bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world outcomes of patients with BRAF-mutated mCRC treated in the United States.
Authors: Braithwaite Matthew , Nevala-Plagemann Christopher Duane , Baron Kelsey , Haaland Benjamin , Pappas Lisa M. , Garrido-Laguna Ignacio 
Published: May 2020

4030 Background: BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Recent trials have hypothesized that using more aggressive triplet-based chemotherapy regimens such as FOLFOXIRI in the frontline setting may improve outcomes in this patient population. In this study, we utilized real-world data to assess whether FOLFOXIRI is being used in the United States (US) and compared survival outcomes in BRAF mutated (BRAFmt) mCRC stratified by first line (1L) therapy. Methods: The nationwide Flatiron Health EHR-derived de-identified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Patients who had documented BRAF mutation testing and received a standard 1L therapy were included for analysis. Patients who did not have a visit or medication order within 90 days of metastatic diagnosis were excluded to ensure patients were engaged with care at the data-providing institution. Kaplan-Meier and Cox proportional hazard modeling were used to compare survival outcomes stratified by BRAF mutation status and 1L therapy received. Results: A total of 4,454 patients with documented BRAF mutational status were included, of which 3,988 (89.5%) were BRAF wild type (BRAFwt) and 466 (10.5%) were BRAFmt. Median OS was 15.4 months (mo) in the BRAFmt group compared to 28.1 mo in the BRAFwt group (HR 0.48, 95% CI 0.41- 0.56, p < 0.001). Only 3% (n = 16) of BRAFmt patients received 1L FOLFOXIRI +/- bevacizumab with a median OS of 13.8 mo compared to 15.5 mo in patients receiving a chemotherapy doublet (FOLFOX, CAPEOX, or FOLFIRI) +/- bevacizumab (95% CI 4.9 – not reached vs 14.3 – 19.0, p = 0.38). In BRAFmt patients, multivariate analysis (MVA) did not detect a significant improvement in OS with the use of FOLFIRI plus bevacizumab (HR 0.88, 95% CI 0.50-1.56, p = 0.67) or FOLFOX/CAPEOX plus bevacizumab (HR 0.89, 95% CI 0.59 – 1.34, p = 0.58) when compared to chemotherapy doublet alone. A MVA comparing 1L therapies in the BRAFwt group did not detect a significant improvement in OS with bevacizumab plus chemotherapy doublet compared to chemotherapy doublet alone. When stratified by 1L treatment regimen, similar proportions of BRAFmt patients received second line therapy. Conclusions: This analysis of real-world data confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the management of these patients in the US. We were unable to demonstrate any significant difference in OS of patients with BRAFmt mCRC based on type of 1L therapy received.
Results from the safety lead-in for a phase II study of pembrolizumab in combination with binimetinib and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).
Authors: Lieu Christopher Hanyoung , Davis Sarah Lindsey , Leong Stephen , Leal Alexis Diane , Blatchford Patrick Jud , Sandhu Gurprataap Singh , Purcell William T. , Kim Sunnie S. , Van De Voorde Zoe , Telles Rachel , Martin Anne , Cull Tiffany , Waring Meredith , Reed Colin , Lee Chimmoua , Siedem Amanda , Lee Matthew R , Pitts Todd , Eckhardt S. Gail , Messersmith Wells A. 
Published: May 2020

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .
Metastases resection in colorectal cancer patients with mutation in oncogene BRAF or tumors located on the right side: Experience at the HGUGM.
Authors: Ortega Laura , Bringas Beranek Marianela , Gutiérrez Alonso Natalia , Soto Alsar Javier , Alva Bianchi Manuel , Arregui Valles Marta , Aparicio Salcedo Inmaculada , Gallego Gallego Iria , García González Gonzalo , Torres Pérez-Solero Gabriela , Muñoz Martín Andres J. , Calvo Ferrándiz Aitana , Blanco-Codesido Montserrat , Martin Miguel , Garcia-Alfonso Pilar 
Published: May 2020

