bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Cardiometabolic risk factors and survival after cancer in the women’s health initiative.
Authors: Simon Michael S. , Hastert Theresa , Luo Juhua , Chlebowski Rowan T. , Ruterbusch Julie J. , Beebe-Dimmer Jennifer Lynn
Published: May 2019

1556

Background: Features associated with metabolic syndrome have been connected to both risk and poorer outcomes for certain cancers. Methods: We used data on 12,107 women enrolled in the Women’s Health Initiative diagnosed prospectively with either local or regional stage cancer to evaluate the association between cardiometabolic risk factors identified at study entry, (elevated waist circumference (WC), hypertension, high cholesterol, and presence of type 2 diabetes), with death from either cancer, cardiovascular disease (CVD), or other causes. Cancer sites included those previously linked in the published literature to metabolic syndrome and cancer risk: breast, colorectal, endometrial, non-Hodgkin’s lymphoma, kidney, pancreatic, ovarian, stomach and liver. Multiple imputation methods were used to account for missing data (6.9%). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusted for other significant predictors of survival. Results: After a median follow-up of 10.0 years, there were 3,612 total deaths with 1,547 (43 %) due to cancer. Most participants (60.3%) had at least 2 cardiometabolic risk factors, and 5.8% had 3 or 4. Having 3-4 risk factors, was associated with significantly higher mortality due to cancer (HR: 1.39, 95% CI: 1.12, 1.71), CVD (HR: 2.62, 95% CI: 1.91, 3.59), and other causes (HR: 1.97, 95% CI: 1.57-2.47) compared with no risk factors. High WC was associated with higher mortality due to cancer and other causes, and history of diabetes, and hypertension were associated with higher mortality due to CVD, and other causes. Conclusions: Among women diagnosed with early or regional stage cancer, the presence of 3-4 cardiometabolic risk factors which is consistent with a diagnosis of metabolic syndrome, are significantly associated with death due to cancer, CVD, and other causes. Attention to primary prevention focused on weight control, physical activity and diet after cancer diagnosis and treatment, can have an important positive influence on survivorship after cancer.
“Early impact” of the lung cancer screening in United States population in the SEER Registries.
Authors: Emmerick Isabel M , Varlotto John M. , Powers Maggie M , Lou Feiran , Lin Poliana , Maxfield Mark , Uy Karl
Published: May 2019

1569

Background: The Lung Cancer Screening Trial (NLST) demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS), likely due to finding early-stage NSCLC. Our study investigates the impact of the NLST publication in 2011 on the lung cancer outcomes in the general US Population by assessing the incidence rates, ratio of early/late stage, and lung cancer mortality in the years immediately prior to and following this publication. Methods: Rate sessions from the SEER18 database were accessed during the years 2008-2015. We analyzed overall lung cancer incidence and mortality rates. The ratio of early/late stage was obtained by dividing the number of stage I and II cases by the number of stage III and IV diagnosed by year. We investigate changes in level and trend using interrupted time series in STATA12, considering 2011 as the intervention. In addition, we performed a T-test for averages ratios comparing the years 2007-2010 to the years 2012-2015 for the entire lung cancer population and for subgroups by median family, ethnicity, Sex, Age and SEER Registry. Results: Although the overall lung cancer rates remained stable during the study period, a significant increase in the ratio of early/late stage was observed following the release of NLST for the overall lung cancer population (p=0.006) and for the screening age group (p= 0.014). The effects of ratio of early/late stage as noted in the overall group persisted for all patient subgroups, except for patients associated with a median income <$40,000, for those there were white, and for the following regions Detroit Metro, Iowa, Greater and Rural Georgia and Louisiana where no association was found between the release of the NLST changes in the ratios of early detection even more, in some cases there was a decrease in late stage detection. There was no impact on lung cancer mortality in the general lung cancer population or in any patient subgroups. Conclusions: Since the publication of the NLST in 2011, there has been no impact on lung cancer mortality or incidence of lung cancer in the general US population. However, favorable increase in the proportion of early stage lung cancers, depending upon median family income, race and location. We expected a greater impact of lung cancer screening after 2015 since CT-screening for lung cancer was adopted by CMS and other insurances during that year.
A pan-cancer analysis of microsatellite instability as a predictor of Lynch syndrome in Chinese population.
Authors: Huang Pinzhu , Deng Yanhong , Zhang Jianwei , Huang Meijin , Huang Jun , Liang Jinglin , Huang Mengli , Zhao Jing , Gao Chan , Xie Wenzhuan , Cai Shangli
Published: May 2019

