tbuckley/cabot-search huggingface dataset:
Subgroup analysis of rucaparib versus chemotherapy as treatment for BRCA-mutated, advanced, relapsed ovarian carcinoma: Effect of platinum sensitivity in the randomized, phase 3 study ARIEL4.
Authors: Amit M. Oza, Alla Sergeevna Lisyanskaya, Alexander A. Fedenko, Mikhail Dvorkin, Andreia Cristina de Melo, Yaroslav V. Shparyk, Irina Rakhmatullina, Igor Bondarenko, Nicoletta Colombo, Valentyn Svintsitskiy, David Cibula, Róbert Póka, Ana Oaknin, Tamar Safra, Beata Mackowiak-Matejczyk, Ling Ma, Karen Retta McLachlan, Sandra Goble, Rebecca Sophie Kristeleit
Journal: Journal of Clinical Oncology (2021)

5517 Background: In ARIEL4 (NCT02855944), rucaparib significantly improved the primary endpoint of progression-free survival (PFS) vs chemotherapy (CT) in patients with advanced, relapsed ovarian carcinoma (OC) harboring a deleterious BRCA1/2 (BRCA) mutation (median PFS 7.4 [95% CI 7.3–9.1] vs 5.7 [5.5–7.3] months; hazard ratio (HR) 0.64 [95% CI 0.49–0.84]; P=0.001). This prespecified exploratory analysis investigated the effect of platinum sensitivity on the efficacy of rucaparib vs CT in ARIEL4. Methods: Patients were randomized 2:1 to oral rucaparib 600 mg twice daily or CT and stratified based on progression-free interval (≥1 to &lt;6 months = platinum resistant; ≥6 to &lt;12 months = partially platinum sensitive; ≥12 months = fully platinum sensitive). In the CT group, patients with platinum-resistant or partially platinum-sensitive disease received weekly paclitaxel 60–80 mg/m 2 ; patients with fully platinum-sensitive disease received investigator’s choice of platinum-based CT (single-agent carboplatin or cisplatin, or platinum doublet). Patients could crossover from CT to rucaparib following radiologic disease progression. Efficacy endpoints were explored in patients with a confirmed BRCA mutation (patients with a reversion mutation were excluded), based on the randomization strata of platinum sensitivity. Results: The visit cutoff date was September 30, 2020. PFS and objective response rates (ORR) per RECIST v1.1 for rucaparib vs CT across subgroups are presented in the Table. The most common treatment-emergent adverse events in the rucaparib group were anemia/decreased hemoglobin (platinum-resistant patients: rucaparib 47% vs CT 40%; partially platinum-sensitive patients: 63% vs 27%; fully platinum-sensitive patients: 58% vs 20%) and nausea (52% vs 21%; 51% vs 23%; 60% vs 68%). In the intent-to-treat population, 74/116 (64%) patients in the CT group crossed over to receive rucaparib: 39/59 (66%) with platinum-resistant, 25/31 (81%) with partially platinum-sensitive, and 10/26 (38%) with fully platinum-sensitive disease. Conclusions: Results from this exploratory subgroup analysis suggest that rucaparib is a reasonable treatment option for heavily pretreated patients across all platinum sensitivity subgroups. Safety was consistent with prior rucaparib studies. Clinical trial information: NCT02855944. [Table: see text]
Integrated computer-aided formulation design: A case study of andrographolide/ cyclodextrin ternary formulation
Authors: Haoshi Gao, Yan Su, Wei Wang, Wei Xiong, Xiyang Sun, Yuanhui Ji, Hua Yu, Haifeng Li, Defang Ouyang
Journal: Asian Journal of Pharmaceutical Sciences (2021)

Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists, which is time-consuming, high cost and waste materials. This research aims to integrate various computational tools, including machine learning, molecular dynamic simulation and physiologically based absorption modeling (PBAM), to enhance andrographolide (AG) /cyclodextrins (CDs) formulation design. The lightGBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy. AG/γ-CD inclusion complexes showed the strongest binding affinity, which was experimentally validated by the phase solubility study. The molecular dynamic simulation was used to investigate the inclusion mechanism between AG and γ-CD, which was experimentally characterized by DSC, FTIR and NMR techniques. PBAM was applied to simulate the in vivo behavior of the formulations, which were validated by cell and animal experiments. Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate (TPGS) significantly increased the intracellular uptake of AG in MDCK-MDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers. The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills, respectively. In conclusion, this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility, dissolution rate and bioavailability. The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.
BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program
Authors: Dae-Hwan Kim, Duanchen Sun, William K. Storck, Katherine Welker Leng, Chelsea Jenkins, Daniel J. Coleman, David Sampson, Xiangnan Guan, Anbarasu Kumaraswamy, Eva S. Rodansky, Joshua A. Urrutia, Jacob A. Schwartzman, Chao Zhang, Himisha Beltran, Mark P. Labrecque, Colm Morrissey, Jared M. Lucas, Ilsa M. Coleman, Peter S. Nelson, Eva Corey, Samuel K. Handelman, Jonathan Z. Sexton, Rahul Aggarwal, Wassim Abida, Felix Y. Feng, Eric J. Small, Daniel E. Spratt, Armand Bankhead, Arvind Rao, Emily M. Gesner, Sarah Attwell, Sanjay Lakhotia, Eric Campeau, Joel A. Yates, Zheng Xia, Joshi J. Alumkal
Journal: Clinical Cancer Research (2021)

Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear.Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity.AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial.E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.
Pan cancer analysis of the intra-tumoral microbiome’s correlation with racial disparities.
Authors: Wei Tse Li, Matthew Uzelac, Jaideep Chakladar, Lindsay M. Wong, Aditi Gnanasekar, Abby C. Lee, Daniel John, Jay Patrick Lopez, Weg M. Ongkeko
Journal: Journal of Clinical Oncology (2021)

2519 Background: Microbiome composition can influence cancer development and is moderated by diet, hygiene, sanitation, and other environmental variables. For example, a Mediterranean diet could increase breast Lactobacillus abundance, while the gut microbiome changes dramatically with fructose intake. Recent studies have revealed correlations between microbial abundance and racial disparities in cancer. Given these reports, it is critical to examine whether environmental influences on the microbiome contribute to racial disparities in cancer incidence and prognosis. Methods: We examined the intra-tumoral microbiome in the lungs, breasts, bladder, colon, rectum, cervix, head and neck, prostate, and pancreas (n = 4,169). Raw tumor RNA sequencing data were downloaded from The Cancer Genome Atlas (TCGA) and aligned to bacterial genomes. Microbial abundance was correlated to race, ethnicity, and prognostic variables (Kruskal-Wallis test or Cox regression, p&lt; 0.05). Results: We identified several microbes correlated with racial disparities for breast and bladder cancer, two microbes for lung squamous cell carcinoma, and one microbe for colon cancer. For breast cancer, African Americans have the highest mortality rate, followed by white Americans and Asian Americans. We found that four microbes, all under the order Burkholderiales, were positively correlated with poor prognosis and were most abundant in African Americans and least abundant in Asian Americans. Therefore, increased abundance of these microbes may contribute to the observed mortality differences between races. For bladder cancer, Asian Americans have the lowest incidence and mortality rates. Seven microbes, including two Geobacillus, two Pseudomonas, and two Burkholderiales, positively correlate with good prognosis and are upregulated in Asian Americans. High Pseudomonas fluorescens abundance is positively correlated with decreased risk of death (HR: 0.57, 95% CI: 0.38-0.85). High abundance of the Burkholderiales R. pickettii (HR: 0.62, 95% CI: 0.42-0.92) and V. paradoxus (HR: 0.59, 95% CI: 0.36-0.98) also exhibit the same trend. Geobacillus and Pseudomonas are both present in food, while Burkholderiales can cause nosocomial infections and are altered by diet. Conclusions: Our study is the most comprehensive to date investigating racial differences in the intra-tumoral microbiome. Our data serve as a starting point for exploring whether environmental influence of microbial abundance contributes to racial disparities in cancer.
Gene expression profiling signatures for immunophenotyping of tumor microenvironment using HTG EdgeSeq Precision Immuno-Oncology Panel.
Authors: Melba C. Jaramillo, Dominic LaRoche, Di Ran, Marian Navratil
Journal: Journal of Clinical Oncology (2021)

