tbuckley/cabot-search huggingface dataset:
De-escalating adjuvant trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer: A systemic review and meta-analysis.
Authors: Hadar Goldvaser, Korzets Ceder Yasmin, Daniel Shepshelovich, Rinat Yerushalmi, Michal Sarfaty, Domen Ribnikar, Paaladinesh Thavendiranathan, Eitan Amir
Journal: Journal of Clinical Oncology (2019)

524 Background: One year of adjuvant trastuzumab in combination with chemotherapy is the standard of care in early-stage HER2 positive breast cancer. Existing data on shortening trastuzumab treatment show conflicting results. Methods: A search of PubMed and conferences identified randomized trials that compared abbreviated trastuzumab therapy to one year of treatment in early-stage HER2 positive breast cancer. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for disease free survival (DFS) and overall survival (OS). Data on the number of DFS and distant relapse events were also collected as were the number of patients at risk in each group. Subgroup analyses evaluated the effect of nodal involvement, estrogen receptor (ER) expression and the duration of abbreviated trastuzumab (9-12 weeks versus 6 months). Odds ratios (ORs) and 95% CI were computed for pre-specified cardiotoxicity events including cardiac dysfunction and congestive heart failure (CHF). Results: Analysis included 6 trials comprising 11603 patients. In most studies adjuvant chemotherapy included anthracyclines and taxanes. Shorter trastuzumab treatment was associated with worse DFS (HR = 1.14, 95% CI 1.05-1.25, p = 0.002) and OS (HR = 1.15, 95% CI 1.02-1.29. p = 0.02). The effect on DFS was not influenced by ER status (p for the subgroup difference = 0.23), nodal involvement (p = 0.44) or the different duration of trastuzumab in the experimental arm (p = 0.08). In absolute terms, after an estimated median follow-up of 71 months, shorter treatment with trastuzumab was associated with an absolute increase in DFS events of 2.3%. Shorter trastuzumab treatment was associated with lower odds of cardiac dysfunction (OR = 0.67, 95% CI 0.55-0.81, p &lt; 0.001) and CHF (OR = 0.66, 95% CI 0.50-0.86, p = 0.003). Conclusions: Compared to one year, shorter duration of adjuvant trastuzumab is associated with significantly worse DFS and OS, despite favorable cardiotoxicity profile. One year of trastuzumab should remain the standard adjuvant treatment in early-stage HER2 positive breast cancer with appropriate cardiac monitoring.
Analytical validation of the Oncomine Pan-Cancer Cell-Free Assay in a CLIA- and CAP-regulated laboratory for detection of solid tumor-derived variants in blood plasma.
Authors: John B. Williamson, Luis Solano, Akemi Yuki, Vanessa D. Burkhart, James Chitwood, Ru Cao, Jeoffrey Schageman, Hannah Saunders, Angie Cheng, Thomas Ha, Cecilia Ojcius, Roxana White, Kimberly McCall, Suzanne Salazar, Kelli Bramlett, Huan Tian, Rajendra Ramsamooj
Journal: Journal of Clinical Oncology (2019)

e14614 Background: Assessing tumor-derived somatic variants from blood plasma provides minimally invasive tumor profiling, decreased cost relative to traditional tissue biopsy and rapid turn-around-time. We describe here the analytical validation of the Oncomine Pan-Cancer Cell-Free assay in a CAP-accredited, CLIA-certified laboratory. The assay is designed to detect somatic DNA single-nucleotide variants (SNV), insertions/deletions (INDEL), copy number variants (CNV), and gene fusions in cell-free total nucleic acid (cfTNA) across 52 genes. For research use only. Not for use in diagnostic procedures. Methods: We assessed the sensitivity, specificity, accuracy, and precision of the assay. Pre-characterized reference materials with alterations at known allelic frequencies (AF) were used to establish performance characteristics for each variant class followed by verification on clinical specimens. Whole blood (n = 73) from