tbuckley/cabot-search huggingface dataset:
Clinical value of measuring T-cell activation and proliferation using multiplexed quantitative fluorescence in non-small cell lung cancer (NSCLC).
Authors: Kurt Alex Schalper, Nikita Mani, Maria Toki, Daniel E. Carvajal-Hausdorf, Roy S. Herbst, David L. Rimm
Journal: Journal of Clinical Oncology (2016)

11610 Background: Elevated tumor infiltrating lymphocytes (TILs) is associated with better prognosis in diverse tumor types, including non-small cell lung cancer (NSCLC). Expression of PD-L1 and pre-existence of TILs or Interferon-g related mRNA signatures are associated with benefit to immune checkpoint blockade. The possible value of measuring TIL cytolytic activity and proliferation in NSCLC is unkown. Methods: We simultaneously stainedDAPI, Cytokeratin (M3515, DAKO), CD3 (E272, Novus Biologicals), Ki-67 (MIB-1, DAKO), and Granzyme-B (4E6, Abcam) using multiplex immunofluorescence in 686 lung carcinomas from three independent retrospective Yale cohorts represented in tissue microarray format (YTMA79, YTMA250 and YTMA310). We quantified the T-cell activation and proliferation in FFPE tumor samples by selective measurement of Granzyme-B and Ki-67 fluorescence signal in CD3 positive cells.The association between the T-cell markers, major clinico-pathological, molecular variables, and survival were studied. Results: The levels of CD3, Granzyme-B and Ki-67 were not highly correlated, indicating independence of the markers.Elevated TIL activation and proliferation were associated with early clinical stage, adenocarcinoma histology and smoking history. No differences were seen according to gender, age, or major molecular adenocarcinoma variants. Elevated T-cell cytolytic activity and proliferation were associated with longer 5-year overall survival. Conclusions: Measuring T-cell activity and proliferation identifies subsets of NSCLC with distinct immunogenic potential and outcome. Localized and T-cell specific function/proliferation could be used to select patients for treatment with immune checkpoint blockers.
Safety and outcome evaluation on cancer patients treated with immune checkpoint inhibitors either from standard of care or clinical trial enrollment.
Authors: Diego Felipe Cabrera Fernandez, Matthew Lei, Angela Michael, Seema Patel, Ding Wang
Journal: Journal of Clinical Oncology (2018)

e18782 Background: This retrospective study included patients (pts) treated with immune checkpoint inhibitors (ICI) as standard of care (SOC) or clinical trial (CT) enrollment at our institute between 3/1/2014-4/1/2017. Objectives of the study: 1) Compare the safety and therapy-related experience from ICI-treated patients either as SOC or CT enrollment; 2) Correlate ICI therapy-associated thyroid dysfunction to clinical outcomes. Methods: The data cut-off for survival analysis was on 12/31/2017, 247 pts were identified, and data from 196 pts were included. 124 pts received an ICI under SOC, 72 were treated via ICI CT protocols. Results: Safety evaluation showed that immune-related grade 1-2 adverse events (AEs) between SOC- and CT-treated pts were 33% vs 18%, respectively (p= 0.023). Severe immune-related adverse events (SAEs) were found in 15% of SOC pts vs 6% of CT pts (p= 0.041). ICI therapies showed an overall response rate (ORR) of 28% for SOC pts and 14% for CT pts (p= 0.020). Disease control rate (DCR) was 54% for SOC pts vs 63% for CT pts (p= 0.274), Progression free survival (PFS) was 5.2 months (MOs) in SOC pts vs 6 MOs in CT pts (p= 0.717). Overall survival (OS) was 23.4 MOs in SOC pts vs 16.5 MOs in CT pts (p= 0.307). Development of ICI-associated thyroid dysfunction during ICI therapy was evaluated using thyroid-stimulating hormone (TSH) as a marker, which was collected from all 196 pts. ICI therapy-associated abnormality correlated with a higher ORR at 44.1% vs 14% without TSH abnormality (p< 0.001), DCR was also higher at 74.6% vs 50% in pts with or without TSH abnormality (p= 0.001). Median PFS was 14.7 MOs for pts with abnormal TSH vs 3.5 months for pts with normal TSH (p< 0.001). Conclusions: ICI are active anti-cancer therapeutics for both SOC and CT pts with various cancer diagnoses. Less AEs and SAEs were observed in CT than SOC pts. Development of abnormal TSH during ICI therapy correlated with favorable responses and survival. Variables contributing to the safety and survival outcomes will be discussed in detail at the meeting presentation.
Association of immune-related genes to neutrophil-lymphocyte ratio (NLR) with survival of cetuximab treatment for metastatic colorectal cancer (mCRC): JACCRO CC-05/06AR.
Authors: Yu Sunakawa, Dongyun Yang, Bonnie LaFleur, John Luecke, Debrah Thompson, Miriana Moran, Stephanie H. Astrow, Jack Hsiang, Wu Zhang, Akihito Tsuji, Takehiro Takahashi, Hiroaki Tanioka, Yuji Negoro, Akinori Takagane, Satoshi Tani, Tatsuro Yamaguchi, Tetsuya Eto, Masashi Fujii, Wataru Ichikawa, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2017)

