bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved coping to mediate the positive effects of integrated palliative care on quality of life and depression.
Authors: Jacobs Jamie M. , Greer Joseph A. , El-Jawahri Areej , Nipp Ryan David , Gallagher Emily R. , Pirl William F. , Park Elyse R. , Muzikansky Alona , Jacobsen Juliet , Jackson Vicki A. , Temel Jennifer S. 
Published: September 2018

10023 Background: In a recent trial, early integrated palliative care (PC) improved quality of life (QOL) and reduced depression symptoms in patients with newly-diagnosed incurable lung and gastrointestinal (GI) cancer. The mechanisms by which PC benefits these outcomes are unclear. Therefore, we examined whether early integrated PC improved patients’ coping strategies and the degree to which changes in coping mediated intervention effects on patient-reported QOL and depression symptoms. Methods: From 5/2011 to 7/2015, we enrolled 350 patients with newly diagnosed incurable lung or non-colorectal GI cancer in a randomized trial of early PC integrated with oncology care vs. oncology care alone at Massachusetts General Hospital. Patients completed self-report measures of QOL (Functional Assessment of Cancer Therapy-General), depression symptoms (Patient Health Questionnaire-9), and use of active and avoidant coping strategies (Brief Cope) at baseline, 12, and 24 weeks. Linear regression was used to assess the effects of the early PC intervention on active and avoidant coping strategies. A multiple mediation regression with bias-corrected bootstrapping was modeled to examine whether changes in use of coping strategies mediated intervention effects on QOL and depression symptoms. Results: Compared to oncology care, early integrated PC improved patients’ use of active coping and reduced use of avoidant coping strategies. Improvements in 24-week QOL in patients assigned to PC were mediated by increased use of active coping strategies (indirect effect = 1.27, bootstrapped SE = 0.65, 95% CI [0.31, 2.86]), but not by decreased use of avoidant coping. Similarly, PC-related reductions in 24-week depression symptoms were mediated by increased use of active coping strategies (indirect effect = -0.39, bootstrapped SE = 0.20, 95% CI [-0.89, -0.08] but not by decreased use of avoidant coping. Conclusions: Patients with newly diagnosed incurable cancer who received early integrated PC showed increased use of active coping strategies, which led to improved QOL and depression symptoms. PC may improve QOL and mood by providing patients with the skills to cope effectively with life-threatening illness. Clinical trial information: NCT01401907.
Predictive value of the patient reported outcome “living with cancer” instrument on overall survival in advanced cancer patients: A tool for guiding timing of palliative care consultations.
Authors: Goldberg Stuart L. , Paramanathan Dhakshila , Arunajadai Srikesh , DeVincenzo Victoria , Pe Benito Ruth , Gruman Brooke , Kaur Sukhi , Goy Andre , Niranjan Usha , Fitzgerald Denis , Childs Julianne Wilkins , Lee James W. , Abdo-Matkiwsky May D. , Choi Kelly , Hervey John , Schultz Eric , Pecora Andrew 
Published: September 2018

10025 Background: The Living with Cancer (LWC) patient reported outcome (PRO) instrument evaluates distress from the point of view of the advanced cancer pt. The 7-item Likert survey measures 4 personhood domains (performance status, pain, burden [financial and family], depression) with scores ranging 0-112. In a pilot study of 433 cancer pts at a single center a score of >28 was associated with an increased likelihood of physician’s (blinded) opinion of need for end-of-life care discussions ( J Palliative Med 2016). Methods: The LWC instrument is a statistically validated PRO (ASCO Palliative Care Symposium 2016). LWC was administered to 1024 cancer pts receiving non-curative therapy at 7 centers (Regional Cancer Care Associates, NJ) from Sept 2015 - Oct 2016. LWC surveys were linked to the Cota database, which extracts and enriches data from EHRs. Date of survey was used as the start point in time-to-event analysis. Results: 290 (28%) pts expired during the study (median f/u 9.9 months). 267 (26%) pts exceeded the threshold score of 28 defined in the pilot set (28 was also independently this study’s optimal cut point). Pts with an LWC score >28 had inferior 6 and 12 mo overall survival (69% and 54%) vs pts with scores <29 (88% and 73%) (log rank p<0.001). A Cox model demonstrated that LWC score and cancer type were significant (LWC: p<0.001, cancer types (compared to B): GI p<0.001, GU: p=0.013, T: p<0.001, M: p=0.334) A one point score increase in LWC resulted in a 1.8% increase in expected hazard. Among solid tumor pts with LWC >28, 20% died within the next 3 mo and 35% died within the next 6 mo, indicating appropriate timing for hospice and palliative care consults, respectively. Conclusions: Pt responses to the LWC instrument predict survival among advanced cancer pts and may be useful in guiding timing of palliative care consultations. [Table: see text]
Autologous stem cell transplant (ASCT) in myeloma to improve patient reported physical function and fatigue.
Authors: Bhatt Geetika , Benson Don M. , Efebera Yvonne Adeduni , Hofmeister Craig C. , Jaglowski Samantha Mary , Devine Steven Michael , Wildes Tanya Marya , Huang Ying , Jones Desiree , Rosko Ashley Elizabeth 
Published: September 2018

