tbuckley/cabot-search huggingface dataset:
DPX-Survivac and intermittent low-dose cyclophosphamide (CPA) with or without epacadostat (E) in the treatment of subjects with advanced recurrent epithelial ovarian cancer (DeCidE<sup>1</sup> trial): T cell responses and tumor infiltration correlate with tumor regression.
Authors: Janos Laszlo Tanyi, Oliver Dorigo, Amit M. Oza, James Fredric Strauss, Tanja Pejovic, Sharad A. Ghamande, Prafull Ghatage, Jeannine A. Villella, Stephan Fiset, Lisa Diana MacDonald, Olga Hrytsenko, Marianne Stanford, Robert C Newton, Lance Leopold, Gabriela Nicola Rosu
Journal: Journal of Clinical Oncology (2019)

5576 Background: DPX-Survivac is a novel T cell activating therapy designed to elicit an effective immune response against recurrent ovarian cancers that express the survivin protein. The survivin specific T cells induced by DPX-Survivac can infiltrate the tumors and are associated with clinical responses. It is likely that achieving an anti-tumor effect requires a favorable ratio of T cells to tumor cells. Epacadostat (E) is an IDO1 enzyme inhibitor that may enhance effector T cell proliferation, shifting the tumor microenvironment (TME) away from an immunosuppressive state toward one supporting productive immune response. Methods: Recurrent ovarian cancer patients with advanced and metastatic progressive disease were treated with DPX-Survivac, intermittent low dose CPA with or without E. In the Phase 1b, 53 subjects were enrolled to receive DPX-Survivac, low dose CPA and E BID. In the Phase 2, 12 subjects were randomized to receive DPX-Survivac and low dose CPA with or without E. The data on immunological responses, biomarkers, and clinical responses were analyzed in relation to the baseline sum of target lesions per RECIST 1.1. Results: The study showed that DPX-Survivac and intermittent low dose CPA with or without E can generate strong T cell responses. The infiltration of tumors with survivin-specific T cells correlates with the observed tumor regression. The sum of target tumor measurements at baseline by RECIST 1.1 correlated with observed clinical benefits. In the group of 15 patients with the baseline sum of target lesions less than 5 cm, all subjects have shown clinical benefits. Four of these subjects reached partial response and remained without progression over a prolonged period. Conclusions: The treatment studied leads to strong survivin-specific T cell responses. Infiltration of tumors by survivin-specific T cells correlated with clinical benefit in treated subjects. A predictive model based on tumor size to improve response to DPX-Survivac in recurrent ovarian cancer is being prospectively explored. Clinical trial information: NCT02785250.
Impact of bilateral oophorectomy on contralateral breast cancer risk in <i>BRCA </i>negative women from site-specific hereditary breast cancer kindreds.
Authors: Kara C Long, Malcolm C Pike, Ebunoluwa Otegbeye, Angela G. Arnold, Zsofia Kinga Stadler, Mark E. Robson, Richard R. Barakat, Kenneth Offit, Dennis Chi, Noah D. Kauff
Journal: Journal of Clinical Oncology (2013)

1511 Background: BRCA negative (BRCAneg) women from site-specific hereditary breast cancer (SSB) kindreds have been shown to have an increased risk of breast cancer (BC), but not ovarian cancer (OC). It is hypothesized that, as in women with BRCA mutations, bilateral salpingo-oophorectomy (BSO) will decrease the risk of developing future BCs in women from these BRCAneg SSB kindreds. Methods: Since 5/1995, all women undergoing genetic counseling and testing for BRCA mutations at our institution were offered participation in an IRB-approved prospective cohort study. This sub-study examines the impact of BSO on contralateral BC risk in BRCAneg SSB kindreds. Inclusion criteria were: a personal history of unilateral invasive BC ≤ age 60, at least one 1 st or 2 nd degree female relative with BC ≤ age 60, testing BRCAneg between 1/1/2002 and 2/28/2011. Exclusion criteria were: bilateral mastectomy (BM) or BSO prior to genetic testing, family history of OC, &lt;6 months of followup (F/U). Demographic data and pedigrees were collected at the start of F/U, which was defined as the date of genetic testing. F/U data was obtained via mailed questionnaire and medical record review. Participants were censored at the time of BM, OC, or last F/U. Data were analyzed using a Cox proportional-hazards model with time from genetic testing as the time variable and BSO as the time dependent covariate. Results: 328 living participants met the inclusion criteria and F/U was obtained on 301 (208 via questionnaire, 93 via record review). Median age at genetic testing was 49.0 years (27.4-73.2 years). Median F/U time was 5.1 years (0.5-10.5 years). During the course of F/U, 43 women underwent BSO and 21 women underwent BM. There were 12 contralateral BCs (8 invasive, 4 DCIS) identified: 3 in the BSO group and 9 in the no-BSO group. After controlling for age, parity, prior hormone use, and estrogen receptor status of the original BC, the risk of contralateral BCs was not decreased in women who underwent BSO vs those who did not (HR 2.07, 95% CI 0.51 – 8.35, P=0.31). Conclusions: In BRCAneg women from SSB kindreds with a personal history of early onset BC, BSO does not decrease the risk of developing contralateral BC.
Ofranergene obadenovec (VB-111) in platinum resistant ovarian cancer: with an immunotherapeutic effect.
Authors: Yael Chava Cohen, Suzanne T. Berlin, Michael J. Birrer, Susana M. Campos, Tamar Rachmilewitz Minei, Dror Harats, Richard T. Penson
Journal: Journal of Clinical Oncology (2019)

