bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular profile of ampulla of vater carcinoma (AVC): A rare tumor type with meaningful molecular alterations.
Authors: Pinto João , Verdaguer Helena , Salcedo Maria Teresa , Pedrola Anna , Hernando-Cubero Jorge , Pastrana Juan David Assaf , Acosta Daniel , Vivancos Ana , Dienstmann Rodrigo , Mercade Teresa Macarulla 
Published: May 2019

4119 Background: AVC is a rare type of cancer with dismal prognosis and limited therapeutic options due to the lack of specific clinical trials. Two histologic subtypes predominate, namely pancreatobiliary and intestinal. A variety of molecular alterations have been described in AVC, but their clinical and therapeutic implications have not been studied in detail. Methods: Retrospective cohort study of patients (pts) diagnosed with AVC treated in our institution from 2010 to 2018. We routinely performed Next Generation Sequencing in all AVC tumors. Our main objectives were to describe the molecular profile of AVC and correlate with clinical outcomes. Results: Out of 26 pts with AVC, 13 pts were male (50%), median age 65 (range 43-83), 7 pts (27%) had stage IV disease at diagnosis. Histologic type was pancreatobiliary in 18 pts (69%), intestinal in 7 pts (27%) and mixed in one case (4%). We identified KRAS mutations (mut) in 10 pts (7 pancreatobiliary, 2 intestinal, 1 mixed), TP53 mut in 6 pts (4/1/1), PIK3CA mut in 3 pts (3/0/0), ERBB2 mut in 3 pts (2/1/0), CTNNB1 mut in 3 pts (2/1/0). In pancreatobiliary we found single cases with RNF43, BRCA1 and CHEK2 mut; while in intestinal we found single cases with NRAS and BRAF mut. One tumor of intestinal subtype had microsatellite instability (MSI). Three pts were included in phase I clinical trials, 2 of them with trials based on tumor profile (ERBB2 mut with pan-HER inhibitor and MSI with immunotherapy). Median overall survival (OS) was 21 months for pts with stage I, II and III disease (95% CI 12.37-not reached) and 13.2 months for stage IV disease at diagnosis (95% CI 5.73-not reached). In cox models, median OS was not dependent on KRAS or TP53 mutation status, or histological subtypes. Conclusions: AVC is a rare type of cancer with two differentiated histological subtypes harboring unique molecular alterations that can be matched to investigational therapies. A broader knowledge of the biology of these tumors is needed to improve patient outcomes.
The effect of neoadjuvant chemotherapy with gemcitabine and S-1 for resectable pancreatic cancer (randomized phase II/III trial; Prep-02/JSAP-05).
Authors: Satoi Sohei , Unno Michiaki , Motoi Fuyuhiko , Matsuyama Yutaka , Matsumoto Ippei , Aosasa Suefumi , Shirakawa Hirofumi , Wada Keita , Fujii Tsutomu , Yoshitomi Hideyuki , Takahashi Shinichiro , Sho Masayuki , Ueno Hideki , Yamamoto Tomohisa , Kosuge Tomoo 
Published: May 2019

4126 Background: Despite recent progress of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), its survival remains limited. We conducted a randomized controlled trial to compare neoadjuvant chemotherapy (NAC) with upfront surgery (UP-S) for patients with resectable PDAC. Methods: Patients with resectable PDAC, all confirmed cytologically or histologically were enrolled. Patients received 2 cycles of gemcitabine and S-1 regimen (GS) followed by surgery (NAC) or UP-S after randomization (1:1). Patients in both arms received adjuvant chemotherapy using S-1 for 6 months after surgical resection. The primary endpoint was overall survival (OS); secondary endpoints included adverse events, resection rate, recurrence-free survival, residual tumor status, nodal metastases, and tumor marker kinetics. Results: A total 362 patients were randomly assigned to NAC-GS (n=182) or UP-S (n=180) for 3 years (2013-16). The median OS was 36.7 months in NAC-GS and 26.6 months in UP-S; HR 0.72 (p=0.015, stratified log-rank test) at 2.5 year after final enrollment. Crude resection rate for NAC and UP-S were 77%, 72% respectively. There was no operative mortality in both groups. Although G3/4 adverse events were observed frequently (73%) during NAC, no significant difference for both groups was observed for perioperative outcomes including blood loss, operation time, R0 resection rate and post-operative morbidity. Significant decrease of pathological nodal metastases in NAC was noted compared to those in UP-S by pathological evaluation for resected patients(p<0.01). Although significant decrease of viable tumor cells was observed in primary tumor after NAC compared to UP-S (p<0.01), Evans IIb or more was found in only 14 % of resected patients in NAC. Hepatic recurrence after surgery was significantly reduced in NAC (30.0%) compared to UP-S (47.5%) in observed period. Conclusions: The strategy of NAC showed significant longer survival compared to that of UP-S with acceptable feasibility. The effect of NAC might imply the control of subdiagnostic liver metastases before surgery for resectable PDAC. Clinical trial information: UMIN000009634.