healthy (10), breast cancer (9), colorectal cancer (32), and lung cancer (22) donors were collected in K 2 EDTA tubes and plasma was separated within 8 hours of collection. cfTNA was isolated using the MagMAX Cell-Free Total Nucleic Acid Isolation Kit on the KingFisher Flex. Libraries were prepared following kit instructions. Templating and sequencing were performed using the Ion 550 Kit on the Ion Chef and S5 XL systems. Alignment to hg19 and variant calling were performed using Torrent Suite and Ion Reporter software. Results: We observed a sensitivity of 80% at 0.1% AF and &gt; 99.9% at 0.5% AF for SNV/INDEL. Sensitivity was &gt; 99.9% at 1.34 fold-change for CNV, and &gt; 99.9% at 0.4% fusion fraction. Specificity and accuracy were &gt; 99% for all variant classes. Precision was 98% for SNV/INDEL and &gt; 99.9% for CNV/fusions. Analysis of donor plasma demonstrated clinical feasibility; on average, we detected 1 hotspot SNV/INDEL (range 0-4) across the 3 cancer types. For SNV/INDEL in plasma where matched tissue genotyping was available (n = 17), we observed &gt; 99% concordance (AF range 0.09%-52%). Conclusions: We have demonstrated that this assay is a sensitive method for evaluating tumor-derived somatic variants in blood plasma. It may provide an alternative and minimally invasive method for mutation profiling.
Improved overall survival (OS) for advanced pancreatic cancer (PDAC) patients (pts) enrolled in the Know Your Tumor (KYT) program whose tumors harbored highly actionable molecular alterations and who received molecularly-matched therapies (tx).
Authors: Michael J. Pishvaian, Edik Matthew Blais, Patricia DeArbeloa, Jonathan Robert Brody, Lola Rahib, Andrew Eugene Hendifar, Sameh Mikhail, Vincent Chung, Davendra Sohal, Vincent J. Picozzi, Kimberly Mason, Lisa Tibbetts, Emily Lyons, Lynn McCormick Matrisian, Subha Madhavan, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2019)

4138 Background: Initial results from the KYT program demonstrated that 27% of PDACs harbor highly actionable molecular alterations (herein labelled “actionable biomarkers”), defined as biomarkers that predict for a high response rate to appropriately targeted tx, in any cancer type. Within this cohort, the median progression-free survival on molecularly-matched tx was 2 months longer than unmatched tx. Here, we present OS data emphasizing the 125 pts with “actionable biomarkers” who did or did not receive molecularly-matched tx. Methods: PanCAN and Perthera have coordinated tumor molecular profiling through commercial labs (NGS/IHC panels) for PDAC pts since 2014. Results are reviewed by a molecular tumor board, and tx options are prioritized based on the actionable biomarkers, in the context of the pt’s tx history. Pts are followed longitudinally to track physician tx choices and survival outcomes. Cox regression was used to assess differences in OS (measured from date of diagnosis until death). Results: Of 1053 pts who received a Perthera Report, 25% had “actionable biomarkers”. OS analyses across 454 pts with adequate tx history are shown in the Table below. Notably, pts with “actionable biomarkers” who received a molecularly-matched tx had a significantly increased OS compared to those with “actionable biomarkers” but who did not receive molecularly-matched tx. Subgroup analyses related to tx history and specific molecular pathways that warrant further investigation will be discussed. Conclusions: When the ~25% of PDAC pts whose tumors harbored “actionable biomarkers” received molecularly-matched tx, they had a better OS. These findings support the need to test all pts with PDAC, and just as importantly, to maximize access to molecularly-matched tx for appropriate pts, to achieve the best pt outcomes. [Table: see text]
Association of BAFFR expression in CAFs with overall survival and response to platinum-based chemotherapy in NSCLC.
