tbuckley/cabot-search huggingface dataset:
Immunotherapy discontinuation and outcome: A multicenter real-life experience.
Authors: Maria Bassanelli, Diana Giannarelli, Maria RITA Migliorino, Marco Russano, Alain Gelibter, Fabiana Letizia Cecere, Viola Barucca, Silvana Giacinti, Emilio Bria, Enzo Ruggeri, Fabio Calabro, Daniele Santini, Annamaria Rauco, Anna Ceribelli
Journal: Journal of Clinical Oncology (2019)

e14075 Background: Unlike chemotherapy, the optimum treatment duration with Immune checkpoint inhibitors (ICIs) is not clearly established. The aim of this study was to assess the outcome of patients (pts) who discontinued immune-based therapies for any reason except progressive disease. Methods: We conducted an observational, retrospective analysis of 46 consecutive pts with advanced cancer who received ICIs as clinically indicated, at eight Italian institutions. Tumor response to treatment was defined according to RECIST. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan -Meier method. Results: 46 pts (median age 68 years [range 41-86]; male: 65.2%) with advanced cancer (n.39 non-small-cell lung cancer, n.15 renal cell carcinoma and n.2 melanoma) were treated with ICIs: 44 pts received programmed death 1 (PD-1) inhibitors (n.31 nivolumab, n.13 pembrolizumab) and 2 pts programmed death ligand 1 (PD-L1) (n.1 durvalumab, n.1 atezolizumab). A median of 8 cycles were administered [range 1 to 52]. 36 pts discontinued ICIs due to toxicities (diarrhoea, pneumonitis, hepatotoxicity) and 10 pts for reasons non immune-related. The median progression free survival (PFS) from the beginning of ICIs was 12.4 months (mo) [95% CI: 8.2-16.6] and the median OS was 20.0 mo (95% CI: 11.8-28.2). Median PFS from discontinuation of therapy was 5.0 mo [95% CI: 2.7-7.3] and median OS was 16.1 mo (95% CI: 5.4-26.8). Best response achieved according RECIST criteria were: 1 complete response (CR), 18 partial response, 21 stable disease (SD), 2 progressive disease (PR) and 3 non evaluable (NE). During interruption of ICIs 1 pts achieved a PR. Conclusions: This study shows the activity of ICIs, in terms of outcome and durable immune-response, in pts with advanced cancer even after treatment discontinuation.
Voxel Forecast for Precision Oncology: Predicting Spatially Variant and Multiscale Cancer Therapy Response on Longitudinal Quantitative Molecular Imaging
Authors: Stephen R. Bowen, Daniel S. Hippe, W. Art Chaovalitwongse, Chunyan Duan, Phawis Thammasorn, Xiao Liu, Robert S. Miyaoka, Hubert J. Vesselle, Paul E. Kinahan, Ramesh Rengan, Jing Zeng
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Prediction of spatially variant response to cancer therapies can inform risk-adaptive management within precision oncology. We developed the “Voxel Forecast” multiscale regression framework for predicting spatially variant tumor response to chemoradiotherapy on fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. Experimental Design: Twenty-five patients with locally advanced non–small cell lung cancer, enrolled on the FLARE-RT phase II trial (NCT02773238), underwent FDG PET/CT imaging prior to (PETpre) and during week 3 (PETmid) of concurrent chemoradiotherapy. Voxel Forecast was designed to predict tumor voxel standardized uptake value (SUV) on PETmid from baseline patient-level and voxel-level covariates using a custom generalized least squares (GLS) algorithm. Matérn covariance matrices were fit to patient- specific empirical variograms of distance-dependent intervoxel correlation. Regression coefficients from variogram-based weights and corresponding standard errors were estimated using the jackknife technique. The framework was validated using statistical simulations of known spatially variant tumor response. Mean absolute prediction errors (MAEs) of Voxel Forecast models were calculated under leave-one-patient-out cross-validation. Results: Patient-level forecasts resulted in tumor voxel SUV MAE on PETmid of 1.5 g/mL while combined patient- and voxel-level forecasts achieved lower MAE of 1.0 g/mL (P &amp;lt; 0.0001). PETpre voxel SUV was the most important predictor of PETmid voxel SUV. Patients with a greater percentage of under-responding tumor voxels were classified as PETmid nonresponders (P = 0.030) with worse overall survival prognosis (P &amp;lt; 0.001). Conclusions: Voxel Forecast multiscale regression provides a statistical framework to predict voxel-wise response patterns during therapy. Voxel Forecast can be extended to predict spatially variant response on multimodal quantitative imaging and may eventually guide optimized spatial–temporal dose distributions for precision cancer therapy.
