tbuckley/cabot-search huggingface dataset:
Dose-Response Association of Low-Intensity and Nondaily Smoking With Mortality in the United States
Authors: Maki Inoue-Choi, Carol H. Christensen, Brian L. Rostron, Candace M. Cosgrove, Carolyn Reyes-Guzman, Benjamin Apelberg, Neal D. Freedman
Journal: JAMA Network Open (2020)

<h3>Importance</h3> An increasing proportion of US smokers smoke at low intensity and not every day. Some nondaily smokers have always had this pattern, whereas others previously smoked daily. The effect of reducing the level of smoking from daily to nondaily smoking and the dose response at low smoking levels are poorly understood. <h3>Objective</h3> To evaluate risk of all-cause and cause-specific mortality among nondaily and daily cigarette smokers, by cigarettes per month, years after reducing from daily to nondaily smoking, and years since quitting. <h3>Design, Setting, and Participants</h3> A prospective cohort study using harmonized data from multiple cycles of the Tobacco Use Supplements to the Current Population Survey (TUS-CPS), linked to the National Death Index, were analyzed during the period from 2018 to 2020. Adults completed the 1992-1993, 1995-1996, 1998-1999, 2000, 2001-2002, 2003, 2006-2007, or 2010-2011 TUS-CPS. Cigarette smokers were classified as daily or nondaily users; current nondaily smokers were further categorized by whether they previously smoked every day. <h3>Main Outcomes and Measures</h3> Hazard ratios (HRs) and 95% CIs for risks of mortality vs never smoking. Age was the underlying time metric, adjusted for sex, race/ethnicity, education, survey year, and household income. <h3>Results</h3> Among 505 500 participants (aged 18-103 years), approximately 47 000 deaths occurred. The median number of cigarettes smoked per month was 600 (interquartile range, 300-600) (20 cigarettes per day [interquartile range, 10-20 cigarettes per day]) for daily cigarette smokers and 40 (interquartile range, 15-90) for lifelong nondaily smokers. Nevertheless, both current daily (HR, 2.32; 95% CI, 2.25-2.38) and lifelong nondaily (HR, 1.82; 95% CI, 1.65-2.01) smokers had higher all-cause mortality risks than never smokers. Associations were observed for 6 to 10 cigarettes per month and increased with greater-intensity use. Nondaily smokers who previously smoked every day had lower mortality risks than daily smokers, with similar HRs after 10 or more years of nondaily smoking as lifelong nondaily smokers (HR vs never smokers, 1.73; 95% CI, 1.56-1.92). Yet, their risks were higher than former smokers who quit 10 or more years before (HR vs never smokers, 1.18; 95% CI, 1.15-1.22). <h3>Conclusions and Relevance</h3> Although reducing smoking from daily to nondaily was associated with decreased mortality risk, cessation was associated with far greater benefit. Lifelong nondaily smokers have higher mortality risks than never smokers, even among those smoking 6 to 10 cigarettes per month. Thus, all smokers should quit, regardless of how infrequently they smoke.
Adjunctive local therapy in metastatic colorectal cancer in an unselected cohort: Improved patient-survival in comparison to systemic therapies.
Authors: Jan Schroeder, Evrim Tasci, Claus Nolte-Ernsting, Peter Michels, Natalie Wetzel, Renate Scheiner-Sparna, Andreas Stang
Journal: Journal of Clinical Oncology (2020)

4096 Background: Patients with distant metastases in colorectal cancer have a poor prognosis and a low overall survival (OS). In addition to systemic treatments and irradiation, the tumor burden can be reduced by loco-regional therapeutics, including microwave ablation (MWA), radiofrequency therapy (RFA) and trans-arterial chemoembolization (TACE) available. To evaluate the benefit of such local therapies, we compared OS of a single-centre study population to a reference population of patients who underwent no loco-regional treatment within the German Tumor Registry Colorectal Cancer (TKK). Methods: The study population consists of a cohort of 51 patients (n = 51) treated loco-regionally in addition to systemic therapy. The patients were recruited in a single cancer centre in Mülheim, Germany during the years 2006 to 2015. A reference population of 788 patients was chosen from a prospective, longitudinal registry of the TKK. Time to event data analysis included the estimation of Kaplan-Meier cumulative survival probabilities and hazard ratios (HR) with corresponding 95% confidence intervals (95% CI) from Cox proportional hazards regression. Results: The median OS was 31.3 months (95% CI 26.8 - 41.6) in the study population, as compared to the reference population, where it was 21.9 months (95% CI 20.1 – 24.6). Patients with liver and lung metastases in the study population had an OS of 41.6 months (95% CI 30.5 – 78.2), the corresponding patients from the reference population 21.7 months (95% CI 16.7 – 24.6). Furthermore, patients in the reference group had a 1.79-fold death-rate, as compared to patients treated with additional loco-regional therapy (HR = 2.02; 95% CI: 1.29-3.16). Conclusions: Additional treatment with loco-regional therapies of distant metastases in patients with metastatic colorectal cancer appears to be associated with improved OS by nearly 10 months compared to systemic treatments only. [Table: see text]
POLO: Radiologic assessment of the impact of maintenance olaparib in patients (pts) with metastatic pancreatic cancer (mPaC).
