tbuckley/cabot-search huggingface dataset:
PDL-1 expression in oral squamous cell carcinoma and implications for treatment.
Authors: Vijay Kumar Srinivasalu, Narayana Subramaniam, Subramania Iyer, Ajit Nambiar, Manzoor Koyakutty, Krishnakumar Thankappan, Manjula Das, Sujan Kumar Dhar, Deepak Balasubramanian, Pavithran Keechilat
Journal: Journal of Clinical Oncology (2019)

e17527 Background: PDL-1 expression has been shown in multiple tumours to be a key factor in treatment response and immunogenicity. In oral squamous cell carcinoma (OSCC), its role is controversial; the expression levels, prognostic significance and therapeutic relevance are unclear. This study was performed to determine the incidence of PDL-1 expression in OSCC, and to determine its correlation with demographic, clinical and pathological features, recurrence and survival. Methods: PDL-1 IHC (Dako kit) was determined on 64 samples of OSCC obtained during curative intent resection. PDL-1 expression levels were determined in tumour (T) and tumour infiltrating lymphocytes (TILs). Statistical analysis was performed. Results were validated on the mRNA-seq data from the Cancer Genome Atlas (TCGA) for head and neck squamous cell carcinoma (HNSCC). Results: 64 patients were included in the final analysis with a mean age of 54 years. &lt; 1% expression was the most common for T (92%) and TILs (56%). Tumour PDL-1 expression &lt; 1% had higher risk of lymphovascular invasion (LVI) (p = 0.044) and bone invasion (p = 0.010). TIL PDL-1 expression &lt; 1% was more common in patients ≤45 years (p = 0.023) with higher chances of local recurrence (p = 0.020) and reduced local recurrence free survival (p = 0.047). For the TCGA data, low ( &lt; 1%) PDL-1 expression was associated with a significant reduction in OS and DFS in the young (≤45 years) (p = 0.0078 and 0.0089 respectively), but not for older patients ( &gt; 45 years) (p = 0.21 and 0.88 respectively). Conclusions: PDL-1 expression in OSCC was low. TIL PDL-1 expression &lt; 1% was more common in those ≤45 years, and associated with a higher chance of local recurrence and poorer survival. The role of PDL-1 expression in prognosis of OSCC is controversial, with our data being the first to correlate low PDL-1 expression and poorer outcomes with younger patients. These results were validated by the TCGA data for HNSCC across multiple subsites. Further study is required to determine if this pathway plays a significant role in local control and survival.
Retrospective analysis of outcomes in patients with non metastatic cholangiocarcinoma: A single network experience.
Authors: Jyothika Mamadgi, Kristina Lundeen, Shaakir Hasan, Sunita Patruni, Ahmed Khattab, Amulya Yellala, Alexander V. Kirichenko, Moses S. Raj
Journal: Journal of Clinical Oncology (2019)

e15643 Background: Biliary tract cancers are rare cancers with an annual incidence of about 8,000. In resected non-metastatic BTCs (NM-BTCs), cure rates decrease significantly due to local and distant recurrence. However, guidelines to use adjuvant therapies are not well established due to the lack of well-structured phase three randomized trials, given the rarity of the disease. We present a retrospective study analyzing outcomes of NM-BTCs managed within Allegheny Health Network (AHN) with specific focus on patients who underwent resection and received different adjuvant treatment modalities. Methods: Data of all patients with NM-BTCs treated at AHN from January 2012 to December 2017 was collected and outcomes analyzed for patients treated with surgery vs no surgery We then sub-stratified the patients who received surgery into three groups based on the modality of adjuvant therapy. Group 1 included patients with no additional therapy , Group 2 with adjuvant chemotherapy and Group 3 with adjuvant chemotherapy+radiation. We compared Mean Progression-Free Survival (PFS) and Overall Survival (OS) in these three groups. Results: Of the 59 NM-BTCs treated at AHN, 32(52.4%) underwent surgery. The OS for surgical vs non-surgically treated patients was 23 vs 17 months (p = 0.008) and PFS 26 vs 19 months (P = 0.06) respectively. Of the resected –patients, PFS for patients in Group1 vs Group2 vs Group3 was 16 vs 21 vs 34 months (pooled P = 0.05) and OS was 19 vs 22 vs 19 months respectively (pooled P = 0.5). PFS for patients in Group1 vs Group (2+3),i.e, patients treated surgery only vs surgery+ any adjuvant treatment was 16 vs 28 months (P = 0.1), OS was 19 vs 22 months (P = 0.7)respectively. PFS in patients in Group 3 vs Group (1+2),i.e, patients treated with adjuvant chemotherapy+radiation vs others was 34 vs 19 months. (p = 0.0183) respectively. Conclusions: This analysis revealed a statistically significant improvement in OS in patients with NM-BTCs who received surgery. There was a trend towards improvement in PFS/OS in patients who received adjuvant therapy, though not statistically-significant. Use of adjuvant chemotherapy+radiation resulted in statistically significant improvements in PFS as compared to other treatment modalities.
HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial.
Authors: Otto Metzger Filho, Giuseppe Viale, Lorenzo Trippa, Tianyu Li, Denise A. Yardley, Ingrid A. Mayer, Vandana Gupta Abramson, Carlos L. Arteaga, Laura Spring, Adrienne Gropper Waks, Michalina Janiszewska, Eileen Wrabel, Michelle Demeo, Aditya Bardia, Tari A. King, Kornelia Polyak, Eric P. Winer, Ian E. Krop
Journal: Journal of Clinical Oncology (2019)

502 Background: HER2 targeted therapy without chemotherapy may be insufficient to completely eradicate a HER2+ cancer in cases of significant intratumor HER2 heterogeneity (ITH-HER2). Methods: We conducted a single-arm phase II study enrolling centrally confirmed HER2+ breast cancer. Pts received 6 cycles of T-DM1 plus Pertuzumab before surgery. Central ITH-HER2 was assessed on baseline ultrasound-guided core biopsies from 2 distinct areas of each tumor (3 cores/site). ITH-HER2 was defined as at least one of the six areas demonstrating either 1) HER2 positivity by FISH in &gt; 5% and &lt; 50% of tumor cells (i.e., CAP guideline) or 2) an area of tumor that tested HER2 negative. The primary objective is the association between pathologic complete response (pCR) and ITH, stratified by ER status. pCR defined as residual cancer burden (RCB) 0. Results: 164 pts with centrally confirmed HER2+ tumors were enrolled from 1/2015 to 1/2018. 2 pts withdrew consent. Median tumor size by imaging was 2.8 cm (IQR 2.1-3.8cm); 111 (69%) were ER+ and 51 (32%) ER-. 8 pts discontinued tx (6 due to disease progression, 2 due to toxicity). 49% of pts had a pCR (RCB-0), 14% RCB-I, 26% RCB-II and 11% RCB-III. Higher rates of RCB-0 were seen in ER- (65%) versus ER+ (42%). ITH-HER2 was detected in 10% (16/157) of evaluable cases. No pCR was observed among cases classified as heterogeneous (RCB-I 25%, RCB-II 25%, RCB-III 50%). The study met its primary endpoint by demonstrating a significant association between ITH-HER2 and pCR stratified by ER status (p &lt; .0001). Secondary analysis also demonstrated a significant association between ITH-HER2 and pathologic response defined as RCB 0 or I (OR = 5.6, p = 0.004). Exploratory analysis revealed higher rates of RCB-0 among tumors centrally classified as HER2 3+ (56% [66/118]) versus HER2 2+ (27% [10/37]), (OR = 3.4, p = 0.002). The association of ITH-HER2 and pCR was maintained when stratifying by ER status and HER2 IHC (2+ vs. 3+), (p = 0.002). Conclusions: ITH-HER2 assessed by routine pathology evaluation is a strong predictor of pCR to a dual-HER2 targeted therapy regimen. If validated, ITH-HER2 may need to be considered in selection of pts for HER2-targeted regimens without chemotherapy in the curative setting. Clinical trial information: NCT02326974.
