tbuckley/cabot-search huggingface dataset:
A prognostic score for metastatic hormone sensitive prostate cancer in the era of high and low volume disease.
Authors: Yasser Ged, MinYuen Teo, Eoin Moriarty, Olubukola Ayodele, Dayle Jeremy Hacking, Paula Calvert, Miriam O'Connor, Anne M. Horgan
Journal: Journal of Clinical Oncology (2016)

e16536 Background: Prognostic scores exist for metastatic castrate resistant prostate cancer. We tested the impact of a prognostic score in patients (pts) with high and low volume metastatic hormone sensitive prostate cancer (mHSPC). Methods: Pts with mHSPC were retrospectively identified from 2012-2014 and classified as high or low volume as per ECOG 3805 trial. Potential prognostic factors examined included (PSA > 131ng/ml, ALP > 260IU/l, Albumin ≤ 4g/dl, neutrophil-to-lymphocyte ratio > 3, HB < 12g/l and ECOG performance status ≥ 2) Patients with 0-1, 2-3 or > 3 risk factors were classified into good, intermediate or poor risk groups. Study end points were time to castration (TTC) and overall survival (OS). Results: 83 pts were identified. Median age was 75yrs (49-80), high volume (n = 53; 64%),de-novo metastases(n = 57; 69%), visceral metastasis (n = 6; 7%), superscan (n = 7; 8%). Thirty-four pts (41%) were classified as good risk, 32(39%) intermediate risk and 17(20%) poor risk. A greater proportion of pts with high volume disease (32%) had poor risk features compared to pts with low volume disease (0%); p = 0.0005. Pts with low volume disease had a median OS of 43 mths compared to 24 mths with high volume disease (p = 0.0001). In the overall population, there was no difference in median OS or TTC between good and intermediate risk pts. There was a significant difference in OS (48 vs 10mths; p < 0.0001) and TTC (30 vs 6mths; p < 0.0001) between good and poor risk pts, respectively. In pts with low volume disease, the risk score did not impact OS or TTC. In pts with high volume disease, there was a difference in OS (43 vs 10mths; p = 0.0006) and TTC (18 vs 6mths; p = 0.01) between good and poor risk pts, respectively; there was also a difference in OS (p = 0.002) and TTC (p = 0.004) when comparing intermediate to poor risk disease. Pts with high volume, poor risk disease had a worse OS (10 vs 43 mths; p = 0.0046) and TTC (6 vs 14 mths; p = 0.0014) compared to high volume and good/intermediate risk, respectively. Conclusions: Our preliminary data supports the role of these prognostic scores in mHSPC. There may be distinctive subsets of high volume disease pts with varying prognosis and this needs validation in a larger cohort of mHSPC pts.
Safety of self-expandable metal stents (SEMS) or emergency surgery for acute malignant colonic obstruction in patients treated with bevacizumab.
Authors: Vilma Pacheco-Barcia, Rebeca Mondejar, Olga Martinez Saez, Federico Longo, Elena Bermejo, Jose Andres Moreno Monteagudo, Cristina Marin, Alba Correa, Rocio Maqueda, Jacobo Rogado Revuelta, Ana Garcia de Paredes, Enrique Rodriguez de Santiago, Vanessa Pachon, Reyes Ferreiro Monteagudo, Mercedes Rodríguez Garrote, Alfredo Carrato, Olga Donnay, Elena Martin, Cecilio Santander, Ramon Colomer
Journal: Journal of Clinical Oncology (2018)

