bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of mechanisms of resistance to ipilimumab therapy with a pre-surgical trial in patients with high-risk, localized prostate cancer.
Authors: Gao Jianjun , Ward John Francis , Pettaway Curtis Alvin , Shi Lewis Z , Subudhi Sumit Kumar , Vence Luis M , Zhao Hao , Chen Jianfeng , Chen Hong , Efstathiou Eleni , Troncoso Patricia , Allison James Patrick , Logothetis Christopher , Wistuba Ignacio Ivan , Wargo Jennifer Ann , Blando Jorge M , Sepulveda Manuel A , Sun Jing Jing , Sharma Padmanee 
Published: September 2018

5081 Background: Anti-CTLA-4 therapy ipilimumab (BMS) has led to clinical benefit in patients with metastatic melanoma. However, in multiple clinical trials in patients with prostate cancer, ipilimumab has not demonstrated significant clinical benefit. To identify potential immune inhibitory pathways responsible for resistance to ipilimumab therapy, we evaluated tumor samples from a pre-surgical clinical trial and performed correlative laboratory studies. Methods: We carried out a pre-surgical clinical trial with androgen deprivation therapy (ADT), (leuprolide acetate, Tap Pharmaceuticals) plus ipilimumab in patients with localized, high-risk prostate cancer. Each patient received one injection of leuprolide (22.5 mg) on week 0 and ipilimumab (10 mg/kg) on weeks 1 and 4. Patients then underwent surgery at week 8. Tumor tissues were collected at baseline and then at surgery for flow cytometry, IHC, multiplex immunofluorescence, and gene profiling analyses. In vitro studies were carried out for functional analysis. Results: Sixteen patients completed treatment with ipilimumab plus ADT and surgery. We observed a significant increase of immune cells including T cells and macrophages into prostate tumors after ipilimumab therapy, similar to data observed in ipilimumab-treated melanoma samples. However, compared to melanoma tumors, we found higher expression of PD-L1 and VISTA inhibitory molecules on CD68+ macrophages in prostate tumors. Interestingly, PD-L1 and VISTA were expressed on distinct subset of CD68+ macrophages, with high expression of CD163, suggesting an M2 subtype. In vitro studies demonstrated that engagement of PD-L1 and/or VISTA pathways inhibited T cell responses. Co-culture with monocytes resulted in suppression of T cell function, which can be reversed with anti-VISTA blocking antibody. Conclusions: These data suggest that evolving compensatory inhibitory pathways including PD-L1 and VISTA may mediate resistance of prostate cancer to ipilimumab therapy. Concurrent blockade of other immune checkpoints such as PD1/PD-L1 and/or VISTA may be necessary to provide significant clinical benefits for patients with prostate cancer. Clinical trial information: NCT01194271.
Refined estimates of local recurrence risks and the impact of the DCIS score adjusting for clinico-pathological features: Meta-analysis of E5194 and Ontario DCIS cohort studies.
Authors: Rakovitch Eileen , Gray Robert James , Baehner Frederick L. , Miller Dave P. , Sutradhar Rinku , Crager Michael , Gu Sumei , Nofech-Mozes Sharon , Badve Sunil S. , Hanna Wedad , Hughes Lorie L. , Wood William C. , Paszat Lawrence Frank , Shak Steven , Sparano Joseph A. , Solin Lawrence J. 