10044 Background: Patients with Multiple Myeloma (MM) report some of the poorest Health-related quality of life (HRQoL). Few studies show how ASCT influences global health outcomes as measured by a Geriatric Assessment (GA). We performed a prospective GA evaluating the dynamic changes in health pre- and post-ASCT. Methods: 100 pts with plasma cell dyscrasia (median (m) = 60 yrs, range (r) = 36-75 yrs) underwent GA pre-ASCT, 90 days and 1-yr post-ASCT. GA included nutritional survey, Hospital Anxiety and Depression Scale (HADS), Brief Fatigue Inventory (BFI), Medical Outcomes Study-Social Support Survey (MOS-SSS), Short Physical Performance Battery (SPPB), handgrip strength, self-reported Human Activity Profile (HAP) Maximum Activity Score (MAS) and Adjusted Activity Score (AAS). Data were analyzed using paired t-test (p < 0.05). Results: Pts reported moderate fatigue pre-ASCT (m = 4.6, r: 0-9.8) which normalized at 1-yr (m = 2.5, r: 0-7.3; p = 0.008). Self-reported pre-ASCT physical function (MAS) (m = 73, r = 20-94) improved at 1-yr (m = 75.5, r = 52-94; p = 0.014); AAS (m = 64, r = 18-94) also improved at 1-yr (m = 70.5, r = 38-91; p = 0.025). In contrast, MD-reported KPS decreased. Screens for deficits in anxiety, depression, social support, objective physical function, handgrip strength and wt loss did not change significantly at 1-yr. Conclusions: Our data indicate that ASCT significantly improves patient-reported fatigue and physical function, unlike MD-reported KPS. [Table: see text]
Association of a four-gene decision tree signature with response to platinum-based chemotherapy in patients with triple negative breast cancer.
Authors: Quist Jelmar , Mirza Hasan , Cheang Maggie Chon U , Telli Melinda L. , Lord Christopher J. , Tutt Andrew Nicholas James , Grigoriadis Anita 
Published: September 2018

1006 Background: Approaches to capture the molecular complexity of triple negative breast cancers (TNBCs) are lacking. We sought to classify TNBCs into subgroups with common biological features based on transcriptomic and genomic data using a Bayesian algorithm. Methods: Matched gene expression and copy number microarray data was available for the Guy’s (n = 88) and METABRIC (n = 112) TNBC cohorts. CONEXIC was used to derive a decision tree signature for classification. Performance of the signature was tested in 7 TNBC cohorts (total n: 1,368), including 2 clinical trials assessing the efficacy of gemcitabine and carboplatin with and without iniparib. In the early-stage PrECOG 0105 Phase II neoadjuvant trial (n = 43), subtypes were evaluated in relation to response by residual cancer burden (RCB). In the metastatic Sanofi Phase III trial (n = 224), subtypes were assessed by RECIST. Results were compared to the BL1 TNBCtype-4 subtype and assessed using a multivariate analysis. Results: The integrative analysis using CONEXIC identified a four-gene signature. Across 7 TNBC cohorts this classification identified 6 entities, including 5 smaller groups and 1 major. Characterisation of the latter subgroup, referred to as MC6, revealed enrichment of CD4+ and CD8+ immune signatures, increased genomic instability and reduction in negative regulation of the MAPK signalling pathway. In PrECOG, 25 out of 41 MC6-TNBCs (61%, OR = 1.19, 95% CI = 0.37 to 3.81, P = 0.79) had RCB 0/I. Similarly, 65% of the BL1-TNBCs had an RCB 0/I, however in a smaller population (11 out of 17, OR = 1.30, 95% CI = 0.35 to 5.31), P = 0.77). In Sanofi Phase III, the objective response rate (ORR) in MC6-TNBCs was 46% versus 30% in non-MC6-TNBCs (OR = 1.97, 95% CI = 1.03 to 3.77, P = 0.04), in comparison to BL1-TNBCs with an ORR of 41% versus 32% in non-BL1-TNBCs (OR = 1.47, 95% CI = 0.75 to 2.86), P = 0.26). Conclusions: These results demonstrate that a four-gene signature can identify a subgroup of TNBCs responsive to platinum-based chemotherapy in the metastatic setting. The distinct features of these TNBCs suggest investigation of alternative actionable interventions with immunotherapy or MEK inhibitors in relation to this signature.
Evaluating the addition of bevacizumab (Bev) to endocrine therapy as first-line treatment for hormone-receptor positive (HR+)/HER2-negative advanced breast cancer (ABC): Pooled-analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.
Authors: Martin Miguel , Loibl Sibylle , Hyslop Terry , de la Haba-Rodriguez Juan , Aktas Bahriye , Cirrincione Constance , Carrasco Eva Maria , Mehta Keyur , Barry William Thomas , Morales Serafin , Carey Lisa A. , Garcia Saenz Jose Angel , Partridge Ann , Martinez Noelia , Hahn Olwen Mary , Winer Eric P. , Guerrero Angel , Hudis Cliff , Casas Maribel , Dickler Maura N. 
Published: September 2018

