tbuckley/cabot-search huggingface dataset:
Phase II study of neoadjuvant chemotherapy with modified FOLFOXIRI in borderline resectable or unresectable stage III pancreatic cancer.
Authors: Enrico Vasile, Nelide De Lio, Carla Cappelli, Luca Pollina, Niccola Funel, Aldo Sainato, Laura Ginocchi, Maurizio Lucchesi, Chiara Caparello, Sara Caponi, Vittorio Perrone, Francesco Pasqualetti, Fabio Caniglia, Stefano Signori, Salvatore Mazzeo, Carlo Greco, Alfredo Falcone, Daniela Campani, Franco Mosca, Ugo Boggi
Journal: Journal of Clinical Oncology (2013)

4062 Background: FOLFIRINOX has shown high activity in metastatic pancreatic cancer (PC) patients and could be an interesting regimen also for patients with inoperable locally advanced disease. Our group had developed a similar schedule in metastatic colorectal cancer named FOLFOXIRI with good tolerance and activity. Therefore, we have decided to perform a phase II trial to prospectively evaluate the activity of modified FOLFOXIRI in borderline resectable or unresectable PC. Methods: Modified FOLFOXIRI consisted of a lower dose of irinotecan (150 mg/sqm) and of infusional 5-fluorouracil (2800 mg/sqm as a 48-hour continuous infusion on days 1 to 3) with no bolus 5-fluorouracil. Folinic acid and oxaliplatin (85 mg/sqm) remained unchanged. The study enrolled patients with diagnosis of pancreatic adenocarcinoma, stage III borderline resectable or unresectable disease (cT4,cN0-1,cM0), ECOG PS 0-1, age 18-75. The primary end-point of the study was the percent of patients who undergo radical surgical resection after chemotherapy. Results: Thirty-two patients have been enrolled; M/F=12/20; PS 0/1=16/16. Median age was 60 years (range 44-75). Median number of FOLFOXIRI cycles was 6 (range 2-14). Grade 3-4 toxicities was experienced by 20 patients during chemotherapy. Twelve partial responses (37%) and 14 stable diseases (45%) have been observed; 2 patients had progressive diseases (6%). The remaining 4 patients (12%) have not been yet evaluated because are still in the first months of treatment. A local treatment was received after chemotherapy by 18 patients until now: 13 (41%) received radical surgical resection and 5 received concomitant chemo-radiotherapy. Three explorative laparotomy showed occult metastases. In other 7 cases surgery is planned while 2 patients refused surgery. Median progression-free survival is 14.0 months and median overall survival is 24.2 months with a two-year survival rate of 54%. Conclusions: Chemotherapy with FOLFOXIRI seems active in locally advanced PC and may allow to obtain a downstaging of disease leading to achieve a curative surgical resection in some cases. Longer follow up is needed to better evaluate long-term outcome of this strategy.
Rational combination therapy in young vs older patients with advanced colorectal cancer (CRC).
Authors: Anna Capasso, Todd M. Pitts, John J. Tentler, Peter J Klauck, Stacey M Bagby, Anna Nguyen, John Arcaroli, Fiore Cattaruzza, Joshua E. Meyer, Caitlin Connelly, S. Gail Eckhardt, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2017)

