bluuebunny/crossref_metadata_2025 huggingface dataset:
ACRIN 6698 trial: Quantitative diffusion-weighted MRI to predict pathologic response in neoadjuvant chemotherapy treatment of breast cancer.
Authors: Partridge Savannah C. , Zhang Zheng , Newitt David C , Gibbs Jessica E , Chenevert Thomas L , Rosen Mark Alan , Bolan Patrick J , Marques Helga , Esserman Laura , Hylton Nola M ,   ACRIN 6698 Trial and I-SPY 2 TRIAL Investigators Group
Published: September 2018

11520

Background: Diffusion-weighted (DW) MRI is a non-contrast technique that can reflect treatment-induced alterations in tumor microstructure and cellularity. ACRIN 6698 was performed as a sub-study of the I-SPY 2 TRIAL to evaluate quantitative DW MRI for early assessment of breast cancer response to neoadjuvant chemotherapy (NAC) in a multisite, multiplatform trial. Methods: The IRB-approved trial was performed at ten institutions. Of 406 enrolled breast cancer patients, 272 were randomized to treatment (12 weekly cycles paclitaxel+/-experimental agent, followed by AC) and underwent breast DW MRI at four time points: pre-NAC (T1), early-NAC after 3 cycles paclitaxel (T2), mid-NAC between paclitaxel and AC (T3) and post-NAC (T4). Tumor apparent diffusion coefficient (ADC) was measured at each time point and compared for patients with and without complete pathologic response (pCR) by Wilcoxon signed rank test. Exploratory analyses were performed across subtypes defined by hormone receptor (HR) and HER2 expression. Performance for predicting pCR was assessed by calculating the area under the ROC curve (AUC). Results: Of 272 treated patients, 227 comprised the final cohort (14 were excluded for missing MRI exams, 31 for poor image quality). Median patient age was 48 (range, 25-77) years, and 71/227 (31.3%) achieved pCR. Subtype groups were HR+/HER2+ (n = 38), HR+/HER2- (n = 95), HR-/HER2+ (n = 20), and HR-/HER2- (n = 74). For the full cohort (all subtypes and treatments), both ADC and change in ADC from T1 were significantly predictive of pCR at T3 (AUC = 0.63, 95% CI 0.55-0.71; AUC = 0.62, 95% CI 0.53-0.70, respectively), and also at T4. ADC measures were not predictive of pCR at either T1or T2. Stratifying by subtype showed change in ADC at T3 was more predictive in HR-/HER2+ (AUC = 0.86) and HR+/HER2- (AUC = 0.75) tumors than HR-/HER2- and HR+/HER2+ tumors (AUC = 0.59 and 0.56, respectively). Conclusions: DW MRI reflects cytotoxic effects of chemotherapy, and mid-treatment ADC was a predictive marker of pCR. The predictive value of ADC varied across biologic subtypes. Further work is needed to determine the comparative predictive value of ADC to other imaging metrics. Clinical trial information: NCT01564368.
Prospective characterization of circulating tumor cells using a nanotechnology-based capture system in oligometastatic patients undergoing definitive radiation therapy.
Authors: Lindsay Daniel Paul , Caster Joseph Michael , Wang Kyle , Myung Ja Hye , Chen Ronald C. , Chera Bhishamjit S. , Gupta Gaorav P. , Jones Ellen , Tepper Joel E. , Varia Mahesh A. , Zagar Timothy , Hong Seungpyo , Wang Andrew
Published: September 2018

11533

Background: Circulating tumor cells (CTCs) can provide prognostic information in select patients with advanced cancers. We have developed a sensitive and specific CTC capture system (Oncosensor) which may predict clinical outcomes in patients undergoing definitive radiation for head and neck cancers. There is increasing interest in utilizing potentially curative metastasis-directed therapy for patients with oligometastatic solid-tumor malignancies. There is currently no biomarker to predict the success of this approach in most patients. The purpose of this prospective study is to investigate the potential utility of CTCs as a predictive biomarker for patients with oligometastatic cancer undergoing potentially curative therapy. Methods: Eligible patients had a metastatic solid-tumor malignancy with 3 or fewer metastases. All sites of disease were treated with definitive radiation or surgery. Concurrent chemotherapy was allowed. Peripheral blood (7 ml) was collected prior to starting, first week, mid-point, end RT, and every 4 to 12 weeks post RT. CTCs were quantified using the Oncosensor platform. We then assessed correlations between CTCs (baseline, end treatment, and changes during treatment) and clinical outcomes using multivariate analysis. Results: Baseline CTCs were detected in 20/20 enrolled patients with a mean baseline of 32/ml which decreased to a mean of 14/ml at the end of treatment. There was no association between pretreatment CTCs and clinical outcomes (p = 0.81). There was a significant association between post-RT CTCs and PFS (p = 0.039, HR 1.07 per CTC). Our data also suggest that post-treatment CTC monitoring may be able to detect early disease recurrence. Among the 4 patients with documented clinical failures and post-treatment CTC monitoring, all 4 had increases in CTCs with or prior to clinical or radiographic disease progression, with 1.6 to 7.3 fold increase at the time of progression compared to the prior time point. Conclusions: Our pilot data suggest CTCs may provide a predictive biomarker for patients with oligometastatic disease and could potentially provide a novel marker of disease recurrence.
Association of early reduction in circulating tumor DNA (ctDNA) with improved progression-free survival (PFS) and overall survival (OS) of patients (pts) with urothelial bladder cancer (UBC) treated with durvalumab (D).
Authors: Kuziora Michael , Higgs Brandon W. , Brohawn Philip Z. , Raja Rajiv , Bais Carlos , Ranade Koustubh
Published: September 2018