5542 Background: VB-111 is a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response. We report final results of a phase I/II study of VB-111 in combination with paclitaxel in patients with platinum-resistant ovarian cancer. Methods: Study NCT01711970 was a prospective, open label, dose escalating study assessing combination treatment of VB-111 Q8W and weekly Paclitaxel. In the phase I part of the study patients were treated with escalating doses of intravenous VB-111 and Paclitaxel. In phase 2 patients were treated with therapeutic doses of VB-111 1x10 13 Viral Particles and paclitaxel 80mg/m 2 . Assessments included safety, overall survival (OS), PFS, tumor response (CA-125 and RECIST) and histopathology. Results: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled and treated in 2 US sites. Patients received a mean of 2.3 ±1.8 repeat doses of VB-111. 17/21 received the therapeutic dose. Median age was 65 (41-79) with a median of 3 (1-4) prior lines of therapy. Half of the subjects were Platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and was associated with generally mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients including durable responses, and responses in patients with platinum refractory disease and post anti-angiogenic failure . The median OS was 498 days in patients treated with Therapeutic Dose compared to 173 days in Sub-therapueutic dose (p = 0.028). Tumor Specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells and regions of apoptotic cancer cells. Conclusions: Treatment with VB-111 in combination with weekly Paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect manifested as tumor infiltration with CD-8 T cells. Encouraging results are the basis for further exploration in the ongoing, placebo controlled, pivotal OVAL study. Clinical trial information: NCT01711970.
Immunohistochemical expression of GRP78 in relation to angiogenesis markers VEGF-a and CD31 and other histopathological parameters in NSCLC.
Authors: Maha S. Al-Keilani, Basima A. Almomani, Mohammad A. Alqudah, Moath M. Alrjoub, Hiba W. Alzoubi, Batool A. Shhabat
Journal: Journal of Clinical Oncology (2019)

e20500 Background: Neovascularization is essential for the growth and progression of tumor tissues. GRP78 is frequently overexpressed in various types of cancers and has been suggested as a proangiogenic factor. Methods: In order to evaluate GRP78 expression and its role in angiogenesis of non-small cell lung cancer (NSCLC), paraffin-embedded NSCLC tissue samples (66 adenocarcinoma and 24 squamous cell carcinoma) were retrospectively collected from 90 patients who underwent surgical resection between 2008 and 2015; and did not receive chemotherapy or radiotherapy prior to surgery. Then we performed immunohistochemistry to examine GRP78 expression and we analyzed the relationships between GRP78 and the angiogenesis marker VEGF-A and the microvessel density marker (MVD) CD31. Additionally, we analyzed the association of GRP78 with clinicopathological characteristics of the patients. Results: Strong GRP78 expression was evident in about 86% of the tumor tissues (77/90). There was significant difference in GRP78 expression between poorly-differentiated and well-differentiated tumors (OR = 0.023, 95% CI = 0.001-0.419, p = 0.011). Moreover, there was a statistically significant association between VEGF-A and CD31 (χ² = 12.00, p = 0.001). Indeed, CD31 and VEGF-A expression significantly associated with histological type. Among the tissues expressing high CD31, approximately 86% of them were adenocarcinoma (χ² = 5.009, p = 0.025); and among the tissues expressing positive VEGF-A, about 79% were adenocarcinoma tissues (χ² = 6.545, p = 0.021). Conclusions: Strong GRP78 may be related to good prognosis of NSCLC. Nevertheless, further studies investigating large number of samples of all histological subtypes are required.
Comprehensive genomic analysis of mucinous ovarian cancer reveals unique therapeutic vulnerabilities.
Authors: Dane Anthony Cheasley
Journal: Journal of Clinical Oncology (2019)

