tbuckley/cabot-search huggingface dataset:
Genomic profiling of young adults with colorectal cancer: A single-institution experience.
Authors: Kristin Lynn Koenig, Christina Sing-Ying Wu, Wei Chen, Wendy L Frankel, Daniel Jones, Weiqiang Zhao, Sameh Mikhail, Sameek Roychowdhury, John L. Hays, Anne M. Noonan, Richard M. Goldberg, Tanios S. Bekaii-Saab, Kristen Keon Ciombor
Journal: Journal of Clinical Oncology (2017)

e15168 Background: 2-8% of all colorectal cancer (CRC) cases are in younger adults (YAs), patients (pts) less than age 50. However, current understanding of CRC in YAs is inadequate, especially that of sporadic onset. We conducted a study to describe the landscape of genomic alterations in YA CRC pts presenting to a large academic practice. Methods: Adult pts with CRC presenting to The Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing (NGS) through a customized 22-gene Ion AmpliSeq Mutation Panel as part of clinical care. Commonly mutated areas of select genes (including AKT1, ALK, BRAF, EGFR, ERBB2/4, FBXW7, FGFR1/2/3, KRAS/NRAS, MET, NOTCH1, PIK3CA, PTEN, TP53) were sequenced from tumor sections. Institutional review board approval was obtained to retrospectively analyze this NGS testing between 1/2013-3/2016. Results: 258 CRC pts underwent genomic profiling. 57 pts (22.1%) were YAs at diagnosis (range 22-49 years); 20 pts (7.8%) were 40 years old or younger. 31 YA pts (54.4%) had metastatic disease. Of the YAs with CRC, 18 pts (31.6%) were diagnosed with R-sided colon, 16 pts (28.1%) with L-sided colon, and 22 pts (38.6%) with rectal cancer. 110 genomic alterations were found in YA pts, with a mean of 1.9 mutations per tumor (range 0-6); 35 (31.8%) of these in 32 (56.1%) YA pts were actionable. Of these 110 alterations, 41.8% were in TP53, 28.2% in KRAS/NRAS, 10.0% in PIK3CA, 3.6% in BRAF, 3.6% in FBXW7, and 2.73% in PTEN. 6 YA pts (10.5%) had microsatellite instability (MSI-H). Only 1 pt had concomitant MSI-H and a BRAF mutation; 4 pts with BRAF mutations were microsatellite stable. Comparing our YA pts to a separate cohort of pts age &gt; 50 who had testing done, no significant difference was seen in mutation incidence in KRAS/NRAS (p = 1.0), TP53 (p = 0.3), PIK3CA (p = 0.128), or BRAF (p = 1.0). Conclusions: Genomic profiling through a targeted NGS panel is feasible as part of routine clinical practice. There is disagreement in the literature on genetic mutations in YA compared to older age CRC pts. Knowledge of the genomic landscape in YAs with CRC will lead to improved understanding of the underlying biology of CRC in YAs as it differs from CRC in older pts, and could impact future care of this cohort.
Expanded IgG lineages from antibody repertoires of melanoma patients to reveal anti-tumor antibodies.
Authors: David R. Minor, Jeff Defalco, Michael Harbell, Alex Scholz, Amy Manning-Bog, Jeremy Sokolove, William H. Robinson, Daniel Emerling
Journal: Journal of Clinical Oncology (2016)

