tbuckley/cabot-search huggingface dataset:
ASA and the role of thrombocytosis as a predictor of poor prognosis in colorectal cancer patients.
Authors: Ravi Ramjeesingh, Amie Jones, Christine Orr, Corey Sean Bricks, Wilma M Hopman, Nazik Hammad
Journal: Journal of Clinical Oncology (2016)

e15087 Background: Thrombocytosis has been identified as a prognostic factor in many cancer types. In colorectal cancer (CRC), the literature is conflicting. Some case studies suggest a negative prognosis in CRC patients with pre-operative thrombocytosis (TCS), while others have not found a similar correlation. Methods: We performed a retrospective chart review of CRC patients treated at the Cancer Center of Southeastern Ontario diagnosed from Jan. 2005 to Dec. 2011. 1304 confirmed CRC patient charts were identified and patient, tumor, blood work and treatment variables were extracted. Results: 1096 patients with platelet (PLT) count performed within the time of oncology consult were identified. 222 (20.3%) were characterized as having TCS defined as a PLT count above 400. No difference was identified between those with or without TCS for variables including age, sex, various co-morbidities, and BMI. Statistically significant differences were observed in several pathological characteristics. Significantly more patients with TCS presented with stage 4 disease (p < 0.001). Additionally less early T-stage (T1: p < 0.05, T2: p < 0.0001), lymph node positivity (p < 0.05) and LVI (p < 0.05) was identified. Univariate analysis identified a statistical difference in survival between those with TCS and those with normal PLT counts at presentation (1yr: 71.6% vs 88.1%, p < 0.0001; 2 yr: 58.1% vs 78.1%, p < 0.0001; 5yr: 48.2% vs 64.7%, p < 0.0001). Multivariate Cox regression analysis identified a statistically significant effect of TCS on risk of dying (HR = 1.67, C.I 1.20-2.32, p = 0.002). The use of ASA did not significantly improve survival in patients with TCS (HR = 0.67, C.I 0.39-1.16, p = 0.153). A survival difference was primarily identified in the Stage 3 (5yr OS: 52.8% with TCS vs 68.7% with normal PLT count, p = 0.014). and Stage 4 populations (5yr OS: 22.1.0% with TCS vs 40.0% with normal PLT count, p = < 0.001). Conclusions: We have identified thrombocytosis at the time of oncology consult as a predictor of poor survival in our colorectal cancer population. ASA was unable to mitigate this risk factor. Further work is required to elucidate the mechanism of action between elevated PLT counts and survival.
Trends in aggressive care at the end-of-life for stage IV lung cancer patients.
Authors: Chebli Mrad, Marwan S Abougergi, Robert Michael Daly
Journal: Journal of Clinical Oncology (2017)

6614 Background: Prior studies have demonstrated that high-intensity end-of-life care improves neither survival nor quality of life for cancer patients. The National Quality Forum endorses dying from cancer in an acute care setting, ICU admission in the last 30 days of life, and chemotherapy in the last 14 days of life as markers of poor quality care. Methods: Discharge data from the National Inpatient Sample database was analyzed for 3,030,866 acute care hospitalizations of metastatic lung cancer patients between 1998 and 2014. Longitudinal analysis was conducted to determine trends in aggressive care at the end-of-life and multivariate logistic regression was performed to determine associations with age, race, region, hospital characteristics, and aggressive care. Results: In-hospital mortality for metastatic lung cancer patients decreased from 17% to 11%. Among terminal hospitalizations, utilization of radiation therapy and chemotherapy decreased from 4.6% to 3.0% and from 4.8% to 3.0%, respectively. However, the proportion admitted to the ICU increased from 13.3% to 27.9% and invasive procedures increased from 1.2% to 2.0%. Reflecting this aggressive end-of-life care, mean total charges for a terminal hospitalization rose from $29,386 to $72,469, adjusted for inflation. Among patients who died in the inpatient setting, the ICU stay translated into higher total costs (+$16,962, CI: $15,859 to $18,064) compared to patients who avoided the ICU. Promisingly, palliative care encounters for terminal hospitalizations increased during this period from 8.7% to 53.0% and was correlated with a decrease in inpatient chemotherapy (OR = 0.56, CI: 0.47 to 0.68), radiotherapy (OR = 0.77, CI: 0.65 to 0.92), and ICU admissions (OR = 0.48, CI: 0.45 to 0.53) but had only a modest impact on terminal hospitalization cost (-$2,992, CI: -$3,710 to -$2,275). Multivariable analysis showed variation by patient and hospital characteristics in aggressive care utilization. Conclusions: Among patients with metastatic lung cancer there has been a substantial increase in ICU use during terminal hospitalizations, resulting in high cost for the health care system. Inpatient palliative care has the potential to reduce aggressive end-of-life interventions.
Endocrine Therapy Nonadherence and Discontinuation in Black and White Women
Authors: Stephanie B Wheeler, Jennifer Spencer, Laura C Pinheiro, Caitlin C Murphy, Jo Anne Earp, Lisa Carey, Andrew Olshan, Chiu Kit Tse, Mary E Bell, Morris Weinberger, Katherine E Reeder-Hayes
Journal: JNCI Journal of the National Cancer Institute (2018)