Published: September 2018

528 Background: Better tools are needed to estimate the risk of local recurrence (LR; DCIS or invasive) after breast-conserving surgery (BCS) for DCIS to inform treatment decisions. The DCIS Score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS Cohort (ODC) after BCS without radiation (Solin,2013; Rakovitch,2015). We performed a meta-analysis (MA) combining data from E5194 and ODC with additional follow-up from E5194 adjusting for pertinent clinico-pathologic factors to provide refined prediction estimates of LR risk after BCS alone. Methods: The MA used data from E5194 and ODC. Patients with positive margins and multifocality were excluded. Identical Cox regression models were fit including age at diagnosis ( < 50, ≥50 yr), tumor size (1cm, > 1cm), DCIS Score and year of surgery (before vs after 2000). Grade was not significant. MA was used to calculate precision-weighted estimates of 10 year LR risk by DS. Results: Combined cohort includes 773 pts (tamoxifen used in 20% E5194, 17% of ODC > 65 yr). The DS and the clinico-pathologic variables age, tumor size and year provided independent prognostic information on 10 yr LR risk (p≤.009). Hazard ratios from E5194 and ODC cohorts were similar for tumor size ≤1 vs. > 1cm (1.45, 1.47), age ≥50 vs. < 50 yr (0.61, 0.84) and surgery year after 2000 (0.67, 0.49). 10 yr LR risks by combinations of age, tumor size, and DS are detailed in Table. For patients ≥50 yr with tumors ≤1cm and low risk DS, the 10 yr LR risks range from 5.3-10.0%. A high risk DS is associated with a higher 10 yr predicted risk of LR in all subsets. 10 yr risk of contralateral BC was 5.4%. Conclusions: This MA provides refined estimates of 10 yr LR risk after BCS alone for DCIS. Adding clinico-pathologic factors to the DCIS Score provides enhanced prognostic LR risk estimates to guide individualized treatment decision-making. [Table: see text]
A propensity score analysis exploring the impact of adjuvant chemotherapy (aCT) in a multi-center series of resected early stage pure invasive lobular breast carcinoma (ILC).
Authors: Carbognin Luisa , Sperduti Isabella , Arpino Grazia , Dieci Maria Vittoria , Schettini Francesco , Griguolo Gaia , Guarneri Valentina , Brunelli Matteo , Nortilli Rolando , Fiorio Elena , Parolin Veronica , Pilotto Sara , Orvieto Enrico , Manfrin Erminia , Pellini Francesca , Pollini Giovanni Paolo , Conte Pier Franco , De Placido Sabino , Tortora Giampaolo , Bria Emilio 
Published: September 2018

539 Background: Patients (pts) resected for early breast cancer are assigned to receive aCT according to international guidelines based upon immunophenotype and clinical/pathological features, regardless of the histotype, given the lack of prospective data for ILC. Thus, the magnitude of the benefit of aCT for ILC is still not sizable. The aim of this analysis was to investigate the effect of aCT in a multi-center series of early stage pure ILC. Methods: Clinical-pathological data of consecutive pts affected by pure ILC, undergone surgery at 3 Italian institutes, were correlated with disease-free and overall survival (DFS/OS) using a Cox model. A propensity score analysis was performed to evaluate the prognostic impact of aCT. Kaplan-Meier curves were compared with Log-Rank analysis. Results: Data from 739 pts were gathered (median age 57 years (yrs); Luminal/Triple-Negative/HER2 pos.: 98%/1.6%/0.4%). At median follow-up of 78 months, 5-/10-yrs DFS and OS were 79.4%/66.0% and 91.4%/76.5%, respectively. Tumor-size according to TNM (T, HR 1.34, 95% CI 1.04-1.72, p=0.025) and lymph-node (N) status (HR 2.39, 95% CI 1.47-3.89, p<0.0001) were independent predictors for DFS at multivariate analysis. T (HR 1.87, 95% CI 0.99-3.54, p=0.05), N status (HR 3.24, 95% CI 1.69-6.22, p<0.0001), Ki67 (HR 2.48, 95% CI 0.95-6.42, p=0.06), and age (HR 2.23, 95% CI 1.16-4.30, p=0.016) were predictors for OS. A significant prognostic effect of aCT upon OS was found after adjusting for independent factors with the propensity score method, as shown in the table below. Particularly, aCT significantly prolongs OS and DFS in pts with T >1, with an absolute difference of 17%/35% and 15%/13% at 5 and 10 yrs, respectively ( p=0.003 and p=0.04). OS was longer for pts with positive N ( p=0.02), Ki67 >4% ( p=0.01) and grading >1 ( p=0.01). Conclusions: Despite the retrospective nature of this analysis, the propensity score analysis indicates that pts with ILC may significantly benefit from aCT in terms of long-term survival, particularly for larger and more aggressive tumors. [Table: see text]
An NCDB analysis of trends in male breast cancer from 2004-2009 and 2010-2014.
