tbuckley/cabot-search huggingface dataset:
BRAF inhibitor acquired resistance: A multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms.
Authors: Douglas Buckner Johnson, Alexander M. Menzies, Lisa Zimmer, Zeynep Eroglu, Fei Ye, Shilin Zhao, Antje Sucker, Helen Rizos, Willy Hugo, Ralf Gutzmer, Richard Kefford, Helen Gogas, Xiangju Kong, Richard A Scolyer, Levi A. Garraway, Jeffrey Alan Sosman, Antoni Ribas, Roger Lo, Georgina V. Long, Dirk Schadendorf
Journal: Journal of Clinical Oncology (2015)

9008 Background: Acquired resistance (AR) to BRAF inhibitors (BRAFi) in melanoma is a near-universal phenomenon driven by numerous genetic and non-genetic alterations. Clinical implications of these AR mechanisms have not been described in a large cohort. We assessed the spectrum of BRAFi AR mechanisms and their associated timing of onset, pattern of disease progression (DP), and clinical outcomes. Methods: We compiled clinical and genetic data from 100 patients (pts) with 132 melanoma samples obtained at BRAFi DP from three previously published studies of BRAFi resistance. Whole exome sequencing and/or PCR-based genetic testing were performed on all samples. Associations between AR mechanisms and clinical features/outcomes were assessed with multivariate logistic regression models. Results: In 132 DP samples, putative AR mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAFV600E/K amplifications (13%), MEK1/2 mutations (7%), and non-MAPK pathway alterations (11%). Marked heterogeneity was observed within tumors and patients. BRAFV600E/K amplifications and non-MAPK alterations often co-occurred with other genetic changes, whereas NRAS mutations, MEK1/2 mutations, and BRAF splice variants largely arose in isolation (p = 0.02). Of 19 pts with ≥ 2 DP biopsies, identified AR mechanisms were concordant in only 1 pt (5%). NRAS mutations were associated with vemurafenib use (p = 0.045) and baseline intracranial metastases (p = 0.036). Progression-free survival and patterns of DP were similar across AR mechanisms. The median survival after DP was 6.9 months, and subsequent responses to combined BRAF/MEK inhibition were uncommon (2/15; 13%); no patients responded to ipilimumab (0/24). Post-progression outcomes did not correlate with specific BRAFi AR mechanisms. Conclusions: This is the largest study of acquired BRAFi resistance in pts with BRAF mutant melanoma. Despite marked heterogeneity of AR mechanisms within pts and tumors, NRAS mutations were associated with vemurafenib use and intracranial disease. Further investigation into non-genetic AR mechanisms and immune features of BRAFi progression is warranted.
A phase I dose-escalation study evaluating the effects of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with select relapsed or refractory hematologic malignancies.
Authors: Alexander M. Lesokhin, Martin Gutierrez, Ahmad Sami Halwani, Stephen Maxted Ansell, Philippe Armand, Ivan Borrello, Zdenka E Segota, Adam D. Cohen, Moshe Talpaz, Deepika Cattry, Tracy Turner, Maria Mezes, Christina Hartman, Ashok Kumar Gupta, Su Young Kim, Jon M. Wigginton, John Timmerman
Journal: Journal of Clinical Oncology (2013)

TPS3113 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.
Will Chinese oncologists refer cancer survivors to psychological support for survivorship care? A cross-sectional survey.
Authors: Lingyun Sun, Yufei Yang, Xia Wang, Dongmei Chen, Jun J. Mao
Journal: Journal of Clinical Oncology (2017)

