bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of ipilimumab and nivolumab (ipi/nivo) in metastatic uveal melanoma (UM).
Authors: Pelster Meredith , Gruschkus Stephen K. , Bassett Roland , Gombos Dan S. , Shephard Michael , Posada Liberty , Glover Maura , Diab Adi , Hwu Patrick , Patel Sapna Pradyuman
Published: May 2019

9522

Background: UM is the most common primary intraocular malignant tumor in adults. Approximately 40-50% of patients (pts) with UM will ultimately develop metastatic disease. There is currently no standard approach for metastatic UM. Early studies of single agent immunotherapy (IO) in metastatic UM have yielded meager results. Combination checkpoint inhibitor IO has the potential to improve response rates and survival. Herein, we report the safety and efficacy of ipi/nivo in metastatic UM. Methods: We performed a single-arm phase II study in metastatic UM (CA184-187) for pts with at least 1 measureable lesion and ECOG PS 0-1. Any number of prior treatments were permitted. Pts received nivolumab 1mg/kg IV plus ipilimumab 3mg/kg IV every 3 weeks for a total of 4 doses; maintenance nivolumab was dosed 3mg/kg every 2 weeks or 480mg IV every 4 weeks. The primary efficacy endpoint was best overall response rate (BORR) as determined by irRC. Secondary endpoints were median progression free survival (PFS), median overall survival (OS), and one-year OS. Results: As of the January 31, 2019 data cutoff, 39 pts were enrolled. 35 pts received at least one treatment and were evaluable for toxicity. 5 pts were inevaluable for response due to lack of follow-up imaging, leaving 30 pts evaluable for efficacy. 32 pts (91%) experienced any adverse event (AE), and 29 pts (83%) experienced any treatment related AE (TRAE). Grade 3-4 TRAEs occurred in 14 pts (40%). 10 pts (29%) were removed from the study due to AEs. There were no treatment-related deaths. Median duration of follow up is 60.5 weeks. 19 pts (63%) completed all 4 cycles of ipi/nivo; median duration of treatment was 16 weeks. The BORR was partial response for 5 pts (17%), stable disease (SD) for 16 pts (53%), and progression of disease for 9 pts (30%). 8 pts had SD for at least 6 months. Median PFS was 26 weeks. Median OS was 83 weeks (1.6 years), and one-year OS was 62%. Conclusions: Full results of ipi/nivo safety and efficacy including immune-related AE and clinical characteristics of the responders will be presented at the meeting. Preliminary translational tumor work including RNA analysis has been performed on a subset of responders. Clinical trial information: NCT01585194.
Immunotherapy disparities in metastatic melanoma.
Authors: Oliver Thomas , Pezzi Todd A. , Pezzi Ashley E. , Shreders Amanda , Dao Henry , Crozier Jennifer A. , Pezzi Christopher
Published: May 2019

9525

Background: Historically, patients with advanced malignant melanoma had a dismal prognosis with an estimated median overall survival of nine months. Therapy response rates and long-term survival have significantly improved with the advent of immunotherapies and targeted chemotherapies. First approved in 2011, there has been subsequent development of more advanced immunotherapeutic agents and targeted chemotherapies, with continued improvement in median overall survival. We examined patterns in the use of immunotherapy and other systemic therapies for metastatic melanoma, as well as the demographic and socioeconomic predictors for the use of these therapies, in order to identify and understand potential barriers to access in the United States. Methods: We used the NCDB for all patients aged 18-years and older who were diagnosed with metastatic melanoma of cutaneous origin from 2004-2014. Patients were included if they had distant metastases or American Joint Committee on Cancer (AJCC) Stage IV. Sociodemographic data, including race, age, insurance status, facility providing care, Charlson/Deyo comorbidity score11, and education by patient’s zip code, were collected. Results: In patients under age 65 with a Charlson-Deyo score of zero, immunotherapy utilization ranged between 8.5–13.4% during 2004 to 2010. In 2011, the usage increased to 16.5% and rose every subsequent year to 29.6% in 2014. Patients were less likely to receive immunotherapy if they had no insurance, were of older age, or received care at a community practice rather than an academic center. Those who received immunotherapy had greater overall survival compared with those who did not. Conclusions: Immunotherapy and targeted agents have become standard of care in those with metastatic melanoma. Adoption of immunotherapy use for metastatic melanoma has been relatively slow despite evidence showing an overall survival benefit; our analysis suggests this is explained in part by socioeconomic barriers.
Palbociclib (P) in advanced acral lentiginous melanoma (ALM) with CDK4 pathway gene aberrations.
Authors: Mao Lili , Cao Yabing , Sheng Xinan , Bai Xue , Chi Zhihong , Cui Chuanliang , Wang Xuan , Tang Bixia , Lian Bin , Yan Xieqiao , Li Siming , Zhou Li , Wei Xiaoting , Li Caili , Qi Zhong Hui , Si Lu , Guo Jun
Published: May 2019