e15505 Background: Colorectal cancer presents with malignant bowel obstruction in about 10% of cases. SEMS can be an alternative for immediate surgery although long-term data is limited regarding clinical outcomes and safety of Bevacizumab (BV) in this subset of patients. Methods: We performed a retrospective review of 2850 cases of locoregional or metastatic colon cancer diagnosed from January 2012 to October 2017, and identified those patients with malignant bowel obstruction that were initially treated with either SEMS or emergency surgery. Differences in procedure-related morbidity were assessed in relation to the type of previous or subsequent medical treatment used, which could include BV. Results: We selected 256 cases, 134 were treated with SEMS and 124 with surgery. Median age was 76. Median follow-up time was 16 months. No differences in sidedness or RAS status between cohorts. Locoregional disease was observed in 137 patients: 58 had SEMS and 79 surgery. Metastatic disease was present in 119 patients: 79 had SEMS and 40 surgery. In locoregional disease, SEMS reduced significantly the incidence of complications compared to surgery (14% vs 33%; RR 2.1, p = 0.008), had a similar time to complications (12d vs 8d, p = 0.2), and showed a similar OS compared to surgery (32m vs 49m, p = 0.1). In metastatic patients, SEMS had a similar rate of complications compared to surgery (32.5% vs 35.5%, p = 0.45), showed longer time to complications (18m vs 1m, p = 0.004), and a similar OS (14m vs 15m, p = 0.5). In metastatic patients with BV, complications were similar in SEMS and surgery groups (40% vs 31%, RR 1.3, p = 0.45) and the incidence of perforation was similar in patients with SEMS (16% vs 7%, RR 1.09, p = 0.16) compared to surgery. Conclusions: SEMS as a bridge-to-surgery was associated with lower morbidity and had a similar long-term clinical outcome compared to emergency surgery. SEMS was associated with a similar outcome than emergency surgery in metastatic patients and using BV was not associated with a higher risk of complication. In conclusion, in patients with malignant colonic obstruction, SEMS, either localized or metastatic, is a safe option, including patients that were treated with BV.
Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors
Authors: Gregory W. Schwartz, Bryan Manning, Yeqiao Zhou, Priya Velu, Ashkan Bigdeli, Rachel Astles, Anne W. Lehman, Jennifer J.D. Morrissette, Alexander E. Perl, Mingyao Li, Martin Carroll, Robert B. Faryabi
Journal: Clinical Cancer Research (2018)

Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk FLT3-ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of FLT3-ITD mutations, we investigated the effects of FLT3-ITD structural features on the response of AML patients to treatment.Experimental Design: We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in FLT3-ITD-positive AML patients.HeatITup accurately identifies and classifies ITDs into newly defined categories of "typical" or "atypical" based on their nucleotide composition. A typical ITD's insert sequence completely matches the wild-type FLT3, whereas an atypical ITD's insert contains nucleotides exogenous to the wild-type FLT3. Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical FLT3-ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypical FLT3-ITDs.These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing toward personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software.See related commentary by Gallipoli and Huntly, p. 460.
Comparative effectiveness of anti-diabetic drugs in morbidity and mortality of breast cancer in diabetic patients: A network meta-analysis.
Authors: Cong Dai, Meng Wang, Tian Tian, Peng Xu, Kang Liu, Yi Zheng, Yujiao Deng, Qian Hao, Zhijun Dai
Journal: Journal of Clinical Oncology (2018)

e24330 Background: Different anti-diabetic drugs may modify breast cancer (BC) morbidity and mortality in diabetic patients. We aimed to examine mortality and mortality of BC using a network meta-analysis. Methods: We searched PubMed, Embase and Web of Science databases in January 2018 to identify relevant articles reporting mortality and mortality of BC with different anti-diabetic drugs: metformin, sulfonylureas, thiazolidinedione (rosiglitazone and pioglitazone), dipeptidyl peptidase-4(DPP4) inhibitors (sitagliptin), insulin and insulin analogues (human insulin, Glargine and Detemir). The articles, in which the comparisons of different anti-diabetic drugs were monotherapy or adjusted for other anti-diabetic drugs, included in the study. Network meta-analysis using a bayesian statistical model were performed to combine the direct and indirect comparisons. Results: A total of 33 articles (2 randomized controlled clinical trials (RCTs), 29 cohort studies, and 2 case-control studies) were identified, including 3523402 patients. Our result demonstrated that the use of sitagliptin (RR = 0.72, 95% CI 0.57-0.90), metformin (RR = 0.80, 95% CI 0.78-0.84), rosiglitazone (RR = 0.84, 95% CI 0.78-0.90) and sulfonylureas (RR = 0.94, 95% CI 0.90-0.99) was associated with a lower risk of BC morbidity. Conversely, the use of insulin glargine (RR = 1.22, 95% CI 1.06-1.40) increased risk of BC incidence. P-scores results revealed that insulin glargine (P-scores = 0.0391) was related to the highest risk of BC incidence, sitagliptin (P-scores = 0.9623) and metformin (P-scores = 0.8686) were the lowest risk. On the other hand, use of metformin, sulfonylureas, thiazolidinedione or insulin was not significantly associated with BC mortality. P-scores results revealed that metformin (P-scores = 0.8323) was related to the lowest BC mortality. Conclusions: Our network meta-analysis demonstrated that, for the diabetic patients concerned about BC or at increased risk for BC, sitagliptin and metformin might be a better choice and insulin glargine should be cautiously used.
Long-term cardiovascular outcomes and overall survival of early-stage breast cancer patients with early discontinuation of trastuzumab.
Authors: Inna Y Gong, Sunil Verma, Andrew T Yan, Dennis T Ko, Craig Earle, George A. Tomlinson, Maureen E. Trudeau, Monika K. Krzyzanowska, Christine Brezden-Masley, Scott Gavura, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2016)