1574

Background: Microsatellite instability (MSI) and mismatch repair deficiency (dMMR) are primarily tested in colorectal (CRC) and endometrial cancer (EC) to aid Lynch Syndrome (LS) diagnosis. A pan-cancer study presented at 2018 ASCO, however, revealed that up to 50% of LS patients had tumors not typically associated with LS, suggesting that patients with an MSI-high (MSI-H) phenotype should proceed to germline testing regardless of tumor type or family history. We thus set out to examine this potentially practice changing notion in Chinese population. Methods: MSI status and germline mutations in MLH1, MSH2, MSH6 and PMS2 genes were determined using a targeted next generation sequencing panel covering 100 MSI loci as well as MMR genes. Tumor mutation burden (TMB) levels were calculated for LS patients with MSI-H and MSS tumors, and intergroup differences were assessed using Mann Whitney U test or Fisher’s exact test. Results: Of 6,288 advanced tumors spanning > 27 cancers, 0.8% (48/6,288) were EC, 21.6% (1,362/6,288) were CRC, and 77.6% (4,878/6,288) were other malignancies. 3.6% (224/6,288) of the samples were found to be MSI-H and 3.5% (217/6,288) harbored MMR mutations (somatic and germline). Germline mutations indicative of LS were identified in 0.1% (8/6,064) of the MSS group and 17% (38/224) of the MSI-H group (p < 0.001). In contrast with the 2018 ASCO report, up to 63.8% of the 224 MSI-H tumors were CRC/EC, and only 8.9% (3/38) of the LS patients had MSI-H non-CRC/EC tumors (1 ovarian clear cell, 1 small bowel, and 1 gastric cancer). LS patients with non-CRC/EC tumors were more likely to be MSS compared to those with CRC/EC (70.0% vs 2.7%, p < 0.001). Alterations in MLH1/ MSH2 were present in 78.3% (36/46) of the LS patients, and they demonstrated significantly better correlation with a MSI-H phenotype than MSH6/PMS2 alterations (94.4% vs. 40.0%, p = 0.0005). Additionally, in line with previous reports showing co-ocurrence of MSI-H and high TMB in gastrointestinal cancers, the LS patients with MSS tumors had a significantly lower median TMB compared with the MSI-H population (4.6 muts/Mb vs. 91.8 muts/Mb, p < 0.001). Conclusions: Our study showed that in Chinese population, CRC/EC still predominated among LS-associated cancers, while non-CRC/EC LS patients were more likely to present with an MSS phenotype. The value of MSI-H/dMMR as a predictor of LS across different tumor types warrant further investigation.
Blood-based genomic profiling of circulating tumor DNA from patients with advanced biliary tract cancer.
Authors: Wang Junying , Song Jia , Zhao Jing , Zhang Yuzi , Cai Shangli , Chen Chen
Published: May 2019

