew Warwick , Rosenthal Mark , Visvader Jane
Published: September 2018

1044

Background: The anti-apoptotic protein BCL2 is overexpressed in ~85% of ER+ breast cancer (BC). Venetoclax (ABT-199), a BCL2 inhibitor approved for CLL (400 mg/day), synergizes with tamoxifen in preclinical patient derived xenograft models by increasing apoptosis. In the first study to evaluate venetoclax in solid tumors, we tested the safety and efficacy of this combination in ER+BCL2+ metastatic BC. Methods: A ‘3+3 design’ dose escalation phase 1b study enrolled women with ER+ ( > 1%), BCL2+ ( > 10%, mod-high) and HER2 non-amplified metastatic BC. Patients received escalating doses of venetoclax 200, 400, 600 or 800 mg/day with tamoxifen 20 mg/day. The primary objective was to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) over 4 weeks. There was no limit to the number of prior lines of therapy. Results: Fifteen patients were enrolled (mean age 62 years, range 44-78; previous tamoxifen, 10 pts). Mean lines of prior therapy for metastatic BC was 2.5 (median 2, range 0-6) and included tamoxifen (6 pts). ESR1 mutations were present in ctDNA of 4 patients. Treatment was well tolerated, with no DLT observed. MTD was not reached; 6 patients received the maximal planned dose (800 mg). The most common adverse event (AE) was lymphopenia (67% Grade 1-2; 13% Grade 3; No Grade 4), followed by nausea (46%, Grade 1-2), which was readily managed. Of 13 women with measurable disease (RECIST v1.1), 4 (31%) had a partial response and 5 (38%) had stable disease (clinical benefit rate, 69%). For patients with a partial response, tumor regression was rapid (evident at first restaging) and occurred in the 400-800 mg dose levels. Two patients with non-measurable bone-only disease had clinically stable disease (1 ongoing > 64 weeks). The median duration of response has not yet been reached (range, 12 to > 64 weeks). Conclusions: We demonstrated the safety of tamoxifen and venetoclax in ER+BCL2+ metastatic BC, with preliminary evidence of clinically relevant activity. A dose expansion study including serial biopsy, ctDNA and PET scans is ongoing at the 800 mg/day recommended phase 2 dose. Sponsor: Royal Melbourne Hospital Clinical trial information: ISRCTN98335443 , ACTRN12615000702516.
Age-associated vulnerability to treatment-related late cardiotoxicity: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Bates James Edward , Liu Qi , Yasui Yutaka , Howell Rebecca M. , Mulrooney Daniel A. , Dhakal Sughosh , Leisenring Wendy M. , Indelicato Daniel J. , Gibson Todd M. , Armstrong Gregory T. , Oeffinger Kevin C. , Constine Louis S.
Published: September 2018

10501

Background: Cardiovascular disease (CVD) is the most common non-cancer cause of death in long-term survivors of pediatric cancer. We investigated the role of age at diagnosis in modifying treatment-related late CVD risk in the CCSS population. Methods: We evaluated CTCAE grade 3 – 5 CVD events occurring ≥5 years after diagnosis in 23,465 5-year survivors of pediatric cancer diagnosed 1970-1999. We estimated the rates of developing any CVD, including coronary artery disease (CAD) or heart failure (HF). Modifications of treatment effects by age at diagnosis were analyzed using piecewise exponential models adjusting for current age, race, and smoking. Results: At a median age of 28.4 years (range 5.6 –58.3) and follow up of 20.2 years (5 – 39.3), 239 CAD and 359 HF events occurred. The cumulative incidence of CVD, CAD, and HF were 4.8% (95% CI: 4.3-5.3), 2.4% (95% CI: 2.2-2.9), and 2.5% (95% CI: 2.2-2.9) by 30 years from diagnosis. Mean cardiac radiotherapy (CRT) doses of ≥10 Gy were associated with a progressively increasing risk of CVD (10 - < 20 Gy: RR 3.6, 95% CI 2.1 – 6.2, p < 0.01; 20 - < 30 Gy: RR 4.4, 95% CI 2.7 – 7.2, p < 0.01; ≥30 Gy: RR 7.5, 95% CI 4.9 – 11.5, p < 0.01) relative to those receiving no CRT. In those receiving a low mean CRT dose (0.1 - < 10 Gy), younger children had higher rates of CVD (0 – 4 years: RR = 2.2, 95% CI = 1.0 – 4.6, p = 0.04; > 4 - ≤13 years: RR = 2.1, 95% CI = 1.1 – 4.1, p = 0.03) compared to those > 13 years, an effect not seen at higher doses. Among survivors exposed to anthracycline doses ≥250 mg/m2, those age 0 – 4 at diagnosis had increased risk of both CAD (RR = 4.9, 95% CI 1.5 – 16.3, p = 0.01) and HF (RR = 3.0, 95% CI 1.6 – 5.0, p < 0.01). Cisplatin exposure ≥300 mg/m2 was associated with increased risk of any CVD (RR = 1.8, CI = 1.2 – 2.6, p < 0.01), primarily attributable to increased risk of HF (RR = 2.3, 95% CI = 1.5 - 3.5, p < 0.01). Conclusions: Among long-term survivors of pediatric cancer, increasing CRT dose is associated with increased risk for CVD in a dose-response relationship. Young children are at higher risk for CVD after low-dose CRT or high-dose anthracycline exposure. Cisplatin exposure significantly increases risk for CVD. These findings should inform future treatment and surveillance protocols.
Intensive multi-modality therapy for extra-ocular retinoblastoma (RB): A Children's Oncology Group (COG) trial (ARET0321).
Authors: Dunkel Ira J. , Krailo Mark D. , Chantada Guillermo L. , Banerjee Anuradha , Abouelnaga Sherif , Buchsbaum Jeffrey , Merchant Thomas E. , Granger Meaghan , Jubran Rima Fuad , Kellick Michael , Weinstein Joanna , Abramson David H. , Rodriguez-Galindo Carlos , Chintagumpala Murali M.
Published: September 2018