196 Background: Cancer survivors often experience substantial psychological distress, such as anxiety and depression, due to cancer diagnosis and treatment. As psychological support is still not a standard part of survivorship care in China, little is known about Chinese oncologists’ attitudes towards referring cancer survivors to this service. Methods: We conducted a cross-sectional survey among oncologists who were attending the 18 th annual meeting of Chinese Society of Clinical Oncology (CSCO, September 16 th - 20 th 2015) in Xiamen, China. Participants voluntarily completed a questionnaire measuring their demographics and occupational information. The outcome variable was willingness to refer cancer survivors to psychological support. We used a multivariate logistic regression model to evaluate the factors associated with such willingness. Results: Among 351 responders, 53% were male, with a mean age of 38±9 years. Half of the oncologists were senior attendings, 34% were junior attendings, and 17% were residents. More than half of the physicians (58%) had an additional Masters or PhD degree. The majority of oncologists (263, 79%) were willing to refer their patients to psychological support as part of survivorship care. Physicians over 40 years old were more likely to recommend psychological support than their younger colleagues (85% versus 76%, p = 0.048). In multi-variable logistic regression model, controlled by gender and education level, physicians &gt; 40 years were associated with more willingness to refer their patients to psychological support than physicians ≤ 40 years (odds ratio [OR] 2.9, 95% confidential interval [C.I.]1.4-6.1, p= 0.01); compared to residents, junior attendings were more likely to recommend psychological support (OR 2.8, 95% C.I. 1.1-7.1, p= 0.03). Conclusions: The majority of Chinese oncologists were willing to refer cancer survivors for psychological support; age and position appeared to impact such willingness. By further educating young Chinese oncologists about the importance of psychological care during survivorship, we can help develop a health care delivery system that better meets Chinese cancer survivors’ psychosocial needs.
Preoperative breast MRI: Who should get it?
Authors: F. Nakhlis, S. Hurwitz, K. A. Mayzel, E. Levin, M. M. Duggan, M. J. Lawler
Journal: Journal of Clinical Oncology (2004)

614 Background: Prospective randomized studies of surgical therapy for breast cancer have shown that surgical decision-making, based on clinical data and conventional imaging, results in low rates of IBTR and contralateral cancers. Breast MRI has emerged as an imaging adjunct suggested to better define the true extent of subclinical ipsilateral and contralateral disease. Due to high sensitivity but low specificity of MRI, its accuracy and cost-effectiveness require further evaluation. The purpose of this study was to identify the subset of breast cancer patients with the greatest potential to benefit from preoperative MRI. Methods: The records of 130 primary breast cancer patients treated between 12/97 and 12/01 were reviewed. Mammography and ultrasound (bilateral or focused) were supplemented by bilateral breast MRI prior to definitive surgery. Patients in whom MRI changed surgical plans (group 1) were compared to those in whom it did not (group 2). Nonparametric methods were used for data analysis. Results: MRI altered surgery in 20 patients (15.4% of total) by showing more ipsilateral disease in 14 women, leading to mastectomy, and by finding 1 contralateral cancer. In both groups mean age, menopausal status, HRT use, mammographic breast density, clinically obvious tumors, and the mean number of surgeries to achieve clear margins were similar. Based on MRI results, the two groups did not differ in tumor size, but group 1 had more multifocal (p=0.000011) and multicentric (p=0.02) disease. On final pathology, the invasive tumor size, infiltrating lobular phenotype and multicentricity were similar in both groups, but group 1 had more multifocal disease (p=0.02). Overall, tumor size determined by MRI and pathology correlated well. More women in group 1 had mastectomy (90% vs 38%, p<0.0001). Conclusion: MRI can help in planning surgical therapy for primary breast cancer. Although we found a correlation between tumor size and multifocality determined by MRI and pathologic measurement, multicentricity did not correlate. In this study, we could not identify a patient profile, which would benefit from preoperative MRI, thus if large-scale prospective data become available, its routine use could be better justified. No significant financial relationships to disclose.
A phase I/II multi-center study of intravesical nanoparticle albumin-bound rapamycin (ABI-009) in the treatment of BCG refractory non-muscle invasive bladder cancer.
Authors: James M. McKiernan, Danny Lascano, Jennifer Ahn, Rashed Ghandour, Jamie Sungmin Pak, Arindam RoyChoudhury, Sam Chang, Guarionex Joel DeCastro, Neil Desai
Journal: Journal of Clinical Oncology (2015)