1576

Background: Biliary tract cancer (BTC) is a highly lethal malignancy as diagnosis occurring at late stages and marginally sensitive to chemotherapy. Increasing evidence indicates targeted therapeutics may provide new hope for improving clinical response in BTC, hence better comprehending the genomic profile is particularly important. However, tissue of BTC is highly wide tumor heterogeneity and often inadequate for molecular characterization, a proper method is urgently needed. Circulating tumor DNA (ctDNA) is an emerging technology for detecting actionable alterations, and may be regarded as a reliable tool to reveal genomic signature. Methods: Next-generation sequencing (NGS) targeted 150 cancer-related genes was used to detect blood-based ctDNA from 154 Chinese patients with BTC. The mean sequencing depth was more than 3000×. Somatic genomic alternations (GA) including single nucleotide variation (SNV), copy number variation (CNV) and fusion were analyzed and compared with an internal tissue genomic database (545 Chinese patients with BTC) tested by NGS and TCGA database (n = 227) tested by the whole exome sequencing (WES). Allele frequency (AF) represented the percentage of mutant allele reads relative to total allele reads (mutant plus wild type). Maximum somatic allele frequency (MSAF) was defined as the maximum AF (0.1% < AF < 35%) of all the somatic alterations identified per sample. Results: Among ctDNA database, at least one GA was found in 95% (147/154) of samples (a median of 4 GA per patient). The median MSAF across all cases was 6.47% (range, 0%-34.8%). Pathologic type (P < 0.001) and sex (P < 0.001) were significantly related with MSAF, respectively. Frequencies of SNV in commonly mutated genes from ctDNA were similar to those observed among tissue samples, like TP53 (35.1% vs 40.4%) and KRAS (20.1% vs 22.6%), however, a little lower in TCGA database (TP53 24.2%; KRAS 10.1%). Besides, the consistency of CNV detected from ctDNA and tissue was relatively poor, and tumor heterogeneity might be in charge of this phenomenon. Among the highly frequent mutations (AF > 5%) in ctDNA, 45% of genes was considered as druggable targets, such as EGFR/RAS/RAF pathway and AKT/mTOR/PI3K pathway. Conclusions: These findings demonstrated that ctDNA tested by NGS was feasible in revealing genomic profiles and identifying potential therapeutic targets. Noninvasive ctDNA could be used as a complementary approach to tissue testing in patients with metastatic BTC.
Implications of incidental germline findings identified in the context of clinical whole exome sequencing (WES) for guiding cancer therapy.
Authors: Schneider Bryan P. , Stout Leigh Anne , Philips Santosh , Hunter Cynthia , Kiel Patrick , Radovich Milan
Published: May 2019

1581

Background: The identification of incidental germline mutations in the context of next-generation sequencing to guide therapy for cancer patients has become an unintended consequence of advancing technologies. While not the primary goal, additional information buried within the genomic data generated could be important for family members to better understand inherited disease risks and take action. While targeted gene panels are predominantly used in practice, comprehensive WES is becoming increasingly more common. The broader use of WES increases the complexity and scope of potential cancer and non-cancer pathogenic germline variation. Methods: 582 adult metastatic cancer patients from the Indiana University Health Precision Genomics Program were sequenced with tumor and germline CLIA-based WES. The primary intent was for guiding cancer therapy. Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database. Clinvar classifications were narrowed only to high quality submitters. Results: We identified 1,454 P/LP variants in 209 genes. 92% of patients harbored at least one variant. 72 P/LP variants were identified in 19 cancer predisposition genes with BRCA2 being the most common. 63 patients (10.8%) carried a P/LP variant in a gene that would be recommended by the ACMG to be reported due to clinical actionability with the most common being ATP7B (N = 17), BRCA2 (n = 13), MUTYH (n = 8), and BRCA1 (n = 5). We observed a preponderance of patients who carried autosomal recessive non-cancer pathogenic mutations of varying penetrance. Notable mutated genes included CFTR (cystic fibrosis, n = 16), BTD (biotinidase deficiency, n = 43), and CBS (homocystinuria, n = 90). Of 209 mutated genes, 173 genes had mutations present in less than 1% of our population, demonstrating significant genetic heterogeneity. Conclusions: The majority of patients undergoing clinical cancer WES harbor pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes commonplace.
Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices.
Authors: Gierman Hinco Jasper , Goldfarb Seth , Labrador Monica , Weipert Caroline M. , Getty Bill , Skrzypczak Stan M , Catasus Casey , Carbral Steve , Singaraju Mallika , Singleton Nick , Pai Nikhil , Sanchez Jose , Webster Jennifer , Raymond Victoria M. , Lanman Richard B. , Malik Ash , Scott Jeffrey A.
Published: May 2019

