tbuckley/cabot-search huggingface dataset:
Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies
Authors: Victoria M. Kim, Alex B. Blair, Peter Lauer, Kelly Foley, Xu Che, Kevin Soares, Tao Xia, Stephen T. Muth, Jennifer Kleponis, Todd D. Armstrong, Christopher L. Wolfgang, Elizabeth M. Jaffee, Dirk Brockstedt, Lei Zheng
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitors are not effective for pancreatic ductal adenocarcinoma (PDAC) as single agents. Vaccine therapy may sensitize PDACs to checkpoint inhibitor treatments. Annexin A2 (ANXA2) is a pro-metastasis protein, previously identified as a relevant PDAC antigen that is expressed by a GM-CSF-secreting allogenic whole pancreatic tumor cell vaccine (GVAX) to induce an anti-ANXA2 antibody response in patients with PDAC. We hypothesized that an ANXA2-targeting vaccine approach not only provokes an immune response but also mounts anti-tumor effects. <h3>Methods</h3> We developed a Listeria-based, ANXA2-targeting cancer immunotherapy (Lm-ANXA2) and investigated its effectiveness within two murine models of PDAC. <h3>Results</h3> We show that Lm-ANXA2 prolonged the survival in a transplant model of mouse PDACs. More importantly, priming with the Lm-ANXA2 treatment prior to administration of anti-PD-1 antibodies increased cure rates in the implanted PDAC model and resulted in objective tumor responses and prolonged survival in the genetically engineered spontaneous PDAC model. In tumors treated with Lm-ANXA2 followed by anti-PD-1 antibody, the T cells specific to ANXA2 had significantly increased INF<b>γ</b> expression. <h3>Conclusions</h3> For the first time, a listeria vaccine-based immunotherapy was shown to be able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a "cold" tumor such as PDAC and sensitize the tumor to checkpoint inhibitor therapy. Moreover, this combination immunotherapy led to objective tumor responses and survival benefit in the mice with spontaneously developed PDAC tumors. Therefore, our study supports developing Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.
Comparative efficacy of neoadjuvant to adjuvant chemotherapy for the treatment of early-stage HER2 negative breast cancer: A population-based analysis.
Authors: Nathalie LeVasseur, Christine E. Simmons, Lovedeep Gondara, Caroline Speers, Rekha M. Diocee, Julia Sun, Alan Nichol, Caroline A. Lohrisch, Stephen K. L. Chia
Journal: Journal of Clinical Oncology (2019)

e12100 Background: The use of neoadjuvant treatment has increased over the past decade due to its ability to assess tumour sensitivity to systemic treatment in vivo, and to downstage women for increased breast conserving surgery. Recent studies have stratified patients with residual disease to receive additional treatment, which has resulted in meaningful improvements in survival. However, meta-analysis data suggest similar long-term outcomes for patients treated with neoadjuvant chemotherapy (NACT) compared to adjuvant chemotherapy (ACT) in historical randomized trials. The comparative efficacy in a real-world setting utilizing modern chemotherapy regimens is unknown. Methods: A retrospective review of the BC Cancer Breast Cancer Outcomes Unit (BCOU) was performed to identify patients with stage I-III HER-2 negative breast cancer treated with chemotherapy at the BC Cancer Agency from 2005-2010. Patients were then divided into 2 groups: those who received neoadjuvant chemotherapy (NACT) and those who received adjuvant chemotherapy (ACT). A matched analysis (age, stage, subtype) for patients treated with NACT vs ACT (matched 1:3) was then performed using a propensity scoring method to compare distant disease-free survival (DDFS), breast cancer specific survival (BCSS) and overall survival (OS). No patients received adjuvant chemotherapy for residual disease after NACT. Results: A total of 656 patients met the inclusion criteria, consisting of 164 NACT and 492 ACT cases. Median age was 49 years (37-68) in the NACT group vs 49 (37-65) in the ACT group (p = 0.71). The majority had stage 3 disease, 64% in both groups (p = 1.0). Most were hormone receptor positive (HR+), 67.1% vs 70.7% in the NACT vs ACT groups, respectively (p = 0.41). 5-year DDFS was 75% with NACT (95%CI 67, 82) and 77% with ACT (95%CI 72, 81), p = 0.87. 5-year OS for patients treated with NACT was 77% (95%CI 71, 84) and 80% (95%CI 75, 85) for patients treated with ACT, p = 0.33. 5-year BCSS was 80% with NACT (95% CI 70, 86) and 82% (95%CI 77, 86) with ACT, p = 0.75. Multivariate analysis for tumour size, nodal involvement and subtype are ongoing. Conclusions: The use of NACT compared to ACT in a population-based setting did not result in significant differences in DDFS, OS or BCSS. Acknowledging the comparative efficacy of these approaches will be informative to determine if the addition of subsequent adjuvant treatment for patients with residual disease after NACT will lead to differential benefits in a population-based setting.