A multicenter, randomized, double-blind, placebo-controlled phase III study of anlotinib or placebo in combination with gemcitabine and cisplatin (GP) as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC).
Authors: Yunpeng Yang, Yan Huang, Wenfeng Fang, Yuxiang Ma, Qingqing Cai, Zhi-Ming Li, Hongyun Zhao, Yuanyuan Zhao, Ting Zhou, Shaodong Hong, Yaxiong Zhang, Li Zhang
Journal: Journal of Clinical Oncology (2019)

TPS6089 Background: GP is the standard first-line chemotherapy for R/M NPC. However, the outcome of patients who are refractory to first-line chemotherapy is poor. There remains an unmet need for more effective first-line treatment. Overexpression of vascular endothelial growth factor (VEGF) is common in NPC and the higher expression is related to lower OS. This feature makes NPC potentially suitable for antiangiogenic treatment. Anlotinib is a novel multitarget tyrosine kinase inhibitor that targets VEGFR 1 to 3, fibroblast growth factor receptor 1 to 4, and platelet-derived growth factor receptor α and β. Our phase I study of anlotinib in R/M NPC patients who failed from standard treatment had shown a manageable safety profile and promising antitumor activity with an ORR of 25%. This phase 3 trial aims to compare the efficacy and safety of anlotinib versus placebo in combination with GP in patients with R/M NPC in the first-line setting. Methods: Key eligibility criteria of this study are that the patient has metastatic disease after curative radiotherapy, or is primarily metastatic; has an ECOG PS of 0 or 1; has adequate organ function; and has at least 1 measurable lesion according to RECIST 1.1. Eligible patients will be randomized in a 1:1 ratio to receive intravenous gemcitabine at 1 g/m² on days 1 and 8, cisplatin at 75 mg/m² on day 1, plus anlotinib or placebo 12 mg daily orally on days 1–14 every 3 weeks for a maximum of 6 cycles followed by anlotinib or placebo 12 mg daily on days 1–14 every 3 weeks as maintenance therapy. The primary endpoint is PFS. Secondary endpoints include OS, ORR, quality of life and safety profile. Independent Data Monitoring Committee and Independent Review Committee will be used in this study. We assume that the median PFS will be 10 mos in anlotinib group and 7 mos in placebo group. To detect a 3-month improvement of PFS in anlotinib group at a two-sided significant level of 0.05 and power of 0.8, allowing for a dropout rate of 10%, a total of 336 patients will be enrolled. From August 2018, 58 patients have been enrolled. Clinical trial information: NCT03601975.
Modulation of autophagy: A phase II study of vorinostat (VOR) plus hydroxychloroquine (HCQ) vs regorafenib (RGF) in chemo-refractory metastatic colorectal cancer (mCRC).