Authors: Fotinos-Ioannis D. Dimtrakopoulos, Anastasia E Kottorou, Anna G Antonacopoulou, Achilleas Nikolakopoulos, Nikolaos Panagopoulos, Melpomeni Kalofonou, Dimitrios Dougenis, Angelos Koutras, Thomas Makatsoris, Vasiliki Tzelepi, Haralabos Kalofonos
Journal: Journal of Clinical Oncology (2019)

8537 Background: Β-cell activating factor receptor (BAFFR) is a surface receptor, which leads to activation of the Nuclear Factor-kappaB (NF-κB) alternative pathway, a pathway with an important role in non-small cell lung cancer (NSCLC). In addition, cancer associated fibroblasts (CAFs) are major players of the tumor microenvironment promoting NSCLC. The aim of this study was to assess the possible associations of BAFFR expression in CAFs with response to first-line chemotherapy doublet and clinical outcome of NSCLC patients. Methods: Immunohistochemical analysis of BAFFR expression on CAFs was performed on tumor and tumor-adjacent formalin fixed and paraffin embedded tissue samples from 124 operated patients with NSCLC. Patients were under follow-up for at least 60 months, while response to chemotherapy was evaluated in patients who relapsed during this period. Results: BAFFR expression, which was noted exclusively in the cytoplasm of CAFs, was associated with OS only in patients with no infiltration of regional lymph nodes. Higher expression levels of BAFFR in CAFs were related to worse 2-, 3- and 5-year survival (P = 0.015, P = 0.027 and P = 0.040, respectively). This finding persisted after multivariate analysis with age, gender, histological subtype, histological differentiation and disease stage as coefficients (P = 0.009; HR, 2.734; 95% CI, 1.283-5.828). In addition, response to first line chemotherapy was associated with BAFFR expression in CAFs (P = 0.025). Patients who progressed had lower BAFFR levels. Furthermore, BAFFR expression in CAFs was associated with patients’ age. In particular, older patients had higher expression of BAFFR compared to patients younger than 55 years (P = 0.010). Additionally, carcinomas with better differentiation had lower expression of BAFFR in CAFs (P = 0.005). Finally, BAFFR expression in CAFs was related to development of metastatic disease (P = 0.033) and particularly in liver (P = 0,017) and in bones (P = 0.003). Conclusions: The present findings suggest that the expression of BAFFR in CAFs may be a useful biomarker with prognostic and predictive value, representing possibly an unknown biological relation, which merits further investigation.
Correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC: A retrospective analysis.
Authors: Yao Yu, Rongbo Lin, Ning He, Yadong Yang, Ge Jin, Jianfei Wang
Journal: Journal of Clinical Oncology (2019)

e20019 Background: To investigate the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in tumor tissue of patients with NSCLC. Methods: 79 patients with confirmed NSCLC admitted from January 2018 to January 2019 were included. Tumor DNA was isolated from FFPE samples or fresh tissue samples. Mutation profiles were obtained by targeted deep sequencing of 620 selected genes. Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per 1Mbp and divided into tertiles. PD-L1 expression, CD8 + T cell and tumor infiltrating lymphocyte density were evaluated by immunohistochemical analysis. The correlation coefficient of TMB, tumor microenvironment and alterations of driver genes was calculated by chi-square test. Results: Median TMB of these patients is 6.915 Muts/Mbp (4.22-9.44 Muts/Mbp). Prevalence of PD-L1 expression is 28.0% (n = 7/25) at a tumor proportion score cutoff of at least 5% evaluated by Dako 28-8 PharmDx Assay kit and prevalence of CD8+ T cell density is 95.8% (n = 23/24). TP53 mutations are the most common alteration (n = 49/79, 62.0%), followed by EGFR alterations (n = 31/79, 39.2%), CDKN2A alterations (n = 11/79, 13.9%), KRAS mutations (n = 10/79, 12.7%), STK11 mutations (n = 5/79, 6.3%), ALK fusions (n = 4/79, 5.1%) and POLE mutations (n = 4/79, 5.1%). According to results of chi-square test, squamous cell carcinoma has higher TMB (p= 0.023) than adenocarcinoma. Metastatic NSCLC has higher PD-L1 expression (p= 0.049) than non-metastatic NSCLC. Furthermore, EGFR alterations are associated with lower TMB (p=0.020) and POLE mutations are associated with higher TMB (p= 0.015). There are no correlations among CD8 + T cell density, tumor infiltrating lymphocyte density and other variants. Conclusions: Our study highlights the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC. This result may be the reference of anti-PD-1 therapy.
