tbuckley/cabot-search huggingface dataset:
Cancer of unknown primary (CUP) with disseminated-lymphadenopathy presentation: Clinicopathological features, prognostic factors, and survival outcomes.
Authors: Kanwal Pratap Singh Raghav, Jignesh Modha, Elizabeth A Lano, Huamin Wang, Aurelio Matamoros, Michael J. Overman, Gauri R. Varadhachary
Journal: Journal of Clinical Oncology (2017)

465 Background: Aside from traditional favorable localized-nodal CUP (LNC) subsets including solitary nodal disease, women with isolated axillary adenocarcinoma and squamous cell carcinoma of cervical/inguinal lymph nodes, there is limited data on disseminated nodal CUP (DNC) presentation. Our study describes the clinicopathologic features and outcomes in nodal CUP (NCUP) highlighting the DNC subset. Methods: We performed a retrospective review of 61 NCUP patients (pts) at UTMDACC (2008 - 2015). For control group (CG), we utilized a cohort of consecutive non-NCUP pts (N = 201) from MDACC CUP database (2012 - 2013). Kaplan-Meier method was used to estimate median overall survival (mOS) and compared with log-rank tests. Results: Median age of NCUP was 61 y, similar to CG (59 y; P = 0.26). In this cohort, 19/61 (31%) and 42 (69%) were classified as LNC and DNC. DNC pts were predominantly women (65%), had good performance status (0/1: 90%), and presented with intrabdominal lymphadenopathy (79%). Sixty percent had carcinoma and majority were high grade (74%). Median immunohistochemical stains performed were 9; most common positive stains were CK7 and pan-keratin. The mOS for entire NCUP cohort was 76 months (m). The mOS for LNC was not reached and was 33.1 m for DNC (HR 0.36; P = 0.04). The mOS of DNC was better than CG (18.8 m; HR 0.62; P = 0.03). Male sex and high neutrophil-lymphocyte ratio (NLR &gt; 5) were poor prognostic factors in DNC ( P &lt; 0.01). Among NCUP pts, 21 reported subsequent development of extra-lymphatic disease [peritoneum/retroperitoneum (29%), liver (24%), lung (19%), muscle/soft tissue (19%), bone (10%)]. Among 36 pts, who had first-line systemic therapy, combination platinum-taxane was used substantially (44%) and was associated with better mOS compared to other regimens (HR 0.20; P &lt; 0.01). Conclusions: Disseminated–lymphadenopathy CUP presentation is a unique clinical subset of CUP which is associated with a significantly better survival than non-NCUP. This distinct entity warrants dedicated research efforts towards understanding biology, developing a cost effective integrated clinical algorithm for management and developing novel therapies.
Hepatic artery therapies for unresectable colorectal liver metastases: Pooled survival analysis of 968 patients from TACE, yttrium-90, and HAI studies.
Authors: Vitor Moutinho, Louise Catherine Connell, Michael Ian D'Angelica, Nancy E. Kemeny
Journal: Journal of Clinical Oncology (2017)

747 Background: Approximately 140,000 people are newly diagnosed with colorectal cancer (CRC) annually, while 50,000 will die from the disease. Median survival has increased with use of modern chemotherapy and biologic agents. Sixty percent of advanced CRC patients (pts) present with or develop liver metastases, with additional treatment options such as hepatic artery therapies. However, there is no strong scientific evidence to support the use of transarterial chemoembolization (TACE), Yttrium 90 (Y90) or chemotherapy infusion (HAI). Methods: Pooled survival analysis of 968 pts with unresectable colorectal liver metastases (CLRM) treated with hepatic artery therapies, including HAI, Y90 or TACE. A rigorous selection of studies was conducted to ensure exchangeability across studies and adequate comparison of groups. Kaplan Meier survival curves were reconstructed from original publications. Data was further stratified into presence or absence of extra-hepatic disease (EHD). Results: Total of 968 pts with mean age 60.5 years, 65.5% male, 64.9% ECOG 0 and 42.4% with EHD. Patient characteristics in the various studies as per Table. Initial analysis showed a significant reduction in the hazard of death comparing HAI &amp; Y90 (HR = 0.45[0.38, 0.55]). There was a 67% reduction in the hazard of death comparing HAI to TACE (HR = 0.33[0.27, 0.41]). Median survival in pts without and with EHD was 32 &amp;16 months for HAI, 11 &amp; 6 months for Y90 and 11 &amp; 8 months for TACE (p &lt; 0.0001). Conclusions: Based on our analysis, HAI offers better survival rates when compared to TACE and Y90. This survival advantage for HAI is not only limited to CRC pts with hepatic disease only, but also is evident in those pts with unresectable CLRM in the setting of co-existent EHD. [Table: see text]
Relationships between food effects, patient adherence to treatment, and pharmacokinetics of oral anticancer drugs.
