tbuckley/cabot-search huggingface dataset:
Mechanisms of Primary Drug Resistance in <i>FGFR1</i>-Amplified Lung Cancer
Authors: Florian Malchers, Meryem Ercanoglu, Daniel Schütte, Roberta Castiglione, Verena Tischler, Sebastian Michels, Ilona Dahmen, Johannes Brägelmann, Roopika Menon, Johannes M. Heuckmann, Julie George, Sascha Ansén, Martin L. Sos, Alex Soltermann, Martin Peifer, Jürgen Wolf, Reinhard Büttner, Roman K. Thomas
Journal: Clinical Cancer Research (2017)

Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. Clin Cancer Res; 23(18); 5527-36. ©2017 AACR.
The role of nasal endoscopy screening for NCMH in the DICER1 syndrome.
Authors: Rosamma M Decastro, Shannon Givens, Jeffrey H Kim, Lesley Doros, Laura A Harney, Ann G Carr, Anne Harris, Gretchen M. Williams, Louis P Dehner, Yoav H. Messinger, Kris Ann P Schultz, D Ashley Hill, Douglas R Stewart
Journal: Journal of Clinical Oncology (2016)

e13045 Background: Pleuropulmonary blastoma (PPB), a rare pediatric lung sarcoma, is the hallmark tumor of the familial tumor DICER1 syndrome. Nasal chondromesenchymal hamartoma (NCMH) is a rare tumor of the sinonasal tract that typically occurs in young children. Although benign, NCMH can be locally aggressive and extend into the intracranial space. We have previously published 1 case of NCMH and 1 case of a Schneidarian papilloma from the National Cancer Institute DICER1 study cohort. The prevalence of and need for screening for NCMH in the DICER1 syndrome is unknown. We provide an update on NCMH from our study and investigated the role of screening nasal endoscopy in DICER1 mutation carriers (“cases”)and family controls. Methods: As part of a study on the natural history of the DICER1 syndrome at the National Institutes of Health (NIH) and in collaboration with the International PPB Registry, DICER1 cases and controls were evaluated at the NIH, including exam and nasal endoscopy in ENT clinic. In this analysis of NCMH, we reviewed medical records, imaging studies if available, medical history questionnaires, and abstracted data from the ENT evaluation. Results: 79 cases and 43 controls were evaluated at NIH, including 1 woman with history of two NCMH (22 and 26 years) and 1 man with a Schneiderian papilloma (23 years), both previously reported. An additional female with a history of NCMH at 10 years enrolled in the study. 122 individuals (79 cases, 43 controls) were referred to ENT; 66 (84%) cases and 31 (72%) controls had nasal endoscopy. On endoscopy, 7 cases (11%) and 6 controls (19%) had benign polyps or polypoid changes (P > 0.05). Seven cases and one control were recommended for follow-up nasal CT scan. Of the 6 cases with sinus CT at NIH, five had minimal sinusitis. One 30-year-old woman had a right sinonasal mass. Endoscopic excision of the mass showed allergic fungal sinusitis. There were no lesions suspicious for NCMH in the cases or controls. Conclusions: Clinical and nasal endoscopic screening in our cohort did not reveal occult NCMH and there was no significant difference in the frequency of nasal polyps between cases and controls. Clinical suspicion is needed to correctly diagnose NCMH, a rare tumor even in the DICER1 syndrome.
Preliminary analysis and assessment of breast cancer risk in Japanese women.
Authors: Michiyo Yamada, Takashi Ishikawa, Sadatoshi Sugae, Kazutaka Narui, Eiji Arita, Peter Tonellato, Itaru Endo, Takashi Chishima
Journal: Journal of Clinical Oncology (2017)