612 Background: Although CRC is rare in young adults, the incidence has increased recently and patients present more commonly with Stage III or IV disease which may reflect differing biology. Prior analyses revealed a statistically significant increase in the risk of death in young patients with metastatic CRC compared to older patients. Methods: To assess age-dependent genetic changes, DNA and RNA from younger ( &lt; 40) and older ( &gt; 65) CRC were isolated, and whole exome and transcriptome sequencing analysis from 4699 FFPE CRC clinical specimens were performed. Hybridization capture was performed on up to 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Samples were sequenced to high (average 688X) uniform coverage. CRC PDXs were injected into athymic nude mice and randomized into vehicle control, refametinib (MEKi), OMP-18R5 (monoclonal Ab against FZD 1, 2, 5, 7, and 8), or the combination and treated for at least 28 days. Results: Gene alteration rates in the younger and older cohorts were similar in a majority of the genes analyzed. Alterations in CTNNB1 [p &lt; 0.001, False Discovery Rate (FDR) = 0.07] and MLH1 (p &lt; 0.001, FDR = 0.017) were found to be more common in younger patients. Older patients were more likely to have alterations in APC (p &lt; 0.01, FDR &lt; 0.01) and FAM123B (p &lt; 0.01, FDR = 0.03). The CTNNB1 data provided support to explore the WNT pathway as a potential target for younger patients. Therefore, we conducted an in vivo study of MEKi and OMP-18R5 to assess efficacy in molecularly defined young CRC PDX models. In a young PDX models, we observed enhanced combination effects with tumor growth inhibition index (treated/control) of 13% in the combination arm (compared to tumor growth of 150 %, and 116%, respectively with MEKi and OMP-18R5 alone). Interestingly, in this PDX models, RNA sequencing data showed baseline enrichment in the WNT and mTOR pathway, not observed in the older PDX models. Conclusions: The combination of refametinib and OMP-18R5 showed enhanced antitumor activity in combination compared to the single agent arms. Studies investigating predictive biomarkers of response are currently underway.
Concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for HER2 determination and correlation with clinical and pathological data.
Authors: Hector Randhall Callata-Carhuapoma, Miguel Sotelo Lezama, Santiago Cabezas, Jose Angel Garcia Saenz, Fernando Moreno, Gloria Serrano, Julian Sanz, Jose-Luis Gonzalez-Larriba, Daniel Acosta Eyzaguirre, Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2015)

e11616 Background: In November 2013 the American Society of Clinical Oncology (ASCO) and the College of American Pathologists updated the guidelines for determining HER2 status in order to improve their accuracy and usefulness as a predictive marker in breast cancer (AC Wolff et al. 2013). We studied the correlation between IHC and FISH in our hospital using the previous 2007 ASCO guidelines. These data serve as a reference for comparison with the new recommendations. Methods: Patients diagnosed with HER2-positive invasive breast cancer with HER2 status determined by both IHC and FISH between January 2012 and August 2013, were retrospectively analyzed. Clinical and pathological data, response, and correlation between IHC and FISH were evaluated. Results: One-hundred and thirteen patients were included. Median age: 58 years, ECOG 0-1: 99%, hormonal status: positive 68%, metastatic disease at diagnosis: 4%. HER2 status by IHC was: negative (1+), borderline (2+) and positive (3+) in 11%, 53% and 36%, respectively. HER2 status by FISH (HER2/CEP17 ratio) was negative ( < 1.8), borderline (1.8-2.2) and positive ( > 2.2) in 43%, 4% and 53%, respectively. Seventeen percent of IHC1+ and 32% of IHC2+ were HER2 (+) by FISH and 5% of IHQ3+ were FISH HER2 (-). After excluding borderline (2+) results by IHC, the correlation between IHC and FISH was 80% among FISH HER2 (-) patients and 95% among FISH HER2 (+) patients. Twenty-two FISH HER2 (+) patients received neoadjuvant anti-HER2 treatment, achieving a complete pathological response rate (CPR) of 52%. CPR was considerably higher (57%) when a HER2/CEP17 ratio cut-off > 3 was considered, compared to those patients with a ratio < 3 (43%). Conclusions: We evaluated IHC and FISH for HER2 determination based on the 2007 ASCO guidelines finding an 80% correlation for negative and 95% correlation for positive results. Given the high concordance between IHC 1+/2+ results and FISH, the latter test should be considered the
Is best supportive care really best supportive care?
Authors: R. Lee, J. Von Roenn
Journal: Journal of Clinical Oncology (2009)