Authors: Huamao Mark Lin, Ajit Suri, Iain James Webb, Saurabh Aggarwal
Journal: Journal of Clinical Oncology (2014)

e17614 Background: Taking oral anticancer drugs with food has the potential to influence their bioavailability and exposure. The objective of this literature review was to identify oral anticancer drugs with food restrictions in the label, to assess the effects of food on their pharmacokinetics, and to explore food restrictions as a potential barrier to adherence. Methods: A review of U.S. Food and Drug Administration (FDA) labels identified oral anticancer drugs with food restrictions. The effect of food on exposure was quantified by comparing the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) in fed and fasted states. A systematic literature review identified studies investigating the impact of food restrictions on adherence to treatment; sources included PubMed, EMBASE, and Cochrane Reviews. Results: Among 14 oral anticancer drugs approved by the FDA since 2009, 7 have food restrictions: 4 must be taken without food, 2 must be taken with food, and 1 must be taken consistently with or without food. The AUC ratio (fed/fasted) of oral anticancer drugs ranged from 0.78 with axitinib to 10.0 with abiraterone (median = 1.20); the Cmax ratio ranged from 0.4 with everolimus to 17.0 with abiraterone (median = 1.00). A limited number of relevant food restriction studies were identified: 5 of anticancer drugs and 7 of noncancer drugs. Overall, these studies suggest that food restrictions are burdensome, confusing, and associated with reduced adherence to treatment. In one cancer study, 43% of patients who received agents with significant food effects reported that they did not consider the timing of meals before dosing, and 23% were unaware of food restrictions (Muluneh B, et al. ASCO 2012;6042). The incidence of missed doses was also found to be higher for anticancer drugs with food restrictions than those without (Gupta S, et al. ASH 2011;2077). Conclusions: A significant variation in systemic exposure observed with oral agents is related to food intake. Food restrictions are often difficult to comply with and are potentially associated with reduced adherence. Patients receiving oral anticancer drugs with food restrictions must be closely monitored for compliance.
Escape of <i>EML4-ALK</i> NSCLC to early phase precision therapy through <i>TGFβ2-HOX</i>-bioenergetics reprogramming.