Rebiopsy in patients with or without prior TKIs revealed complicated histology of lung cancer.
Authors: Kuikui Zhu, Qianwen Li, Sheng Zhang, Gang Wu, Qun Xiang, Zhili Fang, Rui Meng
Journal: Journal of Clinical Oncology (2019)

e20525 Background: The important of rebiopsy is well known in lung adenocarcinomas (ADs) after acquiring resistant to TKIs, for they may transform to SCLC. But histology transformation in non-ADs or ADs without TKIs seems infrequent. Methods: We performed a retrospective collection of cases with changed histology after rebiopsy in patients presenting from January 2015 to April 2018 in a single center. Results: Among 188 patients who conducted rebiopsy, there were 20 cases presenting changed histologic type, which can be divided into two groups based on if TKIs were used before histology change. Group1 (TKIs used, N = 14) including ADs changing to SCLC (N = 9), squamous cell carcinoma (SQ) (N = 2), carcinosarcoma combined with few AD component (N = 1), SCLC combined AD (N = 1), and adenosquamous carcinoma changing to SCLC (N = 1). Four cases in group 1 went through surgery, and one of them who never smoke was diagnosed as AD (pT2N0M1a, EGFR exon 19del), with no small cell carcinoma (SCC) component found, but rebiopsy of metastasis revealed SCC without any AD component after 3 months of gefitinib. The disease continued to progress during the following chemotherapy (CT), and biopsies with other two metastases also presented SCC without AD component. Group 2 were 6 cases without TKIs before the rebiopsy (Table). Case 2, 4, 6 were all heavy smokers. Rebiopsy of case 2 was ALK+, so the patient took 4 months crizotinib and then 2 months alectinib, the disease was still stable on January 6, 2019. Case 5 was a classic extensive-stage SCLC with fast response to EP therapy, but fast relapse and resistance to the following CT, and the primary lesion at right upper lobe showed AD-like imaging, so rebiopsy was performed and carcinoma favor AD was found. EGFR exon 19del was detected in the plasma, and the lesion gain PR after one month of icotinib. The third biopsy of the progress lesion came back to SCC after resistance to TKI. Conclusions: Rebiopsy of lung cancers with or without TKIs therapy revealed diversity histology changes. This reminded us the important of rebiopsy, not only for TKIs resistant lung ADs. [Table: see text]
Cell-free methylated DNA (cfMeDNA) immunoprecipitation and high throughput sequencing technology (cfMeDIP-seq) in patients with clear cell renal cell carcinoma (ccRCC).
