tbuckley/cabot-search huggingface dataset:
The association of tumor infiltrating CD8+ and Foxp3+ cells with overall response rate (ORR) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose aldesleukin (HD IL-2).
Authors: Jean-Christophe Pignon, Opeyemi Jegede, Jesse Novak, Kathleen Margaret Mahoney, James Walter Mier, Gordon J. Freeman, Michael B. Atkins, Paul J. Catalano, Sabina Signoretti, David F. McDermott
Journal: Journal of Clinical Oncology (2017)

4576 Background: In the prospective, biomarker validation HD IL-2 “Select” study, durable remissions and prolonged survival were seen in both proposed “good” and “poor-risk” patients, based on clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining. Given the toxicity and limited efficacy of HD IL-2, efforts to improve its therapeutic index are warranted. Since the high-affinity receptor of IL2 is expressed on both T regulatory cells and activated effector T lymphocytes, we explored the association between HD IL-2 response and tumor infiltration of CD8 + T and FoxP3 + cells. Methods: Archival tumor tissue was collected for pathologic analysis on 120 mRCC patients enrolled in the HD IL-2 “Select” trial.Density of tumor infiltrating CD8 + T cells and Foxp3 + cells (cell/mm 2 ) were evaluated in the invasive margin (IM) and the tumor center (TC) by IHC and automated image analysis using Aperio algorithms. The association between ORR and immune cell density was assessed using Fisher exact test. Results: Tumor specimens of 89 patients were available for analysis. 24 pts experienced response (R, including 2 CR and 22 PR) and 65 pts did not respond (NR, including 11 SD and 54 PD). Baseline patient characteristics were similar between R and NR groups. A very high density of CD8 + cells in the IM, or a high density of Foxp3 + cells in the TC were significantly associated with ORR. A stronger association with ORR was found for patients having both high density of CD8 + cells in the IM and Foxp3 + cells in the TC. Conclusions: In this prospective, biomarker validation study, response to HD IL-2 was associated with a high density of CD8 + cells in the invasive margin, and a high density of Foxp3 + cells in the tumor center. Independent validation is ongoing. To improve the predictive value of Foxp3, characterization of Foxp3 expressing cells (Tregs vs activated effector T cells) in highly infiltrated tumors is underway. [Table: see text]
The addition of adjuvant chemotherapy to radiation in high-risk endometrial cancer: Survival outcomes and patterns of care.
Authors: Dustin Boothe, Ned Williams, Bismarck Odei, Matt Poppe, Theresa Louise Werner, Gita Suneja, David K. Gaffney
Journal: Journal of Clinical Oncology (2016)

5587 Background: High risk endometrial cancer (HREC) treated with adjuvant radiation (aRT) alone has been associated with an increased risk of distant relapse. The addition of chemotherapy to radiation (aCRT) may benefit overall survival (OS). We investigated the patterns-of-care and OS benefit of aCRT in HREC by analyzing the National Cancer Database. Methods: Our query was limited to patients with FIGO stage IB and II with either papillary serous, clear cell, or grade 3 adenocarcinoma, diagnosed between 2004 and 2013. Logistic and Cox regression were utilized to identify predictors of aCRT use and OS, respectively. Survival analysis was performed with Kaplan Meier and log-rank methods. Propensity score matching was employed to decrease the potential influence of selection bias. Results: A total of 12,724 patients were identified for analysis with 8,887 (63.0%) receiving aCRT, and 2,254 (37.0%) received aRT. Predictors of aCRT were FIGO stage II (OR 1.3; 95% CI 1.08-1.57), papillary serous (OR 9.51; 95% CI 1.68-11.78) or clear cell (OR 4.02; 95% CI 2.90-5.58) histology, LVSI (OR 1.63; 95% C, 1.36-1.94), lymph node surgery (OR 1.71; 95% CI 1.31-2.23), and receipt of brachytherapy alone (OR 1.58; 95% CI 1.28-1.94). Estimated 5-year and 10-year overall survival (OS) were respectively 79.0% and 63.6% for patients receiving aRT only, and 83.1% and 68.8% for those receiving aCRT (P < 0.001). When compared to aRT, aCRT was associated with improved OS on multivariate (HR 0.83, 95% CI 0.72-0.96) analysis. A univariate shared frailty Cox regression following propensity score matching revealed persistence of the OS benefit with aCRT (HR 0.72; 95% CI 0.55-0.91). Conclusions: The addition of adjuvant chemotherapy to radiation in HREC is associated with improved OS. Multiple demographic and clinical factors significantly influence the choice of adjuvant therapy in this setting.
Randomized trial of FOLFOX alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient DNA mismatch repair or microsatellite instability (ATOMIC, Alliance A021502).
Authors: Frank A. Sinicrope, Fang-Shu Ou, Qian Shi, Andrew B. Nixon, Kabir Mody, Alexandra Levasseur, Amylou C. Dueck, Asha R. Dhanarajan, Christopher Hanyoung Lieu, Deirdre Jill Cohen, Federico Innocenti, Robert J. Behrens, Walter Peters, Daniel J. Sargent, Nicolas Sommer, Eileen Mary O'Reilly, Jeffrey Meyerhardt
Journal: Journal of Clinical Oncology (2017)