Analysis of IL-6 measurement in patients with GCA treated with tocilizumab should consider concomitant treatment with prednisone
Authors: Maxime Samson, Bernard Bonnotte
Journal: Annals of the Rheumatic Diseases (2019)

We read with great interest the letter published by Berger et al in which the authors showed that relapse-free survival for giant cell arteritis (GCA) treated with tocilizumab (TCZ) was longer in patients with an interleukin (IL) 6 decline (slope ≤0.1).1

In contrast with Berger et al ,1 IL-6 levels at the last TCZ infusion were not found to predict the risk of relapse in our phase 2 prospective open-label clinical trial that included 20 patients with GCA (19/20 patients with new-onset GCA) treated with prednisone and TCZ (8 mg/kg/4 weeks from inclusion to week 12 (W12)). These patients were followed for 52 weeks, and IL-6 levels were monitored by luminex (eBioscience) at inclusion (W0), W12 and W26.2 As a consequence of the blockade of the IL-6 pathway, acute-phase reaction proteins (erythrocyte sedimentation rate, C-reactive protein …
Intraoperative radiotherapy in early-stage breast cancer: Multidiciplinary management and analysis of outcome.
Authors: Elizabeth Min Hui Kim, Hani AL-Halabi, Lily Shakibnia, Sean Cavanaugh
Journal: Journal of Clinical Oncology (2019)

e12036 Background: The TARGIT-A trial investigated the efficacy of using single-dose targeted intraoperative radiotherapy (IORT) in place of whole-breast external beam radiotherapy (EBRT) for treating breast cancer. IORT is an effective alternative to EBRT for adjuvant treatment of select patients with estimated conversion rate of 15%, who required additional EBRT following complete pathologic staging. An institutional study was performed to evaluate the rate of patients who received IORT but still required EBRT, in-breast-tumor recurrence rate (IBTR) and overall survival (OS). Methods: Institutional retrospective review of patients treated with IORT was performed, including age at the time of IORT, histology, AJCC stage, margin, and clinical features as outlined in ASTRO and ABS guideline. Conversion rate, IBTR and OS was calculated. Reason for conversion to EBRT assessed. Results: From 1/1/2016 to 1/1/2019, 35 patients underwent IORT concurrent with lumpectomy and sentinel node biopsy within the ASTRO and ABS guideline. Patients median age 60 (51-79 yo) and all had ER+, clinical T(0.5 -2.5cm)N0 with intraoperative sentinel node frozen section evaluation. Zeiss IORT consisted 50 KV x-rays with spherical applicators, and a dose of 20Gy was prescribed at the surface of the applicator. 14.2% (5/35) were recommended EBRT. Conversion was due to microscopic disease found on final surgical pathology (3 node positive and 2 positive surgical margin). 4 patients successfully completed EBRT and 1 patient declined EBRT. 100% underwent adjuvant endocrine treatment. IBTR was 0% and OS was 100% with a median follow-up of 18.6 months (range of 2 – 35 months). Conclusions: Pathologic false negative rate contributed to EBRT conversion rate but remained below 15% TARGIT-A threshold. IORT concurrent with lumpectomy within a risk adapted approach is a good option for eligible patients using evidence-based guideline and multidisciplinary team model. Continued cohort assessment for IBTR, OS and toxicity outcome will be prospectively assessed.
