bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized, optimal dose-finding, phase II study of tri-weekly nab-paclitaxel in patients with metastatic breast cancer (ABROAD).
Authors: Hara Fumikata , Kitada Masahiro , Takahashi Masato , Kikawa Yuichiro , Kato Hiroaki , Sakata Eiko , Naito Yoichi , Hasegawa Yoshie , Saito Tsuyoshi , Iwasa Tsutomu , Tsurutani Junji , Taira Naruto , Takashima Tsutomu , Kashiwabara Kosuke , Aihara Tomohiko , Mukai Hirofumi 
Published: May 2019

1070 Background: Although nab-paclitaxel (nab-PTX) has shown superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), chemotherapy induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In a single arm Phase 2 trail (CA002-0LD), low dose nab-PTX (175mg/m2) every 3 weeks (q3w) demonstrated a good objective response rate (39.5%) without grade 3 or higher CIPN. Herein, we conducted multicenter randomized controlled study to evaluate optimal dose of nab-PTX comparing lower dose (LD or MD) to standard dose (SD). Methods: This study compared three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) in patients with HER2 negative metastatic breast cancer. Primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates in the three doses are estimated by the logistic regression. Optimal dose was selected by 2 step selection. At first, if hazard ratio (HR) for PFS was less than 0.75 or more than 1.33, the inferior dose was dropped. Then, if estimated incidence rate of grade 3/4 neurotoxicity exceed10%, that dose was also dropped. This trial is registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). Results: In this study, 141 patients were randomly assigned to SD (n = 47), MD (n = 46) or LD (n = 48). Median PFS was 6.66 vs 7.34 vs 6.82 months, respectively. HR was 0.73 (95% confidence interval (CI): 0.42-1.28) in MD vs SD. SD was dropped due to inferiority to MD. HR was 0.77 (95%CI 0.47-1.28) in LD vs SD, and 0.96 (95%CI 0.56-1.66) in LD vs MD. LD and MD were carried over to next step due to equivalence. Overall survival was not different among all dose arms. Rate of dose reduction by treatment course was significantly higher in SD arm. Estimated incidence of grade 3/4 neurotoxicity rate was 29.5% in SD, 14.0% in MD and 5.9% in LD. Final selected dose was LD 180mg/m2. HR-QOL results will be presented. Conclusions: Low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose with good clinical efficacy and tolerability for patients with MBC. Clinical trial information: C000012429.
Reversion and non-reversion mechanisms of resistance (MoR) to PARP inhibitor (PARPi) or platinum chemotherapy (chemotx) in patients (pts) with BRCA1/2-mutant metastatic breast cancer (MBC).
Authors: Waks Adrienne Gropper , Cohen Ofir , Kochupurakkal Bose , Kim Dewey , Wander Seth Andrew , Buendia-Buendia Jorge , Helvie Karla , Matulonis Ursula A. , Krop Ian E. , Tolaney Sara M. , Winer Eric P. , D'Andrea Alan D. , Shapiro Geoffrey , Lin Nancy U. , Wagle Nikhil 
Published: May 2019

1085 Background: Little is known about MoR to PARPi and platinum chemotx in MBC pts with BRCA1/2 mutations. Biomarkers predictive of response/resistance have not been identified, but could have clinical utility. Methods: We obtained 8 BRCA-mutant metastatic tumor biopsies from MBC pts with acquired resistance to DNA-damaging tx (PARPi/platinum) on a prospective tissue collection protocol. In 7/8 patients, we also obtained pre-tx biopsies. Whole exome sequencing (WES) was performed on each tumor and on germline DNA from blood. We performed immunohistochemical (IHC) staining for RAD51 foci for functional assessment of intact homologous recombination (HR). Results: 4/7 pts with complete WES analysis acquired a somatic reversion mutation likely to result in functional BRCA1/2 protein in the post-tx tumor specimen after platinum (2 pts) or PARPi (2 pts; Table). 4/7 pts had plausible non-reversion MoR identified by WES, including alterations in genes involved in replication fork protection and DNA end resection. As expected, in all pts with genomic reversion, RAD51 foci were acquired in the post-resistance tumor, consistent with reconstitution of HR. In 2 pts without reversion, presence of RAD51 foci post-resistance was mixed. Reversion mutations occurred both with and without other alterations that could possibly lead to fork protection, suggesting > 1 MoR could occur in the same tumor. 3 pts whose tumors demonstrated RAD51 foci post-resistance were later re-exposed to DNA-damaging tx, to which all had intrinsic resistance. Conclusions: BRCA1/2 reversion was identified as a MoR in the majority of pts. WES identified potential novel MoR in fork protection and end resection genes. The presence of RAD51 foci by IHC was consistent with BRCA protein functional status from genomic data and predicted response to later DNA-damaging tx, suggesting RAD51 IHC may be a clinically useful biomarker. [Table: see text]
Hyperprogressive disease in advanced triple-negative breast cancer (aTNBC) treated with immunotherapy (IO).
