tbuckley/cabot-search huggingface dataset:
Potency of bortezomib in combination with MP0250, a bispecific VEGF- and HGF-targeting darpin, in a preclinical multiple myeloma model.
Authors: Ulrike Fiedler, Andreas Cornelius, Savira Ekawardhani, Keith Martin Dawson, Pat Gilboy, Michael Tobias Stumpp, Ignacio Dolado
Journal: Journal of Clinical Oncology (2014)

e19574 Background: In multiple myeloma, tumor cells and stroma exert a reciprocal effect on each other that leads to tumor expansion in the bone marrow and bone destruction. Hepatocyte growth factor (HGF) is a main player in osteolytic bone destruction and also stimulates myeloma cell proliferation, migration and adhesion in the bone marrow. Additionally, VEGF plays a key neovascularization role in multiple myeloma. Therefore, we investigated whether MP0250, a bispecific DARPin simultaneously inhibiting tumor stroma HGF and VEGF, could potentiate the anti-tumor effect of the standard of care proteasome inhibitor bortezomib. Methods: MP0250 was tested as monotherapy and in combination with 0.6 mg/kg of bortezomib in an orthotopic murine model, where human multiple myeloma cells are implanted in the murine bone marrow. Tumor growth and invasion into the muscle were monitored by X-ray, whereas bone destruction was analyzed by microCT. Results: MP0250 significantly inhibited bone lysis and tumor invasion both as monotherapy and in combination with bortezomib. MicroCT and X-ray imaging showed superior inhibition of bone lysis by the combination of MP0250/bortezomib versus bortezomib monotherapy (p≤0.05), as measured by the total and cortical bone volumes. CT scans registered a highly significant reduction of tumor infiltration into the tibial muscle relative to vehicle (p<0.0001) in both the MP0250 and MP0250/bortezomib groups, as assessed by volume measurements of the leg muscle (vehicle 1187mm3, MP0250 180mm3, MP0250/bortezomib 143mm3). Altogether, this indicates that blockade of HGF and VEGF by MP0250 impairs myeloma cell migration, invasion and bone destruction. Importantly, no toxicity was observed for MP0250 as monotherapy or in combination with bortezomib. Conclusions: MP0250, a DARP in specifically blocking HGF and VEGF in tumor cells and in the tumor microenvironment, is a potent inhibitor of multiple myeloma-mediated bone lysis and myeloma cell invasion. MP0250 improves the efficacy of the standard of care therapy bortezomib with no added toxicity. This suggests a potential therapeutic opportunity in combining cytotoxic therapies with MP0250.
A single arm, open-label multicenter phase II trial of everolimus in patients with relapsed/refractory germ cell cancer (RADIT).
Authors: Martin H Fenner, Annette Dieing, Karin Oechsle, Marcus Hentrich, Thomas Christoph Gauler, Anja Lorch, Hans-Georg Kopp, Joerg Beyer, Carsten Bokemeyer, Viktor Gruenwald, Friedemann Honecker
Journal: Journal of Clinical Oncology (2014)

e15535 Background: Patients (pts) with relapsed or refractory metastatic germ cell cancer (GCC) after multiple lines of standard chemotherapy have a very poor prognosis. The mTOR inhibitor everolimus has been approved for the treatment of patients with renal cancer, neuroendocrine tumors, or breast cancer, and was assessed as a treatment option for GCC pts. Methods: GCC pts with disease progression or relapse after high-dose chemotherapy and/or at least two lines of cisplatin-based chemotherapy were eligible for study inclusion. In addition, prior combination chemotherapy with gemcitabine, oxaliplatin +/- paclitaxel was mandatory. The primary trial endpoint was treatment efficacy, defined as ≥25% of pts progression-free at 12 weeks. Twenty-five evaluable pts were needed, assuming a 20% two-sided type 1 error and 95 % power to reject the null hypothesis of 5% of patients progression-free after 12 weeks. Secondary endpoints were objective response rate, disease control rate (SD + PR + CR), progression-free survival, overall survival, and the safety profile of everolimus. Results: Twenty-five patients from 6 German study centers were treated with everolimus 10 mg orally daily until disease progression, unacceptable toxicity, or study discontinuation for other reasons between December 2010 and January 2014, when the trial was closed for recruitment. No unexpected serious safety events were observed requiring premature termination of the trial. At a pre-planned interim analysis after inclusion of 13 pts, predefined efficacy criteria for study continuation were met. Efficacy and safety analyses are ongoing. Conclusions: Efficacy of everolimus in heavily pretreated GCC pts was sufficient to justify continuation of the trial in the second stage. Accrual was concluded in January 2014, and primary and secondary endpoint analyses are ongoing. Clinical trial information: NCT01242631.
Evidence for a Mesothelial Origin of Body Cavity Effusion Lymphomas
Authors: David Sanchez-Martin, Thomas S. Uldrick, Hyeongil Kwak, Hidetaka Ohnuki, Mark N. Polizzotto, Christina M. Annunziata, Mark Raffeld, Kathleen M. Wyvill, Karen Aleman, Victoria Wang, Vickie A. Marshall, Denise Whitby, Robert Yarchoan, Giovanna Tosato
Journal: JNCI Journal of the National Cancer Institute (2017)