Authors: Lihong Yin, Wei Zhang, Ivy Shi, Yan Feng, Humberto Choi, Rakesh K. Bagai, Hideki Makishima, Christopher Lanigan, Joseph Cicenia, Thomas Gildea, Wei-Li Liao, Todd A. Hembrough, Jon Burrows, Raymond R. Tubbs, Daniel Lindner, Francisco Almeida, Jaroslaw P. Maciejewski, Patrick C. Ma
Journal: Journal of Clinical Oncology (2014)

e19044 Background: ALK inhibitor (TKI) is currently the standard precision therapy for advanced EML4-ALK(+) NSCLC. Acquired clinical resistance unavoidably still develops limiting clinical outcome. Methods: EML4-ALK(+) H3122 and patient-derived TKI acquired resistant biopsied-lung tumor tissue cells were used to investigate drug escape mechanisms. Stem cell transcription factors QPCR array and RNA-sequencing profiling were performed on H3122 cells under ALK TKI up to day 14, compared with untreated and drug-washout controls. Cell viability assays using ALK TKIs, in vivo xenograft IHC analyses and quantitative tumor tissue proteomics assay coupled with laser microdissection were also performed. Results: We identified that H3122 cells can escape ALK TKIs (TAE-684, crizotinib) early after precision therapy initiation, with upregulated prosurvival signaling via upregulated autocrine TGFβ2, but not TGFβ1 or β3, during escape as early as at treatment day 14. We validated both in vitro and in vivo the upregulated TGFβ2-HOX-BCL-2/BCL-xL mitochondrial priming during drug escape. A coordinated reprogramming with adaptive induction of stem cell transcription factor genes, especially HOX family genes, was evident in the early drug escape cell state. RNA-sequencing analysis revealed increased EMT-ness (VIM, AXL, GAS6) and cancer stemness (OCT4, NANOG) in these cells undergoing drug adaptation. Moreover, our RNA-seq and proteomics findings strongly suggest a “reverse Warburg” cell state during drug escape. The adaptive cellular plasticity was verified also in patient-derived bronchoscopic biopsied lung adenocarcinoma tissues (Ma0083) with ALK inhibitor resistance. Interestingly, inhibiting mitochondrial priming using dual BCL-2/BCL-xL BH3-mimetics ABT-263 was effective to suppress early drug escape, but not with the BCL-2-specific agent ABT-199, suggesting BCL-xL is a key target. Conclusions: Our study findings provide novel insights into the initial process of evolution of ALK precision therapy drug resistance and highlighted the unique importance of understanding the role of adaptive tumor cell plasticity in the early drug escape emergence, with therapeutic implications.
Multiplex TaqMan assays for a 7-gene prognostic immune response score to differentiate risk among women with ER-negative breast cancer.
Authors: John J. Sninsky, Cindy Christopherson, Robert Lagier, Monica Chang, Shirley Kwok, Vickram Tandon, Dan H. Moore, Frederic Waldman, Amy C. Degnim, James N. Ingle, Christina Yau, Christopher Benz, Cheryl Gillett, Andrew Tutt, Alice M. Wang, Laura Esserman
Journal: Journal of Clinical Oncology (2012)

10586 Background: Teschendorff et al. (Breast Cancer Res 2008) reported a 7-gene, immune response-enriched gene expression classifier using microarrays that was prognostic in women with ER-negative breast cancer. To facilitate further evaluation of the prognostic value of a classifier in archival fixed tumor tissue, we developed two multiplex TaqMan assays to quantify the expression levels of these genes, then trained and validated a 7-gene immune response score (IRS). Methods: RNA was extracted from FFPE sections of 185 ER-negative breast cancer patient samples from Mayo Clinic (n=81), Guy’s Hospital (n=50) and California Pacific Medical Center (CPMC) (n=27). Patients (N+ and N-) did not receive adjuvant therapy and were followed for a minimum of 5 years. Amplification of i) LY9, TNFRSF17, HLA-F, and IGLC2 and ii) XCL2, SPP1, C1QA and two reference genes NUP214 and PPIG were carried out in two multiplex RT-PCR TaqMan reactions and relative expression levels were determined using the DDCT method. The training set, comprised of the Mayo Clinic samples, was used to develop an IRS by using a summation of expression levels of the 7 genes. Association of the IRS with distant metastasis was assessed using a Cox proportional hazards model. The score was subsequently tested in a validation set (Guy’s + CPMC). Results: The amplification efficiency of each gene within the multiplex reactions was comparable to singleplex reactions. Duplicate amplifications showed excellent assay reproducibility and sensitivity (R 2 =0.98). The hazard ratio for a single standard deviation decrease in the IRS was 1.45 (95% CI 0.99-2.12, p=0.056) in the training set and 2.18 (1.32-3.61, p=0.002) in the validation set. ROC curves of continuous IRS to predict distant metastasis within 5 years had AUC of 0.74, 95% CI = 0.60-0.88. Conclusions: Robust multiplex TaqMan assays for FFPE tissue extracted RNA were developed for a 7-gene IRS. Increases in risk are associated with decreases in the IRS. Immune related gene expression clearly plays an important role in the spectrum of risk of ER-negative tumors. Additional signatures are in development that further support this conclusion.