Authors: Tan Tira Jing Ying , Cescon David W. , Wang Lisa , Amir Eitan , Vieira Daniella , Zammit Kaitlyn , Warr David , Elser Christine , Butler Marcus O. , Abdul Razak Albiruni Ryan , Hansen Aaron Richard , Spreafico Anna , Siu Lillian L. , Bedard Philippe L. 
Published: May 2019

1086 Background: Hyperprogression of disease (HPD), a rapid acceleration of tumor growth rate (TGR) has been reported with IO in other tumor types. Here, we explore HPD in aTNBC. Methods: A retrospective chart review identified aTNBC patients who consented for IO clinical trials at Princess Margaret Cancer Centre between June 2013 and June 2018. Demographic data, medical history, details of trial enrolment and RECIST 1.1 response to study treatment were recorded. Patients with RECIST 1.1 measurable disease on CT scans or physical examination before trial entry, at trial baseline and at protocol-defined interval following IO start were evaluable for TGR as defined by Champiat et al. Clin Cancer Res 2017. HPD defined as a ≥2-fold increase in TGR between baseline and on-trial restaging assessment. Univariable logistic regression used to identify variables [age, co-morbidity index, prognostic index, performance status, distant disease free interval (dDFI), lactate dehydrogenase, no. of metastatic sites, visceral disease and no. of prior treatment lines] associated with HPD. Overall survival (OS) curves were estimated with the Kaplan-Meier method and compared by the log-rank test. Results: 99 patients with aTNBC consented for 15 IO clinical trials, 60% IO monotherapy, 22% chemotherapy+/-IO and 18% IO combinations. Median age 52 (range 25-78), median no. of lines of prior systemic therapy for advanced disease 1 (range 0-8). 15% had de-novo metastatic disease, 58% recurred after a dDFI of < 3 years and 25% after a dDFI of > 3 years. 61% had < 3 metastatic disease sites, and 71% had metastases involving the viscera. 66 received IO treatment, 40 patients (20 monotherapy, 7 IO combination, 13 chemotherapy+/-IO) were evaluable for TGR. Median TGR pre-IO was 74.3 (range -17 – 1680) and post-IO was 2.5 (-71.4 – 223). 4 patients (10%) met criteria for HPD. All 4 treated with monotherapy PD1 inhibitor and received at least 2 further lines of therapy post-trial; 1 patient treated with IO as first-line therapy, 3 in the second or later lines. There was no significant difference in the overall OS of patients with HPD and patients who did not meet definition for HPD HR 0.89, (95% CI: 0.26-3.01; p = 0.41). Univariable analysis did not identify factors associated with HPD. Conclusions: HPD was observed in 10% of aTNBC treated on IO clinical trials. HPD was not associated with worse survival outcomes or known prognostic factors in our analysis.