Overall survival (OS) of African-American (AA) and Caucasian (CAU) men who received sipuleucel-T for metastatic castration-resistant prostate cancer (mCRPC): Final PROCEED analysis.
Authors: A. Oliver Sartor, Andrew J. Armstrong, Chiledum Ahaghotu, David G. McLeod, Matthew R. Cooperberg, David F. Penson, Philip W. Kantoff, Nicholas J. Vogelzang, Arif Hussain, Christopher Michael Pieczonka, Neal D. Shore, David I. Quinn, Eric Jay Small, Elisabeth I. Heath, Ronald F Tutrone, Paul F. Schellhammer, Matthew Harmon, Nancy N. Chang, Stephen J. Freedland, Celestia S. Higano
Journal: Journal of Clinical Oncology (2019)

5035 Background: Prostate cancer risk and mortality are higher in AAs versus CAUs. Post-hoc analyses of pooled Phase 3 data (n = 737) suggested substantial OS benefit for AA men receiving sipuleucel-T (n = 33) vs placebo (n = 10) (McLeod 2012). Compared with pooled placebo patients (n = 249), number needed to treat for OS benefit at 3 years was 3 for AAs and 8 for all sipuleucel-T-treated patients (n = 488) (Moses 2019). Herein we analyzed PROCEED (NCT01306890), a large real-world registry, in which all patients received sipuleucel-T. Methods: In PROCEED, 1902 mCRPC patients received ≥1 sipuleucel-T infusion. OS of all AA (n = 221) and CAU (n = 1649) men were compared. Baseline prostate-specific antigen (PSA), the most important prognostic variable for OS after sipuleucel-T (Schellhammer 2013), substantially differed by race. Thus, OS for a PSA-matched cohort (n = 219 AA; n = 438 CAU) was compared and univariable/multivariable analyses were performed. Post-sipuleucel-T use of OS-prolonging anticancer interventions was also assessed. Results: After a median follow-up of 46.6 mo, median OS was 35.2 (all sipuleucel-T-treated AAs) and 29.9 mo (all sipuleucel-T-treated CAUs): HR 0.81, 95% CI 0.68–0.97; P = 0.03. In the PSA-matched cohort, median OS was 35.3 and 25.8 mo, respectively (HR 0.70, 95% CI 0.57–0.86; P &lt; 0.001). Sipuleucel-T-treated AAs with lower baseline PSA had markedly longer median OS vs sipuleucel-T-treated CAUs. Among those with ≤ median baseline PSA (29.48 ng/ml), median OS was 54.3 mo (AA) vs. 33.4 (CAUs); HR 0.52, 95% CI 0.37–0.72; p &lt; 0.001. Along with other known prognostic factors, AA race was independently associated with prolonged OS on detailed multivariable analyses (HR 0.60, 95% CI 0.48–0.74; p &lt; 0.001) and confirmed on sensitivity analyses. Post-sipuleucel-T life-prolonging anti-cancer therapies were balanced between groups. Conclusions: Sipuleucel-T-treated AAs had significantly improved OS vs sipuleucel-T-treated CAUs. This analysis marks the largest known racial difference in OS in response to any therapy for mCRPC, a finding with implications for both prostate cancer pathophysiology and cancer immunotherapy. Clinical trial information: NCT01306890.
A prospective study of the impact of chemotherapy-related toxicities on the quality of life in elderly patients with cancer.