Primary effusion lymphoma (PEL) is a Kaposi's sarcoma herpes virus (KSHV)-induced lymphoma that typically arises in body cavities of HIV-infected patients. PEL cells are often co-infected with Epstein-Barr virus (EBV). "PEL-like" lymphoma is a KSHV-unrelated lymphoma that arises in body cavities of HIV-negative patients. "PEL-like" lymphoma is sometimes EBV positive. The derivation of PEL/"PEL-like" cells is unclear.Mesothelial cells were cultured from body cavity effusions of 23 patients. Cell proliferation, cytokine secretion, marker phenotypes, KSHV/EBV infection, and clonality were evaluated by standard methods. Gene expression was measured by quantitative polymerase chain reaction and immunoblotting. A mouse model of PEL (3 mice/group) was used to evaluate tumorigenicity.We found that the mesothelia derived from six effusions of HIV-infected patients with PEL or other KSHV-associated diseases contained rare KSHV + or EBV + mesothelial cells. After extended culture (16-17 weeks), some mesothelial cells underwent a trans-differentiation process, generating lymphoid-type CD45 + /B220 + , CD5 + , CD27 + , CD43 + , CD11c + , and CD3 - cells resembling "B1-cells," most commonly found in mouse body cavities. These "B1-like" cells were short lived. However, long-term KSHV + EBV - and EBV + KSHV - clonal cell lines emerged from mesothelial cultures from two patients that were clonally distinct from the monoclonal or polyclonal B-cell populations found in the patients' original effusions.Mesothelial-to-lymphoid transformation is a newly identified in vitro process that generates "B1-like" cells and is associated with the emergence of long-lived KSHV or EBV-infected cell lines in KSHV-infected patients. These results identify mesothelial cultures as a source of PEL cells and lymphoid cells in humans.
Pathologic nodal response in gastric cancer: Do all patients need adjuvant therapy?
Authors: Brandon George Smaglo, Yvonne Sada, Hop Sanderson Tran Cao, Mehmet Akce, Henry Mok, Benjamin Leon Musher, Nader Nabile Massarweh
Journal: Journal of Clinical Oncology (2017)