e23113 Background: Analyzing anti-cancer immune responses gives insights into the mechanisms that underlie successful cancer immunotherapies, and may find potentially useful antibodies. Methods: To identify humoral activities coincident with successful immunotherapy, we used flow cytometry to isolate blood plasmablasts from 16 melanoma patients. We used Immune Repertoire Capture technology to sequence the full-length variable regions of natively paired immunoglobulin heavy and light chain genes. Sequences were grouped into putative clonal families based on IgG gene usage and other sequence features. Paired heavy and light chain antibody sequences were gene synthesized from the repertoire and recombinantly expressed as IgG1 monoclonal antibodies. Expressed antibodies were screened for binding and cell-killing activity against tumor cell lines. Results: Diversity of germline gene usage, CDR lengths, and high levels of somatic hypermutation (SHM) were observed. The vast majority of IgG genes had accumulated silent and non-silent mutations ( < 1% were non-mutated). Over 5800 putative antibody clonal families were identified from 11,410 expressible pairs of IgG sequences. A few dominant families, each comprising > 1% of the plasmablasts in a patient repertoire, were identified among hundreds of smaller putative families, many of which also had high SHM levels. A striking level of similarity was seen between antibody families in different melanoma patients. Over 15% of the families, containing over 35% of the total pairs, are families that appear similar in more than one patient. Some antibodies mediated tumor cell cytotoxicity in antibody dependent cytotoxicity and antibody dependent cellular cytotoxicity assays. Three of 16 total patients were on active ipilimumab treatment at the time of repertoire capture, and two of these had the highest plasmablast levels ( > 5% of B cells). Conclusions: Initial results show many shared antibody families between melanoma patients despite the high degree of diversity seen in the antibody repertoires. Antibodies discovered through these techniques may have clinically useful features. Ipilimumab therapy may raise plasmablast levels.
Baseline quality of life (QOL) as a predictor of stopping chemotherapy early, and of overall survival, in platinum-resistant/refractory ovarian cancer (PRROC): The GCIG symptom benefit study (SBS).
Authors: Felicia Roncolato, Rachel O'Connell, Luke Buizen, Florence Joly, Anne Lanceley, Felix Hilpert, Aikou Okamoto, Eriko Aotani, Sandro Pignata, Paul P. Donnellan, Amit M. Oza, Elisabeth Avall-Lundqvist, Jonathan S. Berek, Katrin Marie Sjoquist, Kim Gillies, Martin R. Stockler, Madeleine Trudy King, Michael Friedlander
Journal: Journal of Clinical Oncology (2016)

5508 Background: 110 (19%) of the 570 women with PRROC enrolled in SBS stopped chemotherapy within 8 weeks. We sought to identify baseline characteristics, including QOL and clinical factors, that were associated with overall survival and stopping chemotherapy early. Methods: QOL domains were measured with the EORTC QLQ-C30 and QLQ-OV28. QLQ-C30 subscales were dichotomised using cut-points recommended by Diouf et al (The Oncologist 2015). Cox's Proportional Hazards regression was used to assess univariable and multivariable associations with overall survival. Clinical factors for the multivariable model were selected using backward elimination; candidate variables included those with P<0.05 in univariable analyses. The association between baseline QOL domains and stopping chemotherapy early was determined by categorising the QOL domains and using a chi-squared test. Results: Univariable analyses of baseline QOL data (N=545) showed that physical function (PF), role function (RF), global health status (GHS) and abdominal/GI symptoms (AGIS) were significantly associated with OS (all p<0.001). Multivariable analyses included haemoglobin, ascites, neutrophil to lymphocyte ratio, platelet count, log serum CA125, and abdominal/GI symptoms. All 4 QOL domains remained significant in multivariable models (p=0.001, p=0.005, p=0.014, p=0.027 respectively). Low GHS, RF, PF and high AGIS were all significantly associated with stopping chemotherapy within 8 weeks (all p<0.007). Conclusions: GHS, PF, RF and AGIS were independent predictors for OS and are significantly associated with stopping chemotherapy early. Assessment of QOL could help identify patients with PRROC unlikely to benefit from palliative chemotherapy. Clinical trial information: ACTRN12607000603415.
Variance in Multidisciplinary (MultiD) recommendations in a conference only vs co-located clinic model.
Authors: Fedoria Elaine Rugless Stewart, Matthew Smeltzer, Nicholas Ryan Faris, Courtney Foust, Bianca Michelle Jackson, Kristina S. Roark, Laura McHugh, Raymond S Signore, Georgia Oliver, Edward T Robbins, Lisa Klesges, Raymond U. Osarogiagbon
Journal: Journal of Clinical Oncology (2016)

