tbuckley/cabot-search huggingface dataset:
Circulating tumor DNA(ctDNA) testing to detect identical gene mutation rates of KRAS, NRAS, PIK3CA and P53 compared to tissue-based testing and reflects treatment efficacy in patients with colorectal cancer.
Authors: Yanhong Deng, Weiwei Zhao, Liu Yang, Jiayu Ling, Linlin Mao, Huabin Hu, Yue Cai, Jianwei Zhang, Shihui Yu
Journal: Journal of Clinical Oncology (2016)

e23066 Background: Molecular profiling for CRC commonly utilizes tissue, however, there are two major limitations. It is hard to overcome the complications of tumor heterogeneity and inconvenient to do multiple biopsies during the surveillance. While the alterations in KRAS have been shown to have a high degree of concordance between tissue and ctDNA testing, a detailed survey of other commonly mutated genes, and the influence of intervening treatment in CRC has not been conducted Methods: Tissue and blood samples underwent sequencing on a 50-gene hotspot AmpliSeq panel (IonTorrent) in a CLIA-compliant setting. The mutation rate and the concordance of gene mutations in tissue and in ctDNA were compared. Follow up blood draw was conducted in some patients Results: 161 patients with colorectal cancer underwent the test. 148 patients had tissue test, and 84 had ctDNA test, 63 had pairs of tissue and ctDNA. With the 50-gene hotspot tissue test, only 9.5% (14 in 148) of the patients did not have any mutation. The most common mutation gene was P53(72.3%, 107 in 148). The mutation rate of KRAS, NRAS, BRAF and PIK3CK in tissue was 45.1%, 4.6%, 5.1%, and 1.5% respectively. Whereas in blood, the mutation rate was 43.9%, 4.9%, 5.1% and 10.9% respectively. Both values are identical and in accord with the known prevalence of mutations observed in mCRC patient populations. In the paired 63 patients, the concordance for KRAS,NRAS, BRAF, PIK3CA and P53 was 96.6%, 100%, 96%, 97.9% and 90.9% respectively. In 25 patients who had more than twice ctDNA surveillance, the dynamic change of mutations in the blood was totally corresponding with the efficacy. 13 patients had no mutations detected after R0 resection, and 6 patients in 14 who received cetuximab treatment gain new mutations(RAS,EGFR,P53,SMARCB) before disease progression. 6 patients had dynamic gain and loss mutationS Conclusions: The common gene mutations rate in CRC detected in ctDNA is identical to that detected in tissue, is thus an appropriate surrogate testing in determining treatment options. And ctDNA reflects treatment efficacy, which warrants routine use in clinical practice
Outcomes of patients 60 and older with ALL: Analysis of the SEER Database.
Authors: Mark Blaine Geyer, Meier Hsu, Sean Devlin, Dan Douer, Jae Hong Park
Journal: Journal of Clinical Oncology (2016)

7021 Background: Cure rates among children and younger adults with ALL have improved significantly in recent decades, but outcomes remain poor in patients (pts) ≥ 60 yrs old. Prohibitive toxicity limits use of pediatric-inspired cytotoxic approaches. Outcome data for large, unselected populations of older adults with ALL is scant. We hereby describe secular trends and define historical context by which studies of emerging novel therapies (e.g. drug-conjugated monoclonal antibodies, bispecific antibodies, genetically modified T cells) may be evaluated. Methods: Using data reported between 1980 and 2011 to SEER 9 registries, we identified 1675 adults age ≥ 60 diagnosed with ALL with known survival time. Overall survival (OS) was defined as months (m) from diagnosis until death or our study’s cutoff of Dec. 31, 2012; median OS and 95% confidence intervals (CI95 ) were estimated using Kaplan-Meier methods. Demographic, county-level and clinical characteristics were assessed for association with OS using Cox regression; variables significant (p < 0.05) in univariate analysis were assessed in a multivariable Cox regression model. Results: Median OS in the entire cohort was 4 m (CI95 3-5); 3 yr OS was 12.8% (CI95 11.2-14.5%). Median follow-up among survivors was 26 m (range 0-286). Age at diagnosis, diagnosis yr, prior cancer history and region of registry were significantly associated with OS and further evaluated in multivariable analysis. OS did not differ significantly by sex, race or median household income. Age and yr of diagnosis remained significantly associated with OS in the multivariate analysis (p < 0.0001 for each), as did region (p = 0.04). Pts diagnosed in 2000 or later had 20% lower risk of death than patients diagnosed pre-1990 (HR 0.8, CI95 0.71-0.91) after adjusting for covariates. Compared to registries in the East, registries in the Northern Plains had significantly higher risk of death after controlling for the other factors (HR 1.21, CI95 1.05-1.39). Conclusions: Despite a modest decrease in early mortality during the study period, possibly reflecting improved supportive care and TKI therapy for Ph+ ALL, long-term OS rates remain low in older ALL pts. There remains an unmet need for tolerable and effective therapies in geriatric ALL pts.