e14528 Background: Immunotherapy has revolutionized cancer treatment by harnessing the power of the patient’s immune system to fight the disease. While immunotherapies have become increasingly effective, the proportion of patients not responding to immunotherapy ranges between only 20-50%. New breakthroughs in the understanding of the tumor immune biology have led to the development of new, more effective therapies; however, these breakthroughs often hinge on tools that can elucidate the role and abundance of individual components of the patient’s immune system in the tumor microenvironment. Methods: This poster describes the performance of 26 gene enrichment signatures that allow for the measurement of the relative abundance of 23 individual immune and stromal cells in the tumor environment, in addition to providing composite inflammation, stroma and tumor microenvironment scores. These Research Use Only (RUO) signatures are based on gene expression profiling (GEP) data for 1,392 genes implicated in tumor-immune interaction generated using the HTG EdgeSeq Precision Immuno-Oncology Panel (RUO). The signatures were developed and validated using GEP data from 1,073 colorectal, gastric and ovarian cancer formalin-fixed paraffin-embedded (FFPE) tissue specimens. Results: The signature accuracy was independently verified by spiking known numbers of representative immune and stromal cells into an FFPE tissue lysate; the signature outputs were highly correlated to the number of immune and stromal cells present in the sample, with Pearson correlation coefficients ranging from 0.71 to 0.98. In addition, the outputs of some of the signatures were compared to multiple commonly used immunohistochemistry markers of immune cells in 61 non-small-cell lung carcinoma FFPE samples. The results showed a high degree of correlation, with Pearson correlation coefficients of 0.77 and 0.81 for CD4 and CD8, respectively. Conclusions: These immunophenotyping signatures provide a suite of robust tools for the characterization of the tumor microenvironment in order to better understand the tumor immune biology and mechanisms of resistance to immunotherapy. The signature scores can typically be generated from a single section of FFPE tissue using HTG’s extraction-free GEP technology and a fully automated bioinformatic pipeline available in the HTG EdgeSeq Reveal software.
Trends in breast cancer incidence among young women aged 20 to 49 years in the United States.
Authors: Shuai Xu, Yunan Han, Fei Wan, Adetunji T. Toriola
Journal: Journal of Clinical Oncology (2021)

10573 Background: Breast cancer in young women is diagnosed at more advanced stages and has a less favorable prognosis. We investigated trends in breast cancer incidence by race/ethnicity, hormone receptor status, and tumor stage in women aged 20-49 years over the past 25 years, as well as the impact of period and cohort effects on these trends. Methods: We used data from Surveillance, Epidemiology, and End Results (SEER) 13 registries for 1993-2002 and SEER 18 registries for 2003-2017. We calculated age-standardized incidence rates and annual percent change (APC), and stratified by race/ethnicity, hormone receptor status (estrogen receptor [ER] and progesterone receptor [PR]), and tumor stage (I-IV) for 222,424 women aged 20-49 years with a primary invasive breast cancer. We performed age-period-cohort analysis (presented as incidence rate ratios [IRR]) to investigate the effects of age, period, and cohort on incidence trends using the 1948 cohort and 1993-1997 period as the reference groups, respectively. Results: Between 2010-2017, invasive breast cancer incidence increased (APC = 0.67%, 95%CI: 0.32 to 1.03) among women aged 20-49 years, after being stable from 1993-2010. There were differences by race over the 25-year period (1993-2017). We observed significant increases in incidence among non-Hispanic White (NHW) (APC = 0.25%, 95%CI: 0.16 to 0.34), non-Hispanic Asia/Pacific Islander (NHAPI) (APC = 0.58%, 95%CI: 0.34 to 0.82), and Hispanic women (APC = 0.59%, 95%CI: 0.34 to 0.83), but not among non-Hispanic black (NHB) women (APC = 0.14%, 95%CI: -0.06 to 0.34). Incidence increased for ER+ tumors but decreased for ER- tumors: ER+/PR+ (APC = 2.39%, 95%CI: 2.20 to 2.58), ER+/PR- (APC = 1.46%, 95%CI: 1.05 to 1.87), ER-/PR+ (APC = -6.33%, 95%CI: -7.31 to -5.33), and ER-/PR- (APC = -0.70%, 95%CI: -1.09 to -0.32). The decrease in ER-/PR- tumors appeared largely driven by decreases among HNW women. Incidence for stages I (APC = 0.31, 95%CI: 0.07 to 0.55), II (APC = 0.99, 95%CI: 0.82 to 1.16), and IV (APC = 2.88, 95%CI: 2.37 to 3.39) tumors increased while that for stage III tumors decreased (APC = 0.81%, 95%CI: -1.04 to -0.59). Both the cohort and period effects impacted incidence, with the cohort effect almost 10 times larger than the period effect. Age-specific relative risk by birth cohort initially decreased between 1948 and 1958 but steadily increased from 1958 to 1993. Breast cancer incidence was higher among women born in the 1988 (IRR = 1.17, 95%CI: 1.07 to 1.28) and 1993 (IRR = 1.22, 95%CI: 0.99 to 1.51) cohorts than for those born in 1948 cohort. Conclusions: Breast cancer incidence is increasing among young women, mainly driven by increases in ER+ tumors. Prevention efforts need to focus on how we can address factors driving the increase in ER+ tumors and also learn from what has worked for decreasing ER- tumors.
Investigating reasons for discontinuation of first-line adjuvant chemotherapy among ovarian cancer patients in the midwestern United States.
Authors: Kristin S. Weeks, Sherri L. Stewart, Michele West, Ryan Carnahan, Jacob Oleson, Charles F. Lynch
Journal: Journal of Clinical Oncology (2021)