A phase II study of enzalutamide (Enz) with dutasteride (Dut) or finasteride (Fin) in men ≥ 65 years with hormone-naive systemic prostate cancer (HNSPCa): Tolerability and geriatric asssessment (GA) results.
Authors: Jason Zittel, Chunkit Fung, Dilip Sankar Babu, Elizabeth A. Guancial, Deepak M. Sahasrabudhe, Kathryn A. Bylow, John D. Burfeind, Kaylinn Musto, Bokai Wang, Amita Patil, Edward M. Messing, Supriya Gupta Mohile, Deepak Kilari
Journal: Journal of Clinical Oncology (2019)

e16518 Background: Older men are at a high risk for adverse events (AEs) from androgen deprivation therapy (ADT). In this phase II study, we evaluated Enz and Dut/Fin in lieu of ADT for at-risk older patients with HNSPCa. Methods: Eligible patients were ≥65 years (y); at high risk of AEs from ADT by GA or treating physicians; metastatic (M1) or non-metastatic (M0) HNSPCa with a PSA doubling time ≤ 9 months and testosterone &gt; 50ng/dl. They received Enz 160 mg/day and Dut 0.5 mg/day or Fin 5 mg/day until disease progression. GA was performed at baseline and week (wk) 61 and/or at the time of progression. GA included validated tests: Instrumental Activities of Daily Living (IADL), fall history, Short Physical Performance Battery (SPPB), Geriatric Depression Scale (GDS), and Montreal Cognitive Assessment (MOCA). The prevalence of impairment for each assessment was calculated; change in prevalence from baseline to wk 61 was analyzed using paired sample t-test. Results: 43 patients were enrolled in the study. Median age at enrollment was 78 y (range 66-94) and 93% were ECOG 0-1; 37% (n = 16) had M0 and 63% (n = 27) had M1 HNSPCa, with the majority (67%) having Gleason 6 or 7 disease. At baseline, 18.6% met the cutoff for impairment for IADLs, 53.7% for SPPB, 7.9% for GDS and 64.3% for MOCA; 9.8% had a recent fall. Median baseline PSA was 11.38 ng/ml (range: 2-145). At the time of analysis, 29 men (67.4%) remain on study treatment. 95.3%, 74.4% and 46.5% of patients reported at least one Grade 1, 2 or 3 AE respectively. No patient had a Grade 4 AE and one Grade 5 AE was reported but was an unrelated event. The most common Grade 3 AEs were hypertension (27.8%), GI (19.4%), and cardiac (8.3%); all Grade 3 GI AEs reported were deemed unrelated to the study drugs. Only impairment in ≥ 1 IADL showed a statistically significant increase in prevalence at wk 61 of treatment (40.6%) compared to baseline (18.6%, p = 0.036). Conclusions: For older men with HNSPCa, Enz with Dut/Fin demonstrated efficacy with reasonable toxicity profile, and no significant impact on the majority of GA domains. Clinical trial information: NCT02213107.
Preoperative chemosensitivity testing as predictor of treatment benefit in adjuvant stage III colon cancer: Preliminary analysis of the PePiTA study.