Authors: Lawrence Howard Schwartz, Hedy L. Kindler, Pascal Hammel, Michele Reni, Eric Van Cutsem, Teresa Macarulla, Michael J. Hall, Joon Oh Park, Daniel Hochhauser, Dirk Arnold, Do-Youn Oh, Anke C. Reinacher-Schick, Giampaolo Tortora, Hana Algül, Eileen Mary O'Reilly, Jeremie Fromageau, Dana C. Ghiorghiu, David McGuinness, Gershon Y. Locker, Talia Golan
Journal: Journal of Clinical Oncology (2021)

412 Background: The phase III POLO study (NCT02184195) demonstrated a benefit of maintenance olaparib over placebo in the radiologically assessed primary endpoint of progression-free survival (PFS) in pts with mPaC (median 7.4 vs 3.8 months [mo]; 12-mo rate 34% vs 15%). The impact of radiologic assessment of pancreatic lesions, which is considered challenging, was explored. Methods: Tumors were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review (BICR) in pts with mPaC treated with maintenance olaparib or placebo. PFS was analyzed in subsets of pts based on various event criteria. Results: All 154 randomized pts had mPaC prior to chemotherapy, of whom 122 had disease in the pancreas at POLO baseline (BL); 34% (53/154) had pancreas-only target lesions (TL), 26% (40/154) also had ≥1 TL outside of the pancreas, and in 19% (29/154) pancreatic disease was recorded as non-TL. Sensitivity analyses were consistent with the primary PFS analysis (Table), including when all pancreas lesion assessments were discounted (median PFS 7.4 vs 4.7 mo; 12-mo rate 38% vs 22%). Of 53 pts with pancreas-only TLs at BL, 34 had disease progression (PD); in 20 pts this was not solely based on TL measurements (16 had new lesions; 4 had multiple-cause PD). Confirmed objective responses occurred during study maintenance treatment in 20% of olaparib pts (18/92) and 10% of placebo pts (6/62). In pts with pancreas-only TLs at BL there were 7 responses in the olaparib arm (1 complete response [CR], 6 partial responses [PR]) and 2 (2 PR) in the placebo arm. In pts who had ≥1 TL outside of the pancreas at BL there were 11 (1 CR, 10 PR) and 4 (4 PR) responses, respectively. Responses were generally durable irrespective of TL location. Conclusions: The significant PFS benefit with maintenance olaparib over placebo shown in the primary analysis was consistent across all sensitivity analyses and was not impacted by radiologic assessment of pancreatic TLs. Taken together, these findings suggest that contrary to historically held belief, primary pancreas TLs may be appropriate for inclusion as sites of RECIST-evaluable disease and for assessment of treatment outcome. Clinical trial information: NCT02184195. [Table: see text]
Development and validation of an early death risk score for older patients treated with chemotherapy for cancer.
