tbuckley/cabot-search huggingface dataset:
Nivolumab for hepatocellular carcinoma (HCC) in a real-world context.
Authors: Nisha Rao, Emanuelle M. Rizk, Regina Hwang, Robyn Denise Gartrell, Jasnit Makkar, Jay Oza, Marc Najjar, Jean Emond, Alyson Fox, Elizabeth Verna, Sidney Brejt, Stephen Reis, Vladimir Sheynzon, David Sperling, Joshua Weintraub, Yvonne M. Saenger
Journal: Journal of Clinical Oncology (2019)

e15675 Background: Novel immunotherapies may be effective in patients with HCC; however, patients with advanced liver disease are often excluded from clinical trials. The goal of our study was to evaluate the safety and efficacy of nivolumab for HCC in a real-world context, including among patients with advanced liver disease. Methods: We examined all cases of HCC initiated on off-study nivolumab alone or in combination with locoregional therapy at our institution from 2/2017 to 7/2018. Our sample included 14 patients. We report participant demographics, baseline liver function, treatment toxicity, and overall survival (OS). Results: The majority of participants were male (71%) and Caucasian (57%). NAFLD (36%) and HCV (43%) were the most frequently cited risk factors for HCC. Patients had variable liver disease at baseline, with 36% Child-Turcotte-Pugh (CTP) A, 36% CTP B, and 21% CTP C disease. Patients received either nivolumab only (50%), or nivolumab with locoregional therapy (LRT) (50%). All patients with CTP C disease received nivolumab alone. Treatment was generally safe, with only grade 1 or 2 toxicities reported, most commonly fatigue. Median OS was 7 months. Of note, one patient with baseline CTP C disease showed complete response to nivolumab treatment but experienced recurrence off nivolumab. Conclusions: Our study is the first to report the use of nivolumab in patients with HCC and CTP C disease. Nivolumab was well-tolerated in a real-world context in this small patient cohort, including among patients with advanced cirrhosis. Further study in larger patient populations is warranted. [Table: see text]
Treatment delay and outcomes in stage IV lung cancer: The reality of a public hospital in a developing country.
Authors: Nicolas Peruzzo, Juliano Ce Coelho, Gustavo Gössling, Pedro Grachinski Buiar, Gabriel de Souza Macedo, Gabriel Lenz, Débora Leite Rocha, Pedro Emanuel Rubini Liedke, Gilberto Schwartsmann
Journal: Journal of Clinical Oncology (2019)

e20709 Background: Lung cancer is the leading cause of cancer deaths globally. Despite the development of a number of new therapeutic options for stage IV non-small cell lung cancer (NSCLC), many patients (pts) still face difficulties in accessing proper treatment in adequate time, especially in developing countries. We analyzed clinical outcomes in a population with stage IV NSCLC treated at a public hospital in Southern Brazil. Methods: In this retrospective cohort study, we enrolled 57 pts with stage IV NSCLC treated at Hospital de Clinicas de Porto Alegre (HCPA) between 2016 and 2018. Results: Median follow-up was 20.3 months, 53% were men, mean age was 65 years, 86% had smoked, 84% had de novo metastatic disease, 96% had non-squamous histology, and 16% had EGFR mutations. At the point of therapeutic decision-making, 72% had ECOG performance status (PS) 0-2 (deemed as good), whereas 28% had PS 3-4 (poor). Among pts diagnosed at HCPA (91%), median time from symptoms to diagnosis was 23 days, and median time from diagnosis to palliative systemic therapy (PST) was 65 days. PST was delivered to 60% of pts, and the most used first-line protocol was Taxol-Carboplatin (79%). Two or more lines of PST were delivered to 23% of pts. In the subgroup of pts with sensitizing EGFR mutations, 75% received anti-EGFR therapy (Gefitinib). The main reason for upfront best supportive care (BSC) was poor PS. In the poor PS subgroup, 44% initially presented at HCPA with good PS; however, PS deterioration precluded them from starting PST. No pts with poor PS received PST. In the whole cohort, median overall survival (OS) was 7.7 months. In the Cox regression multivariate analysis, poor PS (HR 3.80, P &lt; 0.0001, 95% CI 1.90–7.61) and second-line PST (HR 0.23, P = 0.002, 95% CI 0.09–0.58) were independent predictors of OS. Median OS was 10.3 months vs. 2.4 months in PST and BSC subgroups, respectively. Conclusions: In our cohort, which reflects the reality of a publicly insured population and thus most of Brazilian lung cancer pts, poor PS deprives nearly one-third of pts from PST and is associated with a worse prognosis. Postponement of PST may lead to a loss of opportunity for pts to being treated; therefore, it is crucial to develop strategies to improve time to PST.
Targeting MHC-linked wild type p53 with TCR mimic single chain diabody for cancer immunotherapy.
Authors: Suman Paul, Jacqueline Douglass, Annika Schaefer, Emily Han-Chung Hsiue, Alexander Pearlman, Brian Mog, Michael Hwang, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou
Journal: Journal of Clinical Oncology (2019)

