bluuebunny/crossref_metadata_2025 huggingface dataset:
Image processing of seismic attributes for automatic fault extraction
Authors: Qi Jie , Lyu Bin , AlAli Abdulmohsen , Machado Gabriel , Hu Ying , Marfurt Kurt
Published: September 2018

Along with horizon picking, fault identification and interpretation is one of the key components for successful seismic data interpretation. Significant effort has been invested in accelerating seismic fault interpretation over the past three decades. Seismic amplitude data exhibiting good resolution and a high signal-to-noise ratio are key to identifying structural discontinuities using coherence or other edge-detection attributes, which in turn serve as inputs for automatic fault extraction using image processing or machine learning techniques. Because seismic data exhibit not only structural reflectors but also seismic noise, we have developed a fault attribute workflow that contains footprint suppression, structure-oriented filtering, attribute computation, “unconformity” suppression, and our new iterative energy-weighted directional Laplacian of a Gaussian (LoG) operator. In general, tracking faults that exhibit a finite offset through a suite of conformal reflectors is relatively easy. Instead, we evaluate the effectiveness of this workflow by tracking faults through an incoherent mass-transport deposit, where the low-frequency contribution of multispectral coherence provides a good fault image. Multispectral coherence also reduces the “stair-step” fault artifacts seen on broadband data. Application of statistical filtering can preserve the discontinuity’s boundaries and reject incoherent backgrounds. Finally, iterative application of an energy-weighted directional LoG operator provides improved fault image by sharpening low-coherence anomalies perpendicular and smoothing low-coherence anomalies parallel to fault surfaces, while at the same time attenuating locally nonplanar anomalies.
Impact of intensity of post-treatment surveillance on survival in colorectal cancer.
Authors: Snyder Rebecca A , Hu Chung-Yuan , Cuddy Amanda , Francescatti Amanda B. , Schumacher Jessica R. , You Y. Nancy , Schrag Deborah , McKellar Daniel , Winchester David P , Kozower Benjamin D. , Greenberg Caprice Christian , Chang George J.
Published: September 2018

10016

Background: The optimal strategy for CRC post-treatment surveillance is unknown. The frequency and type of testing remains controversial, and it is unclear whether surveillance impacts rates of detection or survival. The purpose of this study was to determine if the intensity of post-treatment surveillance is associated with time to recurrence detection, treatment, or overall survival (OS). Methods: Primary records of a random sample of 10,636 Stage I-III CRC patients from Commission on Cancer accredited hospitals (2006-2007) were abstracted, and detailed results of surveillance testing were reviewed. Data was merged with records in the National Cancer Database (NCDB). A predicted and observed number of imaging and CEA tests per patient were determined and clustered by hospital to categorize patients into high (HI, O/E ≥ 1) or low intensity (LI, O/E < 1) categories. Results: 6,279 patients underwent imaging or CEA surveillance in the 3 years after CRC treatment. Patients with HI imaging (50.6%) or CEA (51.2%) had a mean of 2.9 imaging studies and 4.7 CEA tests. Patients with LI imaging underwent a mean of 1.4 imaging studies and 1.6 CEA tests. 5-year recurrence rates did not differ based on intensity of surveillance. Stage II and III patients who underwent HI imaging and CEA testing had a slightly higher resection rate, but this did not translate into an improvement in 5-year OS. Conclusions: High vs. low intensity surveillance was not associated with earlier detection of recurrent disease or improved OS. HI surveillance was associated with a slightly higher resection rate, but this did not result in a survival benefit. Our findings within a national hospital registry cohort failed to demonstrate a survival benefit of HI surveillance and suggest that an effective surveillance strategy may involve less frequent testing. [Table: see text]
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]
Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC).
Authors: Hortobagyi Gabriel N. , Stemmer Salomon M. , Burris Howard A. , Yap Yoon Sim , Sonke Gabe S. , Paluch-Shimon Shani , Campone Mario , Petrakova Katarina , Blackwell Kimberly L. , Winer Eric P. , Janni Wolfgang , Verma Sunil , Conte Pier Franco , Arteaga Carlos L. , Cameron David A. , Xuan Fengjuan , Miller Michelle Kristine , Germa Caroline , Hirawat Samit , O'Shaughnessy Joyce
Published: September 2018