Authors: Dubrovsky Esther , Schwartz Shira , Chun Jennifer , Guth Amber , Axelrod Deborah M. , Shapiro Richard L. , Schnabel Freya Ruth 
Published: September 2018

544 Background: To examine the trends in clinicopathologic features, treatment, and survival of male breast cancer (MBC), utilizing the National Cancer Data Base (NCDB). Methods: MBC patients entered in the NCDB from 2004-2009 were compared with those from 2010-2014 for demographics, stage at diagnosis, tumor characteristics, treatment type, and overall survival (OS). Male patients were also compared to female patients from the same time periods. Statistical analysis included Pearson’s chi-square test. Results: Of 2,047,868 breast cancer cases, a total of 19,409 (0.95%) men were available for analysis. The group of MBC patients from 2004 to 2009 included 9,790 men with a median age of 65. The group from 2010 to 2014 included 9,619 men with a median age of 66. In the later group there was a decreased rate of DCIS, increased rate of invasive ductal carcinoma, and increased rate of hormone positive tumors. Among the earlier and later MBC groups, 24% vs. 27% of patients underwent lumpectomy. Of these, 61% vs 68% received post-lumpectomy radiation, respectively. Patients in the later group (2010-2014) were more likely to receive adjuvant hormonal therapy (61% vs. 84%, p < 0.0001). MBC patients were older than female patients (65 vs. 61 years, p < 0.0001), had larger tumors (20mm vs. 16mm, p < 0.0001), slightly later stage at diagnosis, and more likely to undergo mastectomy (74 vs. 42%, p < 0.0001). MBC patients also had higher rates of hormone positive tumors, but lower rates of adjuvant hormonal therapy (55% vs. 58%, p < 0.0001). The OS for male vs. female patients in the 2004-2009 groups was 66% vs. 77% (median follow-up 73.9m vs 80.4m) respectively. Similarly, in the 2010-2014 groups, survival was 84% vs. 90% (median follow-up 33.85m vs 35.91m), respectively. Conclusions: Although men have higher rates of hormone positive tumors, they are less likely to receive adjuvant hormonal therapy. There was a significant trend over time towards more standard therapies in men, such as post-lumpectomy radiation and hormonal therapy use. There has been an improvement of OS in men which mirrors that in women. The disparities in outcomes between male and female patients, however, still require further investigation.
Breast Cancer Index (BCI) prognostic and predictive classification in older versus younger patients with early-stage HR+ breast cancer (BC) and correlation with clinical risk factors.
