tbuckley/cabot-search huggingface dataset:
Correlation between mutation landscape and clinical outcomes of neoadjuvant therapy in HER2-positive breast cancer patients.
Authors: Ning Liao, Yulei Wang, Kai Li, Bo Chen, Guo-Chun Zhang, XueRui Li, Liping Guo, Li Cao, Chong-Yang Ren, Ling-Zhu Wen, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Xiaoqing Chen, Guangnan Wei, Jiali Lin, Ting Hou, Han Han-Zhang, Zhou Zhang, Jing Liu
Journal: Journal of Clinical Oncology (2019)

579 Background: The standard management of early stage human epidermal growth factor receptor 2 (HER2) positive (+) breast cancer (BC) involves neoadjuvant therapy with combination of chemotherapy and HER2-targeted therapy followed by surgery. However, diverse pathologic responses were observed. We interrogated whether baseline genomic heterogeneity contributes to the varied therapeutic responses. Methods: Capture-based targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6MB of human genome, was performed on tissue biopsy samples, obtained prior to neoadjuvant therapy, of 33 HER2+ women with stage I-III BC. The median age of the cohort was 53. The correlation between genomic alterations and pathologic response were analyzed by multivariate analysis. Results: A majority of them was diagnosed with stage II (67%, 22/33), while 30% (10/33) had stage III and 3% (1/33) had stage I disease. 58% (19/33) were HR+ and 42% (14/33) were HR-. Mutation profiling of baseline samples revealed 349 mutations spanning 145 genes, with TP53, CDK12 and PIK3CA being the top 3 most frequently mutated genes. Neoadjuvant regimen was comprised of trastuzumab and HER2 inhibitor (i.e. pertuzumab or lapatinib). 15 patients used single HER2 inhibitor;18 used dual HER2 inhibitors. Endocrine therapy was also administered to HR+ patients (19/33) in combination with trastuzumab and HER2 inhibitor. Complete pathologic response (pCR) was observed in 45.5% (15/33) of patients. Interestingly, ROS1 copy number amplifications (CANs) were only identified in patients achieved pCR (p = 0.033). In contrast, missense mutations in PIK3CA and CNAs in CCND1, FGF19, FGF3, FGF4, SPOP, HNF1B and BRIP1 showed a trend of being less likely to mutate in pCR patients (p values between 0.05-0.1). Previous reports have suggested that pCR rates in HER2+ patients are associated with HR status. However, our data revealed comparable pathologic response of patients based on either HR status or neoadjuvant regimen. Conclusions: Our data revealed a distinct mutational profile between patients achieved pCR vs patients did not. Further studies with a larger cohort are required to confirm these findings.
Characteristics of preceding trials associated with the outcome of subsequent phase III (P3) trials of targeted and immunological therapies in advanced cancers.
Authors: Nicola Jane Lawrence, Andrew James Martin, Felicia Roncolato, Monica Tang, Martin R. Stockler
Journal: Journal of Clinical Oncology (2019)

e14576 Background: Decisions to conduct P3 trials are based on evidence of activity from preceding trials. We sought the characteristics of preceding trials that were associated with a positive outcome in subsequent P3 trials of targeted and immunological therapies in oncology. Methods: We identified P3 trials of targeted and immunological therapies in advanced, solid-organ malignancies published from 2005 to 2015, and the preceding trials that were cited as their justification. We extracted characteristics and outcomes of the preceding trials and the subsequent P3 trials. We performed univariable and multivariable analyses to identify characteristics of preceding trials that were associated with a positive outcome in P3 trials. Results: We included 205 P3 trials with 542 citations of preceding trials. The experimental agent evaluated was (P3 trial, preceding trial respectively): small molecule (47%, 39%), immunotherapy (10%, 16%), monoclonal antibody (28%, 32%), hormonal therapy (7%, 6%), and other agent (8%, 6%). The primary endpoint was positive in 40% of P3 trials. The findings of preceding trials were reported ‘positively’ by their authors in 87%, but a priori criteria for judging their findings ‘positive’ were specified in only 74%, and met in only 53%. Characteristics of preceding trials that were associated with a positive primary endpoint in the subsequent P3 trial on multivariable analysis were: conduct in the same tumour type (odds ratio 2.35, 95% CI 1.0 to 5.6, p = 0.05), and sponsored by industry (odds ratio 2.02, 95% CI 1.2 to 3.5, p = 0.01). Conclusions: Researchers designing and conducting phase 2 trials should pre-specify and report criteria for concluding that the findings are ‘positive’. Researchers designing and conducting P3 trials of targeted and immunological therapies should require evidence of activity for the specific type(s) of tumour and therapy in question. [Table: see text]
Co-occurring genetic alterations and primary EGFR T790M mutations detected by next-generation sequencing in pre-TKI treated patients with non-small cell lung cancer.