Authors: Sukeshi Patel Arora, Laura LaNiel Tenner, John Sarantopoulos, Jay Larry Morris, Lisa Longoria, Qianqian Liu, Joel Michalek, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2019)

3551 Background: Agents targeting the angiogenic pathway have been a cornerstone therapy in mCRC. In chemo-refractory mCRC, RGF, an oral multikinase inhibitor with considerable angiogenic inhibition, has shown modest effects on survival. We reported that autophagy modulation using the autophagy inhibitor, HCQ, enhances the anti-cancer activity of the histone deacetylase inhibitor, VOR, via ubiquitinated protein accumulation in CRC. A phase 1b study confirmed VOR/HCQ is active and tolerated in refractory mCRC. We conducted a prospective randomized study to evaluate efficacy of VOR/HCQ vs RGF in mCRC patients (NCT02316340) and report a planned interim analysis. Methods: Randomized, controlled trial of VOR 400 mg and HCQ 600 mg PO daily vs RGF 160 mg PO daily (3 weeks on, 1 week off), Q4weeks, in advanced CRC patients. Crossover was optional after first progression. A total of 76 patients are planned. Primary endpoint: mPFS. Secondary endpoints: mOS; adverse events (NCI-CTCAEv3.0); PD analysis: 27-plex Human Cytokine Array, NGS analysis (Guardant Health) on cell-free, ctDNA. Results: At interim analysis, n = 42 patients enrolled from 2/2015-10/2017: n = 20 VOR/HCQ (5 crossed to RGF), n = 22 RGF (13 crossed to VOR/HCQ). 38 patients evaluable (at least C1 completed). Median age 58.4, 40% NH vs 60% H. mPFS on first arm: 1.90 mo VOR/HCQ vs 4.35 mo RGF [p = 0.032, HR: 2.277]. mOS: 6.77 mo VOR/HCQ vs 7.23 mo RGF [p = 0.90, HR: 1.05]. Grade 3/4 AEs (see table). In both arms, there was trend towards decreased IL-1b, IL-2, IL-6, IL-10, TNFα, IFNγ but an increase in GM-CSF after treatment. Responders (4+ cycles) had lower baseline Max MAF versus nonresponders for both arms. In responders, there was trend toward a decrease in Max MAF at C2 and then increase at progression. Conclusions: VOR/HCQ did not improve survival when compared to RGF. VOR/HCQ has a favorable safety profile, but further planned subgroup analysis is pending to identify biomarkers of efficacy in responders. Clinical trial information: NCT02316340. [Table: see text]
The efficacy and safety of irinotecan plus raltitrexed as second-line treatment in advanced colorectal cancer (ACC) patients: An interim analysis of a multicenter, phase II trial.
Authors: Yunpeng Liu, Zan Teng, Xiujuan Qu, Yan qiao Zhang, Zhendong Zheng, Fugang Wen, Yuxian Bai, Ying Piao, Ying Wang, Yuee Teng, Mingfang Zhao, Bo Jin, Xin Li, Jing Shi, Ping Yu, Jinglei Qu, Ying Luo
Journal: Journal of Clinical Oncology (2019)

e15061 Background: There are limited therapeutic options for the treatment of advanced colorectal cancer which fail first-line chemotherapy. Phase I studies have shown that the combined application of the irinotecan (CPT-11) and raltitrexed has significant synergistic effect and acceptable toxicity. The aim of this multicenter study was to assess the efficacy and toxicity of second-line raltitrexed plus irinotecan in Chinese patients with advanced colorectal cancer. Methods: This is an open-label,single-arm, multicenter, phase II trial (Registered in clinicaltrials.gov with NCT03053167).Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of oxaliplatin and fluorouracil therapy. Enrolled patients received CPT-11 (180 mg /m 2 , d1) and raltitrexed (3 mg/m 2 , d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were disease control rate (DCR), objective response rate (ORR), overall survival (OS), quality of life (QOL) and safety. In all, 100 patients were required for primary point testing. Results: Between November 2016 and December 2018, a total of 70 patients were screened for enrollment and 53 patients reached the primary endpoint. Nine patients achieved a partial response and twenty-seven stable disease. The overall response rate was 17% (9/53) and the disease control rate was 67.9% (36/53). Median progression-free survival (mPFS) was 4.3 months and median overall survival was not observed. The most common adverse events were elevated transaminases (21/53), fatigue (14/53), diarrhea (12/53), neutrocytopenia (10/53), erythrocytopenia (9/53), hypohemoglobin (8/53) and leukocytopenia (6/53). The total incidence of grade 3/4 toxicity was 17% (9/53) , mainly diarrhea (2/53), neutrocytopenia (2/53) and elevated transaminases (2/53). There were no treatment-related deaths. Conclusions: We have demonstrated that CPT-11 plus raltitrexed is active and feasible in patients with second-line treatment in advanced colorectal cancer. This trial will progress as planned. Clinical trial information: NCT03053167.
Delays from neoadjuvant chemotherapy to interval debulking surgery and survival in ovarian cancer.