Authors: Sanketh Kotne, Bharadwaj Ponnada, Arun Philip, Pavithran Keechilat
Journal: Journal of Clinical Oncology (2019)

e23013 Background: Treatment of cancer in elderly is challenging. Majority of the elderly cancer patients are offered chemotherapy based on their performance scale and geriatric assessment tools are not routinely employed in clinical practice as they are time consuming and cumbersome. Aim: The primary objective was to estimate the incidence of chemotherapy related adverse events in newly diagnosed elderly cancer patients above 65 years of age treated at a tertiary cancer institute in southern India. The secondary objective was to predict and assess the factors associated with chemotherapy related toxicities in the elderly patients using the Cancer and Aging Research Group's (CARG) scoring tool and to study the quality of life and to assess the nutritional status and the mental status in elderly cancer patients above 65 years of age. Methods: A prospective cross-sectional study was done among 179 patients with age ≥ 65 years, a solid organ cancer (any type or stage) from February 2017 to August 2018. Prechemotherapy comprehensive geriatric assessment (CGA) with Older People’s Quality of Life Questionnaire (OPQOL-35), Mini Nutritional assessment (MNA) and Folstein’s Mini Mental status examination (MMSE) was done at baseline, 2 months and 6 months. CARG tool was used to predict the risk of chemotherapy toxicity with the standard and modified dose. Results: The mean age was 68.53 years. Majority of the patients had breast cancer 29.60%. The proportion of lung cancer, prostate cancer, stomach cancer, colorectal and ovarian cancers were 21.80%,10.60%, 9.50%, 14.5% and 7.30% respectively. Other cancers were seen in 5 patients (2.79%). 40 (22.30%) patients had received anthracycline based chemotherapy. 143 (79.90%) had received standard dosing chemotherapy.118 (65.90%) &amp; 125 (69.80%) out of 179 patients had developed hematological toxicities and non- hematological toxicities respectively. According to the ROC curve for the CARG tool risk of toxicity with standard &amp; modified dosing and hematological &amp; non- hematological toxicities, the accuracy of the test is 60.89% indicating its poor predictive validity. There is a decline in the CGA at 2 months follow-up, but there was an improvement after assessment at 6 months. Conclusions: Comprehensive geriatric assessment at base line is required to adequately analyse patient’s risk of chemotherapy related toxicities. In our study, the patients have tolerated the chemotherapy well in spite of receiving standard dosing.
RAS analysis of circulating tumor cells from advanced colorectal cancer using BEAMing technology.
Authors: Santiago Cabezas-Camarero, Vanesa García-Barberán, Virginia De la Orden-García, Beatriz Mediero-Valeros, Mateo Paz Cabezas, Ana López-Alfonso, Antonio Carlos Sánchez Ruiz, Ana Ruiz-Casado, Isabel Díaz-Millán, Javier Sastre, Miguel Sotelo Lezama, Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2019)

e15151 Background: RAS mutations predict a lack of response to anti-EGFR therapies in metastatic colorectal cancer (mCRC). BEAMing technology is useful for detecting hot-spot mutations in ctDNA in mCRC. Analysis of these mutations in DNA from Circulating Tumor Cells (CTC) may increase the predictive value in mCRC patients (pts). Our aim was to explore the feasibility of studying RAS status using BEAMing in DNA from CTC. Methods: First, spiking experiments (SE) using wild-type (WT) and KRAS-mutated (MUT) cell lines were performed to establish the limit of detection (LOD) for RAS analysis with BEAMing. Second, SE were performed with CTC collected by CellCelector (removes non-CTC background achieving 100% purity of CTC). Finally, BEAMing was used for RAS analysis in ctDNA and in DNA from CTC isolated either with IsoFlux or with CellCelector in 9 mCRC pts with confirmed RAS mutation in primary tumor. Total DNA from CTC was preamplified using RepliG. Results: In SE, 10 and 5 KRAS MUT-cells using different backgrounds of WT-cells (10-0.2% MUT-cells) were detected using BEAMing. However, 3 and 1 MUT-cells (0.009-0%) were not detected. In SE of CTCs collected with CellCelector, BEAMing detected KRAS mutations with 50, 20, 10, 6, 4, 2 and 1 cell (MAF: 23.8%±3.8). A mutation (codon 13) was detected in CTC from one patient positive in tissue and ctDNA (CellCelector; 15 CTCs; MAF: 11.4%). Discordant results were found in 8 patients when CTCs were isolated using Isoflux (min: 0, max: 9 CTCs). CTC from another patient were possibly mutated but WT in ctDNA. Conclusions: This pilot study indicates that RAS mutations can be detected in CTCs using BEAMing. Reducing the non-CTC cellular background may be needed in cases with low CTC number. Molecular information provided by CTC and ctDNA may prove complementary and useful for taking therapeutic decisions in mCRC. These results merit confirmation in larger, prospective studies.