Authors: Yuan Tang, Bing Wei, Yang Yu, Yun Gao, Nanying Che, Huaiyin Shi, Shijun Fu, Min Gao, Dongmei Lin, Jie Ma
Journal: Journal of Clinical Oncology (2019)

e13128 Background: With the development of targeted drugs, there are more therapeutic options for patients with non-small cell lung cancer (NSCLC) harboring corresponding genetic alterations. However, cancers are frequently caused by alterations on multiple genes, which collaborate to promote tumor development. Methods: A total of 1353 NSCLC patients from five different clinical institutions were enrolled in this study. Concurrent DNA and RNA NGS analysis was performed using the Ion Ampliseq Colon and Lung Cancer gene panel v2 and the AmpliSeq RNA Lung Cancer Research Fusion Panel using FFPE samples from surgically resected NSCLC tumors. Results: Of the 1293 mutations that were detected, 2338 variants were identified in 24 genes, while 27 of the tumor samples were identified to have co-occurring DNA mutations (including insertions, deletions and point mutations) and RNA fusion mutations. Analysis of the 975 patients with EGFR-gene mutations revealed that the incidence of dual EGFR L858R/T790M mutations were higher compared to EGFR 19del/T790M, and the MAF of T790M was lower compared to 19del in dual EGFR 19del/T790M patients. Conclusions: Even with the non-random cohort of patients in this study, the genetic alterations detected in this study had a certain degree of representation of NSCLC (especially lung adenocarcinoma) in the Chinese population. The differences in the MAF of EGFR T790M may determine different responses to TKI therapy in patients harboring dual mutations.
Frequency and prognostic impact of KIT and other genetic variants in indolent systemic mastocytosis
Authors: Javier I. Muñoz-González, Iván Álvarez-Twose, María Jara-Acevedo, Ana Henriques, Esther Viñas, Carlos Prieto, Laura Sánchez-Muñoz, Carolina Caldas, Andrea Mayado, Almudena Matito, Noelia Dasilva-Freire, Alberto Orfao, Andrés C. García-Montero
Journal: Blood (2019)
TCR repertoire analysis from peripheral blood for prognostic assessment of patients during treatment.