10506

Background: Metastatic RB is associated with a poor prognosis. Previous small series suggested that intensified systemic chemotherapy with or without radiation therapy (RT) may improve outcomes in this population. COG opened this prospective, multi-institutional, international trial to study the effectiveness of this approach. Methods: Patients with regional extra-ocular RB (stage 2 or 3) were treated with 4 cycles of intensive conventional chemotherapy (vincristine 0.05 mg/kg/day, cisplatin 3.5 mg/kg/day, cyclophosphamide 65 mg/kg x 2 days, etoposide 4 mg/kg x 2 days) followed by involved-field RT (4500 cGy). Two strata of patients with metastatic RB [stage 4a: distant metastases not involving the central nervous system involvement (CNS); and stage 4b (CNS metastases)/trilateral RB)] were treated with 4 cycles of the same chemotherapy. Patients with ≥ partial response then received 1 cycle of high-dose carboplatin (Calvert formula with AUC = 7/day, maximum 16.7 mg/kg/day) on days -8 to -6, thiotepa (10 mg/kg/day), & etoposide (8.3 mg/kg/day) on days -5 to -3 with autologous hematopoietic stem cell rescue on day 0. Patients with metastatic RB who did not achieve an adequate response to chemotherapy also received RT. Results: Sixty subjects (20 in each stratum) were enrolled; 57 were eligible and included in the analyses (based on data current to June 30, 2016). Toxicity was significant as expected and there were 2 therapy related deaths. Event-free survival (EFS) at 36 months was 87.7% (90% CI 65.4 to 96.0%) for subjects with stage 2 or 3 disease, 79.3% (90% CI 54.2 to 91.6%) for subjects with stage 4a disease and 8.0% (90% CI 1.0 to 25.1%) for subjects with stage 4b/trilateral disease. The observed results significantly improved the EFS in each stratum compared with historical results used for planning the study. Conclusions: This is the first prospective, multi-institutional, international study to show that intensive multi-modality therapy is highly effective for patients with regional extra-ocular RB and metastatic RB not involving the CNS. More effective therapy is required for patients with CNS RB. Clinical trial information: NCT00554788.
The INFORM personalized medicine study for high-risk pediatric cancer patients.
Authors: Worst Barbara Christine , Pfaff Elke , Van Tilburg Cornelis M. , Balasubramanian Gnana Prakash , Fiesel Petra , Pajtler Kristian W. , Freitag Angelika , Witt Ruth , Kulozik Andreas E. , von Deimling Andreas , Eggert Angelika , Dirksen Uta , Lichter Peter , Capper David , Pfister Stefan M. , Jones David T. W. , Witt Olaf
Published: September 2018

10509

Background: Relapses from high-risk tumors pose a major clinical challenge in pediatric oncology. The German INFORM registry (INdividualized therapy FOr Relapsed Malignancies in children) addresses this problem using integrated next-generation sequencing to rapidly identify patient-specific therapeutic targets. Methods: Whole-exome, low-coverage whole-genome and RNA sequencing is complemented with microarray-based DNA methylation profiling. Identified alterations are discussed and prioritized according to biological significance and potential druggability in a weekly molecular tumor board. Results: To date, 214 tumor samples of high-risk pediatric cancer patients have been profiled from 47 German centers, with 39% being sarcomas, 30% brain tumors, 13% neuroblastoma and 18% hematological or other malignancies. Turnaround time from tissue arrival to molecular results was 21 calendar days on average. In 14/214 patients (7%) we identified an underlying germline predisposition syndrome. In several cases there were discrepancies between the original histological diagnosis and our molecular findings, especially in brain tumors. We detected one or more potentially druggable alterations in 147/214 (69%) cases. Tyrosine kinases, the PI3K/mTOR pathway, MAPK pathway, and cell-cycle as well as transcriptional regulators were commonly affected. Based on these findings, targeted therapeutics were incorporated into the therapy regime in one-third of patients, with anecdotal reports of marked responses, including a patient with a pleomorphic sarcoma, where we detected a previously undescribed RAF-fusion, showing a partial remission upon RAF-inhibition. Conclusions: In summary, real-time comprehensive profiling of pediatric tumors provides valuable diagnostic information and identifies potential therapeutic targets. In parallel, the implementation of a systematic program for reverse-translational evaluation is ongoing. Recently, this nationwide effort has expanded to include patients from other countries. We will also recruit patients to the complementary eSMART and INFORM2 biomarker-driven, phase I/II combination trial series, to provide unprecedented access to targeted therapies in Europe.
Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL).
Authors: Bhojwani Deepa , Sposto Richard , Shah Nirali , Rodriguez Vilmarie , O'Brien Maureen Megan , McNeer Jennifer Lynn , Loh Mignon L. , Rheingold Susan R.
Published: September 2018

10512

Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1st-5threlapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( > 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.