e13092 Background: No comprehensive breast cancer risk assessment model for Japanese women exists. Consequently, we have collected Japanese women’s data to investigate key BC risk factors with an objective of deriving a Japanese-women specific BC risk assessment model. Methods: We conducted a retrospective case-control study (paper-based with postal survey) at 15 institutions during 2014-2015. A survey was distributed to Japanese females aged 20-80 who had BC check-up. All pertinent data of a total of 34 factors including demographic and reproductive factors, social history and eating habits was collected. Cases and controls were divided into three groups respectively, premenopausal (PRE; 20 ≤ age &lt; 45), perimenopausal (PERI; 45 ≤ age ≤ 55) and postmenopausal group (POST; 55 &lt; age ≤ 80). Cases and control variables were compared by t-test, chi-square test and Wilcoxon rank sum test. Preliminary BC risk was calculated by logistic regression analysis. Results: A total of 3975 female Japanese datasets were collected, of which 2494 were complete (all variables present) with 1401 controls and 1093 cases were used. There were 222 cases and 332 controls for PRE, 404 cases and 537 controls for PERI, and 467 and 532 controls for POST. The univariate analysis demonstrated that BMI was significantly higher in cases than in controls in all groups (P &lt; 0.01) as was “number of deliveries” in PRE and POST (P &lt; 0.001) and Brinkman index in PRE and PERI (p = 0.017). Multivariate analysis revealed that BC risk was positively associated with BMI (OR 1.080, 95% CI 1.017–1.148, p = 0.012) in PRE, BMI (OR 1.121, 95% CI 1.072–1.174, p &lt; 0.01) and brinkman index (OR 1.000005, 95% CI 1.000002–1.000008, p &lt; 0.01) in PERI, age (OR 1.054, 95% CI 1.028–1.081, p &lt; 0.010), BMI (OR 1.153, 95% CI 1.076-1.171, p &lt; 0.01) and family history (OR 1.497, 95% CI 1.103–2.033, p = 0.001) in POST, while negatively associated with regular exercise (OR 0.672, 95% CI 0.517–0.873, p = 0.003) in POST. Conclusions: BMI in all groups, in addition, the Brinkman index in PERI and age and family history in POST are BC risk factors. Exercise is a protective risk factor in POST. However, the preliminary results are incomplete and further analysis will be conducted before a full risk assessment model is proposed for Japanese women.
Localization of non-receptor tyrosine kinase (nRTK) variants in solid tumor patients using next-generation sequencing (NGS).
Authors: Srishti Sareen, Matthew Stein, Lindsay Kaye Morris, Saradasri Karri, Kruti Patel, David Shibata, Ari M. Vanderwalde, Lee Steven Schwartzberg, Michael Gary Martin
Journal: Journal of Clinical Oncology (2017)

1536 Background: Non-synonymous SNPs (nsSNPs) in nRTKs may serve as oncologic targets and predictive biomarkers, with significant lesions described in various nRTK regions including the tyrosine kinase domain (TKD). NGS allows the entire coding sequence to be evaluated, facilitating the identification of novel lesions. Methods: We searched all nsSNPs in 14 nRTKs in the tumors of patients (pts) at our institution that received NGS with Caris from 2013-2015 with a diagnosis of advanced breast, colon or lung cancer. Substitutions were classified as either within or extra-TKD; in the case of JAK1-3, pseudokinase domain lesions were also identified. In order to predict the pathogenicity of nsSNPs, in silico analysis with PolyPhen-2 (Harvard) was completed. Results: 356 pts (79 breast, 110 colon and 165 lung (156 NSCLC, 11 small cell)) were identified with a median age of 61 years (range 26-86); 58% female; 62% white, 35% black. 245 variants were found, with 200 nsSNPs and 45 known pathologic mutations (Pmut); Pmut were PIK3CA (21 breast, 13 colon, 5 NSCLC) and AKT1 (6 breast). 169/356 (47%) pts had ≥1 nRTK lesion (0-8). 52/200 (26%) nsSNPs were predicted-damaging (pnsSNPs) with in silico analysis among 49 pts (6 breast, 13 colon and 30 NSCLC). pnsSNPs were found in 14/14 nRTKs with median 3 (1-10). The most frequently mutated nRTKs in breast were SRC (2/2 variants were pnsSNPs) and ABL2 (1/5); in colon ABL1 (5/10), JAK3 (3/27) and CDK12 (2/8); and in NSCLC JAK3 (6/20), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). Of 180 nsSNPs with in silico results, 68% were extra-TKD (29/122 variants were pnsSNPs), 23% within the TKD (13/42) and 9% in pseudokinase domains of JAK1-3 (10/16). Notably, 8/10 pseudokinase domain pnsSNPs were in NSCLC pts (3 JAK1, 2 JAK2 and 3 JAK3). Conclusions: &gt; 13% solid tumors held an nRTK nsSNP that was predicted-damaging by in silico analysis, with 69% of these mutations occurring outside of the TKD-proper. Further work is needed to determine how these pnsSNPs affect function and if they are clinically actionable.
The athlete monitoring cycle: a practical guide to interpreting and applying training monitoring data
Authors: Tim J Gabbett, George P Nassis, Eric Oetter, Johan Pretorius, Nick Johnston, Daniel Medina, Gil Rodas, Tom Myslinski, Dan Howells, Adam Beard, Allan Ryan
Journal: British Journal of Sports Medicine (2017)