11538

Background: Mutation variant allele frequencies (VAFs) in ctDNA indicate the frequency of cancer clones harboring the specific variant in the primary lesion and metastases, thus providing a surrogate for tumor burden. We previously reported that early reduction in VAF in ctDNA was associated with improved survival on durvalumab in NSCLC subjects. Here we replicated this association in UBC pts treated with durvalumab. Methods: CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating D in pts with advanced UBC or other solid tumors. By 24OCT2016, 103 UBC pts received 10 mg/kg Q2W of D with median 8.4 mos follow up. A panel of 70 genes was assayed for DNA variants using the Guardant360 cancer panel in plasma ctDNA from 33 UBC pts pre-treatment and 29 pts pre and 6 wks on-treatment. The mean VAF pre or on treatment of patient single nucleotide variants (SNVs) and insertion/deletions was correlated with clinical outcomes. Objective response rate (ORR) was calculated according to RECIST v1.1 and a Cox proportional hazard ratio (HR) was calculated adjusting for baseline ECOG, sex, age, and smoking status. Results: Complete and partial responders (CR/PRs) showed a significant decrease (Δ = -2.4%, p = 0.02) in ctDNA mean VAF post-treatment with D (i.e. reduction in tumor burden) compared to an increase in mean VAF (i.e. increase in tumor burden) in progressive disease (PD) pts (Δ = +2.7%, p = 0.31). This correlation was also observed in total mutation count in CR/PR (Δ = -4.6, p = 0.003) compared to PD pts (Δ = +2.8, p = 0.44). Pts with a decrease in ctDNA VAF at week 6 had longer median PFS (9.3 mos, 95%CI = [3.0, not reached(NR)] and OS (median NR, 95% CI = [20.3,NR]) compared to those with an increase in VAF (median PFS = 1.4 mos, 95%CI = [1.3,NR];HR = 0.29; p = 0.05 and median OS = 8.2 mos, 95% CI = [2.3,NR]; HR = 0.12; adjusted p = 0.04). DCR was 85%/14% for pts with a decrease/increase in VAF (p = 0.002). Conclusions: CtDNA VAFs were reduced in responders but not non-responders after six wks of D. A decrease in VAFs 6 wks following treatment with D correlated with longer PFS and OS, suggesting utility as an early indicator of clinical benefit. Clinical trial information: NCT01693562.
Evaluation of liquid biopsies for molecular profiling in untreated patients with stage III/IV non-small cell lung cancer (NSCLC).
Authors: Besse Benjamin , Remon Jordi , Lacroix Ludovic , Mezquita Laura , Jovelet Cecile , Howarth Karen , Plagnol Vincent , Morris Clive D. , Pannet Chloe , Nicotra Claudio , Green Emma , Soria Jean-Charles
Published: September 2018

11540

Background: Molecular profiling is limited by tumour heterogeneity and access to sufficient tissue for comprehensive analysis. Circulating tumour DNA (ctDNA) can be used as a minimally-invasive liquid biopsy for mutation detection, quantification and monitoring for personalised treatment strategies. Methods: We recruited 110 patients into a prospectively-designed study for Stage III/IV NSCLC patients intended to initiate 1stline platinum-based chemotherapy. Blood collections (10ml K2-EDTA) were performed prior to treatment and analysed by InVision (enhanced tagged-amplicon sequencing) using a 34-gene panel. Tissue biopsies, when available, were analysed by NGS (Ion-Torrent, Sanger) for concordance analysis. To evaluate correlation with outcome, repeat blood collections were performed in selected patients. Results: 110 NSCLC pts were included (61% male, 14% never-smoker, and 70% adenocarcinoma). ctDNA profiling detected mutations in 83 pts (79%). TP53 (44%), KRAS (17%), STK11 (18%; 11/19 with KRAS/STK11) and EGFR (10%) were the commonest abnormalities detected. Additionally, MET (6%), ERBB2 (6%), PIKC3A (6%) and BRAF (4%) mutations and EGFR, MET, ERBB2 amplifications were detected in 2% of patients, respectively. 20% of the mutations detected in ctDNA were observed at < 0.5% allele fraction, with 6% between 0.03%-0.25% AF. Tissue was available in 44 pts; somatic mutations were detected in 73%. Tissue & liquid concordance was 92.3%. 10 pts (23%) reported as tissue negative had a positive liquid biopsy. 33 advanced NSCLC patients were evaluated for longitudinal serial ctDNA monitoring up to cycle 4 of chemotherapy; the ratio of mutated molecules between D1 and D42 was significantly correlated with change in RECIST 1.1 measurement at D42 (p-value = 0.002625 CI 95% 0.298, 0.875). Conclusions: ctDNA can be used as a ‘liquid biopsy’ for molecular profiling of NSCLC patients to detect clinically relevant and actionable mutations when tissue biopsy is unavailable. Liquid biopsies can be used longitudinally and may provide an early surrogate for response evaluation by radiographic RECIST.
Predictive impact of PD-L1-expressing circulating tumor cells in NSCLC patients treated with nivolumab.
Authors: Shibaki Ryota , Koh Yasuhiro , Akamatsu Hiroaki , Kurita Kazuki , Yagi Satomi , Kanai Kuninobu , Hayata Atsushi , Tokudome Nahomi , Higuchi Masayuki , Kanbara Hisashige , Akamatsu Keiichiro , Ueda Hiroki , Nakanishi Masanori , Yamamoto Nobuyuki
Published: September 2018