107 Background: Recent data from the MAGIC trial show that pathologically positive lymph nodes (ypN+) despite neoadjuvant (NA) chemotherapy are associated with poorer survival. Although the use of NA therapy has increased, pathologic disease response to multimodality therapy (MMT) and its impact on outcome have not been well-defined. Methods: This retrospective cohort study of the National Cancer Database included patients with cN+ gastric cancer who underwent NA therapy followed by surgical resection between 2006 and 2012. Patients were categorized by NA treatment (chemotherapy or concurrent chemoradiation). Pre-treatment clinical (cN) and pathologic nodal staging (ypN) were used to determine downstaging rates from cN+ to ypN0. The association between overall risk of death and NA treatment, nodal response, and the use of adjuvant therapy was evaluated with multivariable Cox regression. Results: Among 1,489 patients with cN+ gastric cancer receiving NA therapy, 45.5% were treated with chemotherapy and 54.5% with chemoradiation. Rates of nodal downstaging were 29.9% for chemotherapy and 45.4% for chemoradiation. On multivariable analysis, treatment sequence and type were not associated with risk of death. Median survival was significantly lower in patients with ypN+ compared to those with ypN0 disease (27.7 vs 79.7 months; log-rank, p &lt; 0.001).Among patients with ypN+ disease (n = 918), median survival was greater if adjuvant therapy was received (32.6 months vs. 25.3 months, log-rank, p &lt; 0.001); adjuvant therapy was associated with a 19% decreased risk of death (Hazard Ratio [HR] 0.81; 95% CI 0.66-0.99), with further reduction among those who underwent a margin negative resection (HR 0.73; 95% CI 0.58-0.92). In patients with ypN0, adjuvant therapy was not associated with a lower risk of death. Conclusions: Over one third of node-positive gastric cancers demonstrated pathologic nodal downstaging with NA treatment, with chemoradiation yielding a higher response than chemotherapy. Patients with ypN+ had worse survival, and appeared to benefit from adjuvant therapy. Future gastric cancer trials should better define the role for NA chemoradiation and help individualize the use of adjuvant therapy based on nodal response.
Leptomeningeal disease and breast cancer: Relationship of outcome and subtype.
Authors: Sausan Abouharb, Joe Ensor, Monica Elena Loghin, Ruth Katz, Ana M. Gonzalez-Angulo, Francisco J. Esteva, Stacy L. Moulder, Vicente Valero, Gabriel N. Hortobagyi, Amal Melhem-Bertrandt
Journal: Journal of Clinical Oncology (2013)

601 Background: Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. Outcome of leptomeningeal disease (LMD) across BC subtypes is not well documented. We aimed to characterize clinical features and outcomes of LMD based on BC subtypes. Methods: We retrospectively reviewed medical records of patients diagnosed with LMD from BC (1997 to 2012). All patients had BC. Cases of LMD were based on the presence of neoplastic cells on cerebrospinal fluid examination and/or evidence of LMD by imaging studies. Survival was estimated by the Kaplan-Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Results: 232 patients were included, 189 of them had available tumor subtype classified as: hormone receptor positive (HR+) BC N=67 (35.5%), human epidermal growth factor receptor 2 positive (HER2+) N=55 (29%), and 67 (35.5%) triple-negative BC (TNBC). Median age at diagnosis of LMD was 49.7 years. (Range 24-89). Median overall survival (OS) from LMD diagnosis across all subtypes was 3.1 months (95% CI, 2.5 to 3.7). Median OS correlated with BC subtype: 3.7 months (95% CI: 2.4, 6.0) in HR+, 4.0 months (95% CI: 2.6, 6.9) in HER2+, and 2.2 months (95% CI: 1.5, 3.0) in TNBC, (p=0.0002). There was an 11.4% chance a patient diagnosed with LMD would survive 1 year and the chance of surviving at least 3 years was 1.3%. When age was used as a continuous variable, older age was associated with worse outcome (p&lt;0.0001). Patients with HER2+ BC and LMD were more likely to have received systemic therapy (ST) (70%), compared to HR+ (41%) and TNBC (41%) (p=0.002). 38% of patients with HER2+ BC received HER2 directed therapy. There was no difference in the use of intrathecal therapy (IT) (52%) across subtypes (p=0.3). Use of IT therapy (p&lt;0.0001) and ST (p&lt;0.0001) were both associated with improved age-adjusted OS. After adjusting for age, ST, there was no difference in OS between patients with HR+ and HER2+ BC (p =0.14), but a significant difference remained between TNBC and HER2+ BC (p &lt; 0.0001). Conclusions: LMD carries a dismal prognosis. Our data shows that OS correlates with tumor subtype. Patients with TNBC had a significantly shorter OS compared to patients with HER2+ BC. New treatment strategies are needed.
ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced (adv) non-small cell lung cancer (NSCLC)—A randomized double-blind phase III study.
Authors: Michael J. Boyer, Pasi A. Janne, Tony Mok, Kenneth John O'Byrne, Luis G. Paz-Ares, Suresh S. Ramalingam, Jane Q Liang, Ian Taylor, Alicyn Campbell, Joseph P. O'Connell, Stephen P. Letrent, Vladan Antic
Journal: Journal of Clinical Oncology (2012)