Homologous recombination deficiency (HRD): A biomarker for first-line (1L) platinum in advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Park Wungki , Wong Winston , Yu Kenneth H. , Varghese Anna M. , Riaz Nadeem , Balachandran Vinod P. , El Dika Imane H. , Raj Nitya Prabhakar , Khalil Danny , Ku Geoffrey Yuyat , Segal Neil Howard , Li Jia , Chalasani Sree Bhavani , Chong Curtis Robert , Kelsen David Paul , Abou-Alfa Ghassan K. , Berger Michael F. , Schultz Nikolaus , Iacobuzio-Donahue Christine A , O'Reilly Eileen Mary 
Published: May 2019

4132 Background: HRD is an emerging biomarker for platinum therapy in PDAC. The clinical implications regarding differences in outcome between germline and somatic HRD in advanced PDAC treated with 1L platinum is unexplored. Methods: We evaluated overall survival (OS) for advanced PDAC (stage III/IV) based on their pathogenic germline (gHRD) and somatic HRD (sHRD) using integrated genomic profiling from MSK-IMPACT and 1L platinum use. HRD defined by pathogenic alterations from the following genes: BRCA1/2, PALB2, ARID1A/B/2, ATR, ATRX, ATM, BAP1, RAD50/51C/D, BRIP1, NBN, CHECK1/2, FANCA/C, CDK12, and MRE11. Results: Advanced PDAC patients (n=461) treated at MSK enrolled in a prospective database, were evaluated. Median follow-up was 27.6 months (95% CI, 24.6-30.6). Both germline and somatic profilings were available for n=350 (76%) but only somatic profiling was available for n=111 (24%). We identified n=52 patients with gHRD (11.3%), n=42 patients with sHRD (9.1%), and 48 patients with somatic VUS for HRD genes. From all 461 patients, the OS was not different between 1L non-platinum vs. 1L platinum groups (19 M vs. 19.3 M), regardleess of their HRD status. (Table) The OS was superior for gHRD vs. non-gHRD (28.7 M vs. 18.2 M), regardless of 1L treatment choice. However, similar significant OS superiority was neither observed in sHRD vs. non-sHRD, nor in VUS sHRD vs. non-VUS sHRD. In a subgroup analysis of 1L platinum treated patients, the OS was superior in gHRD vs. non-gHRD (NR vs. 17.9 M); however, there was no OS difference between sHRD and non-sHRD. Conclusions: In advanced PDAC patients, only gHRD predicted better overall survival for first-line platinum chemotherapy. These findings emphasize the importance of germline mutation testing of HRD in PDAC. Biomarker validation and functional definition of HRD such as loss of heterozygosity analysis is underway. [Table: see text]
Hereditary cancer genetic testing among patients with pancreatic cancer.