Sunitinib malate in advanced alveolar soft part sarcoma (ASPS): A final update after the closure of the named use program.
Authors: Nadia Hindi, Silvana Pilotti, Roberta Maestro, Angelo Paolo Dei Tos, Elena Palassini, Carlo Morosi, Antonella Messina, Salvatore Provenzano, Tiziana Negri, Marco Fiore, Alessandro Gronchi, Monica Brenca, Paolo Giovanni Casali, Silvia Stacchiotti
Journal: Journal of Clinical Oncology (2015)

10562 Background:We already reported on the activity of sunitinib (SM) in 9 patients (pts) of ASPS. This series is an update. In addition, based on recent evidence demonstrating a role for lactate metabolism in ASPS pathogenesis, we explored the role of MCT1 and MCT4 lactate transporters in SM response Methods: From July 2007 to September 2013, 16 pts with progressive, advanced ASPS (M/F: 10/6; median age: 28 yrs; site of primary: extremities 14, other 2; site of metastases: lung 15, brain 4, bone 3; pretreated with chemotherapy: 10) were put on continuous SM 37.5 mg/day, on a named-use program. Response was evaluated at 2 mos from baseline, then every 3 mos by CT and/or MRI, by RECIST. The expression of MCT1 and MCT4 was analyzed by qRT-PCR in 8 of these cases (7 responders, 1 non-responder) Results:All pts are evaluable for response. 14 pts stopped SM: 9 for PD observed while receiving SM 37.5, 4 for PD observed while receiving SM at a low dose (25 or 12.5 mg/day; SM had to be definitively reduced due to leukopenia and/or renal failure), 1 for definitive surgery. Best response was 1 CR, 9 PR, 4 SD, 2 PD. Median OS has not yet been reached, with 6 pts dead at the time of the present analysis. At a median FU of 32 mos (range 7-75), the median PFS was 13 mos (range 2-59), 9 pts being disease-free at > 12mos. One pt underwent complete surgery plus RT after 6 mos of SM; she is progression-free at 19 mos. Four pts progressed to the CNS, being stable to all other sites of disease, and underwent radiotherapy (RT) of brain lesions; 2 of them continued on SM with no further evidence of progression after 18 and 22mos (these pts were considered PD at the time of CNS progression). Two pts who had to stop SM for progression occurring after reducing SM due to toxicity responded to the rechallenge of SM after having been treated with a MET inhibitor; they are still on SM and progression-free at 5 and 2mos, respectively. The role of MCT genes in response to SM is currently assessed Conclusions:SM is confirmed to be active in ASPS, with long-lasting, dimensional responses. Near 70% of pts maintained responses for > 6mos. Almost 30% of progressions were isolated to CNS. Re-challenge with SM could be an option in previously responding pts who had to stop their therapy due to toxicity
A model-based approach to dose optimization of neurotoxic chemotherapy for metastatic breast cancer (MBC).
