bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor DNA (ctDNA) using Guardant360 to predict response in BRAF V600 WT metastatic melanoma (MM) patients (pts) receiving immune checkpoint inhibitors (ICI).
Authors: Lee Jenny HJ , Carlino Matteo S. , Menzies Alexander M. , Odegaard Justin Iver , Lefterova Martina , Scolyer Richard A. , Long Georgina V. , Rizos Helen 
Published: May 2020

10050 Background: ctDNA detected by ddPCR predicts ICI response in MM, although its utility is limited to pts with known recurring mutations eg. BRAF, NRAS, KIT. We sought to overcome this limitation by using a next generation sequencing approach in BRAF V600 wild type (WT) MM pts. Methods: Plasma was collected at baseline and Week (wk) 6 in 35 BRAF V600 WT MM pts treated with ICI. Cell free (cf)DNA was analyzed using Guardant360 and only somatic non-synonymous and promoter variants were considered. Pts who failed cfDNA extraction at baseline were excluded (n = 3). Favorable ctDNA was defined as undetectable ctDNA at wk 6 and unfavorable ctDNA defined as detectable ctDNA at wk6. Response was according to RECIST at first restaging. Results: Of the evaluable 32 pts (64 plasma samples), median baseline cfDNA quantity was 33ng (range 4-657ng) and ctDNA was detected in 29/32 pts (91%). All 3 pts with undetectable baseline ctDNA had less than 10ng cfDNA compared to only 1/29 pts with detectable baseline ctDNA. Number of mutations identified in the 29 ctDNA-positive pts was 4 per pt (range 1-22). Response assessment was performed on 30 evaluable pts. Candidate driver mutation(s) in BRAF, NF1, or N/K/HRAS were identified in 26/30 pts. These mutations were often detected with other established mutations involved in tumorigenesis (eg. TERT promoter), or passenger mutations (eg. clonal hematopoiesis). Analysis of driver mutations revealed a sensitivity and specificity in predicting treatment failure of 92% and 93%, respectively (table). When all mutations identified were evaluated for treatment response, 9/18 responding pts retained some ctDNA at wk 6, although this never included TERT variants. The resulting sensitivity and specificity in predicting treatment failure changed to 100% and 50%, respectively, when all cfDNA variants were included. Conclusions: The extensive coverage of Guardant360 improves ctDNA detection in BRAF V600 WT MM pts, allowing non-invasive, rapid, and longitudinal assessment of response in a broader population. The expanded coverage also identifies passenger variants of potential non-MM origin, eg. clonal hematopoiesis, and with significant overlap with ctDNA, it is not possible to distinguish between the two in the circulation. We therefore recommend identification and monitoring of known cancer driver mutations only. [Table: see text]
The use of plasma proteomic markers to understand the biology of immunotherapy response.
Authors: Mehta Arnav , Rucevic Marijana , Sprecher Emmett , Hultin Rosenberg Lina , Lieb David , Kasumova Gyulnara G. , Kim Michelle S. , Bai Xue , Frederick Dennie T. , Flaherty Keith , Sullivan Ryan J. , Hacohen Nir , Boland Genevieve Marie 
Published: May 2020

10062 Background: Despite recent successes with immune checkpoint blockade (ICB) in melanoma, the prognosis for most patients remains dire. Whereas small fraction of patients are able to achieve disease control, most do not respond or are limited by immune-related toxicities. Robust non-invasive predictors of ICB response have the potential to guide clinical decision and alter management of patients, however, no such predictors currently exist. Methods: We applied a highly-multiplex Proximity Extension Assay to simultaneously detect > 1000 proteins in the plasma of anti-PD-1 treated melanoma patients. Our cohort comprised 116 patients, 66 responders (R) and 50 non-responders (NR). Additional 65 patients comprised a validation cohort with 30 R and 35 NR, and included 50 patients who developed treatment-related toxicities. Plasma samples were collected at baseline, 6-weeks and 6-months after starting the treatment. A subset of patients had single-cell RNA-seq performed on tumor tissue. Group differences and treatment effects were evaluated by linear model with maximum likelihood estimation for model parameters and Benjamini and Hochberg multiple hypothesis correction. Results: At baseline, 6 significantly differentially expressed (DE) proteins were identified between R and NR. Elevated expression of ST2 and IL-6, two key immunoregulatory proteins were found in NR. At 6-weeks, more dynamic changes occurred and 79 significantly DE proteins were identified between R and NR, including proteins implicated in primary or acquired resistance as IL-8, MIA, TNFR1 and potential novel targets as MCP-4/CCL13, ICOSLG and VEGF. Proteomic changes identified at baseline and 6-weeks were more profound at 6-months, and moreover 238 proteins were confirmed significant between R and NR. Importantly, we were able to leverage these differences to build classifiers of R and NR subsets. We compared mRNA expression of DE proteins within the tumor microenvironment by leveraging scRNAseq data from a subset of these patients. Enriched expression of these genes was uncovered in certain myeloid and exhausted T cell subsets, thus shedding insight into the potential role of these cell subsets in ICB response. Conclusions: Plasma proteomic profiling of anti-PD1 treated patients identified important tumor and immune changes associated with response. Non-invasive means discovery of circulatory protein biomarkers may predict sensitivity to immunotherapy and uncover biological insights underlying primary resistance.