e18039 Background: New MultiD models can provide healthcare systems with improvements in care for high risk populations. Deviation from MultiD recommendations has been associated with worse survival in lung cancer patients. We compared the concordance rate of recommendations developed out of a MultiD conference for patients who were seen or not seen within a co-located MultiD clinic. Methods: From 2014 to 2015, NCCN guideline driven recommendations for care, generated out of a weekly MultiD conference for patients seen and not seen within a co-located clinic were prospectively recorded. MultiD case recommendations were communicated to the relevant clinical care providers by verified closed-loop communication, within 48 hours of review. After an interval of 30 days, we recorded the concordance between MultiD recommendations and actual care provided, and categorized the causes of discordance into 3 areas: provider-, patient-, or insurance-induced. We used the Fishers Exact test to compare the discordance rate of patients seen within the co-located clinic vs those not seen in the co-located clinic (conference-only model). Results: The discordance rate in the co-located model (n=182) was 6%, compared to 17% in the conference only model (n= 184) (p=.002). In both models, approximately 50% of the discordance was patient-induced, and 50% was provider induced (Table 1). The greatest amount of discordance occurred among recommendations for additional biopsy, additional radiologic studies, and definitive treatment. Conclusions: Even with closed-loop communication with providers, the conference only MultiD model of care was associated with a threefold higher discordance rate than care in a co-located clinic (Table 1). The cause of discordance was proportionally similar. Further careful evaluation of models of MultiD care is needed. Variable Conference Only Patients N=184 Co-located Clinic Patients N=182 p-value Mean Age (years) 62 64 N.S. % Private Insurance 48 42 N.S. % African American 29 40 0.02 % Female 56 56 N.S. % Stage III/IV 58 63 N.S. % PS: ECOG (0) 69 63 N.S. % Adenocarcinoma 52 56 N.S. % Discordance rate 17 6 0.002 % Patient Induced 50 55 % Provider Induced 50 45 *Only significant values (p<0.05) given.
Abstract 18284: Incidence of Epilepsy is Elevated in Children and Young Adults With Congenital Heart Defects Compared With the General Population: A Nationwide Cohort Study
Authors: Morten Olsen, Bradley S Marino, Michelle Leisner, Jessica G Woo, Nicolas L Madsen
Journal: Circulation (2015)

Perioperative seizures related to surgery for congenital heart defects (CHD) are well described; however, few data exist on the long-term risk of epilepsy in patients with CHD. We aimed to estimate the incidence of epilepsy in children and young adults with CHD compared with the general population. Methods: Utilizing data from the Danish National Registry of Patients (DNRP) we identified all patients diagnosed with CHD before the age of 15 years between 1980 and 2010 who were born during the same period. The DNRP is a nationwide hospital discharge registry covering all Danish hospitals. Previously validated methodology using the DNRP was applied to measure the outcome, epilepsy, as well as presence of extra cardiac defects (ECD) and/or syndromes. We used the Danish Medical Birth Registry to identify preterm birth (gestational age&lt;37 weeks). For each CHD subject, we identified 10 controls from the general population using the Danish Civil Registration System, matched by sex and birth year. A unique personal identifier assigned at birth and used in all Danish public registries enabled virtually complete follow up for migration, death, or epilepsy until January 1, 2013. We computed cumulative incidences and hazard ratios (HR) (split at 5 years of age to obtain proportional hazards) of time from CHD diagnosis (index date for controls) to epilepsy. Results: We identified 14,665 CHD subjects with a median age at diagnosis of 2 (IQR 19) months. By 15 years of age, the cumulative incidence of epilepsy was 4% among CHD subjects. The HR of epilepsy among CHD subjects compared with the control cohort was 3.7 (95% CI: 3.2-4.3) below 5 years of age, and 2.4 (95% CI: 2.1-2.7) from 5 to 33 years of age. In the older age group, HR for patients with severe CHD was 2.8 (95% CI: 2.3-3.5), and for mild and moderate CHD was 2.2 (95% CI: 1.8-2.6). After exclusion of all subjects with ECDs and/or syndromes and preterm birth, corresponding HRs were 2.2 (95% CI: 1.6-3.0) and 1.7 (95% CI: 1.3-2.2), respectively. Conclusion: The epilepsy risk was markedly increased in CHD subjects compared with the age and gender matched controls. These findings add evidence to support the importance of developing neuro-protective measures and potentially long-term epilepsy surveillance strategies in the CHD population.
Short course enzalutamide monotherapy in biochemically recurrent prostate cancer: Clinical and immunologic impact.
Authors: Ravi Amrit Madan, Renee Nicole Donahue, Harpreet Singh, Fatima Karzai, Marc Robert Theoret, Christopher Ryan Heery, Julius Strauss, Nancy Harold, Anna Couvillon, Jennifer L. Marte, Amy Hankin, Italia Grenga, Guinevere Chun, Lisa M Cordes, William Douglas Figg, Philip M. Arlen, William L. Dahut, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2016)