11613 Background: The antitumor activity of cetuximab (cet) may be affected by extracellular immune mechanisms. We have reported that immune-related genes are associated with survival in mCRC patients (pts) treated with cet (ASCO 2016 abstract#11591). NLR reflects cancer-related inflammation and is a validated prognostic maker in many types of cancers; however, it is not currently used for treatment decision-making. The association between NLR and clinical outcome of cet treatment for mCRC is unknown, and which genes are affecting the NLR remain to be identified. Methods: We enrolled 77 pts (57% males and 15% right-colon cancer) with KRAS exon 2 wild-type from 2 phase II trials (JACCRO CC-05 or CC-06) of 1st-line therapy with FOLFOX or SOX plus cet. All patients’ tissues were measured for expression levels of 354 immune-related genes by HTG EdgeSeq Oncology Biomarker Panel using next generation sequencing for quantitative analysis of targeted RNAs. The association between the NLR and clinical outcome was evaluated using Spearman’s rank correlation coefficient. In addition, the two-sample t-test was performed to investigate which genes had significantly different expression level between NLR-low and high groups in top 100 genes associated with survival among all measured genes. Results: Seventy-one of 77 pts were available for NLR data. The NLR was associated with progression-free survival (PFS) and overall survival (OS) (r = 0.24; p= 0.04, r = 0.29; p= 0.01, respectively). When stratified by median value of NLR, the Kaplan-Meier curve of NLR-low (n = 36) vs. high (n = 35) had a significant difference in both PFS (median 11.8 vs. 9.1 m, p= 0.036) and OS (median 42.8 vs. 26.7 m, p= 0.029). The two-sample t-test revealed that LYZ, TYMP, and CD68 genes expressed significantly differently between NLR-low and high groups (t-test p-value &lt; 0.005, FDR p-value &lt; 0.150). Conclusions: NLR is significantly associated with survival of 1st-line cet treatment for mCRC. Genes encoding for activities on tissue macrophages and endothelial cells may affect the level of NLR associated with outcome of cet combination chemotherapy. Clinical trial information: UMIN000010635.
Dissemination of 21-gene assay testing among female breast cancer patients in the US.
Authors: Kathleen Cronin, Valentina I. Petkov, Nadia Howlader, Will Howe, Nicola C. Schussler, Allison W. Kurian, Lynne Penberthy
Journal: Journal of Clinical Oncology (2016)

6553 Background: The 21-gene assay has been used in clinical practice since 2004 to predict the recurrence and chemotherapy benefit of breast cancer in patients with hormone receptor positive (HR+) disease. This analysis evaluates how the test disseminated in the patient population over time. Methods: Genomic Health data on tests ordered was linked to SEER Registries for women diagnosed with invasive breast cancer between Jan 2004 and Dec 2012. The percent of women for whom Oncotype DX was ordered was calculated for SEER areas covering 30% of the US population. Results: The percent of women for whom the Oncotype DX test was ordered increased from 1.1% in 2004 to 23.1% in 2012. Percent ordering was higher among women with N0 disease, isolated tumor cells and micrometastases (28.8, 37.1, and 34.5 in 2012, respectively). The percent ordering for women with N+ disease (excluding micrometastasic disease) began increasing in 2008 and reached 12.2% by 2012. After restricting the analysis to women with HR+ and N0 disease, a pattern of more rapid dissemination was evident and reached higher levels in younger women with continued low usage in older women. Although there was little difference by race/ethnicity or SES measures overall, differences became apparent when data was stratified by age with non-Hispanic whites and high SES groups showing earlier dissemination and higher usage for women < 65 years of age. For women ≥ 65, there was no difference. Conclusions: In N0, HR+ breast cancer, age is the strongest predictor of whether a woman will receive an Oncotype DX test. This strong dependence on age masks differences among important subgroups of women with earlier age of onset when not controlling for age. This difference may have implication in treatment received and health disparities associated with race/ethnicity and SES.
Creation of a high-fidelity simulation tool to teach competency in radiation oncology treatment plan evaluation.
Authors: Jenna Adleman, Jeff Winter, Tom Purdie, Andrea McNiven, Jennifer M. Croke
Journal: Journal of Clinical Oncology (2018)