11541

Background: PD-L1 expression on tumor tissue is associated with response to PD-1 blockade in NSCLC. Here, we conducted a serial evaluation of PD-1-expressing circulating tumor cells (CTCs) as a potential real-time diagnostic modality in NSCLC patients treated with nivolumab. Methods: Advanced NSCLC patients after failure of at least one prior chemotherapy regimen received nivolumab monotherapy (3mg/kg, q2W) until progressive disease (PD) or unacceptable toxicity. Peripheral whole blood (3 mL) was collected for CTC evaluation at baseline and at week 4. CTCs were detected using microcavity array system (Hitachi Chemical Co., Ltd, Chikusei, Japan). PD-L1 expression was immunohistochemically examined on both tumor tissues and CTCs. This study was registered at UMIN (ID: 000024414). Results: Thirty patients were registered in the study between January 2016 and September 2016 at Wakayama Medical University Hospital and 29 were included in the analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 86); male 73 %; stage IV, 100 %; squamous/non-squamous, 27/73 %. At baseline, CTCs were detected in all patients (median, 15; range, 1 to 90) and PD-L1-expressing CTCs were detected in 87% of patients. Tumor proportion score (TPS) of PD-L1 expression on CTCs ranged from 6% to 100%, indicating intrapatient heterogeneity. Matched tumor tissues were available from 14 patients and 7 showed the PD-L1 TPS ≥ 50%. No positive correlation was observed on PD-L1 expression between tumor tissues and CTCs based on TPS (R2 = 0.0035). Overall response rate was 25% (7/29), and disease control rate was 54% (15/29). Total CTC count was significantly decreased after nivolumab treatment at week 4 (p < 0.05), but no significant change was observed in PD-L1 TPS on CTC. Patients harboring CTCs with PD-L1 TPS 50% or more at baseline were significantly more likely to achieve non-PD than those harboring CTCs with TPS less than 50% (p < 0.05). Conclusions: This is the first report on a serial monitoring of PD-L1 expression on CTCs in patients treated with nivolumab. PD-L1-expressing CTCs are suggested to hold potential for predicting clinical benefit. Clinical trial information: 000024414.
Assessing tumor heterogeneity using circulating tumor DNA to predict and monitor therapeutic response in metastatic breast cancer.
Authors: Ma Fei , Guan Yanfang , Yi Zongbi , Chang Lianpeng , Xia Xuefeng , Li Qiao , Chen Shanshan , Yi Xin , Yang Ling , Xu Binghe
Published: September 2018

11543

Background: Within metastatic breast cancer (mBC), tumor heterogeneity limited efficacy and duration of response to treatment. In this study, circulating tumor DNA (ctDNA) was used to evaluate tumor heterogeneity as a prognostic factor and monitor therapeutic response in patients with mBC. Methods: We collected plasma samples from 37 HER2-positive mBC patients treated with pyrotinib. Target-capture deep sequencing was performed to detect somatic mutations in plasma ctDNA. Clonal population structures were identified based on variations from ctDNA using Bayesian cluster with PyClone. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population. Results: Mutations in TP53 and genes of PI3K/Akt/mTOR pathway were associated with drug resistance for pyrotinib. The result showed that patients with resistant mutations occurring as a truncal event, who receiving monotherapy of pyrotinib, presented worse therapeutic effect (HR, 4.52; P = 0.03). The median PFS of patients with versus without resistant mutations in trunk clonal population was 7.8 weeks (95% CI 7.4 to 26.8 weeks) versus 31.6 weeks (95% CI 15.7 to 60 weeks), respectively. Patients with high heterogeneity (clonal population ≥3) had a significantly worse PFS (HR, 2.79; 95% CI 1.23 to 6.34; P = 0.014). The median PFS among patients with high versus low heterogeneity was 30.0 weeks (95% CI 13.9 to 53.5 weeks) versus 60.0 weeks (95% CI 31.4 to 84 weeks), respectively. Longitudinal monitoring of 21 patients during treatment showed positive correlation between mTBI in ctDNA and tumor size evaluated by CT imaging (P < 0.0001). Monitoring the mTBI in serial ctDNA increased sensitivity for prediction of progressive disease in 6 of 21 patients, with a mean time of 12.7 weeks earlier than using CT scan. ROC curve analysis showed an area under the curve value was 0.97 (p < 0.0001). Conclusions: Assessing tumor heterogeneity in ctDNA provides genetic predictors of treatment outcome. Molecular tumor burden in ctDNA is a potential indicator of therapeutic response. These observations might be supplements for the current therapeutic response evaluation.
Analysis of T-cell repertoires in early-stage breast carcinomas to evaluate tumor immunogenicity.
Authors: Carrasco Javier , Schröder David , Galant Christine , Berliere Martine , Canon Jean-Luc Re , Machiels Jean-Pascal H. , Delrée Paul , Hilbert Pascale , Duhoux Francois P. , Bar Isabelle , Coulie Pierre
Published: September 2018

