tbuckley/cabot-search huggingface dataset:
Neoadjuvant chemotherapy with cisplatin and gemcitabine followed by chemoradiation with cisplatin in locally advanced cervical cancer: A phase II, prospective, randomized, trial.
Authors: Samantha Silva, Renata RC Colombo Bonadio, Flavia Gabrielli, Andrea souza Aranha, Maria Luiza Genta, Vanessa Costa Miranda, Daniela Freitas, Elias Abdo Filho, Patricia Alves De Oliveira Ferreira, Karime Kalil, Mariana Scaranti, Maria Del Pilar Estevez-Diz
Journal: Journal of Clinical Oncology (2018)

5523 Background: Chemoradiation with cisplatin (CRT) is the standard treatment for patients (pts) with locally advanced cervical cancer (LACC). However, 40% of pts has disease relapse. Adjuvant chemotherapy with gemcitabine plus cisplatin improves overall survival, with high toxicity. The role of the addition of neoadjuvant chemotherapy (NAC) to definitive CRT is still a matter of debate. We conducted a trial to investigate if NAC with cisplatin and gemcitabine followed by CRT would improve outcomes. Methods: LACC pts (FIGO IIB-IVA) were randomized to 3 cycles of NAC with cisplatin 50 mg/m2 D1 and gemcitabine 1000mg/m2 D1 and D8 followed by standard CRT with weekly cisplatin 40mg/m2/w/6w plus pelvis radiotherapy (50.4Gy) followed by brachytherapy (BCT) or to the standard CRT and BCT alone. Progression-free survival (PFS) in 3 years was the primary endpoint. Secondary endpoint were response rate (RR), overall survival (OS) and toxicity. Kaplan-Meier method was used for survival analysis and curves were compared using log-rank test. RR was evaluated using chi-square test Results: Between July 2012 and July 2017, 107 pts were randomized. Pts characteristics were similar between groups. Median age was 47 years. The majority of the patients had squamous cell carcinoma (87.8%), and FIGO stage IIB (42.9%) or IIIB (44.8%). Median follow up was 25.5 months. PFS rates at 3 years were 41.1% (CI 95% 26.5-55.2%) in NAC group and 59.6% in the CRT alone group (CI 95% 42.5-73.1%), with an absolute difference of 18% (HR 1.48, CI 95% 0.86-2.82, p = 0.13). OS rates in 3 years were 74.2% (CI 95% 58.4-84.7%) and 81.9% (CI 95% 65.2-91.1%), respectively (HR 1.64, CI 95% 0.71-3.77, p = 0.23). CRT alone had superior complete RR (54% NAC vs 82% CRT alone, p = 0.002). No difference was seen in overall RR (92.7% NAC vs 94% CRT alone, p = 0.77). QoL improved after treatment in both groups when compared with baseline. Conclusions: This study showed that NAC is associated with inferior complete RR in comparison with standard CRT alone in the treatment of LACC, which is probably associated with the trend towards inferior PFS in NAC group. There was no statistically significant difference in OS. Clinical trial information: NCT01973101.
Efficacy and safety of triplet versus doublet salvage therapies among relapsed myeloma patients: Meta-analysis of phase 3 randomized controlled trials.
Authors: Ajay K. Nooka, Jonathan L. Kaufman, Sagar Lonial
Journal: Journal of Clinical Oncology (2016)

