tbuckley/cabot-search huggingface dataset:
Accelerating advanced precision medicine through a harmonized data exchange platform and research consortium (PMEC).
Authors: Davendra Sohal, Julien Doudement, Ben George, Brian Michael Alexander, Stefan C. Grant, William Y. Kim, Martin Gutierrez, William Kevin Kelly, Karen E. Knudsen, John McPherson, Christopher J. Hoimes, Elizabeth J. Davis, Gaurav Singal, Jennifer Webster, Lindsay Chan, Massimo Cristofanilli, Vincent A. Miller
Journal: Journal of Clinical Oncology (2019)

6557 Background: Clinico-genomic data sharing is consistently identified by the global oncology community as a critical requirement to accelerate the discovery and development of new targeted therapies. However, lack of effective collaborative models, fragmented and lengthy legal contracting processes, paucity of funding, and inadequate technological platforms have historically been obstacles for effective data sharing. Methods: In 2015, 10 US academic medical centers (AMC) and Foundation Medicine Inc. (FMI) formed PMEC. Feasibility assessments included creation of a master agreement across sites and willingness to use a central IRB. Oversight and research steering committees were created within the consortium. Through a centralized, secure web-based platform, FoundationInsight, we combined and shared de-identified, harmonized comprehensive FoundationOne genomic profiling data. Research proposals mining this data warehouse are invited quarterly from participant AMCs and peer-reviewed; approved studies are executed at all sites. Results: All 10 AMCs collaborated to execute a master registry participation agreement, followed by a master IRB protocol (New England IRB # 120180008), subsequently approved by individual site IRBs. Since its launch, the PMEC database has grown, on average, 60% per year, to now house over 14,000 cases. The shared dataset covers all tumor types (most commonly lung [17.2%], gastrointestinal [13.8%] and breast [9.2%]), encompasses genomic alterations in &gt;300 genes, and reports relevant supplementary data such as tumor mutation burden and microsatellite instability status. To date, 15 studies have been proposed and evaluated using this platform, with 2 projects currently approved and in progress. Conclusions: We demonstrated the feasibility of creating a collaborative academic consortium that facilitates data sharing and potential discovery efforts in oncology. Technology solutions can accelerate the ability of AMCs, in partnership with central labs, to share and harmonize data to advance precision medicine. This approach lays the groundwork for conducting prospective, biomarker-enriched clinical trials among participating AMCs.
Association between age, risk of severe (Grade 3-4) immune-related adverse events (sirAE), and mortality in patients receiving immune checkpoint inhibitors (ICI).
Authors: Asrar Alahmadi, Ariel Ann Nelson, Sadeer Al-Kindi, Fang Liu, Prateek Mendiratta, Ankit Mangla, Nikhil H. Ramaiya, Christopher J. Hoimes
Journal: Journal of Clinical Oncology (2019)

6597 Background: ICI are used in the treatment of advanced malignancies with on-target adverse events of non-tumor inflammation. Many studies have shown conflicting safety results with regard to older vs younger adults where 65 - 70 years of age has been used as the discrete cut-off variable. We sought to investigate the incidence and the association between age and sirAE using age as a continuous variable at a large tertiary cancer center. Methods: Under IRB approval, our ICI outcomes database was queried for those who were hospitalized and received an immunosuppressant. Charts were individually reviewed to identify hospital admissions due to a sirAE (a grade 3 or 4 AE per CTCAE v4.0) and all-cause mortality at 12 months post ICI start. Non-linear analyses using Cox regression models with penalized smoothed splines were performed to explore association between age and sirAE. Results: There were 6.3% of 1043 patients who had a sirAE, and a total of 83 sirAE events. Mean age was 64± 13 years.ICI included anti-PD-1 (77.8%), anti-CTLA-4 (18.1%), and anti PD-L1 (4.1%). Pts with sirAE had a thirty day, and one year mortality of 12% and 49%, respectively. These events included: colitis (30.1%), pneumonitis (16.9%), hepatitis (10.8%), hypophysitis (6%), and thyroiditis (6%). There were 5 neurologic and 4 myocarditis/myositis sirAEs. The 1-year cumulative incidences of sirAE and all-cause mortality were 8.4%, and 48%, respectively. Spline analysis showed a U-shaped association between age and hazard of sirAE (P = 0.03). Every 10 years above age 60 was associated with increased sirAE (HR 1.65 [1.14-2.40], P = 0.008), while every 10 years below 60 was associated with increased sirAE (HR 1.50 [0.99-2.27], P = 0.054). However, age and mortality showed a linear association (P = 0.003). Conclusions: We observed a curvilinear U-shaped association between age and the risk of sirAE, with minimum risk at age of 60, compared with a linear relationship between age and mortality. Further studies are needed to understand this relationship and its impact on outcomes, clinical care, and underlying host immune context.
The treatment option of progressive disease in breast cancer during neoadjuvant chemotherapy: A single-center experience.
Authors: Yurong Zheng, Xiaowen Ding, Dehong Zou, Fanrong Zhang, Chengdong Qin, Hongjian Yang, Wenju Mo, Yu-Qin Ding, Yang Yu
Journal: Journal of Clinical Oncology (2019)

