tbuckley/cabot-search huggingface dataset:
Survival outcome of breast cancer (BC) patients presenting with recurrent and de novo isolated contralateral lymph node metastases (CLNM).
Authors: Aydah Al-Awadhi, Xiudong Lei, Rachel Ann Sanford, Vicente Valero, Sharon Hermes Giordano, Mariana Chavez-MacGregor
Journal: Journal of Clinical Oncology (2018)

12120 Background: In the current staging system, BC patients with isolated CLNM are considered to have distant or stage IV disease. The prognosis of these patients has not been described in contemporary series. In this study we compared the outcomes of patients with CLNM and those with stage IV disease with metastases other than CLNM. Methods: We identified metastatic BC patients treated at MD Anderson Cancer Center between 2000-2015. 235 patients had isolated recurrent CLNM (supraclavicular, infraclavicular and/or axillary) and 7617 patients had metastases other than CLNM. Among patients diagnosed with stage IV de novo, 37 had isolated CLNM and 1544 had distant metastases other than CLNM. Overall survival (OS) and breast cancer-specific survival (BCSS) were calculated from date of distant metastases for the recurrent cohort and from date of diagnosis for the de novo cohort. Descriptive statistics, Kaplan-Meier method with log-rank test and Cox proportional hazards model were used. Results: In the recurrent cohort (median follow-up 20 months) the 3-year OS rate was 43% for CLNM patients and 41% for those with non-CLNM (p = 0.04). After multivariable adjustment, patients with recurrent CLNM had decreased risk of death (HR = 0.66; 95%CI 0.56-0.78) compared to patients with metastases other than CLNM. Patients with CLNM had comparable OS to the subgroup of patients with bone-only metastases (HR = 0.97; 95%CI 0.82-1.16). Among stage IV de novo patients (median follow-up 31 months) the 3-year OS was 62% for patients with CLNM and 57% for patients with metastases other than CLNM (p < 0.001). In multivariable analyses, CLNM patients had decreased risks of death (HR = 0.63; 95%CI 0.39-1.00) compared to patients with metastases other than CLNM. BCSS analysis was similar. Conclusions: Metastatic BC patients with isolated CLNM have better outcomes compared to patients with non-CLNM metastases. The prognosis of patients with isolated CLNM was similar to the prognosis of patients with bone-only metastases. Our data can be helpful in identifying patients with limited regional disease that may potentially benefit from multidisciplinary treatment given improved outcomes.
Health-related quality of life in patients with metastatic pancreatic cancer in usual care settings.
Authors: Vincent J. Picozzi, Siva Narayanan, X. Henry Hu
Journal: Journal of Clinical Oncology (2016)

e15746 Background: Metastatic pancreatic cancer (mPC) has a high mortality rate with a 5-year survival of about 8%. Its clinical course is typically marked by severe symptoms and poor quality of life (QoL). The purpose of this pilot project was to assess real-world QoL in patients with mPC at different stages of treatment. Methods: A cross-sectional survey was conducted in newly diagnosed mPC patients before initiation of 1st line chemotherapy with gemcitabine ± nab-paclitaxel (Group 1); patients who achieved stable or partial response upon receipt of ≥ 3 cycles of 1st line chemotherapy with nab-paclitaxel plus gemcitabine (Group 2) or gemcitabine monotherapy (Group 3); patients who failed ≥ 1 lines of chemotherapy and experienced disease progression and were not currently receiving an nab-paclitaxel-containing regimen (Group 4). Eligible participants were asked to complete three QoL instruments (EORTC QLQ-C30, EORTC QLQ-PAN26, and EQ-5D) during their routine clinical visits at 14 participating cancer care clinics across US. Results: A total of 74 patients were surveyed (Group 1 = 29; Group 2 = 26; Group 3 = 2; Group 4 = 17); 2 patients in group 3 were not included in the data analysis. Demographic characteristics were generally similar between the groups. The mean age was 66.4 years old and 60% were males. Patients in group 2 and 4 had statistically significant lower pain scores as captured in EORTC QLQ-C30 compared to Group 1 (27.6 and 24.5 vs 47.1; p = 0.018 and p = 0.018, respectively) and lower pancreatic pain scores as reported via EORTC QLQ-PAN26 (27.9 and 26.0 vs. 45.4; p = 0.017 and p = 0.024, respectively); Patients in Group 2 and 4 also reported less appetite loss (37.2, 27.5, and 51.7, respectively; p = 0.06). There were no statistically significant differences between the 3 analyzed groups on other QoL domain or subdomain scores. Conclusions: mPC patients who achieved stable or partial responses while treated with 1st line nab-paclitaxel plus gemcitabine had no discernible deterioration in QoL compared to mPC patients who had not received any chemotherapy. There was improvement on pain and pancreatic pain in patients receiving chemotherapy.