8020 Background: Triplet therapies exert deeper responses and result in prolonged progression free survival (PFS) while the argument to favor doublets is their better toxicity profile. The objective of the current analysis is to test the hypothesis that triplets are tolerable, improve ≥ CR, ≥ VGPR, ORR rates and would translate to an improved PFS. Methods: We searched Pubmed, Cochrane databases and ASH, ASCO conference proceedings from 01/2000 through 01/2016 to identify the phase 3 RCTs that have randomized early relapsed myeloma patients ( ≤ 3 prior lines) to receive a triplet vs. doublet salvage regimen. A meta-analysis of 5 RCTs (PANORAMA1, MMVAR, ASPIRE, ELOQUENT2, TOURMALINE consisting of 3197 patients) was performed using the fixed (Mantel-Haenszel) and random (DerSimonain and Laird) models to calculate the impact of triplets versus doublets by evaluating the CR, ≥ VGPR, ORR, PFS and toxicities. Results: The pooled odds ratios of ORR, ≥ VGPR and ≥ CR with triplets vs. doublets were 1.811 (P< 0.000), 1.962 (P< 0.001), 2.325 (P< 0.000) respectively, indicating that the odds of achieving deeper responses are higher with triplets. The pooled hazard ratios (HR) for PFS was HR 0.674 (95% CI 0.613-0.741; P= 0.000) in favor of triplets. Q-statistic for PFS (P= 0.719; df= 4; I2 = 0.00) suggests homogeneity across studies. Though the relative risk (RR) of selected ≥ grade 3 serious adverse events (G3 SAE) was higher with triplets (diarrhea, fatigue, thrombocytopenia 2.232, 1.654 and 2.161 respectively (P= 0.000), the overall G3 SAE were almost comparable with a RR 1.438 (P= 0.000), though favoring doublets. Conclusions: Our meta-analysis demonstrates that triplet regimens result in improved ORR, ≥ VGPR, ≥ CR and PFS compared to doublets. G3 SAEs are higher with triplets, however this appears to be influenced by the regimen-related toxicity from PANORAMA1 trial. Appropriate dose modifications or using selective HDAC inhibitors in future may mitigate the toxicities of the regimen. The pooled estimates of response and survival strongly favor triplets in the early relapsed setting.
Phase I/II study of an anti-CD20-interleukin-2 immunocytokine DI-Leu16-IL2 in patients with relapsed b-cell lymphoma (NHL).
Authors: Frederick Lansigan, Ryotaro Nakamura, Donald Quick, Daniel Vlock, Andrew Antony Raubitschek, Stephen D Gillies, Veronika Bachanova
Journal: Journal of Clinical Oncology (2016)

e19046 Background: DI-Leu16-IL2 has been shown to maintain the activities of both antibody and cytokine components but is also involved in tumor targeting, engagement of the immune system and induction of an anti-cancer vaccine effect. Methods: This multicenter, dose escalation trial evaluates the safety, efficacy, tolerability, maximum tolerated (MTD) and optimal biological dose of subcutaneous (SC) DI-Leu16-IL2 in pts with relapsed/refractory NHL. Following peripheral B cell depletion with low-dose rituximab (50mg/m2), DI-Leu16-IL2 was administered 3 consecutive days every 21 days. A 3+3 dose escalation trial design began at 0.5 mg/m2. Response evaluable patients had to receive > 2 cycles of therapy. Results: To date, 18 pts in 5 cohorts have been enrolled. The median age is 63 (48-83 yrs), median prior therapies 4 (range 1-11). The most common drug-related adverse events (AEs) were grade 1-2 transient skin reactions with erythema, painless induration of injection site, pruritus, edema and mild constitutional symptoms. All AEs resolved completely within one week. DLT occurred in 2 pts at 6 mg/m2 with delayed (8-10 days) grade 3 cytokine release syndrome, suggesting effector cell expansion as the cause. 5 pts have been enrolled at 4mg/m2 and no DLTs have been encountered. Stable or responding pts had higher pre-treatment absolute lymphocyte counts than PD pts (P < 0.01) and repetitive SC dosing elicited lymphocyte expansion associated with clinical activity. A high T-reg expansion in the blood was not associated with a worse response. There was a trend for CR pts to have a very low % of G-MDSC cells. Durable tumor regression or stabilization was noted in 13/15 evaluable pts with 3 CRs, 2 PRs and 8 pts with SD for a disease control rate of 87%. Of the responders, the median tumor reduction was 70% 5 pts have had responses of > 11 months duration. 1 CR continues 7+ months after stopping therapy at cycle 6. Conclusions: Promising clinical efficacy of DI-Leu16-IL2 has been observed with long-term responses. DLT occurred at 6 mg/m2. It was well tolerated at lower doses where significant responses were observed. Expansion cohorts are planned to further evaluate the safety and efficacy of DI-Leu16-IL2 at lower doses. Clinical trial information: NCT01874288.
Genetic differences between primary and metastatic tumors from cross-institutional data.
Authors: Julie Wu, Jordan Byran, Lucy L. Wang, Michele LeNoue-Newton, Mia Alyce Levy, Christine Micheel, Yaomin Xu, Lester Mackey, Jeremy Warner
Journal: Journal of Clinical Oncology (2018)