Authors: Jaime Feliu Batlle, Alvaro Pinto, Laura Basterretxea, Irene Paredero Pérez, Elisenda Llabres, Beatriz Jimenez-Munarriz, Maite Antonio Rebollo, Beatriz Losada Vila, Enrique Espinosa, Regina Girones, Ana B. Custodio, María del Mar Muñoz, Mariana Díaz-Almirón, Jeniffer Gómez-Mediavilla, Maria Dolores Torregrosa, Gemma Soler, Patricia Cruz, Oliver Higuera, MJ Molina-Garrido
Journal: Journal of Clinical Oncology (2020)

12030 Background: Determining life expectancy in older patients is needed to select the best treatment strategy. We aimed to develop and validate a score to predict early death risk ( &lt; 6 months) in elderly patients with cancer that are planned to initiate chemotherapy treatment. Methods: Patients over 70 years starting new chemotherapy regimens were prospectively included in a multicenter study. A pre-chemotherapy assessment that included sociodemographics, tumor/treatment variables, and geriatric assessment variables, was performed. Association between these factors and early death was examined by using multivariate logistic regression. Score points were assigned to each risk factor based on their b coefficient. We validated the risk score with an external validation cohort of 206 patients. Results: Three hundred forty two patients were included in the training cohort. The independent predictors for early death were metastasic cancers (odds ratio [OR] 4.8, 95% confidence interval [CI], [2.4-9.6]), ECOG performance status (OR 2.3, 95% CI:1.084-5.232), ADL (OR 1.7, 95% CI:1.08-3.5), serum albumin levels (3.3, 95% CI: 1.6-6.6), BMI (OR 2.4, 95% CI:1,2-4.8), serum GGT levels (OR 1.5, 95% CI:1.05-1.8) and hemoglobin levels (OR 2.3, 95% CI:1.2-4.6). With these results, a score was to stratify patients regarding their risk of early death: low (0 to 2 points; 5%), intermediate (3 to 5 points; 19%) or high (6 to 14 points; 50%) (p &lt; 0.001). The area under the curve of the receiver-operating characteristic (ROC) curve was 0.79 for the training cohort (95% CI, 0.74 to 0.85), and 0.70 (95% CI: 0.60-0.80) for the validation cohort (difference between cohorts not statistically different). Conclusions: We developed a highly accurate tool that uses basic clinical and analytical information to predict the probability of early death in elderly patients with cancer that are planned to initiate chemotherapy treatment. This tool can help physicians in decision making for this population of patients.
12-chemokine gene expression score in breast cancer patients treated with neoadjuvant chemotherapy.
Authors: Hatem Hussein Soliman, Sangeetha Prabhakaran, Marilin Rosa, Charles E. Cox, Pat W. Whitworth, Sahra Uygun, Heather M. Kling, Erin Yoder, William Audeh
Journal: Journal of Clinical Oncology (2020)

591 Background: Although advances in immunotherapy for the treatment of breast cancer have been minimal compared with other cancers, studies demonstrating tumor-infiltrating lymphocytes and immunomodulatory gene activation in the tumor microenvironment suggest the importance of antitumor immune responses in clinical outcomes. A 12-chemokine gene score has been shown to predict the presence of ectopic lymph node-like structures (ELN) in the tumor microenvironment and improved survival in melanoma, colon cancer, and breast cancer patients (Prabhakaran, 2017). Here, we evaluated this signature in an independent dataset of breast cancer patients treated with neoadjuvant chemotherapy. Methods: Tumor specimens used in this retrospective analysis (n = 92) were from breast cancer patients enrolled in either MINT (NCT0151487) or NBRST (NCT01479101) neoadjuvant registry trials from 2011 to 2016. Clinical data were captured with informed consent, and 70-gene signature (70-GS), 80-gene signature (80-GS), and full transcriptome data were generated by Agendia, Inc. Gene expression data were quantile normalized using R limma package. Principal component analysis (PCA) was performed on the normalized dataset using R princomp package. Chemokine score (CS) was defined as the first principal component values resulting from PCA. 70-GS/80-GS and clinical data were evaluated in relation to CS. CS were compared using Mann-Whitney test. Results: Of 92 breast tumors available for analysis, 84% were 70-GS High Risk (HR). Tumors were 39% Luminal-type, 24% HER2-type, and 32% Basal-type by 80-GS. HR tumors had higher CS than 70-GS Low Risk (LR) tumors (p &lt; 0.001). 80-GS Basal-type, HER2-type, and Luminal B tumors had higher CS than Luminal A tumors (p &lt; 0.01 for each comparison). High grade and ER-negative tumors seemed to have a high CS, although not significantly. Tumors from patients who achieved a pathological complete response (pCR) following neoadjuvant chemotherapy had higher CS than patients with residual cancer burden (p = 0.048). Conclusions: The current study demonstrated a significantly higher CS in 70-GS HR tumors and those which achieved pCR following neoadjuvant chemotherapy. Although further study is needed to evaluate the association of high CS with tumor-associated ELN, these results support previous work demonstrating that, although high CS is associated with aggressive clinical features, it also predicts superior clinical outcomes. The current study suggests validation of the 12-chemokine gene score in an independent dataset of breast cancer patients.