TPS3630 Background: In metastatic colorectal cancer with deficient DNA mismatch repair (MMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for proficient MMR tumors (Le, M, et al, NEJM 2016). We propose a phase III randomized trial to determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech™), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR or microsatellite instability (MSI). By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that may serve as ‘immune priming.’ Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR or MSI will be randomized to modified FOLFOX6 for 6 months (12 cycles) alone or combined with atezolizumab (840 mg IV q2 wk) continued as monotherapy for an additional 6 months (total duration of 12 months). Patients will be stratified by T, N stage and tumor sidedness. Local testing for MSI or MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. The targeted accrual goal of 700 patients provides 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. This study will be conducted by the Alliance for Clinical Trials in Oncology. The protocol has been approved by NCI CTEP and is expected to be activated in mid 2017. Clinical trial information: NCT02912559.
Detection of drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) therapy in advanced non-small cell lung cancer (NSCLC) with functional (PET/CT) imaging.
Authors: Amit Bhoil, B.R. Mittal, Navneet Singh
Journal: Journal of Clinical Oncology (2016)

e20515 Background: The early response evaluation with functional imaging is cost effective in prediction of drug response. Drug resistance to EGFR TKI is seen in patients through activation of other oncogenes as KRAS or with secondary EGFR mutations. The aim of the study is to detect the drug resistance to EGFR TKI treatment in NSCLC with PET quantitative parameters. Methods: Prospective serial imaging with 18F-FDG-PET /CT for response evaluation was performed in 23 patients (14M 9F; range 28-86yrs) with Stage IIIB-IV NSCLC before start of therapy, at 3weeks (early) and at 6 (late) weeks. The metabolic response was assessed using PERCIST criteria for percentage changes of SUVpeak and TLG (Tumour Lesion Glycolysis) in the hottest lesion per scan. The statistical analysis using Kaplan Meier analysis and log rank test were performed to analyse the association with the median overall survival (OS). Results: The change in metabolic disease response suggestive of progressive disease was seen in 2 patients at 6 weeks with disease control (DC) (n = 20) and no disease control (NDC) (n = 3) compared to that at 3 weeks (DC = 22, NDC = 1), suggestive of drug resistance. The response evaluation with SUVpeak showed median OS among disease control (DC) 258 d was statistically significantly greater (p = 0.049) compared to patients with no disease control (NDC) 129d at 3 week, the median survival time at 6 weeks (p = 0.115) among DC 271d was greater compared to NDC 172d. The response evaluation with TLG showed no change in disease classification in terms of disease control (DC) (n = 19) and no disease control (NDC) (n = 4) in patients at 6 weeks compared to 3 weeks. The median OS was similar at 3 weeks (p = 0.496) and at 6 weeks with among DC 227d was less compared to NDC 353d and no change in survival was seen at 6 weeks Conclusions: Late imaging is of value in detection of drug resistance esp. in patients presenting with stable metabolic disease in early imaging. Two different clinically time point imaging: first at early time period for initially response assessment and another at later time point to access any disease progression especially with cytostatic drugs can be considered.
Phase 1/2 study of veliparib (V) combined with carboplatin (Cb) and etoposide (E) in patients (pts) with extensive-stage disease (ED) small cell lung cancer (SCLC) and other solid tumors: Phase 1 results.
Authors: Florence Atrafi, Harry J.M. Groen, Lauren Averett Byers, Elena Garralda, Martijn P. Lolkema, Randeep S. Sangha, Santiago Viteri Ramirez, Young Kwang Chae, D. Ross Camidge, Nashat Y. Gabrail, Tina Waskiewicz, Beibei Hu, Tu Xu, Silpa Nuthalapati, Elizabeth Hoening, Philip Komarnitsky, Antonio Calles Blanco
Journal: Journal of Clinical Oncology (2017)