Using digital-image analysis of tumor-infiltrating lymphocytes to predict survival outcomes in primary melanoma.
Authors: Chou Margaret , Illa-Bochaca Irineu , Minxi Ben , Giles Keith M. , Darvishian Farbod , Jour George , Moran Una , Shapiro Richard L. , Berman Russell S. , Osman Iman , Zhong Hua 
Published: May 2020

10066 Background: Inclusion of tumor-infiltrating lymphocytes (TIL) into AJCC staging criteria has been proposed due to evidence suggesting its prognostic significance. However, subjective inter-observer discordance prevents adoption of semi-quantitative TIL grading (e.g. absent, non-brisk, brisk) into clinical practice. We hypothesize that digital-image analysis (DIA) of TIL can provide a standardized, quantitative scoring system that more accurately predicts survival compared to currently used semi-quantitative grading methods. Methods: Clinical data and tumor specimens were analyzed from prospectively enrolled primary melanoma patients in the New York University Interdisciplinary Melanoma Cooperative Group with median follow-up of 5 years. H&E-stained slides were digitized using an Aperio ScanScope at 20X magnification. QuPath software was used for automated TIL quantification. Cox regression analysis was used to assess the improved prognostic value of TIL on recurrence-free (RFS) and overall survival (OS). Patients were separated into high- and low-TIL groups using a score threshold determined by the Youden Index. Results: 453 patients (18% stage I, 42% stage II, 40% stage III) were scored using automated TIL assessment and scores were significantly correlated with better RFS and OS per 10% increase in TIL (stage adjusted hazard ratio [aHR] = 0.92 [0.84-1.00] for RFS and aHR = 0.90 [0.83-0.99] for OS). A model combining TIL score with stage increased prognostic ability for both RFS (0.68 to 0.70, P = 0.02) and OS (0.62 to 0.64, P = 0.01), as assessed by concordance indices (C-index). Kaplan-Meier curves of high- ( > 16.6%) versus low-TIL (≤16.6%) patients showed clear separation in RFS and OS (median RFS = 155 vs 48 months, P < 0.001; median OS = 155 vs 89 months, P = 0.002). For comparison, a subset of the cohort (n = 250) was semi-quantitatively graded (absent, non-brisk, brisk) by an attending melanoma pathologist; however, this did not significantly differentiate RFS between groups (P > 0.05). Conclusions: A standardized, quantitative TIL scoring system significantly improved prediction of RFS and OS in primary melanoma patients compared with semi-quantitative TIL grading. Incorporation of quantitative TIL scoring into prognostic algorithms, such as AJCC criteria, should be considered.
Using a clinicopathologic and gene expression model to identify melanoma patients at high risk for disease relapse.
