bluuebunny/crossref_metadata_2025 huggingface dataset:
The dynamic detection of drug area under curve (AUC) guides clinical usage of docetaxel in solid tumors.
Authors: Zhang Yan , Wu Yuan , Zhang Xiaomei , Yang Deliang , Shen Bo , Liang Geyu , Qi Martin
Published: May 2019

3024

Background: The dosage of most chemotherapy drugs were performed based on the patients’ body surface area (BSA), including docetaxel (DTX). Previous studies showed that this conventional administration of DTX might cause adverse event, such as neutropenia, and neutropenia was proved to associate with DTX area under curve (AUC). This study was designed to evaluate the effect of dose-administration of DTX based on dynamic detection of DTX AUC on clinical outcomes. Methods: A total of 209 patients with DTX chemotherapy (one cycle every 3 weeks) were enrolled, and all patients received 2-6 cycles of treatment. In the first cycle, dosage of DTX based on BSA was administrated in all study population. From the second cycle, one group patients (control group) received DTX according to traditional BSA and the other group patients (experimental group) on the basis of dynamic detection of DTX AUC. The primary outcome was incidence rate of neutropenia and the second outcome was disease control rate (DCR). Results: Patients with grade 3 or higher neutropenia from the fourth to sixth cycle of DTX chemotherapy were significantly lower in the experimental group compared with the control group (P= 0.039, 0.012, and 0.001, respectively). In the experimental group, compared with the first cycle, and the number of patients falling within the therapeutic window increased by 27.19% in the sixth cycle after dose adjustment according to the AUC value of previous cycle. The DCR in the experimental and control group is 85.32% and 72.00%, respectively (P= 0.018). Conclusions: The administration method based on dynamic detection of AUC of DTX could significantly reduce incidence rate of neutropenia and received a higher DCR, but the result needed to be confirmed in further studies.
Prospective cohort study of the impact of hospital-wide dihydropyrimidine dehydrogenase (DPYD) genotype testing for fluoropyrimidine-based chemotherapy on adverse events and hospital costs.
Authors: Wigle Theodore John , Povitz Brandi , Teft Wendy , Legan Robin , Lenehan John Gordon , Gulilat Markus , Nevison Stephanie , Kritzinger Justin , Punaganty Veera , Keller Denise , AlShanteer Suhair , Francis Robin , Siebring Victoria , Sarma Sisira , Choi Yun-Hee , Welch Stephen , Winquist Eric , Schwarz Ute , Kim Richard B.
Published: May 2019

3028

Background: Fluoropyrimidines remain integral components of modern chemotherapy for solid tumors, and their toxicities can be reduced by pretreatment DPYD genotyping. Our main objective was to demonstrate the feasibility of implementing a hospital-wide pretreatment DPYD testing service based on the CPIC 2013 guideline on fluoropyrimidines and DPYD. Methods: We enrolled participants prior to planned fluoropyrimidine treatment as well as those who had experienced adverse events (AEs) after initiation of therapy, from December 1, 2013 to November 30, 2018. The patients tested pretreatment were analyzed as a prospective cohort to assess AEs within 90 days of fluoropyrimidine initiation and associated hospital cost. The primary outcome was the rate of severe global fluoropyrimidine-related toxicity in the pretreatment cohort (grade≥3, CTCAE v.4.0.3). Results: Of 1362 patients genotyped for DPYD within the study period 1041 were enrolled pretreatment and included in the primary analysis. The median age was 65 years (19-90), 57% male, 51% 5-FU, and 49% capecitabine. Dose reductions were recommended for 21 DPYD variant carriers who were detected pretreatment. There was no significant difference in the primary outcome between DPYD variant (29%) and wild type (18%) patients (Fisher’s exact test p = 0.25). Costs associated with ER visits and hospitalizations at our tertiary care centre were $1,268 (89-8,562) (Median (IQR)) and $2,961 (341-13,567) for DPYD variant (n = 4) and wild-type (n = 99) patients respectively. Post-AE genotyping (n = 70) found five DPYD variant patients; all experienced grade≥3 toxicity, costs were $15,825 (10,962-25,310), and one poor metabolizer died due to complications. Targeted next generation exome sequencing of DPYD wild-type patients who experienced severe AEs identified five potentially deleterious genetic variants in ABC efflux transporters. Conclusions: Pretreatment DPYD genotype guided dosing of fluorouracil and capecitabine is feasible and benefits patients, health care providers, and hospitals. Our data supports adoption of pretreatment DPYD genotyping as a standard of care.
Phase I study of the Aurora A kinase (AurA) inhibitor TAS-119 with paclitaxel (P) in advanced solid tumors.
Authors: Cardin Dana Backlund , Park Haeseong , Diamond Jennifer Robinson , Drilon Alexander E. , VerMeulen Wendy L. , He Xiaomin , Hirai Hiroshi , Soni Nital , Berlin Jordan
Published: May 2019