1012 Background: Data from randomized trials comparing ET v ET-Bev in 1st line HR+/HER2- ABC pts showed controversial results. We performed a pooled-analysis of two randomized trials (LEA and CALGB 40503) to refine the Bev value in this patient population. Methods: We analysed 749 ABC pts with ET (letrozole-673, tamoxifen-39, fulvestrant 250mg-37) +/- Bev. Primary objective was to compare progression-free survival (PFS). Secondary endpoints were: safety; other efficacy (overall response rate [ORR], clinical benefit rate [CBR] and overall survival [OS]) in all pts; and efficacy in de novo pts and by previous endocrine-sensitivity (-/+ 24 months [mo] without recurrence under ET in adjuvant setting). Multivariable Cox models were fitted for PFS adjusted by study co-variables and controlled for study level differences. Results: Median age was 61 years (yr) (range: 25-87); 40% had de novo ABC and 60% recurrent disease (with disease free interval of ≤ 1 yr in 5%, 1-2 yr in 7% and > 2 yr in 88%); 82% of recurrent pts had previous ET sensitivity. Median PFS was 14.3 mo in the ET arm v 19 mo in the ET+Bev arm (HR 0.77; 95% CI 0.66-0.91; p<0.01). ORR and CBR with ET v ET+Bev were 40 v 61% (p<0.01) and 64 v 77% (p<0.01). OS did not differ between arms (HR 0.96; 95% CI 0.77-1.18; p=0.68). PFS for de novo ABC pts was 14.6 and 19.3 mo in the ET and ET+Bev arms (HR 0.82; 95% CI 0.63-1.06; p=0.13). PFS differed between arms for previous sensitive pts (HR 0.68; 95% CI 0.53-0.89; p=0.004) but not for ET-resistant pts (HR 0.73; 95% CI 0.4-1.3; p=0.29). Grade 3-5 hypertension (2.2 v 20.1%), proteinuria (0 v 9.3%), cardiovascular events (0.5 v 4.2%) and liver events (0 v 2.9%) were significantly higher in the ET+Bev arm (all p<0.01). Multivariable analyses showed age (p<0.01), PgR status (p<0.01), type of prior ET (p<0.01) and treatment arm (p<0.01) to be associated with PFS. Conclusions: The addition of Bev to ET increased PFS but not OS. Analyses to define subgroups with prolonged benefit from ET alone or ET-Bev are ongoing. Support: U10CA180821, U10CA180882, Breast Cancer Research Foundation, Genentech, Roche. Clinical trial information: NCT00545077 / NCT00601900.
Next generation sequencing in community oncology practice: Beneficial or economical burden?
Authors: Ammakkanavar Natraj Reddy , Bedano Pablo M. , Agarwala Anuj Krishna , Bhatia Janvi , Bolla Arya , Poojary Priti , Siddiqui Bilal Karim , Parshad Shiroo , Walling Radhika , Smith Gregory William , Mayer Mary Louise , Bhatia Sumeet 
Published: September 2018