Conceptualization of an indication-specific pricing model to assess potential savings to a U.S. health plan.
Authors: Sandip Shah, Joseph Black, Vidya Ramesh, Dong Shao, Siva Narayanan
Journal: Journal of Clinical Oncology (2017)

e18315 Background: Value based pricing has become a topic of increasing public attention and scrutiny. An Indication Specific Pricing (ISP) allows price setting relative to the level of benefit provided in a given indication and patient population, with the potential for price to vary based on value in the concerned indication(s). We quantified the impact of deploying an ISP scheme on 5-year Afinitor (everolimus) expenditures for a hypothetical health plan of 5M covered lives in the U.S., taking into account three indications: HER2- breast cancer, renal cell carcinoma, and pancreatic cancer. Methods: We constructed an Excel-based model to understand future expenditures on an annual basis utilizing an ISP scheme against a more traditional single contracted price. Key inputs for the model include price per pill (average selling price (ASP)), forecasted annual number of patients per indication (based on 5M covered lives), and compliance rate. Results from the Sloan Kettering “DrugAbacus” pricing project were leveraged to estimate indication-level prices based on their assessment of efficacy, tolerability, and unmet need for Afinitor in each of the indications; actual ISP prices originally used by Sloan Kettering in their model were reweighted and adjusted. Results: As the DrugAbacus price calculated for each indication was lower than the current ASP for Afinitor, use of an ISP methodology resulted in a 9.3% decrease in five year expenditures for Afinitor ($136.9M for a traditional single price vs. $124.1M for an ISP model). Conclusions: US Payers could consider assessing the value a therapeutic intervention brings to each approved indication using ISP in an effort to lower total pharmaceutical-related healthcare costs. Drug manufacturers may benefit from considering relative product value in each potential indication to assess commercial attractiveness and focus evidence generation strategies on those indications seen as most valuable, to support price negotiations.
Effect of YAP1 on pancreatic stellate cell activation and tumor microenvironment.
Authors: Ying Xiao, Hui Zhang, Huanwen M. Wu, Junyi Pang, Liangrui Zhou, Zhiyong Liang
Journal: Journal of Clinical Oncology (2018)

e16199 Background: Activated pancreatic stellate cells (PSCs) secrete excessive molecules to support tumor microenvironment. Yes-associated protein 1(YAP1) can regulates cellular mechanics, which is associated with fibroblasts activating. We aimed to investigate the effect of YAP1 on PSCs activation, secretion and pancreatic cancer cells (PCCs) progression. Methods: Influence of all-transretinoic acid (ATRA) on YAP1 expression in PSCs was evaluated by western blot and immunofluorescence. Expressions of α-SMA and collagen I, cell morphology, contraction, proliferation, apoptosis and cell cycle were assessed after YAP1 knockdown. YAP1-regulated genes were screened in a q-PCR array, and validated by western blot, q-PCR and ELISA. The proliferation of PCCs was assessed in models of PSCs-supernatant incubation and co-culture systems. Stromal immunohistochemistry expressions of YAP1 and SPARC were evaluated on PDAC tissue microarrays and analyzed in different clinicopathological parameters. Results: ATRA decreased nuclear expression of YAP1 in PSCs. After YAP1 knockdown, α-SMA and collagen I expressions decreased, cell morphology turned into triangular outline, capacity of proliferation and contraction decreased, apoptosis cells increased, and cell cycle was arrested in G2. SPARC was screened as the most outstanding PSCs-secreted protein positively regulated by YAP1 on transcribed, translated and secreted levels. YAP1-depleted PSCs enhanced the proliferation ability of PCCs by reducing SPARC paracrine. YAP1 and SPARC were highly expressed in PDAC stromal cells (P< 0.05). Nuclear expression of YAP1 in stromal cells were significantly correlated with SPARC expressions (r = 0.433, P< 0.001) and fibrosis degree (r = 0.543, P< 0.001). High expression of stromal SPARC was significantly associated with larger tumor size (P= 0.04). It was also an independent unfavorable prognostic factor for PDAC overall survival (HR = 3.216, P= 0.005). Conclusions: Our study verified that YAP1 can change PSCs quiescent-activated phenotype and affects PCC proliferation via SPARC paracrine. And excessive expression of stromal SPARC is an indicator for larger tumor size and poor outcome.