1585

Background: While aNSCLC is a leading cause of US cancer deaths, targeted therapies and immune checkpoint inhibitors (ICPi) have emerged as important new treatment options for these pts NCCN guidelines recommend testing of eight genes in aNSCLC patients at diagnosis. Targetable alterations (TA) in four genes, EGFR, ALK, ROS1, and BRAF, are associated with FDA-approved therapies. The labels for ICPis indicate that pts with TAs in EGFR and ALK are not candidates for first line treatment with ICPi. Methods: The Integra Connect database, which includes electronic medical record (EMR) and claims data on approximately 600,000 cancer patients, was queried across five community oncology practices (289 oncologists) to identify aNSCLC patients (stage 3B or 4) treated since January 2017. Manual review of charts was done to abstract tumor type/stage, drug regimens, and evidence of somatic genetic testing. A Wilcoxon rank sum test was used to test difference in time to results (TTR) for blood- vs tissue-based tests. Results: A total of 1,203 aNSCLC patients were identified. Testing rates varied from 54% for EGFR to 22% for all 4 genes (table). 163 patients had a TA in EGFR, ALK, ROS1 or BRAF, and 55% of these pts did not receive targeted therapy. 84 pts with TA’s in EGFR or ALK had no evidence of progression on targeted therapy, yet 31 (37%) received an ICPi; 24% had the TA test result prior to ICPi use and 13% received the TA result after starting ICPi. Median TTR for blood-based somatic tests was shorter than tissue-based tests (4 vs 14 days, p-value= 3.5-e07). Conclusions: Our analysis in the community oncology setting for aNSCLC pts finds evidence of underutilization of genomic testing, underutilization of targeted therapies, and ICPi use outside of label. Further research is needed to identify strategies to increase testing in aNSCLC pts to provide physicians with the information needed to make optimal treatment decisions. [Table: see text]
NRG Oncology CC001: A phase III trial of hippocampal avoidance (HA) in addition to whole-brain radiotherapy (WBRT) plus memantine to preserve neurocognitive function (NCF) in patients with brain metastases (BM).
Authors: Gondi Vinai , Deshmukh Snehal , Brown Paul D. , Wefel Jeffrey Scott , Tome Wolfgang , Armstrong Terri , Bruner Deborah , Bovi Joseph A , Robinson Cliff Grant , Khuntia Deepak , Grosshans David R , Konski Andre A. , Roberge David , Kundapur Vijayananda , Devisetty Kiran , Shah Sunjay A , Usuki Kenneth , Anderson Bethany Marie , Mehta Minesh P. , Kachnic Lisa A.
Published: May 2019

2009

Background: NRG CC001, a phase III trial of WBRT plus memantine (WBRT+M) with or without HA, sought to evaluate the neuro-protective effects of lowering the hippocampal radiation dose. Methods: Patients (pts) with BM were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized NCF tests were performed at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory Brain Tumor module and analyzed using mixed effects models and t-tests. Results: From 7/2016 to 3/2018, 518 pts were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted hazard ratio (HR) = 0.74, p = 0.02) due to lower risk of deterioration in executive function at 4 mos (p = 0.01) and encoding (p = 0.049) and consolidation (p = 0.02) at 6 mos. Age≤61 predicted lower NCF failure risk (HR = 0.60, p = 0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p = 0.036), difficulty speaking (p = 0.049) and problems remembering things (p = 0.013) at 6 mos favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p = 0.011) and symptom interference (p = 0.008) at 6 mos. Treatment arms did not differ in toxicity, overall survival, or intracranial progression. Conclusions: HA during WBRT+M for BM better preserves NCF and patient-reported symptoms, while achieving similar intracranial control and survival. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute. Clinical trial information: NCT02360215.
SurVaxM with standard therapy in newly diagnosed glioblastoma: Phase II trial update.
Authors: Ahluwalia Manmeet Singh , Reardon David A. , Abad Ajay P , Curry William T. , Wong Eric T. , Belal Ahmed , Qiu Jingxin , Mogensen Kathleen , Schilero Cathy , Hutson Alan , Casucci Danielle , Mechtler Laszlo , Uhlmann Erik J , Ciesielski Michael J , Fenstermaker Robert
Published: May 2019