4041 Background: Approximately 25% of patients with colorectal cancer (CRC) debut with metastatic disease. In addition, 25-35% of patients with localized disease at diagnosis develop metastatic lesions during the evolution of their disease. Consequently, approximately 50-60% of patients with CRC will present metastatic lesions at some point in their lives. Metastasis resection has improved the prognosis of these patients, achieving overall survival (OS) that exceed 40 months. However, there are doubts about the benefit of this approach in patients with mutations in oncogene BRAF or tumors located on the right-side, due their poor prognosis. The aim of the study is to analyze the impact of metastases resection on OS of these populations. Methods: We conducted a retrospective analysis of patients with mCRC attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Spain) between January 2010 and 2018. Results: 487 patients were identified and included in the analysis. Median age was 71 years (62-81). Most patients were males (62.4%). 55.2% had metastatic lesions at diagnosis. Most patients had ECOG 0-1 at diagnosis of metastatic disease (91.0%). 8.9% of patients had BRAF mutations (n = 21) and 31.8% of patients had primary tumors located on the right-side (n = 152). 474 patients received first-line chemotherapy (97.3%). OS of the entire cohort was 29.67 months; 30.69 months in BRAF mutated patients vs 35.89 in wild-type patients (p = 0.161); 25.29 months in right-side tumors vs 31.02 in left-side tumors (p = 0.044). 306 patients (62.8%) underwent metastases resection. Most common location was liver (51.4%). 147 patients (30.2%) underwent a second metastases resection. Mean number of metastases surgeries was 1.35 (+/-1.40). OS since metastases resection was 24.83 months in BRAF mutated patients vs 41.55 months in wild-type patients (p = 0.020). According to location, it was 35.49 months in right-side tumors vs 43.78 months in left-side tumors (p = 0.106). In BRAF mutated patients, OS was 38.19 months in patients underwent metastases resection vs 18.52 months in non-surgical patients (p = 0.043); 41.51 months vs 16.18 months respectively in patients with tumors located on the right-side (p < 0.001). Conclusions: Metastases resection has a positive impact on overall survival of patients with mutations in oncogene BRAF or right-side tumors, even though their prognosis is still poor compared to patients without these alterations.
TAS-116, an oral HSP90 inhibitor, in combination with nivolumab in patients with colorectal cancer and other solid tumors: An open-label, dose-finding, and expansion phase Ib trial (EPOC1704).
Authors: Kawazoe Akihito , Yamamoto Noboru , Kotani Daisuke , Kuboki Yasutoshi , Taniguchi Hiroya , Harano Kenichi , Naito Yoichi , Suzuki Mitsuko , Fukutani Miki , Shima Hikari , Higuchi Tsukiko , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Nishikawa Hiroyoshi , Shitara Kohei 
Published: May 2020

4044 Background: Regulatory T cells (Tregs) potentially induce the resistance of anti-PD1/PD-L1 inhibitors (A-PD1). TAS-116, a novel HSP90 inhibitor, enhanced antitumor immunity via reducing Tregs in vitro and in vivo. Combination of TAS-116 plus A-PD1 showed a superior tumor growth suppression compared with either treatment alone in vivo. Based on the above, we investigated safety and efficacy of TAS-116 in combination with nivolumab in patients with solid tumors. Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the maximum tolerated dose and the recommended phase 2 dose (RP2D). Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80mg on level 1, 120mg on level 2, and 160mg on level 3) was administrated for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLTs) during the first cycle (4 weeks). PD-L1 combined positive score (CPS) and tumor mutation burden (TMB) were assessed. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 44 patients with colorectal cancer (CRC, n = 29), gastric cancer (GC, n = 8), sarcoma (n = 5), non-small cell lung cancer (NSCLC, n = 1) and melanoma (n = 1) after standard of cares were enrolled. One patient had MSI-H CRC, but all other patients had MSS tumors. No DLTs were observed at all levels and TAS-116 160 mg was determined as RP2D. The common grade 3 or worse treatment-related adverse included AST/ALT increased (7%), creatinine increased (5%) and platelet count decreased (5%). Objective tumor response was observed in 6 patients including 4 MSS CRC, 1 MSI-H CRC and 1 sarcoma, resulting in objective response rate (ORR) of 16% in MSS CRC without prior A-PD-1. PD-L1 CPS and TMB could be evaluated in 18 and 17 MSS CRC without prior A-PD-1, respectively. ORR was 27% in patients with CPS ≥1 and 0% in patients with CPS < 1. ORR was 33% with TMB-high (median as the cut-off) and 12% with TMB-low. Analysis of tumor-infiltrating lymphocytes before treatment and after TAS-116 monotherapy demonstrated reduction of FoxP3hiCD45RA−Tregs fraction in the tumor microenvironment. Conclusions: The combination of TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients, which warrants further investigations in a large cohort. Clinical trial information: UMIN000032801 .
Patient-reported gastrointestinal outcomes in patients with anal cancer.
Authors: Kouzy Ramez , Abi Jaoude Joseph , Lin Daniel , El Alam Molly Blue , Minsky Bruce D. , Koay Eugene Jon , Das Prajnan , Holliday Emma B. , Klopp Ann , Colbert Lauren Elizabeth , Taniguchi Cullen M. 
Published: May 2020