TPS4576 Background: Inactivation of p53 and PTEN mutations promotes progression in bladder cancer via deregulation of the mammalian target of rapamycin signaling pathway (mTOR). mTOR expression increases as a function of the disease stage as it progresses from superficial to invasive bladder cancer. Our group has proven the efficacy of intravesical rapamycin to treat bladder cancer in a mouse model. With the advent of the nanoparticle albumin bound (nab) version of rapamycin (ABI-009), this hydrophobic entity can now be tested intravesically. We sought to investigate the safety and efficacy in the management of Bacillus Calmette-Guerin (BCG) refractory non-muscle invasive urothelial carcinoma of the bladder (NMIBC). Methods: Funded via the NIH small business innovation research program (grants 1R42CA171552 and 3R42CA171552), this combined phase I/II study is currently enrolling patients with BCG refractory NMIBC at Columbia University and Vanderbilt University. BCG refractory is defined as disease recurrence after BCG therapy ( > 9 doses). This population was chosen given the dearth of effective, non-surgical second line options. Inclusion criteria include: histologically confirmed NMIBC including CIS and/or papillary lesions of high-grade Ta/T1, refractory to BCG; be eligible and refuse radical cystectomy; have all grossly visible disease fully resected. A maximum of 15 patients will be recruited in phase I with a dose-escalation scheme starting at 100 mg and escalating in the 3 remaining cohorts by 100 mg following a 3+3 rule. After the dose is determined, the phase 2 segment will enroll 29 patients. Success will be defined by a complete response in 20% of patients with negative biopsy 6 weeks post-treatment. This trial is enrolling with Cohorts 1 and 2 complete with no DLTs. Cohort 3 has 2 patients who received treatment and 1 receiving treatment with no DLTs thus far. In conclusion, ABI-009 will be the first-in-human molecularly guided mTOR pathway intravesical therapy to be studied for patients with BCG refractory NMIBC. Clinical trial information: NCT02009332.
SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy
Authors: Apurva Sarathy, Ryan D. Wuebbles, Tatiana M. Fontelonga, Ashley R. Tarchione, Lesley A. Mathews Griner, Dante J. Heredia, Andreia M. Nunes, Suzann Duan, Paul D. Brewer, Tyler Van Ry, Grant W. Hennig, Thomas W. Gould, Andrés E. Dulcey, Amy Wang, Xin Xu, Catherine Z. Chen, Xin Hu, Wei Zheng, Noel Southall, Marc Ferrer, Juan Marugan, Dean J. Burkin
Journal: Molecular Therapy (2017)
Effect of aberrantly regulated dysadherin and Bcl-2/Bax2 on tumorigenesis and DNA targeting drug resistance of liver cancer stem cells.
Authors: Nan Jiang, Yang Li, Dan-yun Ruan
Journal: Journal of Clinical Oncology (2015)

e15167 Background: Presence of cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) are highly potential to evade current therapeutic regimen and responsible for tumor recurrence. Studies reported that expression of dysadherin in CSCs could be used as a prognostic indicator, also responsible for treatment failure and poor survival rates. In the current study, we analyzed the role of enhanced dysadherin in drug and apoptosis resistance in human HCC SP cells. Methods: SP cells from 19 human HCC patients were sorted by FACs. RNA interference evaluated the expression of stemness genes(CD133, ABCG2, OCT-4, EpCAM, BCL-2, BAX) in SP cells before and after dysadherin knock down using RT-PCR analysis. Immunohistochemistry (IHC) assays assessed dysadherin protein expression in SP cells. Multidrug resistance assay tested the capacity of SP cells before and after dysadherin knock down treatment with chemotherapy drugs (carboplatin, 5-Flurouracil and doxorubicin).Tumor xenograft experiment evaluate the tumorigenic potential of SP cells. Results: By FACs, we have sorted around 3.7% SP cells from human HCC and they displayed elevated level of dysadherin, stemness proteins, highly drug and apoptosis resistance(P < 0.05). In order to reveal the possible link between dysadherin and tumorigenesis of SP cells, we used SiRNA technology to compromise the expression of dysadherin in SP cells. Interestingly, the SiRNA transfected SP cells showed dramatically reduced stemness proteins, became more sensitive to DNA targeting drugs and apoptotic cell death(P < 0.05). Further, we showed that dysadherin expressing SP cells are highly tumorigenic and able to induce tumor growth in NON/SCID mice. The SP cells derived tumor tissues in turn showed elevated dysadherin. Conclusions: Our study demonstrated that knockdown of dysadherin suppresses the tumorigenic properties of cancer stem like SP cells. Hence, dysadherin is a valuable potential target for the development of novel anti-cancer drugs.
The cachexia score (CASCO) as a tool for staging cachectic cancer patients.
Authors: Clelia Madeddu, Roberto Serpe, Silvia Busquets, Giorgia Antoni, Angelica Betancourt, Silvia Gabba, Francisco Lopez-Soriano, Antonio Maccio', Giovanni Mantovani, Josep Argiles
Journal: Journal of Clinical Oncology (2014)