The association between functional impairment pre- and post-cystectomy with neoadjuvant chemotherapy use in patients with muscle-invasive bladder cancer.
Authors: Chelsea K. Osterman, Allison Mary Deal, Kirsten A. Nyrop, Matthew I. Milowsky, Hyman B. Muss, Angela Smith
Journal: Journal of Clinical Oncology (2020)

e17008 Background: Standard of care treatment for muscle-invasive bladder cancer (MIBC) includes neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), which can be associated with major toxicity. It is unknown whether patients who receive NAC have differences in functional impairment prior to RC, degree of functional decline post-RC, or time to return to baseline functional status post-RC compared to patients who do not receive NAC. Methods: A total of 80 patients were included in this study. Patients completed an initial geriatric assessment (GA) post-NAC but prior to RC, which was repeated at 30, 90 days, and 1 year post-cystectomy. Patients were classified as impaired or not impaired on each GA domain based on previously established cut points. Percentage impairment was calculated as the number of domains impaired out of the total number of domain assessments completed for each patient at each time point. Results: Median age was 68 for patients who received NAC (66% received gemcitabine/cisplatin) and 72 for patients who did not (p = 0.06), with elevated creatinine as the most common reason for not receiving NAC (57%). Overall, 74% of patients were impaired on at least 1 GA domain pre-surgery (NAC 75%; no NAC 71%) and 86% at 30 days post-RC (NAC 86%; no NAC 87%). Groups did not differ significantly in percentage of patients impaired on each GA domain or median percentage impairment at any time point. For both groups, median percentage impairment increased significantly at 30 days post-RC compared to pre-RC (NAC: 36% vs. 15%, p &lt; 0.001; No NAC: 32% vs. 15%, p = 0.002), followed by a decrease in percentage impairment at 90 days post-RC compared to 30 days post-RC (NAC: 14% vs. 36%, p &lt; 0.001; No NAC: 16% vs. 32%, p = 0.15). There was no difference in impairment at 90 days post-RC compared to pre-RC (NAC: 14% vs. 15%, p = 0.41; No NAC: 16% vs. 15%, p = 0.31). Conclusions: Patients with MIBC frequently have functional impairments at baseline, and their degree of impairment worsens in the short term post-RC. However, patients return to their baseline function by 3 months post-RC. Receipt of NAC was not associated with increased levels of functional impairment at any time point or a delayed return to baseline.
Phase III study of pembrolizumab (pembro) plus chemoradiotherapy (CRT) versus CRT alone for patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-992.
Authors: Arjun Vasant Balar, Nicholas D. James, Shahrokh F. Shariat, Neal D. Shore, Michiel Simon Van Der Heijden, Andrew James Weickhardt, Xiao Fang, James Luke Godwin, Ekta Kapadia, Jeff M. Michalski
Journal: Journal of Clinical Oncology (2020)

TPS5093 Background: Pembro has shown clinical activity across many stages of bladder cancer (BC), including metastatic BC, MIBC, and NMIBC. Current NCCN and AUA/ASCO/ASTRO/SUO guidelines recommend CRT as a bladder-preserving treatment option for selected pts with MIBC. This phase 3 study was designed to investigate the safety and efficacy of pembro + CRT in pts with MIBC who opt for bladder preservation. Ongoing phase 2 studies (NCT02662062; NCT02621151) have shown that pembro + CRT may be a promising therapeutic option in MIBC. Methods: KEYNOTE-992 (NCT04241185) is a phase 3, global, multicenter, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and safety of pembro + CRT versus placebo + CRT in pts with previously untreated MIBC. Adults (≥18 years) opting for bladder preservation with histologically confirmed cT2-T4a, nonmetastatic (N0M0) MIBC after maximal TURBT are eligible. An estimated 636 pts will be randomly assigned 1:1 to receive CRT + either pembro 400 mg IV every 6 weeks (Q6W) or placebo. Treatment will continue with pembro or placebo Q6W for up to 9 doses. CRT regimens will be decided by the investigator before randomization. Accepted radiotherapy regimens are conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Accepted concurrent radiosensitizing chemotherapy regimens are cisplatin monotherapy (35 mg/m 2 IV weekly), 5-fluorouracil (500 mg/m 2 on days 1-5 and days 22-26) + mitomycin C (12 mg/m 2 on day 1), or gemcitabine monotherapy (27 mg/m 2 IV twice weekly). Randomization will be stratified by ECOG PS (PS 0/1 vs 2), PD-L1 combined positive score ( &lt; 10 vs ≥10), T stage (T2 vs T3/4), and geographic region (US vs Europe vs rest of world). Pts must provide tissue for biomarker analysis. Efficacy will be assessed by cystoscopy (± biopsy), CT or MRI (with blinded independent central review), and urine cytology at 10 weeks after CRT, then Q12W up to the end of year 2, and then Q24W thereafter. The primary end point is bladder-intact event-free survival, defined as time from randomization to residual/recurrent MIBC, nodal or distant metastasis, radical cystectomy, or death from any cause. Key secondary end points are OS, metastasis-free survival, time to occurrence of NMIBC, and safety. Clinical trial information: NCT04241185 .