Authors: Yuan Yuan , Cao Yu , Israel Mason , Liu Junmei , Schnabel Catherine A. , Hurria Arti 
Published: September 2018

546 Background: Older patients with HR+ BC may present distinct challenges for treatment decision-making. BCI is a validated gene expression assay for pts with early stage HR+ BC that provides 2 results: BCI Predictive, based on HoxB13/IL17BR (H/I ratio), reports a prediction of likelihood of benefit from extended endocrine therapy (EET); BCI Prognostic, based on the combination of H/I and proliferation-based genes, reports individualized risk of late distant recurrence (DR). Here, the predictive and prognostic value of BCI results across the aging spectrum ( < 64y, 65-74y, ≥75y) and correlation with clinical risk factors were examined. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains > 50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice (N = 14,463). Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. Chi-squared tests were used to compare BCI results between age groups and clinical subsets. Results: Analyses included LN- pts (N = 3,395): median age 59.1y; 5.5% ≥75y (N = 188), 24.0% 65-74y (N = 814), 70.5% ≤64y (N = 2,393). BCI Prognostic had a wide distribution of individual risk assessments in all age groups. The proportion of pts classified as high risk was similar between age groups (48.4%, 48.4% and 49.8% in ≥75y, 65-74y and ≤64y; p = 0.76). The proportion of pts with high risk results increased with increasing tumor size and grade in all age groups (P < 0.05 for all). Notably, in pts ≥75y, BCI identified 31.9% of T1a/b and 21.1% of Grade 1 tumors as high risk of late DR. BCI Predictive (H/I) also identified similar proportions as High H/I across age groups (42.0%, 41.8%, and 40.6% in ≥75y, 65-74y, and ≤64y; p = 0.81). Similar proportions of pts ≥75y were identified as high H/I across size and grade subsets (P = 0.702, P = 0.193, respectively). Conclusions: BCI identifies pts with high risk disease and who may benefit from EET across the aging spectrum. Individualized decisions for EET also must include life expectancy, competing comorbidities and potential toxicities from therapy.
Health-related quality of life (HRQOL) and patient-centered outcomes with maintenance olaparib compared with placebo following chemotherapy in patients with germline (g) BRCA-mutated (m) platinum-sensitive relapsed serous ovarian cancer (PSR SOC): SOLO2 phase III trial.
Authors: Friedlander Michael , Gebski Val , Gibbs Emma , Bloomfield Ralph , Hilpert Felix , Wenzel Lari B. , Joly Florence , Eek Daniel , Rodrigues Manuel , Clamp Andrew R. , Penson Richard T. , Provencher Diane M. , Korach Jacob , Huzarski Tomasz , Vidal Laura , Salutari Vanda , Scott Clare L. , Nicoletto Maria Ornella , Tamura Kenji , Pujade-Lauraine Eric 
Published: September 2018

5507 Background: The median PFS after chemotherapy in PSR SOC is less than 6 months in many patients. In SOLO2 (ENGOT Ov-21; NCT01874353), maintenance olaparib (O) given after response to chemotherapy resulted in a significant improvement in PFS vs placebo (P) in patients with g BRCAm PSR SOC (hazard ratio [HR] 0.30, 95% CI 0.22, 0.41; P<0.0001; median 19.1 vs 5.5 months; 63% data maturity; Pujade-Lauraine et al. SGO 2017). Our a priori hypothesis was that maintenance therapy with O would not negatively impact HRQOL compared with P and would be associated with additional patient-centered benefits to support the prolongation of PFS, the primary endpoint of SOLO2. Methods: HRQOL was evaluated by the Functional Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI) in all 295 patients. This measures functional and physical well-being and symptoms, including adverse events. Change from baseline in FACT-O TOI score during the first 12 months was the primary HRQOL analysis (mixed model repeated measures). Secondary planned analyses included duration of ‘good quality of life’ by time without symptoms of disease or toxicity (TWiST) and quality-adjusted PFS (QAPFS; a single measure of PFS and HRQOL outcomes). Results: There was no significant detrimental effect of O vs P on HRQOL analyzed by change from baseline in TOI score (–3.1 vs –2.9, respectively, difference (O minus P) –0.2; 95% CI –2.4, 2.1; P=0.88). There was a significant improvement for patients on maintenance O in TWiST (13.5 vs 7.2 months, difference 6.3; 95% CI 2.9, 8.6; P<0.001) and QAPFS (mean 14.0 vs 7.3 months for O and P, respectively, difference 6.7; 95% CI 5.0, 8.5; P<0.0001). Conclusions: Maintenance O did not detrimentally impact HRQOL relative to P. The significant improvement in PFS with O was associated with additional patient-centered benefits, including a longer duration without symptoms of disease or treatment toxicity and longer QAPFS. Clinical trial information: NCT01874353.
Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer.