e20700 Background: An effective treatment for cancer cachexia requires an early recognition of its development by the identification of a staging system. The CAchexia SCOre (CASCO) has been conceived to fulfill the existing gap in the classification of cachectic cancer patients. Methods: CASCO includes 5 main different factors: 1) body weight and lean body mass loss; 2) anorexia; 3) inflammatory, immunological, and metabolic disturbances; 4) physical performance; and 5) quality of life. The scoring scale goes from 0 to 100: mild cachexia (< 25), moderate (> 26 and < 50), severe (> 51 and < 75), and terminal phase (> 76 and ≤100). The score also defines a condition known as pre-cachexia (no lean body weight loss and the sum of the other 4 factors more than 25). Results: 169 cancer patients with tumors at different sites referring at the Department of Medical Oncology, University University of Cagliari, Italy were enrolled. The utilization of CASCO resulted in the following percentages: 36% non-cachectic; 8% pre-cachectic; 8% mild; 32% moderate; 15% severe and 1% terminal phase. Conclusions: CASCO is an useful tool for the identification of pre-cachectic patients, and classification and staging of cachexia according to its main defining components, including laboratory and patient-centered variables. CASCO could allow for a more adequate multidimensional approach for cancer cachexia.
Ikaros expression levels to predict response and survival following pomalidomide and dexamethasone in multiple myeloma (MM).
Authors: Yuan Xiao Zhu, Esteban Braggio, Chang-Xin Shi, K. Martin Kortüm, Laura A Bruins, Jessica E Schmidt, Xiu-bao Chang, Paul Langlais, Luo Moulun, Patrick Jedlowski, Betsy LaPlant, Kristina M Laumann, Rafael Fonseca, P. Leif Bergsagel, Joseph Mikhael, Martha Lacy, Mia D. Champion, A. Keith Stewart
Journal: Journal of Clinical Oncology (2014)