e18572 Background: Recurrent and metastatic cancers have been underrepresented in cancer genomics databases until the creation of AACR Project GENIE, a large multi-institutional database derived from clinically-driven genomic testing. These often heavily treated tumors may have characteristics distinct from early stage specimens. We sought to identify genotypic differences between primary and metastatic breast, colon, and lung tumors in GENIE. Methods: We performed cohort matching based on age, race, and gender of 5210 patients stratified by cancer type and sample site (primary or metastatic). We used Fisher’s exact test to determine whether detected variants, at the gene level, were associated with primary or metastatic tumors. P values were adjusted for multiple hypothesis testing. Specific mutations in ESR1 were compared to previously known mutations in the COSMIC Drug Resistance database and ClinVar. Results: Across 620 genes, there were significant differences in all cancer types. In colon cancer, FBXW7 variants were more common in primary samples (OR 2.51, p 0.016) and in lung cancer, INPP4B variants were more common in metastatic samples (OR 7.81, p 0.039). In breast cancer, ESR1 variants were more common in metastatic samples (OR 5.44, p < 10-6). Of the 39 distinct breast cancer ESR1 missense variants in GENIE, 30 (75%) were not annotated in ClinVar or COSMIC. 5 variants were found in more than one sample, including 3 in samples from different institutions. Conclusions: We replicated a known association in metastatic breast cancer, ESR1, which is implicated in hormone therapy resistance. INPP4B inhibits AKT activation and loss of this tumor suppressing function may explain enrichment in metastatic lung cancer. Focusing on ESR1, we identified novel missense variants, some of which were recurrent. As more clinical data are incorporated into GENIE, we can validate the association of ESR1 mutation with treatment resistance. Our findings suggest that Project GENIE may become a platform for cross-validation of variants of unknown significance, realizing one of the promises of precision oncology at scale. Primary (avg # variants) Metastatic Breast (826 matched pairs) 3.64 4.68 Lung (761) 6.43 7.33 Colon (531) 9.87 6.65
Analysis of genomic alterations in matched circulating tumor cell DNA (CTC DNA) and plasma tumor DNA (ctDNA) in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Santosh Gupta, Daniel H Hovelson, Scott A. Tomlins, Gabor Kemeny, Chia-Jen Liu, Daniel J. George, Colin Rothwell, Monika Anand, David M. Nanus, Paraskevi Giannakakou, Simon Gregory, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2018)

5065 Background: CTC and ctDNA-based, actionable genomic alterations are being increasingly utilized for precision oncology therapies. However, the concordance of genomic alterations in CTC DNA vs. ctDNA is not established. Methods: After CTC/ctDNA isolation, we performed whole genome copy number alteration (CNA) analysis in 88 men with mCRPC treated with enzalutamide (E) or abiraterone acetate (A) (n = 72), and radium-223 (n = 16). We performed comparative genomic hybridization (aCGH) and low-pass whole genome sequencing (~0.1x, lpWGS) for CNA assessment and evaluated the concordance between gains/losses in matched CTCs, ctDNA and germline DNA in 63 samples; 32 from 16 men receiving radium-223, and 31 from 16 men receiving E/A. Results: Of the 88 enrolled men with mCRPC, 51% had ≥5 Cellsearch CTCs. We identified common genomic gains in 63 CTCs and matched ctDNA in FOXA1 (56 vs. 75%), KDM6A (51 vs. 21%), AR (48 vs. 64%), MYCN (30 vs. 5%), and MYC (18 vs. 24%). Common copy losses included ZFHX3 (60 vs. 44%), FGFR2 (43 vs. 32%), PHLPP1 (33 vs. 33%), BRCA1 (29 vs. 30%), and RB1 (13 vs. 21%). We analyzed AR copy gain status in 21 ctDNA specimens by aCGH and lpWGS, finding a concordance of 89%; detection correlated with high ctDNA content and CTC number. However, we found only 33% AR gain concordance in 38 CTC aCGH samples vs ctDNA lpWGS samples, and 63% AR gain concordance for CTC aCGH vs. ctDNA aCGH samples collected at the same time points. In 63 matched CTCs and ctDNA samples, we observed high concordance in gain of FOXA1 (91%) and AR (63%), moderate concordance for gain of MYC (55%), NCOR2 (41%), loss of ZFHX3 (53%) and PHLPP1 (48%), but low concordance for gain of KDM6A (25%) and loss of BRCA1 (39%), RB1 (38%), and FGFR2 (37%). Conclusions: Detection of genomic alterations at the whole genome level is feasible in ctDNA and CTC DNA and concordance across ctDNA platforms was high. However, we found variable concordance in CTC DNA vs. ctDNA copy number alterations depending on the specific gene, type of alteration, ctDNA concentration, and CTC enumeration likely reflecting biologic variability or differences in assay sensitivity. Clinical trial information: NCT02269982, NCT02204943.
Exploring open-label bias in patient-reported outcome (PRO) emotional domain scores in cancer trials.
Authors: Paula Banerjee Chakravarti, Ethan M. Basch, Kim M. Hirshfield, Bellinda King-Kallimanis, Kevin J Clark, Pamela Ohman Strickland, Elektra J Papadopoulos, Kitaw Demissie, Paul Gustav Kluetz
Journal: Journal of Clinical Oncology (2018)