1038

Background: Endocrine therapy (ET) is the basis of first-line (1L) treatment for HR+ ABC. However, ET resistance are almost universal. At the first interim analysis (IA) of MONALEESA-2 (NCT01958021), ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in patients (pts) with HR+, HER2– ABC.1 Here we report updated efficacy and safety data from MONALEESA-2 with a further ~11 months of follow-up. Methods: Postmenopausal women with no prior therapy for ABC were randomized 1:1 toRIB (600 mg/day, 3-weeks-on/1-week-off) + LET(2.5 mg/day, continuous) vs PBO + LET. The primary endpoint was locally assessed PFS. Secondary endpoints include overall survival (OS; key) and safety. OS significance was defined by a p-value threshold of 3.15 x 10-5. Tumor assessments were performed every 8 weeks for the first 18 months, and every 12 weeks, thereafter. Results: 668 pts were enrolled (334 in each arm). At the second IA for OS (data cut-off Jan 2, 2017), the median duration of follow-up was 26.4 months; 116 deaths and 345 PFS events had occurred. OS data remain immature, with 15.0% vs 19.8% of pt deaths in the RIB + LET vs PBO + LET arm (HR = 0.746; 95% CI: 0.517–1.078; p= 0.059). Updated PFS analyses confirmed continued treatment benefit in the RIB + LET vs PBO + LET arm. The 24-month PFS rates (RIB + LET vs PBO + LET) were 54.7% vs 35.9%. Treatment benefit was consistent across pt subgroups. The most common Grade 3/4 laboratory abnormalities (≥10% of pts; RIB + LET vs PBO + LET) were decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), decreased lymphocytes (16.2% vs 3.9%), and elevated alanine aminotransferase (11.4% vs 1.2%). Conclusion: After 26+ months of follow-up, treatment benefit with 1LRIB + LET persists in postmenopausal women with HR+, HER2– ABC. The study remains immature for OS analysis. The safety profile of RIB + LET remains manageable. 1. Hortobagyi G, et al. N Engl J Med 2016;375:1738–48. Clinical trial information: NCT01958021.
Is androgen receptor useful to predict the efficacy of anti-estrogen therapy in advanced breast cancer?
Authors: Rocca Andrea , Bronte Giuseppe , Ravaioli Sara , Puccetti Maurizio , Tumedei Maria Maddalena , Scarpi Emanuela , Maltoni Roberta , Sarti Samanta , Cecconetto Lorenzo , Bedei Lucia , Fedeli Anna , Andreis Daniele , Pietri Elisabetta , Calistri Daniele , Amadori Dino , Bravaccini Sara
Published: September 2018

1042

Background: The androgen receptor (AR) is widely expressed in breast cancers but its role in estrogen receptor (ER)-positive tumors is still controversial. However, the AR/ER ratio may impact prognosis and the response to antiestrogen endocrine therapy (ET). Methods: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced breast cancer (ABC). We evaluated patients treated with first-line ET (2002–2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy. ER, progesterone receptor (PgR), Her2, Ki67 and AR expression was determined by immunohistochemistry. A cut-off of < 1% immunostained cells was used to categorize AR expression. AR expression was analyzed in relation to the other conventional biomarkers (ER, PgR, Her2 and Ki67), best response (CR, PR, SD, PD), and time to progression (TTP) (months). TTP was estimated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios and their 95% confidence intervals (95% CI) were estimated using the Cox regression model. The Chi-square test was used to evaluate correlations between categorical variables and best response. p values < 0.05 were considered statistically significant. Results: Of the 102 evaluable patients (93% were treated with an aromatase inhibitor), biomarkers were assessed in primary tumors in 70 cases, in metastases in 49 and in 17 in both). Median TTP was 17 months (95% CI 14-21.5, median follow-up 75 months). The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR expression. Differences in TTP according to AR status were not statistically significant. AR/PgR ≥ 0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.030). AR status in primary tumors or metastases was not associated with PD as best response. In contrast, Ki67 > 20% and PgR < 10% showed a significant association with PD as best response. Using a cut off of ≤10% for AR expression, results did not change. Conclusions: AR expression does not appear to be useful to predict the efficacy of ET in ABC. Ki67 and PgR exert a greater impact on the efficacy of hormone therapy than AR.
Molecular alterations to predict survival and response to chemotherapy of pediatric low-grade glioma.
Authors: Zapotocky Michal , Ryall Scott , Arnoldo Anthony , Mistry Matthew , Lassaletta Alvaro , Guerreiro Stucklin Ana Sofia , Krishnatry Rahul , Ramaswamy Vijay , Laughlin Suzanne , Dirks Peter , Huang Annie , Bartels Ute Katharina , Bouffet Eric , Tabori Uri , Hawkins Cynthia
Published: September 2018