10093 Background: There is little information on cardiovascular (CV) outcomes and survival of breast cancer (BC) pts who had cardiotoxicity during adjuvant trastuzumab (Tmab) treatment requiring discontinuation in the real world. Methods: This was a retrospective population-based study of early-stage (I-III) BC pts diagnosed before 2010 and treated with Tmab in Ontario. Patients were stratified based on Tmab doses received: early discontinuation as 1-8 or 9-15, and ≥16 as completion. Time-dependent multivariable Cox models (adjusting for known cardiac risk factors, comorbidities, stage and chemotherapies received) were used to analyze the primary endpoint overall survival (OS), and the following composite endpoints: hospitalization/emergency room visit for heart failure (HF) or death; non-HF CV event (myocardial infarction, stroke) or death; clinically significant relapse (initiation of palliative systemic therapy > 90 days after last Tmab dose) or death. Results: Of the 3134 women (83% <65 years), 6%, 10%, and 85% received 1-8, 9-15, and ≥16 doses, respectively. Over 5-year median follow-up, early discontinuation was significantly associated with worse outcomes (Table) and lower OS (77%, 80%, and 93%; p<0.001). Early discontinuation (Table) and clinically significant relapse (HR 34.0, 95% CI 24.9-46.6) were both independent predictors of mortality. These results were confirmed using propensity score methods. Conclusions: Early Tmab discontinuation, a marker of cardiotoxicity, is a powerful independent predictor of adverse cardiac events and clinically significant relapse, both likely contributing to poor overall survival. Both optimal cancer and cardiovascular treatment strategies are needed for to improve the outcome of these high-risk patients. Outcome Total No. Events 1-8 doses† Adjusted HR (95% CI) P value 9-15 doses† Adjusted HR (95% CI) P value HF or death 291 4.0 (2.7-6.0) <.001 3.0 (2.1-4.3) <.001 Non-HF or death 323 4.3 (3.0-6.1) <.001 3.1 (2.2-4.4) <.001 Clinically significant relapse or death 403 3.1 (2.2-4.4) <.001 2.4 (1.8-3.3) <.001 OS 278 2.4 (1.5-3.8) <.001 2.9 (2.0-4.1) <.001 † Modeled as time-dependent covariate (≥16 doses as reference).
Genomic profiling of lymph node metastases in endometrial cancer and association with volume of metastasis.
Authors: Stephanie Sullivan, Abhishek Sripad, Nerlyne Desravines, Dario R. Roque, David N. Hayes, Victoria Lin Bae-Jump, Emma Caroline Rossi
Journal: Journal of Clinical Oncology (2018)