Authors: Alain Hendlisz, Rafael Caparica, Amélie Deleporte, Jean-Luc Van Laethem, Philippe Vergauwe, Marc Van Den Eynde, Guido Deboever, Jozef Janssens, Gauthier Demolin, Stephane Holbrechts, Marylene Clausse, Thierry De Grez, Joanna Vermeij, Lionel A. D'Hondt, Karen Paula Geboes, Tatiana Besse-Hammer, Alexis Buggenhout, Marianne Paesmans, Martine Piccart, Patrick Flamen
Journal: Journal of Clinical Oncology (2019)

3610 Background: Although being the standard-of-care for stage III colon cancer, no biomarkers can identify patients (pts) who benefit from adjuvant chemotherapy. In metastatic pts, the lack of metabolic response (mR) in FDG-PET/CT after 1 chemotherapy cycle predicts the absence of treatment benefit. The PePiTA study aims to evaluate if the absence of mR after 1 cycle of pre-operative chemotherapy is predictive of recurrence in non-metastatic colon cancer pts. Herein, we report a preliminary analysis on surgical outcomes, adverse events and mR assessment after 1 cycle of pre-operative chemotherapy after completing the study accrual objective. Methods: Colon cancer pts eligible for curative resection and ECOG ≤1 received 1 cycle of mFOLFOX followed by surgery in this prospective, multicentre, non-randomized trial. FDG-PET/CT was performed at baseline and after 1 cycle of mFOLFOX. Adjuvant mFOLFOX was administered for up to 12 cycles for stage III pts, whereas for stage II pts the decision to pursue adjuvant chemotherapy was at investigator’s discretion. A decrease ≥15% in SUVmax after 1 cycle of chemotherapy was defined as mR (EORTC criteria) at central review. Results: mR was assessable on the primary tumor in 204/240 pts (85%). In 11 pts (4.6%), staging was modified by the baseline FDG-PET/CT, which detected metastatic disease or other tumors. Pre-operative mFOLFOX was administered to 218 pts, of which 14 (6%) had a grade ≥3 adverse event. Surgery was performed in 218 pts, with a median delay of 20 days (6 to 59) after chemotherapy. Surgical complications occurred in 28 (13%) pts, however no deaths occurred. The median SUVmax decrease between baseline and 2 nd FDG-PET/CT was 24%. A mR was observed in 65.2% of the pts, whereas 34.8% showed no mR, including 3% who had progressive disease. Conclusions: One cycle of pre-operative mFOLFOX followed by a mR assessment has shown to be a feasible and safe strategy, raising interest on the potential of neoadjuvant chemotherapy in colon cancer. The early mR assessment identified pts that may not benefit from chemotherapy and might have a worse prognosis. The substantiation of this hypothesis is expected with the study’s long-term results. Clinical trial information: NCT00994864.
T cell repertoire analysis of non-small cell lung cancer patients treated with neoadjuvant nivolumab alone or in combination with ipilimumab (NEOSTAR trial).
Authors: Alexandre Reuben, Jianjun Zhang, Heather Y. Lin, Latasha Little, Curtis Gumbs, Hai T. Tran, Linghua Wang, Cara L. Haymaker, Reza J. Mehran, David C. Rice, Garrett L. Walsh, J. Jack Lee, Ignacio Ivan Wistuba, Stephen Swisher, Ara A. Vaporciyan, Andrew Futreal, Boris Sepesi, John Heymach, Don Lynn Gibbons, Tina Cascone
Journal: Journal of Clinical Oncology (2019)

8532 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) are being explored in resectable non-small cell lung cancer (NSCLC). Here, we studied the composition and changes in the T cell repertoire in a cohort of NSCLC patients (n = 44) treated with neoadjuvant nivolumab (N) alone or in combination with ipilimumab (NI) followed by surgery (NEOSTAR trial). Methods: Sequencing of the variable CDR3β chain of the T cell receptor (TCR) involved in antigen binding was performed in pre-treatment and surgical tumors, matched adjacent uninvolved lung specimens, as well as paired longitudinal blood at baseline, prior to each dose of therapy, prior to surgery, and within 8 weeks post-surgery. T cell