Treatment decision priorities and decisional support experiences of gastric cancer survivors.
Authors: Linda S. House, Melissa F Miller, Alexandra Katherine Zaleta, Shauna McManus, Crystal S. Denlinger, Julie S. Olson, Joanne S. Buzaglo
Journal: Journal of Clinical Oncology (2018)

e16037 Background: With newer gastric cancer (GC) treatment combinations and targeted therapies, it is important for patients to understand treatment options and their impact. We examined GC patient priorities in treatment decision-making (TDM) and satisfaction with health care team (HCT) communication. Methods: Through the Cancer Experience Registry, 50 GC survivors (42% stomach, 42% esophageal, 16% GIST) rated importance of cost of care (CoC), length of life (LoL), quality of life (QoL), and family impact for TDM, and satisfaction with TDM and treatment outcomes. We evaluated associations between treatment, socio-demographic, and clinical variables via Spearman correlations. Results: Participants (pts) were 82% White, 58% female, mean age 62 years (SD= 11); 5 (SD= 8.3) years since diagnosis. 76% received chemotherapy; 71% radiation; 21% biological and 33% targeted therapy. The most important TDM factor was QoL (94% quite a bit or very much), then family impact (74%), LoL (72%), and CoC (25%). Pts felt involved in TDM (69%), but less knowledgeable about options (54%) or prepared to discuss options with the HCT (43%). Few received decision support prior to TDM (34%), though only 38% wanted more support. Few were satisfied with discussions around CoC (27%), but were largely satisfied, however, with how decisions were made (63%), level of participation (65%), treatment outcome (65%), and HCT explanation of risks and side effects (65%) (p< .01). TDM satisfaction was associated positively with knowledge (ρ = .63, p< .001), level of involvement (ρ= .40, p< .01), and preparedness to discussion options (ρ= .41, p< .01), and negatively with age (ρ= -.30, p= .049). Treatment outcome satisfaction was associated positively with knowledge (ρ= .42, p< .01) and preparedness (ρ= .36, p= .02). LoL and CoC importance were positively associated with preparedness (ρ= .46, p< .01 and ρ= .58, p< .001, respectively); CoC importance was negatively correlated with age (ρ= -.45, p= .02). Conclusions: Many GC survivors are not fully prepared to discuss treatment options with their HCT. Pts were largely unsatisfied with CoC discussions. Enhanced HCT communication about treatment options, especially regarding symptom burden and finances, is necessary.
Randomized, double-blind, phase III trial of monosialotetrahexosylganglioside versus placebo in GI cancer patients with oxaliplatin induced peripheral neurotoxicity (TJMUCH-GI-001).