9528

Background: Genetic Aberrations in the CDK4 Pathway occur in 82% of the ALM pts (Clin Cancer Res,2017, 23(22):6946-6957), which is predominant subtype in China. This study is to evaluate the anti-tumor activity of palbociclib, a CDK4/6 inhibitor, in advanced ALM pts with CDK pathway gene aberrations. Methods: In this phase II trial, patients with advanced ALM with CDK pathway gene aberrations (CDK4 or/and CCND1 amplification or/and CDKN2A loss) were treated with palbociclib 125 mg po, d1-21 of 28 day cycles. According to the study design, this trial will be closed if less than 2 patients yield objective response (OR) or stable disease (SD) at a preset 8-week landmark analysis. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Fifteen pts were enrolled from April to Nov 2018. All pts are included in the data analysis for demographics, safety, ORR, PFS and OS. Median age was 54 y (range, 25-74y), 6(40%) were males,5( 33.3%) had the primary sites of subungual, 4(26.7%) were of stage III. Median numbers of prior therapies: 2 (range: 0-5). Three (20.0%) pts achieved tumor shrinkage at 8 wks, including 1 confirmed partial responses (PR). Two pts had treatment ongoing at the data cutoff (January 2019). Median PFS was 2.5m (range, 1.5-8.8m), estimated mean OS was 8.1m (range, 6.7-9.4m). Four pts deceased due to disease progression. The most common treatment related adverse events (TRAEs) were leukopenia/neutropenia (87%; G3, 33%), thrombocytopenia (27%; G3, 7%), anemia (40%; G3, 7%). Conclusions: Monotherapy with palbociclib demonstrated preliminary activities in advanced melanoma pts with CDK pathway gene aberrations. Therefore, the study met its primary endpoint. Palbociclib had an acceptable safety profile as previous studies. Combination of CDK4/6 inhibitor with other agents is under consideration. Clinical trial information: NCT03454919.
Real-world efficacy of anti-PD-1 antibodies in advanced acral melanoma patients: A retrospective, multicenter study (JAMP study).
Authors: Nakamura Yasuhiro , Namikawa Kenjiro , Yoshino Koji , Yoshikawa Shusuke , Uchi Hiroshi , Goto Katsunobu , Nakamura Yoshiyuki , Fukushima Satoshi , Kiniwa Yukiko , Takenouchi Tatsuya , Uhara Hisashi , Kawai Toru , Hatta Naohito , Funakoshi Takeru , Teramoto Yukiko , Otsuka Atsushi , Doi Haruki , Ogata Dai , Matsushita Shigeto , Yamazaki Naoya
Published: May 2019

9529

Background: Anti-PD-1 antibodies are used worldwide for patients (pts) with advanced melanoma. Clinical trials have demonstrated its efficacy and safety for nonacral cutaneous melanoma (NACM) in controlled settings. Since acral melanoma (AM) is epidemiologically and molecularly distinct from NACM, data on the real-world efficacy of anti-PD1 antibodies in advanced AM is still lacking. Thus, we aim to analyze the real-world efficacy and safety of anti-PD-1 antibodies in advanced AM. Methods: We retrospectively reviewed clinical records of advanced AM treated in any line with an anti-PD1 antibody at 21 Japanese institutions. Clinical response was assessed by (Response Evaluation Criteria in Solid Tumors) RECIST criteria. Survival was estimated using Kaplan-Meier analysis. Toxicity was assessed according to CTCAE 4.0. Results: A total of 193 pts (median age, 71 years) with advanced AM (subungual, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 pts (74.1%). Nivolumab was used in 168 pts and pembrolizumab in 25 pts. Base-line lactate dehydrogenase (LDH) was within normal level in 102 pts (52.8%). The objective response rate (ORR) of all pts was 16.5% (complete response 3.1%, partial response 13.5%), and median overall survival (OS) was 18.1 months. Normal LDH level was significantly associated with better prognosis than abnormal level (median OS 24.9 vs 10.7 months; P < 0.001). Although baseline demographics and characteristics were almost similar between subungual group and palm and sole group, ORR was significantly lower in the subungual group than in palm and sole group (6/70 pts [8.6%] vs 26/123 pts [21.1%]; P = 0.026); median OS was significantly poorer as well (12.8 vs 22.3 months; P = 0.031). Immune-related adverse events of grades 3 to 5 occurred in 27 pts (14.0%). One patient (0.5%) died of grade 5 myasthenia gravis. Conclusions: Real-world efficacy of anti-PD-1 antibodies in AM pts is limited. Notably, pts with subungual melanoma showed poorer response and survival, making them strong candidates for further research of efficacy of anti-CTLA-4 and anti-PD-1 combination therapy.
Clinical models to predict response and survival in metastatic melanoma (MM) patients (pts) treated with anti-PD-1 alone (PD1) or combined with ipilimumab (IPI+PD1).
Authors: Pires Da Silva Ines Esteves Domingues , Ahmed Tasnia , Lo Serigne , Rai Rajat , Smith Jessica Louise , Park John J. , Nabhan Caroline , Scolyer Richard A. , Carlino Matteo S. , McQuade Jennifer Leigh , Johnson Douglas Buckner , Long Georgina V. , Menzies Alexander M.
Published: May 2019

9542

Background: Currently there are no robust biomarkers to predict immunotherapy response in MM. Specific clinical and molecular variables have been proposed, but in most cases, these factors have been studied individually. We sought to build a predictive model for response rate (RR), progression-free survival (PFS) and overall survival (OS), by including clinical data available at the point of treatment selection for MM pts treated with PD1 or IPI+PD1. Methods: 786 MM pts were included in 4 cohorts; 447 pts treated with PD1 (discovery, n = 343; validation, n = 104) and 339 pts treated with IPI+PD1 (discovery, n = 229; validation, n = 110). Demographics, disease characteristics and baseline blood parameters were examined. Predictive models were selected using multivariate Cox proportional hazard model, logistic regression and LASSO. ROC curve analyses were performed for each model and validation was measured by discrimination índex (c-statistic). Results: Predictive models for RR and PFS in PD1 pts (AUC = 0.69 and AUC = 0.71, respectively) included mutational status (HR for PFS: BRAF 1; NRAS 0.68; WT 0.57; P = 0.002), primary melanoma site (HR for PFS: occult 1; head and neck 0.67, others 1.04; P = 0.052), elevated LDH (HR for PFS: 1.77, P < 0.0001) and monocyte count > median (HR for PFS: 1.56, P = 0.003). Predictive models for RR and PFS in IPI+PD1 treated pts (AUC = 0.71 and AUC = 0.73, respectively) included AJCC stage M1C/M1D (HR for PFS: 2.12, P = 0.009), elevated LDH (HR for PFS: 2.65, P < 0.0001), liver mets (HR for PFS: 1.63, P = 0.038) and basophil count > median (HR for PFS: 0.50, P = 0.003). ECOG ≥ 1, elevated LDH and brain mets associated with worse OS and were included in predictive models for OS in PD1 (AUC = 0.74) and IPI+PD1 (AUC = 0.85). These models showed consistency with internal and external validation (c-statistic: < 10% difference between the original model and validations for all outcomes). Conclusions: A combination of routinely collected clinical factors are highly predictive of outcome in MM pts treated with PD1 and IPI+PD1. A prognostic index will be presented for each treatment. Such tools may be practical, cheap and valuable for clinical decision making.
Use of immunotherapy for stage-III and IV melanoma and likelihood of regional and distant lymph node resection and surgical resection for distant metastasis.
Authors: Molina George , Kasumova Gyulnara G. , Qadan Motaz , Boland Genevieve Marie
Published: May 2019