Authors: Taherian Nassim , Saam Jennifer , Larson Katie , Lancaster Johnathan M. , Permuth Jennifer 
Published: May 2019

4134 Background: Pancreatic cancer (PC) is typically diagnosed at a late, untreatable stage, with a 5-year survival rate of only ~8%. Genetic testing for individuals with PC may aid in therapy decisions, as those with a germline or somatic pathogenic variant (PV) in a DNA-repair gene may benefit from PARP inhibitors. In addition, germline genetic testing for unaffected family members can identify high risk individuals who may be appropriate for surveillance studies. We assessed the results of hereditary cancer genetic testing among individuals with a personal history of PC and evaluated several possible risk factors. Methods: Individuals with PC who had germline testing for 25-29 cancer-susceptibility genes between September 2013 and November 2018 were included in this analysis (N = 1,676). Clinical characteristics were obtained from provider-completed test request forms and included personal cancer history (PHx), family cancer history (FHx), and age at diagnosis. Results: Overall, 12.6% (212/1676) of patients with PC carried a PV, most commonly in BRCA2 (3.8%), ATM (2.7%), and PALB2 (1.2%). PVs were more common in men and for individuals who had a PHx of additional cancer(s) (see Table). Age at PC diagnosis did not impact the positive PV rate. The PV positive rate was elevated among individuals with PC and at least two relatives with PC (15.1%) and for individuals with a FHx of cancer at an early age (14.2%). The PV positive rate remained > 10% regardless of nearly all other FHx characteristics evaluated, including the absence of any FHx (see Table). Conclusions: In this cohort, a substantial proportion of individuals with a PHx of PC carried PVs, regardless of age at diagnosis and personal and family cancer history. [Table: see text]
A pilot randomized study evaluating nivolumab (nivo) or nivo + bevacizumab (bev) or nivo + ipilimumab (ipi) in patients with metastatic renal cell carcinoma (MRCC) eligible for cytoreductive nephrectomy, metastasectomy or post-treatment biopsy (Bx).
Authors: Gao Jianjun , Karam Jose A. , Tannir Nizar M. , Campbell Matthew T , Slack Tidwell Rebecca , Ahrar Kamran , Rao Priya , Ng Chaan S. , Jonasch Eric , Matin Surena F. , Zurita Amado J. , Shah Amishi Yogesh , Shen Yu , Blando Jorge M. , Vence Luis M. , Basu Sreyashi , Zhao Hao , Allison James Patrick , Wood Christopher G. , Sharma Padmanee 
Published: May 2019

4501 Background: Cytoreductive surgery (CS) including cytoreductive nephrectomy and metastasectomy provides clinical benefits to patients with MRCC. However, CS has not been evaluated in the setting of immune checkpoint (IC) therapy. We performed a pre-surgical/biopsy trial to evaluate biological and clinical activity of nivo +/- (bev or ipi) in patients with MRCC. Methods: In this open-label, randomized trial (NCT02210117), patients with MRCC w/o prior IC therapy and anti-VEGF therapy were randomized 2:3:2 to receive nivo (3mg/kg q2wks x3), nivo + bev (10mg/kg q2wks x3) or nivo + ipi (1mg/kg q3wks x2), followed by CS or Bx, and then nivo maintenance therapy up to 2 yrs. Clinical response per RECIST criteria was assessed at ≥12 wks. Pre- and post-treatment blood and tumors were obtained for correlative studies. Results: All of 105 patients have been accrued and 104 are evaluable for response. For all patients, best overall response (BOR = complete response [CR] + partial response [PR]) including surgery effect was 55% nivo, 44% nivo + bev, 43% nivo + ipi. Median PFS (95% confidence interval) was 14.5 months (5.5, not reached [NR]) nivo, 7.6 (4.8, 8.9) months nivo + bev, 7.5 (2.0, 12.4) months nivo + ipi. Overall survival (OS) at one year was 86% nivo, 73% nivo + bev, 83% nivo + ipi. Grade 3 or higher toxicities related to therapy were 38% for nivo, 42% for nivo + bev (including 18% hypertension), and 47% for nivo + ipi. For patients with CS, BOR including surgery effect was: 86% nivo, 88% nivo + bev, and 69% nivo + ipi. Median PFS was 17.3 months (6.1, NR) nivo, 7.6 (5.7, 10.3) months nivo + bev, 8.9 (2.9, 23.0) months nivo + ipi. OS at one year was 100% nivo, 94% nivo + bev, 92% nivo + ipi. Median OS has not yet reached with a median follow-up of 24.6 months. Immune and gene profiling analyses demonstrate: 1) tumor infiltrating CD8 T cells correlate with clinical responses to nivo or nivo + bev, but not to nivo + ipi; 2) tumor IFN pathway gene expression correlates with responses; and 3) PD-L1 status, tumor mutation or mutation burden, neoantigens did not correlate with response. Conclusions: IC therapy plus CS is safe and beneficial to patients with MRCC and therefore, warrants testing, along with a few correlative biomarkers, in a larger phase 3 trial. Clinical trial information: NCT 02210117.