Impact of timing of adjuvant chemotherapy following radical cystectomy for bladder cancer on patient survival.
Authors: Camilla Marisa Grunewald, Alina Henn, Matt D. Galsky, Elizabeth R. Plimack, Lauren Christine Harshman, Evan Y. Yu, Simon J. Crabb, Sumanta K. Pal, Ajjai Shivaram Alva, Thomas Powles, Ugo De Giorgi, Neeraj Agarwal, Aristotelis Bamias, Sylvain Ladoire, Andrea Necchi, Ulka N. Vaishampayan, Cora N. Sternberg, Joaquim Bellmunt, Jack Baniel, Guenter Niegisch
Journal: Journal of Clinical Oncology (2019)

e16017 Background: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start approximately 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome. Methods: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Uni- and multi-variate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed. Uni- and multivariate analysis of progression-free and overall survival (starting from day 1 of adjuvant chemotherapy) was analysed in relation to SAC interval (both continuous and dichotomous with a cut-off at 90 days), patient characteristics, surgical factors and tumor characteristics by Kaplan-Meier and COX regression analysis. Results: Two hundred thirty-eight eligible patients were identified (83% male, median age: 64 years, 76% T3/T4, 66% pN+, 15% R+, 75% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). Median S-AC-interval was 57 days (range 10-321 days, ≤ 90 days: 87%, 91-120 days: 6%, &gt; 120 days: 7%). S-AC-interval did not have association with any patient/tumor characteristics or surgery related factors (type of surgery, diversion). S-AC-interval did not impact patients´ outcomes when adjuvant chemotherapy was initiated 90 days after surgery. Median PFS and OS in patients with an S-AC-interval of 90 days was 37 and 73 months, respectively, as compared to 24 and 48 months in patients with an S-AC-interval &gt; 90 days. Only differences in PFS reached statistical significance (37 (95% CI 26-48) months vs. 24 (95% CI 12-36) months p = .042; Log Rank test). When analyzed by different multivariate models, the impact of S-AC-interval on PFS and OS was negated by tumor related factors (pathological T-stage and N-stage). Conclusions: An S-AC-interval of below 90 days is likely to be optimal in bladder cancer patients requiring adjuvant therapy. However, regarding prognosis, tumor related pathological factors seem to be more important than the S-AC-interval.
Receptor-triggered lymphocyte apoptosis PC to replace Cy/Flu PC for CART.