9558

Background: Immunotherapy (IMT) for stages-III and IV melanoma has dramatically changed overall prognosis and treatment strategies. The aim of this study was to evaluate if use of IMT significantly changed the likelihood of regional/distant lymph node (LN) resection and surgical resection for distant metastases (DM) among patients with stages-III and IV melanoma, respectively, in the pre- and post-2011 era. Methods: The National Cancer Database (2004-2015) was used to evaluate the likelihood of regional/distant LN resection and surgical resection for DM among patients with stages-III and IV melanoma, respectively, with use of IMT. Multivariable stepwise with forward selection Poisson regression with robust standard errors was used to adjust for potential confounders (age, gender, race, year of diagnosis, Charlson-Deyo Score, facility type, facility location, insurance status, 2012 median income quartile, and 2013 urban/rural status). A stratified analysis was performed to evaluate differences among facility type. Results: There were 28,847 patients (median age 62 (IQR 53-73); 36.3% female) with stage-III melanoma and 14,443 patients (median age 66 (IQR 56-76); 31.7% female) with stage-IV melanoma. Overall, 24.3% (n = 7,018) and 17.0% (n = 2,459) with stage-III and IV melanoma, respectively, received IMT. The adjusted relative risk (aRR) of regional/distant LN resection among patients with stage-III melanoma was significantly higher with use of IMT (aRR 1.16, 95% CI 1.05–1.28, P = 0.004), while the aRR of surgical resection for DM was significantly lower with use of IMT for stage-IV melanoma (aRR 0.85, 95% CI 0.78–0.92, P < 0.001). Stratified analysis demonstrated that the findings were principally reflective of academic/research hospitals. Conclusions: The higher likelihood of regional/distant LN resection in stage-III melanoma may be due to the curative role of surgery and preceded the post-MSLT-II era. Conversely, in stage-IV melanoma, surgery may be limited to resectable oligometastatic disease given the durable and systemic benefit of first-line IMT.
A phase II study of oral azacitidine (CC-486) in combination with pembrolizumab (PEMBRO) in patients (pts) with metastatic melanoma (MM).
Authors: Burton Elizabeth M. , Woody Timothy , Glitza Isabella Claudia , Amaria Rodabe Navroze , Keung Emily Zhi-Yun , Diab Adi , Patel Sapna Pradyuman , Wong Michael K.K. , Yee Cassian , Hwu Patrick , McQuade Jennifer Leigh , Woodman Scott Eric , Tetzlaff Michael T. , Davies Michael A. , Wargo Jennifer Ann , Rai Kunal , Tawbi Hussein Abdul-Hassan
Published: May 2019

9560

Background: Immune checkpoint blockade (ICB) have improved survival for many pts with MM, offering durable responses in up to 35% of pts, but many have short-lived or no response ( > 40%). A potential immune escape mechanism is the subversion of cellular epigenetic machinery to impact multiple aspects of the immune response such as suppression of Cancer Testis Antigen (CTA), which can be reversed in preclinical models by DNA hypomethylating agents (HMA), thereby increasing cancer cell immunogenicity. HMAs can also increase T cell infiltration and T cell-mediated tumor killing, and they achieve synergy with CBI in preclinical models. This suggests that epigenetic therapy with CBI is a rational combination to target MM. We hypothesize that CC-486 (an oral HMA) + PEMBRO will be tolerated at biologically relevant doses and enhance response to PEMBRO in pts with MM who are PD-1 naïve and reverse resistance to (ICB) in pts refractory/resistant to PD-1. Methods: This study (NCT02816021) evaluated the safety and efficacy of CC-486 (300 mg PO QD on days 1-14/21 day cycle) + PEMBRO (200mg IV Q 21 days) defined by Objective Response Rate (ORR) by RECIST 1.1 in pts with MM. PD-1 naïve pts were assigned to Arm A and pts with progression on prior PD-1 therapy to Arm B. Unlimited prior systemic therapies were allowed on Arm B. Continuous monitoring for toxicity and futility was performed and assumes an ORR of > 35% (Arm A) and > 15% (Arm B) at 95% power. Tumor biopsies at baseline and post treatment were mandated. Results: 22pts, 11 in each arm, have been treated. The most common AEs were nausea, vomiting, diarrhea, fatigue, and anemia. The most common gr 3/4 toxicities were neutropenia (3), diarrhea (2), dehydration (2), and rectal hemorrhage (1). 5 of 9 evaluable pts in Arm A achieved a PR (55% ORR); 0 of 9 evaluable pts in Arm B pts have responded. Conclusions: Although this regimen was tolerated in both arms, Arm B met futility stopping rules and was closed. The initial response rate in Aim A (55%) is promising, and accrual to this Arm continues. Analyses of longitudinally collected tumor biopsies are underway to interrogate the effects of HMA on the immune response to both arms. Clinical trial information: NCT02816021.
Integrative molecular analysis of metastatic Merkel cell carcinoma to identify predictive biomarkers of response to avelumab.
Authors: Georges Sara , Shah Parantu K. , Shapiro Irina , Hicking Christine , Lu Lei , Hennessy Meliessa , D'Angelo Sandra P. , Cai Ti
Published: May 2019