2016

Background: SVN53-67/M57-KLH (SurVaxM) is a novel cancer vaccine designed to stimulate an immune response targeting the tumor-specific antigen survivin. A multi-center, single-arm phase 2 clinical trial of SurVaxM in survivin-positive newly diagnosed glioblastoma (nGBM, NCT02455557) is now fully enrolled and data updated. Methods: Patients (n = 63) with nGBM were enrolled at 5 US cancer centers and followed for safety, 6-month progression-free survival (PFS6), 12-month overall survival (OS12) and immunologic response. All patients underwent craniotomy with near-total resection ( < 1 cm3 residual contrast enhancement), TMZ chemoradiation, adjuvant TMZ and SurVaxM. Patients received 4 doses of SurVaxM (500 mcg) in Montanide with sargramostim (100 mcg) biweekly, followed by maintenance SurVaxM with adjuvants every 12 weeks until tumor progression. Immunogenicity of SurVaxM was assessed by detection of survivin-specific antibody (IgG) and CD8+ T-cell levels. Results: Median age was 60 yrs (range, 20-82), 53% methylated MGMT, 46% unmethylated MGMT (1 N/A) and 60% were male. Survivin expression ranged from 1-40% (median 12%) by immunohistochemistry. Median time to first immunization was 3.0 mo (1.9-4.0 mo) from diagnosis. There have been no RLT or grade ≥ 3 SAE attributable to SurVaxM. The most common AE was grade 1-2 injection site reactions. OS12 was 86% from first immunization and 93.4% from diagnosis. OS12 for meMGMT was 93.1% and unMGMT was 78% from first immunization. Median time to tumor progression (mPFS) was 13.9 months from diagnosis. Median OS has not yet been reached. SurVaxM produced an increase in survivin-specific IgG titre from pre-vaccine baseline to ≥ 1:10,000 in 67% of pts and ≥ 1:100,000 in 27%. CD8+ T cell responses were observed. Anti-survivin IgG and OS were correlated. Conclusions: SurVaxM immunotherapy generated encouraging efficacy and immunogenicity in nGBM and has minimal toxicity. A randomized, prospective trial of SurVaxM in nGBM is planned. Clinical trial information: NCT024455557.
Updated phase I trial of anti-LAG-3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM.
Authors: Lim Michael , Ye Xiaobu , Piotrowski Anna F. , Desai Arati Suvas , Ahluwalia Manmeet Singh , Walbert Tobias , Fisher Joy D. , Desideri Serena , Belcaid Zineb , Jackson Christina , Nabors Louis B. , Wen Patrick Y. , Grossman Stuart A.
Published: May 2019

2017

Background: Preclinical GBM data targeting the checkpoint molecules Lag-3 and CD137 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and anti-CD137. Methods: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients at first recurrence of GBM. The primary objective is to define MTD for the mono and combinational treatment. The major secondary objective is to explore for a signal in efficacy. The key inclusion criteria are adults, first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, stable corticosteroid regimen, measurable disease, and written informed consent. Sequential allocation was used for the treatment assignment at starting dose of 80mg for anti-LAG-3 and 8mg for anti-CD137. Anti-PD-1was given at a flat dose of 240 mg in the combination treatment arms. The 3+3 design is used for the dose finding with a target DLT rate < 33%. Results: to date 44 patients were enrolled into the trial with median age at 57, median KPS at 90. Median treatment cycle was 3 and 39% tumors were MGMT methylated. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. The safe dose for anti-CD137 alone arm is 8mg with 1 DLT, and 2 grade 3 elevated serum ALT at end of cycle 2. Combination arms of Anti-LAG-3 +anti-PD-1 (160 mg/240mg as the highest dose combination) had one DLT (hypertension) and no toxicities were seen in the combination arm of Anti-CD137+Anti-PD-1 (3 mg/240 mg). mOS was 14 months for anti-CD137 alone, 8 months for Anti-Lag-3, and 7 months for Anti-Lag-3 + Anti-PD-1. Correlative data will be discussed. Conclusions: The trial is ongoing. The RP2D is 800mg for anti-LAG-3 as a monotherapy and 8mg for anti-CD137. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 and 3 mg of anti-CD137 and 240 mg antiPD-1 were the RP2D. Clinical trial information: NCT02658981.
Plasma cell-free circulating tumor DNA (ctDNA) detection in longitudinally followed glioblastoma patients using TERT promoter mutation-specific droplet digital PCR assays.
Authors: Cordova Christine , Syeda Mahrukh M. , Corless Broderick , Wiggins Jennifer M. , Patel Amie , Kurz Sylvia Christine , Delara Malcolm , Sawaged Zacharia , Utate Minerva , Placantonakis Dimitris , Golfinos John , Schafrick Jessica , Silverman Joshua Seth , Jain Rajan , Snuderl Matija , Zagzag David , Shao Yongzhao , Karlin-Neumann George Alan , Polsky David , Chi Andrew S.
Published: May 2019