11554

Background: Breast carcinomas (BC) are often considered to be weakly immunogenic and thus poorly sensitive to immunotherapy. Methods: We analyzed the repertoire of tumor-infiltrating T cells (TILs) in 41 early BC by sequencing their T cell receptor β genes (TCRβ). Libraries were built using a digital sequencing approach, barcoding each sequenced molecule to improve accuracy and quantification. T cell repertoires were also obtained from paired blood samples allowing identification of T cell clones enriched in the tumors as compared to blood. For 5 patients, CD8+ TILs were cloned ex-vivo from a tumor sample and screened for recognition of autologous predicted neoepitopes. Results: T cell infiltration differed from one tumor to another. Its amount varied of more than 30 fold and its diversity ranged from < 100 to > 5000 different clonotypes. In 34% of the tumors, there was an important T cell infiltration and we detected several clonotypes with a ≥500 fold enrichment as compared to blood. In 22% of the tumors, an important T cell infiltration was observed but without significantly enriched clonotypes. In 43% of the tumors the T cell infiltration was very limited. For 5 tumors with a high T cell infiltration, we screened ex-vivo isolated CD8+ T cell clones for recognition of predicted neoepitopes. In 4 of these tumors, with no enriched clonotypes, no recognition was observed. In 1 of these tumors, with enriched clonotypes, 6 different CD8+ T cell clones recognized 4 predicted neoepitopes. Three of these clones were > 100 fold more frequent in the tumor as compared to blood. Conclusions: About 30% of early BC were infiltrated by T cell clonotypes significantly enriched relative to blood. In one of these tumors some of the most enriched clonotypes recognized neoepitopes, demonstrating that some primary BC are spontaneously immunogenic. About 20% of the tumors had an important T cell infiltration without enriched clonotypes. None of the TIL clones isolated from 4 such tumors recognized predicted neoepitopes. Our results suggest that the detection of intratumorally enriched T cell clonotypes could identify immunogenic tumors, which may be sensitive to treatment with immunostimulatory antibodies.
Characterisation of CCS1477: A novel small molecule inhibitor of p300/CBP for the treatment of castration resistant prostate cancer.
Authors: Pegg Neil , Brooks Nigel , Worthington Jenny , Young Barbara , Prosser Amy , Lane Jordan , Taddei David , Brown Richard , Harbottle Gareth , Shannon Jonathan , Paoletta Silvia , Knudsen Karen E.
Published: September 2018

11590

Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related transcriptional activators of AR. We have developed CCS1477 which is a potent, selective and orally active small molecule inhibitor of the bromodomain of p300/CBP and investigated its role in regulating androgen receptor expression and function. Methods: Binding of CCS1477 to p300, CBP and BRD4, was measured in a surface plasmon resonance (SPR) assay. Potency and functional activity (proliferation and biomarker knockdown) was demonstrated in prostate cell lines in vitro (22Rv1, VCaP). Cross species in vivo pharmacokinetic (PK) properties were assessed, and in vivo efficacy, linked to inhibition of biomarkers, was determined in 22Rv1 and LNCaP xenograft models. Results: CCS1477 binds to p300 and CBP with high affinity (Kd = 1.3/1.7nM) and selectivity (Kd = 222nM; BRD4). It is a potent inhibitor of cell proliferation in prostate cell lines (IC50 = 96nM,22Rv1; 49nM,VCaP) with minimal effect in AR-ve lines. In 22Rv1 cells, p300/CBP inhibition down-regulates AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with the BET inhibitor, JQ1 at equivalent proliferation IC50s. Inhibition of p300/CBP also reduces c-Myc, KLK3 and TMPRSS2 gene expression (qPCR) in 22Rv1 cells in vitro. The in vivo PK properties of CCS1477 are consistent with qd or qod oral dosing in mouse. CCS1477 dosed at 10mg, 20mg/kg qd or 30mg/kg qod, caused complete tumour growth inhibition over 28 days in a 22RV1 xenograft model, including extended duration in the absence of the drug for a further 24 days. This was accompanied by complete inhibition of plasma PSA and significant knockdown of tumour AR-FL, AR-V7, and C-Myc protein as well as C-Myc and TMPRSS2 mRNA expression. Conclusions: Taken together these data support the clinical testing of CCS1477 in castrate resistant prostate cancer by down-regulation of AR, AR-SV and c-MYC expression and function.
A novel prognostic signature based on centrosome amplification-based genes to predict clinical outcomes in breast tumors.
Authors: Ogden Angela , Rida Padmashree C.G. , Aneja Ritu
Published: September 2018

11604

Background: A majority of breast tumors exhibit centrosome amplification (CA), which imparts aggressive phenotypes like chromosomal instability and invasive behavior. Nevertheless, it is unclear whether CA is associated with poor clinical outcomes after adjusting for potentially confounding factors, like stage and age at diagnosis. Methods: We developed a twenty-gene signature, “CA20,” composed of genes related to centrosome structure and/or whose dysregulation induces CA and tested its prognostic value compared with that of CIN25, a chromosomal instability (CIN) signature, in combined multivariable Cox models using the METABRIC and TCGA microarray breast datasets. The n = 1,969 primary breast cancers of the METABRIC dataset were split randomly and approximately equally into training and validation sets, unlike the n = 524 primary invasive breast cancers of the TCGA dataset, which could not be split to preserve power ≈ 0.80, so bootstrapping was instead used. CA20 and CIN25 were dichotomized by average scores and optimal cutpoints based on the log-rank test. Results: In both discovery and validation METRABRIC sets, CA20 was a significant independent predictor of worse breast cancer-specific survival (HR = 2.9, p < 0.001 and 2.4, p < 0.001, respectively, using average scores as cutpoints; similar results obtained using optimal cutpoints) in multivariable Cox models, unlike CIN25. CA20 score was highly correlated with CIN25 score (ρ = 0.93, p < 10-6). In the TCGA dataset, high CA20 score was associated with 3.8- and 3.7-fold worse overall survival (bootstrap-p = 0.001 and 0.002, respectively, for average and optimal cutpoints) after adjusting for tumor stage and age at diagnosis, unlike CIN25. Also in the TCGA dataset, CA20 correlated very strongly with CIN25 (ρ = 0.95, p < 10-6). Finally, using the TCGA dataset, we identified processes and pathways enriched in the CA20-high group (q < 0.05) that may be potential therapeutic targets, such as DNA repair processes, the DNA integrity checkpoint, and regulation of microtubule dynamics. Conclusions: CA20 is a novel signature with robust prognostic value in breast cancer and identifies patients who might respond to centrosome declustering drugs.
Germline genetic testing in unselected pancreatic ductal adenocarcinoma (PDAC) patients.
Authors: Peters Mary Linton Bounetheau , Brand Randall , Borazanci Erkut Hasan , Stobie Lindsey , Dudley Beth , Karloski Eve , Moser A James , Colvin Arlene , Lim Cynthia , Bahary Nathan , Sun Weijing , Rhee John C. , Lembersky Barry C. , Stoller Ronald G. , LaDuca Holly , Dolinsky Jill S , Dalton Emily , Speare Virginia , Black Mary Helen , Tung Nadine M.
Published: September 2018