9639 Background: With the growth of palliative medicine over the past decade, the paradigm of supportive care has evolved to create new standards for cancer patients. The aim of this study was to define “best supportive care” (BSC) during clinical trials of advanced solid tumors. Methods: Systematic review of the literature using Medline and the Cochrane Central Register of Controlled Trials databases. These were searched for randomized controlled trials in which anticancer therapy was compared with a BSC only arm. Results: A total of 43 studies met our inclusion criteria (publication dates, 1980–2008) with the following cancer types: 22 lung cancer, 6 colorectal, 6 pancreas, 2 gastric, and 7 other cancer types. Thirty-eight studies (88%) provided some definition of supportive care and sixteen studies (37%) used the term BSC. The average survival across treatment arms was 27.5 weeks. All but one study described the use of palliative therapies at the discretion of the treating physician without standardization. Over half of all studies (56%) specifically mentioned analgesics and radiotherapy (RT) for pain control. Other specific interventions listed were steroids (14), antibiotics (10), psychological support (10), nutritional support (9), blood transfusions (8), anti-emetics (6), and anti-depressant or anxiolytic medications (3). One-third of trials (15) reported an equivalent clinical evaluation schedule for both the BSC and treatment arms. Quality of life (QoL) was measured with a validated instrument (e.g., QLQ-30) in 55% of trials and 37% compared the utilization of at least one palliative treatment between groups. Trials using the term BSC were more likely to provide multidisciplinary therapy beyond RT and analgesics (50% vs. 19%; p&lt;0.05). Conclusions: The management of subjects in a BSC arm of clinical trials are highly variable. Overall, the trials compare treatment versus no treatment as subjects in the BSC group likely did not receive care according to current palliative medicine standards. Future randomized clinical trials with a BSC arm should provide a comprehensive, multidisciplinary approach that is consistent with practice guidelines. A standardized BSC approach developed with palliative medicine specialists is warranted for further study. No significant financial relationships to disclose.
RESORCE: An ongoing randomized, double-blind, phase III trial of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) progressing on sorafenib (SOR).
Authors: Jordi Bruix, Richard S. Finn, Masatoshi Kudo, Josep M. Llovet, Shukui Qin, Marie-Aude Le Berre, Andrea Wagner, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2014)

TPS4156^ Background: No standard treatment options are available for patients with HCC that has progressed despite SOR treatment. The oral multikinase inhibitor REG has been shown to have an acceptable safety profile and evidence of antitumor activity in patients with SOR-pretreated HCC (Bruix et al. Eur J Cancer 2013): disease control was achieved in 26/36 patients (72%), and median time to progression (TTP) was 4.3 months; median overall survival (OS) was 13.8 months. On the basis of these results, a phase III trial was designed. Methods: This randomized, double-blind, placebo (Pbo)-controlled, multinational study (ClinicalTrials.gov identifier NCT01774344) will compare the efficacy and tolerability of REG vs Pbo in adults with HCC that has progressed on SOR. Inclusion criteria include Barcelona Clinic Liver Cancer stage B or C disease that cannot benefit from established treatments, Child–Pugh Class A liver function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Patients discontinuing SOR >10 weeks before study entry or who received other previous systemic therapy for HCC will be excluded. Patients are randomized 2:1 to receive REG 160 mg or Pbo once daily for weeks 1–3 of each 4-week cycle; all patients also receive best supportive care. Treatment continues until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Doses of study drug may be delayed or reduced to manage clinically significant drug-related toxicities. The primary endpoint is OS; secondary endpoints are TTP, progression-free survival, objective tumor response, disease control, and safety. Analysis will be according to randomized group, stratified by geographic region (Asia vs rest of world), ECOG PS (0 vs 1), alfa-fetoprotein level (<400 vs ≥400 ng/ml), extrahepatic disease (yes vs no), and macrovascular invasion (yes vs no). In addition, blood, plasma, and archival tissue will be assessed for pharmacokinetic and biomarker analyses, and health-related quality of life will be measured. As of February 2014, 137 out of the planned 530 patients have been randomized. Clinical trial information: NCT01774344.
Comparing Outcomes between Antibody Induction Therapies in Kidney Transplantation
Authors: Neel Koyawala, Jeffrey H. Silber, Paul R. Rosenbaum, Wei Wang, Alexander S. Hill, Joseph G. Reiter, Bijan A. Niknam, Orit Even-Shoshan, Roy D. Bloom, Deirdre Sawinski, Susanna Nazarian, Jennifer Trofe-Clark, Mary Ann Lim, Jesse D. Schold, Peter P. Reese
Journal: Journal of the American Society of Nephrology (2017)