Survival outcomes in elderly patients with muscle invasive bladder cancer: An analysis of the National Cancer Database.
Authors: Benjamin Walker Fischer-Valuck, Yuan Rao, Soumon Rudra, Caressa Hui, Brian Baumann, Hiram Alberto Gay, Jeff M. Michalski
Journal: Journal of Clinical Oncology (2017)

4538 Background: Many elderly patients are precluded from radical cystectomy (RC) due to existing comorbidities or morbidities associated with RC. Chemoradiation therapy (CRT) is an alternative treatment in this population, but remains widely under-utilized with many receiving chemotherapy (CT) or radiation therapy (RT) alone. This population-based analysis sought to determine if CMT has similar overall survival (OS) to RC, and if CRT is associated with improved OS compared to monotherapy in these patients. Methods: We queried the National Cancer Database (NCDB) for all newly diagnosed MIBC (cT2-T4a N0 M0) cases in patients aged 80 years or older from 2004 to 2013. All included patients underwent TURBT followed by RC, RT alone, CT alone, CRT, or no further treatment. Only patients with radiation doses ( &gt; = 50Gy) were included as receiving RT. Kaplan-Meier, log-rank, and multivariate Cox proportional hazards regression was performed with OS as the primary outcome. Results: 10,055 patients aged &gt; = 80 years were identified. 1,588 underwent RC, 839 received RT, 1,013 received CT, 1,035 had CRT, and 5580 had no further treatment. Mean age was 85.1 years (range, 80-90). 82.1% of patients had Stage II disease. Mean follow-up was 27.6 months (range, 0-137.8). Mean survival of the entire cohort was 28.0 months (95% CI, 27.2-28.8). Mean survival was 43.8 months (95% CI, 41.2-46.3) for patients with RC and 40.8 months (95% CI, 38.2-43.3) for CRT (P = 0.85). Mean survival was 29.1 months (95% CI, 26.8-31.4) and 30.7 months (95% CI, 28.2-33.2) for RT alone vs. CT alone, respectively (P &lt; 0.0001 for both RC and CRT comparisons). 5-year OS for CT alone, RT alone, CRT, and RC was 15.7%, 15.1%, 24.0% and 29.6%, respectively. Multivariate analysis adjusting for age, year of diagnosis, gender, race, treatment location, treatment facility, insurance status, Charlson/Deyo Score, grade, and stage demonstrated an OS benefit in favor of CRT (HR 0.70; 95% CI, 0.63-0.77; P &lt; 0.0001) and RC (HR 0.69; 95% CI, 0.63-0.76; P &lt; 0.0001). Conclusions: For elderly patients with MIBC, both RC and CRT were associated with improved OS compared to CT or RT alone. CRT has similar OS compared to RC, and could be considered standard treatment in this population.