Authors: Ying L Liu, Qin Zhou, Alexia Iasonos, Olga T. Filippova, Dennis Chi, Oliver Zivanovic, Yukio Sonoda, Ginger J. Gardner, Vance Broach, Roisin Eilish O'Cearbhaill, Jason A. Konner, Carol Aghajanian, Kara C. Long-Roche, William P. Tew
Journal: Journal of Clinical Oncology (2019)

5552 Background: Prolonged time from primary surgery to chemotherapy is associated with worse survival in ovarian cancer (OC); however, the impact of prolonged time from neoadjuvant chemotherapy (NACT) to interval debulking surgery (IDS) is unknown. Given increasing utilization of NACT, we seek to evaluate the role of delays from NACT to IDS (T IDS ) on survival. Methods: At a single center, we prospectively identified 224 women with newly diagnosed stage III/IV OC given NACT from 7/1/15 to 12/1/17. Clinical characteristics were abstracted by two independent reviewers. Delays in T IDS were defined as time from last preoperative carboplatin to IDS &gt; 6 weeks. Fisher’s exact/Wilcoxon rank sum tests were used to compare clinical characteristics by delay in T IDS . Kaplan Meier method was used to estimate progression-free (PFS) and overall survival (OS) from date of IDS. Log-rank test/multivariate CoxPH models were used to examine differences by delay groups, adjusting for covariates. Results: Of the 224 women, 159 underwent IDS, and 34 (21%) experienced T IDS delays. These women were older (median 68 vs. 65 years, p = 0.05) and had more preoperative NACT cycles (median 6 vs. 4, p = 0.003). Patients with delays in T IDS also had a longer interval from pathological diagnosis to start of NACT (T NACT ), median 22 vs. 17 days, p = 0.01, and interval from IDS to postoperative chemotherapy (T POC ), median 37 vs. 30 days, p = 0.01; however, neither T NACT nor T POC predicted survival, p &gt; 0.05. On univariate analysis, delays in T IDS were significantly associated with worse OS (HR 2.4 95% CI 1.2-4.8, p = 0.01); however, this was attenuated in multivariate models (HR 1.66 95% CI 0.8-3.4, p = 0.17), adjusting for age, stage and complete gross resection (CGR). On univariate analysis, delays in T IDS were not associated with PFS (HR 1.55 95% CI 0.97-2.5, p = 0.062), and in multivariate models, increase in number of preoperative NACT cycles (p = 0.005) and lack of CGR (p &lt; 0.001) were the only variables predictive of worse PFS. Conclusions: Delays in T IDS are associated with OS, but not after adjustment for age, stage and CGR, suggesting a need to maximize cytoreduction regardless of delays in NACT. The role of preoperative NACT cycles on survival should be further studied.
Design and development of the molecular analysis for Therapy Choice (NCI-MATCH) Designated Laboratory Network.
Authors: James V. Tricoli, Linda Zane, Robin Harrington, Laura Yee, Kneshay N. Harper, Ting-Chia Chang, Lyndsay Harris, Alice P. Chen, Keith Flaherty, Peter J. O'Dwyer, Barbara A. Conley, Cynthia Winter, Jennifer Lee, Paul M. Williams, Jeffrey Sklar, David Patton, Gregory J. Tsongalis, Stanley R. Hamilton, A. John Iafrate, Chris Alan Karlovich
Journal: Journal of Clinical Oncology (2019)

3016 Background: NCI-MATCH is a precision medicine trial that assigns treatment to refractory cancer patients by tumor mutation profile rather than by histology. After screening fresh tumor biopsies from nearly 6000 patients many treatment arms did not meet accrual due to the low prevalence of the eligible variants. NCI MATCH developed an approach to identify patients for the remaining arms utilizing a network of academic and commercial CLIA-certified labs that perform NGS assays as routine care at MATCH participating sites. Methods: Candidate labs were recruited through a notice in the Federal Register and posted on the NCI and ECOG ACRIN web sites. Twenty-seven labs (17 academic/10 commercial) submitted applications. After acceptance each lab analyzed a common set of 10 DNAs extracted from 8 cell lines and 2 clinical samples for concordance with the central NCI-MATCH NGS assay. Results: For the 17 labs with concordance