tbuckley/cabot-search huggingface dataset:
Clinical and pathological characterization of patients (pts) with functional deficiency of the fanconi anemia (FA) pathway.
Authors: Sameh Mikhail, Luay Mousa, Lai Wei, Wenrui Duan, Weiqiang Zhao, Miguel Angel Villalona-Calero
Journal: Journal of Clinical Oncology (2016)

e23247 Background: Genetic and epigenetic FA disruption is expected to occur in a significant proportion of solid tumors. Intact FA pathway is associated with FancD2 repair foci formation in response to DNA damage. We developed an immunofluorescence based method, (Fanconi Anemia Triple Stain Immunofluorescence - FATSI), which permits the observation of FancD2 foci formation and thus test for functional deficiency of the FA pathway. We have previously screened > 640 patients for a trial that evaluates the use of mitomycin +/- ABT888 in pts with FA pathway deficiency. 25% of solid tumors demonstrated functional deficiency of the FA pathway. Our study herein compares clinical characteristics of pts with and without functional deficiency (intact) of FA pathway based on our FATSI assay. Methods: We retrospectively compared clinical and histological features of pts with (def) and without (intact) functional deficiency of the FA pathway as determined by the FATSI assay. Variables included tumor type, histology, grade, stage at presentation, number of metastatic sites and chemotherapy lines, family history, and overall survival (OS). We used Chi-square, Fisher’s exact test and Wilcoxon test as appropriate. Multivariate analysis of OS was conducted using Cox regression model to adjust for confounding variables Results: 361 patients were included in the analysis (def = 183; Intact = 178). The majority of FA def pts were White; 4/18 (22%) pts were African American. Other clinical characteristics were not different between pts with intact and def FA pathway. However, median OS was longer in def pts (40.7 vs 30.6 m; p = 0.038) compared to those with intact FA pathway. Strikingly, FA def was associated with longer OS (HR = 0.29; 95% CI 0.14-0.60; p = 0.001) after adjusting for known prognostic variables. Conclusions: Patients with tumors with FA pathway def have improved survival compared to those with intact FA pathway. This could be due to unique biologic characteristics or to higher susceptibility to DNA interactive cytotoxic treatment. Further research is needed to confirm our findings and determine the utility of FATSI assay as a prognostic marker and its possible use to risk-stratify pts for adjuvant therapy.
A modular, multi-arm, multi-part, first time in patient study to evaluate the safety and tolerability of the dual MET kinase/OCT2 inhibitor, OMO-1, alone and in combination with anti-cancer treatments, in patients with locally advanced, unresectable or metastatic solid malignancies.
Authors: Elizabeth Ruth Plummer, Martijn P. Lolkema, Joachim G.J.V. Aerts, Filip Yves Francine Leon De Vos, Martin Forster, ERIC ANGEVIN, Rebecca Sophie Kristeleit, Tim Perera, Glen Clack, Ann Meulemans, Marion Libouban, Prashanth Hari Dass, Yvette Drew, Nadina Tinsley, Shankar Balaratnam, Sarah Patricia Blagden, Matthew Krebs
Journal: Journal of Clinical Oncology (2018)

TPS2614 Background: OMO-1, a highly selective, oral, small molecule MET kinase/OCT2 inhibitor, demonstrated single agent cellular and in vivo anti-tumour activity, including regression in MET driven xenograft models. Preclinical studies to identify optimal drug combinations Predicted efficacious exposures of OMO-1 were reached without clinically relevant adverse events in healthy volunteers, data from this study expedited the ongoing patient study. Methods: This novel study design consists of distinct study modules, each investigating a different hypothesis. Module 1, investigating OMO-1 monotherapy, commenced in Aug 2017. It consists of Part A (dose finding) and an optional Part B (cohort expansions in relevant clinical indications eg MET amplification or exon 14 skipping mutation). Part A is a traditional 3 + 3 dose escalation design. Part B expansions are powered to compare response rates to historical data. The option to start Part B and add further modules will be based on emerging data, a substantial protocol amendment being put in place before starting a new module. The dosing schedule/sequence of OMO-1 in each module may be adapted in response to emerging data. The maximum tolerated dose of OMO-1 for individual modules may differ based on the emerging safety profile for each combination. For all modules, Part A cohorts may be expanded by up to 12 additional patients, mandatory serial tumour biopsies will be taken and assessed for relevant PD biomarkers. This design allows one protocol to respond to emerging data, supporting studies in both monotherapy and multiple combinations, reducing the time to ‘first subject in study’ compared with multiple individual studies. It also allows investigators to pre-empt emerging data and changes to the treatment landscape. These challenges emphasize the need for flexible designs as the landscape of drug development continues to quickly evolve. Clinical trial information: NCT03138083.
Onset of side effects and adherence to endocrine therapy in the Breast Cancer Endocrine Therapy Adherence (BETA) pilot study.
Authors: Lianne N. Epstein, Ami P. Jhaveri, Gang Han, Maysa M. Abu-Khalaf, Erin Wysong Hofstatter, Tara Beth Sanft, Michael DiGiovanna, Andrea Silber, Kerin B. Adelson, Gina G. Chung, Cary Philip Gross, Lajos Pusztai, Sarah Schellhorn Mougalian
Journal: Journal of Clinical Oncology (2016)