Authors: Lim Myong Cheol , Chang Suk-Joon , Yoo Heong Jong , Nam Byung-Ho , Bristow Robert , Park Sang-Yoon 
Published: September 2018

5520 Background: Cytoreductive surgery followed by taxane and platinum-based chemotherapy is standard treatment for advanced ovarian cancer. We compared results of randomly allocated HIPEC in primary advanced epithelial ovarian cancer who have optimal cytoreductive surgery in this prospective randomized multicenter trial. The study endpoint is to evaluate progression free survival (PFS) and overall survival (OS). Methods: 184 patients staged III and IV were randomly allocated to trial arm (HIPEC, cisplatin 75 mg/m2, 90 min) or control arm (no HIPEC), intraoperatively based on residual tumor (size <1cm) from July 2010 to January 2016. The groups were well balanced according to the age, body mass index, performance status, stage, histology, serum CA125 level, and use of neoadjuvant chemotherapy (NAC) at study entry. Results: 184 pts (HIPEC, 92; control, 92) were included in this preplanned analysis. No mortality after surgery ± HIPEC was identified in both groups. Postoperative outcomes including extent of surgery, estimated blood loss, residual tumor, and hospitalization day were not different between both group, except operation time (487 vs. 404 min, p<0.001) due to HIPEC procedure. The most common adverse event was anemia: 67.4% in HIPEC and 50% in control group (p=0.025). The other toxicity common in HIPEC group is the elevation of creatinine (15.2% vs. 4.3%, p=0.026). There were no differences between both groups for transfusion (35.9 vs. 29.3, p=0.432), neutropenia (19.6 vs. 10.9%, p=0.151), and thrombocytopenia (9.8 vs. 3.3%, p=0.136). Two-year PFS was 43.2% and 43.5% and 5-year PFS was 20.9% and 16.0% in HIPEC and control group, respectively (p=0.569). Five-year OS was 51.0% and 49.4% in HIPEC and control group, respectively (p=0.574). In women who received NAC, the median PFS for HIPEC and control group were 20 and 19 months, respectively (log-rank test, p = 0.137) and the median OS for HIPEC and control group were 54 and 51 months, respectively (log-rank test, p = 0.407). In the subgroup with NAC, 2-year PFS was 37.2% in HIPEC group and 29.5% in control group and 5-year OS was 47.9% in HIPEC group and 27.7% in control group. After 20 months in PFS and 30 months in OS, two survival curves in women who received NAC showed the trend of gradual distinction, favoring HIPEC group. Conclusions: No mortality was identified and postoperative morbidities were not statistically different between two groups except anemia and creatinine elevation in HIPEC group. The survival analysis did not show the statistical superiority of the HIPEC arm. More follow-up is required to confirm the impact of HIPEC on long-term survival outcome in ovarian cancer, especially in NAC group. Clinical trial information: NCT01091636.
Phase II study of cabozantinib (cabo) in patients (pts) with recurrent/metastatic endometrial cancer (EC): A study of the Princess Margaret, Chicago, and California phase II consortia.
Authors: Dhani Neesha C. , Hirte Hal W. , Burnier Julia V. , Jain Angela , Butler Marcus O. , Lheureux Stephanie , Hurteau Jean , Welch Stephen , Matsuo Koji , Method Michael , Jimenez Waldo , Johnston Carolyn , Stringer Erica , Cristea Mihaela C. , Mehta Anjali , Quintos Judy , Tan Susie , Wang Lisa , Wright John Joseph , Oza Amit M. 