A predictive model for survival in non-small cell lung cancer (NSCLC) based on electronic health record (EHR) and tumor sequencing data at the Department of Veterans Affairs (VA).
Authors: Fillmore Nathanael , Ramos-Cejudo Jamie , Cheng David , Tuck David P. , Sheikh Ayesha Rizwan , Chen Daniel , Elbers Danne , Sung Feng-Chi , Johnson Brett , Shannon Colleen , Pierce-Murray Karen , Gaynor Kelly , Dedomenico Corri , Schiller Sarah , Ajjarapu Samuel , Hall Robert , Ayandeh Siamack , Meng Frank , Brophy Mary T. , Do Nhan 
Published: May 2019

109 Background: Machine learning tools based on EHR data hold promise to help avoid unnecessary risks associated with lung cancer and its treatment. Additionally, molecular genetic profiling is becoming an integral tool for clinicians to individualize treatment for lung cancer. However, relatively few survival models have been built that integrate this data in individualized predictive models. Here, we combine real-world EHR and tumor sequencing data from the VA Precision Oncology Data Repository (PODR) to build accurate individualized survival predictions in newly-diagnosed NSCLC patients. Methods: We identified a cohort of 356 VA patients newly diagnosed with NSCLC for whom EHR, cancer registry, and targeted tumor sequencing data is available in PODR. We defined 41 features reflecting 15 baseline clinical and demographic characteristics from the EHR and registry, such as age, race, stage, histology, and therapy. We also defined features reflecting 206 clinically actionable somatic variants. We selected 5 important variants for inclusion in the model, as well as the total number of mutations. We trained a random forests algorithm to predict 1-year survival. Precision, recall, and area under the ROC curve (AUC) were assessed using 5-fold cross validation. Results: Mean age at diagnosis was 66 years. The majority of patients had late stage disease (15% stage I, 6% II, 15% III, 44% IV), and 59% of patients received systemic therapy. 45% died within 1 year of diagnosis, and 55% survived past 1 year. Our predictive model for 1-year survival achieves strong results. Cross-validated AUC is 0.79 (SD 0.08), precision is 0.79 (SD 0.07), recall is 0.74 (SD 0.07), suggesting that the trained model combining clinical and genomic features is effective at predicting 1-year survival. Conclusions: By integrating real-world EHR and sequencing data, we built a highly accurate predictive model of 1-year survival in NSCLC patients at the VA. Such a model, after ongoing validation in a larger cohort, offers the ability to make individualized predictions that could inform patient care to improve outcomes.
Effect modifiers in a randomized phase III trial of low-dose tamoxifen in breast preinvasive disease.
Authors: De Censi Andrea , Puntoni Matteo , Guerrieri-Gonzaga Aliana , Caviglia Silvia , Avino Franca , Cortesi Laura , Ponti Antonio , Paquola Maria Grazia , Falcini Fabio , Gulisano Marcella , Digennaro Maria , Cariello Anna , Cagossi Katia , Johansson Harriet Ann , Pinotti Graziella , Lazzeroni Matteo , Buttiron Webber Tania , Corradengo Davide , Boni Luca , Bonanni Bernardo 
Published: May 2019

1500 Background: Low-dose tamoxifen (babytam) at 5 mg/day for 3 years decreases local or contralateral recurrence by 52% in women with hormone sensitive breast pre-invasive neoplasia after surgery (DeCensi et al JCO 2019). Here we report the results of exploratory analyses to assess whether the benefit of babytam varies among subgroups of patients defined by individual characteristics. Methods: Post-hoc subgroup analyses were performed according to a mixed approach based on the test for interaction and biological plausibility. Incidence of invasive breast cancer or DCIS was the primary endpoint. HRs were estimated using Cox proportional-hazards modeling. Results: Age at menopause, smoking status and Ki-67 exhibited a significant interaction with treatment. Specifically, the effect of babytam was greater in women aged > 50y (n = 293, HR = 0.27, 95%CI: 0.10-0.73) than in women aged ≤50y (n = 207, HR = 0.86, 0.35-2.07), p-interaction = .09. Never smokers (n = 307) had a greater benefit than former (n = 68) or current smokers (n = 97): HR = 0.28, 0.11-0.70 vs HR = 0.57, 0.09-3.45 vs HR = 1.51, 0.41-5.64, respectively (p = .05). Tumors with Ki-67 above the median level of 10% (n = 133) had a greater effect (HR = 0.27, 0.09-0.81) than Ki-67 ≤10% (n = 145, HR = 1.58, 0.45-5.60, p = .04). Weaker statistical interactions (p > .1) were also found for waist circumference and hot flashes (HF) at baseline. Women with waist circumference ≥89 cm (metabolic syndrome, n = 208) had a greater effect (HR = 0.22, 0.07-0.78) than women < 89 cm (n = 228, HR = 0.61, 0.25-1.46). Compared with placebo and no HF, babytam effect was stronger in women with HF (HR = 0.13, 0.02-0.96) than in women on babytam and no HF (HR = 0.50, 0.24-1.03) or placebo and HF (HR = 0.72, 0.31-1.69, log-rank p-trend = .004). Additional subgroups according to obesity, family history of breast or ovarian cancer, alcohol use, extent of surgery, radiotherapy for DCIS, ER and HER2 expression, positive margins and treatment compliance showed no significant heterogeneity of treatment. Conclusions: Exploratory analyses showed a trend to a higher effect of babytam in women aged 50 or older, never smokers, women with hot flashes or abdominal obesity and tumors with Ki-67 above 10%. Our results provide insight into the efficacy of babytam towards a personalized preventive approach. Clinical trial information: NCT01357772.
Inherited DNA repair and cell cycle gene defects in chronic lymphocytic leukemia.
Authors: Moore Nicholas S. , Aldubayan Saud H. , Taylor-Weiner Amaro , Stilgenbauer Stephan , Getz Gad , Wu Catherine J. , Van Allen Eliezer Mendel , Brown Jennifer R. 
Published: May 2019

1508 Background: Chronic lymphocytic leukemia (CLL) is among the most heritable cancers, with 60% of disease risk genetically determined. However, most of the genetic heritability of CLL remains unexplained. Previously, we identified ATM as the first CLL risk gene. Here, we leverage a deep-learning-based germline variant calling algorithm to explore germline mutational enrichment in DNA repair and cell cycle genes in CLL. Methods: A two-stage case-control analysis was conducted using gene-based mutational enrichment analysis of 50 established cancer predisposition DNA repair and cell cycle genes. In the discovery phase, a total of 285 Spanish patients and 5,608 ancestry-matched controls were evaluated. In the validation stage, an independent cohort of 514 European patients and 27,173 ancestry-matched controls were analyzed. An FDR correction was applied to both datasets and genes with a q-value < 0.2 in both cohorts were considered significant. Results: Our joint analysis of 799 CLL patients from 2 genetically distinct cohorts and 32,781 ancestry-matched cancer-free controls identified ATM and CHEK2 as significantly enriched in both CLL datasets. First, our analysis recaptured the previously reported finding of ATM variant enrichment in CLL patients. Carriers of pathogenic ATM mutations in our cohorts (n = 9 patients, discovery: 1.05%, validation: 1.17%) were 2.8–3.7 times more likely to develop CLL compared to cancer-free individuals (discovery: OR = 2.8, 95%CI = 0.7–9.0, q-value = 0.181; validation: OR = 3.7, 95%CI = 1.6–8.3, q-value = 0.0454). In addition, our analysis identified 21 CLL patients carrying pathogenic CHEK2 alterations (discovery: 1.40%, validation: 3.31%), making CLL patients 4.4-8.0 times more likely to carry such alterations compared to controls (discovery: OR = 8.0, 95%CI = 2.3–27.0, q-value = 0.026; validation: OR = 4.4, 95%CI = 2.5–7.3, q-value < 0.001). Conclusions: Our analysis of genetically distinct CLL cohorts, using a high-sensitivity variant calling algorithm, supports CHEK2 as a potentially novel CLL predisposition gene that may explain a portion of the missing monogenic heritability of CLL. In addition, this study highlights the DNA repair and cell cycle regulation pathways as potential drivers of CLL susceptibility.