e17523 Background: Receipt of surgery and adjuvant chemotherapy greatly impact survival outcomes for ovarian cancer, the deadliest gynecologic malignancy with a high recurrence/progression rate. Most patients receive first-line, platinum-based chemotherapy. Platinum-based chemotherapy causes severe side effects, including nephrotoxicity and myelosuppression. Evidence for other chemotherapeutic agents is lacking and options are limited for women who cannot tolerate first-line chemotherapy. We aimed to determine the prevalence of premature first-line chemotherapy discontinuation and to detail reasons for discontinuation. Methods: We used the population-based cohort, Patterns of Ovarian Cancer Care and Survival in the Midwestern Region of the United States—a CDC Investigation, comprised of women diagnosed with histologically confirmed, stage IB-IV ovarian cancer in 2010-2012 in the Midwestern United States (i.e., Iowa, Kansas and Missouri) between the ages of 18 and 89 years. We limited the cohort to patients who received cancer-directed surgery and initiated adjuvant chemotherapy. Chemotherapy lines, completion, and reasons for discontinuation were abstracted from patient medical records by cancer registrars using standardized protocols. Results: Nineteen percent (N= 107/559) of ovarian cancer patients who initiated adjuvant chemotherapy did not complete first-line treatment. Reasons for chemotherapy discontinuation included toxicity or other kinds of intolerance (39%), poor quality of life or comorbid conditions (19%) or exhibited no response (17%) (Table). No significant differences were observed between gynecologic oncologists and non-gynecologic oncologist chemotherapy providers (p=0.109). Conclusions: One in 5 women who initiated did not complete first-line chemotherapy. Reasons were varied and suggested that lack of tolerance is not the only factor in discontinuation. Lack of response and the presence of comorbid conditions are considerations that can be taken into account during decision-making processes for treatment. More clinical research into additional chemotherapy options that may be useful in these patients is necessary.[Table: see text]
Increased transmissibility and global spread of SARS-CoV-2 variants of concern as at June 2021
Authors: Finlay Campbell, Brett Archer, Henry Laurenson-Schafer, Yuka Jinnai, Franck Konings, Neale Batra, Boris Pavlin, Katelijn Vandemaele, Maria D Van Kerkhove, Thibaut Jombart, Oliver Morgan, Olivier le Polain de Waroux
Journal: Eurosurveillance (2021)

We present a global analysis of the spread of recently emerged SARS-CoV-2 variants and estimate changes in effective reproduction numbers at country-specific level using sequence data from GISAID. Nearly all investigated countries demonstrated rapid replacement of previously circulating lineages by the World Health Organization-designated variants of concern, with estimated transmissibility increases of 29% (95% CI: 24-33), 25% (95% CI: 20-30), 38% (95% CI: 29-48) and 97% (95% CI: 76-117), respectively, for B.1.1.7, B.1.351, P.1 and B.1.617.2.
Subsequent primary cancers among survivors of adolescent and young adult onset cancers in the United States.
Authors: Hyuna Sung, Rebecca Siegel, Kimberly Miller, Ahmedin Jemal
Journal: Journal of Clinical Oncology (2021)