10503

Background: RAS/MAPK pathway mutations have been identified as the major drivers of pediatric low-grade glioma (pLGG). The impact of these alterations on outcome and response to therapy is still unknown. Methods: We performed a large population based study of all pLGG diagnosed from 1985-2015. Detailed treatment and very long term outcome data was collected on all patients. Known pLGG-related alterations were detected using NanoString and QX200™Droplet Digital™PCR. Molecular data was correlated with outcome and response to chemotherapy. Results: In our cohort of 614 patients, BRAF was found to be altered in 57% and wild-type (WT) in 43% of patients without neurofibromatosis 1 (NF1). Among BRAF-WT we identified H3.3K27M, FGFR1-TACC1, MYBL1 and other alterations. Molecular alterations stratified pLGG into several risk groups. Ten-year progression free survival (PFS) was 72.3% for NF1, 69.5% for KIAA1549-BRAF, 53.5% for BRAF-WT, 30.3% for BRAF-V600E and 0% for H3.3K27M mutations (p < 0.0001). Similarly, overall survival (OS) at 10 years delineated difference between excellent survival of KIAA1549-BRAF and NF1 compared to BRAF-V600E and BRAF-WT (p = 0.0005). Interestingly, all patients with FGFR1-TACC1 and MYBL1 were alive despite observed progressions. Strikingly, response to chemotherapy determined by changes in tumor size at 6 months of therapy correlated with pLGG alteration. Objective response to first line chemotherapy was observed in 46% of patients with KIAA1549-BRAF and 35% of NF1. In contrast, only 15% BRAF-V600E and 18% BRAF-WT responded and 41% tumors grew after six months of chemotherapy. Moreover, 5-year PFS after chemotherapy was strikingly low for BRAF-V600E and BRAF-WT (25% and 31.9% respectively) compared to KIAA1549-BRAF (50%) and NF1 (76.7%) (p = 0.001). This translated to decreased OS for BRAFV600E and BRAF-WT patients (p = 0.042). Conclusions: Our study provides evidence that molecular alterations dictate the outcome of pLGG. KIAA1549-BRAF harbors excellent prognosis and choice of therapy should be made in favor of less toxic agents to minimize deleterious late effects. In contrast, poor prognosis is associated with lack of response to chemotherapy in BRAF-V600E and BRAF-WT tumors.
Measuring mercaptopurine (6MP) adherence using red cell 6MP metabolite levels in children with acute lymphoblastic leukemia (ALL): A COG AALL03N1 study.
Authors: Hoppmann Anna Lynn , Hill Torrey , Chen Yanjun , Landier Wendy , Hageman Lindsey , Evans William E. , Angiolillo Anne L. , Bostrom Bruce C. , Casillas Jacqueline N. , Lew Glen , Maloney Kelly W. , Mascarenhas Leo , Ritchey A. Kim , Termuhlen Amanda M. , Carroll William L. , Wong Florence Lennie , Relling Mary V. , Bhatia Smita
Published: September 2018