Differential use of endocrine therapy (ET) by race may contribute to breast cancer outcome disparities, but racial differences in ET behaviors are poorly understood.Women aged 20-74 years with a first primary, stage I-III, hormone receptor-positive (HR+) breast cancer were included. At 2 years postdiagnosis, we assessed nonadherence, defined as not taking ET every day or missing more than two pills in the past 14 days, discontinuation, and a composite measure of underuse, defined as either missing pills or discontinuing completely. Using logistic regression, we evaluated the relationship between race and nonadherence, discontinuation, and overall underuse in unadjusted, clinically adjusted, and socioeconomically adjusted models.A total of 1280 women were included; 43.2% self-identified as black. Compared to white women, black women more often reported nonadherence (13.7% vs 5.2%) but not discontinuation (10.0% vs 10.7%). Black women also more often reported the following: hot flashes, night sweats, breast sensitivity, and joint pain; believing that their recurrence risk would not change if they stopped ET; forgetting to take ET; and cost-related barriers. In multivariable analysis, black race remained statistically significantly associated with nonadherence after adjusting for clinical characteristics (adjusted odds ratio = 2.72, 95% confidence interval = 1.75 to 4.24) and after adding socioeconomic to clinical characteristics (adjusted odds ratio = 2.44, 95% confidence interval = 1.50 to 3.97) but was not independently associated with discontinuation after adjustment. Low recurrence risk perception and lack of a shared decision making were strongly predictive of ET underuse across races.Our results highlight important racial differences in ET-adherence behaviors, perceptions of benefits/harms, and shared decision making that may be targeted with culturally tailored interventions.
"The Inertia of Practice": Challenges in addressing infertility in young women with cancer.
Authors: Andrea Marie Covelli, Marcia Facey, Corinne Daly, Erin Diane Kennedy, Nancy N. Baxter
Journal: Journal of Clinical Oncology (2016)

10079 Background: Infertility can be a devastating side effect of cancer treatment for young women. Fertility preservation is of great importance and may influence women’s treatment decisions. The American Society of Clinical Oncology (ASCO) guidelines recommend that health care providers (HCPs) discuss the possibility of infertility with their cancer patients. Despite this nearly 50% of young women with cancer remain uninformed. Methods: We conducted a qualitative study examining HCPs discussions’ around infertility in young women newly diagnosed with cancer. HCPs who routinely treat young women across Canada were purposively sampled. HCPs varied in length/location of practice, clinical focus and gender. Data were collected via semi-structured telephone interviews. This continued until saturation was reached. Constant comparative analysis identified key ideas. Results: 22 HCPs consisting of medical and surgical oncologists, gynecologists, fertility specialists and nurse practitioners completed interviews. ‘The inertia of practice: challenges in addressing infertility’ was the key concept. Knowledge, beliefs and access all influenced HCPs discussions’. HCPs felt that there is a general unfamiliarity with the guidelines amongst oncologists. They described lacking detailed knowledge about preservation options and their efficacies. Due to this lack of knowledge HCPs were reluctant to initiate discussions around infertility. Many providers also voiced concerns around potential delays in cancer treatment and worsening oncologic outcomes. Some HCPs felt that infertility is ‘non-fatal’ and therefore a lesser priority. Many providers also described having limited access to fertility centers and resources, feeling ill-equipped in their discussions around infertility. Only a minority of HCPs believed that patients are not concerned about potential infertility and/or they would be unable to afford fertility treatments. Conclusions: We present an understanding of those factors which contribute to inertia of practice in discussing fertility preservation to young women with cancer. Active strategies will be required to overcome the current inertia in order to improve care of young women with cancer.
Real world treatment patterns, time to next treatment and economic outcomes in relapsed multiple myeloma patients treated with pomalidomide or carfilzomib.
Authors: Kejal Parikh, Lea Purnomo, Safiya Abouzaid, Chi-Chang Chen, Catherine Balderston McGuiness, Mohamad A. Hussein, Rolin L. Wade
Journal: Journal of Clinical Oncology (2016)