9569

Background: Avelumab, an FDA-approved human anti–PD-L1 IgG1 monoclonal antibody for patients (pts) with metastatic Merkel cell carcinoma, showed an objective response rate (ORR; by RECIST v1.1) of 31.8% in a second-line phase 2 trial (NCT02155647). We assessed the association of tumor mutational burden (TMB; nonsynonymous somatic variants/megabase), PD-L1 expression, Merkel cell polyomavirus (MCPyV) status, and CD8+ tumor-infiltrating T-cell density with ORR and survival. Molecular profiles (RNAseq and WEX) also were analyzed. Methods: Baseline tumors (n = 36) were profiled using RNAseq and WEX sequencing. PD-L1 expression (≥1% cutoff), MCPyV status, and CD8+ T-cell density at the tumor invasive margin were evaluated by IHC. MHC locus expression was measured with OptiType and loss of heterozygosity (LOH) with LOHHLA. Results: Of 36 pts profiled, 12 had a response, 27 were PD-L1+, and 23 were MCPyV+. The TMB upper tertile and quartile values were 1.34 and 3.16, respectively. Consistent with literature, MCPyV− pts had a higher median TMB (2.72) than MCPyV+ pts (0.49). PD-L1+ tumors trended toward a higher TMB. An empirical cohort-specific TMB cutoff of ≥2 was chosen to include sufficient pts per subgroup. Pts with TMB ≥2 vs TMB < 2 had higher ORR (5 of 11 [45.5%] vs 7 of 25 [28.0%]) and 6-mo PFS rates (60% vs 38%). Among pts with TMB ≥2, the highest ORRs were reported in MCPyV− (4 of 7 pts), PD-L1+ (5 of 9 pts), and CD8+ T-cell density higher than median (5 of 6 pts) subgroups. MHC expression trended with ORR and survival. Higher mean MHC expression was found in pts with CD8+ T-cell density higher than median (p < 0.05). Mutations in antigen presentation genes were detected: LOH at the HLA locus in 9 of 30 pts (28%), including 4 with a response; an NK cell activation signature was also associated with response. These data may suggest that ADCC contributes to response. Factorial analysis of gene signature scores identified signatures (eg, IFNγ, TP53 pathway) associated with MCPyV status and response. Conclusions: Responses in this data set were not attributed to any specific biomarker alone. Future analysis is focused on validating these results and identifying rational drug combinations with avelumab. Clinical trial information: NCT02155647.
Neutrophil to Lymphocyte ratio (NLR): A prognostic marker in melanoma patients receiving immunotherapy.
Authors: O'Dwyer Richard Thomas , Dennehy Colum , Sui Jane Sze Yin , Kelly Catherine Margaret , Calvert Paula , McCaffrey John
Published: May 2019

9573

Background: Cancer related inflammatory processes have been shown to have an important role in tumourigenesis, disease progression, and patient prognosis. An elevated neutrophil to lymphocyte ratio (NLR) is associated with a worse outcome in several malignancies. The relationship between NLR and immune checkpoint blockade is poorly understood. We sought to investigate the role of NLR in patients receiving immune checkpoint inhibitors for metastatic melanoma (MM). We aimed to do this by comparing outcomes of patients with MM with high ( > 3) and low ( < 3) NLRs receiving immunotherapy, and investigating whether NLR acts as a prognostic biomarker. Methods: We performed a retrospective review of electronic medical records and collected data on 40 patients with MM treated with immunotherapy from 2013 to 2018 in MMUH, Dublin. NLR was defined as absolute neutrophil count divided by absolute lymphocyte count. Continuous variables were expressed as a median. We examined NLR at baseline and at 6 weeks (+-2 weeks). We also examined percentage change in NLR. These parameters were tested for association with PFS and OS using the log rank test. Results: 40 patients received immune checkpoint inhibitors in the form of ipilimumab, nivolumab, and pembrolizumab. The median age was 61.2 ( 29.7 to 77.1). The median baseline NLR was 3.39 ( 1.05 to 26.03). The median NLR at 6 weeks (+-2 weeks) was 2.86 ( 0.83 to 19.9). The median change in NLR was -8.02% (- 80.99% to 409.38%). Median time to progression was 4.7 months (0.4 to 51.4 months). Overall survival was 12.9 months (0.4 to 67.7 months). When baseline NLR < 3 patients had a significantly longer PFS: 11.7 vs 2.8 months (p = 0.02). When NLR at approximately 6 weeks was < 3, patients also had significantly longer PFS: 10.8 vs 2.9 months (p = 0.04). When NLR decreased by > 20% from baseline, there was no significant difference in PFS (p = 0.82). When NLR < 3, patients had significantly longer OS: 18 months vs 8.2 months (p = 0.02). When NLR at approximately 6 weeks was < 3, patients had significantly longer OS: 20.3 months vs 7.4 months (p = 0.003). Conclusions: Baseline NLR < 3 and NLR < 3 approximately 6 weeks after initiation of treatment is associated with improved PFS and OS. Change in NLR after initiation of treatment is not significantly associated with improved outcomes, however our sample size was small. NLR may be used as a readily available and cheap prognostic marker in MM patients receiving immunotherapy.
Plasma proteomic analyses and treatment predictive biomarker candidates in melanoma patients receiving immune checkpoint blockade or targeted therapy.
Authors: Eriksson Hanna , Babacic Haris , Lehtio Janne , Pernemalm Maria
Published: May 2019