Kidney transplant recipients often receive antibody induction. Previous studies of induction therapy were often limited by short follow-up and/or absence of information about complications. After linking Organ Procurement and Transplantation Network data with Medicare claims, we compared outcomes between three induction therapies for kidney recipients. Using novel matching techniques developed on the basis of 15 clinical and demographic characteristics, we generated 1:1 pairs of alemtuzumab–rabbit antithymocyte globulin (rATG) (5330 pairs) and basiliximab-rATG (9378 pairs) recipients. We used paired Cox regression to analyze the primary outcomes of death and death or allograft failure. Secondary outcomes included death or sepsis, death or lymphoma, death or melanoma, and healthcare resource utilization within 1 year. Compared with rATG recipients, alemtuzumab recipients had higher risk of death (hazard ratio [HR], 1.14; 95% confidence interval [95% CI], 1.03 to 1.26; P &lt;0.01) and death or allograft failure (HR, 1.18; 95% CI, 1.09 to 1.28; P &lt;0.001). Results for death as well as death or allograft failure were generally consistent among elderly and nonelderly subgroups and among pairs receiving oral prednisone. Compared with rATG recipients, basiliximab recipients had higher risk of death (HR, 1.08; 95% CI, 1.01 to 1.16; P =0.03) and death or lymphoma (HR, 1.12; 95% CI, 1.01 to 1.23; P =0.03), although these differences were not confirmed in subgroup analyses. One-year resource utilization was slightly lower among alemtuzumab recipients than among rATG recipients, but did not differ between basiliximab and rATG recipients. This observational evidence indicates that, compared with alemtuzumab and basiliximab, rATG associates with lower risk of adverse outcomes, including mortality.
Analysis of resistance mechanisms to ALK kinase inhibitors in ALK+ NSCLC patients.
Authors: Robert Charles Doebele, Dara L Aisner, Anh T Le, Eamon M Berge, Amanda B. Pilling, Tatiana G. Kutateladze, Andrew James Weickhardt, Wilbur A. Franklin, Marileila Varella-Garcia, D. Ross Camidge
Journal: Journal of Clinical Oncology (2012)

7504 Background: Patients with anaplastic lymphoma kinase (ALK) gene fusions derive significant clinical benefit from crizotinib, an ALK inhibitor; moreover, next generation ALK kinase inhibitors are in development. Unfortunately, drug resistance develops after initial benefit (acquired) or occurs in patients who never derive a benefit (intrinsic). This study aimed to define molecular mechanisms of resistance to ALK kinase inhibitors in ALK+ non-small cell lung cancer (NSCLC) patients. Methods: 30 ALK+ crizotinib-treated NSCLC patients experienced radiologic disease progression, of whom 7 progressed only in the CNS. Of the 23 patients with extra-CNS progression, a biopsy was attempted on 19. One of the patients without tissue post-crizotinib then proceeded to a second generation ALK inhibitor and tissue was obtained post progression on this drug. We performed molecular analysis and initiated cell lines from tumor tissue for these 19 patients. Results: 15 patients had material evaluable for molecular analysis. Six patients (40%) developed secondary mutations in the kinase domain of ALK. Two novel mutations were identified in samples from ALK+ NSCLC patients, F1174C and D1203N. Two patients each demonstrated G1269A or L1196M mutations. Two patients each, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). Four patients demonstrated the presence of another oncogenic driver (1 with EGFR mutation; 3 with KRAS mutation) with or without a persistent ALK gene rearrangement. One patient lacked an ALK gene fusion on progression biopsy, but had no identifiable alternate oncogene alteration. 3 patients retained ALK positivity with no identifiable resistance mechanism. Data on additional patients and an in vitro model of copy number gain will be presented. Conclusions: ALK kinase inhibitor resistance in ALK+ NSCLC occurs through a diverse array of kinase domain mutations, ALK gene fusion CNG, and emergence of second (same cell) or separate (different cell) oncogenic drivers. In order to overcome resistance it will be important to differentiate patients that preserve ALK dominance (secondary mutations and CNG) versus those that have diminished ALK dominance (separate or second oncogenic drivers).
Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation
Authors: V N Thiel, B D Giaimo, P Schwarz, K Soller, V Vas, M Bartkuhn, T J Blätte, K Döhner, L Bullinger, T Borggrefe, H Geiger, F Oswald
Journal: Leukemia (2017)