3031

Background: AurA is a key regulator of cell division, including mitotic spindle assembly. However, elevated levels of AurA have been reported to abrogate the mitotic spindle checkpoint activated by taxanes leading to treatment resistance. Preclinical studies of TAS-119 + P showed enhanced antitumor activity and suggested an optimal timing window of the combination. Study objective was to assess the safety of TAS-119 + P in adult patients (pts) with advanced solid tumors. Methods: Dose escalation used a 3+3 design to determine the maximum tolerated dose (MTD); 7 dose levels (DLs) were explored, starting with 25 mg TAS-119 BID dosed 4 days/week (d/wk) and weekly 90 mg/m2 P for 3 weeks of a 4 week cycle (DL1). Plasma samples were collected during cycle 1 to evaluate pharmacokinetics. In expansion, pts with advanced breast/ovarian cancers were treated at the MTD. Results: Dose escalation enrolled 26 pts with various cancers, the majority being pancreas, colon, and ovarian; 2 pts were not evaluable for DLT assessment and replaced. A DLT (neutropenia and elevated AST) was observed in 2/3 pts in DL1. Dosing was modified to 25 mg TAS-119 BID 2 d/wk and P 70 mg/m2 (DL2) and no DLTs were observed. Zero DLTs were observed in the next 4 doses: 70 mg/m2 P + TAS-119 2 d/wk at 50 mg BID (DL3) or 75 mg BID (DL4), or 80 mg/m2 P + TAS-119 at 75 mg BID 2 d/wk (DL5) or 75 mg BID 3 d/wk (DL6). TAS-119 was escalated to 100 mg BID 3 d/wk (DL7) and 3 DLTs (n=1, elevated ALT; n=1, diarrhea and mucositis) occurred in 2/3 pts. Three additional pts were then enrolled at DL6 to confirm the MTD. One breast and 2 ovarian pts were enrolled in expansion before the trial was suspended by the company. Toxicities observed in ≥30% of pts were diarrhea, nausea, and fatigue (most ≤Gr2). Plasma TAS-119 exposure increased dose-proportionally in 2 d/wk and 3 d/wk schedules; no impact of TAS-119 on PK of paclitaxel was found. The disease control rate was 59% (17/29); 4 of these pts had a partial response. Conclusions: The combination had a manageable toxicity profile at the MTD of 80 mg/m2 P + TAS-119 at 75 mg BID 3 d/wk. Preliminary clinical activity was seen in 59% of pts, including tumor responses in a majority (4/7) of pts with ovarian/fallopian tube cancers. Clinical trial information: NCT02134067.
A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.
Authors: Jimeno Antonio , Opyrchal Mateusz , Diamond Jennifer Robinson , Fountzilas Christos , Corr Bradley , Bezi Ildiko , Wang Hui , Kwan Rudolf , Zhi Jay , Cutler David , Boland Patrick McKay
Published: May 2019

3032

Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]
Tumor specific DNA in bronchial lavage as a new diagnostic tool in lung cancer.
Authors: Thomsen Caroline Brenner , Hansen Torben , Andersen Rikke Fredslund , Hager Henrik , Rasmussen Kristian , Jakobsen Anders Kristian Moeller , Hilberg Ole
Published: May 2019

3047

Background: A considerable fraction of lung cancer patients raise diagnostic challenges requiring invasive procedures with a certain risk of complications. Therefore, new diagnostic tools are of major interest. Aberrant methylation of the HOXA9 gene occurs in almost all malignant lung tumors and HOXA9 methylated DNA (meth-ctDNA) is shed into the circulation. The present study aimed at a prospective investigation of the possible diagnostic value of HOXA9 meth-ctDNA in bronchial lavage (BL). Methods: Patients enrolled were referred from the general practitioner suspecting lung cancer. The diagnostic package according to national guidelines includes chest and abdominal CT scan, bronchoscopy, relevant blood tests, and histopathological or cytological verification. Twelve ml liquid was collected at bronchoscopy for analysis of meth-ctDNA based on ddPCR technology according to our published method. The analysis was performed blinded to the clinical data and compared to the final diagnosis. Results: Eighty-nine patients were consecutively included from the 1 November 2018 to 31 January 2019. Fifty-six patients (62.9%) were diagnosed with lung cancer and 33 (37.1%) with a variety of benign diseases. Meth-ctDNA was found in 42/56 of the patients with a malignant tumor, sensitivity = 75.0% (95%CI=61.6-85.6%), whereas 31/33 of the patients without cancer were negative, specificity = 93.9% (95%CI= 79.8-99.3%). Table summarizes the results. The false negative samples were mainly from patients with peripheral tumors. The two false positive patients included one patient with Cryptogenic Organizing Pneumonia and one with unspecific nodule. Conclusions: The presence of meth-ctDNA in BL has a high sensitivity and specificity. If validated, the analysis represents a valuable adjunct in the diagnosis of lung cancer. Potentially, it could save the patients from numerous examinations with potential harmful risks and ensure a fast diagnosis. The relation between meth-ctDNA and final lung cancer diagnosis (N= 89). [Table: see text]
Polymorphisms in the dopamine (DA) signaling to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE, MAVERICC, and FIRE-3 phase III trials.
Authors: Battaglin Francesca , Cao Shu , Loupakis Fotios , Stintzing Sebastian , Parikh Aparna Raj , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Berger Martin D. , Arai Hiroyuki , Millstein Joshua , Lonardi Sara , Zhang Wu , Cremolini Chiara , Mancao Christoph , Falcone Alfredo , Heinemann Volker , Lenz Heinz-Josef
Published: May 2019