TPS7615 Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.
Serum tumor markers among patients (pts) with nasopharyngeal carcinoma (NPC): A single institution experience.
Authors: Justin D. Kaner, Jesus Del Santo Anampa Mesias, Adam Gersten, Thomas J Ow, Christine Nayar, Ricklie Julian, Missak Haigentz
Journal: Journal of Clinical Oncology (2015)

e17078 Background: NPC is not known to have associated elevations in known tumor markers other than EBV viral loads. We report a case of metastatic, EBV-associated NPC with elevations in serum CEA, CA-19-9 and CA125 levels, all of which markedly improved and correlated well with responding disease. A retrospective review was therefore initiated to evaluate the frequency of elevated levels of serum tumor markers among pts with NPC. Methods: Using unique data mining software, all patients who were diagnosed with tumor registry-defined NPC from 1/1/1997 through 12/31/2014 at our institution were included. These records were searched for several tumor markers at the time of cancer diagnosis (± 1.5 months), including CEA, CA 19-9, CA125, AFP, LDH, uric acid, and alkaline phosphatase. Results: A total of 124 NPC pts were identified during the 18 year study interval. At least one elevated serum marker was observed in 31 out of 87 pts (36%). Elevated CEA was found in 3 of 4 tested pts (75%). Other than the index case above, no pts had CA 19-9 or CA125 tested. Serum LDH, uric acid, and alkaline phosphatase levels were elevated in 10 of 45 tested pts (22%), 5 of 41 pts (12%), and 12 of 84 pts (14%), respectively. Serum AFP was elevated in 1 of 4 tested pts. Correlations with NPC histology and disease stage are ongoing. Conclusions: Despite the small numbers of NPC pts with available test results, consistent with the unproven role of these markers in NPC, elevated serum markers were found among tested pts. Moreover, markers traditionally associated with adenocarcinoma histology were detected in NPC pts, with serum CEA elevations in most tested cases. The results are intriguing and warrant further evaluations of the prognostic and predictive value of these markers in NPC management.
Impact of squamous histology on the response to treatment and long-term outcomes of patients with distal esophageal cancer.
Authors: Parth Kishore Shah, Miles Cameron, Jessica M. Frakes, Jacques Fontaine, Domenico Coppola, Sarah E. Hoffe, Khaldoun Almhanna, Jose Mario Pimiento
Journal: Journal of Clinical Oncology (2017)

135 Background: Squamous cell carcinoma (SCC) has been traditionally linked to a better response to treatment and overall survival when compared to adenocarcinoma (AC) of the esophagus. Recent advances in staging, neoadjuvant therapy (NAT) and increasing surgical management of patients with EC have led to improved overall survival of these patients. The aim of this study is to analyze the impact of squamous histology on treatment response and long term outcomes in patients with distal EC. Methods: A retrospective review of patients who underwent esophagectomy for EC at a single institution over a 16 year period (1999-2015) was performed. Pre-operative clinical parameters, stage as well as oncologic management were compared between SCC and AC of the distal esophagus and the difference in response to treatment and overall survival were analyzed using descriptive statistics. Results: Esophagectomy was performed on 945 patients with EC of which 839 patients (89%) had distal EC. The mean age of this group was 63 years and majority were male (87%). Histology was SCC for 78 patients (9.4%) and AC for 747 patients (90.6%). Pretreatment clinical stage was similar between groups (p = 0.16). NAT administration was similar between groups (p = 0.13). Although SCC patients had higher rate of complete response (54% v/s 36%, p = 0.01) we found no difference in the overall survival after surgery (33 months for SCC v/s 40 months for AC, p = 0.72) irrespective of whether they received NAT (p = 0.95) or not (p = 0.55). Conclusions: Squamous cell histology had a favorable impact on the rate of pathologic response for patients with distal EC; however, this improvement did not alter their overall survival. This could provide an insight into the decreasing significance of the histology in the management and expectations from treatment of EC while emphasizing the continuing need for multimodality therapy to assure good outcomes on these patients.
Correlation of large brain edema with favorable prognosis in patients with single brain metastases.
Authors: Matthias Preusser, Anna Sophie Berghoff, Carina Dinhof, Markus Hutterer, Adelheid Woehrer, Monika Hackl, Rupert Bartsch, Peter Birner, Christoph Zielinski, Georg Widhalm, Christine Marosi, Daniela Prayer, Thomas Spannberger
Journal: Journal of Clinical Oncology (2012)