e12082 Background: Patients’ responses to breast cancer neoadjuvant chemotherapy (NACT) differ because of heterogeneous tumor characteristics. Reports about NACT progression are sporadic. In this study, we aimed to evaluate the characteristics and treatment option of progressive disease in breast cancer after neoadjuvant chemotherapy in China. Methods: We enrolled 1187 patients who received NACT in our cancer center between January 1, 2007, and December 31, 2016. We analyzed the characteristics and treatments of patients with progressive disease (PD) or non-PD or pathological complete response (pCR). Results: In total, 45 (3.8%) patients had PD. PD patients were associated with a significantly worse disease–free survival (DFS) (hazard ratio (HR) = 3.77; 95% CI, 1.77 to 8.00; P = .001) and overall survival (OS) (HR = 3.85; 95% CI, 1.77 to 8.35; P = .001). For the PD patients, 28 (62.2%) patients received mastectomy immediately after PD, and 17 (37.8%) changed to chemotherapy. DFS and OS exhibited no significant differences between these two salvage therapies. After a change to second chemotherapy, 58.8% (10/17) patients had PD or SD. With the exception of tumor size, pretreatment T stage, and histology type, no other significant differences were noted between PD and pCR patients. Conclusions: Our results demonstrated that PD patients were associated with a significantly worse prognosis. Based on these results, we suggest to give the addition of trastuzumab to HER-2 positive patients instead of changing the chemotherapy regimen and proceeding to surgery instead of further chemotherapy once patients have PD during NACT. Given that some similar characteristics exist between PD and pCR patients, more studies to identify novel molecular markers to predict disease response to NACT should be performed.
Effects of a personal trainer led exercise intervention on physical activity and physical function of breast cancer survivors.
Authors: Linda F. Wang, Yvonne L. Eaglehouse, Janette T. Poppenberg, Jill Brufsky, Emily Geramita, Shuyan Zhai, Kelliann Davis, Bethany Gibbs, Jason Metz, G J. Van Londen
Journal: Journal of Clinical Oncology (2019)

e23053 Background: Regular exercise is an important tool to address physical and emotional effects of breast cancer treatment. However, many breast cancer survivors do not meet minimum recommended levels of physical activity. This study examines effects of a personal trainer led exercise intervention on physical activity levels and physical function in breast cancer survivors. Methods: Women who completed active treatment for breast cancer were recruited from oncology clinics and survivorship programs from September 2015-to September 2017. Subjects were randomized to an immediate exercise or a wait-list control group. The intervention included 3 personal training sessions over a period of up to 30 weeks. Physical activity and function were assessed before and after intervention by pedometer (7-day record) and endurance step test (steps in 2 minutes). Results: 60 women were randomized to immediate intervention (n = 31) or wait-list control (n = 29). Subjects were an average of (mean ± SD) 56 ± 10 years old and 2 ± 1 years since breast cancer diagnosis. At baseline, the exercise group averaged (mean ± SD) 5236 ± 2214 steps/day and 101 ± 23 steps on 2-minute step test while the control group averaged 5856 ± 2916 steps/day and 106 ± 23 steps on 2-minute step test. After intervention, change (mean ∆ ± SD) was 143 ± 1842 steps/day in the exercise group and 79 ± 1862 steps/day in the control group ( p= 0.9). On the 2-minute step test, the exercise group increased 18 ± 20 steps and the control group increased 9 ± 12 steps ( p= 0.07). Conclusions: While there was some improvement in physical function after the personal-trainer led intervention, the short duration and intensity of the intervention may have diminished the effects. Our results suggest a multi-faceted approach may be needed to support significant changes in breast cancer survivors’ physical activity. Future efforts employing a multidisciplinary team, which includes a certified personal trainer, and with larger patient samples may help address this possibility. Clinical trial information: NCT02770781.
Impact of age on safety and efficacy of first-line FOLFOXIRI/bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies.
Authors: Federica Marmorino, Daniele Rossini, Giuseppe Aprile, Mariaelena Casagrande, Sara Lonardi, Sabina Murgioni, Emanuela Dell'Aquila, Gianluca Tomasello, Carlotta Antoniotti, Beatrice Borelli, Gemma Zucchelli, Federica Urbano, Monica Ronzoni, Alberto Zaniboni, Sara Manglaviti, Angela Buonadonna, Giuliana Ritorto, Giacomo Allegrini, Alfredo Falcone, Chiara Cremolini
Journal: Journal of Clinical Oncology (2019)