2524 Background: Increased tumor suppressor protein p53 expression is observed in a wide range of human cancers. As a result there is intense interest in targeting p53 for cancer therapy. Intracellular p53 is inaccessible to therapeutic antibodies that bind cell surface proteins. However, intracellular proteins including p53 are degraded into peptides that are presented on cell surface in association with HLA class I molecules. Thus p53 peptide-HLA (p53-HLA) complexes can be antibody targets. Methods: Using phage display we identified a novel anti-p53-HLA single chain variable fragment (scFv) clone-43 that recognizes a wild-type p53 10-mer epitope bound to HLA-A*2402. By coupling our clone-43 scFv with an anti-CD3 scFv, we generated a single chain diabody (scDb) designed to activate T-cells against p53-expressing target cells. Results: In-vitro co-culture of clone-43 scDb with donor human T-cells and p53 expressing SIG-M5 cancer cells results in SIG-M5 cell killing and concomitant T-cell interferon gamma (IFNγ) release. In contrast, similar co-culture with SIG-M5 p53-knock out (KO) cells showed no cell killing and minimal IFNγ release demonstrating specificity of clone-43 to p53 expressing cells. Additionally, in-vivo growth of p53 expressing SW480 cancer cell xenografts in NSG mice was completely terminated by clone-43 scDb injections. A major concern for wild-type p53 epitope targeting is potential on-target off-tumor effect on non-cancerous tissue. We observed significant in-vitro clone-43 scDb mediated killing of human HLA-A*24:02 peripheral blood mononuclear cells. To better evaluate effect of clone-43 scDb on non-neoplastic human cells, we engrafted HLA-A*24:02 human CD34+ hematopoietic stem cells into NSG mice to generate a humanized mouse model with circulating mature human CD45+ cells. Clone-43 scDb treatment resulted in selective depletion of circulating human cells while the same cells persisted in mice treated with unrelated control scDb. Conclusions: Our observation that immune targeting of wild-type p53 epitope results in significant off-tumor hematopoietic cell death is contrary to previously published reports and carries important implications for future anti-p53 antibody and vaccine design for cancer immunotherapy.
Staging the development and implementation of a Coordinated Cancer Care Model using risk-based survivorship care: A deliberative discussion among multiple stakeholders.
Authors: Dominique Tremblay, Karine Bilodeau, Catherine Prady, Nassera Touati
Journal: Journal of Clinical Oncology (2019)