e18136 Background: The standard of care for hormone receptor (HR) positive breast cancer is 5-10 years of adjuvant endocrine therapy (ET). It is estimated that up to 40% of patients may not take ET daily or may discontinue it early, in part due to associated side effects (SEs). Little is known about the time to onset of SEs, as patients might not be seen for 3-6 months after ET initiation. Methods: We completed a single-arm pilot study in 100 patients with stage I-III HR-positive breast cancer initiating ET to evaluate a novel bi-directional text messaging intervention that assessed SEs and adherence to ET during the first 3 months of ET. The intervention texted daily questions about adherence and weekly questions about SEs and their severity directly to participants’ cell phones. Data on patient acceptance of the intervention has previously been presented. Adherence was defined as taking 80% or more of the prescribed pills (correct dose and correct day), and data was collected via participants’ text message responses. Results: Participants were enrolled between November 2014 and October 2015. Patients were prescribed either tamoxifen (36%) or an aromatase inhibitor (64%). On average, participants reported taking ET 85% of days on study; 85% of our participants took at least 80% of their ET daily doses. During the study, 86% of participants reported SEs: 67% reported hot flashes (17% severe), 60% reported arthralgias (14% severe), and 32% reported vaginal symptoms (5% severe). Severe SEs triggered an alert to the clinical team; 35% of participants generated 133 SE alerts. Of those reporting hot flashes, 33% reported onset in the first week, 22% in the second, and 18% in the third. Of those reporting arthralgias, 12% reported onset in the first week, 30% in the second, and 13% in the third. Of those reporting vaginal symptoms, 9% reported onset in the first week, 16% in the second, 16% in the third, and 19% in the fourth. Conclusions: Patients had high overall adherence to ET. Most patients experienced SEs of ET; the majority reported SEs within the first 4 weeks after ET initiation. Despite a small sample, we found higher rates of SEs than described in previous randomized control trials. The time to onset of SEs was short. Clinical trial information: NCT02256670.
The impact of multiple prostate biopsies on radical prostatectomy outcomes: A population-based analysis.
Authors: Daniel Olvera-Posada, Blayne Welk, J. Andrew McClure, Jennifer Winick-Ng, Jonathan Izawa, Stephen E. Pautler
Journal: Journal of Clinical Oncology (2016)

e16554 Background: The impact of multiple transrectal ultrasound-guided prostate biopsies (TRUS-Bx) on the complexity of radical prostatectomy (RP) remains unknown. Data analyzing the effect of multiple previous biopsies in surgical outcomes is sparse and no information about immediate postoperative outcomes is available. We evaluated the impact of repeated TRUS-Bx before RP on surgical outcomes. Methods: A population-based cohort study was designed to compare surgical outcomes between patients with one previous biopsy to patients with ≥ 2 biopsies before RP. All patients who had a RP performed in the province of Ontario from April 1, 2002 to March 31, 2013 were categorized according to the number of prior TRUS-Bx. The primary end point was a composite complication index encompassing the need of postoperative treatment of urinary or rectourethral fistula, intestinal diversion, upper urinary tract obstruction or ureteral injury. Secondary outcomes included functional and health care related. Follow-up time for all outcomes ranged from 12-24 months. Results: Among 27,637 patients, 4780 (17.3%) had ≥ 2 biopsies performed before RP. The proportion of cases who experienced the composite end point was similar between patients with one TRUS-Bx compared to those with ≥ 2 TRUS-Bx (1.1% vs 1.2%, p = 0.38). Patients with ≥ 2 biopsies were more likely to have a blood transfusion during RP hospitalization compared to patients with only one biopsy (15.5% vs 12.8%, OR 1.25 95% CI 1.15-1.37, p < 0.01), while readmission rate and 30-day mortality were similar (3.6% vs 3.3% p = 0.35, 0.2 vs 0.1% p = 0.43). Patients with multiple TRUS-Bx were more likely to require post RP urodynamic evaluation (OR 1.53, 95% CI 1.23-1.91, p < 0.01) but were not at increased risk of incontinence or erectile dysfunction invasive therapies. Conclusions: Perioperative outcomes after RP are similar between men with single or mutiple TRUS-Bx. Multiple TRUS-Bx before RP is associated with slightly increased risk of perioperative blood transfusion and postoperative urodynamic evaluation. This information can be used to counsel patients about similar postoperative outcomes after RP despite having multiple biopsies, including those under AS protocols.
Abstract 18173: Coronary Microvascular Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Mark M Gajjar, Nikhil Narang, Kathryn Dryer, Ranya Sweis, Daniel Schimmel, Jeanette Y Cheng, Sumeet S Mitter, Ajay Yadlapati, Hamorabi Mkrdichian, Keith Benzuly, Margaret Lee, Sanjiv J Shah, John Blair
Journal: Circulation (2016)