5571 Background: Mucinous ovarian carcinoma (MOC) is a rare subtype of epithelial ovarian cancer that responds poorly to ovarian chemotherapies and has an unknown etiology. It is diagnostically challenging and can be confused with metastases from gastro-intestinal tract primaries. The GAMuT study is a multi-national effort to understand molecular drivers and cell of origin of this rare tumour, including identification of a genetic progression model and novel therapeutic options. Methods: We performed RNAseq (n = 67), exome sequencing (n = 61), SNP arrays (n = 67) and whole genome sequencing (n = 5) on MOC and precursor lesions. A subset of ~500 genes was further evaluated by targeted sequencing, including 129 MOC, 23 borderline mucinous tumours (non-invasive) and 23 extra-ovarian mucinous metastases. Immunohistochemistry data was collected for CK7, CK20, ER, PAX8, p53 and HER2 (n = 162-256). Extensive pathology review was performed and associated clinical data obtained. Results: Comparison with TCGA and other data sets showed that MOC are distinct from mucinous tumours from other organs, including colorectal, appendiceal and gastric cancers. Our data supports a clear genetic progression model from benign and borderline precursors to both low- and high-grade MOC. TP53 mutation, ERBB2 amplification and increasing copy number changes were key events associated with progression to invasive disease, including a novel amplicon on 9p13. Copy number aberration burden was significantly associated with poor survival. We identified several recurrent mutational events suggesting utility of an existing targeted therapy, including ERBB2 amplification (26%), ERBB3 mutation (4%) and BRAF mutation (9%). MOC could be included in clinical trials for novel agents targeting TP53 missense mutation (46%), RNF43 mutation (12%), PIK3CA mutation (8%) and KRAS/ NRAS mutations (66%). Other frequent events included CDKN2A inactivation (57%), ARID1A mutation (9%) and TP53 inactivating mutations (15%). Conclusions: MOC of any grade can derive from a primary ovarian tumour precursor, and is distinct from extra-ovarian metastases. MOC is genetically diverse and advanced disease should be assessed for targetable mutations which may provide novel therapeutic options.
CTLA-4–mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells
Authors: Vitalijs Ovcinnikovs, Ellen M. Ross, Lina Petersone, Natalie M. Edner, Frank Heuts, Elisavet Ntavli, Alexandros Kogimtzis, Alan Kennedy, Chun Jing Wang, Clare L. Bennett, David M. Sansom, Lucy S. K. Walker
Journal: Science Immunology (2019)

CTLA-4 transendocytosis is elicited by self-antigens and down-regulates costimulatory ligands on migratory dendritic cells.
Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.
Authors: Susana Cedres, Santiago Ponce Aix, Ana Callejo, Nuria Pardo, Alejandro Navarro, Alex Martinez Marti, Irene Sansano, Ana Belen Enguita, Gisela Rodriguez, Victor Monton, Josep M Miquel, Cristina Viaplana, Rodrigo Dienstmann, Enriqueta Felip
Journal: Journal of Clinical Oncology (2019)