9574

Background: The introduction of immune checkpoint inhibitors (ICIs) or therapies targeting the MAPK-pathway (MAPKis) has significantly improved clinical outcomes in metastatic melanoma patients. Still, a large proportion of the patients become resistant to therapy and there is a need for treatment predictive biomarkers. The aim of this study was to analyze the treatment predictive biomarkers based on the plasma proteome of patients with metastatic melanoma treated with ICIs or MAPKis. Methods: We analyzed serial plasma samples from 48 patients with metastatic melanoma collected; 24 patients were treated with ICIs and with MAPKis, respcetively. A non-biased, high-resolution isoelectric focusing of peptides-liquid chromatography-mass spectrometry (HiRIEFLC-MS/MS)-based method, and with proximity ligation assays (PEA) targeting 92 immuno-oncology-related proteins were used.We analyzed the change in protein levels during treatment with a paired t-test, and their association with progression free survival (PFS) with Cox proportional hazards models. Results: HiRIEFLC-MS/MS detected 1,835 proteins.We detected statistically-significant log2-fold-changes in 109 protein levels out of 1,160 proteins tested (not corrected for multiple testing). PDCD-1 had the highest log2-fold change (FC = 1.27) after treatment (p = 0.02). After stratifying for treatment type, PDCD-1 levels increased in patients treated with ICIs (FC = 2.13, p= 0.0008), but not in MAPKis-treated patients. PEA analyses confirmed this observation. The PEA panel showed association between 44 proteins and shorter PFS (pcoefficient <0.05, pLRT<0.05, qLRT<0.05), among them: LGALS1, CSF1, VEGFA, CASP8, CCL2, TNFSF14, ANGPT2, IL10, IL6, and ADGRG1. Of these, increase in plasma levels during treatment of LGALS1, CCL2 and ADGRG1 were associated with longer PFS. HiRIEF LC-MS/MS detected 69 proteins associated with PFS (pcoefficient< 0.05, pLRT< 0.05, qLRT < 0.05). Conclusions: By using HiRIEFLC-MS/MS, we could detect putative treatment predictive proteins in plasma from patients with metastatic melanoma treated with ICIs or MAPKis. Our findings require further validation.
Prediction of distant melanoma recurrence from primary tumor digital H&E images using deep learning.
Authors: Robinson Eric , Kulkarni Prathamesh M. , Pradhan Jaya Sarin , Gartrell Robyn Denise , Yang Chen , Rizk Emanuelle M. , Acs Balazs , Rohr Bethany , Phelps Robert , Ferringer Tammie , Horst Basil , Rimm David L. , Wang Jing , Saenger Yvonne M.
Published: May 2019

9577

Background: Patients with resected melanoma are at high risk for systemic recurrence. Quantifying the risk of recurrence can help identify the need for adjuvant immunotherapies, and accelerate the acquisition of survival statistics in clinical trials. Methods: 75 patients with stages I, II, and III melanoma seen at Columbia University Medical Center between 2001 and 2014 and The Icahn School of Medicine at Mount Sinai between 2000 and 2010 were included based on availability of tissue and 24 months of clinical follow-up. Images were scanned into tiff files (Aperio Biosystems). Deep neural net (DNN) architecture was designed consisting of convolutional and recurrent neural networks (CNN, RNN). Using QuPath open source software for nuclear segmentation and cell classification, we generated cell location, density, and clustering features to identify tissue areas for training of network parameters. DNN analyzes image and feature information locally within an H&E image, generating a prediction vote per region, and votes are averaged. Results: The model was validated on two independent external sets of stage I-III primary melanomas. Cohort 1 (Yale Medical Center), had n = 86 patients, of whom 49 were alive or had no evidence of disease at death (no DMR) and 37 died from melanoma. The second set, Cohort 2 (Geisnger Health Systems), had n = 29 patients, 15 without DMR and 14 with DMR. Prediction scores correlated with DMR status in both sets (AUC = 0.94 and 0.77 for Cohorts 1 and 2, respectively). A multivariable Cox proportional hazard model showed DNN recurrence prediction to be an independent prognostic factor for both Cohort 1 (HR = 2.54, 95% CI: 1.54-4.19, p = .0004***) and Cohort 2 (HR = 8.43, 95% CI: 2.58-27.51, p = .001**). Conclusions: We designed a DNN for quantitative prediction of melanoma recurrence from a H&E stained tissue. The prediction score warrants further study in larger patient cohorts and may constitute a novel digital pathology tool for the selection of melanoma patients for adjuvant immunotherapy. [Table: see text]
Association of baseline body mass index (BMI) with response and survival in patients (Pts) with advanced melanoma (MEL) receiving PD-1 inhibitors.
Authors: Hemadri Amit , Lin Huang , Lin Yan , Rose Amy , Sander Cindy , Najjar Yana , Zarour Hassane M. , Kirkwood John M. , Davar Diwakar
Published: May 2019