5586 Background: Lymph node (LN) metastasis and genomic profiles are important prognostic factors in endometrial cancer (EC). However, the prognostic significance of the volume of metastatic disease found in sentinel lymph node (SLN) specimens is unknown. We sought to determine if particular genomic mutations were associated with LN metastasis and volume of LN metastasis. Methods: Surgically staged women with EC at a single institution were enrolled in a genetic sequencing institutional protocol. Relevant targets were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. A subset of the EC population underwent SLN biopsy with completion lymphadenectomy and hysterectomy as part of the FIRES study. SLN specimens underwent ultrastaging to detect low volume disease such as isolated tumor cells (ITCs). Results: 345 patients with EC completed surgical staging and tumor sequencing between 3/2007 and 9/2016; median age 63 yrs and median BMI 34.2 kg/m2. 55 patients (16.0%) were LN positive (LN+) while 290 (84.0%) were LN negative (LN-). The LN+ group were less likely to have endometrioid histology than the LN- group (54.5% vs 77.2%) and more likely to have grade 3 disease (65.5% vs 33.1%) (p < 0.001 for both). LN+ patients were more likely than LN- patients to have p53 mutations (44.4% vs 27.0%, p = 0.02), and less likely to have PTEN mutations (38.9% vs 59.1%, p = 0.01). Polyclonality of PIK3CA mutations (defined as > 2 mutations in the same tumor) was only observed in the LN- patients (p = 0.08). 44 patients had a staging with SLN biopsy. Of these, 8 (18.2%) had ITC’s as their only metastatic disease. All ITC patients with p53 mutations were of non-endometrioid histology (3/8). PTEN (80.0%) and PIK3CA (60.0%) mutations were observed in the endometroid ECs. No patients with ITCs had a recurrence. Conclusions: Primary tumors associated with LN metastases have both genomic mutations and histologic features consistent with more aggressive disease. In patients with low volume (ITC’s) metastases, genomic mutations aligned with histology. More work is needed to better define the relationship between genomic mutations, histology, metastatic volume and prognosis.
Preclinical efficacy studies of DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd.
Authors: Daisuke Okajima, Satoru Yasuda, Yusuke Yokouchi, Tomomichi Fujitani, Ken Sakurai, Junko Yamaguchi, Michiko Kitamura, Tomoko Terauchi, Tomoko Shibutani, Tetsuo Aida, Takashi Nakada, Shinya Tokuhiro, Tadashi Toki, Yutaka Noguchi, Yuki Abe, Toshinori Agatsuma
Journal: Journal of Clinical Oncology (2018)

e24206 Background: DS-1062a is a trophoblast cell surface protein 2 (TROP2)-targeting antibody-drug conjugate (ADC) comprised of a humanized anti-TROP2 monoclonal antibody, enzymatically cleavable peptide-linker, and a novel topoisomerase I inhibitor DXd which is a derivative of Exatecan (DX-8951). TROP2 is a 36-kDa single-pass transmembrane protein overexpressed in various epithelial tumors including non-small cell lung cancer (NSCLC) with relatively low and restricted expression in normal tissues, and is associated with aggressive tumor behavior. Therefore, TROP2 could be an attractive target for cancer therapy. Methods: In vitro cell growth inhibitory and in vivo anti-tumor activities of DS-1062a were evaluated using TROP2-positive and negative tumor cell lines and xenograft mice models. Pharmacokinetic and safety profiles of DS-1062a were also assessed in cynomolgus monkeys. Results: DS-1062a showed in vitro cell growth inhibitory activity to TROP2-positive tumor cells (CFPAC-1, BxPC-3 (pancreas adenocarcinoma)) with IC50 values of 706 ng/mL and 74.6 ng/mL, respectively, but not to TROP2-negative tumor cells (Calu-6 (anaplastic carcinoma)) with IC50 value of > 20000 ng/mL. DS-1062a induced dose-dependent tumor growth inhibition and tumor regression at more than 1 mg/kg of single dosing in the TROP2-positive CFPAC-1 xenograft mice model in contrast to an isotype control IgG-ADC and anti-TROP2 antibody which showed no efficacy. DS-1062a exhibited stronger anti-tumor activity with higher concentrations of DXd in TROP2-high tumors compared to TROP2-low or negative tumors of several xenograft mice models. In addition, DS-1062a showed favorable pharmacokinetic profiles and acceptable safety profiles in cynomolgus monkeys. Conclusions: Based on these preclinical results, DS-1062a could provide a valuable therapy with a potential benefit in TROP2-positive cancers in the clinical setting. A first-in-human phase 1 study in patients with advanced solid tumors is in progress (NCT03401385).
Mobidity and mortality related to therapy in cirrhotic breast cancer patients.
Authors: Yu Liu, Zhan-Yi Li, Jiani Wang, Yong Huang, Renbin Liu
Journal: Journal of Clinical Oncology (2018)