Authors: Sadanand Vodala, Andrew Nguyen, Noe Rodriguez, Peter Sieling, Charles Joseph Vaske, Jon Van Lew, Kayvan Niazi, John H. Lee, Patrick Soon-Shiong, Shahrooz Rabizadeh
Journal: Journal of Clinical Oncology (2019)

e14040 Background: Immune checkpoint inhibitors offer substantial clinical advantage to a subset of patients but predictive/novel prognostic indicators are still scarce. T cell receptors (TCRs) play a crucial role in adaptive immunity and anti-tumor immune responses. Net diversity of TCR repertoires are altered in patients receiving immune checkpoint inhibitors. To study the prognostic significance of T cell repertoires as a biomarker of immune responses in cancer patients, we characterized TCR repertoires from peripheral blood using high throughput sequencing. Methods: Total RNA from peripheral blood mononuclear cells (PBMCs) was extracted and used to generate sequencing libraries from five pancreatic cancer patients, four triple negative breast cancer (TNBC) patients and two squamous cell carcinoma (SCC+) patients. Blood draws were collected pre- and post-treatment and target lesion analysis was performed using immune-related response criteria (irRC) and Recist1.1. TCR alpha and beta CDR3s were clonotyped for each sample, and profiles of clonotype proportions were tracked through time/serial biopsies. Additionally the Shannon-Wiener diversity metric was calculated for each time point. Results: Patient samples showing consistent positive responses as measured by irRC and Recist1.1 showed TCR clones persisting throughout all time points. A TNBC super responder showed dramatic increases in mean Shannon-Wiener index from 74 prior treatment to 1177 at first biopsy post treatment (34% decrease by irRC and 26% by Recist1.1 analysis) and achieved an index as high as 3516 in a subsequent biopsy (83% and 64% decrease by irRC and Recist 1.1 respectively). Patients that showed poor response by irRC and Recist1.1 showed TCR clones that were in constant flux. Loss of clonality and/or decrease in absolute numbers was observed in previous and later time points. Conclusions: Patients that show positive response had TCR clones that were stable, which may indicate an existing immune related response towards their tumor. Therapy would allow these existing T-cells to overcome blockade by tumor cells. Patients showing poor response show a TCR repertoire that is constantly changing potentially indicating that the tumor cells are not eliciting a strong T cell specific response. Further functional studies of T cell populations would expand our understanding of T cell based immune therapies.
Detection of circular RNA expression and related quantitative trait loci in the human dorsolateral prefrontal cortex
Authors: Zelin Liu, Yuan Ran, Changyu Tao, Sichen Li, Jian Chen, Ence Yang
Journal: Genome biology (2019)

Circular RNAs (circRNAs) are implicated in various biological processes. As a layer of the gene regulatory network, circRNA expression is also an intermediate phenotype bridging genetic variation and phenotypic changes. Thus, analyzing circRNA expression variation will shed light on molecular fundamentals of complex traits and diseases. We systematically characterize 10,559 high-quality circRNAs in 589 human dorsolateral prefrontal cortex samples. We identify biological and technical factors contributing to expression heterogeneity associated with the expression levels of many circRNAs, including the well-known circRNA CDR1as. Combining the expression levels of circRNAs with genetic cis-acting SNPs, we detect 196,255 circRNA quantitative trait loci (circQTLs). By characterizing circQTL SNPs, we find that partial circQTL SNPs might influence circRNA formation by altering the canonical splicing site or the reverse complementary sequence match. Additionally, we find that a subset of these circQTL SNPs is highly linked to genome-wide association study signals of complex diseases, especially schizophrenia, inflammatory bowel disease, and type II diabetes mellitus. Our results reveal technical, biological, and genetic factors affecting circRNA expression variation among individuals, which lead to further understanding of circRNA regulation and thus of the genetic architecture of complex traits or diseases.
Quality of life (QOL) in patients undergoing CAR-T therapy versus stem cell transplant (SCT).