Response by Kaier et al to Letter Regarding Article, “Direct Comparison of Cardiac Myosin-Binding Protein C With Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction”
Authors: Thomas E. Kaier, Raphael Twerenbold, Christian Puelacher, Jack Marjot, Nazia Imambaccus, Jasper Boeddinghaus, Thomas Nestelberger, Patrick Badertscher, Zaid Sabti, Maria Rubini Giménez, Karin Wildi, Petra Hillinger, Karin Grimm, Sarah Loeffel, Samyut Shrestha, Dayana Flores Widmer, Janosch Cupa, Nikola Kozhuharov, Òscar Miró, F. Javier Martín-Sánchez, Beata Morawiec, Katharina Rentsch, Jens Lohrmann, Wanda Kloos, Stefan Osswald, Tobias Reichlin, Ekkehard Weber, Michael Marber, Christian Mueller
Journal: Circulation (2018)
Racial disparity in late mortality among older early-stage breast cancer survivors (BCS).
Authors: Kelly Kenzik, Joshua Richman, Meredith L. Kilgore, Maria Pisu, Smita Bhatia
Journal: Journal of Clinical Oncology (2016)

10041 Background: Over 40% of all breast cancer (BC) is diagnosed in women age > 65y; majority will survive the initial diagnosis (dx), especially those with stage 0/1 disease. While disease biology contributes to the inferior outcome among non-Hispanic blacks (NHBs) observed in the early post-diagnosis phase, racial differences in latemortality – overall and cause-specific – and the contribution of comorbidity is not known. Methods: We used SEER data linked with Medicare claims to identify a cohort of 70,385 NHW and NHB BCS diagnosed with incident stage 0/1 disease between 2000 and 2011, at age > 65y, and surviving ≥ 2y from dx. Pre-cancer comorbidity was evaluated using Charlson Comorbidity Index (CCI), and pre-cancer depression, hypertension, and osteoporosis/fractures. Late mortality was defined as 5y survival conditional on surviving 2y after dx. Results: Median age at dx was 75y (66-105); 6.3% were NHB; CCI = 0: 66%, CCI = 2+: 12%. Compared to NHW, NHB BCS were younger at breast cancer dx ( < 75y: 56% vs. 51.5%, p < 0.01), had a higher level of poverty ( > 20% below poverty: 50.8% vs. 11.8%, p < 0.01), higher pre-cancer comorbidity (CCI = 2+ (24.3% vs. 10.7%, p < 0.01), and more often received no treatment for BC (4.5% vs. 2.1%, p < 0.01). 16,628 (23.6%) late deaths were observed (median follow-up: 7y [2-14]). Overall survival was 72.5% for entire cohort; NHW: 73% vs. NHB: 64.9%, p < 0.001; unadjusted HR = 1.4, p < 0.001). The racial difference in late mortality was mitigated after adjustment for age, treatment, poverty and pre-cancer comorbidity (HR = 1.13, p < 0.001). Cause-specific late mortality at 5y was higher in NHBs vs. NHWs for the most common causes of death (primary cancer: 8.2% vs. 4.1%, p < 0.001; CVD: 11.6% vs. 8.9%, p = 0.01; second cancer: 7.5% vs. 6.4%, p = 0.01). After adjustment for factors listed above, racial differences were nonsignificant for CVD- (HR = 1.10, p = 0.09) and second cancer-related mortality (HR = 0.98, p = 0.78). Conclusions: The significantly higher late mortality experienced by NHBs is partially explained by differences in sociodemographics, pre-cancer comorbidity and receipt of treatment, allowing identification of targetable causes for racial differences in late mortality in early-stage breast cancer patients.
Effects of a temporal break between mobilization and conditioning on complications and hospitalization charges in multiple myeloma patients undergoing autologous stem cell transplant (ASCT).