8530 Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m 2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.
Assessment of screening and preventive practices for allogeneic hematopoietic cell transplantation survivors.
Authors: Sunn Sunn Htet Thaw, Shernan Holtan, Nyan Pyae, Qing Cao, Anne Hudson Blaes
Journal: Journal of Clinical Oncology (2016)

e21580 Background: Given the medical complexity of hematopoietic cell transplant (HCT) survivors, long-term follow up remains challenging. This study assesses the utilization and effectiveness of the established guidelines for HCT survivors in the era of the updated guidelines. Methods: We reviewed 78 adult allogeneic HCT recipients between 2012 and 2013 at the University of Minnesota with a 2-year anniversary visit. We collected data based on the establish guidelines in 2012 by the collaborative led by the Center for International Blood and Marrow Transplant Research (CIBMTR). A scoring system that provided 1 point for each of 13 individual organ systems as well as an overall assessment for follow up care was developed. Chi-square test and Wilcoxon rank sum test were applied to compare the categorical and overall scores between focused-provider groups, provider gender and provider’s year of practice. Results: Median overall follow up care scores were higher for survivorship-focused providers versus others (median 9 vs. 8, p<0.01) (table). Female providers had higher median overall scores versus male providers (median 9.5 vs. 8, p<0.01) as well as higher median system scores in ocular, cardiovascular, and musculoskeletal systems (p<0.01), but no differences in remaining system scores. There were no differences in overall or individual organ system scores based on provider’s year of experience (p = 0.43). Conclusions: Post-transplant care provided by survivorship-focused providers was more likely to achieve the longterm screening recommendations. However, even within this group, there is room for improvement in adherence to screening and preventative practice guidelines. New comprehensive but efficient tools to improve adherence to these guidelines are needed. Systems assessed Scores by Other Pro viders scores Median (Min-Max) N=57 Scores by Survivorship- focused Providers Median (Min-Max) N=21 P-value Overall 8.0(6.0-12.0) 9.0(7.0-13.0) <0.01 Ocular system 0.0(0.0-2.0) 1.0(0.0-2.0) <0.01 Oral system 1.0(0.0-2.0) 2.0(0.0-3.0) <0.01 Cardiovascular system 1.0(0.0-3.0) 2.0(1.0-3.0) <0.01 Musculoskeletal system 0.0(0.0-4.0) 2.0(0.0-5.0) <0.01
Positive Psychological Well-Being and Cardiovascular Disease
Authors: Laura D. Kubzansky, Jeff C. Huffman, Julia K. Boehm, Rosalba Hernandez, Eric S. Kim, Hayami K. Koga, Emily H. Feig, Donald M. Lloyd-Jones, Martin E.P. Seligman, Darwin R. Labarthe
Journal: Journal of the American College of Cardiology (2018)
SMK/SM88 toxicity, efficacy, and patient reported outcomes in metastatic pancreas cancer.
Authors: Steve Hoffman, Jeanetta Stega, Giuseppe Del Priore, John Rothman
Journal: Journal of Clinical Oncology (2017)

e14060 Background: SMK/SM-88 is a combination of novel tyrosine isomer ( TI) and 3 low dose repurposed agents that are generally recognized as safe for typical use. Its mechanism of action is based on the Warburg effect. It has previously been reported to have clinical benefit with little toxicity in a variety of cancers (J. Clin. Oncol. 2013 31: e22095). We now report on a subset of subjects with pancreas cancer. Methods: Retrospective chart review. Results: Subjects received all four SMK/SM-88 components orally and subcutaneously, consisting of a proprietary altered TI, CYP3a4 inducer, mTOR inhibitor and mitochondrial oxidative stress catalyst, five days per week for a period of six weeks (1 cycle). A total of 11 pancreatic cancers cases were identified. The average age was 63.2 (44-81), 36.4% (4/11) were female. Prior treatment included surgery only (n = 3); chemo only (n = 4); multi-modality therapy (n = 2) and unknown or none (n = 2). Duration on study regimen was 3-57 weeks (mean = 28.5). Clinical benefits documented for all subjects included: 1-3 points improvement in ECOG performance status; 1-5 point mean improvement on EORTC questionnaire (scale 1-7); weight gain (1-5 lbs.); and reduction in pain levels (1-9 points/10 scale) with cessation of all analgesics by the end of cycle 1 in 36% (4/11). Overall reduction in tumor size was seen in 27.3% (3/11) including one CR with PFS of at least 6 months duration, and 2 PRs with one known PFS of 15wks. 72.7% (8/11) had stable disease for 6-61wks. One patient had an overall survival of 23.3 months with no further treatment, and one had an overall survival of 43.2 months. All subjects developed hyperpigmentation. Overall, all subjects tolerated the SMK/SM-88 compounds well. No serious or unexpected adverse events related to the agent have been reported. Conclusions: SMK/SM-88 is a promising treatment for metastatic pancreatic cancer with no significant toxicity. Additional studies are on going in other cancers and confirmatory pancreas investigations are planned.
Genetic and chemical screens in 2-D vs. 3-D generate distinct leads for target and drug discovery.
Authors: Piyush Gupta, Dexter X Jin, Yu-xiong Feng, Ethan Sokol, Daniel H Miller
Journal: Journal of Clinical Oncology (2018)