Given the relationships among athlete workloads, injury1 and performance,2 athlete monitoring has become critical in the high-performance sporting environment. Sports medicine and science staff have a suite of monitoring tools available to track how much ‘work’ an athlete has performed, the response to that ‘work’ and whether the athlete is in a relative state of fitness or fatigue. The volume of literature, coupled with clever marketing around the ‘best approaches’ to optimising athlete performance, has resulted in practitioners having more choices than ever before. Furthermore, the range of different practices used in sport and the lack of agreement between parties emphasise the importance of having a clear rationale for athlete monitoring. The aim of this paper is to provide a practical guide to strategic planning, analysing, interpreting and applying athlete monitoring data in the sporting environment irrespective of data management software.

When deciding on the athlete monitoring tools to use with your athletes, the first question one should ask is “What do I want to achieve through athlete monitoring?” Quite commonly, the answer is to maximise the positive effects (eg, fitness, readiness and performance) and minimise the negative effects (eg, excessive fatigue, injury and illness) of training. Once practitioners know the reasons for athlete monitoring, appropriate tools can be chosen in order to answer the athlete monitoring question.

For example, if practitioners wish to maximise ‘fitness’ and minimise ‘fatigue’, then appropriate monitoring tools to measure these outcomes are necessary. Measurement of fitness improvements for a Premier League football player (eg, a Yo-Yo test) …
Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies.
Authors: David R. Spigel, Alexa Betzig Schrock, David Fabrizio, Garrett Michael Frampton, James Sun, Jie He, Kyle Gowen, Melissa Lynne Johnson, Todd Michael Bauer, Gregory Peter Kalemkerian, Luis E. Raez, Sai-Hong Ignatius Ou, Jeffrey S. Ross, Philip J. Stephens, Vincent A. Miller, Siraj Mahamed Ali
Journal: Journal of Clinical Oncology (2016)

9017 Background: Immune checkpoint inhibitor (ICPI) therapies, including nivolumab and pembrolizumab, have been FDA-approved in squamous and non-squamous non-small cell (LC). Current IHC based diagnostics are challenged by assay and slide scoring issues, and more robust and comprehensive biomarkers of ICPI efficacy are needed. Methods: Comprehensive genomic profiling (CGP) was performed on FFPE specimens during the course of clinical care. TMB (mutations/Mb) was assessed as the number of somatic, coding, base substitution and indel alterations per Mb of genome. The top quartile of LC was classified as TMB high. Microsatellite instable (MSI-H) or stable (MSS) status was determined using a proprietary computational algorithm. Results: TMB was similar across all LC histologies, but elevated compared to an average TMB of 7.3 for all 60,000+ samples in the database. TMB was consistently low in LC harboring known drivers, with the exception of BRAF or KRAS mutant tumors. (See Table.) 22/5,895 LC cases (0.4%) assessed were MSI-H and 5,849 (99%) were MSS. 21/22 MSI-H cases had high TMB, and represented 9 Adeno, 7 NSCLC NOS, 5 SCC, and 1 SCLC. Alterations in BRCA1, BRCA2, and POLE were significantly enriched in LC with high TMB. 85 (0.7%) of 11,662 LC had PD-L1amplification. Responses to PD-1/PD-L1 targeted therapies and dependence on TMB will be presented. Conclusions: TMB was consistent across LC histologies and was significantly reduced in most LC with confirmed druggable oncogenic drivers, but not in KRAS or BRAF mutated cases. MSI-H status strongly correlated with high TMB. CGP of LC to simultaneously determine TMB, MSI status, PD-L1 amplification, and the presence of driver alterations may provide clinically useful predictors of response to ICPI and other targeted therapies. Adeno (n=7,925) SCC (n=1,324) NSCLC NOS (n=1,773) SCLC (n=640) EGFR mutation (n=1,775) ALK or ROS1 fusion (n=489) METex14 alteration (n=286) BRAF mutation (n=493) KRAS mutation (n=3,155) Mean 9.1 11.3 11.0 10.3 4.5 3.1 6.2 9.7 10.3 TMB > 10 (%) 2350 (30) 541 (41) 711 (40) 269 (42) 129 (7) 17 (3) 27 (9) 153 (31) 1,238 (39) TMB > 20 (%) 760 (10) 113 (9) 233 (13) 42 (7) 21 (1) 4 (1) 4 (1) 51 (10) 298 (9) Wilcoxon signed-rank test vs KRAS P<0.001 P<0.001 P<0.001 P<0.001
Ten-year survival results of ACOSOG Z0011: A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive sentinel node (Alliance).
Authors: Armando E. Giuliano, Kelly Hunt, Karla V. Ballman, Peter D. Beitsch, Pat W. Whitworth, Peter William Blumencranz, A. Marilyn Leitch, Sukamal Saha, Linda Mackie McCall, Monica Morrow
Journal: Journal of Clinical Oncology (2016)