e18027 Background: Risk-based survivorship care has become one of the best practices care recommended by the Institute of Medicine. It involves coordinated follow-up services based on the risk of long-term and late effects, cancer recurrence and an individualised care plan. Risk-based care requires specific knowledge about cancer histology, treatments, and potential consequences of cancer and its treatment to guide surveillance, screening and counseling. Diagnostic and treatment details and their associated health risks may not be known by survivors or their multiple care providers. Implementing risk-based survivorship care is often challenging for providers. This presentation report on a deliberative workshop on the development and planning of a risk-based survivorship care model. Methods: The deliberative workshop is part of a larger study in two regional cancer networks in Quebec, selected for there differences (geographic location, population size, academic mandate). A total of 25 key informants (researchers, managers, family physicians, oncologists, cancer survivors, nurses, social workers) participated into the workshop on October 2 nd , 2018. Deliberative discussion between local stakeholders followed by videoconference, getting together stakeholders from both networks was drawn from Gupta et al 3 steps: 1) identify the problem; 2) develop the innovation; 3) design the pilot test. Results: Although the context of the network was different, main issues were similar: 1) there is no common understanding of the concept “risk-based survivorship care”, either for survivors, primary care providers and cancer specialist; 2) “silo functioning” within and between teams is a main barriers to ensure care coordination based on risk assessment; 3) organizational assets should be formalized to insure safe coordination of survivorship care based on cancer risk assessment. Conclusions: Given the recognized importance of risk-based survivorship care and implementation challenges, deliberative discussions may provide a useful lens to inform translation of this model into real practices and guide empirical studies.
IL12 Abrogates Calcineurin-Dependent Immune Evasion during Leukemia Progression
Authors: Jennifer L. Rabe, Lori Gardner, Rae Hunter, Jairo A. Fonseca, Jodi Dougan, Christy M. Gearheart, Michael S. Leibowitz, Cathy Lee-Miller, Dmitry Baturin, Susan P. Fosmire, Susan E. Zelasko, Courtney L. Jones, Jill E. Slansky, Manali Rupji, Bhakti Dwivedi, Curtis J. Henry, Christopher C. Porter
Journal: Cancer Research (2019)

Exploitation of the immune system has emerged as an important therapeutic strategy for acute lymphoblastic leukemia (ALL). However, the mechanisms of immune evasion during leukemia progression remain poorly understood. We sought to understand the role of calcineurin in ALL and observed that depletion of calcineurin B (CnB) in leukemia cells dramatically prolongs survival in immune-competent but not immune-deficient recipients. Immune-competent recipients were protected from challenge with leukemia if they were first immunized with CnB-deficient leukemia, suggesting robust adaptive immunity. In the bone marrow (BM), recipients of CnB-deficient leukemia harbored expanded T-cell populations as compared with controls. Gene expression analyses of leukemia cells extracted from the BM identified Cn-dependent significant changes in the expression of immunoregulatory genes. Increased secretion of IL12 from CnB-deficient leukemia cells was sufficient to induce T-cell activation ex vivo, an effect that was abolished when IL12 was neutralized. Strikingly, recombinant IL12 prolonged survival of mice challenged with highly aggressive B-ALL. Moreover, gene expression analyses from children with ALL showed that patients with higher expression of either IL12A or IL12B exhibited prolonged survival. These data suggest that leukemia cells are dependent upon calcineurin for immune evasion by restricting the regulation of proinflammatory genes, particularly IL12. SIGNIFICANCE: This report implicates calcineurin as an intracellular signaling molecule responsible for immune evasion during leukemia progression and raises the prospect of re-examining IL12 as a therapeutic in leukemia.
A real-world evidence study of CDK4/6 inhibitor treatment patterns and outcomes in metastatic breast cancer by g<i>BRCA</i> mutation status.
Authors: Kimmie McLaurin, Tapashi Dalvi, Jenna M Collins, Beth L Nordstrom, Susan McCutcheon, James C Bennett, Brian R Murphy, Puneet K Singhal, Josefa Maria Briceno
Journal: Journal of Clinical Oncology (2019)