Published: September 2018

5524 Background: Recurrent/metastatic EC has a poor prognosis with no standard 2ndline therapy. Cabo is a multi-targeted kinase inhibitor of MET, VEGFR, TIE2, AXL & KIT, relevant in epithelial-stromal cross-talk. The role of MET/HGF in aggressive EC biology, where transient benefit of VEGF-targeting is due to MET/HGF, TIE2 & AXL, provides rationale for MET targeting in EC. Methods: PHL86 (NCI#9322/NCT01935934) is a multi-centre, phase II trial of cabo (60mg oral daily dose) in pts with EC recurring within a year of adjuvant chemotherapy (ctx), or with progression after 1 line of ctx for metastatic disease. Experimental (E) cohort was stratified by histology (serous (SER) vs endometroid (END)) in a Simon two-stage design for co-primary endpoints of response rate ( > 30%) & 12-week progression-free-survival (PFS) ( > 55%). Activity was defined as > 7 partial responses (PRs) or > 15 instances of 12 wk-PFS in 36 pts. Pts with rare histology EC were treated in a parallel exploratory (Ex) cohort. Results: From May 2013 to Nov 2016, 102 pts (E: 71; Ex: 31) have been treated with cabo after prior radiation (59) and/or ctx (no. lines: 1(77); 2(22)). Cabo was well tolerated with common toxicities of fatigue, nausea, diarrhea & hand-foot syndrome. Most frequent Grade 3/4 toxicity was hypertension (32/101 pts). Fistula/perforation occurred in 4 of 71 SER/END pts & 4 of 31 Ex pts; no risk factors were identified. In 33 END pts, 6 PRs & 24 instances of > 12-wk PFS were observed; median PFS is 4.8 mths (95% CI: 4.4 – 6.4) with estimated 6-mth PFS of 43% (95% CI: 27 to 59%). In 34 SER pts, 4 PRs & 20 instances of > 12-wk PFS were observed; median PFS is 4.0 mths (95% CI: 2.7 – 4.7) with estimated 6-mth PFS of 30% (95% CI: 15 to 46%). 4 pts have had PFS > 12 mths, 1 SER pt remains on study after 25mths. Mutational analysis demonstrated presence of KRAS with PTEN or PIK3CA mutations in 9 (SER/END) pts, of whom 8/9 pts met 12-wk PFS endpoint, with a median PFS 5.9 mth (4.1 to 15.4). Conclusions: Cabo has single agent activity in END and SER EC with durable disease control. Concurrent mutation in KRAS/PTEN/PIK3CA may enrich for response. The current data support further evaluation of cabo in EC. Clinical trial information: NCT01935934.
The neoantigen landscape and immune regulators in cervical cancer.
Authors: Roszik Jason , Qin Yong , Ekmekcioglu Suhendan , Forget Marie-Andree , Hwu Patrick , Grimm Elizabeth A. , Jazaeri Amir A. 
Published: September 2018

5528 Background: Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. Methods: To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides using exome and RNA sequencing data of a large number of tumors in two independent data sets (n = 194 and 79), and analyzed whether mutation and neoantigen load correlate with expression of genes involved in antigen presentation, infiltrating immune cell type markers, and HPV oncoprotein-associated genes. Normal tissue expression analyses were also performed using data from the Genotype-Tissue Expression project (n = 8,555). Results: We found that potentially immunogenic and targetable neoantigens can be predicted for almost all cervix tumors, including recurrent neoantigens from mutations of known oncogenic driver genes (KRAS G12D, MAPK1 E322K, PIK3CA E545K, PIK3CA E542K, ERBB2 S310F, and ERBB3 V104M). Furthermore, we found that expression of HPV-associated “master regulator” genes is associated with mutation, neoantigen, and HPV load, and also with expression of several important markers in the immune microenvironment. Notably, the OVOL1 master regulator positively correlated with mutation and neoantigen load, and also with PD-L1 and TGFB1 expressions. Furthermore, ENO1 over-expression in cervical cancer was associated with high HPV load, and ENO1 level also positively correlated with PD-L1 and TGFB1 expressions, suggesting that it may be a potential target in cervical cancer. Conclusions: For most of the cervix tumors we report predicted neoantigens, and we also identified recurrent neopeptides derived from mutations in known oncogenes. We have also identified statistically significant associations between neoantigen availability, antigen presentation, cytotoxic T-cell function, suppressive mechanisms, and expression of HPV master regulators to help guide immunotherapies of cervical cancer.