Authors: Theresa Deisher, Arya Ashok, Peter Jarzyna, Yumna Zahid, Kendra Poulin, Stephanie Lee-Diaz, Vaishnavi Parthasarathy, Margaret Taylor
Journal: Journal of Clinical Oncology (2019)

e14011 Background: Chimeric antigen receptor T-cell (CAR-T) therapy is a relatively novel regimen for the treatment of acute lymphoblastic leukemia that has already shown promising results. Two FDA-approved CAR-T therapies, Kymriah and Yescarta have an 80% success rate in sending patients into remission. However, both of these treatments require preconditioning (PC) with chemotherapy to ensure CarT expansion and engraftment. Chemotherapy severely compromises patient’s immune-system, a further economic burden up to $70K per patient due to hospitalization, and fuels side effects of CAR-T therapy such as cytokine release syndrome (CRS) and neuroedema, driven by the release of IL-6 and GM-CSF respectively. Also, up to one third of cancer patients are too frail to tolerate chemotherapy and do not qualify for potentially life-saving therapies. A single acute dose of AVM0703 induces lymphodepletion equivalent to chemotherapy, and transiently eliminates the sites in the spleen where therapeutic cells accumulate without inducing toxicities associated with chemotherapy. Methods: Mice with subcutaneously implanted melanoma were preconditioned with AVM0703 prior to treatment with a mouse Pmel CAR-T therapy. Tumor growth was tracked and spleens were analyzed after dissection for binding of labeled CAR-T cells. In a separate study, four human patients were dosed with low doses of AVM0703 and the levels of released cytokines in the blood were quantified. Results: The mice demonstrated reduced T-cell sequestration in the spleen as noted by a reduction of fluorescently labeled cells. AVM0703 alone significantly delayed tumor growth, and as PC before Pmel T-cells, dramatically improved CAR-T-driven delay of tumor growth. In humans, a significant increase in beneficial IL-2 and IL-15 was observed, as well as a lack of released IL-6. In addition, existing literature demonstrate that AVM0703 reduces the release of GM-CSF. Conclusions: AVM0703 shows efficacy as preconditioning agent in a mouse solid tumor model of melanoma, reduces the binding of CAR-T cells in the spleen, and stimulates the release of beneficial cytokines. AVM0703 could be a non-toxic, effective preconditioning agent for patients receiving CAR-T therapy.
Menopausal symptoms in epithelial ovarian cancer survivors: The GINECO VIVROVAIRE2 study.
Authors: Florence Joly, Patricia Pautier, Elsa Kalbacher, François Gernier, Raffaele Fauvet, Anne Floquet, Dominique Berton-Rigaud, Olivier Tredan, Philippe Follana, Jerome Alexandre, Alain Zannetti, Nadine Dohollou, Stephanie Trager, Idlir Licaj, Jean-Michel Grellard, Bénédicte Clarisse, Djihane Ahmed-Lecheheb, Christine Rousset-Jablonski, Anne Gompel
Journal: Journal of Clinical Oncology (2019)

5555 Background: We have previously shown that Epithelial Ovarian Cancer and its treatments have significant negative effects on Quality of Life (QoL) and long term fatigue. The aim of the present multicentric VIVROVAIRE2 study was to report the main menopausal, VasoMotor Symptoms (VMS) of Epithelial Ovarian Cancer survivors (EOCS). Methods: 166 patients of the 322 EOCS without relapse ≥3 years after first line of treatment accepted to participate to a gynecological consultation carried out by a gynecologist, including a questionnaire related to menopausal symptoms, a clinical examination, and an osteodensitometry. VMS (hot flashes and/or night sweats) were described according to natural menopause (NM) or surgically induced menopause (SIM). QoL and Fatigue were measured with the validated questionnaires FACT-G and FACT Fatigue. Results: Median age was 62 years [20-83], FIGO stage III/IV (48%) and &lt; 10% BRCA1&amp;2 mutated. Histological subtypes were: high grade serous 31%, low grade serous 23%, endometrioid G2-3 (14%) endometriod G1( 4%), clear-cell 21%, mucinous 5%. All EOCS had surgery, 97% of patients received platinum and taxane chemotherapy, median delay from treatment was 5 years [3-24] and 59 (36%) had SIM. 14% of EOCS had osteoporosis; this rate was similar to the general population. 52% of patients (85) reported either hot flashes (47%) or night sweats (32%). 72% with SIM had VMS compared to 41% with NM (p &lt; 0.001). VMS were not associated with poor global QoL or fatigue. At the time of the survey, only 8 (5 SIM &amp; 3 NM) EOCS received hormone replacement therapy (HRT). Among the 85 EOCS with VMS, 80 (94%) (38 SIM (93%) 42 NM (95%)) did not benefit from HRT after cancer treatment. Among 80 EOCS with VMS and no HRT, 25 (66%) with SIM and 34 (81%) of NM had high grade serous, endometriod G2-3, clear cell and mucinous histology. Conclusions: Vasomotor symptoms are frequently reported by EOCS, particularly among surgically induced menopause patients. A majority of EOCS with these symptoms might have beneficiated from hormone replacement therapy.