3048

Background: Strong evidence supports the critical role of the gut-brain axis in modulating gastrointestinal function and homeostasis. Available data suggest an involvement of the dopaminergic pathway in CRC dynamics. DA could inhibit proliferation and migration of tumor endothelial cells and enhanced 5-fluorouracil efficacy in CRC preclinical models. Hence, we hypothesized that genetic variants in DA signaling may predict treatment outcomes in mCRC pts. Methods: The impact on outcome of 22 selected single nucleotide polymorphisms (SNPs) in 9 genes of the DA signaling pathway ( DRD1, DRD2, DRD3, DRD4, DRD5, TAAR1, SLC6A3, SLC18A2, PPP1R1B) was analyzed on a total of 884 pts enrolled in three independent randomized first-line trials: TRIBE (n = 324), MAVERICC (n = 324), and FIRE-3 (n = 236). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. A meta-analysis approach using the METASOFT software was used to quantify SNPs prognostic effects and heterogeneities across treatment arms. P values were adjusted for multiple testing using the false discovery rate (FDR) method. Results: Overall, DRD3 rs3732790, rs9817063 and rs2134655 showed a significant nominal p value ( P) in association with tumor response (TR) across trials ( P= 0.032, P= 0.021, P= 0.027, respectively). TAAR1 rs8192620 showed an association with both progression free survival (PFS) ( P= 0.01) and overall survival (OS) ( P= 0.033), similar to DA transporter SLC6A3 rs6347 ( P= 0.016 and P= 0.002, respectively). SLC6A3 rs6347 association with OS remained significant after FDR ( PFDR= 0.045). Subgroup analyses showed a significant association with PFS for DRD1 rs267410 and SLC6A3 rs2652510 in females ( PFDR= 0.056), and between SLC6A3 rs6347 and OS ( PFDR= 0.041) and SLC6A3 rs6876890 and TR ( PFDR= 0.05) in KRAS wild type. Conclusions: Our results suggest that SNPs in DA signaling may have a prognostic value in mCRC pts receiving first-line treatment. Upon validation, these findings may provide novel insight on the role of DA signaling in CRC and possibly contribute to open novel therapeutic perspectives.
Genome-wide cell-free DNA (cfDNA) methylation signatures and effect on tissue of origin (TOO) performance.
Authors: Liu Minetta C. , Jamshidi Arash , Venn Oliver , Fields Alexander P. , Maher M. Cyrus , Cann Gordon , Amini Hamed , Gross Samuel , Bredno Joerg , Miller Meredith , Schellenberger Jan , Kurtzman Kathryn N. , Fung Eric T. , Maddala Tara , Oxnard Geoffrey R. , Klein Eric A. , Spigel David R. , Hartman Anne-Renee , Aravanis Alex , Seiden Michael
Published: May 2019

3049

Background: For multi-cancer detection using cfDNA, TOO determination is critical to enable safe and efficient diagnostic follow-up. Previous array-based studies captured < 2% of genomic CpGs. Here, we report genome-wide fragment-level methylation patterns across 811 cancer cell methylomes representing 21 tumor types (97% of SEER cancer incidence), and define effects of this methylation database on TOO prediction within a machine learning framework. Methods: Genomic DNA from 655 formalin-fixed paraffin-embedded (FFPE) tumor tissues and 156 isolated cells from tumors was subjected to a prototype 30x whole-genome bisulfite sequencing (WGBS) assay, as previously reported in the Circulating Cell-free Genome Atlas (CCGA) study (NCT02889978). Two independent TOO models, one with and one without the methylation database, were fitted on training samples; each was used to predict on the test set. A WGBS classifier was used to detect cancer at 98% specificity; reported TOO results reflect percent agreement between predicted and true TOO among those detected cancers (166 cases: 81 stage I-III, 69 stage IV, 16 non-informative). Results: Genome-wide methylation data generated from this database allowed fragment-level analysis and coverage of ~30 million CpGs across the genome (~60-fold greater than array-based approaches). Incorrect TOO assignments decreased by 35% (20% to 13%) after incorporating methylation database information into TOO classification. Improvement was observed across all cancer types and was consistent in early-stage cancers (stage I-III). Respective performances in breast cancer (n = 23) were 87% vs 96%; in lung cancer (n = 32) were 85% vs 88%; in hepatobiliary (n = 10) were 70% vs 90%; and in pancreatic cancer (n = 17) were 94% vs 100%. Results using an optimized approach informed by these results in a large cohort of CCGA participants will be reported. Conclusions: Incorporating data from a large methylation database improved TOO performance in multiple cancer types. This supports feasibility of this methylation-based approach as an early cancer detection test across cancer types. Clinical trial information: NCT02889978.
Training and validation study for sequential monitoring of CAMLs in circulation to predict ongoing progression in lung cancer patients undergoing definitive radiotherapy.
Authors: Adams Daniel , He Jianzhong , Qiao Yawei , Xu Ting , Gao Hui , Reuben James M. , Komaki Ritsuko , Liao Zhongxing X. , Wistuba Ignacio Ivan , Raghavakaimal Ashvathi , Tang Cha-Mei , Augustyn Alexander , Lin Steven H.
Published: May 2019

3053

Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common in the peripheral blood of cancer patients that are prognostic for progressive disease. Further, it has been shown that changes in CAML size (i.e. enlargement above 50µm) can predict progression free survival (PFS) in thoracic cancers (e.g. lung). We enrolled 104 unresectable non-small cell lung cancer (NSCLC) patients, with an initial training set review of 54 patients, to determine if change in CAML size after radiation therapy was predictive PFS. Methods: A 2 year single blind prospective study was undertaken to test the relationship of ≥50µm CAMLs to PFS based on imaging in lung patients before and after induction of chemo radiation, or radiation therapy. To achieve a 2-tailed 90% power (α = 0.05) we recruited a training set of 54 patients and validation set of 50 patients all with pathologically confirmed unresectable NSCLC: Stage I (n = 14), Stage II (n = 16), Stage III (n = 61) & Stage IV (n = 13). Baseline (BL) blood samples were taken prior to start of therapy & a 2nd blood sample (T1) was taken after completion of radiotherapy (~30 days). Blood was filtered by CellSieve filtration and CAMLs quantified. Analysis by CAML size of < 49 µm or ≥50 µm was used to evaluate PFS hazard ratios (HRs) by censored univariate & multivariate analysis. Results: CAMLs were found in 95% of samples averaging 2.7 CAMLs/7.5mL sample at BL, with CAMLs ≥50 µm having reduced PFS (HR = 2.2, 95%CI1.3-3.8, p = 0.003). At T1, 18 patients had increased CAML size ≥50 µm with PFS (HR = 4.6, 95%CI2.5-8.3, p < 0.001). In total, ≥50 µm CAMLs at BL was 76% accurate at predicting progression within 24 months while ≥50 µm CAMLs at T1 was 83% accurate at predicting progression. Conclusions: In unresectable NSCLC patients, enlargement of CAMLs during treatment is an indicator active progression. We identify that a single ≥50 µm CAML after induction of radiotherapy, in our training set and confirmed in our validation set, is an indicator of poor prognosis. We suggest that changes in CAML size during therapy may indicate the efficacy of therapy and could potentially help shape subsequent therapeutic decisions.
Analytical validation of a tumor-agnostic integrated multianalyte circulating tumor DNA (ctDNA) assay in early-stage cancer.
Authors: Hartwig Anna , Artieri Carlo , Jaimovich Ariel , Van Seventer Emily E. , Parikh Aparna Raj , Corcoran Ryan Bruce , Baca Arthur , Talasaz AmirAli
Published: May 2019