Authors: Manish Sharma, Elizabeth Gray, Shailly Mehrotra, Kehua Wu, William Thomas Barry, Clifford A. Hudis, Eric P. Winer, Alan P. Lyss, Deborah Toppmeyer, Alvaro Moreno-Aspitia, Hope S. Rugo, Mark J. Ratain, Jogarao Gobburu
Journal: Journal of Clinical Oncology (2015)

1041 Background: CALGB 40502 (Alliance) randomized patients (pts) with MBC to paclitaxel 90 mg/m2, nab-paclitaxel 150 mg/m2, or ixabepilone 16 mg/m2 on days 1, 8 and 15 every 28 days, with or without bevacizumab. The aims of this analysis were to develop a model of chemotherapy-induced peripheral neuropathy (CIPN) using dosing data and patient-reported symptoms, and to use this model to inform a dose adjustment algorithm to reduce CIPN. Methods: FGSUM4 is the sum of scores from 4 questions of the FACT/GOG Neurotoxicity subscale, which are scored 0-4 on a Likert scale and inquire about numbness/tingling and discomfort in the hands and feet. Of 799 pts, data from 655 with baseline FGSUM4 ≤ 4 were used to develop a kinetic-pharmacodynamic model of CIPN. Baseline height, weight, age, race and prior taxane therapy were evaluated as covariates. The model was evaluated by standard diagnostic plots and bootstrapping. Simulations evaluated the model’s ability to predict later CIPN from early CIPN data. Simulations were also used to explore dose adjustments to minimize later CIPN. Results: The model identified paclitaxel as the least neurotoxic drug in the study: for paclitaxel, the median average dose per day divided by SDK50 (a parameter that reflects clearance and intrinsic toxicity) was 0.56, compared to 0.95 for nab-paclitaxel and 1.02 for ixabepilone. Using the first 3 cycles of data, the model predicts mean FGSUM4 ≥ 5 at later time points with 73% sensitivity and 73% specificity. Simulations support a dose adjustment algorithm in which pts with 4 ≤ FGSUM4 < 8 after 3 cycles skip the day 8 dose in subsequent cycles, while pts with FGSUM4 ≥ 8 skip the day 8 dose and reduce the day 1 and 15 doses by 50%. This algorithm reduces the number of pts with FGSUM4 ≥ 8 after 6 cycles by 33% compared to no dose adjustment. Conclusions: A model of CIPN in pts with MBC treated with neurotoxic chemotherapy was developed using patient-reported symptoms from CALGB 40502. The model can use early CIPN assessments to predict later CIPN with good sensitivity and specificity. Simulations support a dose adjustment algorithm after the first 3 cycles of therapy that reduces later CIPN. Validation of the model with an independent data set is necessary before clinical use.
Therapy of refractory/relapsed metastatic triple-negative breast cancer (TNBC) with an anti-Trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): Phase I/II clinical experience.
Authors: Aditya Bardia, Linda T. Vahdat, Jennifer Robinson Diamond, Alexander Starodub, Rebecca L. Moroose, Steven J. Isakoff, Allyson J. Ocean, Jordan Berlin, Wells A. Messersmith, Sajeve Samuel Thomas, Francois Wilhelm, William A. Wegener, Pius P Maliakal, Robert M. Sharkey, David M. Goldenberg, Ingrid A. Mayer
Journal: Journal of Clinical Oncology (2015)

1016 Background: Patients with metastatic TNBC have an aggressive disease with limited therapy options. The duration of response with standard chemotherapy is usually short, with median PFS of about 3-4 months, and there is an unmet need for better therapies. Trop-2 is highly expressed in most epithelial cancers, including TNBC ( > 90%). IMMU-132 is a conjugate of a humanized anti-Trop-2 (trophoblast cell-surface antigen) mAb coupled site-specifically to SN-38 (7.6 moles SN-38/IgG), the active metabolite of irinotecan, using a proprietary linker. Methods: In an ongoing Phase I/II clinical trial (ClinicalTrials.gov, NCT01631552), patients with metastatic TNBC patients refractory or relapsing to prior therapies, including topoisomerase inhibitors, received IMMU-132 i.v. on days 1 and 8 of 21-day treatment cycles. Treatment was continued based on tolerance or until progression, with safety and response assessments (RECIST1.1) made every week and at 8-12 weeks, respectively. Dose reductions/delays allowed most patients to continue treatment until progression. Results: As of Feb 2, 2015, a total of 174 pts with relapsed/refractory diverse epithelial tumors have been treated with IMMU-132. Forty-eight pts with TNBC were treated: median age = 51 ys (range, 33-81), median of 4 prior chemotherapies (range, 1-11). In TNBC, Grade 3/4 toxicities included neutropenia (G3, 24%; G4, 6%) and febrile neutropenia (G4, 3%). Other G3 toxicities included diarrhea (3%), anemia (3%), leucopenia (3%), lymphopenia (3%), caecitis (3%). No pt developed antibodies to the conjugate; no one discontinued due to toxicity. Thirty-four TNBC pts had at least 1 response assessment, with an objective response rate (ORR) of 21% (including one complete response), a disease stabilization rate (CR+PR+SD) of 74%, and a clinical benefit ratio with CR+PR+SD ≥ 6 mo = 37% (7 of 15 pt with SD are still on treatment). Conclusions: IMMU-132 therapy is associated with encouraging clinical activity and limited toxicity in patients with metastatic TNBC s/p multiple prior lines of therapy. It warrants further evaluation for this refractory disease. Clinical trial information: NCT01631552.