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with high mortality; however, clinical trials have yet to definitively demonstrate improved outcomes. Coronary micro...
Modified FOLFIRINOX (mFOLFIRINOX) as second-line chemotherapy in pancreatic adenocarcinoma.
Authors: Andrew Peter Dean, Domenic Higgs, Alex James, Tegan Van Gemert, Alena Talia James
Journal: Journal of Clinical Oncology (2017)

e15747 Background: FOLFIRINOX is a highly effective combination chemotherapy regimen with the reputation of only being tolerable to young patients with good performance status. As the original ACCORD study was carried out at specific French university hospitals with patients performance status 0 or 1 many oncologists feel uncomfortable administering mFOLFIRINOX as a second-line therapy. We have previously reported our experience in 24 patients ages 27 - 84 where we concluded that dose modified FOLFIRINOX can be safely administered to elderly patients with appropriate initial dose reductions and subsequent escalation. There is a lack of consensus on a standard second-line regimen for metastatic pancreatic cancer. We conducted a review of dose intensity and outcome for all patients treated with 2 nd or 3rd-line mFOLFIRINOX for pancreatic adenocarcinoma at St John of God Hospital, Subiaco, Western Australia in order to assess efficacy and tolerability Methods: Electronic records were used to identify 35 patients who had received 1st-line gemcitabine-based chemotherapy who then went on to receive 2nd or 3rd line mFOLFIRINOX. Case files, laboratory and radiology records were then examined to determine outcomes and toxicities. Results: 35 patients were identified with an age range of 27- 85, both locally advanced and metastatic disease, with 12 over the age of 70. All patients except 2 had gemcitabine plus abraxane in the first line setting. Dose intensity was 65% for oxaliplatin, 68% for irinotecan, 18% for bolus 5-FU and 68% fir infusional 5FU. Toxicity was acceptable with a grade 3 toxicity rate of 10%. Overall survival in this group ranged from 5-67 months (median 23 months for locally advanced / 15 months for metastatic). Notably, 20 patients received greater than 6 cycles of treatment and 8 patients received more than 12 cycles. One patient has received 70 cycles. Conclusions: Our experience demonstrates the safety, tolerability and efficacy of mFolfirinox as a second-line therapy after gemcitabine failure. The disease control rate, even with the reduction in dose intensity, suggests that modified Folfirinox should be formally tested in the 2nd line setting in a clinical trial.
Numerical, dimensional or mixed progression disease to imatinib as prognostic factor in patients with metastatic GIST.
Authors: Giuseppe Badalamenti, Lorena Incorvaia, Antonio Galvano, Giovanni Manfredi Assanto, Emmanuela Musso, Ida De Luca, Alessandra Cesarin, Chiara Ancona, Francesco Passiglia, Bruno Vincenzi, Giovanni Grignani, Maria A. Pantaleo, Lidia Gatto, Tommaso Vincenzo Bartolotta, Adele Taibbi, Antonio Russo
Journal: Journal of Clinical Oncology (2017)