e16619 Background: Enzalutamide (enz) is FDA approved for advanced prostate cancer, but studies are evaluating enz in earlier stages of disease. We have conducted a clinical trial (NCT01875250) of enz ± a therapeutic vaccine in biochemically recurrent prostate cancer. Methods: Eligible patients (pts) had a PSA between 2-20, no metastatic disease and normal testosterone (T). Treatment for all pts included enz 160 mg daily for 84 days (D), but no T lowering therapy was permitted. This analysis evaluated all pts for the impact of enz on PSA and T regardless of randomization. Pts treated with Enz alone were evaluated for immune responses.The impact of the vaccine will be evaluated after protocol-defined requisite follow-up. Results: Median age for all pts (n = 34) was 66 years (range: 52-87), with a median on-study baseline PSA of 4.55 ng/ml (2.02-19.43). Common adverse events included fatigue and breast tenderness, but no pts discontinued enz for toxicity. The median PSA decline was 99% (range: 52% to > 99%) with 11/34 pts having undetectable nadirs. Median time to first PSA rise after 84 D course of enz was 29 D (13-70) and median recovery to baseline in 25 evaluable pts was 190 D (84-469). T increased above normal limits in 18/34 pts (median Tmax = 802 ng/dl). Immune analysis (n = 12) indicated enz alone increased naïve T-cells and NK cells, and decreased several subsets of myeloid derived suppressor cells with a highly suppressive phenotype. Conclusions: The preliminary findings from this study suggest that short-course enz is well tolerated, leads to prolonged PSA suppression and enhanced immune responses in patients with biochemically recurrent prostate cancer. These immune studies provide the rationale for the use of enz in combination with immunotherapeutics in this and other malignancies. Clinical trial information: NCT01875250.
Regional and practice setting differences in the management of EGFR rash among mCRC patients treated with panitumumab: Results of a national survey in the United States.
Authors: Kristina Hool, Kimberly Lowe, Tamer Garawin, Rachel Bergstresser, George Kafatos, Michelle McNamara, Seth Collins, Bruce A. Bach
Journal: Journal of Clinical Oncology (2017)

e15170 Background: Skin toxicity can be a limiting factor for the use of anti-EGFR therapies, such as panitumumab, and there are currently no standard practice guidelines for rash management in the United States (U.S.). This study aimed to evaluate if there were regional or practice setting differences in strategies used among oncologists to manage EGFR rash, including utilization of dermatologic and nursing support. Methods: 250 practicing oncologists who had treated at least three mCRC patients with panitumumab in the last year completed an online survey to report their opinions and perceptions regarding skin toxicity management strategies. Participants reported if they were affiliated with an academic/university or a community-based practice. Participants were stratified into years of practice post-fellowship ( &lt; 10 and &gt; 10 years) and geographic region of primary practice (West, Midwest, Northeast, Southern U.S.). Results: Oncologists surveyed did not consistently utilize dermatology support. 40% (n = 99) of practicing oncologists surveyed reported consulting a dermatologist “occasionally.” Less than 5% reported “always” consulting dermatology and 6% reported “never” utilizing dermatology support. Utilization of dermatology support varied significantly by region. In the Southern US more oncologists reported “never” consulting dermatology while in the Midwest more oncologists reported “always” utilizing dermatology support (p = 0.05). While dermatology was inconsistently utilized, oncologists frequently utilized nursing support to minimize and manage anti-EGFR skin toxicity. 73% (n = 182) of oncologists engaged nursing support to “monitor skin toxicity during treatment” and 70% (n = 175) of oncologists had nursing support to “educate on skin toxicity prior to starting treatment.” Conclusions: While nursing support is consistently utilized by oncologists in the management of EGFR rash in mCRC patients treated with panitumumab, use of dermatology support was inconsistent and varied significantly by region. This lack of consistency in toxicity management strategies highlights the need for increased physician education.
Activity of brigatinib (BRG) in crizotinib (CRZ)-resistant ALK+ NSCLC patients (pts) according to ALK plasma mutation status.
Authors: Lyudmila Bazhenova, J. Graeme Hodgson, Corey J. Langer, George R. Simon, Scott N. Gettinger, Sai-Hong Ignatius Ou, Karen L. Reckamp, Howard Jack West, Alberto Chiappori, Han A. Koh, Julian R. Molina, Alice Tsang Shaw, Jyoti D. Patel, Justin Peter Favaro, Jeff Haney, William Reichmann, David Kerstein, Victor M. Rivera, D. Ross Camidge
Journal: Journal of Clinical Oncology (2017)