The AML1/Runx1 transcription factor and its heterodimerization partner CBFβ are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFβ in AE-mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia-initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFβ interaction (AE9aNT). We report that the AE9a/CBFβ interaction is not required for the AE9a-mediated aberrant expression of AML1 target genes, while upregulation/derepression of Notch target genes does require the interaction with CBFβ. Using retroviral transduction to express AE9a in murine adult bone marrow-derived hematopoietic progenitors, we observed that both AE9a and AE9aNT lead to increased myeloproliferation in vivo. However, both development of leukemia and long-term replating capacity are only observed with AE9a but not with AE9aNT. Thus, deregulation of both AML1 and Notch target genes is required for the development of AE9a-driven leukemia.
Tyrosine kinase inhibitors (TKI) treatment of non-small cell lung cancer (NSCLC) patients (p) based on EGFR mutations (m) status in serum only.
Authors: Laia Capdevila, Enric Carcereny, Itziar de Aguirre, Sara Cros, Cristina Queralt, Teresa Moran, Cristina Buges, Erika Mijangos, Nuria Pardo, Rafael Rosell
Journal: Journal of Clinical Oncology (2013)

e19088 Background: Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy. However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless, so far, no data exists for NSCLC p treated according to EGFR m status in serum alone. Methods: We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue. We analyzed p treated with an EGFR TKI for whom EGFR m status was known in serum only (status in tissue unknown due to insufficient material). At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters: PFS, ORR and overall survival (OS). EGFR m analysis was performed in cell free circulating DNA (cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit. Results: 9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS &gt; 2 5.2 mo). Conclusions: Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.
Use of phosphoprotein profiling with high-density fluorescence protein microarray to reveal a response predictor to a multikinase inhibitor sorafenib.
Authors: Tesshi Yamada, Mari Masuda, Wei-Yu Chen, Chi-Long Chen, Kazufumi Honda
Journal: Journal of Clinical Oncology (2013)

e15080 Background: The efficacy of sorafenib in patients with unresectable hepatocellular carcinoma (HCC) has been revealed in the recent phase III SHARP (Sorafenib HCC Assessment Randomized Protocol) clinical trial, but only a small proportion of patients achieved the anticipated therapeutic outcomes. It is essential to identify biomarkers that will discriminate such patients. Methods: We newly developed high-density fluorescence reverse-phase protein arrays and used them to profile the phosphorylation status of 180 signaling molecules in the 120 pathways registered on the NCI-Nature curated database in 23 HCC cell lines with different sensitivities to sorafenib. Results: Among the 180 signaling nodes, we found that the level of ribosomal protein S6 phosphorylated at serine residues 235/236 (p-rpS6 S235/236) was the most significantly correlated with the sensitivity of HCC cells to sorafenib. The high expression of p-rpS6 S235/236 was confirmed immunohistochemically in biopsy samples obtained from HCC patients who responded poorly to sorafenib. Sorafenib-resistant HCC cells showed constitutive activation of the mammalian target of rapamycin (mTOR) and/or the mitogen-activated protein kinase (MAPK) pathways downstream of c-RAF. Conclusions: The present results indicate that p-rpS6 S235/236 is a potential predictor of unresponsiveness to sorafenib. Cross-talk between the mTOR and MAPK signaling pathways in sorafenib-resistant HCC cell lines was also revealed. A combination of mTOR and MAPK inhibitors may improve the efficacy of molecular targeting therapy against HCC.