e20062 Background: The increasing incidence and poor outcome associated with MPM demand identification of effective treatment options. Promising results have been reported with immunotherapy (IO) in a small proportion of MPM patients (p). MMR deficiency (dMMR) has been well described in several malignancies and was recently approved as a tumor biomarker for IO with anti-PD-1 checkpoint inhibitor. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM p. Methods: Tumors of 159 MPM p from Vall d´Hebron University Hospital and October 12 th University Hospital diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR when any MMR protein expression was negative and MMR intact when all MMR proteins were positively expressed. Associations between clinical variables and outcome were assessed with Cox regression models and survival data were calculated by the Kaplan-Meier method. Results: P characteristics: median age: 69 years (29-88 years), males: 71%, performance status (PS) 1:69%, asbestos exposure: 52%, stage III at diagnosis: 42%, epithelial subtype: 65%, systemic treatment 81% (57% chemotherapy with cisplatin plus pemetrexed in first line), 50% received second line and 28% third line. MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8m). In a multivariate model factors associated to improved mOS were PS 0 vs PS2 (13 v 2 m, HR 12.8, p &lt; 0.01), neutrophil-lymphocyte ratio (NLR) &lt; 5 (18 v 9 m in NLR ≥5,HR 1.5, p &lt; 0.05) and epitheliod vs sarcomatoid histology (18 vs 4 m HR 4.7, p &lt; 0.01). Thirteen p received IO with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1m). Conclusions: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate novel predictive biomarkers benefit from IO in MPM.
Efficacy and safety of CAR19/22 T-cell “cocktail” therapy in patients with refractory/relapsed B-cell non-Hodgkin lymphoma.
Authors: Liang Huang, Na Wang, Chunrui Li, Yi Xiao, Yang Cao, Min Xiao, Yicheng Zhang, Tongcun Zhang, Jianfeng Zhou
Journal: Journal of Clinical Oncology (2019)

2534 Background: Antigen escape relapse has emerged as a major challenge for long-term disease control post CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. Methods: Between Mar 2016 and Jan 2018, we conducted a pilot study (ChiCTR-OPN-16008526) in 38 patients (pts), who had refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, two single-specific, third-generation CAR19/22 T-cell “cocktail”. The cutoff date for data collection was Apr 30, 2018. Results: At a minimum follow-up of 3 months (mos), 26 of the 36 evaluable pts achieved an overall response (ORR), including 18 with a complete response (CR) and 8 with a partial response (PR). The ORR at mo 3 was consistent in different subgroups, irrespective of pathologic subtypes, cell of origin, cytogenetic or genomic aberrations. At the data cutoff, 15 of the 18 pts who had a CR at mo 3 maintained their responses, 2 of 8 pts who had a PR within 3 mos continued to have a CR without additional therapies. Collectively, the best ORR was 83.3%, with a best CR rate of 55.5% and a best PR rate of 27.8%. With a median follow-up of 5.3 mos (range, 0.4 to 16.2), the median PFS was 5.8 mos, and the median OS was not reached (NR). Pts received therapy at first relapse had better PFS than those who received therapy at the time with primary refractory diseases or at multiple relapses. Notably, pts who achieved an overall response at mo 3 (R3m) had significantly extended PFS and OS when compared with pts who did not. Repeated biopsy and IHC was conducted in 3 of the 13 pts. However, loss of CD19 or CD22 was not detected. Of the 9 pts with IgH/MYC translocation, with a median follow-up of 10.1 mos, the median PFS and median OS were NR. At data cutoff, 7 pts who had achieved R3m maintained their responses, including all the 4 pts with double-hit lymphoma. However, of the 10 pts with del(17p) or TP53 mutation, with a median follow-up of 5.3 mos (range, 2.7 to 14.5), the median PFS was 3.6 mos and the median OS was 9.9 mos. All pts experienced reversible CRS, with 21.1% were of high-grade. Neurotoxicity developed in 13.2% pts and were all low-grade. Conclusions: Our results indicated that sequential infusion of CAR19/22 T-cell is efficient and safe for pts with B-NHL. Dual antigen targeting is a promising approach to circumvent antigen loss relapse after CAR T-cell therapy. The impact of genetic subtypes and clinical parameters further underscores the critical importance of personalized immunotherapies. Clinical trial information: ChiCTR-OPN-16008526.
Efficacy of a stepped collaborative care intervention for comorbid cancer and depression: Health care utilization and costs.
Authors: Geena Richards, Jennifer Lynne Steel, David A. Geller, Timothy Billiar, Judith Procopio, Barbara Kucinski, Emily Murphy, Allan Tsung, Wallis Marsh, Michael Antoni, Yoram Vodovotz, Michael Spring, Ritambhara Pathak, Hannah Cheng, Blake Sidleck
Journal: Journal of Clinical Oncology (2019)