10514

Background: Non-adherence to 6MP (monitored with medication event monitoring system [MEMs]) is associated with an increased risk of relapse in children with ALL.(JAMA Oncol, 2015) Self-report over-estimates true medication intake, particularly in non-adherent patients.(Blood, 2017) However, monitoring adherence using MEMs is logistically difficult. We investigated whether red cell 6MP metabolite levels (thioguanine nucleotide [TGN] and methylated mercaptopurine [MMP]) taken together, could identify non-adherent patients. Methods: The analysis included children with ALL in maintenance. To minimize variability in TGN and MMP levels due to pharmacogenetics, we excluded TPMT heterozygotes and homozygote mutants. We also excluded Asians to remove variability due to NUDT15. TGN and MMP levels were drawn at 6 consecutive monthly time points for each patient and averaged. TGN and MMP levels (pmol/8 x 108red cells) were standardized, adjusted for 6MP dose intensity, and then analyzed using cluster analysis (Spath, H. [1980]). Results: The 373 patients eligible for analysis yielded 5 clusters. Cluster #1 (n = 119; mean MMP: 15,656; mean TGN: 158); Cluster #2 (n = 211; MMP: 6,042; TGN: 135); and 3 very small outlying clusters (total N = 43). Adjusting for age, sex, race/ethnicity, cytogenetics and NCI risk, we found that patients in Cluster #2 were 2.6 times as likely to be non-adherent (MEMs-based adherence < 95%) compared to Cluster #1 (95% CI 1.5-4.4; P= 0.0007). Mean MEMs-based adherence was significantly higher for patients in Cluster #1 (94.3%) when compared to those in Cluster #2 (87.8%, p = 0.0002). Using Fine-Gray proportional subdistribution hazards models for competing risks and adjusting for clinical and sociodemographic factors, we found that patients in Cluster #2 were at a 2.3-fold higher risk of relapse compared with those in Cluster #1 (95%CI, 1.0-6.4, p = 0.058). Conclusions: These findings illustrate the potential for using a combination of red cell TGN and MMP levels in identifying non-adherent patients. We propose to use these and clinical and demographic factors associated with non-adherence in creating an adherence calculator.
Genomic index in pediatric synovial sarcoma (SYNOBIO study): The European Pediatric Soft Tissue Sarcoma Group (EpSSG) experience.
Authors: Orbach Daniel , Mosseri Veronique , Pissaloux Daniel , Brennan Bernadette , Ferrari Andrea , Chibon Frederic , Bisogno Gianni , De Salvo Gian Luca , Chakiba Camille , Corradini Nadege , Minard-Colin Veronique , Kelsey Anna , Ranchère-Vince Dominique
Published: September 2018

10529

Background: A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has recently been developed, and shown a high prognostic value in adult soft tissue sarcomas. GI correlates with genomic instability, and has emerged as independent prognostic factor associated with the risk of metastases developing in synovial sarcoma (SS). The aim, therefore, was to assess GI in pediatric patients with SS, to assess its value as a prognostic factor and its role in risk stratification. Methods: All pediatric/adolescent/young adults’ (<25 years) with localized SS prospectively included in the European EpSSG-NRSTS05 protocol with a contributive aCGH were selected. Tumors had a central pathological review or harbored the specific fusion transcript (SYT-SSX). Definition of GI was A2/C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on aCGH results. GI1 group corresponds to cases with no or few alterations (flat profile, GI≤1) and GI2 group cases with many alterations (complex CGH profile; GI>1). Results: A total of 48 patient’s samples were available. The median age of the cohort was 13 years (range: 4-24). Patients received surgery only (19%), with adjuvant therapy (17%) or perioperative therapy (64%). GI1 group corresponded to 54.2%, and GI2 to 45.8%. After a median follow up of 58 months (range: 0.1-107), 10 tumor events occurred and 5 patients died. Patients with high GI have more axial (P<0.01), invasive (P=0.04) and higher therapeutic risk groups’ tumors (unresectable/axial tumors; P<0.015). Respectively for GI1 vs. GI2 groups, 5-year event free survival (EFS) rates were 91.8±5.6% vs. 58.9±11.2% (P<0.0084) and 5Y-Metastatic Free Survival 91.8±5.5% vs. 68.6±10.6% (P=0.055). In multivariate analysis, GI adjusted for IRS groups, site and tumor size remains prognostic for EFS (P<0.025). Conclusions: Although tumor events were rare for SS in NRSTS 2005, high GI selected patients with high risk tumor features and predicted a poorer outcome. GI may explain aggressive behavior of some pediatric SS. Founding sources: “Enfant-et-santé/SFCE,” “Info sarcome,” and “La ligue contre le cancer.”
Palbociclib exposure-response analyses in second-line treatment of hormone-receptor positive advanced breast cancer (ABC).
Authors: Sun Wan , Yu Yanke , Hoffman Justin , Turner Nicholas C. , Cristofanilli Massimo , Wang Diane Dan
Published: September 2018