Genetic identification and characterization of Lynch syndrome in a multi-ethnic biobank.
Authors: Rosenblum Rachel , Suckiel Sabrina A. , Belbin Gillian M. , Cullina Sinead , Cho Judy H. , Kenny Eimear E. , Lucas Aimee L. , Ang Celina , Abul-Husn Noura S. 
Published: May 2019

1520 Background: Lynch syndrome (LS), caused by germline pathogenic variants in mismatch repair (MMR) genes, results in increased risk of colorectal, endometrial, and other cancers. LS has a prevalence of ~1 in 440 in European ancestry populations; prevalence data in other populations are limited. We identified and characterized carriers of pathogenic MMR gene variants in the multi-ethnic Bio Me Biobank in New York City. Methods: Exome sequence data from ~31,000 Bio Me participants were evaluated for known (per ClinVar) and predicted (loss-of-function) pathogenic variants in MMR genes. Population groups were defined by genetic ancestry. Participant questionnaires and electronic health records (EHRs) of carriers were reviewed for personal or family history of malignancy. Results: We identified 48 carriers of 33 distinct pathogenic variants in PMS2 (48%), MLH1 (27%), MSH6 (15%), and MSH2 (10%), for an estimated prevalence of ~1/640 in the Bio Me Biobank. Prevalence was higher among individuals of Non-Jewish European (N = 14; 1/400) and African (N = 14; 1/490) ancestries, compared to Puerto Rican (N = 8; 1/640), Ashkenazi Jewish (N = 6; 1/690), and other/mixed (N = 6) ancestries. Carriers had a median age of 56 (range 27 to 77) years and were 50% female. Overall rate of malignancy among carriers was 38%, with the lowest rate in PMS2 (26%) and the highest rate in MSH6 (57%) variant carriers. We found a high prevalence of endometrial cancer (21% of female carriers) and a lower prevalence of colorectal cancer (4% of all carriers). Only 2 carriers (4%) had a diagnosis of LS in their EHRs, and only 1 carrier met Amsterdam diagnostic criteria for LS. Conclusions: These data show that ~0.15% of participants in a multi-ethnic biobank are carriers of pathogenic MMR gene variants and suggest that the prevalence is higher in European and lower in non-European ancestry populations. Notably, most carriers do not have a clinical diagnosis of LS and do not meet diagnostic criteria for LS. Carriers demonstrate variable rates of cancer, which may contribute to under-diagnosis of LS. Genomic screening for pathogenic MMR variants may lead to earlier diagnosis of LS and improved outcomes.
Tumor mutation burden and PD-L1 expression in SDH/FH mutated solid tumors.