The clinical trial assessment of infrastructure matrix tool (CT AIM) to improve the quality of research conduct in the community.
Authors: Eileen P. Dimond, Robin Zon, Diane C. St. Germain, Andrea Denicoff, Angela Carrigan, Kandie Dempsey, Worta J. McCaskill-Stevens, Maria Magdalena Gonzalez, Mitchell Z. Berger, Lucy Jean Gansauer, James D. Bearden, Kathy Wilkinson, Donna M. Bryant, Maria Caroline Bell, Beth Lavasseur, Phil Stella, Marjorie J. Good, Kathleen Igo, Octavio Quiñones, Stephen S. Grubbs
Journal: Journal of Clinical Oncology (2014)

6512 Background: ASCO described minimum standards and exemplary attributes for CT sites to improve research quality (Zon et al JCO 2008, JOP 2011; Baer et al JOP 2010). Based on these attributes, the NCI Community Cancer Centers Program (NCCCP) developed and piloted the CT AIM Tool to facilitate research program improvements through self-assessment and benchmarking. The tool identified 9 attributes (see Table) each with 3 progressive levels for research sites to “score” their program from less (Level 1) to more (Level 3) exemplary CT infrastructure (e.g. Level 1- only phase 3 treatment trials open vs. Level 3 – Phase 1/2/3, cancer control and prevention trials open). Methods: From 2011-13, 21 NCCCP sites self assessed their CT programs annually using the tool. Results: See Table. Conclusions: Statistically significant increases (p < 0.0001) occurred in Level 3 (more exemplary) infrastructure ratings from 2011 to 2013 across all 9 attribute categories assessed at the 21 sites. Statistically significant gains were seen in two attributes: CT Portfolio – increases in site early phase and cancer control trial implementation; CT Communication /Awareness - shifts observed from institutionally focused CT education to broader community outreach/engagement. The tool showed utility across the sites for promoting quality improvement, benchmarking research performance, progress reporting and providing metrics for communicating infrastructure needs. Use in research beyond oncology and outside the community setting is plausible. NCI Contract HHSN261200800001E. Attribute and year Level (1-3) and No. of sites (n=21) 1 2 3 CT communication/awareness* p 0.0281 2011 6 11 4 2012 2 10 9 2013 1 10 10 Accrual 2011 5 10 6 2012 4 6 11 2013 4 5 12 Education standards 2011 3 12 6 2012 3 7 11 2013 3 5 13 Multidisc. involvement 2011 2 8 11 2012 3 3 15 2013 2 4 15 Participation in CT process 2011 1 11 9 2012 2 6 13 2013 2 6 13 Physician CT engagement 2011 1 10 10 2012 1 5 15 2013 1 3 17 CT portfolio * p 0.0228 2011 1 12 8 2012 1 6 14 2013 1 3 17 QA 2011 4 11 6 2012 3 8 10 2013 3 4 14 Community outreach/underserved accrual 2011 8 6 7 2012 6 6 9 2013 4 7 10 Level 3 scores for ALL attribute categories from 2011 to 2013* p < 0.0001 67 107 121 * Significant p value for change over time.