9065 Background: BRG is a potent and selective ALK inhibitor with preclinical and clinical activity against wild-type ALK and a broad range of mutants associated with clinical CRZ resistance, including G1202R. Herein we examine the association between BRG efficacy and ALK mutation status using plasma specimens from the initiation of BRG treatment (baseline [BL]) and the end of BRG treatment (EOT) in CRZ-resistant ALK+ NSCLC pts enrolled in the BRG Ph1/2 or pivotal Ph2 (ALTA) trials. Methods: Plasma samples were analyzed using the Resolution Bioscience ctDx Lung Panel v3.0. BRG activity was described using the confirmed objective response rate (cORR) (RECIST v1.1). Data are reported as of May 31, 2016 for the Ph1/2 (NCT01449461) and ALTA (NCT02094573) trials. Results: Of 291 CRZ-resistant ALK+ NSCLC pts enrolled in the Ph1/2 (N = 69) and ALTA (N = 222) trials, evaluable plasma samples were obtained from 67 pts at BL. cORR to BRG in these pts was 49% (33/67). An ALK fusion was detected in plasma in 45% (30/67) of these pts (cORR 57% [17/30]), of whom 33% (10/30) had secondary ALK mutations (cORR 50% [5/10]) and 67% (20/30) did not (cORR 60% [12/20]). Best responses in pts with secondary ALK mutations were: 2 CR (ALK amplification [Amp] copy number [CN] = 10; T1151M); 3 PR (L1196M; E1408V; Amp CN = 6); 4 SD (L1196M; E1419K; F1174C; C1156Y+S1206F+G1269A); 1 PD (T1151R+C1156Y+E1161D+F1174L). Of 67 pts with evaluable plasma at BL, 35 discontinued BRG therapy, of whom 20 had evaluable samples collected at EOT. No new mutations were detected at EOT in 75% (15/20) of pts. Complex mutation patterns were associated with resistance in the remaining 25% (5/20): High-level ALK-Amp (CN = 58); ALK-Amp (CN = 14)+MET-Amp (CN = 6); ALK-S1206F+S1206C+Amp (CN = 6); ALK-G1202R+L1196M+L1198Q; ALK-G1202R+BRAF-V600E+KRAS-G12D. Conclusions: ALK fusions were detected in plasma in &lt; 50% of CRZ-resistant ALK+ NSCLC pts. BRG had substantial activity in ALK fusion–positive pts with a range of CRZ-resistance mutations. Neither primary nor secondary resistance to BRG was associated with any single plasma ALK mutation. The therapeutic implications of complex secondary resistance patterns associated with BRG require further exploration. Clinical trial information: NCT01449461, NCT02094573.
Need for re-evaluation of current guidelines based on results from germline genetic testing in prostate cancer.
Authors: Piper L.W. Nicolosi, Scott T. Michalski, Brandy Freschi, Erin O'Leary, Rita Quintana, Ian Wilson, Martin P. Powers, Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

5009 Background: Inherited risk for prostate cancer (PCa) is potentially associated with more aggressive disease. Recent data indicate that DNA repair gene abnormalities may be much more common than previously appreciated, especially BRCA2, ATM, CHEK2, BRCA1, RAD51D, and PALB2. Herein, we investigate the efficacy of a targeted gene panel in men with PCa and evaluate clinical factors in relationship to current guidelines for genetic screening. Methods: DNA sequencing and exon-level copy number analysis were performed in 1158 PCa patients (pts) between 2013 and 2016 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary PCa panel, most of which were DNA repair genes. Evaluation included Gleason scores and eligibility for genetic screening based on any NCCN testing criteria in pts with positive findings (pathogenic, likely pathogenic, and risk allele). Results: Pathogenic findings were identified in 199 of 1158 (17.2%) pts, 13 pts (1.0%) had two variants. Roughly 75% of detected variants were in genes on the hereditary PCa panel, of which 34.4% were BRCA1/2. Positive variants in HOXB13, a gene associated only with PCa risk, were identified in eight (3.8%) pts. DNA mismatch repair variants, alterations with substantial known therapeutic implications, were detected in 1.7% of samples. A total of 12.4% of pts with Gleason scores of ≤6, compared with 15.4% of those with scores of ≥7 had a pathogenic variant. Within this cohort, 126 (63%) patients with positive results were eligible for genetic testing based on currently available NCCN guidelines, whereas 73 (37%) would not have qualified. Conclusions: Current NCCN guidelines and Gleason scores cannot be used to reliably stratify PCa pts for the presence/absence of pathogenic germline variants. Most positive results identified in this study have important management implications for pts and their families. The percentage of pts with germline variants who did not meet current genetic screening criteria underscores the need for revisiting current guidelines which cannot, at this time, reliably be used to predict pathologic findings on genetic testing.