1053

Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinases 4 and 6 approved for ABC. Exposure-response analyses for efficacy and safety endpoints were performed to evaluate the current PAL clinical dosing regimen (125 mg daily, 3 weeks on and 1 week off) and dose modification strategy in 2nd-line ABC. Methods: The present analyses used data from PALOMA3, a phase 3 study comparing the safety and efficacy of fulvestrant plus either PAL or placebo in 2nd-line ABC patients (PTs). A Bayesian pharmacokinetic (PK) analysis was conducted to estimate PAL PK parameters for individual PTs. Average concentration of PAL over the entire treatment (Cavg) was derived from average daily dose intensity divided by post hoc estimates of clearance for each PT. Time varying Cavg (Cavgt) was also derived to account for dose modifications up to each observation point. Kaplan-Meier method and the Cox proportional hazards model were employed to explore relationship between progression-free survival (PFS) and Cavg, Cavgt, as well as other prognostic factors. A semi-mechanistic PK-pharmacodynamic (PD) model was built to quantify the relationship between PAL concentration and absolute neutrophil count (ANC). Results: The median PFS for low and high PAL exposure groups divided according to Cavg were similar (9.47 and 10.9 months, respectively) and significantly higher than that of the control arm (4.57 months). While Cavgtwas found to be a significant predictor for PFS in univariate analysis (P-value < 0.05), this relationship was not significant in the multivariate analysis where other significant prognostic factors were also included. The PK-PD analysis for safety endpoint indicated higher PAL concentrations were associated with lower ANC, which is consistent with the fact that ANC profiles were well managed by dose modification strategies, i.e., dose interruption, delay and reduction. Conclusions: The analysis results suggested PTs were benefited similarly from fulvestrant plus PAL treatment with manageable safety profile, supporting a favorable benefit-risk profile of PAL under the current dosing regimen and dose modification strategy in 2nd-line ABC. Funding: Pfizer Inc. Clinical trial information: NCT01942135.
Intensified induction therapy with reduced total anthracycline exposure in pediatric low-risk acute myeloid leukemia.
Authors: Minson Katherine Ashley , Herring Caitlin , Metts Jonathan , Sabnis Himalee , Cooper Todd Michael , Woods William G. , Keller Frank G.
Published: September 2018

10533

Background: Despite advances in risk stratification and therapy, the post-induction disease free survival (DFS) and overall survival (OS) for children with low-risk acute myeloid leukemia (LR-AML) remain low with DFS and OS of 50% and 68%, respectively, on the standard arm of the recent Children’s Oncology Group (COG) trial, AAML1031. Additionally, current therapy for pediatric LR-AML contains anthracycline doses exceeding thresholds known to increase the risk of adverse cardiac effects. In an effort to decrease exposure to cardiotoxic therapy, the Aflac Cancer and Blood Disorders Center adopted an institutional practice to treat LR-AML patients with a regimen of intensified induction therapy with decreased anthracycline exposure (Aflac-AML consisting of ADE10, Mitox/HiDAC, HiDAC/VP, Capizzi II). The aim of this study is to describe the associated toxicities and outcomes of this regimen in pediatric LR-AML. Methods: We retrospectively reviewed medical records of patients diagnosed with de novo LR-AML and treated per the Aflac-AML regimen from 2011-2014. Charts were reviewed for cardiac outcomes, ICU admissions, and the rate of infectious toxicities. DFS and OS were determined using Kaplan-Meier survival analysis. Results: We identified 11 LR-AML patients treated with Aflac-AML therapy. Patients received a planned 317 mg/m2 cumulative anthracycline dose vs 442 mg/m2for those treated on AAML1031. There was no decrease in LVEF with a mean change of +2.17% for Aflac-AML patients from the time of diagnosis to therapy completion (p = 0.23). The primary infectious toxicities observed were febrile neutropenia and bacterial infections with a median of 36.4±6% documented bacterial infections per cycle. Fungal and viral infections were rare as were ICU admissions – median 4.5±4% per cycle – and there were no toxic mortalities. The 3-year DFS and OS from end of induction I for Aflac-AML patients were 72.7% and 90.9%, respectively. Conclusions: The Aflac-AML regimen resulted in short-term toxicities and outcomes comparable to current chemotherapy regimens for pediatric LR-AML but with reduced anthracycline exposure. These data support use of this regimen for pediatric LR-AML patients.
Targeting the cell cycle for cancer therapy in rhabdomyosarcoma.
Authors: Stewart Elizabeth , Honnell Victoria , Ocarz Monica , Blankenship Kaley , Dapper Jason , Freeman Burgess , Shelat Anang , Pappo Alberto S. , Dyer Michael A.
Published: September 2018