1501

Background: The aim of this study is to assess the prevalence of known heritable germline mutations in unselected PDAC patients and to determine how well current guidelines for genetic testing identify mutation carriers. Methods: Consecutive, unselected patients with recently diagnosed PDAC from three centers were enrolled from May to December 2016 in an ongoing prospective study. A three-generation pedigree was obtained. Germline mutations in 12 genes associated with PDAC risk ( APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, PALB2, PMS2, STK11, TP53) and in 19 genes related to other cancer risks were screened for by NGS. American College of Gastroenterology and NCCN criteria for genetic testing for BRCA1/2, Lynch syndrome, and Familial Pancreatic Cancer (FPC) were assessed. Results: Among 183 patients, 46% are female, 79% are Caucasian and 10% are Ashkenazi Jewish, with median (IQR) age 68 (62,75) years at diagnosis. 41% of patients met ³1 criteria for genetic testing (35.5% BRCA1/2, 2.7% Lynch, 9.3% FPC). Twenty patients (11%) were found to have a total of 21 pathogenic mutations (table). Mutation status was not associated with age at diagnosis, sex, or personal history of cancer (all p > 0.05). Six mutation carriers (30% of positives) did not meet current criteria for genetic testing. Conclusions: Preliminary results show that 6.6% of unselected PDAC patients carry a germline mutation in a gene known to increase PDAC risk and 4.3% have a mutation in genes not previously linked to PDAC. Existing testing criteria did not identify 30% of carriers. Continued refinement of guidelines is necessary to align genetic testing with inherited PDAC risk. Clinical trial information: NCT02790944. [Table: see text]
Lung cancer screening patient navigation for current smokers in community health centers: A randomized controlled trial.
Authors: Percac-Lima Sanja , Ashburner Jeffrey M , Rigotti Nancy , Park Elyse R. , Chang Yuchiao , Atlas Steven J
Published: September 2018

1506

Background: Annual chest computed tomography (CT) can decrease lung cancer mortality in high risk individuals. Patient navigation (PN) has been shown to improve cancer screening rates in underserved populations. We evaluated the impact of PN on lung cancer screening (LCS) in current smokers in community health centers (CHC). Methods: Current smokers aged 55-77 receiving care in five CHC affiliated with an academic medical center were randomized to intervention (n = 400) or control (n = 800) groups. In the intervention arm, patient navigators (PNs) determined eligibility for LCS, provided brief smoking cessation counseling, introduced shared decision making about LCS, scheduled appointments with the primary care provider (PCP), reminded patients about appointments and PCPs to order CTs, and helped patients attend testing and follow-up any abnormal results. Control patients received usual care. The primary outcome was the proportion of patients in each group who had any chest CT during the study period. Secondary outcomes included proportion of patients receiving lung screening CTs and the number of lung cancers diagnosed in each group. Results: Baseline patient characteristics were similar between randomized groups. From March 2016-January 2017, PNs contacted 332 (83%) of intervention patients; 76 refused further participation. Of participating patients, 130 (51%) were eligible for LCS. Exclusions included insufficient smoking history (n = 117), competing comorbidities (n = 5), moved (n = 2), and died (n = 2). In intention-to-treat analyses, 124 intervention patients (31%) had chest CT vs. 138 control patients (17.3%, p < 0.01). Lung cancer screening CTs were performed in 94 intervention patients (23.5%) vs. 69 control patients (8.6%, p < 0.01). Eight lung cancers were diagnosed in intervention patients (2%) vs. 4 in controls (0.5%). Conclusions: A patient navigation program implemented in community health centers significantly increased lung cancer screening among current smokers. PNs may help underserved low-income current smokers complete LCS and improve equity in care while decreasing lung cancer mortality. Clinical trial information: 2015P002239.
Multigene hereditary cancer testing in sarcoma patients.
Authors: Jackson Sarah A. , Baxter Melanie D. , Mester Jessica , Susswein Lisa , Marshall Megan L. , Hruska Kathleen S. , Klein Rachel T.
Published: September 2018