4055 Background: Among patients with anal cancer, chemoradiotherapy tends to offer an excellent prognosis but is often associated with undesirable toxicities that diminish quality of life. We sought to quantify the gastrointestinal-related patient-reported outcomes (PROs) of anal cancer patients receiving chemoradiotherapy in order to improve patient-physician communication and shared decision making. Methods: We prospectively followed patients with non-metastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients reported outcomes were collected using the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before treatment and at 4 subsequent timepoints. We used descriptive statistics to summarize the patients’ characteristics and EPIC scores, then used the paired Wilcoxon test to compare EPIC scores at different timepoints. Results: The study included 21 patients (16 women and 5 men), whose median age was 57 years. Most patients (52%) had T2, and either N0 (38%) or N1 (43%) disease. Most patients (91%) received standard of care chemoradiotherapy. Compared with the patients’ median overall summary score at baseline (66), their median score at 1 week (82) was significantly higher (p = 0.009), whereas their median score at 5 weeks (54) was significantly lower (p = 0.025). However, the patients’ median overall summary score at baseline and at 3 months did not differ significantly (p = 0.919). Three months after radiotherapy, most patients (73%) reported rarely or never having bloody stools, and most (82%) reported rarely or never being bothered by bloody stools. Overall, EPIC scores show initial improvement of all domains, followed by some worsening of symptoms before returning to baseline levels. Conclusions: Anal cancer patients’ gastrointestinal-related PROs tend to fluctuate during radiotherapy but return to baseline by 3 months, at which time most patients report few or no residual side effects. Our data provide a clear timeline of gastrointestinal acute toxicity using sequential PRO measurements that will improve patient-physician communication regarding expectations for cancer treatment and help in shared decision making.
Socioeconomic status based on race in early-stage anal squamous cell carcinoma undergoing locoregional therapy.
Authors: Goksu Suleyman Yasin , Ozer Muhammet , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali , Sanjeevaiah Aravind , Hsieh David , Aguilera Todd Anthony , Maxwell Mary Claire , Sanford Nina Niu 
Published: May 2020

4056 Background: Anal Squamous Cell Cancer (ASCC) is a highly curable cancer. Underserved and vulnerable populations are particularly at risk of developing this disease. We aimed to study racial disparities and overall survival (OS) in patients with ASCC who received radiation therapy (RT) or chemo-RT (CRT) using the National Cancer Database. Methods: We identified adult patients with early-stage (stage I-II) ASCC diagnosed between 2004-2016 who underwent RT or CRT. We compared the clinical and treatment characteristics of white and black patients. The chi-square test was used for categorical variables. Kaplan-Meier and Cox regression method performed for survival analyses. We used 1:1 nearest neighbor propensity score matching to eliminate selection bias. Results: A total of 10,014 patients; 90.2% were white and 9.8% were black. White patients were more likely to be female, older age, have higher rate high-school education, private insurance, higher income, and travel a longer distance (all p < .001). Black patients were more likely to be higher comorbidity score and be treated at an academic/research facility. White patients had a higher rate of CRT and significantly better overall survival (OS) as compared to black patients (5-year survival 76% vs. 70%, p < .001) which persisted after propensity score matching (5-year survival 76% vs. 70%, p = .002). This difference continued after adjusting for clinically important factors, including HPV status (unmatched p < .03, matched p = .008). In the patients who received CRT, white patients were associated with improved OS versus black patients (unmatched 77% vs. 71%, p < .001; matched 77% vs. 71%, p = .011), and even after multivariate Cox analysis (unmatched p < .001; matched .014) (Table). Conclusions: White patients had significantly better OS as compared to black patients with early-stage ASCC as well as in the patients who received CRT. White patients were associated with high education level, higher income, and private insurance. The rate of HPV positive was similar among groups. Further investigations are needed to enlighten these disparities and target the increase education of the population at risk. [Table: see text]
Utilization and trends in palliation-directed treatments for stage II-IV anal squamous cell carcinoma patients.
Authors: Radhakrishnan Srinidhi , Goksu Suleyman Yasin , Radhakrishnan Saikripa , Morales-Oyarvide Vicente , Sanford Nina Niu , Soleja Mohsin , Haff Stephen , Beg Muhammad Shaalan , Kazmi Syed Mohammad Ali 
Published: May 2020