8540 Background: Cereblon (CRBN) binding mediates immunomodulatory drug (IMiD) action in MM. Methods: We identified CRBN binding proteins in the presence or absence of IMiD and examined the clinical significance of binding proteins. Results: The abundance of 46 CRBN binding proteins deceased after IMiDs and the most downregulated proteins include Ikaros transcription factors IKZF1 and IZKF3 (recently identified as rapidly downregulated subsequent to cereblon-IMiD interaction). We then explored the clinical significance of IKZF1/IKZF3 in MM. IZKF gene expression was similar across all MM stages or subtypes however on western blot in a subset of IMiD resistant cell lines IKZF1 is substantially lower. Genetic mutation in IZKF1/3 is observed in < 1% of MM patients however 6/69 MM cell lines (8.7%) have nonsynonymous SNVs including a L208R substitution and codon deletion in the FR4 cell line which has very low levels of IZKF1 and is highly IMiD resistant. Recurrent SNV at Q156K (XG1 and H1112) and at G158R in OCI-MY7 all occur within the critical binding domain of IZKF1/ IZKF3 to CRBN. The significance of the Q156K SNV is unknown as XG1 cells are sensitive to IMiDs. Next, we analyzed IKZF1 and IKZF3 expression levels in 55 refractory MM patients in whom gene expression was measured prior to pomalidomide and dexamethasone therapy on phase II clinical trials. Responders were defined as ≥ PR after 2 cycles of treatment. We determined the quartile cut-off points for IKZF1 expression (for all MM patients) to be 7.6, 8.1 and 8.48, respectively. Response rate was 6% in the lower quartile of IKZF1 expression vs. 39% in the highest 3 quartiles (P = 0.02). IKZF3, IKZF4 and IKZF5, had no difference in expression in responding patients. We demonstrate that IZKF1 levels also correlate with significant differences in progression free survival (3.0 vs. 13 months (m), p < 0.005) with the longest PFS in the highest expression cohort. The median OS for patients with highest 2 quartile IZKF1 expression was 46.6 m and 31.7 m respectively, whereas patients in the lowest quartile had only 7.2 months median OS (p=0.002). Conclusions: IKZF1 binds CRBN and measured prior to pomalidomide therapy is a biomarker for response, PFS and OS.
A phase 1 study of INCB040093, a PI3Kδ inhibitor, alone or in combination with INCB039110, a selective JAK1 inhibitor: Interim results from patients (pts) with relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL).
Authors: Andres Forero-Torres, Paul M. Barr, Catherine S. Magid Diefenbach, Taimur Sher, Richard Schaub, Li Zhou, Jennifer Pulini, Lance Leopold, Matthew A. Spear, Moshe Talpaz, Tycel Jovelle Phillips
Journal: Journal of Clinical Oncology (2015)

8558 Background: Efficacy of treatment options for pts with r/r cHL is limited. Evidence suggests blocking the PI3K or JAK-STAT pathways may be efficacious in cHL directly and through modulation of the tumor microenvironment. Blocking both pathways may provide synergistic efficacy. Methods: Adult pts with r/r B-cell malignancies were enrolled in this ongoing open-label, dose escalation study. INCB040093 was given at doses of 100–300 mg QD or BID alone or 150–300 mg QD or BID with INCB039110 400–600 mg QD. Safety, efficacy, and pharmacodynamics were evaluated. Data from the r/r cHL pts are reported herein. Results: A total of 17 pts with r/r cHL have been enrolled: median age = 34 yrs, 59% men, median of 5 prior regimens, 82% underwent HSCT, and all had failed brentuximab vedotin. Median exposure was 209 days (range: 22+ [ongoing] – 388). The most common nonhematologic AEs (all grades) in this cHL cohort were fatigue (41%), headache (35%), and decreased appetite (35%). One nonhematologic grade ≥ 3 AE occurred in > 1 pt, pneumonia (12%). All grade neutropenia, thrombocytopenia, and anemia occurred in 47%, 47%, and 41%, respectively. Grade ≥ 3 thrombocytopenia occurred in 18%. Of 6 evaluable pts receiving INCB040093, ORR was 50% (1 CR); of 9 evaluable pts receiving INCB040093 + INCB039110, ORR was 67% (2 CRs). In this limited dataset of proximate dose cohorts, a dose response in efficacy was not evident. In the overall study population, INCB040093 100 mg BID and INCB040093 100 mg BID + INCB039110 400 mg QD were selected for expansion based on pharmacodynamics and the safety profile of higher dose levels. At the selected doses, ORR in the cHL cohort was 50% for INCB040093 and 75% (1 CR) for INCB040093 + INCB039110. Conclusions: INCB040093 ± INCB039110 was tolerable in this heavily pretreated population of pts with r/r cHL. Although the number of evaluable pts is limited, efficacy compares well to approved and promising investigational agents. These results warranted further investigation of INCB040093 alone and in combination with INCB039110 in pts with r/r cHL, leading to the initiation of a phase 2 study. Clinical trial information: NCT01905813.