Authors: Zhou Likun, Yi Ba, Rui Liu, Dingzhi Huang, Hongli Li, Tao Ning, Le Zhang, Shaohua Ge, Ming Bai, Xia Wang, Rubing Han, Yuchong Yang, XinYi Wang, Zhiying Gao, Xinyun Chen, Kaijun Niu, Laizhi Luo, Ting Deng, Yan Li, Yuanquan Yang
Journal: Journal of Clinical Oncology (2018)

10017 Background: Neurotoxicity is the most common dose-limiting toxicity of oxaliplatin. There is no treatment for cumulative sensory neuropathy. This trial is designed to study the efficacy of Monosialotetrahexosylganglioside (GM1) in GI cancer patients with oxaliplatin-induced peripheral neurotoxicity (OIPN). Methods: In this single center (TJMUCH),double-blind, phase Ⅲ trial, patients were randomized in a 1:1 ratio to receive GM1 or placebo. Patients with OIPN persisting during or after oxaliplatin-based chemotherapy were eligible. The patients who remained on oxaliplatin after enrollment, received concurrent placebo or GM1 x 7 days with each chemotherapy cycle. The patients who stopped taking oxaliplatin, were treated with placebo or GM1 x 14 days every 3 weeks. GM1 was dosed at 60mg daily for every 3-week or 40mg daily for every 2-week schedule. Trial was continued until visual analogy score (VAS) decreased by ≥30% or stayed unchanged after two more treatments beyond completion of oxaliplatin. The primary endpoint was reduction of modified EORTC QLQ-CIPN20(MCIPN20) score by ≥30%. Secondary endpoints were improvement of VAS by ≥30%, CTCAE grade by≥1. Patients who received ≥1 treatment cycle were included in the analysis. Chi-square tests were used for statistical analysis. Results: From May 2015 to Dec 2017, 73 patients were enrolled in GM1 and 72 in placebo arm. 39 (53%) patients in GM1 and 10 (14%) in placebo arm achieve ≥30% reduction in MCIPN20 (RR = 3.85, 95% CI, 2.08-7.11, P < 0.0001). 36 (49%) patients in GM1 and 16 (22%) in placebo arm had ≥30% improvement of VAS (RR = 2.22, 95% CI,1.36-3.623, P = 0.001). The median treatment cycles of GM1 was 2 (range,1-7). Majority of patients in both arms (89% in GM1 and 83% in placebo) continued receiving oxaliplatin on the trial. There were no significant differences in CTCAE and acute neurotoxicity grading between the two arms. There was no ≥G3 GM1 related adverse events. Conclusion: GM1 effectively reduces OIPN in GI cancer patients. The observed clinical benefit is independent of oxaliplatin discontinuation. Trial: NCT02486198 (Drug was afforded by Qilu Pharmaceutical Co., Ltd, China). Clinical trial information: NCT02486198.
Phase III trial to evaluate the efficacy of neoadjuvant chemotherapy with S-1 plus oxaliplatin followed by D2 gastrectomy with adjuvant S-1 in locally advanced gastric cancer: Japan Clinical Oncology Group study JCOG1509 (NAGISA trial).
Authors: Masanori Tokunaga, Junki Mizusawa, Nozomu Machida, Takeo Fukagawa, Hitoshi Katai, Yasunori Nishida, Hiroshi Yabusaki, Seiji Ito, Takeshi Sano, Mitsuru Sasako, Narikazu Boku, Takaki Yoshikawa, Hiroshi Katayama, Haruhiko Fukuda, Masanori Terashima
Journal: Journal of Clinical Oncology (2017)

TPS4134 Background: In Japan, while post-operative adjuvant chemotherapy with S-1 or capecitabine plus oxaliplatin is standard care for pStage II/III gastric cancer after curative resection with D2 lymph node dissection, the clinical outcomes of pStage III patients are not satisfactory. In Europe, neoadjuvant chemotherapy (NAC) followed by gastrectomy is standard. The Japan Clinical Oncology Group (JCOG) has conducted several phase II trials of NAC, and deemed NAC as one of the most promising treatment strategies for gastric cancer with lymph node metastasis (Stage III). However, no established criteria exists for diagnosis of lymph node metastasis. JCOG1302A which was a cross-sectional study evaluating the accuracy of preoperative staging by imaging, showed that cT3-4N1-3M0 (positive lymph node was defined as that with a long axis diameter ≥ 10 mm or short axis diameter ≥ 8 mm) included just 6.5% overdiagnosed pStage I patients and accounted for 52.6% of all pStage III patients. Methods: JCOG1509 (UMIN000024065) is designed as a randomized phase III study to confirm the survival superiority of addition of NAC to standard treatment for patients with cT3-4N1-3M0 gastric cancer. In the standard arm, a gastrectomy with D2 lymphadenectomy is performed followed by adjuvant chemotherapy with oral S-1 for 1 year. In the experimental arm, combination of an infusion of oxaliplatin (130 mg/m 2 /day, day 1) and oral S-1 (80 mg/m 2 /day, days 1–14) is repeated every 3 weeks for 3 courses before gastrectomy, followed by surgery and adjuvant chemotherapy with S-1 for 1 year. The primary endpoint is overall survival. The planned sample size is 470 in total with a 1-sided alpha of 5%, a power of 80%, expecting a 10% increase in the 5-year OS (60% vs 70%). Patients will be enrolled from 58 Japanese institutions over 3.5 years. The study was activated in September 2016 and, as of January 2017, 18 patients were enrolled for the study. Clinical trial information: UMIN000024065.