Study EV-103: New randomized cohort testing enfortumab vedotin as monotherapy or in combination with pembrolizumab in locally advanced or metastatic urothelial cancer.
Authors: Nataliya Mar, Terence W. Friedlander, Christopher J. Hoimes, Thomas W. Flaig, Mehmet Asim Bilen, Arjun Vasant Balar, Elizabeth Henry, Sandy Srinivas, Jonathan E. Rosenberg, Daniel Peter Petrylak, Earle Frederick Burgess, Jaime R. Merchan, Scott T. Tagawa, Anne-Sophie Carret, Joyce Leta Steinberg, Marya F. Chaney, Matthew I. Milowsky
Journal: Journal of Clinical Oncology (2020)

TPS5092 Background: Cisplatin-based chemotherapy is the standard for first-line (1L) patients (pts) with locally advanced/metastatic urothelial cancer (LA/mUC). PD-1/PD-L1 inhibitors have promising durability of responses but 1L use is restricted to pts ineligible for cisplatin-containing therapy and whose tumors express PD-L1 (CPS ≥10) or pts ineligible for platinum-containing chemotherapy regardless of PD-L1 status. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with LA/mUC who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy. In the ongoing phase 1b/2 study EV-103/KEYNOTE-869 (NCT03288545), the safety and antitumor activity of EV are investigated as monotherapy (mono) (for the first time in the 1L setting) and in combination with PD-1 inhibitor pembrolizumab (P) +/- chemotherapy in UC. An initial analysis of EV (1.25 mg/kg) + P (200 mg) (both drugs in investigational use here) in this study showed a 73.3% confirmed ORR in 45 1L cisplatin-ineligible LA/mUC pts (dose-escalation + expansion Cohort A) (Rosenberg ASCO 2020). Methods: A new Cohort K randomized 1:1 to 1.25 mg/kg EV mono or 1.25 mg/kg EV + 200 mg P provides additional information on EV + P and the contribution of activity from EV in cisplatin-ineligible pts with LA/mUC in the 1L setting. This cohort will enroll 150 adults (≥18 years) with LA/mUC and measurable disease per RECIST v1.1, and exclude pts with prior systemic treatment for LA/mUC, active CNS metastases, ongoing sensory or motor neuropathy (Grade ≥2), or uncontrolled diabetes. Cisplatin-ineligibility in this study is based on ≥1 of the following: ECOG of 2, creatinine clearance of ≥30 and &lt; 60 mL/min, or hearing loss/dysfunction. In each 3-week cycle of this study, EV is administered on days 1 and 8, and P on day 1. The primary endpoint is ORR per RECIST v1.1 by BICR. Secondary endpoints include ORR per RECIST v1.1 by investigator assessment, DOR, DCR, PFS per RECIST v1.1 by BICR and investigator assessment, OS, safety, and tolerability. Sample size is not based on power calculation for formal hypothesis testing but is selected based on ORR estimate precision based on 95% CIs. Efficacy is summarized by treatment arm with no formal statistical comparisons between arms. The study opened in Oct 2017. Cohort K opened in Jan 2020. Clinical trial information: NCT03288545 .