repertoire density, diversity, and clonality (reactivity) were evaluated in addition to tumor PD-L1 expression pre- and post-neoadjuvant treatment. Results: Median T cell diversity in the blood post-therapy was 3.3-fold higher in NI- compared to N-treated patients (40,993 [NI, n = 3] vs 12,177 [N, n = 4] unique TCR rearrangements, n.s.). However, median T cell clonality in the blood was 3.5-fold higher in N- than NI-treated patients post-therapy (0.093 [N, n = 4] vs 0.026 [NI, n = 3], n.s.). Median clonality was 3.8-fold higher in the tumor post-therapy in patients receiving NI than in those receiving N (0.076 [NI, n = 7] vs 0.020 [N, n = 5], n.s.). Interestingly, diversity in the blood at baseline and in the tumor post-therapy were positively correlated ([n = 7], r = 0.82; p = 0.023), which may reflect an influx of cells from the periphery following ICIs. Importantly, higher baseline T cell clonality in the blood was associated with a lower % of viable tumor at time of surgery in both treatment arms ([n = 7], r = -0.77; p = 0.04). Conclusions: Our study is the first to assess the TCR repertoire in NSCLC patients treated with combination neoadjuvant NI and highlights potential mechanistic differences compared to N alone. Neoadjuvant NI is associated with higher clonality in tumors and lower clonality in blood post-therapy, suggesting increased T cell trafficking into the tumor. Finally, lower pre-treatment clonality in the periphery was correlated with higher % viable tumor post-neoadjuvant ICIs. Clinical trial information: NCT03158129.
Analysis of AKR1B10 levels among various groups of breast cancer patients.
Authors: Krishna A. Rao, Kathy Robinson, Kristin Delfino, Vivekanand Tiwari, Yun Zhu, Xin Wang, Andrew McClintock, Simon Bekker, Joshua Westbrook, Deliang Cao, Zhe Cao
Journal: Journal of Clinical Oncology (2019)

e14548 Background: Aldo-keto reductase 1B10 (AKR1B10) is a protein that is primarily expressed in human colon and small intestine, but induced in hepatocellular carcinoma and non-small cell lung cancer. Our recent studies have revealed that AKR1B10 is overexpressed in primary, metastatic, and recurrent cancers of the breast. Methods: We recruited four cohorts of patients: Patients with breast cancer undergoing primary surgery from whom we procured breast cancer and matched normal adjacent tissue to evaluate AKR1B10 expression in primary tumors. The matched serum samples were collected before surgery and at various time points after the surgery (approximately 3 days, 7 days, and 1 month Patients with recurrent or advanced (metastatic) breast cancer. Serum samples were collected and serially monitored for up to 2years before and during metastatic therapy and correlated with RECIST measurements. Patients with locally advanced disease undergoing neoadjuvant chemotherapy. AKR1B10 serum levels were monitored during therapy and correlated with RECIST measurements. Healthy individuals with normal mammograms were recruited and submitted serum samples for AKR1B10 serum measurements. Results: AKR1B10 rapidly cleared the serum of early stage breast cancer patients with an estimated half-life of 24-30 hours. Serum AKR1B10 levels correlated strongly with tissue IHC staining and PR positivity but not with RECIST levels or Oncotype Dx scores. Neoadjuvant chemotherapy did not affect serum AKR1B10 levels. Individuals with normal mammograms displayed substantially lower levels of AKR1B10 than breast cancer patients. Patients with DCIS also displayed elevated serum AKR1B10 levels. Conclusions: AKR10 may serve as tumor marker to independently identify high risk patients whose tumors have intermediated risk Oncotype Dx scores and may also identify early breast cancers in patients with equivocal breast biopsies.
Race as an independent factor for survival in breast cancer patients according to analysis of the National Cancer Database (NCDB).