3057

Background: ctDNA sequencing has been rapidly adopted for the identification of targetable somatic alterations (alts) in patients with advanced cancers. However, early stage disease detection has been hindered by low levels of ctDNA in circulation and the presence of confounding non-tumor-related somatic alts. We developed and validated a ctDNA assay that combines somatic and epigenomic signals to detect early stage tumors without tumor tissue or white blood cells (WBC). Methods: Using a single input sample, our assay integrates the sensitive detection of genomic alts with quantification of epigenomic signals associated with cancer. Non-tumor alts (e.g., clonal hematopoiesis of indeterminate potential; CHIP) are excluded using a newly developed bioinformatic classifier. To assess analytical sensitivity, specificity, and positive and negative reproducibility, we tested 337 clinical and contrived samples. Results: Clinical specificity was determined using 80 plasma samples from 50-75 year old presumptive cancer-free donors, and resulted in a single false positive (99% specificity). Analytical sensitivity (limit of detection) was established using a dilution series of 4 different late stage CRC pts tested in triplicate at a clinically relevant DNA input (30 ng) across multiple batches. 100% sensitivity was maintained even at the lowest tested level (estimated 0.1% tumor level). Positive/negative reproducibility was assessed by testing triplicates of diluted late stage samples and age-matched healthy donors, respectively, across different cfDNA inputs, and multiple reagent lots. Both positive and negative calls were 100% concordant across all replicates. Independent estimation of tumor levels from epigenomic or genomic signals produced highly concordant results (correlation r-value: 0.82, p-value: 3e-16). Conclusions: We designed and validated a highly specific ctDNA assay that integrates both genomic and epigenomic signals to allow for accurate and quantitative tumor level detection in early stages of the disease without requiring tumor tissue or WBC.
The i3+3 design for phase I clinical trials.
Authors: Ji Yuan , Liu Meizi
Published: May 2019

3066

Background: Other than the 3+3 design, new model-based statistical designs like the mTPI design (Ji and Wang, 2013, JCO) are alternative choices for oncology dose-finding trials, including immune oncology dose-finding trials (Atkins et al., 2018, Lancet Oncology). One major criticism of the 3+3 design is that it is based on simple rules, does not depend on statistical models for inference, and leads to unsafe and unreliable operating characteristics. However, the rule-based nature allows 3+3 to be easily understood and implemented in practice, making it practically attractive and friendly. Can friendly rule-based designs achieve great performance seen in model-based designs? For four decades, the answer has been NO. Methods: We propose a new rule-based design called i3+3, where the letter "i" represents the word "interval". The i3+3 design is based on simple but more clever rules that account for the variabilities in the observed data. In short, the i3+3 design simply asks clinicians to compare observed toxicity rates with a prespecified toxicity interval, and make dose escalation decisions according to three simple rules. No sophisticated modeling is needed and the entire design is transparent to clinicians. Results: We compare the operating characteristics for the proposed i3+3 design with other popular phase I designs by simulation. The i3+3 design is far superior than the 3+3 design in trial safety and the ability to identify the true MTD. Compared with model-based phase I designs, i3+3 also demonstrates comparable performances. In other words, the i3+3 design possesses both simplicity and transparency of the rule-based approaches, and the superior operating characteristics seen in model-based approaches. An online R Shiny tool is provided to illustrate the i3+3 design, although in practice it requires no software to design or conduct a dose-finding trial using the design. Conclusions: The i3+3 design could be a practice-altering method for the clinical community. It may increase the safety and efficiency of dose finding trials.
Radiomics features to identify distinct subtypes of triple-negative breast cancers.
Authors: Itakura Haruka , Ikeda Debra M. , Okamoto Satoko , Chen Shu-Tian , Rister Blaine , Gude Dev , Mattonen Sarah A. , Alkim Emel , Todderud Julia , Schueler Emil , Rubin Daniel , Sledge George W. , Kurian Allison W.
Published: May 2019