1518

Background: In multi-gene hereditary cancer testing, multiple syndromes may be interrogated simultaneously, increasing the likelihood of detecting an underlying cancer predisposition. We characterized the yield and distribution of pathogenic or likely pathogenic variants (PV/LPV) in patients with a personal history of sarcoma undergoing panel testing through our clinical diagnostic laboratory. Methods: We retrospectively reviewed panel test results, demographic data, and personal/family history information from patients reporting a personal history of sarcoma. Patients included in this study underwent panel testing (NGS and del/dup) of up to 61 genes at this laboratory and concurrent or prior TP53 analysis at this or an outside laboratory. Chi-square and Fisher’s exact tests were used to compare groups. Results: Among 374 sarcoma patients, 53 (14.2%) harbored one or more PV/LPV in 14 genes: TP53, BRCA2, CHEK2, BRCA1, ATM, MSH6, MLH1, NBN, BAP1, BRIP1, FLCN, MSH2, PTEN, and RB1. Thirty-nine (10.4%) individuals reported both a personal and family history of sarcoma; however, PV/LPV were not more likely to be detected among this group than those with personal history alone (p = 1.0). PV/LPV were most often detected in BRCA1/2 (15/374, 4.0%) or TP53 (12/374, 3.2%). Notably, four probands with BRCA1/2 PV/LPV reported a family history of sarcoma, including one kindred in which the variant was present in two brothers, both affected with sarcoma. Additionally, seven patients were found to have PV/LPV (1.9%) in genes causative for Lynch syndrome. Among patients with PV/LPV in genes other than TP53, nearly half (17/41, 41.5%) met National Comprehensive Cancer Network TP53 testing criteria. Conclusions: The majority of PV/LPV were identified in genes for which association with sarcoma risk is not well-established. While several of these genes have been implicated in somatic pathways related to sarcoma development, it is unclear whether these germline findings are causative, play no role, or modify sarcoma risk. Although these data do not inherently associate non- TP53 genes with sarcoma risk, they suggest a potential clinical benefit can be gained from performing hereditary cancer risk assessment and multi-gene panel testing in sarcoma patients.
Performance of mutation risk prediction models in a racially diverse multi-gene panel testing cohort.
Authors: Idos Gregory , Roth Katherine G , Naghi Leah , Ricker Charite Nicolette , Culver Julie , Sturgeon Duveen , Kingham Kerry , Koff Rachel , Chun Nicolette M. , Rowe-Teeter Courtney , Hartman Anne-Renee , Allen Brian , Evans Brent , Mills Meredith , Hong Christine , McDonnell Kevin , Ladabaum Uri , Ford James M. , Gruber Stephen B. , Kurian Allison W.
Published: September 2018

1523

Background: Mutation carrier prediction models are clinically useful tools for identifying candidates for genetic counseling and testing. Consensus guidelines recommend germline genetic testing for those with a carrier probability (CP) of approximately 5% or higher. However, prediction models may perform less well among racial/ethnic minorities. Our hypothesis is that pathogenic mutations (PM) are identifiable in a clinically meaningful fraction of racially/ethnically diverse patients with a CP of < 5%. Methods: We conducted a multicenter prospective clinical trial of patients undergoing cancer-risk assessment using a 25 gene panel, which include APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were recruited from August 2014 to November 2016 at three centers. Patients were enrolled if they met standard clinical criteria for genetic testing or were predicted to have a ≥2.5% probability of inherited cancer susceptibility using validated prediction models. We evaluated the CP of patients with a PM in BRCA1, BRCA2, and/or a mismatch repair (MMR) gene using the following models: (1) BRCApro, (2) MMRpro and (3) PREMM1,2,6. Results: Of 2000 patients enrolled in this cohort, 80.6% are female (n = 1612). Regarding race/ethnicity, the cohort is 40.1% Non-Hispanic White (n = 802), 37.4% Hispanic (n = 748), 11.5% Asian (n = 230), 3.9% Black (n = 78), and 7.1% Other (n = 142). Among 241 (12.1%) patients who tested positive for a pathogenic mutation, 76 (31.5%) patients had a BRCA1 or BRCA2 mutation. Of those, 52 (68.4%) patients had a BRCApro CP of < 5%. Thirty-eight (15.8%) patients had a pathogenic mutation in an MMR gene: 19 (50.0%) had an MMRpro CP of < 5%, while 13 (34.2%) had a PREMM1,2,6 CP of < 5%. The racial/ethnic distribution of BRCA1/2 or MMR mutation carriers is similar to that of the whole cohort. Conclusions: In a diverse cohort of patients undergoing 25-gene multiple-gene panel testing, half or more carriers of BRCA1/2 or MMR mutations had a CP of < 5%, the consensus guideline-recommended cutoff for genetic testing. These results support a lower threshold for genetic testing guidelines. Clinical trial information: NCT02324062.
PALB2 mutations in high-risk women with breast or ovarian cancer.
Authors: Metcalfe Kelly A. , Akbari Mohammad R , Narod Steven , Lerner-Ellis Jordan
Published: September 2018

1527

Background: In Canada, genetic testing for BRCA1 and BRCA2 is available free of charge to women who meet eligibility criteria, based on personal and family history of cancer. Less than 10% of women are identified with a BRCA mutation, despite features of hereditary cancer. PALB2 has been identified as a moderate penetrance gene in various populations. In the current study, we examined the frequency of PALB2 mutations in women with breast or ovarian cancer who met criteria for genetic testing for BRCA1 and BRCA2and tested negative. Methods: DNA samples from women with breast or ovarian cancer, who met criteria for provincial BRCA1 and BRCA2 genetic testing and tested negative between the years of 2007 and 2014 were included in this study. All 13 coding exons of PALB2 plus 20 base pairs from the exon boundaries were amplified using Wafergen SmartChip technology. The amplified DNA were paired-end sequenced at 2x250 cycles using an Illumina MiSeq sequencer. Results: 2,225 women with breast cancer and 429 women with ovarian cancer were tested for PALB2 mutations. No PALB2 mutations were found in women with ovarian cancer. Seventeen deleterious PALB2 mutations were detected in women with breast cancer (0.8%). The frequency of PALB2 mutations was significantly higher in women with bilateral breast cancer (2.4%) compared to women with unilateral breast cancer (0.6%) (p = 0.01). There was no significant difference in age at diagnosis between those with and without a PALB2mutation (50.9 years vs 53.8 years; p = 0.34). Conclusions: Genetic testing for PALB2 should be considered for high-risk women with breast cancer, especially those who present with bilateral breast cancer. However, PALB2 does not appear to contribute to ovarian cancer which has implications for counselling women who are identified with a PALB2 mutation.
Association of baseline plasma levels of 25OH vitamin D and breast cancer risk in a chemoprevention trial.
Authors: Bonanni Bernardo , Serrano Davide , Gandini Sara , Johansson Harriet Ann , Macis Debora , Aristarco Valentina , Guerrieri-Gonzaga Aliana , De Censi Andrea
Published: September 2018