Cytoreductive nephrectomy (CN) in metastatic renal cancer (mRCC): Update on Carmena trial with focus on intermediate IMDC-risk population.
Authors: Mejean Arnaud , Thezenas Simon , Chevreau Christine , Bensalah Karim , Geoffrois Lionnel , Thiery-Vuillemin Antoine , Cormier Luc , Lang Herve , Guy Laurent , Gravis Gwenaelle , Rolland Frederic , Linassier Claude , Timsit Marc-Olivier , Albiges Laurence , Oudard Stephane , Lebret Thierry , Treluyer jean-Marc , Colas Sandra , Escudier Bernard , Ravaud Alain 
Published: May 2019

4508 Background: Carmena was a randomized phase III trial, testing the benefit of CN followed by sunitinib (arm A) vs sunitinib alone (arm B), with stratification by MSKCC risk groups in 450 mRCC patients. Based on this trial, CN is not anymore recommended in mRCC (NEJM, Mejean et al, 2018). However there are questions about which patients could still benefit from CN, especially in intermediate risk group. In the present study, we investigated different subgroups from the Carmena trial to answer these questions. Methods: Carmena trial was initially stratified according to MSKCC risk groups. For the purpose of this analysis, we reclassified the patients based on IMDC risk groups. We also analyzed patients with one metastatic site vs more than one, as well as patients with secondary nephrectomy in arm B. Overall survival (OS) was the primary endpoint. Results: With a updated median FU of 61.5 months (mo), the median OS by ITT analysis was 15.6 vs 19.8 mo in arm A and B respectively stratified on MSKCC (HR 0.933 ; 95% CI [0.76- 1.15]) / stratified on IMDC (HR 0.957 ; 95% CI [0.78- 1.18]). Using IMDC risk group factors, 58.6% patients were intermediate and 41.4 % were poor risk. When looking at intermediate risk group only, 48.1% had only one risk factor (interval between diagnosis and treatment < 1y), with a median OS of 30.5 and 25.2 mo in arm A and B respectively (HR 1.24 [0.81 – 1.90]). By contrast, 51.9 % had two risk factors (mostly low hemoglobin, high corrected calcium or neutrophils), with a median OS of 16.6 and 31.2 mo in arm A and B respectively (HR 0.61 [0.41 – 0.91] p = 0.015). Regarding number of metastatic sites, 33% had only one metastatic site. Median OS was 23.6 and 22.7 mo in arm A and B respectively (HR 1.08 [0.75 – 1.57]. Finally, 40 patients had a secondary nephrectomy in arm B, with median OS of 48.5 mo [CI 95%: 27.9-64.4] vs 15.7 mo [CI 95%: 13.3-20.5] in patients who never had surgery. Conclusions: With longer FU, Carmena trial confirms that CN is not superior to sunitinib alone in ITT population, both with MSKCC and IMDC risk groups. However for patients with only one IMDC risk factor, CN might be beneficial. Number of metastatic site is not helpful to define good candidates for surgery. Finally, patients with secondary nephrectomy have very long OS, supporting this strategy. Clinical trial information: NCT00930033.
Interim analysis of ibrutinib plus paclitaxel for patients with advanced urothelial carcinoma previously treated with platinum-based chemotherapy.