11040 Background: The majority of GIST patients with advanced disease initially achieves disease control from imatinib treatment. Approximately 10% of patients progresses within 6 months of starting therapy (primary resistance) and also 50-60% of the responding patients develops progression disease within two years (secondary resistance). Progression disease (PD) can be numerical, dimensional or mixed. The known prognostic factors of risk stratification in local disease are tumor size, mitotic activity and anatomic site. In this retrospective analysis we explore several clinical factors affecting survival in metastatic setting. Methods: The population included in this large database of 128 patients with metastatic GIST was obtained examining data collected from four Oncologic Centres with expertise for the GIST management. The clinical factors analyzed were sex, tumor size, mitotic activity, anatomic site, KIT and PDGFRa mutational status, site of metastasis, FDG-PET status at progressing disease and pattern of tumor progression to I line imatinib 400, II line Imatinib 800 or Sunitinib, evaluated with CT scan or MRI: PD with dimensional growth (dimensional, dPD), with new lesions appearance (numerical, nPD) and with both numerical and dimensional growth (Mixed, mPD). Every factor has been correlated with Overall Survival (OS) measured in months. Survival analyses were performed by using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard regression models were executed to search for association with the outcome. Results: Univariate analysis showed significant value for primary tumor site (p &lt; 0.0001), mitotic activity (p = 0.02), tumor size (p = 0.05) and PD pattern (p = 0.008): OS nPD group was 102.7 months, in dPD group 87 and in mPD group 70. The multivariate analysis confirm significant prognostic factors for OS tumor site (p = 0.0004) and PD pattern (p = 0.02). Conclusions: with the limitations of a retrospective analisys, this study shows for the first time the impact of pattern of progression on OS: patients with dPD have a worse prognosis than those with nPD or mPD, suggesting type of PD as an independent prognostic factor for OS in advanced GISTs.
Sexual activity and function in male cancer patients receiving targeted an immune therapies.
Authors: Katy K. Tsai, Puneet Kamal, Joris Ramstein, Alain Patrick Algazi, Adil Daud, James F Smith
Journal: Journal of Clinical Oncology (2017)

e21594 Background: Survivorship concerns–including sexual function–move increasingly to the foreground in cancer patient care as systemic therapies improve response and survival. Patients are often committed to long-term treatment with tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) despite poor characterization of their effects on sexual function. We sought to assess sexual activity and function in patients receiving TKI or ICI. Methods: A cohort of men receiving TKI/ICI at the UCSF Helen Diller Family Comprehensive Cancer Center were retrospectively identified. Eligible men were on ongoing TKI/ICI therapy. Detailed questionnaires addressing cancer history, treatment history, and sexual activity/function while receiving therapy were completed. Results: Between January 2013 to September 2016, 51 men completed questionnaires. Mean age was 46 years (SD 12, range 21-72). Most (61%) were CML patients, with 12% RCC, 10% GIST, 6% melanoma, and NET, oligodendroglioma, and HCC comprising remaining histologies. 96% were treated with TKI, and 4% with ICI (pembrolizumab). 32% identified as being married or in a domestic partnership, and 18% identified as single. Only 14% reported no attempted sexual activity. Sexual desire was described as low or very low to none in 29%, average in 39%, and high or very high in 29%. Since cancer diagnosis, 21 (41%) of patients noted a reduced amount of semen upon ejaculation, and all but 5 of those patients noted this as at least somewhat bothersome. 35% of patients reported feeling at least somewhat distressed from sexual experiences since cancer diagnosis, including concern that their time to ejaculation may leave their partners feeling unfulfilled (45%), decreased sensation of orgasm (35%), difficulty maintaining erection until completion of intercourse (23%), and pain/discomfort upon ejaculation (12%). Conclusions: The majority of men on TKI or ICI remain sexually active, with a significant portion reporting sexual dysfunction. These findings highlight the need for oncology care providers to proactively manage sexual dysfunction to improve quality of life for cancer patients. Retrospective and prospective studies are ongoing to further characterize this cohort.
IRX4204 in combination with erlotinib to target distinct pathways in lung cancer cells.
Authors: Xi Liu, Jason Roszik, Masanori Karakami, Martin Sanders, Rosh Chandraratna, Ethan Dmitrovsky, Konstantin H. Dragnev
Journal: Journal of Clinical Oncology (2017)