9579

Background: Obesity promotes PD-1–mediated T cell dysfunction but also improves tumor response to PD-1 blockade. Obesity has been linked with positive outcomes in pts treated with PD-1 blockade. To evaluate the prognostic utility of BMI, we performed a retrospective evaluation of BMI and other covariates in 172 pts with stage IV cutaneous MEL. Methods: Pts with stage IV cutaneous MEL who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. BMI was defined based on values at the first treatment date and dichotomized into two groups: ≥30 vs. < 30. Fisher exact test was used to evaluate the correlation between BMI group and ORR. Kaplan Meier method and Cox proportional hazard models were performed to analyzed the time-to-event outcomes (OS and PFS). Results: 172 pts with advanced MEL were evaluated. Greater BMI was associated with greater ORR, PFS and OS across various BMI cutoffs (BMI≥28, BMI≥30 and BMI≥35) although this effect was most obvious at BMI≥30. Pts with BMI≥30 achieved higher ORR than those with BMI < 30 (74% vs. 58%, p-value = 0.04). Concordantly, pts with BMI≥30 had improved PFS and OS: median PFS (BMI≥30 21.1 mos vs. BMI < 30 10.7 mos) and median OS (BMI≥30 35.4 mos vs. BMI < 30 22.8 mos). Higher BMI was independently associated with improved OS (p = 0.018) and PFS (p = 0.047) adjusting for age, Breslow thickness and sex. No significant interaction was observed between the effects of BMI and that of age, sex, or Breslow thickness. Conclusions: Increased BMI was associated with greater ORR in addition to previously reported associations with PFS/OS in a large retrospective series of advanced MEL pts treated with PD-1 blockade. This data was independent of other prognostic factors and underscore the “inflammaging” effects of obesity and age in relation to anti PD-1 therapy in advanced cancer.
Patient-reported outcomes of patients treated with (neo)adjuvant immune checkpoint combination therapy in high-risk stage III macroscopic melanoma: A matched cohort study.
Authors: Boekhout Annelies H. , Józwiak Katarzyna , Rozeman Elisa A. , Janssen Silvie HM , van de Poll-Franse Lonneke V , Blank Christian U.
Published: May 2019

9588

Background: Results from the phase 1b (OpACIN) study comparing neoadjuvant to adjuvant ipilimumab (3mg/kg) plus nivolumab (1mg/kg) demonstrated a high clinical activity of neoadjuvant treatment in high-risk melanoma. However, the toxicity was high, with 90% grade 3 to 4 toxicity. These findings raise questions about long-term quality of life (QoL) in these patients (pts) who were treated with curative intent. Here we present the first analysis of patient-reported outcomes of patients treated with (neo)adjuvant immune checkpoint combination therapy. Methods: Sixteen of 20 pts had completed study treatment and were currently in follow-up (FU). Pts were asked to fill in The European Organisation for Research and Treatment of Cancer QoL questionnaire-C30 (QLQ-C30). The QLQ-C30 was used to assess health-related QoL and is composed of functional, symptomatic dimensions and a dimension of global health/QoL. A reference population (controls without a diagnosis of cancer) was obtained from the ‘Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship’ registry. Pts were individually matched on age, gender, education and marital status with up to 9 controls. Pts and controls were compared on QLQ-30 scores using univariable linear regression analyses. Results: Thirteen out of 16 invited pts (81% response) returned a completed questionnaire. Median FU was 30 months after randomization. Pts scored significantly lower in emotional (std coeff. = -1.0, p = .007), role (std coeff. = -0.7, p = .08), cognitive (std coeff. = -0.8, p = .018) and social (std coeff. = -1.0, p = .014) functioning and higher in symptom burden of fatigue (std coeff. = .9, p = .024) compared to controls, which were all clinically relevant. The physical functioning and global QoL score did not differ between pts and controls. Conclusions: High risk stage III melanoma pts treated with (neo)adjuvant immune checkpoint combination therapy showed significantly lower emotional, role, cognitive and social functioning scores than controls. Pts reported higher levels of fatigue, however, there was no difference on physical functioning and global QoL between pts and controls.
A population-based model for predicting sentinel lymph node (SLN) status for cutaneous melanoma patients and a clinical decision rule (CDR) for sparing a SLN biopsy (SLNB).
Authors: Gimotty Phyllis A. , Karakousis Giorgos , Buckley Meghan A. , Guerry DuPont
Published: May 2019

9589

Background: Generally, a SLNB is offered to the patient whose likelihood of positivity is ≥ 5%. Using population-based cohorts, we sought to [1] develop and validate a predictive model to estimate the individualized risk (IR) of SLNB positivity (SLNBp) and its confidence interval (CI), [2] evaluate an IR-based CDR to identify patients with sufficiently low IRs to avoid SLNB, and [3] compare the performance of the CDR with that of the 2019 NCCN guideline. Methods: The learning cohort (n = 18,214; SLNBp rate = 10.7%; 2010-2014) and validation cohort (n = 3,924; SLNBp rate = 11%; 2015) included SEER patients 18-99 years old who had a SLNB as part of definitive surgery. A multivariable logistic regression model for SLNBp, including 4 AJCC related-factors (thickness, ulceration, level and mitotic rate) and age, was used to estimate the IR of SLNBp and its one-sided 95% CI. The CDR was defined using the IR and CI and then used to classify patients into 3 categories: SLNB not indicated (IR and upper limit of the one-sided CI < 5%), SLNB indicated (IR and lower limit of the one-sided CI ≥ 5%), and borderline. Results: In the learning cohort all 5 factors were significant in the multivariate model, which had a c-statistic of 0.742 (95%CI, 0.731-0.753). In the validation cohort the model c-statistic was 0.728. Based on the CDR, 21.6%, 56.9%, and 21.5% of patients would not be offered SLNB, would be offered SLNB, or would need further shared decision making. Compared to the guideline, the CDR classified more patients as “SLNB not indicated” (21.6% vs. 7.1%) and fewer as “SLNB indicated” (56.9% vs. 68.5%). Of the 16,137 SLNB negative patients, 3815 (23.6%) would not be offered SLNB based on the CDR compared to 1258 (7.8%) who would not be offered SLNB based on the guideline. The false negative rates associated with “not indicated” by the CDR and guideline were 4.6% and 1.2%, respectively. Conclusions: Use of this CDR rather than the NCCN guideline will spare more low-risk patients the expense and harms of SLNB and increase only marginally their likelihood of a false negative test (still < 5%).
Effect of cyclin E overexpression on resistance to trastuzumab and phosphorylation of SMAD3 in HER2+ breast cancer.
Authors: Kandagatla Pridvi , Decker Joseph , Wan Lei , Bernstein Regan , Shea Lonnie , Jeruss Jacqueline Sara
Published: May 2019