10604 Background: Adolescent and young adult (AYA) cancer survivors are at increased risk of subsequent primary cancer (SPC); however, a comprehensive examination of risk patterns across cancer types is lacking in the U.S. Methods: SPC incidence and mortality was calculated among &gt;1-year cancer survivors aged 15 to 39 years at first primary cancer (FPC) diagnosis during 1992-2016 in 12 Surveillance, Epidemiology, and End Results registries. Rates were expressed as number of cases/deaths per 10,000 person-years and compared with those expected in the general population using standardized incidence (SIR) and standardized mortality ratios (SMR). Results: Among 202,440 survivors of AYA-onset cancers (mean age at FPC diagnosis, 31.8 years; 60.7% women), 6,675 SPC cases (34.3 per 10,000) and 3,786 SPC deaths (19.4 per 10,000) occurred during 1,955,119 person-years of follow-up (mean, 9.7 years), corresponding to an SIR of 1.58 (95%CI = 1.54-1.62) and SMR of 4.19 (95%CI = 4.06-4.33. In men, overall incidence and mortality SPC rates were statistically significantly higher for each of 21 FPC types compared with risks in the general population, except for thyroid cancer mortality. In women, risk was statistically significantly higher for 14/23 FPC types for incidence and 19/23 FPC types for mortality. SIRs were highest in survivors of pancreatic cancer (SIR = 5.68, 95% CI = 2.94-9.93; 84 per 10,000), Kaposi sarcoma (SIR = 5.15, 95%CI = 4.62-5.73; 116 per 10,000) and liver cancer (SIR = 4.97, 95%CI = 2.57-8.68; 68.4 per 10,000) in men, and acute lymphoid leukemia (SIR, 3.27, 95% CI = 2.22-4.64; 49.5 per 10,000), Hodgkin lymphoma (SIR = 2.47, 95% CI = 2.22-2.73; 51.6 per 10,000), and bone sarcoma (SIR = 2.41, 95%CI = 1.80-3.16; 47.6 per 10,000) in women. SMRs were highest in survivors of pancreatic cancer, acute lymphoid leukemia, and stomach cancer in men, and liver cancer, acute lymphoid leukemia, and soft tissue sarcoma in women. Conclusions: Overall and type-specific risk patterns of SPCs among AYA cancer survivors differ considerably across FPC type, highlighting the need for targeted approaches for cancer prevention and surveillance in survivorship care planning.
Safety and efficacy of anti-EGFR monoclonal antibody (SCT200) as second-line therapy in advanced esophageal squamous cell cancer.
Authors: Ming Bai, Ting Deng, Yi Ba
Journal: Journal of Clinical Oncology (2021)

e16046 Background: The mainstay treatment of esophageal squamous cell carcinoma (ESCC) involves chemotherapy and immunotherapy. However, alternative therapies are required for patients refractory or intolerant to the existing therapies. Methods: In this single-arm, multicenter, open-label phase Ib study, 30 patients received an intravenous infusion of SCT200, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, 6.0 mg/kg once a week for six weeks, followed by 8.0 mg/kg once every two weeks until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty patients were enrolled between July 2018 and May 2019. The ORR was 16.7% (95%CI: 5.6%–34.7%). The median PFS and OS was 3.1 months (95%CI: 1.5–4.3) and 6.8 months (95%CI: 4.7–10.1) respectively. Numerical difference without a statistical significance in ORR was observed in patients with different EGFR expression (≥50%: 25.0% vs. &lt; 50%: 0%, P = 0.140) or TP53 mutation abundance ( &lt; 10%: 23.8% vs. ≥10%: 0%, P = 0.286). Improved median PFS (3.4 vs. 1.4 months, P = 0.006) and OS (8.0 vs. 4.2 months, P = 0.027) were associated with TP53 mutation abundance of &lt; 10%. The most common treatment-related adverse events of grade 3 or 4 (occurring in ≥2 patients) were hypomagnesemia (7 [23.3%]) and rash (2 [6.7%]). No treatment-related death occurred. Conclusions: SCT200 monotherapy as second- or further-line for advanced ESCC showed favorable efficacy, with an acceptable safety profile. TP53 mutation abundance might serve as potential predictive biomarkers. Clinical trial information: NCT03817567. [Table: see text]