Authors: Surbhi Sidana, Amylou C. Dueck, Michelle Burtis, Joan M. Griffin, Gita Thanarajasingam, Rahma M. Warsame, Carrie A. Thompson, Andrea L. Cheville, Morie A. Gertz, Kathleen J. Yost, Angela Dispenzieri, Jose Villasboas Bisneto, Jonas Paludo, Stephen M. Ansell, S. Vincent Rajkumar, Nabila Nora Bennani, Patrick B. Johnston, Mustaqeem Ahmad Siddiqui, Yi Lin, Shaji Kumar
Journal: Journal of Clinical Oncology (2019)

6594 Background: Given the significant short-term adverse effects of CAR-T cell therapy, it is important to evaluate its impact on QOL of patients in addition to efficacy, compared with established forms of cellular therapy like SCT. Methods: QOL was evaluated prospectively in patients undergoing CAR-T therapy, autoSCT &amp; alloSCT for hematologic malignancies. QOL was assessed with FACT-G at baseline, 2 weeks and monthly for 6 months thereafter. Functional well-being (FWB), physical WB (PWB) emotional WB (EWB) &amp; social WB (SWB) and change over time were compared across groups. Results: 45 patients were recruited (CAR-T: 10; Auto SCT: 22; Allo SCT: 13) with follow up for 2 weeks &amp; 1 month available for 23 &amp;15 patients, respectively (Table). There was no statistically significant difference in baseline total QOL scores (p=0.13), though scores were lower in the alloSCT group (85,84,68). EWB &amp;FWB were numerically higher in the CAR-T group, followed by autoSCT group. At 2 weeks, overall QOL decreased by only 2 points in CAR-T group vs. 22 &amp; 18 points in auto &amp; alloSCT groups (p=0.09). Change in PWB vs. baseline was less pronounced in the CAR-T group (-1, -9, -13, p=0.03). At 1 month, overall QOL was 6 points lower than baseline in CAR-T group vs. 3 and 14 points lower in auto &amp; alloSCT groups, respectively (p=0.34). Importantly, PWB had at least returned to baseline in the CAR-T group. Conclusions: Preliminary data show that patients undergoing CAR-T cell therapy do not experience a more significant decline in QOL compared with auto &amp; allo SCT, and may experience fewer physical side effects in the short-term. Accrual &amp; follow-up are ongoing. [Table: see text]
Upfront EGFR TKI with or without brain radiotherapy (RT) in EGFR-driven non-small cell lung cancer (NSCLC) with brain metastases.
Authors: Nicolas Villanueva, Klarissa Son, Jona Ashok Hattangadi, Daniel Robert Simpson, Parag R. Sanghvi, Sandip Pravin Patel, Hatim Husain, James John Urbanic, Kathryn A. Gold, William M. Mitchell, Lyudmila Bazhenova
Journal: Journal of Clinical Oncology (2019)

e20614 Background: The central nervous system (CNS) remains a common site of metastatic disease for NSCLC, especially in EGFR-driven disease. Surgery and RT are upfront treatment options but have potential early and late onset complications. Osimertinib (Osi) is now approved for use in the front-line setting for EGFR-mutated NSCLC and is highly CNS penetrant. A prior retrospective study showed that the use of early generation EGFR TKIs had an inferior overall survival (OS) compared to upfront RT in newly diagnosed brain metastases, but the applicability of this data in the Osi-era is unknown. Methods: This was a single institution retrospective analysis of patients with EGFR mutated NSCLC and brain metastases who were referred to Radiation Oncology from 1/1/2012 to 12/31/2018. We separated EGFR TKIs between Osi and non-Osi. The primary objectives were to evaluate OS, intracranial progression free survival (icPFS), and intracranial response (icORR) among upfront or delayed RT, and type of EGFR TKI. Results: 67 patients with a median age of 64 years old (33-89) were divided into one of four groups: non-Osi TKI with (N = 38) or without RT (N = 12), and Osi with (N = 14) or without RT (N = 3). Fourteen patients who did not get upfront Osi, received Osi with (N = 7) or without RT (N = 7) after intracranial progressive disease (icPD). Patients were predominantly female, never-smokers, and with an ECOG PS 0-1. Brain metastases were mostly asymptomatic and &lt; 10 mm. The OS for the entire population was 26.7 months (95% CI, 23.9-29.5); there was no difference between groups, and use or type of RT versus TKI. The icPFS was 14.3 months (95% CI, 9.1-19.5), icORR was 64.2%, and icDCR was 82.7%, without any difference between groups. Among those patients who did not receive upfront Osi, use in the post-progression setting resulted in a significantly longer OS (54.8 vs. 23.0 months, p = 0.001). Conclusions: We found no statistical difference in OS, icPFS, or icORR in patients treated with upfront RT or EGFR TKI. Results should be confirmed with a prospective study.