e12006

Background: Trastuzumab, an effective treatment for HER2+ breast cancer, can be limited by development of resistance. Cyclin E (CCNE) overexpression was implicated in trastuzumab resistance, though the association is not well understood. We sought to explore a potential mechanism focusing on altered phosphorylation of the TGFβ signaling protein, SMAD3, in CCNE overexpressing HER2+ breast cancer cells, leading to trastuzumab resistance. Methods: A transcriptional activity cell array (TRACER) was used to examine the relationship between specific transcription factors and trastuzumab resistance in BT474 HER2+ human breast cancer cells. Immunoblotting examined phosphorylation patterns of SMAD3 in trastuzumab sensitive and resistant conditions. Effects of blocking CCNE overexpression with a CDK2 inhibitor were measured. To test the relative influence of SMAD3 and SMAD3 linker region phosphorylation on cell proliferation, BT474R2 cell lines were created overexpressing SMAD3 (BT474R2-SMAD3), a mutant construct blocking CCNE-mediated SMAD3 linker region phosphorylation (BT474R2-5M), and a control (BT474R2-Blank). In vitro and in vivo studies measured response to trastuzumab. Results: Resistance to trastuzumab was confirmed for BT474R2 cells, showing a markedly increased resistance to treatment when compared to the parental line. Network analysis of TRACER data identified decreased SMAD3 activity was central to resistance. Immunoblotting showed SMAD3 expression was significantly downregulated in BT474R2 cells (p < 0.01). Noncanonical phosphorylation of SMAD3 was increased in CCNE-overexpressing cells. Blocking CCNE mediated noncanonical phosphorylation of SMAD3 with CDK2 inhibition resulted in decreased proliferation of BT474R2 cells. In vitro studies examining response to trastuzumab showed an increased sensitivity for BT474R2-5M cells. Findings were validated in NSG mice inoculated with BT474R2-5M cells that developed significantly lower tumor volumes (p < 0.001) when treated with trastuzumab. Conclusions: These results identified a mechanism of CCNE-mediated trastuzumab resistance, regulated through noncanonical SMAD3 phosphorylation, which may be effectively treated with CDK2 inhibition to help enhance the efficacy of trastuzumab for patients with HER2+ breast cancer.
Cardioprotection in patients with cancer undergoing chemotherapy: A network meta-analysis.
Authors: Kancharla Pragnan , Ivanov Alexander
Published: May 2019

e12008

Background: Introduction of anthracycline or trastuzumab based regimen for various types of cancer during the past two decades led to substantial improvement in life expectancy, yet resulting in increased prevalence of unintended side effects. Left ventricular systolic dysfunction is a known complication of the currently employed chemotherapy regimens with anthracycline or trastuzumab which not only affects patient’s cardiac outcome but also limits their therapeutic opportunities, especially continuation or reintroduction of chemotherapy treatment. We aimed to perform comprehensive network meta analysis to synthesize data from randomized clinical trials (RCT) comparing all modern regimens to prevent cardiotoxicity in such patients. Methods: We performed a comprehensive search of pubmed, embase, google scholar and TRIP database for all RCT comparing cardioprotective effects of medication in patients with various types of cancer on chemotherapy with either an anthracycline or trastuzumab based regimen from 1997 to 2019. Left ventricular ejection fraction (LVEF) was measured by transthoracic echocardiogram or cardiac magnetic resonance imaging. Patients treated with either Angiotensin Converting Enzyme-Inhibitor(ACE) or Angiotensin receptor blocker(ARB) were combined into one group. Primary outcome was change in LVEF between start and end of the chemotherapy. Network meta-analyses were conducted using consistency and inconsistency models. Results: A total of 16 studies with 1459 patients were included in the analysis where either an Anthracycline or Trastuzumab based chemotherapy regimen was administered. 369 patients received beta blockers(BB), 351 received either an ACE or ARB, 61 received a combination of BB and either an ACE or ARB, 20 received a statin and 657 were given a placebo. The primary cancer was breast cancer in 8 studies, one each of lymphoma, blood cancers and remaining 6 being mixed. Mean age was 48.81 years. Compared to patients on placebo there was a significant cardioprotective effect (smaller reduction in LVEF) noted with ACE/ARB (beta coef 5.2 (1.5-8.9), p<0.01), BB(beta coef 4.62 (0.8-7.8), p<0.02), and spironolactone beta coef 12.9 (1.9-23.4), p<0.03) There was an evidence of inconsistency with all p>0.3, other than in spironolactone arm as there were suggestion of inconsistency with p<0.01 likely due to the presence of single study. Conclusions: BB and ACE/ARB are associated with reduction in cardiotoxicity in patients with cancer undergoing cancer chemotherapy with an anthracycline or trastuzumab based regimen.
Performance of Oncotype Dx test in patients with T1bN0, grade 1, hormone receptor-positive, HER2-negative breast cancer.
Authors: Gudena Vinay K. , Causey Lindsey , Stuart Dawn , Martini Keisha
Published: May 2019