1546

Background: Observational studies have shown a correlation of higher serum 25-hydroxyvitamin D (25OHD) concentrations and reduced cancer risk, including breast cancer (BC). We assessed the association of 25OHD and Vitamin D Receptor (VDR) polymorphisms (SNPs) with breast cancer events within a chemoprevention trial in premenopausal women at risk for BC. Methods: Premenopausal women with history of intraepithelial neoplasia (IEN) or at risk women according to the Gail model were included in a 4 arm phase II prevention trial (low dose tamoxifen vs fenrerinide vs their combination vs placebo). Level of 25OHD were measured at baseline. VDR SNPs ( FokI, BsmI, TaqI, ApaI, and Cdx2) were determined using the Applied Biosystems’ Taqman Allelic Discrimination Assay according to manufacturer’s instructions. Survival analysis for breast cancer events was performed using competing risk models, adjusted for BMI, age, season and risk strata. Results: Plasma samples were available for 228 subjects. At baseline the median plasma 25OHD concentrations were slightly higher in 53 unaffected women, 19.6 ng/ml (IQR 12.7-27.3 ng/mL) than in 175 women with IEN, 18.8 ng/ml (11.7-25.8). After a median follow up of 15 years, 79 women developed a breast cancer event, 12 had different neoplastic events. The median level of 25OHD was 19.7 ng/ml (IQR 12.8-26.1) in subjects free from oncological events and 17.8 ng/ml (9.7-23.9) in subjects with breast events. Women in the lowest 25OHD quartile (≤12 ng/ml) had an increased risk of breast cancer events: HR = 1.79 (95%CI, 1.07-2.99, p = 0.03). Considering all cancer events, the associations with 25OHD were confirmed (P = 0.005). Among the VDR SNPs the ApaI variant in homozygote or heterozygote versus wild type showed an HR of 1.83 (95%CI, 1.04-3.21 p = 0.03). Conclusions: Our results support a role of plasma vitamin D levels in breast cancer risk. Subjects in the lowest quartile had a two-fold increased risk of a cancer event. Our findings support trials of 25OHD supplementation to prevent breast cancer in 25OHD insufficient subjects.
Prospective randomized biomarker study of metformin and lifestyle intervention for prevention in obese postmenopausal women at increased risk for endometrial cancer.
Authors: Yates Melinda S. , Basen-Engquist Karen , Zhang Qian , Schmandt Rosemarie , Medepalli Meena , Nebgen Denise R , Soletsky Beth , Levy Erma J , Fellman Bryan M. , Urbauer Diana L , Lu Karen H.
Published: September 2018

1551

Background: Obesity significantly increases risk of endometrial cancer (EC) through systemic metabolic effects and local tissue action, driven by estrogen and dysregulated insulin signaling. EC is most commonly diagnosed in postmenopausal women. Metformin, an antidiabetes drug, and lifestyle intervention were evaluated for effects on endometrial proliferation and serum biomarkers, in parallel with weight loss. Methods: Obese postmenopausal women were randomized into 4 groups for a 16 week intervention using a 2 (metformin 1700 mg/day vs placebo) x 2 (lifestyle intervention vs no lifestyle intervention) factorial design based on the Diabetes Prevention Program. Pre- and post-intervention endometrial biopsies were assessed for proliferation (% Ki67+). Body weight and serum markers were measured pre- and post-intervention (estrone, FSH, DHEA-S, SHBG, IGF-1, adiponectin, omentin, insulin, glucose, A1C, ALT, triglycerides, and others). Results: Of 576 women approached for the study, 29 women were randomized and 26 completed the study. Similar adherence was seen for placebo and metformin, with 88% and 94% of doses taken, respectively. Adverse events were grade 1 or 2, most commonly flatulence, headache, and diarrhea. Metformin+lifestyle group lost the most weight (-7.4%), followed by lifestyle (-5.2%), metformin only (-3.1%), and placebo (+0.1%). Endometrial proliferation was not changed. Overall proliferation was low (7.1% at baseline) with substantial variability even in this postmenopausal cohort. Biopsies produced limited endometrium, precluding evaluation of other tissue markers. Metformin significantly increased serum DHEA (p = 0.002). SHBG increased (p = 0.031) and insulin decreased with lifestyle intervention (p = 0.035) but were not statistically significant after multiple comparisons correction. Conclusions: Metformin and lifestyle intervention produced positive changes in serum markers and weight loss. While it is known that obese postmenopausal women are at increased risk for EC, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Clinical trial information: NCT01697566.
Breast cancer screening in transgender patients: Findings from the 2014 BRFSS survey.
Authors: Narayan Anand , Morris Elizabeth Ann , Lebron Lizza
Published: September 2018