e18740 Background: Medical advances have greatly improved the prognosis of breast cancer (BC) patients. However, as randomized clinical trials often have strict enrollment criteria, some special population, are often excluded from clinical trials. Therefore, the morbidity and mortality of adverse events (AEs) of the special population is not well described and maybe under-reported. Liver cirrhosis is a great risk factor for surgery and chemotherapy. Little information is available on the morbidity and mortality related to therapy of cirrhotic BC patients. The purpose of this study was to evaluate the morbidity and mortality related to therapy of cirrhotic BC patients. Methods: A retrospective hospital based case-control study (1:5) was performed at the Third Affiliated Hospital of Sun Yat-sen University and the Guangzhou Women and Children’s Medical Center between 2008 and 2017 to determine the morbidity and mortality related to therapy in cirrhotic BC patients. Results: There were 15 cirrhotic BC patients and 75 matched BC patients. The postoperative morbidity was higher in cirrhotic BC patients (26.7% vs 6.7%, P = 0.039). There was not significant difference of postoperative mortality between the two groups (6.7% vs 0, P = 0.167). The morbidity of liver toxicity was higher in cirrhotic patients (73.3% vs 26.6%, P = 0.001) especially the grade 3 and 4 (46.7% vs 0, P = 0.000). The morbidity of myelosuppression was higher in cirrhotic patients but there was not significantly different (86.6% vs 82.7%, P = 1.000). The morbidity of other AEs (renal injury, gastrointestinal bleeding, ascites and infection) was higher in cirrhotic patients (26.7% vs 0, P = 0.001). The morbidity of disruptions in chemotherapy attributable to AEs was higher and the complete remission rate was lower in the cases group (46.7% vs 4.0%, P = 0.000 and 60% vs 88%, P = 0.042). No patient died during chemotherapy.. Conclusions: Cirrhotic BC patients with compensated liver function can be operated for BC with an acceptable morbidity and mortality. However, they are susceptible to adverse events, disruptions during chemotherapy and poor prognosis. It is critical to seek multidisciplinary cooperation before therapy and monitor AEs especially the hepatic AEs closely during therapy.
NLR as a prognostic factor in solid tumors.
Authors: Yifei Zhang, Patrik Brodin, Shalom Kalnicki, Madhur Garg, Chandan Guha, Rafi Kabarriti
Journal: Journal of Clinical Oncology (2018)

e24057 Background: An elevated serum neutrophil-lymphocyte ratio (NLR) has been reported to be a poor prognostic biomarker of overall survival (OS) in certain cancers. Here we investigate the association between elevated NLR at diagnosis and survival in a large database of patients with solid tumors. Methods: We retrospectively reviewed patients diagnosed with solid tumors in our institution between 2005 and 2016. Elevated NLR was defined as > 4.0 and the association with OS was determined using multivariable Cox proportional hazards regression, adjusting for age, gender, ethnicity, socio-economic status, smoking status, Charlson co-morbidity score, stage, and distant metastasis at diagnosis. Hazard ratios (HRs) were calculated for the cohort overall and stratified for either disease site or stage. Results: 27,373 patients were included in the analysis. An elevated NLR was an independent predictor of OS with HR of 1.87 (95% CI: 1.76-2.00; p < .001), and also an independent predictor for OS in most individual disease sites. The association was strongest in anal cancer and mesothelioma. HRs were 1.6, 2.0, 1.6, 1.8 for stage I, II, III, IV respectively (all p < .001). The differences in HRs were significant between disease sites (p = 0.01), but not significant between stages (p = 0.14). Conclusions: An elevated NLR is an independent poor prognostic marker for OS in certain solid tumors. Serum NLR is easy to obtain and would provide valuable information to clinicians in evaluating prognosis and making clinical decisions. Site (n) HR (95% CI) P-value Anal (304) 4.87 (1.53-15.6) 0.008 Breast (8,909) 2.02 (1.69-2.42) < 0.001 Cervix (1,078) 1.33 (0.91-1.96) 0.145 Cholangio (238) 1.57 (0.88-2.80) 0.123 Colon (2,003) 1.46 (1.20-1.78) < 0.001 Gastroesophageal (1,583) 1.81 (1.49-2.20) < 0.001 GIST (91) 1.56 (0.06-40.0) 0.788 Glioblastoma (291) 0.97 (0.62-1.51) 0.89 Hodgkin (350) 1.11 (0.55-2.22) 0.777 Liver (1,586) 1.98 (1.63-2.42) < 0.001 NSCLC (645) 1.88 (1.48-2.38) < 0.001 Mesothelioma (67) 4.52 (1.07-19.0) 0.040 Nasopharyngeal (116) 2.59 (0.82-8.19) 0.105 Oral (563) 1.53 (1.02-2.29) 0.041 Ovary (907) 1.39 (0.98-1.98) 0.067 Pancreas (1,572) 1.63 (1.37-1.95) < 0.001 Prostate (5,439) 2.22 (1.85-2.67) < 0.001 RCC (747) 1.50 (1.01-2.25) 0.047 Urothelial (883) 2.38 (1.46-3.88) < 0.001