1563 Background: Limited data exist on the real-world treatment patterns and effectiveness of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors in the germline BRCA (g BRCA) mutated breast cancer population. Methods: Adults with human epidermal growth factor receptor 2 negative (HER2-), hormone receptor positive (HR+) metastatic breast cancer (mBC) treated with a CDK4/6 inhibitor from 01Jan2013–31Jan2018 were retrospectively selected from the Flatiron Health Oncology electronic medical record database. Patients with known g BRCA status were classified as having g BRCA mutated (g BRCAm) or wild type (g BRCAwt) disease. Time to first subsequent therapy or death (TFST) and overall survival (OS) were calculated from start of the earliest line of therapy with a CDK4/6 inhibitor. Kaplan-Meier (KM) medians were estimated, and TFST and OS compared between g BRCA groups with Cox models stratified by line of therapy and adjusting for demographic and clinical characteristics that modified hazard ratios (HRs) for g BRCA status by &gt; 10%. Results: Of 2968 HER2- HR+ patients with mBC receiving a CDK4/6 inhibitor, g BRCA status was known for 859 (28.9%). Patients with g BRCAm and g BRCAwt received letrozole plus palbociclib (42.4 and 39.8%, respectively), fulvestrant plus palbociclib (32.9 and 30.7%), or other CDK4/6 regimens (24.7 and 29.5%) across all lines. The g BRCAm group had a non-significant, shorter TFST than g BRCAwt (stratified HR 1.24; 95% CI 0.96–1.59). OS was significantly shorter in g BRCAm than g BRCAwt patients (stratified HR 1.50; 95% CI 1.06–2.14). Conclusions: The results of this real-world study suggest that treatment outcomes with CDK4/6 inhibitors may be poorer in patients with g BRCAm compared with g BRCAwt disease. These findings indicate a higher unmet need among patients with g BRCAm, potentially requiring alternative treatment options. [Table: see text]
Proactive, multidisciplinary approach to supportive medicine: Improving health outcomes and care utilization.
Authors: Brooke Worster, Valerie P Csik, Jared Minetola, Gregory D. Garber, Alison Petok, Liana Yocavitch, Jasmine Tenpa Lama, Krupa Gandhi, Grace L. Lu-Yao
Journal: Journal of Clinical Oncology (2019)

6537 Background: Evidence suggests that cancer patients who receive palliative care early in their disease have improved quality of life, decreased emergency department (ED) visits, and less aggressive end-of-life care. In 2017, the Sidney Kimmel Cancer Center at Jefferson established the Neu Center for Supportive Medicine and Cancer Survivorship (NCSMCS) as a model for integrated care in the outpatient setting for all cancer patients. A multidisciplinary team consisting of palliative care physicians, social work, psychology, and navigation conducts biopsychosocial screening and initiates a personalized care plan for each patient to clarify treatment goals and offer assistance. Objectives: To use biopsychosocial screening at specified time points to identify needs and evaluate the impact of supportive care as part of standardized oncology care regardless of stage. Methods: This assessment utilized Oncology Care Model (OCM) data for Jefferson Medicare patients between 7/1/16 to 7/31/18. Incidence of ED admits ED/Observation and admissions were evaluated as well as ICU utilization and advanced care planning. Poisson regression was used to generate incidence rate ratios (IRR) and 95% confidence intervals (CI) to facilitate the comparison of post- vs. pre- incidence rates of hospitalization. Results: The post-intervention hospital admissions decreased by 31% in NCSMCS (IRR 0.69; 95% CI 0.48-0.98) and by 10% in Non-NCSMCS (IRR 0.90; 0.84-0.96) and advanced care plans were more likely to be on file for NCSMCS (9.0% vs. 4.9%). The intensive care unit (ICU) admissions were decreased by 17% among Non-NCSMCS (IRR 0.83; 95% CI 0.74-0.93). The utilization rates for ED admissions were not statistically different among both the groups. Conclusions: The preliminary data is promising and impact will be monitored as the intervention is expanded. Reducing admissions has benefits from both a cost savings as well as quality of life perspective. Future analyses will consider the impact of the intervention on a patient’s quality of life.
Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy.
Authors: Frederic Anthony Vallejo, Sumedh Shah, Winston Walters, Katrina Kostenko, Ingrid Torrens, Jeffrey Prince, Luis E. Raez, Ziad Khatib, Steven Vanni, Regina M. Graham
Journal: Journal of Clinical Oncology (2019)

e13558 Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer.
Impact of the extent of resection on primary breast angiosarcoma survival.
Authors: Timur Mitin, Shearwood McClelland, Jess Hatfield, Catherine Degnin, Yiyi Chen
Journal: Journal of Clinical Oncology (2019)