3536 Background: FOLFOXIRI/bevacizumab is a valuable upfront option in mCRC based on results of phase III TRIBE and TRIBE2 studies: 1187 pts aged 18–70 years with ECOG performance status (PS) ≤ 2 or between 71–75 years with an ECOG PS of 0 were randomized to receive first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI in TRIBE and mFOLFOX6 in TRIBE2)/bevacizumab. Here, we aimed at assessing the effect of the intensification of the upfront chemotherapy (triplet versus doublet) in terms of safety and efficacy in pts aged &lt; 70 versus 70-75. Methods: Subgroup analyses for ORR, PFS, G3/4 overall adverse events (AEs), chemo-related and bevacizumab-related AEs were performed according to baseline age. Results: 182 (15%) out of 1187 pts were 70-75 years old (97 in the FOLFOXIRI/bevacizumab and 85 in the doublets/bevacizumab arms). The benefit provided by the intensification of the upfront chemotherapy was independent of the age subgroup in terms of both ORR (p for interaction = 0.684) and PFS (p for interaction = 0.634). The risk of overall and chemo-related G3/4 AEs was increased with the triplet independently of age (p for interaction = 0.736 and 0.790), while no difference in bevacizumab-related AEs was observed in both subgroups (p for interaction = 0.566). In the overall population, as compared to younger pts, those aged 70-75 were more susceptible to overall G3/4 AEs (70% vs 57%, p = 0.001). In the FOLFOXIRI/bevacizumab arm a higher incidence of G3/4 diarrhea (27% vs 17%, p = 0.016) and febrile neutropenia (16% vs 6% p = 0.001) and a lower incidence of all grade nausea (51% vs 65%, p = 0.009) and vomiting (26% vs 44% p = 0.001) were reported among elderly pts. Conclusions: The activity and efficacy of FOLFOXIRI/bevacizumab are confirmed among selected pts between 70 and 75 years old, with a relative increase in the risk of chemo-related AEs similar to that of younger pts. However, elderly pts are more susceptible to experience AEs independently of the treatment arm. Considering the increased incidence of febrile neutropenia and diarrhea with FOLFOXIRI/bevacizumab, the use of G-CSF as primary prophylaxis or an initial dose reduction of irinotecan and 5-fluorouracil might be considered in this population.
Survival outcomes by hormone receptor expression in early-stage HER2-positive breast cancer.
Authors: Sagar D. Sardesai, Mahmoud Kassem, Evan Morgan, Marilly Palettas, Julie Stephens, Nicole Olivia Williams, Daniel G. Stover, Jeffery Van Deusen, Robert Wesolowski, Maryam B. Lustberg, Bhuvaneswari Ramaswamy
Journal: Journal of Clinical Oncology (2019)