102 Background: Precision genomics medicine is a fast growing in cancer care. Targeted therapy has yielded substantial benefit when appropriately used. With next generation sequencing (NSG) use increasing in non-academic setting outside clinical trial, we need to consider benefits and economical burden of this. Methods: Retrospective chart analysis of cancer patients (pts) treated at a large community practice was undertaken. With IRB approval, demographic, clinical and NSG data were collected for 209 pts who had NSG in 2015 and 2016. Pts were placed in 1 of 4 categories based on NSG results with available drug for specific mutation and change in management (CIM): a) CIM for current, b) Potential to CIM with subsequent therapy, c) No CIM due to poor performance status, d) No CIM due to lack of new target and/or drug. Alternate economical standard test for the mutation noted. Statistical analysis was done using chi-square and fisher’s exact test. Results: Median age was 64yr. Most common tumor types tested where as listed in table 96% had stage 4 disease. 82% had ≥1 prior systemic therapy. Pts were assigned to categories as per table below. When RAS mutation status where accounted by standard testing, none of the colon cancer pts benefited from NSG test. 6 of 54 pts who had CIM had alternate test option. Financial responsibility for these tests is approximately $1.21 million. 18 pts in 2015 and 17 pts in 2016 where billed for test after exhausting insurance and support option. More financial data may be available at time of presentation. Conclusions: NGS tumor test might benefit small group of selective pts at time of testing. It is likely not prime time to use for colon cancer. Benefits with later therapy are difficult to predict. NSG should be used more judiciously due to financial implications. [Table: see text]
Phase I study of alpelisib (BYL-719) and T-DM1 in HER2-positive metastatic breast cancer after trastuzumab and taxane therapy.
Authors: Jain Sarika , Santa-Maria Cesar Augusto , Rademaker Alfred , Giles Francis J. , Cristofanilli Massimo , Gradishar William John 
Published: September 2018

1026 Background: Constitutive activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a mechanism of trastuzumab resistance in HER2-positive metastatic breast cancer (MBC). Alpelisib (BYL-719) is the first oral PI3K inhibitor that selectively inhibits the PI3Kα isoform. We aimed to determine the maximum tolerated dose (MTD), safety, and activity of alpelisib with ado-trastuzumab emtansine (T-DM1) in HER2-positive MBC that failed standard therapy. Methods: In this phase I study, pts received alpelisib daily (cohort 1: 300 mg, (-1): 250 mg) and T-DM1 3.6 mg/m2 on Day 1 every 21 days using a 3+3 design with dose expansion at MTD. Dose-limiting toxicity (DLT) was defined as CTCAE Grade 3/4 adverse events (AE) during cycle 1. Data cut-off is Jan. 1, 2017. Results: 17 pts were enrolled. Median age was 53 (40-66). Median prior lines of therapy in metastatic setting was 4.5 (0-13) including 9 pts who progressed on prior T-DM1 (after median 8 cycles). Median number of metastatic sites was 2 (1-5). Median number of cycles per pt who completed at least 1 cycle was 8 (1-19). Five pts were enrolled in cohort 1 with 2 DLTs (grade 3 rash), leading to cohort (-)1, in which there were no DLTs. The most common alpelisib-related AEs were hyperglycemia (n = 9, 53%), fatigue (n = 9, 53%), nausea (n = 7, 35%), and rash (n = 8, 47%). Grade 3 alpelisib-related AEs included rash (n = 7), hyperglycemia (n = 3), weight loss (n = 1), hypertension (n = 2), and pancreatitis (n = 1). Grade 3 rash occurred during cycle 1, which resolved with interruption and subsequent dose reduction of alpelisib and use of steroids. Grade 3 hyperglycemia was reversible with oral anti-diabetic treatment. One Grade 4 AE occurred (thrombocytopenia) likely due to T-DM1. MTD for alpelisib was established as 250 mg daily. Median follow-up was 11.6 months (0.3-19.5). Median PFS was 6 months (95% CI 2.9-10.6). In 11 pts without prior T-DM1 mPFS was 4.3 months (95% CI 2.0-8.8) and in 6 pts with prior T-DM1 it was 10.6 months (95% CI 1.6-12.6), p = 0.18. Conclusions: The combination of alpelisib 250 mg daily and T-DM1 appears to be safe in HER2-positive MBC pts with significant anti-tumor activity, even in pts previously treated with T-DM1. A phase II study is planned. Clinical trial information: NCT02038010.
DS-8201a, a HER2-targeting antibody-drug conjugate, to elicit immune responses and benefits in combination with an anti-PD-1 antibody.
Authors: Iwata Tomomi Nakayama , Ishii Chiaki , Ogitani Yusuke , Wada Teiji , Agatsuma Toshinori 
Published: September 2018