1007 Background: The early results of ACOSOG Z0011 showed that selected sentinel node (SN)-positive patients (pts) treated with sentinel node biopsy (SNB), whole breast irradiation, and adjuvant systemic therapy experienced overall survival (OS) and disease-free survival (DFS) not inferior to those treated with axillary lymph node dissection (ALND). There were concerns that the follow-up was inadequate to assure non-inferiority. The 10-year survival results of Z0011 are reported here. Methods: Clinically node-negative pts with 1 or 2 SNs with H&E-detected metastases were randomized to ALND or no further axillary specific treatment. All pts were to receive whole breast irradiation and systemic therapy. OS and DFS were evaluated. Results: 446 pts were randomized to SNB alone and 445 to SNB + ALND. Pts in both arms were similar with respect to age, tumor size, Bloom-Richardson score, estrogen receptor status, adjuvant systemic therapy, tumor type, and stage. Pts randomized to SNB alone had a median of two lymph nodes removed whereas patients randomized to ALND had a median of 17 nodes removed. 17.6% of ALND pts had 3 or more involved nodes compared to 5.0% of SNB pts (p < 0.001). At a median follow-up of 9.25 years, there were no statistically significant differences in local (p = 0.11) or regional recurrence (p = 0.45) There were only 2 nodal recurrences in the ALND arm and 5 in the SNB alone arm. The 10-year locoregional recurrence-free survival was 93.2% for the ALND arm and 94.1% for the SNB alone arm (p = 0.36). The 10-year OS for pts undergoing SNB + ALND was 83.6% compared to 86.3% for SNB (p = 0.40), and DFS was 78.3% compared to 80.3%, respectively (p = 0.30). Eleven percent of pts did not receive radiation, and there were differences in radiation delivery noted upon review of 228 detailed radiation therapy records: supraclavicular field (18.9%) or high tangents (50%). Variations in radiation delivery were equally distributed among the three arms. Conclusions: Long-term results of ACOSOG Z0011 support the initial conclusion that SNB can achieve survival results not inferior to ALND. Support: U10CA180821, U10CA180882. Clinical trial information: NCT00003855.
Metaplastic carcinoma of the breast, clinico-pathological and prognosis comparison with triple negative breast carcinoma: Experience of the Kuwait Cancer Control Center.
Authors: Mohamed Salah Fayaz, Gerges Attia Demian, Heba El-Sayed Eissa, Mustafa El-Sherify, Suzanne Samir, Sadeq Abuzalouf
Journal: Journal of Clinical Oncology (2016)