8042 Background: We sought to fill in gaps in real world data on treatment patterns and outcomes with pomalidomide (POM) or carfilzomib (CAR) for relapsed multiple myeloma (MM) patients. Methods: PharMetrics Plus US claims database was used to identify patients (Pts) with ≥ 2 MM diagnoses (ICD-9 203.0x) and a POM or CAR claim (index date) from 2/1/2013 to 2/28/2015, assumed to be relapse therapy. Treatment (Tx) regimens were defined as all MM therapies observed within 60 days of index. Pts with both POM and CAR within 60 days of index were excluded. Time to next Tx (TTNT), a progression proxy, was defined as the addition of a new agent > 60 days from index, or Tx restart following a > 90 day therapy gap. Plan-paid median monthly-apportioned costs were reported for total follow-up time and Wilcoxon rank-sum tests were used to compare cohorts. Results: There were 454 Pts indexed to POM (n = 264) or CAR (n = 190). The mean age was 61.6 years (SD = 9.3), 60.1% were male, and were similar between groups. Pre-index stem cell transplant occurred at anytime in 34.5% of POM and 26.3% of CAR Pts (p = 0.064). Frequent index POM Tx were POM+dexamethasone (dex) (47.0%) and POM alone (33.0%); and for CAR index, CAR alone (45.3%) and CAR+dex (14.7%). The most frequently observed next line Tx for POM indexed Pts was addition of or switch to CAR +/-dex (29.0%); and for CAR indexed Pts: to POM+dex (9.3%), and CAR alone or CAR+dex+ cyclophosphamide (6.7% each). For Pts followed to progression (POM n = 100, CAR n = 75) mean TTNT was longer for POM-indexed Pts (6.9 months) versus CAR-indexed Pts (5.3 months, p = 0.0164). Mean follow-up time across both groups was 8.9 months, with 22.0% still on index Tx, 9.7% untreated, 17.0% on subsequent Tx (17.8% for POM; 15.8% for CAR), 25.3% with explicit death (25.0% for POM, 25.8% for CAR), and 26.0% lost eligibility prior to classification. Median monthly cost was $18,298 for POM Pts and $24,734 for CAR Pts (p = 0.001). Conclusions: This retrospective study of POM or CAR Tx for relapsed MM found a significantly longer TTNT with POM-based regimens versus CAR-based regimens. POM-based regimens were observed to have lower monthly costs through the end of follow-up compared to CAR-based regimens.
Phase I study of vemurafenib and heat shock protein 90 (HSP90) inhibitor XL888 in metastatic BRAF V600 mutant melanoma.
Authors: Zeynep Eroglu, Geoffrey Thomas Gibney, Jeffrey S. Weber, Ragini Reiney Kudchadkar, Nikhil I. Khushalani, Joseph Markowitz, Leticia F. Tetteh, Howida Ramadan, Xiuhua Zhao, Ann Chen, Ritin Sharma, Jane Messina, John M Koomen, Vernon K. Sondak, Keiran Smalley
Journal: Journal of Clinical Oncology (2016)

9544 Background: BRAF inhibitors are clinically active in advanced BRAFV600 mutant melanoma patients, but resistance is common. Multiple resistance mechanisms involve HSP90 clients and preclinical data have shown abrogation of resistance using concurrent treatment with the HSP90 inhibitor XL888. Methods: The combination of vemurafenib (960 mg PO BID) with dose cohorts of XL888 (30, 45, 90 or 135 mg PO twice weekly [BIW]) was investigated in patients with advanced BRAFV600 mutant melanoma. A modified Ji dose escalation design was used. Primary endpoints were safety and determination of a recommended phase 2 dose (RP2D). Dose-limiting toxicity (DLT) was defined as treatment-related grade ≥ 3 adverse event or inability to deliver 75% of planned XL888 dose in the first 8 weeks. Results: Nineteen patients (14 with M1C disease) were enrolled: cohorts 1 and 2 (n = 3 each), cohort 3 (n = 7), cohort 4 (n = 6). Two DLTs (diarrhea and pancreatitis) occurred in cohort 4, while a third patient received < 75% of planned XL888. Therefore cohort 3 dose was determined to be RP2D: vemurafenib 960 mg BID + XL888 90 mg BIW. Most common grade 3 toxicities (in > 1 patient) were hyperproliferative skin events (n = 5, 26%), diarrhea (n = 2, 11%), rash (n = 2) and headaches (n = 2) and one grade 4 lipase elevation. Skin toxicities were lower in cohorts 3/4. Objective responses were observed in 13 of 18 evaluable patients (72%; 95% CI: 47 - 90%) with 2 complete responses (CRs) and 11 partial responses (PR). Two patients with a PR who underwent surgical resection had a pathologic CR. Median PFS was 7.4 months (95% CI: 3.7 – 16.2); median overall survival was 33.1 months (5.75 – not reached). Targeted proteomics of patients’ baseline and day 8 PBMCs showed significant increases in HSP71 expression (a marker of HSP90 inhibition) (p < 0.05) in cohorts 2 through 4. Analysis of baseline and on-therapy tumor biopsies is ongoing. Conclusions: Promising clinical activity with an acceptable toxicity profile and evidence of HSP90 inhibition was observed with vemurafenib and XL888 in BRAF mutant melanoma patients. As HSP90 inhibitors also abrogate resistance to the combination of BRAF and MEK inhibitors in melanoma, clinical investigation of this approach is also planned. Clinical trial information: NCT01657591.
The efficacy and safety of apatinib in the treatment of chemotherapy-resistant alpha-fetoprotein positive gastric cancer.
Authors: Feng Wang, Xiangrui Meng, Qing Xia Fan
Journal: Journal of Clinical Oncology (2018)