Authors: Jayadev Manikkam Umakanthan, Austin Barry, Valerie Shostrom, Deborah Swanson, Kimberly Schmit-Pokorny, Dawn Jourdan, Muhamed Baljevic, Sarah A. Holstein, Gregory Bociek, Julie Vose, Matthew Alexander Lunning
Journal: Journal of Clinical Oncology (2018)

e20002 Background: ASCT remains an important therapeutic modality in myeloma but can be associated with high cost, prolonged hospitalization and potential complications. We retrospectively analyzed whether a temporal break between stem cell mobilization (SCM) and conditioning (Cn) during ASCT would affect cost efficiency and reduce complications. Methods: Patients (Pts) who underwent melphalan-based ASCT at our hospital between Jan 2013 - Jun 2017 were included in the study. Based on the time interval between SCM and Cn, Pts were divided into two cohorts: No-break (≤ 2 days) Vs Break ((≥3 days). Data including incidence of neutropenic fever, bacteremia, intensive care unit (ICU) care, blood product use and hospitalization charges were collected. Pts with incomplete data or known prior infections were excluded. All Pts received granulocyte colony stimulating factor (GCSF) on day + 7. A Wilcoxon non-parametric test was used to compare the cohorts. Univariate and multivariate analyses were performed. Results: Study population included 127 patients. When compared to the break cohort (N = 62), patients without a break (N = 65) were 5.3 times more likely to have bacteremia (p = 0.0076) and 2.5 times more likely to have neutropenic fevers (p = 0.0315). There was no difference in length of stay but ICU care was lesser in break cohort (p = 0.0334) along with fewer platelet transfusions (p = 0.005). In multivariate analysis, bacteremia remained statistically significant despite method of SCM (GCSF + chemotherapy, GCSF alone, GCSF + Plerixafor) or levofloxacin prophylaxis. Median hospitalization charge was statistically different at $98,674 for Break-cohort Vs $107,111 for No-break cohort (p = 0.0469). Conclusions: Our results support the hypothesis that providing a temporal break between SCM & Cn may be associated with lower rates of infectious complications and better resource utilization. The median hospitalization charge was 8% lower for the break cohort, translating to around $500,000/year of decreased charges at our institution. Further research is required to understand the causal factors. A prospective experience is underway.
A novel prognostic signature based on centrosome amplification-based genes to predict clinical outcomes in breast tumors.
Authors: Angela Ogden, Padmashree C.G. Rida, Ritu Aneja
Journal: Journal of Clinical Oncology (2017)

11604 Background: A majority of breast tumors exhibit centrosome amplification (CA), which imparts aggressive phenotypes like chromosomal instability and invasive behavior. Nevertheless, it is unclear whether CA is associated with poor clinical outcomes after adjusting for potentially confounding factors, like stage and age at diagnosis. Methods: We developed a twenty-gene signature, “CA20,” composed of genes related to centrosome structure and/or whose dysregulation induces CA and tested its prognostic value compared with that of CIN25, a chromosomal instability (CIN) signature, in combined multivariable Cox models using the METABRIC and TCGA microarray breast datasets. The n = 1,969 primary breast cancers of the METABRIC dataset were split randomly and approximately equally into training and validation sets, unlike the n = 524 primary invasive breast cancers of the TCGA dataset, which could not be split to preserve power ≈ 0.80, so bootstrapping was instead used. CA20 and CIN25 were dichotomized by average scores and optimal cutpoints based on the log-rank test. Results: In both discovery and validation METRABRIC sets, CA20 was a significant independent predictor of worse breast cancer-specific survival (HR = 2.9, p &lt; 0.001 and 2.4, p &lt; 0.001, respectively, using average scores as cutpoints; similar results obtained using optimal cutpoints) in multivariable Cox models, unlike CIN25. CA20 score was highly correlated with CIN25 score (ρ = 0.93, p &lt; 10 -6 ). In the TCGA dataset, high CA20 score was associated with 3.8- and 3.7-fold worse overall survival (bootstrap-p = 0.001 and 0.002, respectively, for average and optimal cutpoints) after adjusting for tumor stage and age at diagnosis, unlike CIN25. Also in the TCGA dataset, CA20 correlated very strongly with CIN25 (ρ = 0.95, p &lt; 10 -6 ). Finally, using the TCGA dataset, we identified processes and pathways enriched in the CA20-high group (q &lt; 0.05) that may be potential therapeutic targets, such as DNA repair processes, the DNA integrity checkpoint, and regulation of microtubule dynamics. Conclusions: CA20 is a novel signature with robust prognostic value in breast cancer and identifies patients who might respond to centrosome declustering drugs.