e18702 Background: Concern exists that patients’ self-reports may be biased in open-label trial designs. We compared PRO emotional domain results between investigational arms of paired open label and double-blind trials of the same drug and disease population. We hypothesized that greater improvement in emotional domain scores would be found in the investigational arms of open label compared to their paired blinded trials, providing evidence of bias. Methods: Three oncology drugs approved by the FDA after 2000 were identified in the FDA trial repository with both a blinded and open-label trial for the same disease, and identical PRO tools in both trials. Investigational agents were an endocrine agent (PRO=FACT-G), and two tyrosine kinase inhibitors (PRO=EORTC QLQ-C30). Within each trial pair, we compared the proportion of patients with emotional domain improvements (based on published PRO score thresholds) from baseline to time of first radiologic assessment, for investigational arm participants only. Results: PRO completion rates were similar with no differences >5% between paired trial investigational arms. Initial analysis indicated no clear pattern of over-estimation of improvement in emotional domain scores in the open-label investigational arms when compared to blinded investigational arms. When analyzing the relationship of emotional domain improvements with tumor response data, no consistent differences were seen in subsets of those with tumor response, stable disease or progression by trial blinding status. Conclusions: Preliminary analysis did not find differences to support our hypothesis that patients in open-label trials (versus blinded) randomized to the experimental arm will consistently report better emotional domain results in the 3 selected trial pairs. These preliminary results should be interpreted cautiously as multiple limitations of this analysis are acknowledged including small sample size, selection of a single response threshold and cross-trial comparison. Further exploration and sensitivity analysis of the data are underway.
Implementation of breast cancer pathway for genetic counseling and testing in multi-state health system.
Authors: Stephanie L. Graff, Dax Kurbegov, David Moorman
Journal: Journal of Clinical Oncology (2018)

6521 Background: Genetic counseling and/or testing (GC/T) are important aspects of breast cancer care. The National Comprehensive Cancer Network has guidelines for GC/T but reports demonstrate variable compliance. Across the Sarah Cannon Cancer Network (SCCN), pathways were developed and implemented by physician leadership teams to select patients (pts) who meet criteria for GC/T. Participating physicians receive pathways training. Adherence metrics are tracked in real time. This study evaluates compliance with GC/T for pts treated on and off pathway in the SCCN. Methods: Data was collected from seven SCCN markets in six states to create 3 data sets. 1. Pre-pathway: treated prior to implementation of pathways. 2. Off pathway: treated off pathway by physicians not yet trained on pathways after pathways implementation. 3. On pathway: treated by at least one physician trained on pathways. Pathway criteria for GC/T include: age < 50 years, male breast cancer, ≥ 2 affected relatives, ovarian cancer (family or self), triple negative biology < 60 years of age, 2 primary breast cancers, Ashkenazi Jewish ancestry. All pts were navigated by nurse navigators who entered the data into iNavigate, SCCN’s proprietary software. Data represents all breast cancer pts in iNavigate between December 2012 and November 2017. Pathways were implemented March 2016. Chi-squared tests were performed without continuity correction, using Bonferroni correction methods to account for multiple comparisons Results: Summarized in Table 1. Conclusions: Following implementation of pathways guiding genetic counseling and/or testing (GC/T), patient referral improved by 61.3% (95% CI: 56.1%, 66.4%; p < 0.0001). For pts not managed on pathway, GC/T improved by 15.7% (95% CI: 10.9%, 20.6%; p < 0.0001), possibly due to increased navigator or system awareness. These findings support pathways as one way to ensure best practice and guidelines based care across a large, multi-state health system. Total Patients Eligible GC/T GC/T Offered Pre-Pathway 4321 1151 245 (21.3%; 95% CI: 19.0%, 23.7%) Off Pathway 2711 889 329 (37.0%; 95% CI: 33.9%, 40.2%) On Pathway 1277 453 374 (82.6%; 95% CI: 78.8%, 85.8%)
Identification of gene expression determinants of radiosensitivity in bladder cancer (BC) cell lines.
Authors: Jasmine Pettiford, Summya Rashid, Aysegul Balyimez, Tomas Radivoyevitch, Vadim S. Koshkin, Daniel J. Lindner, Yvonne Parker, Mark L. Day, Kathleen C. Day, Scott Tomlins, Nouri Neamati, Brendan Veeneman, Guadalupe Lorenzatti Hiles, Philip Palmbos, Byron Lee, Petros Grivas, Omar Y. Mian
Journal: Journal of Clinical Oncology (2018)