e16080 Background: Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC), accounting for 1% to 8% of all gastric cancers is very rare. The prognosis of AFPGC was poor.There is no standard treatment for AFPGC. Apatinib, a highly selective inhibitor of VEGFR-2, perhaps could be used in the treatment of AFPGC because of elevated expression level of VEGF in AFPGC. Methods: Patients with AFPGC followed first- or multi-line failed chemotherapy were collected in the First Affiliated Hospital of Zhengzhou University from from January 2015 to January 2017. These patients received continuous treatment of apatinib: qd with initial dose of 500mg, oral administration, 28 days (4 weeks) as a treatment cycle. The dose of apatinib could be reduced to 250mg if adverse reactions in grade 3-4 appeared. Patients received continuous treatment of apatinib until death or progression of disease or intolerable toxicity appeared. Results: Total 26 patients were enrolled in the study and all of them could be evaluated for objective efficacy, safety and survival analysis during use of apatinib. Objective response rate (ORR) and disease control rate (DCR) were 19.2% and 69.2% respectively. Median progression-free survival (PFS) and overall survival (OS) were 5.9 months (95% CI, 6.363-6.69 months) and 13.9 months (95% CI, 11.78--16.92 months), respectively. The serum AFP decreased significantly in patients with part response to apatinib treatment(P < 0.01).The dose of apatinib was reduced to 250 mg in 8 patients because of the appearance of adverse reactions in grade 3-4. For others, adverse reactions including hematological and non-hematological toxicities all remained at grade 1-2. The most common hematologic toxicities adverse reactions at grade 3-4 were neutropenia (3.8%) and anemia (3.8%). While the most common non-hematologic adverse reactions at grade 3-4 were hypertension, fatigue, perforation, hypocalcemia, hypothyroidism and the incidence was all 3.8%. No death was occurred during the studies. Conclusions: Apatinib had a certain effect in treating AFPGC following failed chemotherapy with good safety. Furthermore, AFP could be used as an indicator in predicating treatment efficiency.
Effect of rilimogene galvacirepvec/rilimogene glafolivec on intra/peritumoral immune infiltrate in patients with localized prostate cancer undergoing radical prostatectomy.
Authors: James L. Gulley, Houssein Abdul Sater, Jenn Marte, Renee Nicole Donahue, Beatriz Walter Rodriguez, Christopher Ryan Heery, Mark Stern, Debrah Thompson, Lisa M. Cordes, Guinevere Chun, Fatima Karzai, Marijo Bilusic, Jeffrey Schlom, William L. Dahut, Ravi Amrit Madan, Peter A. Pinto
Journal: Journal of Clinical Oncology (2018)