Authors: Castellano Daniel E. , Morales-Barrera Rafael , Duran Ignacio , Keam Bhumsuk , Chung Ik Joo , Arkenau Hendrik-Tobias , Vaishampayan Ulka N. , Tuthill Mark , Gajate Pablo , Shin Sang Joon , Dang S. Paul , Ju Chia-Hsin , Lin Jennifer , Cole George W. , James Danelle Frances , Reig Oscar 
Published: May 2019

4522 Background: Patients (pts) with advanced urothelial carcinoma (aUC) who progressed after platinum-based chemotherapy (PBCT) have a median overall survival (OS) of ~6 mo on CT and 8-10 mo on novel immune checkpoint inhibitors (ICIs). Treatment (tx) with ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase (BTK) with immunomodulatory properties, plus paclitaxel (pac) may improve outcomes for pts with aUC. Methods: Pts with aUC who had 1-2 prior tx (≥1 PBCT and/or ICIs) formed one cohort of this phase 1b/2 study. Recommended phase 2 dose per phase 1b was ibr 840 mg/d + weekly pac 80 mg/m2 in 21-d cycles; starting ibr dose of 560 mg/d. nanoString gene expression assay (NanoString Technologies) was used for preliminary assessment of ibr-targeted kinases in baseline tumor biopsies. Results: This interim analysis included the first 29 pts treated (ibr 840/560 mg/d, n = 25/4; median age 67 y). 52% had 2 prior regimens (prior PD-L1 inhibitors, 100%). Median time on study/tx was 7.2/2.3 mo (max tx: 11.5 mo). Unconfirmed overall response rate (ORR) was 41% (complete/partial response: 10%/31%). Disease control rate was 62%. ORR was 71% for 7 pts with only lymph node metastases; ORR was 36% for 14 pts with 1 prior tx and 47% for 15 pts with 2 prior tx. Median duration of response was 4.2 mo (90% CI: 1.9-7.1). Median progression-free survival was 3.6 mo (90% CI: 1.6-5.4). Median OS was 14.7 mo (90% CI: 7.7-15.9). Follow-up is ongoing for durability/survival with 6 pts alive without progression, including 4 still on ibr. 76% of pts had grade ≥3 adverse events (AEs); 4 discontinued ibr + pac due to AEs and 1 had major hemorrhage. Pac exposure was not impacted by ibr; pac geometric mean Cmax (2066 ng/mL) and AUC0-∞ (3813 ng·h/mL) were consistent with historical data. Preliminary tumor biopsy data showed a nonsignificant trend of higher BTK/ITK/BMX expression in tx responders; analyses are ongoing. Conclusions: Ibr + pac shows promising results for ORR/OS in pts with aUC previously treated with PBCT and ICIs. No unexpected safety signals were seen; ibr + pac seemed tolerable. Follow-up of these and additional pts will support the activity and safety of ibr + pac in this study. Clinical trial information: NCT02599324.
Pembrolizumab (pembro) for patients (pts) with high-risk (HR) non–muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): Updated follow-up from KEYNOTE-057.
Authors: De Wit Ronald , Kulkarni Girish S. , Uchio Edward M. , Krieger Laurence Eliot Miles , Boormans Joost L. , Roumiguié Mathieu , Singer Eric A. , Bajorin Dean F. , Kamat Ashish M. , Grivas Petros , Seo Ho Kyung , Nishiyama Hiroyuki , Konety Badrinath R. , Nam Kijoeng , Kapadia Ekta , Frenkl Tara L. , Balar Arjun Vasant 
Published: May 2019

4530 Background: Upregulation of the PD-1 pathway has been observed in BCG-unresponsive NMIBC, suggesting that pembro may be beneficial. Efficacy and safety of pembro in pts with HR, BCG-unresponsive NMIBC was evaluated in the single-arm phase 2 KEYNOTE-057 study (NCT02625961); updated results for pts with carcinoma in situ (CIS) with or without papillary tumors (cohort A) are reported. Methods: Pts with histologically confirmed HR, BCG-unresponsive CIS with or without papillary tumors who received adequate BCG therapy and were unable/refused to undergo radical cystectomy received pembro 200 mg Q3W for 24 mo or until recurrence, progression, or unacceptable toxicity. Pts who developed HR NMIBC or progressive disease during treatment were required to discontinue. Key end points were complete response