11007 Background: Although treatment plan evaluation (TPE) is a core competency for radiation oncology residents, gaps in teaching exist. The purpose was to create an interactive TPE case bank for residents to improve competency. Methods: A needs assessment informed case bank development. Residents assessed their confidence in TPE using a 10-point Likert scale (1 = least, 10 = most confident). A list of clinically unacceptable plans were compiled and categorized by clinical site, reason for rejection and relevance. An interactive web-based DICOM-RT tool was used to query and interact with the case bank database. A companion software tool, acting as an interactive simulation platform, was created allowing user interaction. Results: Twenty-three participants (70%) responded to the needs assessment: 6 junior, 7 senior and 10 former residents. Opportunities for improving TPE were identified; the mean confidence scores were: target coverage assessment (6.3+2.7), doses to normal tissue (6.2+2.5), conformity (5.5 +2.6), plan acceptability (5.4+2.5) and ability to suggest improvements (4.8+2.3). Extracted themes for case bank development included incorporating diverse clinical sites, target coverage/normal tissue assessment, conformity and provision of feedback. Of the 677 clinically unacceptable plans, a final list of 50 were selected for inclusion. They were categorized, anonymized and imported. Additional (un)acceptable plans were generated to augment the case bank where required. The companion simulation software platform describes each clinical scenario and allows residents to enter their assessment and suggested corrective action (if applicable). The platform then provides immediate feedback, including error description and correction strategy. Conclusions: An innovative TPE case bank has been created to address a learning gap in radiation oncology training. The high fidelity simulation format allows case interactivity and feedback with the goal of improving TPE competency. This platform can be leveraged for teaching/assessment in competency based medical education. Future work will evaluate resident satisfaction with and effectiveness of the case bank as a learning tool.
Real-world data analysis of immune checkpoint inhibitor utilization by tumor type in the US community oncology setting.
Authors: Jeffrey A. Scott, David Garofalo, Sunita Verma-Kurvari, Bing-e Xu, Jim Montgomery
Journal: Journal of Clinical Oncology (2018)

e15076 Background: Checkpoint inhibitors have been a welcome addition to the armament of drugs for cancer treatment and their utilization has increased dramatically since their introduction. This study looks to quantify utilization of PD-1 and PD-L1 inhibitors by tumor type in the community oncology setting. Methods: This analysis was performed using de-identified data from the Integra Connect DTX database, an aggregated data platform that combines practice management claims, EHR clinical data, and CMS claims data. Data from patients treated by over 700 US community oncologists was analyzed. All patients that had received an immune checkpoint inhibitor treatment (March 2015 through January 2018) were identified through HCPCS J-code, if available, or generic name. Primary cancer diagnosis was assigned to each patient and each data point represented a unique patient. Results: Data from 6,481 cancer patients in the DTX database was analyzed for checkpoint inhibitor utilization. 56% of patients were male with average age of 70.7 years. Overall, nivolumab was used in 67% of the patients followed by pembrolizumab (25%). Over two-thirds of the patients had lung cancer (69%) followed by melanoma (13%) and kidney cancer (8%). Nivolumab and pembrolizumab dominated PD-1/PD-L1 inhibitor utilization in all tumor types except for bladder cancer, in which atezolizumab was used in over half of the patients. Conclusions: Checkpoint inhibitors represent a powerful option for treatment for several tumor types. However, in the community oncology setting, their use differs dramatically based on the tumor type. Overall, nivolumab was used in two-thirds of the patients included in this study. In most cancers analyzed, PD-1 inhibitor utilization was significantly higher than PD-L1 inhibitor utilization. Checkpoint Inhibitor Primary Cancer Diagnosis Lung Melanoma Kidney Bladder Breast Total (n) (%) (n) (%) (n) (%) (n) (%) (n) (%) (n) (%) Nivolumab 3,101 69% 475 58% 497 97% 110 26% 132 57% 4,315 67% Pembrolizumab 1,106 25% 345 42% 14 3% 63 15% 77 33% 1,605 25% Atezolizumab 184 4% 2 0% 2 0% 250 58% 17 7% 455 7% Durvalumab 88 2% 2 0% 0 0% 6 1% 2 1% 98 2% Avelumab 5 0% 1 0% 0 0% 0 0% 2 1% 8 0% Total 4,484 825 513 429 230 6,481
Uncertainty, post-traumatic stress, and quality of life in non-muscle-invasive bladder cancer survivors.
Authors: Ahrang Jung, Matthew Edward Nielsen, Sophia Kustas Smith, Jamie Crandell, Mary Happel Palmer, Ashley Leak Bryant, Deborah Mayer
Journal: Journal of Clinical Oncology (2017)