e12050 Background: The clinical heterogeneity seen in HER 2 positive breast cancer (BC), mostly related to hormone receptor (HR) expression has been suggested to underlie the variability of response not only to endocrine treatments, but also to anti-HER-2 therapies. Herein, we describe our single institution experience with clinical outcomes by HR expression in early HER 2 positive BC. Methods: An IRB-approved single-institution retrospective analysis was performed for 400 consecutive patients with non-metastatic HER 2 + BC treated at the Ohio State University Comprehensive Cancer Center from 2005-2015. Medical records were reviewed for clinic-pathologic, treatment, and survival information. Disease Free Survival (DFS) was defined as time from diagnosis to first recurrence (loco-regional or distant recurrence) including second primary BC or death. Overall survival (OS) was defined as time from diagnosis to death or last known follow up. OS and DFS estimates were generated using Kaplan Meier methods and compared using Log-rank tests. Cox proportional hazard models were used to calculate univariate and multivariate hazard ratios for OS and DFS. Results: a total of 180/400(45%) patients were diagnosed with HR positive disease. The mean age was 54.1y and patients were predominately white (267, 84%), post-menopausal (190, 60%) and presented with invasive ductal cancer (293, 92%). HR negative disease was significantly associated with high tumor grade (72% vs. 52%, p &lt;0.0001) and lower BMI (27.6 vs 30.1, p 0.0218) compared to HR + tumors. The frequency of CNS metastases was not significantly different between both groups (8 (4%) in HR + vs. 8(6%) in HR –, p 0.9909). 173(96%) of HR + patients received anti-estrogen therapy with median duration of therapy of 40.9 months and 22(13%) received adjuvant ovarian suppression. There was no significant difference between the DFS and OS by hormone receptor expression (P= 0.7459 and 0.6518 respectively). However, higher number of HR negative patients undergoing neoadjuvant therapy achieved a complete pathologic response (pCR, 64% vs 44%, p 0.0092). pCR was prognostic for both DFS(p 0.0002) and OS (p 0.0008) in HR negative subgroup and not in HR + subgroup. Conclusions: The triple positive phenotype represents a distinct clinical subtype of HER 2 positive breast cancer associated with low tumor grade and lower frequency of pCR. Consistent with other studies, pCR was not prognostic of long term survival in triple positive disease. Future trials investigating the ER/ HER 2 cross talk are needed for this patient population.
Second-line treatment of metastatic gastric cancer in the era of predictive biomarkers: A cost-effectiveness analysis.
Authors: Brianna Lauren, Elisabeth Silver, Myles Ingram, Aaron Oh, Lindsay Kumble, Sassan Ostvar, Monika Laszkowska, Jacqueline N. Chu, Gulam Abbas Manji, Alfred I. Neugut, Chin Hur
Journal: Journal of Clinical Oncology (2019)

e15517 Background: Gastric cancer is the third leading cause of cancer-related mortality, with only a 30% five-year survival rate. Patients who progress after one round of systemic therapy face an especially poor prognosis. The National Comprehensive Cancer Network guidelines include both pembrolizumab (PEM) and ramucirumab plus paclitaxel (RAM/PAC) as second-line (2L) therapy for gastric cancer based on data from the Phase II KEYNOTE-059 and Phase III RAINBOW trials, respectively. Recently, the Phase III KEYNOTE-061 trial reported on the effectiveness of PEM for patients with programmed death-ligand 1 (PD-L1) expression and high microsatellite instability (MSI-H). Given the high prices of targeted therapies, it is important to determine if cost-effectiveness is possible using personalized treatment strategies. The aim of this study was to assess the cost-effectiveness of these regimens in both the general patient population and specific biomarker populations. Methods: A decision-analytic (Markov) model was constructed using data from the KEYNOTE-059, KEYNOTE-061, RAINBOW, and REGARD trials. The analysis compared PEM and RAM/PAC for all patients, as well as PEM for patients based on MSI status or PD-L1 expression (combined positive score of 1% or 10%) in the 2L setting. Comparators were paclitaxel monotherapy (PAC) for all patients and best supportive care (BSC) for all patients. Costs (USD) and utility values were estimated from Medicare and the literature. The primary outcome was the incremental cost-effectiveness ratio (ICER) with a willingness-to-pay (WTP) threshold of $100,000. Results: The only cost-effective strategy was PAC monotherapy for all patients, with an ICER of $53,705/QALY. PEM for MSI-H patients and RAM/PAC for microsatellite stable patients was the most effective strategy (greatest QALYs), but was not cost-effective with an ICER of $1,074,620/QALY. Conclusions: Despite their effectiveness, PEM and RAM/PAC are not cost-effective as 2L treatments for metastatic gastric cancer. Although personalizing treatment based on biomarkers improved cost-effectiveness, the ICERs surpassed the WTP threshold at current drug prices.
A phase Ia/Ib, open label, multicenter, dose-escalation study of BI 907828 (MDM2-p53 antagonist) in adult patients with advanced or metastatic solid tumors.
Authors: Curtis Robert Chong, Todd Michael Bauer, Scott Andrew Laurie, Manish R. Patel, Noboru Yamamoto, Teffany Davenport, Junxian Geng, Neil Gibson, Markus P. Vallaster, Patricia LoRusso
Journal: Journal of Clinical Oncology (2019)