Benchmarking Cancer Centers: From Care Pathways to Integrated Practice Units
Authors: Anke Wind, Francisco Rocha Gonçalves, Edit Marosi, Lucia da Pieve, Monica Groza, Marco Asioli, Marco Albini, Wim van Harten
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Structuring cancer care into pathways can reduce variability in clinical practice and improve patient outcomes. International benchmarking can help centers with regard to development, implementation, and evaluation. A further step in the development of multidisciplinary care is to organize care in integrated practice units (IPUs), encompassing the whole pathway and relevant organizational aspects. However, research on this topic is limited. This article describes the development and results of a benchmark tool for cancer care pathways and explores IPU development in cancer centers. Methods: The benchmark tool was developed according to a 13-step benchmarking method and piloted in 7 European cancer centers. Centers provided data and site visits were performed to understand the context in which the cancer center operates and to clarify additional questions. Benchmark data were structured into pathway development and evaluation and assessed against key IPU features. Results: Benchmark results showed that most centers have formalized multidisciplinary pathways and that care teams differed in composition, and found almost 2-fold differences in mammography use efficiency. Suggestions for improvement included positioning pathways formally and structurally evaluating outcomes at a sufficiently high frequency. Based on the benchmark, 3 centers indicating that they had a breast cancer IPU were scored differently on implementation. Overall, we found that centers in Europe are in various stages of development of pathways and IPUs, ranging from an informal pathway structure to a full IPU-type of organization. Conclusions: A benchmark tool for care pathways was successfully developed and tested, and is available in an open format. Our tool allows for the assessment of pathway organization and can be used to assess the status of IPU development. Opportunities for improvement were identified regarding the organization of care pathways and the development toward IPUs. Three centers are in varying degrees of implementation and can be characterized as breast cancer IPUs. Organizing cancer care in an IPU could yield multiple performance improvements.
Quantitative spatial profiling of PD-1/PD-L1 interaction and HLA-DR/IDO1 to predict outcomes to anti-PD-1 in metastatic melanoma (MM).
Authors: Douglas Buckner Johnson, Jennifer Bordeaux, Ju Young Kim, Christine Vaupel, David L. Rimm, Thai Huu Ho, Richard Wayne Joseph, Adil Daud, Robert Martin Conry, Elizabeth M Gaughan, Anastasios Dimou, Justin M. Balko, James William Smithy, John S Witte, Svetlana B McKee, Nicole Dominiak, Bashar Dabbas, Jeff Hall, Naveen Dakappagari
Journal: Journal of Clinical Oncology (2017)

9517 Background: Although PD-1/L1 axis directed therapies induce durable responses in some mm patients (pts), biomarkers of response remain elusive. We hypothesized that quantifying key immune suppression mechanisms within the tumor microenvironment would provide superior predictors of response to anti-PD-1 compared with single marker assessment. Methods: Pre-treatment tumor biopsies from 124 mm pts treated with anti-PD-1 at 7 academic centers were fluorescently stained with multiple immune markers in discovery (n = 24) and validation (n = 100) cohorts. Selected biomarker signatures, PD-1/PD-L1 interaction score (proportion of PD-1+ cells co-localized with PD-L1) and IDO1/HLA-DR co-expression were evaluated for anti-PD-1 treatment response and survival. Slides were imaged using Vectra; biomarker positive cells and their co-localization were objectively quantified in pathologist-selected regions using novel Automated Quantitative Analysis (AQUA) algorithms. Results: In the discovery cohort, high levels of PD-1/PD-L1 interaction score and/or IDO1/HLA-DR coexpression was strongly positively associated with response to anti-PD-1 (p = 0.0005). In contrast, other individual biomarkers (PD-1, PD-L1, CD8) were not associated with response or survival (p &gt; 0.10). This finding was replicated in the validation cohort: pts with high PD-1/PD-L1 and/or IDO1/HLA-DR were more likely to respond to treatment (p = 0.009). These pts also experienced a three-fold increase in progression free survival (hazards ratio (HR) = 0.33; p = 0.003) and overall survival (HR = 0.34; p = 0.004). Multivariate analyses revealed that these findings were independent of BRAF mutation, stage, LDH and prior therapy. In the combined cohort (n = 124), 80% of responding pts had higher levels of PD-1/PD-L1 interaction scores and/or IDO1/HLA-DR. In contrast, PD-L1 expression alone (≥1% or ≥50%) was not predictive of PFS or OS (p &gt; 0.1). Conclusions: This novel multiplexed method profiling key tumor-immune suppression pathways identified mm pts likely to respond to anti-PD-1 therapy. This method could help stratify patients for PD-1 monotherapy and be useful in guiding future clinical trials.