e16027 Background: More than 74,000 people are diagnosed with bladder cancer every year in the US, and approximately 75% of them have non-muscle-invasive bladder cancer (NMIBC). Having a NMIBC with high recurrence rates and frequent surveillance cystoscopies followed by repeated treatment can be a source of uncertainty and post-traumatic stress disorder (PTSD) symptoms affecting survivor’s quality of life (QOL). This study was to explore the impact of cancer, cancer treatment, and surveillance procedures on uncertainty, PTSD symptoms, and QOL in patients with NMIBC. Methods: NMIBC patients, diagnosed between 2010 – 2014, were eligible for this study. Of the 5979 NMIBC population identified through North Carolina Central Cancer Registry and met the criteria, 2000 patients were randomly selected. Data were collected by postal mail survey from October to December, 2016. The Mishel Uncertainty in Illness Scale-Survivor (MUIS-S), the PTSD Checklist for DSM-5 (PCL-5), the EORTC QLQ-C30, and QLQ-NMIBC24 were used to measure uncertainty, post-traumatic stress, and QOL, respectively. Descriptive statistics, partial correlations, ANOVA, and t-test were performed. Results: 396 NMIBC survivors returned their surveys (response rate 22%). Subjects averaged 3.5 years post-diagnosis and 72.8 years of age; the majority were male (71.7%) and white (94.4%). The mean score for uncertainty was 53.3±12.0, which means moderate uncertainty. Subjects who scored at or above 33 for PCL-5 were 4.3%, which indicates having PTSD. The mean scores for QOL dimensions (global health status, function, and symptom) were 73.3±21.9, 84.6±18.5, 15.5±17.1, respectively (possible range 0-100, higher score of global health and function = better, higher score of symptom = worse). There were significant correlations between uncertainty, PTSD symptoms, and all QOL dimensions (all p &lt; 0.001). Conclusions: Higher levels of uncertainty and PTSD symptoms were inversely related with QOL. Thus, future work should continue to explore the antecedents of uncertainty and PTSD symptoms and to identify the relationships among antecedents, uncertainty, PTSD symptoms, and QOL for intervention studies in high risk NMIBC survivors.
Real world data on the use and sequence of targeted and immuno-oncology drugs in metastatic melanoma (MM) patients (pts).
Authors: Carolina Ortiz, Esther Zamora, Guillermo Villacampa, Cristina Viaplana, Alberto Hernando, Javier Ros, Vicente García-Patos, Domingo Bodet, Berta Ferrer Fabrega, Juan Recio, Javier Hernandez-Losa, Rodrigo Dienstmann, Eva Muñoz-Couselo
Journal: Journal of Clinical Oncology (2018)