5083 Background: PSA-TRICOM (Prostvac) is a vector-based vaccine designed to generate a robust immune response (IR) against PSA–expressing tumor cells. To date, studies of Prostvac in patients with mCRPC have shown IR in peripheral blood but effects on prostate tumors are unknown. Methods: An open label phase 2 study of neoadjuvant Prostvac (NCT02153918) enrolled patients (pts) with localized prostate cancer undergoing radical prostatectomy (RP). Priming vaccination was given followed by boosts on days 15, 29 and 57 prior to RP (~day 64). The 1° objective evaluated increases in CD4 and CD8 cell infiltrate (RP tissue vs. baseline biopsies) by IHC. IR to tumor associated antigens (TAA) was measured using intracellular cytokine staining (ICS) in PBMC from baseline and ~day 63. Results: 27 pts (median age 64.8 years) enrolled. All pts received 4 pre-RP vaccine injections. Matched tissue IHC analysis and peripheral IR is available on 24 pts. TAA specific T cell peripheral IR to PSA, Muc-1 or Brachyury were observed in 12/24 (50%) pts post vaccine, with 25% of pts responding to each antigen. Table comparing peripheral IR vs. tumoral IR. Clinical trial information: NCT02153918. 19 pts were evaluable for tissue RNA expression profiles pre/post vaccine and observed upregulation of genes such as RANKL (DC maturation), CCL25 (chemotaxis), and FLT3 (T-cell development) suggests vaccine-induced IRs. Conversely, increased expression of immunosuppressive genes (e.g., FOXP3, IL-10) suggests adaptive resistance post vaccination. Conclusions: Prostvac treatment is associated with a ≥2X increase in CD8 and CD4 intra/ peritumoral infiltrate in 17/24 and 21/24 pts, respectively. However only 12/24 had a TAA response in the peripheral blood. Anti-tumor IRs may become broader and more immunologically relevant over time (Ag spreading) and may be underestimated by peripheral IRs to TAA. These data better inform the immunodynamic effects of Prostvac which are incompletely represented by peripheral IR data. Work is ongoing to more fully characterize the IR with multispectral imaging, targeted RNASeq and TCRSeq analysis. ↑ CD8 Infiltrate ↑ CD4 Infiltrate No Yes No Yes No Peripheral IR 5 7 2 10 Peripheral IR 2 10 1 11 Total 17/24 21/24
OS5.2 FGFR a novel target in malignant pediatric ependymoma
Authors: D Loetsch, J Gojo, D Kirchhofer, S van Schoonhoven, K Pajtler, M Kool, C Haberler, T Czech, I Slavc, W Berger
Journal: Neuro-Oncology (2018)

Ependymomas represent the third most common malignant pediatric brain tumor accounting for up to 10% of CNS malignancies in childhood. Recent studies have identified novel molecular subgroups within this histologically defined tumor entity. Supratentorial ependymomas harbor either YAP or RELA gene fusions whereas in the PF compartment PFA and PFB can be discriminated by presence of hypermethylation. The standard of care comprise surgery followed by radiotherapy, while chemotherapy seems to be widely ineffective. Despite intensive treatment, the most frequent ependymoma subtypes - ST-RELA and PFA - frequently recur, highlighting the need for predictive biomarkers in pediatric ependymoma. Recently, FGFR1 and FGFR3 protein levels have been found elevated in aggressive ependymoma and were associated with worse outcome. Accordingly our study follows the hypothesis whether FGFRs represent a novel promising target in pediatric ependymoma. To this end we investigated mRNA levels of FGFR3 and its splice variants FGFR3B and FGFR3C by qPCR in 44 ependymoma tissue samples and compared them to an in silico dataset. The effects of the FGFR inhibitors nintedanib and ponatinib on cell viability and on intracellular signaling were investigated in several ependymoma cell models of different molecular subgroups by MTT-assays and Western blot, respectively. We further tested whether the expression of a dominant negative (dn) FGFR1 or FGFR3 impacts cell survival. Finally, the response to nintedanib was evaluated in a RELA fusion-positive ependymoma xenograft model. Analyses of FGFR mRNA levels in an ependymoma online database exhibited FGFR3 to be highly expressed and point to the highest levels in ST-RELA. We already analyzed mRNA levels of FGFR3 and its splice variants in 44 tissue samples of our ependymoma cohort (n=54). Expression levels were significantly increased in ST and highest in ST-RELA as compared to PF tumors. Regarding alternative splicing, the FGFR3c variant was predominantly detected in our collection. Several of our ependymoma cell culture models exhibited sensitivity towards nintedanib and ponatinib in the low micromolar range. Our results further highlight an impact of FGFR inhibition on MAP-Kinase and PI3K-signaling in two cell models (VBT73 and VBT145) from consecutive recurrent ST-RELA ependymoma. Interestingly, and in contrast to the expression of a dnFGFR3, dnFGFR1 exhibited no effect on cell survival. Finally, treatment of ST-RELA xenografts (VBT145) in immunodeficient mice with nintedanib significantly extended survival as compared to vehicle controls. Summarizing, our findings confirm that FGFR3 plays a role in pediatric ependymoma biology and appears a promising target for several ependymoma subgroups.