Authors: Pier Nuzzo, Sandor Spisak, Ankur Chakravarthy, Shu Yi Shen, Jacob E Berchuck, Amin Nassar, Sarah Abou Alaiwi, John A. Steinharter, Ziad Bakouny, Francesco Boccardo, Guru Sonpavde, Gwo-Shu Mary Lee, Steven Lee Chang, Mark Pomerantz, Daniel De Carvalho, Matthew Freedman, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2019)

3052 Background: CfmeDNA is a promising biomarker for non-invasive assessment of solid tumors: i) MeDNA is tissue- and tumor-specific ii) cfDNA methylation changes are stable unlike DNA alterations iii) ‘methylation target size’ is larger than identifying specific genomic alterations and, therefore, more sensitive. CfMeDIP-seq is a sensitive assay for genome-wide bisulfite-free cfMeDNA profiling, that requires 1-10 ng input DNA. We tested the feasibility of cfMeDIP-seq to detect ccRCC across TNM stages. Methods: We evaluated plasma cfDNA collected prior to nephrectomy in 46 pts with ccRCC: 25 stage I, 7 stage II, 6 stage III, 8 stage IV. cfMeDIP-seq involves four steps: 1) cfDNA end-repair, A-tailing, and adapter ligation 2) cfMeDNA immunoprecipitation and enrichment using an Ab targeting 5-methylcytosine (quality control by qPCR to ensure &lt;1% of unMeDNA and &gt;99% reaction specificity) 3) adapter-mediated PCR to amplify cfMeDNA 4) high-throughput NGS for cfMeDNA data. A previously-derived model (Shen et al, Nature, 2018) was used to classify pts as having ccRCC or not based on cfMeDNA. cfMeDIP-seq paired end data was reduced to 300 bp windows of the genome that map to CpG islands, shores, shelves, and FANTOM5 enhancers; a classifier was then built using the top 1,000 most variable fragments between pts with ccRCC and cancer-free controls. Statistical comparisons were performed in the R statistical environment, with the caret package being used for classifier construction and evaluation. Results: The average amount of cfDNA isolated from 1 ml of ccRCC plasma was 19.8±39.8 ng/µL [1.95-260]. Greater than 99% specificity of reaction and &lt;1% of unMeDNA was achieved in 46/46 samples (100%). The previously-derived classifier of ccRCC correctly predicted 46/46 pts (100%) as having ccRCC. Across 3 rounds of 5-fold cross-validation, the classifier performed with a Cohen’s Kappa of 0.93. Conclusions: CfMeDIP-seq is a non-invasive, cost-effective, and sensitive assay to detect cancer-specific cfmeDNA in ccRCC pts prior to nephrectomy. With further validation, cfmeDNA may detect minimal residual disease after nephrectomy for ‘precision’ adjuvant therapy.
A phase IIb study of ramucirumab in combination with TAS102 versus TAS102 monotherapy in metastatic, chemotherapy refractory colorectal cancer patients: The RAMTAS trial of the German AIO (KRK-0316).
Authors: Stefan Kasper, Gerrit zur Hausen, Alexander Stein, Sebastian Stintzing, Andreas Berger, Sonja Loges, Ralf Hofheinz, Tanja Trarbach, Ullrich Graeven, Ludwig Fischer von Weikersthal, Thorsten Oliver Goetze, Volker A. Hagen, Susen Burock, Albrecht Hoffmeister, Tobias Nicolaas Dechow, Claudia Pauligk, Isabel Virchow, Jens T Siveke, Salah-Eddin Al-Batran, Martin H. Schuler
Journal: Journal of Clinical Oncology (2019)

TPS3617 Background: Patients with metastatic colorectal cancer (mCRC) with progressive disease on/after or who are intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-angiogenic and anti-EGFR therapies have limited therapeutic options and a dismal prognosis, with a median survival below 6 months. Recently, Trifluridin/Tipiracil (TAS102) significantly improved survival in patients with refractory mCRC and ramucirumab has been approved in combination with FOLFIRI for the treatment of patients with mCRC after prior FOLFOX/bevacizumab first line therapy. Previous studies on both components provide a strong rationale to conduct a randomized study evaluating the efficacy and safety of ramucirumab in combination with TAS102 in patients with refractory mCRC to improve efficacy and prevent resistance. Methods: This is an interventional, randomized, open label, multicenter, phase IIb study in patients with advanced mCRC. Eligible patients will be randomized 1:1 and receive either ramucirumab and TAS102 (ramucirumab 8 mg/kg on d1+15, q4w and TAS102 35 mg/m² on d1-5 and d8-12, q4w) or TAS102 alone. Primary endpoint is overall survival as assessed by the Kaplan-Meier method, assuming a 6 months survival probability of 70% with ramucirumab in combination with TAS102 and 58% with TAS102 alone. Treatment groups are compared using the log-rank test. A total of 144 patients will be enrolled at 30 sites (1-sided alpha 0.10, power 0.80). Main secondary endpoints are overall response rate, disease control rate, progression free survival and quality of life. In addition, a large comprehensive translational research program will be conducted to identify novel predictive and prognostic biomarkers. The study started in December 2018. By February 2019, a total of 3 patients have been enrolled. Clinical trial information: NCT03520946.