e18348 Background: The aims of this study were to test the efficacy of a stepped collaborative care intervention for comorbid cancer and depression on outcomes including complication rates, health care utilization and costs. Methods: Patients diagnosed with cancer were enrolled in a randomized controlled trial testing the efficacy of a stepped collaborative care intervention. Patients were administered a battery of questionnaires prior to randomization. Rates and severity of surgical complications, health care utilization and costs were collected for a one-year period after randomization. Descriptive statistics, Chi-square analyses, and Ordered Restricted Inference analyses were performed. Results: Of the 100 patients, the mean age was 64.0 (SD = 10.3), the majority of the patients were male (51%), Caucasian (89%), diagnosed with hepatocellular or cholangiocarcinoma (47%) and stage III and IV (60%). For patients less than 75 years, patients randomized to the collaborative care intervention had lower rates of complications after surgery [Χ 2 = 5.45, P = 0.02]. We observed that 16% of patients randomized to the collaborative care intervention had complications versus 66.7% of the patients in the screening and referral arm. For patients who survived 6 months or less, those who were randomized to the collaborative care intervention had lower rates of 90-day readmissions than patients randomized to the screening and referral arm [Χ 2 = 4.0, P = 0.046]. The patients randomized to the collaborative care intervention did not have any readmissions while 2 patients in the screening and referral arm were readmitted. Patients randomized to the collaborative care intervention arm had lower median costs associated with the loss of workforce productivity ($2340 versus $3001; P = 0.07), hospital costs ($13,008 versus $21,109, P = 0.09), and cost per hospital registration ($1158 versus $2219, P = 0.07) when compared to the screening and referral arm. Conclusions: The stepped collaborative care intervention not only reduced depressive symptoms, but patients randomized to this intervention had lower complication rates, health care utilization, loss of work productivity, and hospital related costs. Clinical trial information: NCT02939755.
Prognostic stratification of locoregional esophageal cancer (EC) patients (pts) treated with definitive chemoradiotherapy (dCRT).
Authors: Hyehyun Jeong, Yeonghak Bang, Hyeon-Su Im, Jihoon Kang, Dok Hyun Yoon, Jong Hoon Kim, Yong-hee Kim, Hyeong Ryul Kim, Hyun Joo Lee, Hwoon-Yong JUNG, Gin-Hyug Lee, Ho June Song, Do Hoon Kim, Kee Don Choi, Jeong Hoon Lee, Ji Yong Ahn, Jin-Sook Ryu, Kyung-Ja Cho, Sung-Bae Kim, Sook Ryun Park
Journal: Journal of Clinical Oncology (2019)

e15578 Background: Although dCRT is the standard treatment for pts who have locally advanced unresectable EC or refuse surgery, the prognosis of these pts remains dismal. There are urgent needs to develop the novel treatment strategy based on prognostic stratification after dCRT. Methods: A total of 382 pts with locoregional EC without distant metastasis except for supraclavicular lymph node who received dCRT at Asan Medical Center in South Korea from 2006 to 2015 were included. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Risk factors were analyzed using Cox regression. Risk scores were calculated by multiplying coefficients in Cox proportional hazard model. Results: Baseline characteristics were as follows: median age = 66 yrs (range: 40-85); male = 359 pts (94.0%); squamous cell carcinoma = 375 (98.2%); cTNM stage (AJCC 8th) I = 40 (10.5%), II = 122 (31.9%), III = 128 (33.5%), IV = 92 (24.1%). During median follow-up of 52.9 mo, median PFS was 13.5 mo (95% CI, 10.9-16.1), and median OS was 26.7 mo (95% CI, 19.8-33.7). In the univariate analyses, sex (only for PFS), weight loss (≥ 5 kg) during dCRT, cT stage, cN stage, cTNM stage, clinical response after dCRT, reason for dCRT were significant prognostic factors for PFS and OS. In the multivariate analyses, clinical response after dCRT, cTNM stage, and weight loss were independent prognostic factors for PFS and OS (Table). Risk-scoring model using these factors stratified pts into four groups: for median PFS (p &lt; 0.0001), group 1 = 58.2 mo (95% CI, 43.5-73.0), group 2 = 17.0 mo (95% CI, 11.9-22.1), group 3 = 9.0 mo (95% CI, 7.0-11.1), and group 4 = 3.9 mo (95% CI, 3.7-4.2); for median OS (p &lt; 0.0001), group 1 = 106.2 mo (95% CI, 44.9-167.6), group 2 = 38.0 mo (95% CI, 24.4-51.5), group 3 = 13.0 mo (95% CI, 8.5-17.6), and group 4 = 8.0 mo (95% CI, 7.4-8.6). Conclusions: In dCRT-treated locoregional EC pts, survival outcome significantly varied according to baseline clinical stage, treatment response, and dynamic change in body weight. Different treatment and surveillance strategies based on the risk score might be needed in these pts.[Table: see text]