rate (CRR), duration of response, and safety. Results: 102 pts (median age, 73 years; CIS alone, 63.7%; median number of prior BCG instillations, 12) had enrolled in cohort A as of enrollment cutoff. Median (range) duration of follow-up was 15.8 mo (4.6-28.2) ; 3-mo CRR was 40.2% (95% CI, 30.6-50.4) by central assessment. Among 41 pts who had CR at 3 mo, median CR duration was 12.7 mo (range, 0+ to 20.5+ mo); 75.4% had a CR duration ≥ 6 mo; 52.6% had a CR duration ≥12 mo (Kaplan-Meier method); 24 pts (58.5%) maintained CR at last follow-up, and 15 (36.6%) experienced recurrent NMIBC after CR; at the time of analysis, none progressed to muscle-invasive or metastatic disease. CRR was 44.6% for pts with CIS alone (n = 65), 41.7% for CIS with T1 tumors (n = 12), and 28.0% for CIS with high-grade Ta tumors (n = 25). Treatment-related adverse events (AEs) occurred in 66 (64.7%) pts; most frequent (≥10%) were pruritus (10.8%), diarrhea (10.8%), and fatigue (9.8%). Grade 3/4 treatment-related AEs occurred in 13 (12.7%) pts. Immune-mediated AEs occurred in 19 (18.6%) pts. Conclusions: Pembro continued to show encouraging antitumor activity in pts with HR, BCG-unresponsive CIS with or without papillary tumors and a safety profile consistent with that of previous experience. Updated data using additional follow-up will be presented. Clinical trial information: NCT02625961.
Increasing use of neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC): Prognostic impact of non-standard of care (SOC) regimens.
Authors: Nyame Yaw A. , Holt Sarah K , Winters Brian , Psutka Sarah P. , Dash Atreya , Schade George R , Lin Daniel W. , Diamantopoulos Leonidas Nikolaos , Grivas Petros , Yu Evan Y. , Gore John L. , Wright Jonathan L. 
Published: May 2019

4532 Background: Cisplatin-based NAC can prolong overall survival (OS) in patients (pts) with MIBC. Utilization of NAC has increased to about 20% of pts with MIBC over the last decade. We evaluated NAC utilization with and without SOC cisplatin-based combination regimens and oncologic outcomes using registry data. Methods: This is a population-based analysis of linked SEER-Medicare data (2004-2011). We identified 4534 pts with MIBC (cT2-4N0-1) undergoing radical cystectomy (RC). Based on pharmacy records data, pts were stratified into 3 groups: SOC, non-SOC, and immediate cystectomy (IC). We used descriptive statistics to compare groups, and multivariate logistic regression to define factors associated with receiving SOC NAC. Competing risk bladder cancer-specific mortality (BCSM) incidence curves were generated and KM analysis was used to assess OS from time of RC. The impact of NAC on OS was evaluated with Cox regression analysis. Results: 694 (15.3%) pts received NAC, increasing from 11% in 2004 to 24.8% in 2011, with 345 (50%) receiving non-SOC, e.g. gemcitabine/carboplatin (49.3%), gemcitabine alone (21.2%), carboplatin alone (14.8%), cisplatin alone (8.4%), and methotrexate/vinblastine/ adriamycin/carboplatin (0.8%). On logistic regression, increasing age (OR 0.91, 95%CI 0.88 – 0.94, p < 0.0001), Hispanic/Latin ethnicity (OR 0.49, 95%CI 0.22 – 1.10, p = 0.08), and ≥moderate renal dysfunction (OR 0.20, 95%CI 0.08 – 0.51, p < 0.001) were associated with lower odds of SOC NAC. Non-SOC NAC was associated with higher BCSM (competing risk) and lower OS (KM) vs. IC and SOC NAC. On multivariable analysis, non-SOC NAC was associated with higher risk of BCSM (HR 1.35, 95%CI 1.06 – 1.72, p = 0.01) and lower OS (HR 1.38, 95%CI 1.11 – 1.70, p = 0.003) vs. SOC NAC. Conclusions: About 50% of pts receiving NAC were not treated with SOC regimens. Non-SOC NAC was associated with higher bladder cancer death risk. This stresses the role of SOC NAC ideally in a multidisciplinary expert setting, as well as the need for timely RC and neoadjuvant clinical trials, including cisplatin-ineligible pts.