Sarcopenia as a predictor of chemotherapy toxicity in patients with ovarian cancer receiving platinum and taxane-based chemotherapy.
Authors: Katherine Tucker, Stuart-Allison Moffat Staley, Meredith Newton, Michelle Ertel, Yingao Zhang, Irene Doherty, Paola A. Gehrig
Journal: Journal of Clinical Oncology (2019)

e17035 Background: Sarcopenia (age-related loss of skeletal muscle mass) is associated with worse oncologic outcomes and adverse events in patients with solid tumors. Limited research in epithelial ovarian cancer (EOC) has shown that sarcopenia is associated with worse patient outcomes. The purpose of this study was to investigate the association of sarcopenia with chemotherapy toxicity in patients with EOC. Methods: EOC patients diagnosed between 6/2000 and 2/2017 who received platinum and taxane-based chemotherapy were included. Age, race, stage, grade, BMI, comorbidities, treatment, and outcomes were collected. Chemotherapy toxicities and associated grades, as well as treatment modifications were recorded. Computed tomography (CT) images within 3 months of diagnosis were evaluated for Skeletal Muscle Area (SMA) at the 3 rd lumbar vertebrae. Measurements were obtained with use of TomoVision(R) radiological software (SliceOmatic – version 5.0, Quebec, Canada). Sarcopenia was defined as Skeletal Muscle Index (SMI = SMA/height 2 ) ≤ 41. This preliminary analysis generated descriptive statistics and compared the distributions of toxicity assessments by sarcopenia, with t-tests, rank-sum, chi-square and fisher’s exact tests. Results: 144 patients were evaluated. The majority presented with Stage III /IV, HGSOC (75%, 73%). Median age was 63 yrs and median BMI was 27.2 (IQR = 23.7-32.8). 61% of patients were sarcopenic. The median SMI was 40 (IQR = 34.2-46.2). There was no significant difference between sarcopenic (S) and nonsarcopenic (NS) patients with respect to dose adjustment (p = 0.37), regimen change (p = 0.998), need for blood transfusion (p = 0.60), toxicity-related hospitalization (p = 0.84) or delay in treatment (p = 0.37). Grade 3-4 toxicity was found in 56.8% of S and 58.9% of NS patients (p = 0.992). Similarly, the distributions of grade 1-2 toxicities in S and NS patients were comparable. Conclusions: In this cohort of patients, there was no significant association between sarcopenia and chemotherapy related toxicities. However, given high prevalence of sarcopenia in ovarian cancer patients, our relatively small sample size, and challenges with retrospective collection of chemotherapy toxicity, further prospective exploration is warranted.
Proton pump inhibitors and response to immune check-point inhibitors: Single center study.