e16507 Background: BC is heterogeneous and associated with high recurrence rate after definitive treatment. Biomarkers to help select patients with muscle invasive BC appropriate for organ preservation with chemoradiation are needed. Methods: We characterized 20 primary BC cell lines, all verified by genomic fingerprinting. Molecular characterization of cell lines has been reported, including mutation analysis, CNA (high density SNP arrays) and gene expression (RNAseq). We performed radiosensitivity screening using 2 methods: cell survival using colony forming assay (CFA) and high throughput cell proliferation using CellTiter Glo (CTG) following treatment with 0, 2, 4, 6, and 8 Gy, single fraction gamma radiation (fixed source Cs 137, Shephard irrad, 125 cGy / min). Area under the survival / proliferation curves (AUC) was calculated and R was used to determine significant associations between radiation response and gene expression (RNAseq). Gene set enrichment analysis (GSEA) and Ingenuity pathway analysis (IPA) were performed to identify biologically relevant networks contributing to differential radiation response. Results: Of the 20 cell lines, CFA data was successfully obtained for 10 lines and CTG data for 13 lines. 11 lines had both high dose rate (HDR) and low dose rate (LDR) CTG data. AUCs for the CFA curves ranged 1.71 - 3.08; 4.03 - 8.36 for HDR CTG; and 2.95- 7.15 for LDR CTG. RNAseq identified 18,634 unique transcripts mapping to distinct loci. 174 genes with mean FPKM > 0.5 and correlation p values < 0.01 with AUC values from CFAs were identified. These genes were strongly enriched for membership in the peroxisome proliferator (PPAR) pathway (IPA, p 8.67E-05) and Toll-like receptor (TLR) signaling pathway (IPA, p = 2.45E-5). Similarly, GSEA demonstrated enrichment for the TLR pathway (P = 3.37E-03, FDR 1.16E-01). Conclusions: In vitro BC radiosensitivity was associated with significant baseline gene expression differences between cell lines. The PPAR pathway, including PPAR alpha and gamma, and TLR pathway demonstrated strong association with differential response to radiation and are novel candidate biomarkers for further validation and mechanistic studies in BC radiosensitivity.
P05.67 Primary Central Nervous System Lymphomas retrospective review of a single hospital center case series
Authors: V L Espírito Santo, R Jesus, B Mesquita, M Guerra, R Taipa, M Melo-Pires, M Cunha, P Guimarães
Journal: Neuro-Oncology (2018)

Primary central nervous system lymphoma (PCNSL) is a rare tumour that accounts for 2% of all CNS tumours. In immunocompetent patients the incidence is increasing, especially in the elderly and tends to have a worse outcome. Retrospective characterization of patients diagnosed with PCNSL between January 2012 and April 2018, considering epidemiological factors, disease presentation, diagnosis, treatment and survival. Eight patients (5 males, 3 females) were identified, with a median age of 70 years-old (range between 61 to 88 years-old). The first neurological manifestation was seizure (n=3), headache (n=2), motor deficit (n=1), language disorder (n=1), visual disorder (n=1). Four patients developed further neurological symptoms and 3 patients had concurrent symptoms of systemic lymphoma during the disease progression. Five patients had a single CNS lesion (4 supratentorial, 1 infratentorial) and 3 patients had multiple lesions. In 7 patients the diagnosis was made by brain biopsy and in 1 by CSF cytometry. Histological diagnosis was diffuse large B-cell lymphoma in 6 patients, marginal zone lymphoma in 1 patient and nodular sclerosis Hodgkin’s lymphoma in 1 patient. Five patients received chemotherapy, 2 cranial radiotherapy and 1 patient only palliative care. All of them received corticotherapy. Four patients had complications from the treatment, leading to stopping the chemotherapy in one patient. The median survival was 303 days (range between 100 to 2317 days), with 3 patients still alive in the end of April 2018. The main causes of mortality were infection (n=3) and progression of the disease (n=2). PCNSL is a tumour with a challenging treatment, not only because about half of the patients end up either having relapsing or refractory disease, but also because it tends to occur in elderly patients who are more prone to complications. In this case series, we emphasize the tumor aggressiveness, and the potential value of early diagnosis and effective combined treatment in the disease prognosis.