Authors: Drew Carl Drennan Murray, Shruti Bhandari, Phuong Ngo, Sarah Mudra, Rachana Shirish Lele, Sudhir Srivastava, Xiaoyong Wu, Shesh Rai, Mounika Mandadi, Elizabeth Carloss Riley
Journal: Journal of Clinical Oncology (2019)

e18155 Background: Black (B) women after early stage of diagnosis have been shown to have double the risk of white (W) women for failing to receive adjuvant chemotherapy. Despite lower incidence of breast cancer in B patients, they are more likely to die of the disease. Worse outcomes in B populations have been related to clinical and socioeconomic factors. However, the determination of improved access and its effects on survival in black patients remains uncertain. Methods: 1042844 patients diagnosed between 2004 and 2014 with stage I-III breast cancer were identified in the NCDB. Only W and B races were analyzed with established risk factors of age, stage, comorbidity score, and insurance status. Data was analyzed using univariable and multivariable logistic and Cox proportional hazards regression models. Odds Ratio (OR) for binary outcome, Hazard Ratio (HR) for time-to-event (survival) outcome along with 95% confidence interval (95% CI) are reported. Results: Among the total population 85.5% were W, 10.6% B, and 3.9% other. B were more likely to be uninsured (OR: 1.66; 95% CI: 1.59 - 1.72; p &lt; 0.0001), or have Medicaid (OR: 2.01; 95% CI: 1.96 - 2.07; p &lt; 0.0001). B were also diagnosed at later stage (stage 3 OR: 1.59; 95% CI: 1.57 - 1.63; p &lt; 0.0001) with higher co-morbidities (OR: 2.49; 95% CI: 2.34 - 2.67; p &lt; 0.0001) consistent with prior studies. B were more likely to experience delayed treatment (OR: 2.15; 95% CI: 2.10 - 2.20; p &lt; 0.0001). B race remained an independent factor associated with higher likelihood of death compared to W patients (HR: 1.32; 95% CI: 1.3 - 1.34; p &lt; 0.0001) in multivariable analysis. Conclusions: This large database study demonstrates that even when controlling for established risk factors such lack of insurance or Medicaid, higher comorbidities, and later stage at diagnosis, B patients were more likely to experience delays in treatment initiation and worse overall survival. This suggests race remains an independent risk factor for poor outcome even when clinical factors are matched. Further analysis including tumor biology should be examined to better understand this persistent disparity.
Genomic profiling for unfavorable carcinoma of unknown primary patients.
Authors: Hsueh-Ju Lu, Hsuan Liu, Jen-Fan Hang, Yee Chao, Ming-Huang Chen, Chun-Yu Liu, Chi-Ying F. Huang, Mu-Hsin Chang
Journal: Journal of Clinical Oncology (2019)

e13140 Background: Cancer of unknown primary site (CUP) is the seventh prevalent cancer around the world. Whether most CUP patients share a distinct molecular genome-phenotype is unclear. Methods: A total of 179 unfavorable CUP patients were retrospectively enrolled from Taipei Veterans General Hospital between Jan 2000 and Dec 2009. 33 qualified FFPE samples were sequenced by 275 target gene panel (QIAseq Human Comprehensive Cancer Panel [DHS-3501Z], QIAGEN). Identified significant variants were enriched by using DAVID software (https://david.ncifcrf.gov/). Results: Among 33 patients’ samples, total 6816 variants, including SNP and INDEL from both germline SNPs and somatic mutations were enrolled. After clustering, 112 variants which accounted for 1.64% were selected. Somatic and germline variants were 63.4% (71/112) and 36.6% (41/112), respectively. Profiles between these two groups were different after enrichment that pathway in cancer (fold enrichment [FE] = 6.64, P = 7.03E-09) is most important for somatic mutation and lysine degradation (FE = 25.6, P = 3.78E-04) for germline SNPs (Table). Conclusions: This genomic profile provides new insight into unfavorable CUP patients. Further studies between genotypes vs. phenotypes and drug targets vs. genotypes are warranted.[Table: see text]
HER2 testing: Insights from pathologists’ perspective on challenging HER2 cases.