e14095 Background: IRX4204 is a Retinoid X Receptor (RXR) specific agonist (rexinoid). IRX4204 has high potency as a RXR agonist with low binding affinity to Retinoic Acid Receptors (RARs), PPAR, FXR or LXR. Our prior work with the less specific rexinoid bexarotene and erlotinib showed clinical activity in patients with lung cancer cases that harbored KRAS mutations. IRX4204 inhibits lung cancer cell proliferation and can chemoprevent carcinogen-induced lung cancers in mice. We sought to explore the underlying mechanisms engaged by the combination of IRX4204 and erlotinib. Materials and Methods: Human (H1703 and HOP62) and murine (ED1 and LKR13) lung cancer cell lines were treated with IRX4204, erlotinib, IRX4204 plus erlotinib, or vehicle. Reverse phase protein array (RPPA) and mRNA microarray analyses were performed to analyze comprehensively for differentially expressed growth regulatory proteins. Results: Combination of IRX4204 and erlotinib suppressed proliferation of both KRAS mutant (HOP62 and LKR13) and wild-type (H1703 and ED1) lung cancer cell lines. Additive effect was observed as compared to IRX4204 or erlotinib treatment alone. Combining IRX4204 with erlotinib markedly increased inhibition of specific therapeutic targets including Src, phosphorylated Akt and ribosomal S6 proteins. At the mRNA level, Ingenuity Pathway Analysis of species significantly increased or decreased by the combination treatment revealed multiple pathways related to oncogenic signaling. Specifically, we found in H1703 cell line regulation of Granzyme A and AMPK signaling and in HOP62 cell line inhibition of angiogenesis was implicated by altering TSP1 expression. Notably, in ED1 cell line PPARα/RXRα activation, PTEN signaling, PI3K/AKT signaling, TGF-β signaling, and AMPK signaling were each associated with effects of IRX4204 combined with erlotinib. Conclusions: Taken together, these data highlight specific mechanisms and candidate pharmacodynamic biomarkers of response to the combination of this rexinoid and EGFR-TKI in lung cancer. Based on these findings, a clinical trial (NCT02991651) with IRX4204 in combination with erlotinib is underway to treat patients with chemotherapy-refractory non-small cell lung cancer.
Effect of anti-CTGF human recombinant monoclonal antibody pamrevlumab on resectability and resection rate when combined with gemcitabine/nab-paclitaxel in phase 1/2 clinical study for the treatment of locally advanced pancreatic cancer patients.
Authors: Vincent J. Picozzi, Michael J. Pishvaian, Kabir Mody, Jordan Michael Winter, John A. Glaspy, Tim Larson, Marc Ryan Matrana, Khalil Saikali, Mairead Carney, Seth Porter, Peony Yu, Elias Kouchakji, Ewa Carrier
Journal: Journal of Clinical Oncology (2018)

4016 Background: Pancreatic ductal adenocarcinomas exhibit high degree of desmoplasia with extensive connective tissue growth factor (CTGF) expression and extracellular matrix production. CTGF overexpression is associated with aberrant fibrous tissue in mouse model, in which progression of tissue adhesion was inhibited by pamrevlumab. We hypothesize that pamrevlumab, an anti-CTGF antibody, may influence resectability of locally advanced pancreatic cancer (LAPC) by inhibiting effects of CTGF. Methods: Pamrevlumab + gemcitabine/Nab-paclitaxel (G/N) (Arm A) vs G/N (Arm B) was given to treatment-naïve LAPC patients to improve resection rate and overall survival (OS). Patients (N = 37) were randomized 2:1 in Arm A vs Arm B. Patients who completed 6 cycles of treatment underwent resectability assessment per protocol criteria (NCCN, CA 19-9, PET, RECIST) and, if found eligible, underwent resection. No adjuvant therapy was given; second line therapy was administered per investigator discretion. Results: In the ITT population, a higher percentage of patients discontinued treatment in Arm B (46.2%) vs Arm A (25%), mainly due to disease progression or adverse events. More patients normalized PET in Arm A (35%) vs Arm B (23%). Thirty percent of patients overall had best objective RECIST response (CR + PR). More patients were eligible for surgery and were resected in Arm A vs Arm B; 70.8% vs 15.4% and 33.3% vs 7.7%, respectively. Improvement in OS was noted in patients eligible for surgery vs not (27.73 vs 18.40 months, p-value = 0.0766) and in patients resected vs not (NE vs 18.56 months, p-value = 0.0141). Progression-free survival showed similar trend (16.39 vs 10.09 months, p-value = 0.1049) and (16.39 vs 10.38 months, p-value = 0.3778), respectively. No increase in serious adverse events or delay in wound healing post-surgery was observed in Arm A vs. Arm B. Conclusions: These findings indicate that pamrevlumab may be a valuable addition to neoadjuvant therapy in LAPC without added toxicity. These results warrant a follow-on study in a larger patient population. Clinical trial information: NCT02210559.