results, a median of 8 (range 2 – 58) copy number variants (CNVs) were evaluated by the NGS assay of each DL, with the number evaluated depending on each lab’s clinical assay panel content. CNV concordance between central and DL assays, as measured by positive percent agreement (PPA), averaged 98.7% (range 87.5% - 100%) with the central assay as referent and 94.1% (range 77.8% – 100%) with the DL assay as referent. For single nucleotide variants (SNVs) and Insertion/deletions (Indels) combined, a median of 19 variants (range 11 – 26) were evaluated by each DL for concordance. PPA between central and DL assays averaged 98.0% (range 87.5% – 100%) and 98.6% (range 90.0% – 100%) with central and DL assay as referents, respectively. Strong correlations were observed between central and DL assays for both CNVs (median r = 0.93; 0.33 – 1.00) and SNV/Indels (median r = 0.98; 0.67 – 0.99). Conclusions: Our results suggest that different NGS assay platforms using diverse strategies for target enrichment and data analysis may still achieve high concordance if pre-analytical variables are minimized and the common genomic regions interrogated by each assay are well-understood. The designated lab network allows for a wider search for rare variants in tumors and provides a model for conducting future clinical trials. Clinical trial information: NCT02465060.
Radiomics features on CT scans to predict response to HER2-targeted therapy of hepatic metastases from colorectal cancer.
Authors: Valentina Giannini, Simone Mazzetti, Arianna Defeudis, Giovanni Cappello, Lorenzo Vassallo, Angelo Vanzulli, Cristina De Mattia, Alberto Torresin, Salvatore Siena, Andrea Sartore-Bianchi, Francesco Leone, Cosimo Martino, Vittorina Zagonel, Silvia Marsoni, Daniele Regge
Journal: Journal of Clinical Oncology (2019)

e15086 Background: Metastatic Colorectal cancer (mCRC) is the 2nd cause of cancer death worldwide. Repeated cycles of therapies, combined with surgery in oligo-metastatic cases, are the therapeutic standard in mCRC. However, this strategy is seldom resolutive. Different lesions in in the same patient could have different responses to systemic therapy. Recently, CT texture analysis (CTTA) had been shown to potentially provide with prognostic and predictive markers, overcoming the limitations of biopsy sampling in defining tumor heterogeneity. The aim of this study is to use CT texture analysis (CTTA) to identify imaging biomarkers of HER2+ mCRC able to predict lesion response to therapy. Methods: The dataset is composed of 39 extended RAS wild type patients with amplified HER2 mCRC enrolled in the HERACLES trial (NCT03225937) that received either a lapatinib+trastuzumab treatment (n = 23) or a pertuzumab+ trastuzumab-emtansine treatment (n = 16). All patients underwent CT examination every 8 weeks, until disease progression. All mCRC on baseline CT were semi-automatically segmented and quantitative features extracted: size, mean, percentiles, 28 texture features. A logistic regression model was created using: (i) the whole dataset of mCRC as training and test set and (ii) 100 randomly generated training sets (with 70% of responder (R+) mCRC and an equal number of non-responder (R-) mCRC), and 100 test sets including the remaining mCRC. A mCRC was classified as R+ if size decreased (-10%) or was stable (±10%); as R- if size increased (+10%), during subsequent CT scans. Results: A total of 199 metastases were included (75R+ and 124R-). The training set was composed of 53R+ and 53R- mCRC and the test set of 22R+ and 71R- mCRC. Using the whole dataset, the model reached an AUC = 0.82 (sensitivity = 84%, specificity = 70%), while it reached a mean AUC of 0.70 (sensitivity = 68%, specificity = 67%) within the 100 repetitions. Conclusions: CTTA might help in stratifying different behaviors of mCRC, opening the way for lesion-specific therapies, with conceivable cost and life savings. Further extended analysis is needed to better characterize and validate predictive value of these biomarkers.