TPS3166 Background: Inactivation of tumor protein 53 (TP53) is a central mechanism of tumors to promote survival and proliferation. The murine double minute 2 ( MDM2) oncogene is the primary cellular negative regulator of TP53. Small molecule inhibitors of the MDM2-p53 interaction are currently being evaluated in clinical trials as new anti-cancer drugs, and clinical data published to date support the rationale to target MDM2-amplified tumors. BI 907828 is a potent MDM2-p53 antagonist that has shown efficacy in mouse models of human cancer. Methods: NCT03449381 is a Phase 1a/1b, open-label, multicenter, dose-escalation trial of BI 907828 in patients aged ≥18 years with advanced/metastatic solid tumors. Primary objectives of the Phase 1a (dose-escalation) part are to determine: the maximum tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle; the recommended dose for expansion (RDE); safety and tolerability. Patients in Arm A will receive one dose of BI 907828 every 21 days, and patients in Arm B one dose on Days 1 and 8, every 28 days. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) [GDF-15 induction in plasma], and preliminary anti-tumor activity. Primary endpoints are the number of patients with DLTs during the first treatment cycle, and the MTD. Phase 1a will include ≈50 evaluable patients with locally advanced or metastatic solid tumors with either a known TP53 wild type (wt) status or unknown TP53 status, regardless of MDM2 amplification status at the time of study entry. The main objectives of Phase 1b (expansion cohorts) are to assess efficacy, safety, and PK profiles at the RDE, and to determine the recommended dose for Phase 2. The primary endpoint is objective response, where best response is determined according to RECIST v1.1, or RANO criteria for patients with glioblastoma. Phase 1b will include up to 150 evaluable patients with TP53 wt tumors, assigned to four different cohorts, including non-squamous NSCLC, soft tissue sarcoma, glioblastoma, urothelial carcinoma, and solid tumors with brain metastases. As of 8th February 2019, 11 patients have been enrolled. Clinical trial information: NCT03449381.
Patterns of systemic treatment utilization in ER+/PgR+/HER2+, early-stage breast cancer (BC): An analysis of the National Cancer Database.
Authors: Zeina A. Nahleh, Brian Hobbs, Elizabeth Elimimian, Wei (Auston) Wei, Annie Gupta, Cassann N. Blake
Journal: Journal of Clinical Oncology (2019)

547 Background: The preferences and trends of treatment utilization of adjuvant endocrine therapy (ET) versus chemotherapy (CH) for small node-negative triple positive (TP) BC are unclear. We sought to determine these preferences and assess the impact on outcome. Methods: This is a retrospective study from the National Cancer Database including patients with TP stage I BC, 2004-2015. Treatment selection was evaluated for association with patient clinical and demographic characteristics using logistic regression. Overall survival (OS) was estimated using the Kaplan-Meier method and compared among patient and treatment cohorts by log-rank test and Cox regression. Results: Of 37,777 patients analyzed, 79% were White (Non-Hispanics), 10% African Americans, and 5% Hispanic/Latinos. 57% were 50-70 years old. 86% received adjuvant endocrine therapy versus 14% CH first. Around 40 % of all patients received anti-Her2 therapy. Patients younger than 70 years, with male BC, diagnosed with poorly differentiated BC, African Americans and Hispanics were more likely to be treated with chemotherapy. OS rate at 5-year was 92.3% (95% CI: 0.918-0.928). In multivariate analysis for patients with survival data, an increased rate of death was associated with: treatment in community versus academic/research centers, CH first versus ET, no treatment with anti-Her2 therapy, government versus private /no insurance, Native American ethnicity. A slight but statistically significant reduction in the in the risk of death at 5 years was evident for patients receiving anti-Her2 therapy plus ET therapy, 5-year OS 93.5% (CI: 89.2-98%), when compared to patients receiving anti-Her2 therapy plus CH 92.7 % (CI: 89.4-96). Conclusions: This study provides real world data of common practices in the US . The majority of patients with node negative Stage I, ER+/PR+/Her2+ BC received adjuvant ET and anti-Her2 therapy, not chemotherapy. These patients had a similar to slightly improved 5 year- survival when compared to anti-Her2 therapy plus CH, supporting the use ET plus anti-Her2 therapy in this setting. Future studies should focus on better selecting patients with hormone receptor positive and Her 2 + early stage BC who would benefit from adjuvant CH. Disparity in outcome also warrants further evaluation. [Table: see text]