Authors: Eggermont Alexander M. , Bellomo Domenico , Tjien-Fooh Félicia , Wever Renske , Quattrocchi Enrica , Sominidi Damodaran Sindhuja , Van Vliet Martin , Dwarkasing Jvalini , Meves Alexander 
Published: May 2020

10068 Background: The identification of early stage melanoma patients at high risk for relapse is still difficult. Roughly 50% of melanoma deaths occur in patients who were initially diagnosed with nonmetastatic melanoma. Therefore, a strong clinical need has emerged for diagnostic tools that can identify melanoma patients at high risk for relapse. Here, we assessed the performance of a recently developed model (Bellomo et al., JCO Precis Oncol. 2020: in press), combining clinicopathologic and gene expression variables (CP-GEP), in identifying melanoma patients that have a high risk for disease relapse. Methods: We assessed the prognostic performance of the CP-GEP model in a cohort of 837 consecutive melanoma patients from Mayo Clinic who had a sentinel lymph node biopsy (SLNb) performed within 90 days of their diagnosis. The CP-GEP model combines Breslow thickness and patient age, with the expression of 8 genes in the primary tumor, to stratify patients according to their risk of relapse: CP-GEP High Risk or CP-GEP Low Risk. The main clinical endpoint of this study was five-year relapse free survival (RFS). Results: Patients were stratified based on SLNb status and CP-GEP classification. 76% of the patients were SLNb negative and had an RFS of 79% versus 52% for SLNb positive patients; HR, 3.21; P < 0.0001. 60% of the patients were identified as CP-GEP High Risk and had an RFS of 62% versus 87% for CP-GEP Low Risk patients; HR, 4.12; P < 0.0001. Within the SLNb negative group (637 patients of which 65% stage I), 51% of patients were classified as CP-GEP High Risk. Here, RFS was 70% for CP-GEP High Risk patients versus 89% for CP-GEP Low Risk patients; HR, 3.61; P < 0.0001. The prognosis of these CP-GEP High Risk patients is similar to stage IIC/IIIA patients with reported RFS ranging from 63% to 77%. This confirms the heterogeneity in prognosis among patients with stage I/II melanoma disease. Conclusions: The CP-GEP model can be successfully used to stratify patients based on their risk for relapse. In particular, it can be used to identify SLNb negative patients with a high risk for disease relapse who may benefit from therapeutic interventions. Independent validation studies are ongoing to validate the CP-GEP model in various patient populations. [Table: see text]
KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53WT) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy.
Authors: Wong Michael K.K. , Kelly Ciara Marie , Burgess Melissa Amber , Lewis Karl , Grewal Jaspreet Singh , Olszanski Anthony J. , McGreivy Jesse , Rothbaum Wayne , Qamoos Hope , DeCaprio James A. 
Published: May 2020

10072 Background: MCC is an aggressive neuroendocrine skin cancer with very poor prognosis. Immune checkpoint inhibition was recently shown to benefit some patients (pts). There are few effective treatments (tx) and no standard of care for those who relapse on or are refractory to anti-PD-1/L1 agents (R/R). In p53WT MCC, oncoproteins from the Merkel cell polyomavirus can inhibit p53 tumor suppressor functions via L-MYC/EP400-dependent activation of MDM2. KRT-232, a potent, selective, orally available MDM2i, is being evaluated in pts with p53WTMCC who are R/R to anti-PD-1/L1 tx. Methods: In stage 1 of this open-label, multicenter, phase 2 study (NCT03787602) pts initially received KRT-232 240mg QD days 1-7 of a 21 day (d) cycle (cy). This cohort was closed due to Grade (Gr) 3/4 cytopenias and pts were moved to 240mg QD days 1-5 of a 28d cy to allow for hematologic recovery. Two new arms were opened: 240mg and 180mg QD days 1-5 of a 28d cy. The primary endpoint is objective response rate (ORR) by RECIST 1.1. Secondary endpoints include duration of response, progression-free survival, overall survival, and safety and tolerability of KRT-232. Results: At the time of this analysis, 11 pts were treated with KRT-232: 6 on the 240mg 7/21d, 3 on the 240mg 5/28d and 2 on the 180mg 5/28d schedules. Median age was 66; 46% of pts had ECOG 1 (range 0-1), the median prior lines of systemic therapy was 3 (range 1-4) and 82% had prior radiation tx. Treatment-emergent adverse events (AEs), regardless of grade or causality, were reported in all pts: 55% had Gr 3-4 AEs and 36% had serious AEs (SAEs). The most common AEs included neutropenia (55%), anemia, leukopenia and thrombocytopenia (each 45%), diarrhea, nausea and fatigue (each 36%), and lymphopenia, hypomagnesaemia, lipase increase and sinus tachycardia (each 27%). SAEs were mainly due to cytopenias. One Gr 5 AE of respiratory failure/ascites was attributed to progression. Median time on study was 11.3 wks (range 1.3-20.9). Two of 11 pts on active tx have not yet reached the first response assessment (wk 6). Of the 9 pts who have reached wk 6, 2 PRs and 1 SD (converted to PR at wk 12) were reported. At the second response assessment (wk 12), 2 PRs were reported; one of the PRs at wk 6 has not yet reached wk 12. The ORR was 33% (3/9 pts) . Conclusions: KRT-232 demonstrates promising monotherapy activity in MCC p53WT pts who failed anti-PD-1/L1 tx. This is the first clinical proof-of-concept for inhibiting the MDM2 pathway in MCC. Safety and efficacy continue to inform KRT-232 dose and schedule optimization. Clinical trial information: NCT03787602.