2026

Background: There is a critical need for more specific and less invasive diagnostic and pharmacodynamic biomarkers in glioblastoma (GBM) patients (pts). Previously, we detected TERT promoter hotspot mutations (C228T and C250T) in the ctDNA of IDH wildtype ( IDHwt) TERT promoter mutant GBM pts with 100% specificity using mutation-specific droplet digital PCR (ddPCR) assays. Here, we explored the dynamics and clinical associations of mutant TERT ctDNA levels in GBM pts undergoing therapy. Methods: We examined 14 pts with suspected IDHwt GBM based on preoperative MRI. Plasma was isolated and frozen from ~15 mL whole blood samples collected pre- and post-op, at end of radiation (RT), and 1, 3, and 6 m after end of RT. TERT promoter mutations were identified in FFPE tumor samples using ddPCR assays for C228T/C250T. Plasma samples were analyzed using ddPCR assays specific for the corresponding tumor mutation. The validated thresholds for positive detection were 1.5 (C228T) and 1.7 copies/mL (C250T). Results: 13/14 (92.9%) IDHwt tumors had TERT mutations (7 C228T and 6 C250T). Six of these 13 (46%) pts had positive plasma TERT ctDNA preop (4 C228T, 2 C250T). The mean cross sectional area of enhancing disease at presentation for positive or negative preop mutant ctDNA was similar. All 4 pts with multiple contrast enhancing lesions had positive preop mutant ctDNA. 2 pts who were negative initially developed detectable mutant ctDNA preceding progression. 3/4 pts with equivocal radiographic pseudoprogression had ctDNA dynamics that correlated with eventual clinical outcome. One patient with unresectable GBM had declining mutant ctDNA in later collections during clinical stability. Conclusions: We detected plasma TERT ctDNA in 46% of TERT mutant GBM pts before surgery, and in 100% of pts with multiple contrast enhancing lesions. TERT mutant ctDNA levels correlated with pseudoprogression or true disease progression and predicted progression before MRI. These data suggest that larger studies to test circulating cell-free TERT mutation as a diagnostic and pharmacodynamic biomarker in GBM are warranted.
Clinical characteristics, treatment (Tx) patterns, and overall survival (OS) in advanced (Adv) NSCLC patients (Pts) with and without brain metastases (BM).
Authors: Nash Smyth Emily Nash , Tiu Ramon Velasquez , Willard Melinda D , Beyrer Julie , Zhu Yajun Emily , Bowman Lee , Sheffield Kristin M , Han Yimei , Brastianos Priscilla
Published: May 2019

2035

Background: BM in NSCLC pts are associated with significant morbidity and mortality. This analysis describes the frequency and timing of BM development, pt characteristics, systemic txs, and OS in NSCLC pts with and without BM. Methods: This retrospective observational study identified pts from the Flatiron-Foundation Medicine NSCLC Clinico-Genomic Database diagnosed from 1 Jan 2011 to 31 Oct 2017 with adv NSCLC and a tumor sample analyzed via FoundationOne. Tx pattern data were summarized by period (1 Jan 2011-1 Mar 2015; 2 Mar 2015-31 Dec 2017), therapy class (eg, anti-VEGF and EGFR, platinum-based), and BM occurrence. Descriptive statistics were used to summarize data; Chi-square and t-tests assessed statistically significant differences. OS was measured by site of met (BM only vs no-BM only vs BM and no-BM) via K-M methods from adv diagnosis until death or last activity date (censored). Results: Of 3257 pts, 1018/3257 (31.3%) had BM during follow-up; 726/1018 (71.3%) presented with BM within 30 days of adv diagnosis. The median age at adv diagnosis was 66.2 yrs. Relative to pts without BM, BM pts were younger, more likely to be female, of Asian descent, have stage IV disease, ≥2 met sites (including BM) at initial presentation, ≥3 met sites (including BM) during follow-up, and non-squamous histology (all p < 0.01). Approximately 78% (n = 2534) were treated with ≥1 systemic tx; platinum-based chemo-combinations were the most common 1st line tx, regardless of BM status. Increased use of PD-1/L1 tx was seen in 1st, 2nd, and 3rdline during the latter vs earlier period. No statistically significant difference in OS was observed in pts with BM only (17.1 mos; 95% CI 12.5-29.9), no-BM only (21 mos; 95% CI 19.4-22.8), or BM and no-BM (20.4 mos; 95% CI 18.9-23.3) (log rank p = 0.3027). Conclusions: In met NSCLC pts with a tumor sample that was molecularly profiled, OS was comparable, regardless of site(s) of disease; additional multivariate analyses including molecular profiles are needed. BM screening at initial diagnosis is important given the frequency in NSCLC. Future studies should assess whether the shift in systemic tx patterns impact the development and clinical outcomes.