Genomic complexity in <i>KRAS</i> mutant non-small cell lung cancer (NSCLC) from never/light-smokers v smokers.
Authors: Amanda J. Redig, Emily S. Chambers, Christine A. Lydon, Suzanne Eleanor Dahlberg, Ryan S. Alden, Pasi A. Janne
Journal: Journal of Clinical Oncology (2016)

9087 Background: KRAS is the most frequently mutated oncogene in NSCLC, and such tumors lack effective targeted therapy. Unlike other activating oncogenes associated with never/light-smokers (NS), KRAS mutations are found in both never/light-smokers and smokers. However, the relationship between smoking status and a KRASm+ tumor’s genomic complexity is unclear. Methods: Targeted next generation sequencing (NGS) data at our institution from 7/13-1/16 was reviewed to identify KRASm+ NSCLC tumors. All patients with a < 10 pack-year (py) smoking history (NS) and a subset of heavy smokers (HS) ( > 40 py) were identified, with clinical and genomic analysis. Fisher’s exact test was used to compare frequency of gene mutations and the Mann-Whitney test was used to compare the distribution of total variants between cohorts. Results: 22 NS and 44 HS patients were evaluated. In the NS cohort, the median age was 64.5y with 17/22 women (77%), 21/22 adenocarcinomas (95%), and limited KRAS variants (G12A = 3, G12C = 6, G12D = 11, G12V = 2). In the HS cohort, the median age was 62.5y with 25/44 women (57%), 43/44 adenocarcinomas (98%), and a wide range of KRAS variants (G12A = 2, G12C = 20, G12D = 4, G12R = 1, G12S = 1, Q61L = 1, G12V = 7, Q61H = 3, G13D = 5) (variant distribution between cohorts p = .005). HS patients were more likely to be diagnosed with Stage IV disease (28/44, 64%) v NS patients (11/22, 50%). Compared to NS patients, tumors from HS patients were also genomically more complex, with increased total nucleotide variants (median = 10 v 5, p < .001). HS tumors were more likely to have: a) concurrent deleterious mutation or 2-copy deletion in TP53 or STK11 (25/44, 57% v NS tumors (6/22, 27%) (.04) and b) concurrent mutations/2-copy deletions in > 1 tumor suppressor (TS)/tumor (panel of TP53, STK11, APC, CDKN2A/B, RB)(15/44, 34% v 1/22, 5%) (p = .01). Finally, median OS for HS patients with Stage IV disease was 9.0m v 14.9m in NS patients (HR = 0.86). Conclusions: The genomic landscape of KRASm+ NSCLC from HS patients is distinct from NS patients and includes increased total mutations and frequency of TS loss. These differences suggest NS KRASm+ tumors may be a genetically distinct cohort within the broader context of KRASm+ NSCLC.
Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study.