Is cancer associated thrombosis (CAT) an underestimated issue in oncology clinical practice? Real-world data regarding long term management of CAT.
Authors: Nikolaos Tsoukalas, Alexandros Bokas, Evangelos Bournakis, Athina Christopoulou, Christos Papandreou, Athina Isaakidou, Georgios Koumakis, Georgios Fotios Samelis, Anna Ntokou, Charalampos Andreadis, Haralabos Kalofonos, Gerasimos Aravantinos, Maria Sougleri, Epaminondas Samantas, Paris Makrantonakis, Davide Mauri, Athanasios Athanasiadis, Nikolaos Ziras, Ioannis I. Varthalitis, Ioannis Boukovinas
Journal: Journal of Clinical Oncology (2019)

e23150 Background: Cancer is associated with thrombosis due to different pathophysiological processes. CAT is the 2 nd cause of death in oncology patients and can occur anytime during the natural history of cancer. CAT is not rare complication, can delay anti-cancer therapy and increase health systems costs. Methods: A prospective observational study (Greek Management of Thrombosis-GMaT) conducted by HeSMO in Greek Oncology units for two years aiming to record clinical practice of CAT management. Patients with active cancer who received CAT treatment or thromboprophylaxis were enrolled after signing informed consent. Results: 546 patients were enrolled from 18 oncology units. Primary cancers were: lung 23.9%, pancreas 13.3%, breast 7.6%, colorectal 8.9%, stomach 8.3%, ovarian 7.6% and other 30.5%. 120 patients received LMWH for Venus Thombo-Embolism (VTE) treatment (Group A) and 426 for thromboprophylaxis (Group B). Group A: 89/120 (74.17%) patients continued in 2 nd year and 58.6% received CAT treatment (6.9±4.4 months). Only 2 had VTE recurrence in 2 nd year (versus 3 in 1 st year). 4/120 (3.33%) had bleeding events (grade 1) in 1 st year while no bleeding events occurred in 2 nd year. Group B: 345/426 (80.98%) patients continued in 2 nd year. 126 (30%) had Khorana score ≥3 and 300 (70%) had Khorana score ≤2. In 2 nd year, 123 (35.65%) received thromboprophylaxis (7.3±3.7 months) while 79.4% of them were initially treated with High Thrombotic Treatment Agents (HTTA: e.g. platinum, 5-FU) and 83.1% had metastatic disease. In 2 nd year, 52.5% received LMWHs at prophylactic dose and 47.5% at therapeutic dose. Overall, 12 (2.82%) had thrombotic events whereas 4 were recorded in 2 nd year. Notably, patients treated with therapeutic doses had lower probability to have a thrombotic event (OR: 5.8, 95% CI: 1.7 to 20.5, p &lt; .05). Six (1.41%) bleeding events (grade 1) occurred in 1 st year and one (0.81%) in 2 nd year. Conclusions: LMWHs can be used for long term CAT management. Therapeutic LMWHs doses as thromboprophylaxis are safe and effective. Khorana score is a useful model for CAT risk assessment but some other factors such as disease stage and HTTA might be taken into account. CAT can occur anytime during the natural history of cancer. Oncologists should be aware about CAT and its negative influences in patients’ prognosis and quality of life.