e12549 Background: Metaplastic breast carcinoma (MBC) is a rare category of breast malignancy of unique biology. The prognosis of MBC is reported to be worse than that of triple negative invasive duct carcinoma (TN-IDC). This study aimed to evaluate the clinico-pathological features and its impact on the treatment outcome of the MBC patients compared to TN-IDC patients who were treated in Kuwait Cancer Control Center (KCCC). Methods: The study population included 31 MBC and 361 TN-IDC patients retrieved between Jan. 2000 and Dec. 2014. Clinico-pathological characteristics of the two disease groups as well as disease recurrence and survival estimates were evaluated. Results: The Median age of patients at presentation was 50 years for the MBC group and 48 years for the TN- IDC group. Compared to TN-IDC, MBC patients presented with a significantly higher T stage (cT3-4, 74% vs. 35%, P < 0.001), non significant less frequent nodal involvement (30% vs. 43%, P = 0.1), similar incidence of distant metastasis at the first diagnosis (6% each) and higher rate of Ki67 overexpression (93% vs. 57%, p < 0.001). The response to neoadjuvant chemotherapy was less frequent in MBC patients (36% vs. 55%, P = 0.2) as well as the rate of conservative surgery (20% vs. 36%, p = 0.06). At a median follow-up of 32 months (range 2 – 136 months), 9/31 MBC and 105/361TN-IDC experienced disease recurrence with a disease free survival (DFS) of 64% and 70% respectively (P = 0.2) and 83 patients died (7/31 MBC, 76/361 TN- IDC) with overall survival (OS) of 67% and 79% respectively (p = 0.2). When patients were stratified according to lymph node status, node negative MBC patients had a significantly worse OS (70% vs.93%; P = 0.01) and DFS (64% vs. 85%; P = 0.03) compared to those TN-IDC. Conclusions: Compared to TN-IDC, MBC patients presented with more advanced T stage, less frequent nodal involvement and higher Ki67 overexpression. Node negative MBC patients seem to have worse outcome compared to the TN-IDC counterpart.
A phase 1 window of opportunity study of valproic acid (VPA) in breast cancer testing a gene expression biomarker.
Authors: Adam Louis Cohen, Leigh Neumayer, Rachel Factor, Kenneth Boucher, Mark L. Wade, John G Lamb, Kylee Arbogast, Stephen Piccolo, Gajendra Shrestha, Joanna Riegert, Matthias Schabel, Andrea H Bild, Theresa Louise Werner
Journal: Journal of Clinical Oncology (2016)

1084 Background: VPA has anti-cancer activity thought to be due to its ability to inhibit histone deacetylase. We have published a 200 gene mRNA signature, called GDSS-VPA, that predicts breast cancer sensitivity to VPA in vitro and in vivo. The Valproic Acid Signature Trial (VAST, NCT01007695) was a window of opportunity study to examine the tolerability of VPA and assess the ability of the GDSS-VPA to predict biologic changes in breast tumors. Methods: Women with histologically confirmed, untreated breast cancer with breast tumors over 1.5cm diameter were recruited. After a DCE-MRI and tumor biopsy from which RNA was isolated for the GDSS-VPA, women took VPA for 7-12 days starting at 15mg/kg PO BID and increasing as tolerated to a maximum of 25mg/kg PO BID. On the last day of VPA treatment, a DCE-MRI was done and serum VPA level was measured followed by definitive breast surgery or, if chemotherapy was planned, a breast biopsy. Tumor proliferation before and after VPA was assessed by Ki-67 immunohistochemistry. Peripheral blood mononuclear cells (PBMC) were assessed for histone acetylation using western blot. Results: 30 women were evaluable. The median age was 54 (range 31-73). 20% of women had triple negative breast cancer (TNBC). 52% of women tolerated the 25mg/kg BID dose, but 10% stopped early or missed more than 2 doses due to adverse events. 76% of women had a VPA level of at least 100 µg/ml at the end of the study. Grade 3 AEs included one patient with vomiting and diarrhea and one with fatigue. The end serum VPA level correlated with change in PBMC histone acetylation (rho = 0.451, p = 0.024). 33% and 50% of women with TNBC had a Ki-67 reduction of at least 20% and 10%, respectively, compared with 9% and 17% for women without TNBC. GDSS-VPA correlated with a Ki-67 decrease of at least 10% (AUC 0.816) but less so for a decrease of at least 20% (AUC 0.646). Conclusions: Most women tolerate VPA, and it can decrease proliferation in breast tumors. The previously generated gene expression biomarker, GDSS-VPA, correlated with decreased proliferation in breast tumors with VPA treatment. HDAC inhibition is a valid strategy for drug development in TNBC using gene expression biomarkers. Clinical trial information: NCT01007695.