3069

Background: We sought to gain new insight into triple-negative breast cancer (TNBC), an aggressive, clinically distinct subgroup of breast cancers, by applying a sequence of computational approaches to tumor segmentation, three-dimensional anatomic characterization, and tumor subtyping. We extracted algorithmically-derived quantitative imaging (radiomics) features from each TNBC lesion in breast magnetic resonance imaging (MRI) to identify underlying subtypes. Methods: We evaluated tumors on pre-treatment, post-contrast MRI from 90 patients with non-metastatic TNBC. We employed active contour segmentation and semi-automated identification of tumor regions-of-interest. We extracted 900 radiomics features from each segmented tumor using an algorithm that characterizes the size, shape, texture, and edge sharpness of tumors at the voxel level. We applied k-means consensus clustering, a statistical tool for unsupervised discovery, and performed 1000 bootstraps with resampling on the feature vectors to examine all resulting clusters from k=2 to 10. Based on two diagnostic metrics of consensus stability, we selected the optimum cluster number. We performed Significance Analysis of Microarrays to identify statistically significant radiomics features for each cluster. Results: We identified three distinct image-based clusters in 117 tumors from 90 TNBC patients (multifocal lesions in n=13). Cluster 1 (n=97) was distinguished by 330 radiomics features (False Discovery Rate [FDR] <5%) and Cluster 2 (n=13) by 85 features (FDR<5%), whereas Cluster 3 (n=7) was not significantly associated with features. Clinical characteristics did not differ across the three clusters, with mean age (49.1±11.7) and clinical stage distributions (stage I: 20.7%, II: 55.4%, III: 23.9%) for the cohort mirroring those of individual clusters. Among those who received neoadjuvant therapy, we observed pathologic complete response in 50% (23 of 46, 95% CI, 0.36-0.64) of patients in Cluster 1, 83% (5 of 6, 95% CI, 0.54-1.0) in Cluster 2, and 0% (0 of 3) in Cluster 3. Conclusions: Radiomics features providing voxel-level characteristics of tumor morphology differentiated TNBC into three distinct subtypes. These subtypes, defined by radiomics biomarkers, may be associated with clinical response to neoadjuvant therapy.
Genomic analysis of metastatic solid tumors in veterans: Findings from the VHA National Precision Oncology Program.
Authors: Poonnen Pradeep , Duffy Jill , Hintze Bradley J. , Shukla Maulik , Brettin Thomas S. , Conrad Neal R. , Yoo Hyunseung , Guertin Christopher M. , Looney Jane A. , Vashistha Vishal , Kelley Michael J. , Spector Neil L.
Published: May 2019

3074

Background:
Scalable next generation sequencing (NGS) technologies have enabled incorporation of precision oncology into clinical practice, informing treatment decisions based on tumor genomics. The Veterans Health Administration (VHA) is the largest integrated healthcare system in the U.S., serving a higher percentage of rural patients (36%) than the national average (14%). To implement and standardize the practice of precision oncology across a diverse healthcare system, the VHA established the National Precision Oncology Program (NPOP).
Methods:
Tumor or peripheral blood specimens were collected from Veterans with advanced solid tumors who were eligible for treatment with targeted or immunotherapeutic drugs. Specimens were sequenced using cancer gene panels at two commercial laboratories. Annotated results were generated by the vendors and independently using IBM Watson for Genomics. Levels of evidence treatment recommendations were based upon OncoKB criteria.
Results:
Between July 2016 and June 2018, 3713 samples were collected from 72 facilities; the sequencing success rate was 86%. The majority of samples came from males with lung, prostate and colorectal cancers. Thirty-four percent of samples submitted were from rural patients. The most commonly mutated genes included
TP53
,
ATM
and
KRAS
. Over 70% of samples sequenced had at least one actionable mutation, and clinical trials were the recommended option in over 50%. The most frequent therapies prescribed in response to NGS testing were immune checkpoint inhibitors, EGFR kinase inhibitors and PARP inhibitors. Interestingly, prostate cancers among Veterans had a higher frequency of mutations in genes associated with a neuroendocrine phenotype compared with the general population.
Conclusions:
Implementation of precision oncology into clinical practice is feasible across the diverse VHA system, including rural community sites. Veterans have unique occupational exposures that might inform underlying causes of distinct mutational signatures identified here. Our results highlight the importance of increasing the availability of clinical trials for Veterans.
First-in-human study of AZD5153, a small molecule inhibitor of bromodomain protein 4 (BRD4), in patients (pts) with relapsed/refractory (RR) malignant solid tumor and lymphoma: Preliminary data.
Authors: Wang Judy Sing-Zan , De Vita Serena , Karlix Janet L. , Cook Carl , Littlewood Gillian M. , Hattersley Maureen M. , Moorthy Ganesh , Edlund Helena , Fabbri Giulia , Sachsenmeier Kris F. , Davison Chris , Clark Edwin , Moore Kathleen N. , Bauer Todd Michael , Ulahannan Susanna Varkey , Patel Manish R. , Hamilton Erika Paige
Published: May 2019