12087 Background: Oncology drug discovery programs commonly utilize genetic or chemical screens with cancer cell lines propagated on two-dimensional (2D) plastic surfaces. While convenient for high-throughput screens, such cultures do not incorporate the extracellular matrix (ECM) present in patient tumors, which plays a critical role in determining cancer cell signaling. This has led to significant concerns about the biological relevance of targets discovered using standard 2D cultures, but the extent to which performing assays in 3D ECM would alter the leads generated by screening is not known. Methods: We have recently developed 3D hydrogel scaffolds that replicate the physical and signaling characteristics of human tissues. We performed both high-throughput CRISPR and chemical screens, doing so in parallel either in standard 2D cultures or in 3D ECM. The CRISPR screen included 10 sgRNAs targeting each of 507 kinases in the human genome. The chemical screen was performed with 780 drugs approved by the FDA for oncology and other indications. Results: The CRISPR screen identified major differences in the kinase pathways utilized by cancer cells in 3D vs. 2D. We discovered 29 kinases that were essential for promoting growth in 3D tissues but had no phenotype when inhibited in 2D. In addition, 3 kinases were essential in 2D culture but were not essential in 3D ECM. The drug screen identified agents that inhibited cancer cell viability or invasion. Drugs that inhibited viability were strongly enriched for FDA-approved oncology drugs. By contrast, most of the 26 drugs that were potent inhibitors of cancer cell invasion in 3D were approved for non-oncology indications (22/26), identifying opportunities to ‘repurpose’ drugs to target cancer invasion. Conclusions: Our findings establish the importance of conducting target and drug discovery efforts in biomimetic 3D conditions that replicate the matrix content of human tissues. Continued use of standard 2D cultures poses a risk of generating both false-positives and false-negatives -- identifying spurious leads that will not validate in follow up studies, or failing to identify novel leads that are promising candidates for follow-up validation.
Biologic diversity of breast cancers in women with African ancestry.
Authors: Evelyn Mawunyo Jiagge, Joseph Kwaku Oppong, Kaitlin Harvey, Jessica Miley Bensenhaver, Ernest Adjei, Xu Cheng, Peter Ulintz, Kofi K. Gyan, Barbara Salem, Ishmael Kyei, Baffour Awuah, Max Wicha, Lisa A. Newman, Sofia Merajver
Journal: Journal of Clinical Oncology (2018)

e13114 Background: 80% of breast cancers - BC are basal; aggressive, and negative for ER, PR and HER2 over expression, termed triple negative - TNBC. In the US, the incidence rate of TNBC is two-fold higher in African American (AA) compared to White women. Data in Africa suggest that > 50% are TNBC. Patient Derived Xenografts - PDXs represents an exciting tool for research in precision medicine. Our goal was to develop a library of BC PDXs from women in western sub-Saharan Africa, which will also serve for the study of BC in AA, who share ancestry with these African women, whiles providing a control for the influence of environment and multiethnic admixture. Methods: IRB approval was obtained at the University of Michigan and the Komfo Anokye Teaching Hospital. Surgical breast tumors samples were obtained from the operating room, slow frozen and transported to the US for immediate orthotopic implantation into NSG2 mice. Saliva samples were collected for genomic DNA. Whole exome sequencing was done on 20 primary tumors (11 Ghanaian, 5 AA and 4 C), their matched normal DNA, and the corresponding PDXs. IHC staining was also done on these samples for receptor status, tumor grade, percentage of stromal and inflammatory cells, and expression of P53, ALDH1, EGFR, PTEN, AR. Results: Over a period of three years, we obtained tumors samples from 54 Ghanaian BC patient who we operated on, including 18 TNBC. We implanted 21 of the tumors into NSG2 mice and established stable PDX lines (passages 2 and above) from 11 (9 TNBC, 1 ER+ and 1 HER2+) tumors. Our PDX take rate is thus above 50%. By IHC, the PDXs reflected the heterogeneity of the primary tumors and maintain marker expression. However, stromal and inflammatory cells were significantly reduced between the primary tumor and the P1 PDX, but was maintained in the PDXs with subsequent passages. No human stroma was maintained in the PDX irrespective of the method of tumor implantation. Analysis of sequencing data is ongoing. Conclusions: We report the establishment of the first ever collection of PDXs from an African population with maintenance of primary tumor phenotype characteristics. This library is available for collaborative research to understand the molecular complexity of African BCs and find possible new drug targets.