Authors: Drusbosky Leylah , Szeto Christopher , Reddy Sandeep K. , Ghotra Maninderjit , Toor Amir A. , Smith Steven , Faber Anthony , Boikos Sosipatros Alexandros 
Published: May 2019

1524 Background: Succinate Dehydrogenases and Fumarate Hydratase (SDH/FH) deficient tumors are characterized by succinate/fumarate accumulation and resultant pesudohypoxia that drives malignant transformation. This state of pseudohypoxia leads to dysregulation of PD-1 receptor-ligand signaling. In this study, we explored tumor mutation burden (TMB), gene expression of PD-L1, and expression of other immune checkpoint- associated genes in a diverse cohort of human tumors harboring SDH A, B, C, D and FH mutations. Methods: Retrospective analysis was performed on whole exome sequencing (WES; ~150x coverage) and whole transcriptomic RNAseq (~200x106 reads per tumor) data from NantHealth to identify tumors harboring SDHx and/or FH mutations. WES was performed on tumor tissue and matched normal for each patient to assess TMB. TMB was measured by counting all somatic-specific non-synonymous exonic mutations, with > 200 mutations qualified as TMB-high. Immune checkpoint therapy-related gene expression was evaluated for PDL1, CTLA4 , IDO, LAG3, FOXP3, PDL2, TIGIT, TIM3 and OX40 . Results: Among tumor samples from 3377 patients analyzed, 42 patients were found to harbor potentially-pathogenic & pathogenic mutations in the SDHA, B, C, D and FH genes. The most common tumor types with SDH/FH mutations were lung (n = 7), breast (n = 6), and colon cancer (n = 6). Our analysis revealed that TMB was positively correlated with the presence of SDH/FH mutations (p < 0.001). High PD-L1 expression was also significantly correlated with the presence of SDH/FH mutation (p < 0.05), while CTLA4, IDO, LAG3, FOXP3, and OX40 expression was significantly higher in SDH/FH mutated samples (p < 0.05). Conclusions: We report for the first time an association between increased TMB and increased PD-L1 expression in a variety of SDH/FH mutated tumors. These key parameters, imply that a higher TMB may drive the evolutionary pressure to select clones with a PDL1 high phenotype. This observation supports a potential therapeutic role for inhibition of PD-1/PD-L1 pathway in these tumors.
Prospective Registry of Multiplex Testing (PROMPT): Follow-up.
Authors: Brower Jamie , Symecko Heather , Hamilton Jada G. , Harstad Tricia , Merrill Margaret , Balmaña Judith , Walsh Michael Francis , Garber Judy Ellen , Offit Kenneth , Domchek Susan M. , Robson Mark E. 
Published: May 2019

1527 Background: Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals who have had multiplex panel testing for cancer susceptibility. The main objective of this registry is to ascertain families to allow penetrance calculations for mutations in less well characterized genes. Methods: Since September 2014, health care providers and commercial laboratories have given PROMPT information with the test results to eligible individuals. Participants with pathogenic mutations or variants of unknown significance in cancer susceptibility genes have self-enrolled in PROMPT. We have sent annual follow-up surveys to participants to capture updated personal and family histories, additional genetic testing in the family, and changes in cancer screening patterns. Results: To date, 5800 participants have enrolled in PROMPT and 2321 follow-up surveys are completed. Of those eligible for follow-up, 1980 (44%) have completed at least one survey. 134 (5.8%) reported a new cancer diagnosis since baseline. Breast cancer (37, 27.6%) and non-Melanoma skin cancer (35, 26.2%) were the most commonly reported new diagnoses. 5.7% of participants with an ATM variant, 5.2% of those with a BRCA2 variant, and 4.3% of those with a CHEK2 variant and at least one follow-up survey have reported a new primary cancer diagnosis (excluding non-Melanoma skin cancer). In addition, 70 (3%) participants reported a cancer recurrence since time of last follow-up. Bone (9, 12.9%) and liver (8, 11.4%) were the most common recurrence sites. 12.7% of those with a TP53 variant, 7.1% of those with a BARD1 variant, and 3.3% of those with an ATM variant and at least one follow-up survey have reported a recurrence. 59 (2.5%) participants had additional clinical genetic testing, and 555 (24%) participants reported clinical genetic testing of family members. Conclusions: PROMPT collects updated health information from participants to achieve the primary goal of determining cancer incidence among carriers of different mutations. Moreover, PROMPT has increased participant contacts through use of annual follow-up surveys and gene-specific surveys with subsets of participants. Ongoing efforts include obtaining pathology reports of new and recurrent cancer diagnoses on study.