2053 Background: The sub-cohort of brain metastases (BM) patients (pts) with single BM has relatively favorable survival times, but novel prognostic factors are needed to individualize patient management. Methods: We retrospectively evaluated pre-operative magnetic resonance images in patients, who underwent neurosurgical resection of a single BM. The localization and largest diameter of the BM was recorded. The extent of brain edema (BE) was graded on contrast-enhanced T1, T2 and fluid-attenuated inversion recovery (FLAIR) images as follows: BE &lt;1cm, BE &gt;1 cm without affection of the contralateral hemisphere, BE &gt;1cm with affection of the contralateral hemisphere. Further, immunohistochemically assessed expression of hypoxia-induced factor 1 alpha (HIF1a) was analyzed in each BM tissue specimen. Results: 159 pts were studied (81 male, 78 female; age range 24 to 80 years, median 58). The primary tumors were lung carcinoma in 74, breast cancer in 26, kidney cancer in 13, colorectal cancer in 11, melanoma in 9 and other tumor types in 26 cases. At univariate analysis, we found a significant positive correlation of overall survival time (OS) with young age, Karnofsky index &gt;80, non-melanoma histology, and, surprisingly, large BE (p&lt;0.05, log-rank test). At multivariate analysis, pts age, histological diagnosis and extent of BE remained independent prognostic parameters (Cox regression model, p&lt;0.05). We found a significant positive correlation of extent of BE with expression of HIF1a (Mann-Whitney-U test, p=0.003). Conclusions: Large BE positively and independently correlates with favorable prognosis in pts operated for single BM. Peritumoral BE correlates with HIF1a expression, indicating a possible role of tumor hypoxia in its formation. [Table: see text]
A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC).
Authors: Toni K. Choueiri, Elizabeth R. Plimack, Hendrik-Tobias Arkenau, Eric Jonasch, Daniel Yick Chin Heng, Thomas Powles, Melanie M. Frigault, Edwin Clark, Amir Handzel, Humphrey Athelstan Gardner, Shethah Morgan, Laurence Albiges, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2017)

436 Background: Savolitinib (HMPL504/Volitinib, AZD6094) is a potent, selective MET inhibitor (IC 50 of 4nM). MET and its ligand, HGF, are known to play an important role in the molecular events underlying oncogenesis in PRCC, a disease without a clear standard of care and marked by alterations of chromosome 7 (containing both MET and HGF genes) in a majority of patients as well as gene amplification or MET kinase domain mutations (Albiges et al. 2014, Linehan et al., 2015). Methods: This study evaluates savolitinib in PRCC patients dosed at 600mg daily until disease progression. ORR is the primary endpoint. PFS &amp; DoR are secondary endpoints. PRO &amp; HRQoL questionnaires are exploratory endpoints. Eligibility includes naive and previously treated metastatic PRCC, ECOG PS 0 or 1. Archival tumor was used to centrally confirm PRCC pathology post hoc and to determine MET status using Next Generation Sequencing (Foundation Medicine Inc, USA). Results: As of 27 June 2016, 109 pts were dosed. Best response was PR n=8, SD n=43, PD n=48 and 10 patients were not evaluable for response. 44 pts are MET-driven (MET/HGF gene copy number gain or kinase domain mutations), 46 pts were MET-negative, 19 pts are status unknown. MET-driven pts included Papillary Type I &amp; II histologies. All 8 responders were in the MET-driven group, 18% RR in this subset. Median PFS in the MET-driven group was 6.2 months (95% CI: 4.1–7.0) vs. 1.4 months (95% CI: 1.4–2.7) in the MET-negative group (p = 0.002). Overall 10/109 pts had AEs leading to discontinuation. 23/109 pts had ≥ Grade 3 toxicity related to savolitinib. The most common AEs (all grades) includes: nausea (39%), fatigue (27%), edema (18%), and abnormal LFTs (17%). One death from hepatic encephalopathy was considered related to savolitinib. PRO &amp; HRQoL data was not statistically analysed, descriptive data support main efficacy findings. Conclusions: In the largest biomarker-profiled trial dedicated to PRCC, savolitinib was generally well tolerated with anti-tumor activity in MET-driven patients. These findings warrant further clinical investigation of savolitinib in MET-driven PRCC. Clinical trial information: NCT02127710.