10535

Background: Rhabdomyosarcoma (RMS) is an aggressive malignancy of childhood with a poor prognosis in patients with metastatic or recurrent disease. Inhibitors of Wee1 kinase and heat shock protein 90 (HSP90) have in vitro activity in RMS and have emerged as potential novel treatment strategies. We performed a comprehensive preclinical phase III study to compare the Wee1 inhibitor AZD1775 and HSP90 inhibitor ganetespib (GANET) in combination with irinotecan (IRN) and vincristine (VCR). Methods: Orthotopic xenografts (O-PDXs) were created by injecting luciferase labeled RMS cells into the hind-leg muscle of CD-1 nude mice. Pharmacokinetic studies on RMS O-PDXs were performed to determine matched human AUC-guided dosing. A total of 540 O-PDXs derived from 4 high risk RMS patients, 2 alveolar and 2 embryonal, were randomly enrolled into 14 treatment groups. Six courses of blinded placebo-controlled therapy were given on a clinically relevant schedule. Mice were classified as having progressive disease if tumor approached 20% body weight at any time in the study. For mice completing all 6 courses, bioluminescence was used to determine complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Results: The addition of AZD1775 to IRN and VCR demonstrated the most significant response for all 4 O-PDX lines tested; 70% of mice achieved a CR or PR. GANET combined with IRN and VCR had a 54% response (CR + PR) which was not significantly better than IRN plus VCR for most O-PDXs tested. Overall response data for select treatment groups is shown in the table below. Conclusions: Comprehensive preclinical testing using multiple O-PDX models of RMS that represent the clinical spectrum of disease is feasible. Comparison of novel treatment regimens to standard of care at clinically relevant doses is warranted as justification for future clinical trials. Observation to assess durable response following completion of therapy is ongoing to determine if AZD1775 remains a promising treatment strategy. [Table: see text]
Effect of PD1/PD-L1 checkpoint blockade on efficacy of anti-GD2 antibody ch14.18/CHO in neuroblastoma.
Authors: Lode Holger N. , Zumpe Maxi , Juettner Madlen , Troschke-Meurer Sascha , Loibner Hans , Siebert Nikolai
Published: September 2018

10548

Background: Immunotherapy (IT) with anti-GD2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients mainly due to induction of GD2-specific Ab-dependent cellular cytotoxicity (ADCC). Methods to further enhance the effect are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± scIL-2. Programmed death-1 (PD-1) is an inhibitory receptor expressed by activated T- and NK-cells, and cancer cells express PD-1 ligand. Here, we report for the first time effect and mechanism of PD-1/PD-L1 blockade in the context of ch14.18/CHO-based IT in preclinical models. Methods: Expression of PD-L1 and PD-1 on NB cells and leukocytes was analyzed by RT-PCR and flow cytometry in the presence of ch14.18/CHO or IL-2. Mechanism of PD-L1 induction was analyzed with anti-CD11b Ab. The effect of PD-1/PD-L1 blockade on ch14.18/CHO-mediated anti-NB immune response was evaluated using anti-PD-1 Ab both in vitro (Nivolumab) and in the syngeneic GD2+ NB NXS2 mouse model (anti-mouse PD-1). Mice (n = 10) were treated with ch14.18/CHO (5x300 µg, i.p.) in combination with anti-PD-1 (8x250 µg, i.p.), and compared to controls. Results: Culture of LA-N-1 (low PD-L1 baseline expression) in the presence of leukocytes and subtherapeutic ch14.18/CHO concentrations for 24h induced strong upregulation of PD-L1 resulting in complete inhibition of ADCC mediated by ch14.18/CHO. Co-incubation with anti-CD11b Ab abrogated this PD-L1 upregulation. Importantly, blockade with Nivolumab reversed the PD-L1-dependent inhibition of ADCC. Mice treated with ch14.18/CHO in combination with PD-1 blockade showed a strong reduction of tumor growth and prolonged survival as well as the highest level of NB cell lysis mediated by serum and leukocytes compared to controls. Conclusions: Ch14.18/CHO-mediated effects upregulate the inhibitory checkpoint PD-1/PD-L1 and combination of ch14.18/CHO with PD-1/PD-L1 blockade results in synergistic treatment effects in mice. This concept will be evaluated in a clinical trial.