4059 Background: Anal squamous cell carcinoma (ASCC) is associated with significant symptom burden including pain, bleeding, and obstructive symptoms. However, the proportion of patients requiring palliation-directed treatments in ASCC is unknown. Palliation-directed treatments can control and improve symptoms and affect quality of life. We aimed to study trends, factors, and outcomes associated with utilization of palliation-directed treatment in ASCC. Methods: Using the National Cancer Database (NCDB), adult patients with stage II-IV ASCC diagnosed 2004-2015 were identified and stratified by receipt of palliation-directed treatments. Using chi-square test and logistic regression, we evaluated the associations of demographic, clinical, and pathological factors with palliation-directed treatment utilization. Results: Out of 17,988 ASCC patients in this study, palliation-directed treatments were used by 504 patients (2.8%) with stages II-IV ASCC as first line treatment. Two percent received palliation-directed surgery, chemotherapy, and radiotherapy, 0.3% received pain management, and 0.4% utilized combination therapy approach. On univariable analysis, palliation-directed treatments were associated with older age, lower income level ( p=0.004), Medicare insurance, and higher comorbidity score ( all other p<0.001). Palliation-directed treatments were also more frequent in academic/research facilities ( p=0.01), in East North Central USA ( p=.001), and in stage 4 versus stage 2/3 ASCC ( p<.001). Palliation-directed treatments have increased in recent years (2004-06 vs. 2013-15; p=.005) and were more frequently used within 6 months of patient death ( p<.001). On multivariable analysis stage 4 disease and life expectancy < 6 months were the only variables that maintained significance. Conclusions: In our study, palliation-directed treatments were used by 2.8% of the patients as codified by NCDB. Its use was higher in stage 4 ASCC and within the last six months of life. Palliation-directed treatment utilization has incrementally increased in recent years. Additional research is warranted in determining the phase of care wherein palliation-directed treatments are utilized in ASCC.
Tumor-infiltrating lymphocytes and tumor budding refine prognostication in patients with low- and high-risk stage III colon cancers (NCCTG N0147)[Alliance].
Authors: Sha Dan , Lee Hee Eun , Foster Nathan R. , Shi Qian , Alberts Steven R , Smyrk Thomas C. , Sinicrope Frank A. 
Published: May 2020

4065 Background: Tumor infiltrating lymphocytes (TILs) and tumor budding (linked to epithelial mesenchymal transition) may influence metastatic potential and patient prognosis. We analyzed these features and their relative contribution to survival among low (T1-3 N1) and high (T4 and/or N2) risk groups, defined by the IDEA study, used to inform the duration of adjuvant chemotherapy in stage III colon cancer. Methods: Among 1,532 patients (low risk n=804; high risk n=728) treated in a phase III adjuvant trial of FOLFOX + cetuximab (x 6 months), intraepithelial TIL densities and tumor budding were quantified at microscopy in routine histologic sections. Optimal cutpoints were determined in association with 5-yr disease-free survival (DFS). Relative contribution of variables to DFS was calculated using χ2 from Harrell’s rms R package based on multivariable Cox regression models. Results: In the overall cohort, the tumor budding/TILs combined variable was more robust for predition of DFS than either alone. Budding/TILs was significantly associated with DFS in both low (HRadj, 1.59; 95% CI, 1.02-2.48; p=.0273) and high (HRadj, 2.82; 95% CI, 1.72-4.63; p<.0001) risk patients. We then determined its relative contribution (%) to DFS (Table). Among low risk, budding/TILs ranked second (24.4%) behind KRAS status (45.5%) and ahead of treatment arm (7.2%) and mismatch repair (MMR) status (6.1%). Among high risk, budding/TILs contributed the most to DFS (45.4%) followed by primary tumor sidedness (13.0%), performance status (12.0%), and MMR (10.4%). Conclusions: Tumor budding/TILs provides robust prognostic stratification by risk group to improve anatomic tumor staging. The relative contribution of budding/TILs to DFS was second only to KRAS status in low risk patients, and was the most important predictor of DFS in high risk patients. Evaluation in patients treated with 3 vs 6 mos of adjuvant chemotherapy is warranted. [Table: see text]