e21541 Background: Immunotherapy (iTx) and BRAF targeted therapy (tTx) have radically changed the outcomes of MM pts. However, data on real life use are scant and optimal sequence is unknown. Our aim was to characterized and compare the outcomes of MM pts treated with iTx and/or tTx in real-world setting identify factors of clinical benefit (CB). Methods: Single-institution experience of 115 consecutive pts with MM treated in our center from 2010 to 2017. Clinicopathological factors (CPF), treatment (Tx) pattern and survival were analyzed. CB was defined as complete, partial response or stable disease more than four months (m). Results: Median (Md) age was 62 y. BRAF-mt was found in 46%. Md follow-up was 23.8 m (3.5-74.5). Most pts (54%) received 2 lines of Tx and 26.1% ≥3 lines. 1º-line (1L) Tx included 40% iTx, 43% tTx and 16% others Tx (oTx). 2º-line (2L) Tx included 77% iTx, 16% tTx and 7% oTx. At 3º-line (3L) iTx was most usual 80%. Md overall survival (OS) was 27.3 m (19–31). Md Time to Tx failure (TTF) was 3.7 m (3.1–4.1). Of the total of 222 Tx, TTF for tTx (n = 64) was 5.3 m (4.1–11.2), while for iTx (n = 129) was 3.3 m (2.9–4.1) and for oTx (n = 26) 2.6 m (1.6 - 4.9). CB was higher with tTx (63%) than iTx (46%) or oTx (25%) (p < 0.01). Toxicity grade 2+ was higher for tTx 65%, being 56% in iTx and 27% in oTx (p < 0.04). For BRAF-mt pts, 87% received tTx at 1L and 54% received additional Tx, the sequence of tTx followed by iTx was more common (n = 16). Regards to iTx, TTF was not influenced by Tx line (p > 0.05 all comparisons). According to iTx regimen, anti-PD1/L1 had higher TTF 4 m (3.2–5.6) as compared to anti-CTLA4 with 2.5 m (2.0-4.1; HR: 0.62; p = 0.04); CB was lower at more advanced lines reaching 61% at 1L, 40% in 2L and 35% in 3L. Five pts received chemotherapy after iTx, one of them had CB. In pts receiving iTx after previous exposure to iTx (n = 42), TTF was 3.3 m (2–4.8) and CB was 34%. In multivariable analysis CPF did not impact on OS but pts with LDH ≥1.5 ULN at 1L had a trend for worse outcomes (HR:2.17; p = 0.17). Conclusions: Our real-world data confirms long-term OS in MM pts exposed to tTx and iTx. Benefit of iTx is seen in all lines. Our tendency in BRAF-mt was tTx follow of iTx. Additional research is needed to define prognostic markers in pts exposed to iTx and tTx.
Treatment, outcomes and prognostic factors of angiosarcoma of breast: A 25 year single institution experience.
Authors: Nischala Ammannagari, Kristopher Attwood, Richard Cheney, Jessica S. Young, John Michael Kane, Kilian Elizabeth Salerno, Mateusz Opyrchal
Journal: Journal of Clinical Oncology (2016)

e22540 Background: Primary (PAS) and secondary angiosarcoma (SAS) of breast account for < 1% of all breast neoplasms. SAS develops following radiation therapy (RT) to the breast or chest wall for treatment of breast cancer. The rarity of this tumor type makes it challenging to determine prognostic factors and develop optimal treatment strategies. Historically, large NCI cancer centers have reported a median overall survival ranging from 28 – 100 months with recurrence rate of 55%. Methods: We reviewed demographic, tumor, and treatment characteristics of breast AS patients diagnosed and treated at our institution between 1990 and 2015. Overall (OS) and recurrence free (RFS) survival were compared using standard statistical methods at a significance level of 0.05. Results: Of 12155 breast cancers, 22 patients (0.008%) with AS (PAS in 34%, SAS in 66%) were identified. Median age of PAS patients was significantly lower than SAS – 45 vs 71 years (p < 0.001). Median tumor size was 6.9 cm (7.3 cm vs 6.9 cm, p = 0.93) with multifocal disease seen in 22.7%. Tumor was high grade in 14 (50% vs 83.3%, p = 0.34). Median time from RT to SAS diagnosis was 7.8 years. Treatment included: mastectomy in 17 (77.3%), wide excision in 4 (18.2%), adjuvant RT in 4 (18.2%), taxane based chemotherapy in 11 (50%) and chemo-RT in 1 (4.5%). No significant differences were noted in tumor (p = 0.9) or treatment characteristics (p = 0.4) between PAS and SAS. Recurrence rate (mainly distant) was 36% (8 pts). The 5-year OS and RFS rates were 51% (95% CI 27–72%) and 36% (95% CI 14–58%) with estimated medians of 64.2 and 55.5 months, respectively with no significant difference between the two groups. Black ethnicity (11.6 vs 64.2 months, p = 0.015), multifocal disease (15.5 vs 64.2 months, p = 0.004) and tumor size of > 6.9 cm (8.3 vs 64.2 months, p = 0.03) were associated with poorer outcomes. Tumor grade was not related to OS. Adjuvant treatment (RT p = 0.49, chemotherapy p = 0.36) conferred no RFS or OS benefit. Conclusions: Patients with PAS were younger than SAS. Black race, multifocal presentation and larger tumor size predict worse clinical outcomes. Our institutional experience confirms the poor prognosis of angiosarcoma, and highlights the need for further research.