Efficacy of imiquimod in the management of lentigo maligna.
Authors: Dréno Brigitte , Dinulescu Monica , NGuyen Jean-Michel , Maillard Hevé , Le Duff Florence , Machet Laurent , Beylot-Barry Marie , Legoupil Delphine , Wierzbicka-Hainaut Ewa , Bedane Christophe , Leccia Marie Thérèse , Debarbieux Sébastien , Meyer Nicolas , Monestier Sandrine , Bens Guido , Denis Marc G. , Bossard Celine , Vergier Beatrice , Khammari Amir 
Published: May 2020

10074 Background: Lentigo maligna (LM), a melanocytic proliferation occurring on photoexposed skin, might progress to LM melanoma. Surgery is recommended as first-line treatment. However, the main challenge is the size of the excision inducing often-aesthetic injuries on the face and thus often refused by patients. The excision margins of 5 to 10 mm remain without international consensus. Several studies have shown that imiquimod induced LM regression, acting by enhancing IFN-γ production and effector function of T cells. The main goal of this study is to investigate the effect of imiquimod versus placebo in neoadjuvant setting to decrease the excision size as from the first surgical procedure. Methods: We performed a prospective, randomized, open, multicenter, phase III clinical study (NCT01720407). The health authority and ethics committee approvals were obtained and all subjects signed an informed consent. The primary endpoint was to demonstrate that in neoadjuvant situation, imiquimod could reduce the surgical excision size of LM with a healthy tissue margin of 5 mm. The main inclusion criteria were: Patients > 18 years fit for surgery. LM of the head histologically confirmed and not previously treated. Surface lesion ≥ to 1cm² and ≤ to 20cm². The two treatment arms were imiquimod or placebo followed by LM excision. Imiquimod or placebo were applied once daily, 5 days/week for 4 weeks followed by 5 mm margin surgery performed four weeks after the last treatment application. For sample size, 268 patients were expected to demonstrate a difference of 15% between the two arms in a bilateral situation with an alpha risk of 5% and a beta risk of 20%. Results: The trial involved 273 patients, 238 (105 men (44%) and 133 women (56%), mean age of 71 ± 10.2 years, were analyzed in modified ITT. Statistical analysis was performed on 122 patients in the imiquimod arm and 116 patients in the placebo arm. For the primary endpoint, the first extralesionnal excision has been achieved for 112 (91.8%) patients in the imiquimod arm and for 98 (84.5%) placebo patients group. There was no significant difference (p value = 0.1067) between the two arms. However, regarding the surface of LM, imiquimod allowed a highly significant reduction (4.2 cm² ± 4.6 to 2.3 cm² ± 3.3) compared to LM treated by placebo (4.0 cm² ± 3.5 to 4.0 cm² ±3.3; p < 0.0001). Conclusions: This randomized prospective study shows that imiquimod reduces the LM area (-50%) after one month of treatment. Reducing the surface of LM with imiquimod is not associated with a higher risk of intralesional excision (marge 5mm), with a significant esthetic result (less excised surface). Clinical trial information: NCT01720407.
Exploring the clinical efficacy of the total body skin exam.
Authors: Harding Tanner , Seyffert Jennifer , Maner Brittany , Kunadia Anuj , Camner Shawn , Yungmann Martin , Cotter Murray , Solomon James A. 