Authors: Andrea Necchi, Alberto Briganti, Marco Bianchi, Daniele Raggi, Patrizia Giannatempo, Roberta Luciano', Maurizio Colecchia, Simona Massa, Marco Bandini, Nicola Fossati, Giorgio Gandaglia, Renzo Colombo, Andrea Gallina, Andrea Salonia, Roberto Salvioni, Siraj Mahamed Ali, Jeffrey S. Ross, Jon Chung, Francesco Montorsi
Journal: Journal of Clinical Oncology (2018)

4507 Background: MIUC is an aggressive disease and cisplatin-based neoadjuvant chemotherapy is administered in a minority of pts. Pembro is an EMA and FDA-approved therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. Methods: PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study. Pts have predominant UC histology and cT≤3bN0 stage. Pts are enrolled regardless of cisplatin eligibility. Disease assessment is made via CT, PET/CT, and multiparametric bladder MRI (mpMRI). Pts receive 3 cycles of pembro 200mg q3w before RC. Pathologic complete response (pT0) in ITT population is the primary endpoint. The H1 is pT0 ≥25% and H0 pT0≤15%. 71 pts will be enrolled, with 43 pts at first stage according to MinMax design. ≥7pT0 are required at first stage. Biomarker analyses include: IHC PD-L1 combined positive score (CPS, Dako 22C3) and genomic sequencing with hybrid-capture based comprehensive genomic profiling. Tumor mutational burden (TMB) is determined on 1.1 Mbp of sequenced DNA and reported as mutations (mut) per megabase (Mb) and microsatellite instability is determined on 114 loci. Results: From 02/17-02/18, the first stage of 43 pts was completed (36M, 7F). 27 had cT3, 16 cT2; 59% had TMB > 10 mut/mb; 9% TMB > 20 mut/mb. All tumors were microsatellite stable. All pts had evident disease at mpMRI before pembro. One pt (2.3%) had G3 irAE (ALT increase) and suspended pembro; 6 (13.9%) had reversible G2 irAE. At the time of this analysis, 25 pts are evaluable for the primary endpoint. There were 8/25 pT0 (32%, 95%CI: 16.7-47.6) and 3 pTa/is (total pT < 2 rate: 44%). In TURB samples, mean CPS score for pT0 pts was 44.8% vs 17.4% non-pT0 pts (p < 0.001), mean TMB was 11.2 mut/mb vs 11.2 mut/mb, respectively. On 9 evaluable pts, substantial differences were found in pre- vs post-pembro genomic alterations (GA). Mean pre-pembro GA/tumor was 8.7; mean post-pembro GA/tumor was 7 (mean 47.5% overlapping GA). Conclusions: Pembro is safe and has already exceeded the pT0 responses required at first stage. PD-L1 CPS may be predictive of pT0 response, and full translational findings at first stage will be presented. Clinical trial information: NCT02736266.
Atorvastatin to inhibit pancreatic cancer cells proliferation and invasion via suppression neurotrophin receptor signaling.
Authors: Shengjun Ji
Journal: Journal of Clinical Oncology (2017)

e15725 Background: Pancreatic cancer is an uncommon but fatal malignant tumor, only 20% of which show any significant response to chemo-radiotherapy. Tumor metabolism research revealed that pancreatic cancer cells highly dependent on cholesterol uptake. So, in the present study, we have determined the effectiveness of atorvastatin, one drug originally used to lower cholesterol, against pancreatic carcinogenesis in various pancreatic cancer cell lines. Methods: To investigate atorvastatin effects in pancreatic cancer cells, two cell lines (PANC-1 and SW1990) were treated with different atorvastatin doses. The anti-proliferative, apoptotic and anti-invasive properties of atorvastatin were evaluated using MTS, cytoplasmic histone-DNA fragmentation and matrigel invasive assays, respectively. And western blot was used to evaluate the neurotrophin receptor signaling of NGF/Trk A, BDNF/TrkB and NT3/Trk C. Results: Atorvastatin suppressed pancreatic cancer cells proliferation, clone formation and invasion in a dose-dependent manner. The dose of atorvastatin at 10^-5mmol/L would be able to achieve obvious anti-tumor effect in vitro. Cell-cycle analysis demonstrated that cells were arrested in the S phase. Western blot showed increased protein expression of cleaved caspase-3, caspase-9, p21, p-chk2 and decrease in protein level of NGF/Trk A and NT3/Trk C. Conclusions: The current results demonstrated the anti-tumor effects of atorvastatin on pancreatic cancer cells, providing initial evidence towards its potential therapeutic use. Acknowledgment:This study was supported by Suzhou Cancer Clinical Medical Center Szzx201506.