Authors: Asaad Trabolsi, Megan Winter, Estelamari Rodriguez
Journal: Journal of Clinical Oncology (2019)

e14092 Background: Checkpoint inhibitors (blocking antibodies to PD-1, PD-L1, CTLA-4) have proven effective against several tumor types. While the response is impressive in some patients, we still don’t understand all the patient factors that determine resistance to this class of medication. Studies of host factors have identified composition of the gut microbiome at baseline as a positive predictor of ICI response. Proton pump inhibitors have been reported to interfere with gut microbiome composition. In this single center, retrospective study, we studied the effect of concomitant treatment of proton pump inhibitors on response to ICIs in patients with locally advanced and metastatic cancer. Methods: A retrospective cohort of Non-small cell lung cancer, renal cell carcinoma and Melanoma patients that were treated from January 2016 to May 2018 at the Mount Sinai Medical Center were included in this study. Demographics, prior systemic treatment, performance status, ICI agent, and use of PPI (with in 30 days prior to 30 days after the first dose of ICI administration) were collected. Primary objective of the study was progression free survival (PFS) by utilization of PPIs. PFS was calculated using the log-rank test and survival curve was generated using the Kaplan-Meier method. Information was collected from electronic medical records. Results: Of the 97 patients that met the study criteria, 63 patients had complete data and included in the analysis. 46 patients had Non-small cell lung cancer, 13 had melanoma and 4 renal cancer. Checkpoint inhibitors most commonly prescribed included: Pembrolizumab (29 patients : 46%), Nivolumab (22 patients:35%), Nivolumab + Ipilimumab (9:14 %). 25 patients were taking PPI upon initiation of ICI treatment. In addition, 26 patients received steroids with in 30 days of treatment initiation. There was no statistically significant difference in PFS between patients on PPIs and not on PPIs. The median PFS was 672 days (95% CI: 32, 1311) for PPI users and 341 days (95% CI: 123, 558) for non PPI users. P = 0.244. Conclusions: In this, single-center, retrospective study, we did not detect a significant difference in PFS between patients who used PPI at baseline and patients who did not. Limitations of this study mainly included retrospective analysis, a small sample size, single center population and heterogeneity in disease pathology. We did not collect information on other tumor and treatment related factors like PDL 1 expression, tumor mutation burden, use of antibiotics, and immunotherapy related adverse reactions.
Body composition change, safety, and efficacy with everolimus use in ethnic minorities with breast cancer.
Authors: Gurbakhash Kaur, Amanda Podolski, Janki Patel, Jesus Del Santo Anampa Mesias
Journal: Journal of Clinical Oncology (2019)

e18145 Background: The mammalian target of rapamycin (mTOR) signaling pathway regulates metabolism and is implicated in pathological conditions including obesity and diabetes. In obese rat models, mTOR inhibition was shown to ameliorate obesity and adipocyte hypertrophy, while exacerbating glucose intolerance. The mTOR inhibitor Everolimus (E), in combination with exemestane, is FDA approved for the treatment of ER+/HER2- metastatic breast cancer (MBC) with hyperglycemia being common toxicity. There is scarce data about the safety &amp; efficacy of E in ethnic minorities. We aimed to assess the effect of E on body composition after 3 &amp; 6 months and to describe toxicity &amp; efficacy in ethnic minorities. Methods: A retrospective study involving patients with MBC treated with E between 1/1/2012-12/1/2018. Total fat area (TFA), visceral fat area (VFA), subcutaneous fat area (SFA), muscle area (MA), and muscle density (MD) were measured before and after 3 &amp; 6 months of E treatment using CT images at the L3 vertebrae. Results: Our cohort included 58 patients with a median age of 69 years (range: 46-97); 22% were Caucasian, 35% were black, and 41.4% were Hispanic. Visceral disease was present in 64%, the median number of prior endocrine therapies was 2 (range: 1-6), and the median number of prior chemo lines was 2 (range 1-7). There was significant decrease in body weight at month 3(-2.9kg, p &lt; 0.0001) and month 6 (-5.2kg, p = 0.006). At month 3, there was a significant decrease in TFA (-2848 mm2, p = 0.004), VFA (-834 mm2, p = 0.004), and SFA (-2021 mm2, p = 0.002), with similar effects at month 6. When compared to baseline, there was no significant change in MA or MD at month 3 or 6. Grade 3/4 adverse events (AEs) were present in 18 patients. The most common AEs were mucositis (22%), rash (21%), fatigue (14 %), hyperglycemia (10%), diarrhea (9%), pneumonitis (9%), and edema (7%). The median PFS was 5.8 months. Conclusions: This is the first report that Everolimus treatment decreases body weight, TFA, VFA, and SFA without significant effect on MA or MD. Our findings are consistent with animal models reports that mTOR inhibition causes a decrease in fat mass in obese rats. We report the median PFS of 5.8 months in a cohort with ethnic minorities.