<i>BRCA</i>-like classification in ovarian cancer: Results from the AGO-TR1-trial.
Authors: Lisa Katharina Richters, Philip C. Schouten, Stefan Kommoss, Jan Hauke, Alexander Burges, Dimo Dietrich, Ahmed El-Balat, Felix Hilpert, Roel Kluin, Martin Leonhard Heubner, Karin Kast, André Heimbach, Elena Ioana Braicu, Sandra Schmidt, Klaus H. Baumann, Christian Jackisch, Sabine C. Linn, Rita K. Schmutzler, Philipp Harter, Eric Hahnen
Journal: Journal of Clinical Oncology (2017)

5546 Background: BRCA associated cancers show a distinct pattern of genomic gains and losses that is associated with impaired repair of DNA double-strand breaks via homologous recombination (HR). We investigated whether BRCA1- and BRCA2-like classifiers could predict BRCA1 and BRCA2 mutation status in ovarian cancer. In addition, we explored whether promoter hypermethylation or mutations in other genes involved in DNA repair associate with a BRCA-like profile in ovarian cancer. Methods: The AGO-TR1 cohort study (NCT02222883 ) enrolled 525 consecutive patients with primary (PR) and platinum sensitive relapsed (RE) ovarian cancer to perform paired mutational analysis of germline and tumor tissue. We performed mutation panel sequencing, BRCA1 promoter hypermethylation and low-coverage whole genome sequencing to classify samples as BRCA1-like or BRCA2-like in 298 ovarian cancer samples (PR: n = 159, RE: n = 139). Results: A BRCA-like profile was observed in 58.1% of the samples without germline or somatic mutation in BRCA1/2 (n = 179; BRCA1-like: n = 26, BRCA2-like: n = 23, BRCA1- and 2-like: n = 55). There was no significant difference between PR- and RE-cases (54.5% vs 61.3%). 64 of 70 BRCA1 germline mutation carriers could be identified by the BRCA1-like classifier (sensitivity: 0.91). The BRCA2-like classifier identified BRCA2 germline mutation carrier with a sensitivity of 0.71 (17 of 24). The complementary use of both classifiers led to the detection of 22 of 25 somatic mutations in BRCA1 (16/16) or - 2 (6/9). Remarkably, 12 of 13 tumor samples from germline RAD51C mutation carriers were recognized by the BRCA1-like classifier (sensitivity: 0.92). No correlation of PALB2 mutation status (n = 7) with BRCA-like profile was observed. Of 28 tumor samples with a BRCA1 promoter hypermethylation 26 had a BRCA1-like profile (sensitivity: 0.93). Conclusions: A high number of ovarian cancer cases display a BRCA-like profile. Mutations (germline and somatic) in BRCA1, BRCA2, RAD51C as well as BRCA1 hypermethylation strongly associate with a BRCA-like profile and can explain 146 of 212 cases. Future studies will investigate whether the classifiers identify patients who benefit from HR-deficiency directed approaches beyond the BRCA mutation status. Clinical trial information: NCT02222883.