1031 Background: DS-8201a, a HER2-targeting antibody–drug conjugate (ADC), with a topoisomerase I inhibitor, exatecan drivative (DX-8951 derivative, DXd) has been shown to have antitumor effects in preclinical xenograft models and clinical trials, but the involvement of the immune system in the antitumor efficacy of DS-8201a has not been elucidated yet. Methods: The antitumor efficacy of DS-8201a individually and in combination with an anti-PD-1 antibody was determined in a syngeneic mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Mice whose tumors had been cured by DS-8201a treatment were rechallenged with CT26.WT-hHER2 cells; their splenocytes were co-cultured with CT26.WT-hHER2 or CT26.WT-mock cells, and IFN-g secretion by these cells was determined. To investigate effects of DXd and DS-8201a on dendritic cells (DCs), the expression of DC markers on bone marrow derived DCs (BMDCs) and intratumoral DCs was analyzed by flow cytometry. Furthermore, MHC class I and PD-L1 expression on tumor cells was analyzed. Results: At a weekly dosage of 10 mg/kg, DS-8201a showed significant antitumor effects in the mouse model. Mice whose tumors had been cured by DS-8201a treatment rejected the rechallenge with CT26.WT-hHER2 cells, and splenocytes from these mice were activated by both CT26.WT-hHER2 and CT26.WT-mock cells. In the mouse model, DS-8201a treatment raised a population of intratumoral DCs (CD45+CD11c+MHC class II+) and increased DC expression of CD86, a DC activation marker; DXd also up-regulated CD86 expression on BMDCs in vitro. Furthermore, DS-8201a up-regulated PD-L1 and MHC class I expression on tumor cells. Notably, antitumor effects of the combination of DS-8201a with an anti-PD-1 antibody were better than those of monotherapy. Conclusions: DS-8201a elicits immune responses via mechanisms other than cytotoxic effects on tumor cells. This finding suggests additional benefits of combining DS-8201a with an immune checkpoint inhibitor (ICI). The combination of DS-8201a and an anti-PD-1 antibody was effective in tumor suppression, indicating that DS-8201a may be successfully combined with an ICI in human clinical applications.
Quantification of intratumoral heterogeneity of HER2 status in breast cancer.
Authors: Horii Rie , Matsuura Masaaki , Nitta Hiro , Ito Yoshinori , Ohno Shinji , Iwase Takuji , Akiyama Futoshi 
Published: September 2018

1036 Background: Intratumoral heterogeneity (ITH) occurs as a consequence of epigenetic aberrations in tumor cells with genetic diversity. HER2 ITH can be classified into genetic (a mixture of tumor cells with and without HER2 gene amplification) and epigenetic ITH (a mixture of HER2 gene-amplified tumor cells with and without HER2 protein overexpression). However, the both effects of genetic and epigenetic ITH on HER2-targeted therapy have not been clearly demonstrated. In order to implement ITH as a referenced factor for treatment selection, the ITH quantification is necessary. Gene-protein assay (GPA), in which immunohistochemistry and dual in situ hybridization are simultaneously performed on a single slide, allows bright-field analyses of both gene and protein status. We aimed to quantify HER2 ITH by the combination of gene and protein status and clarify its clinical significance. Methods: Fifty three patients with HER2-positive breast cancer, who underwent neoadjuvant trastuzumab with chemotherapy, were examined. Five representative microscopic images were captured from a GPA slide of a pre-therapeutic biopsy material. All evaluable tumor cells in the images were scored according to the HER2 status determined by the combination of gene copy number and protein expression (Table). We investigated the relationship between the HER2 scores and pathological complete response (pCR) to the neoadjuvant treatment by the logistic analysis. Results: The average of HER2 scores, indicating the degree of the HER2 status, varied from 2.21 to 5.98. It was significantly related to pCR (Estimate: 1.21, Std. error: 0.46, RR: 3.34, P=0.009, 95%CI: 1.35-8.25). The standard deviation of HER2 scores, indicating the degree of the HER2 ITH, varied from 0.13 to 1.37. It was significantly related to pCR (Estimate: -2.09, Std. error: 0.83, RR: 0.12, P=0.012, 95%CI: 0.02-0.63). Conclusions: HER2 ITH, quantified by GPA, is a predictive factor for the therapeutic effect to trastuzumab-based treatment in HER2-positive breast cancer. [Table: see text]