1564

Background: Transgender patients undergoing transitions often receive cross sex hormonal therapies, placing them at uncertain risk for developing breast cancer. There is limited population-based information about the extent to which transgender patients undergo mammography screening. Our purpose was to determine the extent to which transgender patients undergo mammography screening using nationally representative survey data. Methods: Transgender participants in the 2014 Behavioral Risk Factor Surveillance System survey were included. Proportions undergoing mammography screening in the last year or two years were calculated stratified by age category and transition status (male to female(MtF), female to male(FtM), non-conforming(people who do not follow societal notions how they should look or act based on the sex they were assigned at birth)). For each transition status, predictors of mammography screening (demographics, indices of access to health care) were calculated using logistic regression. Results: 656 transgender patients were included (343 were MtF, 203 were FtM and 110 classified themselves as gender non-conforming). For MtF respondents, 61.5% of women underwent mammography screening within the last year (71.9% within last two years). For FtM respondents, 66.1% underwent mammography screening within the last year (74.2% within the last two years). For gender non-confirming transgender patients, 57.9% underwent mammography screening within the last year (74.4% within the last two years). For all transgender patients, income category (OR 1.16, 0.82 - 1.64), higher education category (OR 1.09, 0.31 - 3.86) and health insurance (OR 0.38, 0.10 - 1.41) were not associated with increased adherence to mammography screening. Adjusted for age, education, race and income, transgender patients were comparably likely to undergo mammography screening compared with non-transgender patients (OR 0.97, 0.58 – 1.62). Conclusions: High proportions of transgender survey respondents undergo mammography screening (57.9 – 66.1% within the last year, 71.9 – 74.4% within the last two years), proportions comparable to non-transgender survey respondents.
The epidemiology of metaplastic breast cancer: A review of 2,500 cases from the national cancer database.
Authors: Campbell Brittany Morgan , Thomas Samantha Marie , Ong Cecilia Tuongquang , Greenup Rachel Adams , Plichta Jennifer Kay , Rosenberger Laura Horst , Force Jeremy Meyer , Hyslop Terry , Hwang Eun-Sil Shelley , Fayanju Oluwadamilola Motunrayo
Published: September 2018

1570

Background: Metaplastic breast cancer (MBC) is a rare, aggressive, sarcomatoid breast cancer that was first described in 1973 but only became recognized as a histologically distinct entity in 2000. Given the paucity of data on the epidemiology of MBC, we performed a population-based analysis to delineate sociodemographic and clinicopathological characteristics associated with increased likelihood of MBC diagnosis. Methods: Adult female breast cancer patients with stage I-III MBC and non-MBC histology diagnosed between 2010 and 2013 were identified in the National Cancer Database (NCDB). Multivariate logistic regression was used to identify factors associated with diagnosis of MBC, and Cox proportional hazards modeling was used to estimate the effect of MBC on overall survival. Results: 2,451 MBC and 568,057 non-MBC patients were identified. After adjusting for receptor status (ER, PR, HER2), age, stage, grade, and treatment variables, MBC patients had worse survival than non-MBC patients (HR 1.45, p < 0.001). Compared to non-MBC patients, a higher proportion of MBC patients were non-Hispanic black (16.7% vs 10.5%), had an annual income < $35k (29.0% vs 25.5%), had lower high school completion rates (36.7% vs 33.9%), were treated at academic centers (35.5% vs 30.8%), and had government-sponsored insurance (48.8% vs 43.7%, all p < 0.01). MBC diagnosis was more likely in patients with triple-negative breast cancer (OR 20.71), higher clinical T stage (cT4 vs cT1: OR 6.18), and lower clinical N stage (cN1 vs cN0: OR 0.38, all p < 0.001). MBC patients were also more likely to be diagnosed based on pathology from their first operation rather than preoperatively (OR 1.41, p < 0.001). Conclusions: Black women and women of low socioeconomic status were at increased risk for diagnosis with MBC. Though MBC was more likely to be treated at academic centers, MBC was less likely to be diagnosed prior to surgical intervention. Many of the sociodemographic factors associated with MBC have also been associated with triple-negative breast cancer. Additional research is needed to determine the contribution of sociodemographic factors to the epidemiology of MBC independent of receptor status.
A phase I study of convection enhanced delivery (CED) of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma (DIPG).
Authors: Souweidane Mark M. , Kramer Kim , Pandit-Taskar Neeta , Zanzonico Pat , Zhou Zhiping , Donzelli Maria , Lyashchenko Serge K. , Haque Sofia , Thakur Sunitha B , Cheung Nai-Kong V. , Larson Steven M. , Dunkel Ira J.
Published: September 2018

2010

Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for augmenting distribution of therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard 3+3 phase I, open-label, dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion or radiation therapy. Seven dose levels of a single injection of 124I-8H9 (range 0.25 to 4.0 mCi, 250 to 4000 mcl) were studied. Results: 25 children were treated. The average age at enrollment 8 years old (range 3-17). There was no dose limiting toxicity (DLT) and adverse events were limited to grade 1 or 2 (CTCAE v4.0). Estimations of distribution volumes were dose dependent and ranged from 1.5 to 20.1 cm3. The mean volume of distribution/volume of infusion (Vd/Vi) was 3.4 (SD 1.2). The mean lesion absorbed dose was 1527 rad/mCi. The mean tumor coverage on dose level 7 was 107%. Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. Up to 4 mCi of 124I-8H9 was well tolerated. An infusion volume of 4000 mcl appears to be a reasonable single dose for good tumor coverage. PET-based dosimetry validates the conceptual basis for direct drug delivery. Based on our finding CED merits further exploration in early phase clinical trials for children with DIPG. Clinical trial information: NCT01502917.