3085

Background: BRD4 is a bromodomain and extraterminal (BET) protein that regulates oncogenic programs by modifying gene transcription and additional mechanisms. AZD5153 is a novel, reversible BRD4 inhibitor with bivalent mechanism of action and enhanced antitumor activity in preclinical models. This phase 1, multicenter, dose escalation study (NCT03205176) assesses AZD5153’s safety, pharmacokinetics (PK), and pharmacodynamics (PD). We report here preliminary, unvalidated data from AZD5153 monotherapy in pts with RR solid tumor, including lymphoma. Methods: Adult pts received oral AZD5153 QD/BID to determine the MTD. During dose escalation, a continual reassessment model was used to estimate toxicity and all final decisions were made by the Safety Review Committee. PK and PD were characterized using standard methods. Results: As of 1 Nov 2018, 28 pts (78.6% female, median age 66.5 y) were treated in 7 cohorts: 2 mg QD (3 pts), 5 mg QD (3 pts), 10 mg QD (3 pts), 10 mg BID (5 pts), 15 mg BID (4 pts), 20 mg BID (7 pts), and 30 mg QD (3 pts). Treatment was ongoing in 8 pts at data cut-off. Safety findings showed 50% of pts experienced treatment-related AEs. 25% of pts experienced treatment-related Grade ≥3 AEs, which were thrombocytopenia and fatigue (7.1% each), and anemia, diarrhea, and platelet count decreased (3.6% each). SAEs were observed in 25% of pts; none of the SAEs was attributable to AZD5153 alone. Dose-limiting toxicities of thrombocytopenia (1 pt) and diarrhea with herpetic rash leading to discontinuation (1 pt) occurred at 20 mg BID. 53.6% of pts discontinued due to disease progression. Total median treatment duration was 1.3 mo (range up to 8.9 mos). Dose proportional increase in Cmax and AUC were observed across the dose range tested. Tmax ranged from 0.5 to 3 h and t1/2 was 6 h. Dose-dependent changes in expression of target genes (eg, HEXIM1, HIST2H2BF, CD274, and CCR2) and platelet counts were observed in the peripheral blood. Conclusions: AZD5153 monotherapy is safe and tolerated at doses up to 30 mg QD and 15 mg BID. Linear increase in PK was observed. Additional safety and efficacy updates will be reported at the annual meeting. Clinical trial information: NCT03205176.
PIPA: A phase Ib study of selective ß-isoform sparing phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (T) plus palbociclib (P) in patients (pts) with advanced solid cancers—Safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the doublet combination.
Authors: Lopez Juanita Suzanne , SelviMiralles Manuel , Ameratunga Malaka , Minchom Anna , Pascual Javier , Banerji Udai , Bye Hannah , Raynaud Florence I. , Swales Karen E , Malia Jason , Hubank Michael , Garcia-Murillas Isaac , Parmar Mona , Ward Sarah Emily , Finneran Laura , Hall Emma , Turner Alison Joanne , De Bono Johann S. , Yap Timothy A , Turner Nicholas C.
Published: May 2019

3087

Background: Oncogenic hyperactivation of the PI3K pathway is common in multiple cancers, with preclinical data showing that CDK4/6 inhibitors sensitise PIK3CA mutant cancers to PI3K inhibitors. We report the activity of the P+T in solid tumors with PI3K pathway activation, along with the PD biomarker analysis. Methods: We previously reported the dose escalation phase identifying 125mg P given 3-weeks-on, 1-week-off in combination with T 2mg as the recommended phase 2 dose (R2PD, Lim, ASCO 2017). We report the results in solid tumors with confirmed activating mutations (mts) in the PI3K pathway, from dose escalation and expansion, with no prior exposure to CDK4/6 or PI3K pathway inhibitors. PD studies include analyses of platelet-rich plasma (PRP) and paired tumour biopsies. Results: 20 pts (median age 61, range 34-72) were treated at the doublet RP2D, M/F 7/13, with a median 4 prior treatments (range 2-11). Tumour types included colorectal, breast, lung, endometrial,oligodendroglioma and head and neck cancers. Durable disease control occurred in 3 patients with ER+ advanced breast cancer with responses lasting >6 months including 1 pt with a H1047R PIK3CAmt with an ongoing RECIST PR>36 cycles, 2 pts with PIK3CAmt colorectal cancer had RECIST SD for >5 months, and 1 patient with a PIK3CGmt anaplastic oligodendroglioma had clinical and radiological benefit lasting 5.5 months. Treatment was well tolerated with predictable G1-2 adverse events (AEs). G3 toxicities of neutropenia (n=6), thrombocytopenia (2), rash (2), mucositis (1) and raised transaminases (1 each) were all transient with no G4/5 AEs. Significant decreases in tumour pRb, and pAKT and pGSK3ß in PRP, confirmed modulation of both CDK4/6 and PI3K pathways at R2PD. Conclusions: Doublet P+T is well tolerated at the combination RP2D, with PD evidence of PI3K and CDK4/6 modulation in both plasma and tumor. Promising preliminary anti-tumor activity is seen in a mixed histology cohort selected for activating PIK3 mutations. Clinical trial information: NCT02389842.
A phase I/II first-in-human trial of oral SRA737 (a Chk1 inhibitor) given in combination with low-dose gemcitabine in subjects with advanced cancer.
Authors: Banerji Udai , Plummer Elizabeth Ruth , Moreno Victor , Ang Joo Ern , Quinton Amy , Drew Yvette , Hernández Tatiana , Roda Desamparados , Carter Louise , Navarro Alejandro , Kristeleit Rebecca Sophie , Arkenau Hendrik-Tobias , Sarker Debashis , Castellano Daniel E. , Walter Harriet , Roxburgh Patricia , Blagden Sarah Patricia , Anthoney Alan , Verdon Ines , Jones Robert Hugh
Published: May 2019