521 Background: The widely accepted standard of care in treating primary breast angiosarcoma involves surgical resection, often followed by adjuvant therapy (radiation and/or chemotherapy). The rarity of this disease has precluded large-scale analyses. The question regarding the impact of resection extent on survival has yet to be examined on a nationwide scale. Methods: The National Cancer Data Base (NCDB) from 2004-2014 identified primary breast angiosarcoma patients throughout the United States having undergone surgical resection. The extent of resection (mastectomy versus lumpectomy) was adjusted for several variables (including patient age, race, income, primary payer for care, tumor size, adjuvant therapies, and medical comorbidities) to assess its impact on breast angiosarcoma-related mortality. Results: Over this eleven-year span, 826 resected primary breast angiosarcoma patients were identified in the United States. Mastectomy was by far the most common surgical modality for primary breast angiosarcoma (86% of patients). Increasing tumor size was predictive for mastectomy over lumpectomy (p &lt; 0.0001), and for involvement of adjuvant radiation therapy (p = 0.001). The extent of surgical resection was inversely predictive of radiation usage (p = 0.017). However, surgical modality was not significantly predictive of breast angiosarcoma-related mortality. Conclusions: Despite the frequent preference of mastectomy for primary breast angiosarcoma treatment (more than 6 of every 7 patients), there is no survival benefit of mastectomy versus lumpectomy. This lack of benefit should be discussed with patients, given the reduced operative morbidity of lumpectomy versus mastectomy. The Class IIB evidence provided from this analysis represents the highest level of evidence to-date governing management of this disease.
Investigating the utility of breast cancer (BC) molecular signatures and immune signature profiling (ISP) as predictors of pathological complete response (pCR) to neoadjuvant chemotherapy + trastuzumab (NAC+T) in HER2+ BC.
Authors: Salomon M. Stemmer, Yulia Shvartser, Itay Israel Shemesh, Idit Peretz, Rinat Yerushalmi, Daniel Hendler, Izhak Haviv, Heather Ann Brauer, Michael Castro
Journal: Journal of Clinical Oncology (2019)

e12109 Background: Trastuzumab targets HER2 directly as well as contributes to activation of the immune system against the tumor. We investigated the utility of BC molecular signatures and ISP as predictors of pCR to NAC+T in HER2+ BC pts. Methods: The analysis included 73 consecutive HER2+ BC pts with pathological samples at diagnosis, who received NAC+T. RNA was extracted from 73/22 biopsy/surgical specimens (FFPE). RNA was analyzed using NanoString PanCancer Immunoncology 360 (IO360) panel with PAM50 spike-in. Raw gene counts were log2-transformed and normalized (using housekeeping genes). The analysis assessed 47 gene signatures including immune related and PAM50 signatures. Signatures were computed after removing samples with low expression of the housekeeping genes and normalization. Signature scores range from ~0 to 10 and have an average value of 5 in tumor samples from The Cancer Genome Atlas. Results: Overall, 46% of the pts achieved pCR; of 13 pts who were IHC 2+ and FISH positive, one achieved pCR. Significant associations were found between response to NAC+T (pCR, no response) and molecular signatures/ISP from the initial biopsy (Table). For pts who did not experience pCR and who underwent surgery, paired sample analysis was performed assessing molecular signatures/ISP in the initial biopsy sample vs the surgical sample. This analysis demonstrated a significant increase post-treatment (compared to the initial biopsy sample) in Risk of Recurrence (ROR) score (p=.036), interferon (IFN) downstream signature (p=.038), and antigen‐processing machinery (APM) loss (p=.002). Conclusions: Combining molecular BC signatures and ISP on biopsy samples may have a predictive value in HER2+BC pts for whom NAC+T is considered. Luminal A pts and IHC 2+ (FISH positive) are unlikely to achieve pCR with NAC+T. [Table: see text]