e12043

Background: NCCN (National comprehensive cancer network) recommends to consider Oncotype DX testing for patients diagnosed with T1bN0 stage 1A breast cancers that are hormone receptor positive and HER-2 negative. This study is a retrospective review of these patients diagnosed at Cone Health Cancer Center between 2012 and 2018 who had Oncotype DX testing. Methods: Patients with T1b hormone receptor positive and HER-2 negative breast cancers, who had Oncotype DX testing performed were queried from tumor registry from 2012 to 2018. Registry provided data on the patients ER/PR and Her 2 neu as well as whether they received chemotherapy. Patient charts were reviewed for grade, Ki 67 and their Oncotype Dx scores. Results: A total of 104 patients with T1b N0 (stage IA ) invasive breast cancers that were ER and PR positive and HER-2 negative between 2012 and 2018 had Oncotype DX test performed. Grade 1 tumors comprised 75 patients. Among these, four patients received adjuvant chemotherapy who had Oncotype scores of 22, 27, 29 and 38. Among patients with Ki 67 ≤ 10% and grade 1, only one patient out of 104 required chemotherapy. Conclusions: This retrospective analysis suggests that 97% of patients with T1b, grade 1, ER/PR positive, HER-2 negative breast cancers had Oncotype scores of less than 25. Hence Oncotype testing may be safely omitted for this group. Grade along with Ki 67 can identify a subset of T1bN0 ER/PR positive and Her 2 negative patients who do not need Oncotype testing.[Table: see text]
Survival outcomes by hormone receptor expression in early-stage HER2-positive breast cancer.
Authors: Sardesai Sagar D. , Kassem Mahmoud , Morgan Evan , Palettas Marilly , Stephens Julie , Williams Nicole Olivia , Stover Daniel G. , Van Deusen Jeffery , Wesolowski Robert , Lustberg Maryam B. , Ramaswamy Bhuvaneswari
Published: May 2019

e12050

Background: The clinical heterogeneity seen in HER 2 positive breast cancer (BC), mostly related to hormone receptor (HR) expression has been suggested to underlie the variability of response not only to endocrine treatments, but also to anti-HER-2 therapies. Herein, we describe our single institution experience with clinical outcomes by HR expression in early HER 2 positive BC. Methods: An IRB-approved single-institution retrospective analysis was performed for 400 consecutive patients with non-metastatic HER 2 + BC treated at the Ohio State University Comprehensive Cancer Center from 2005-2015. Medical records were reviewed for clinic-pathologic, treatment, and survival information. Disease Free Survival (DFS) was defined as time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary BC or death. Overall survival (OS) was defined as time from diagnosis to death or last known follow up. OS and DFS estimates were generated using Kaplan Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate univariate and multivariate hazard ratios for OS and DFS. Results: a total of 180/400(45%) patients were diagnosed with HR positive disease. The mean age was 54.1y and patients were predominately white (267, 84%), post-menopausal (190, 60%) and presented with invasive ductal cancer (293, 92%). HR negative disease was significantly associated with high tumor grade (72% vs. 52%, p <0.0001) and lower BMI (27.6 vs 30.1, p 0.0218) compared to HR + tumors. The frequency of CNS metastases was not significantly different between both groups (8 (4%) in HR + vs. 8(6%) in HR –, p 0.9909). 173(96%) of HR + patients received anti-estrogen therapy with median duration of therapy of 40.9 months and 22(13%) received adjuvant ovarian suppression. There was no significant difference between the DFS and OS by hormone receptor expression (P= 0.7459 and 0.6518 respectively). However, higher number of HR negative patients undergoing neoadjuvant therapy achieved a complete pathologic response (pCR, 64% vs 44%, p 0.0092). pCR was prognostic for both DFS(p 0.0002) and OS (p 0.0008) in HR negative subgroup and not in HR + subgroup. Conclusions: The triple positive phenotype represents a distinct clinical subtype of HER 2 positive breast cancer associated with low tumor grade and lower frequency of pCR. Consistent with other studies, pCR was not prognostic of long term survival in triple positive disease. Future trials investigating the ER/ HER 2 cross talk are needed for this patient population.
Are elderly breast cancer patients offered appropriate therapy i.e. surgery, chemotherapy, radiation, and endocrine therapy, in a rural population?
Authors: Johnson Alexander , Agbisit Christian , Delfino Kristin , Robinson Kathy , Desai Meghna R.
Published: May 2019

e12053

Background: The NCI SEER data demonstrated that age adjusted incidence rate of geriatric breast cancer is 427.5 per 100,000. Mortality rates for breast cancer have improved over the last 20 years,but the risk of breast cancer death has decreased 3 fold more rapidly in younger vs. geriatric population. Comorbid illnesses are more prevalent in elderly & therapy offered is often less aggressive. The objective of this study was examine practice patterns in a rural geriatric breast cancer population. The patients were divided into groups with life expectancies (LE) > 10 years or not. Analysis was also performed in groups based on age ranges. Methods: An institutional database of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 or older at the time of diagnosis was reviewed in an IRB approved fashion. Data was collected on age at diagnosis, LE, and the rates of chemotherapy, surgery, radiation therapy, multidisciplinary discussion, clinical trials, Adjuvant Online!, & endocrine therapy offered. LE data was divided into patients with greater than 10 years of life expectancy or not at the time of diagnosis. A separate analysis examined the rates of the above in age ranges of 65-70, 71-80, and 81 plus. Variations in significance were identified using Fishers Exact Test. Results: 44 patients (16.4%) had a LE at diagnosis of < 10 years. Surgery was offered in n=262 patients (97.4%). Radiation therapy was offered in n=170 patients (64.9%). Endocrine therapy was offered in n= 221 patients (83.1%). Chemotherapy was offered in n= 72 patients (27.2%). In the greater than or less than 10 year LE group, statistically significant variations were noted in the rates of radiation (p=0.0047) & chemotherapy (p=0.0067) treatments offered to patients based on their life expectancy. When patients were grouped by age range, statistically significant variations were noted in the rates of radiation treatment (p=0.0221), endocrine treatment (p=0.032), chemotherapy (p≤0.0001), & participation in clinical trials (p=0.0218). Conclusions: Our study identified statistically significant differences in the rates of radiation & chemotherapy offered to patients based on their life expectancy. Statistically significant differences in rates of radiation, endocrine therapy, chemotherapy, and participation in clinical trials were observed based on the age ranges of patients. No differences were noted in the rates of surgery offered, use of Adjuvant Online, and multidisciplinary discussion based on LE & age range.