3095

Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-02 was designed to investigate the safety, tolerability and preliminary activity of SRA737 in a novel combination with sub-therapeutic doses of gemcitabine (low dose gemcitabine; LDG) utilized to potentiate SRA737’s activity by induction of replication stress in subjects with advanced solid tumors. Methods: Phase 1 dose escalation investigated cohorts of 3 to 6 subjects receiving escalating doses of SRA737 for 2 days after LDG administration on days 1, 8, 15 of 28-day cycles. Phase 2 expansion cohorts explored the hypothesis that LDG strongly synergizes with SRA737 in subjects with genetically-defined tumors hypothesized to be sensitive to Chk1 inhibition: urothelial, high grade serous ovarian, small cell lung, soft tissue sarcoma, and cervical or anogenital cancers. Results: A total of 55 subjects received SRA737 in 13 dose escalation cohorts at doses of 40 to 600 mg SRA737 combined with LDG doses of 50 to 300 mg/m2. No protocol-defined dose limiting toxicities (DLTs) have been observed. The pharmacokinetic profile of SRA737 revealed an AUC0-24 and Cmax of 3550 ng∙h/mL and 548 ng/mL at 150 mg SRA737. At this dose, the Cmin (52 ng/mL) exceeded that determined in preclinical models to be effective. Enrollment into expansion cohorts was initiated at 500 mg SRA737 plus 100 mg/m2 LDG with intra-patient dose escalation permitted to 250 mg/m2 LDG. Approximately 80 subjects were planned and 82 have been treated. Median treatment duration was 51 days (range 1 to 358). The most common treatment-emergent adverse events were nausea (53%), vomiting (45%), fatigue (40%), diarrhea (38%), and anemia (28%); the majority were of mild to moderate severity. Proof-of-concept clinical activity has been seen in tumor types such as anal, cervical, and rectal. Conclusions: The combination of LDG and SRA737 has been well tolerated. This first-in-human clinical study provides proof-of-concept that sub-therapeutic LDG effectively potentiates SRA737. This novel replication stress-targeted therapy warrants further evaluation in genetically pre-defined solid tumors. Clinical trial information: NCT02797977.
FGFR2: A pan-genomic target.
Authors: Madison Russell , Sokol Ethan , Schrock Alexa Betzig , Johnson Adrienne , Pavlick Dean , Elvin Julia Andrea , Vergilio Jo-Anne , Ngo Nhu , Killian Jonathan Keith , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Ali Siraj Mahamed , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Miller Vincent A. , Ross Jeffrey S.
Published: May 2019

3099

Background: FGFR2 genomic alterations (GA) have been described in a variety of solid tumors and emerged as biomarkers for investigational agents undergoing clinical trials. Methods: 201,766 primarily relapsed/refractory malignancies were evaluated with a hybrid-capture based sequencing assay Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and reported as mut/Mb. Microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3 antibody). Results: FGFR2 GA were detected in 2,993 (1.5%) cases featuring short variant (SV) mut (42%), copy number changes (27%), rearrangements/fusions (28%) and multiple GA (3%). The most frequent SV GA were S252W, N549K, C382R, P253R, Y375C, K659E and R664W. A small cohort (2%) of tumors featured the V564I and V564L GA that are associated with resistance to TKI drugs. The FGFR2-altered cases were 69% female/31% male with median age of 61 yrs. Most frequent GA in FGFR2 altered cancers: TP53 (47%), PIK3CA (22%), PTEN (20%), ARID1A (18%), CDKN2A/2B (18/14%) and MYC (12%). FGFR2 SVs most common in endometrial, breast carcinomas (ca) and CUP. FGFR2 amplification most common in breast, gastroesophageal and lung ca. FGFR rearrangement/fusions most common in cholangioca (37%), CUP (15%), pancreatobiliary (12%) and breast ca (6%). The FGFR2- BICC1 was the most frequent fusion followed by fusions with TACC2, AHCYL1, CCDC6, VCL, and KIAA1217. MSI-High status present in 6.8% of evaluable FGFR2 altered cases (63% in endometrial ca). Median TMB was 3.5 mut/Mb with 21.8% featuring ≥ 10 mut/Mb and 12.0% featuring ≥ 20 mut/Mb. Only 63% of MSI-High FGFR2 mut tumors had TMB ≥ 20 mut/Mb. 12.7% FGFR2 mut+ had > 1% PD-L1 staining with 3.4% > 50% staining. 29% of PD-L1 IHC+ cases in NSCLC. FGFR mut ca’s responding to anti-FGFR2 therapies will be presented. Conclusions: FGFR2 GA are most frequent in cholangioca, breast, GI tract, lung ca and CUP, with enrichment of FGFR2 fusions in biliary tract ca. Cases with FGFR2 GA typically do not feature other kinase driver GA and are associated with mut in the MTOR/PIK3CA/AKT pathways. Finally, in contrast with RTK driver GA in EGFR (5.7%) and ERBB2 (7.9%), at 12.0%, across all tumor types, FGFR2 mut cancers may have higher frequency of TMB ≥ 20 mut/Mb suggesting potential immunotherapy responsiveness.
Molecular biology and treatment strategies for non-V600 BRAF-mutant NSCLC.
Authors: Negrao Marcelo Vailati , Raymond Victoria M. , Lanman Richard B. , Ng Patrick Kwok Shing , Nagy Rebecca , Banks Kimberly , Zhu Viola Weijia , Amador Bianca E , Roarty Emily , Chae Young Kwang , Clarke Jeffrey Melson , Crawford Jeffrey , Ou Sai-Hong Ignatius , Gandara David R. , Heymach John , Bivona Trever Grant , McCoach Caroline Elizabeth
Published: May 2019