Published: May 2020

10078 Background: The clinical efficacy of the total body skin exam has long been the subject of debate. A 2016 report by the United States Preventative Services Task Force (USPSTF) found the current body of evidence was “insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in [asymptomatic] adults.’’ However, the USPSTF based its recommendations on studies evaluating mainly the ability of primary care physicians to diagnose melanoma through total body skin exams (TBSE). This study seeks to address this insufficiency in the current literature by exploring the clinical efficacy of the dermatology provider performed TBSEs as a screening tool with respect to the detection of malignant melanoma (MM), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Methods: A search was performed within the electronic medical record of a large multi-state dermatology group practice for all instances of new and established patient office visits occurring from 1 January 2018 to 31 December 2019. Per practice policy, it is denoted whether each office visit includes a TBSE or partial skin exam (PSE). The number of MM, SCC, and BCC diagnoses made within the context of each class of skin exam was analyzed. Results: Of the 930,706 office visits analyzed, 438,027 TBSEs and 492,679 PSEs were performed. For each of the three types of skin cancer surveyed, the number of cancers diagnosed in the context of a TBSE was significantly greater than the number diagnosed in the context of a PSE. One MM was diagnosed per 161.0 TBSEs and 371.3 PSEs ( Χ2 ( df = 1, N = 930706) = 662, p < 0.001). One SCC was diagnosed per 56.7 TBSEs and 108.4 PSEs ( Χ2 ( df = 1, N = 930706) = 1258.5, p < 0.001). One BCC was diagnosed per 10.2 TBSEs and 17.8 PSEs ( Χ2 ( df = 1, N = 930706) = 5884, p < 0.001). Conclusions: Skin cancer is detected at significantly higher rates in TBSEs than PSEs. The finding that one MM is detected in 161 TBSEs may be compared to one cervical cancer is detected in 3,776 Pap smears. Thus, a TBSE is 23.5 times more likely to identify a MM than a Pap smear is to identify a cervical cancer. This trend holds even when adjusted for prevalence. Further analysis will allow for the comparison of exam types with respect to patient age, staging, lesion size, and Breslow depth at time of cancer diagnosis. This continued analysis will allow for a more detailed risk benefit-analysis and insight into the clinical efficacy of the TBSE.
A multiparameter classifier to predict response to lapatinib plus trastuzumab (LT) without chemotherapy in HER2+ breast cancer (BC).
Authors: Veeraraghavan Jamunarani , Gutierrez Carolina , De Angelis Carmine , Wang Tao , Pascual Tomás , Weigelt Britta , Galvan Patricia , Rexer Brent Neil , Forero-Torres Andres , Wolff Antonio C. , Nanda Rita , Storniolo Anna Maria , Krop Ian E. , Goetz Matthew P. , Reis-Filho Jorge S. , Hilsenbeck Susan G. , Prat Aleix , Osborne C. Kent , Schiff Rachel , Rimawi Mothaffar F. 
Published: May 2020

1011 Background: Several trials have shown 25-30% pathologic complete response (pCR) rates in patients with HER2+ BC treated with LT therapy (+ endocrine therapy if ER+), but no chemotherapy (CTX). We hypothesize that a multiparameter classifier, comprised of HER2 gene and protein levels, intratumor heterogeneity (ITH), HER2-enriched (E) subtype, and PIK3CA mutation status can identify patients whose tumors are “addicted” to HER2 signaling and are likely to achieve pCR from a CTX-sparing de-escalation strategy. Methods: Baseline specimens from 2 trials (TBCRC023 [NCT00999804] and PAMELA [NCT01973660]) of neoadjuvant CTX-sparing LT (+ endocrine therapy if ER+) in HER2+ BC were used. HER2 protein and ITH (scored for % 3+ by IHC), and gene amplification (HER2:CEP17 ratio and copy number (CN) by CISH) were measured on the same slide by the dual gene protein assay (GPA). HER2-E and PIK3CA mutation status were assessed by research-based PAM50 and MSK-IMPACT platforms, respectively. A decision tree algorithm was used to determine the GPA cutoffs and to construct the classifier of response (by pCR) in TBCRC023, which was then validated in PAMELA. Results: Of the evaluable patients from TBCRC023 (N = 130) and PAMELA (N = 151), GPA data were available for 121 and 94 cases, respectively. Both cohorts exhibited similar distributions for HER2 ratio, CN, and % 3+, and a strong correlation between HER2 ratio and CN (R > 0.92). In TBCRC023, 73 cases had data from GPA, PAM50, and IMPACT, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio > 4.6 and % 3+ > 97.5% in both the GPA data cohort (N = 121) and complete data cohort (N = 73). With PAM50 and IMPACT data, the model added HER2-E and PIK3CA wild-type (wt). For practical reasons, the classifier was locked as HER2 ratio ≥ 4.5 AND % 3+ ≥ 90% AND PIK3CA-wt AND HER2-E, which yielded a PPV of 55% and NPV of 94%. Validation in PAMELA using 45 cases with data for all 3 assays yielded PPV of 44% and NPV of 82%. 29 TBCRC023 cases without IMPACT data could be predicted to be non-pCR, of which 26 were correct (NPV = 89%). In PAMELA, 66 additional cases could be predicted to be non-pCR, of which 54 were correct (NPV = 81%). Conclusions: We have constructed a multiparameter classifier that can predict pCR with targeted therapy alone that compare to pCR rates of CTX + dual anti-HER2 in unselected patients. Prospective validation in a clinical trial is warranted. [Table: see text]