Authors: Erin V Grimm, Karen K Swenson, Janet Krueger, David G. Hicks, Kimberly H. Allison, Hadi Yaziji, Mara Hester Rendi, Barbara Susnik, Erinn Downs-Kelly, Michaela L. Tsai, Tamera J Lillemoe
Journal: Journal of Clinical Oncology (2019)

e12512 Background: HER2 status dictates treatment decisions in breast cancer making the precision and accuracy of laboratory testing essential. While most HER2 testing is straightforward using ASCO-CAP interpretation guidelines, 5% of cases fall into the less common categories (groups 2-4) and can present unusual diagnostic dilemmas. 6 high volume HER2 FISH laboratories evaluated 10 challenging HER2 cases. The results highlight the challenges and potential for variability in interpreting rare cases with unusual results. Methods: Ten diagnostically challenging HER2 FISH cases were selected from our breast cancer archives (41 months/3863 cases). Unstained slides were evaluated by 6 high volume laboratories. Laboratories performed HER2 FISH testing (along with HER2 IHC as needed) and rendered an interpretation. Participants discussed results during a conference call. Cases included the following situations: low-level amplification (ratio ≥ 2.0, mean HER2 signals/cell between 4.0-5.9), HER2 mean copy number or ratio near a clinically actionable threshold, complex heterogeneity or clones, and a technical challenge (signal clustering). Results: All laboratories elected to perform HER2 IHC in conjunction with FISH in all cases. Only 3/10 cases resulted in 100% agreement between the 6 institutions, all of which were in the category addressing complex heterogeneity. During the study, we identified a problematic subset (low amplified FISH cases) which may have discordant (negative) IHC results. Another problematic scenario is the finding of a small, highly amplified HER2 clone. Lastly, we identified cases with high cell to cell variability, and we saw discordant values resulting in disparate overall HER2 interpretations. Conclusions: Oncologists and pathologists should be aware of these challenges and the potential for variability in interpretation of these rare case scenarios. Evaluation for concordance between IHC and FISH results, correlation with other clinico-pathologic features and additional steps to ensure the accuracy of test results can help resolve unusual results, but grey zones may still remain and should be discussed when making clinical decisions based on HER2 test results.
m6A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1
Authors: Yingmin Wu, Xiangling Yang, Zhuojia Chen, Lin Tian, Guanmin Jiang, Feng Chen, Jiexin Li, Panpan An, Linlin Lu, Nan Luo, Jun Du, Hong Shan, Huanliang Liu, Hongsheng Wang
Journal: Molecular Cancer (2019)

Long noncoding RNAs (lncRNAs) have emerged as critical players in cancer progression, but their functions in colorectal cancer (CRC) metastasis have not been systematically clarified.lncRNA expression profiles in matched normal and CRC tissue were checked using microarray analysis. The biological roles of a novel lncRNA, namely RP11-138 J23.1 (RP11), in development of CRC were checked both in vitro and in vivo. Its association with clinical progression of CRC was further analyzed.RP11 was highly expressed in CRC tissues, and its expression increased with CRC stage in patients. RP11 positively regulated the migration, invasion and epithelial mesenchymal transition (EMT) of CRC cells in vitro and enhanced liver metastasis in vivo. Post-translational upregulation of Zeb1, an EMT-related transcription factor, was essential for RP11-induced cell dissemination. Mechanistically, the RP11/hnRNPA2B1/mRNA complex accelerated the mRNA degradation of two E3 ligases, Siah1 and Fbxo45, and subsequently prevented the proteasomal degradation of Zeb1. m6A methylation was involved in the upregulation of RP11 by increasing its nuclear accumulation. Clinical analysis showed that m6A can regulate the expression of RP11, further, RP11 regulated Siah1-Fbxo45/Zeb1 was involved in the development of CRC.m6A-induced lncRNA RP11 can trigger the dissemination of CRC cells via post-translational upregulation of Zeb1. Considering the high and specific levels of RP11 in CRC tissues, our present study paves the way for further investigations of RP11 as a predictive biomarker or therapeutic target for CRC.