3102

Background: BRAF alterations (alts) account for ~4% of non-small cell lung cancers (NSCLC) with 50% being non-V600 alts. Because these alts are functionally heterogeneous and have a poorly characterized genomic landscape, determining appropriate treatment strategies is a challenge. Methods: The Guardant360 clinical database was queried for NSCLC patients (pts) with BRAF alts. Alts were categorized by clonality, type and class (1 and 2: BRAF monomer and dimer signaling; 3: requires co-occurring upstream RAS-mediated signaling). Functionality and drug screen assays were performed in Ba/F3 cells. Pts with non-V600 mutations were analyzed for sensitivity to MEK +/- BRAF inhibitors (M+Bi). Results: 306 unique BRAF alts were identified and the majority were observed once (233/306; 76%). Amplifications (806/1663; 48.5%) and missense alts (795/1663; 47.8%) were the most common occurrences. Missense alts were predominantly clonal (58%), and of known functionality (428/795; 54%). All class 1-2 alts were activating in Ba/F3 cells, while class 3 alts were found to have variable functionality (activating: 4/9). Functionality was correlated with clonality as demonstrated by class 1-3 alts having higher clonality compared to variants of unknown significance (VUS) (1: 56%; 2: 54%; 3: 45%; VUS: 38%; P<0.01). Drug screens for G469V and L597R alts showed resistance to first generation BRAF inhibitors (IC50 ≥100nM), but sensitivity to M+Bi (IC50 0.02-36nM). Growth inhibition was more pronounced for dabrafenib + trametinib (D+T) (IC50 <0.1nM) compared to encorafenib + binimetinib (IC50 8-35nM) and vemurafenib + cobimetinib (IC50 2-36nM). BRAF D594G mutation (class 3) was not activating in Ba/F3 cells. Three pts with non-V600 alts were treated with M+Bi. G469V and D594G had rapid disease progression (PFS 2 and 4 mos respectively), while pt with L597R has ongoing partial response (PFS 8+ mos). Conclusions: BRAF alts show correlation between clonality and functionality, which provides important clinical information given the numerous VUS in the BRAF non-V600 setting. Drug screens reveal non-V600 alts may be sensitive to M+Bi and suggest D+T is the most active combination. Clinical data supports that some non-V600 BRAF mutations may be sensitive to M+Bi.
The Circulating Cell-free Genome Atlas (CCGA) Study: Size selection of cell-free DNA (cfDNA) fragments.
Authors: Filippova Darya , Larson Matthew H. , Maher M. Cyrus , Calef Robert , Pimentel Monica , Zhou Yiqi , Newman Joshua , Gross Samuel , Nicula Virgil , Liu Ting-Chun , Yakym Christopher , Berman Jennifer , Aravanis Alex , Jamshidi Arash
Published: May 2019

3103

Background: Detection of somatic copy number aberrations in individuals with cancer via cfDNA whole-genome sequencing (WGS) is challenging at low tumor fractions. Given that tumor-derived cfDNA fragments are shorter than those from healthy tissues, this exploratory analysis evaluated the potential effect of size selection on the ability to detect cancer. Methods: CCGA WGS libraries were in silico and in vitro size selected to estimate the change in tumor fraction by tumor types (breast, lung, and colorectal [CRC]) and stage (I-III vs IV). In silico analyses used clinically evaluable training set samples with WGS assay results (n = 1422: 560 non-cancer [NC], 862 cancer [C] stages I-IV); classification (cancer/non-cancer) performance was estimated using fragments within the 90-150 bp range. In vitro analyses used a subset of samples (n = 93: 28 NC, 65 C stages I-IV), including C cases sampled within a range of tumor fractions; tumor fraction was also measured at each progressive removal of maximum-length fragments (intervals of 10 bp: 150 bp down to 50 bp). Results: In silico and in vitro analyses, respectively, resulted in median 2.00±0.58-fold (at 6.91±2.64X depth) and 2.00±0.52-fold (at 23±4.45X depth) increases, in overall tumor fraction (compared to non-size-selected 36X depth). This was consistent across tumor types ( in silico: 1.78±0.73 breast, 2.00±0.58 CRC, 2.00±0.41 lung; in vitro: 2.00±0.82 breast, 2.51±0.52 CRC, 2.53±0.94 lung) and stages ( in silico: 2.00±0.74 I-III, 1.78±0.52 IV; in vitro: 2.00±0.55 I-III, 1.68±0.29 IV). Tumor fraction increased with initial fragment length titrations, but not following size selection to shorter lengths ( < 140 bp). Classifier trained on in silico size-selected data had increased sensitivity at 98% specificity compared to those trained on non-size-selected data (p < 1e-5). Conclusions: In silico and in vitro size selection consistently increased tumor fraction across cancer types and stages, and this increase was maximized by tuning the length range of size selection. Relative to full-depth data, classification performance improved significantly. These data suggest that size selection targeting cfDNA under 140 bp may enhance cfDNA-based cancer detection. Clinical trial information: NCT02889978.
Targeting the p300/CBP interactome through blockage of the CH1-domain triggers tumor regression in AR-positive and AR-negative xenograft models of castration-resistant prostate cancer (CRPC).
Authors: Cattori Valentino , Hentsch Bernd , Kessler Ulrich
Published: May 2019

3105

Background: In advanced prostate cancer, the paralog transcription co-activators p300/CBP are often highly expressed and have been associated with disease progression and poor prognosis. While several inhibitors of the bromo- and histone acetyltransferase domains of p300/CBP have been described, past efforts to develop drug-like ligands of other regions of this attractive target have been unsuccessful. Methods: A rationally designed small molecule modulator of the CH1-domain of p300/CBP was tested in a panel of prostate cancer cell lines, followed by cell cycle analysis and beta-galactosidase staining. Inhibition of the p300-dependent androgen receptor (AR) related transcriptional response was determined in a luciferase reporter assay and by qPCR analysis of expression of downstream genes like prostate-specific antigen (PSA), transmembrane protease-serine 2 (TMPRSS2) and prostein (SLC45A3). In vivo effects were evaluated in cell line- and patient-derived xenograft models of CRPC. Results: Selective blockage of the CH1 domain of p300/CBP results in sustainable anti-proliferative effects in AR-positive and AR-negative prostate cancer cells inducing apoptosis and/or senescence. Transcriptome and gene expression analyses revealed the downregulation of various drivers of cell cycle progression as well as decreased expression of hormone-induced, AR-regulated genes. In enzalutamide-resistant xenograft models of CRPC, oral administration of the compound triggered tumor regression/eradication at well tolerated doses. Serum PSA levels were strongly decreased in treated animals. Conclusions: Simultaneous inhibition of both, AR-signaling and downregulation of p300/CBP activity, may cause profound and long lasting antitumoral effects in patients with advanced prostate cancer. Future clinical investigation of this novel oral small molecule agent is warranted.