bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma cell free DNA (cfDNA) based somatic aberrations detected in treatment naïve metastatic hormone sensitive prostate cancer (mHSPC), hormonally ablated mHSPC and metastatic castration resistant prostate cancer (mCRPC) states and their impact on survival.
Authors: Kohli Manish , Tan Winston , Zheng Tiantian , Wang Amy , Wong Calvin , Tan Meng-Yao , Jia Shidong , Yu Jianjun 
Published: May 2019

5047 Background: We identified plasma cell free DNA (cfDNA) based copy number variations (CNV); single nucleotide variants (SNVs) & TMPRSS-ERG fusion in four sub states of metastatic prostate cancer (mPCa) and determined the impact on survival. Two mHSPC cohorts included treatment naïve, gp-1 and mHSPC patients (pts) responding to chronic androgen ablation (AA) (gp-2). Two mCRPC cohorts included mHSPC pts with PSA relapse on chronic AA (gp-3) and a clinically progressive mCRPC cohort post AA (gp-4). Methods: Enrollment of mPCa pts was performed from 2009-14 who were followed until 2018. Plasma from collected blood was used for extracting cfDNA. NGS was performed using Illumina HiSeq X for a preselected target panel of 129 genes including DNA damage repair genes. Statistical analyses of genomic aberrations were performed in R 3.5.1 and Cox proportional-hazard models were used for survival analyses. Results: A total of 255 pts were enrolled with 215 having adequate cfDNA that passed NGS QC. Median study follow up was 90.2 (Range:73;99) months. The table highlights pts in each gp with CNV, SNV, fusion events. ARamplification was higher in mCRPC gps3&4 (20/103 pts) compared to 3/106 pts in mHSPC gps1&2 (p < 0.001) and was prognostic for poor survival in mCRPC (p < 0.001;HR:3.34; 95%CI: 1.9-5.76). 54/103 pts in gp3&4 had SNVs in TP53 compared to 34/106 pts in mHSPC gps1&2 (P < 0.01). SNVs in APC, AR, CDK12 and BRIP1 were also increased in gps3&4 (p < 0.01). Gp1 mHSPC pts with SNVs in ATM/ CHEK2 had shorter response to AA (p < 0.001; HR:3.66; 95%: CI:1.81-7.39). Conclusions: Plasma cfDNA based somatic aberrations are detected with increased prevalence in mHSPC to mCRPC states. The ease of specimen collection and the need for molecular profiling in mPCa increases its potential for clinical applications in pt care. [Table: see text]
AR changes in circulating-tumor DNA (ctDNA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with high-dose testosterone.
Authors: Moses Marcus W. , Ledet Elisa , Manogue Charlotte , Cotogno Patrick , Lewis Brian E. , Sartor A. Oliver , Barata Pedro C. , Layton Jodi Lyn 
Published: May 2019

5058 Background: High-dose testosterone (HDT) is active in mCRPC pts and may allow successful re-sensitization to previously utilized androgen-axis targeted therapies. The relationship of genomic alterations in AR gene to HDT responsiveness is unclear. Methods: Analysis of consecutive pts treated with ≥1 dose of HDT (testosterone cypionate q 2-4 weeks n = 29; continuous gel n = 4). Baseline characteristics, ctDNA data (Guardant360), and clinical outcomes were assessed. Presence of genomic AR alterations included amplifications (amps) and mutations (muts); all muts had allele fraction ≥0.3%. PSA response rates included PSA declines of > 30% or ≥50%. PSA-progression-free survival (PSA-PFS) was defined as HDT start date to PSA ≥ 25% over baseline after a second confirmed PSA rise. Results: Between May 2016 and Feb 2018, 33 mCRPC pts had median age 73 (58-85), 39% Gleason 8-10, 100% bone mets, 24% nodes + bone, and median baseline PSA level 36.1 ng/mL (0.04-1290). HDT was given post-median of 2 (1-10) CRPC therapies. 73% (24/33) of pts previously received abiraterone (n = 14), enzalutamide (n = 4), or both sequentially (n = 6) prior to HDT for a median of 10.5 months (0.7-56.8). Baseline ctDNA showed 42% AR alterations (amps = 8, muts = 4, both = 2); 33% TP53, and 6% DNA repair (ATM n = 1; BRCA2 n = 1). With median follow-up 4.4 months, HDT given for median of 4.2 months (95% CI, 3.6-4.8); 29% had PSA ≥50% response and 45% PSA ≥30% response. Median PSA-PFS is immature at 5.5 months (95% CI, 1.5-9.5); 14 pts still on HDT treatment. Grade ≥3 AEs were observed in 6% of pts (G4 thrombocytopenia = 1; G4 asthenia = 1). For pts with baseline AR alterations and HDT treatment, repeated ctDNA assays (n = 7) showed that 100% had decreased AR alterations. No relationship between PSA response and baseline ctDNA AR characteristics are discerned at this time. Conclusions: HDT was safe and active in a subset of mCRPC. Responses were clearly noted for men receiving continuous daily testosterone gels, thus continuously high testosterone levels are active in addition to injection-induced bipolar changes. Further understanding of the genomic alterations predicting responsiveness to HDT in mCRPC is required.
Prevalence of pathogenic germline variants in DNA repair by race, age, and ethnicity in men with prostate cancer.
Authors: Mara Alexandria , Zhu Jason , Wu Yuan , Callis Tom , Yang Shan , Esplin Edward D. , Nussbaum Robert L. , Zhang Tian , McNamara Megan Ann , Harrison Michael Roger , George Daniel J. , Cooney Kathleen A. , Armstrong Andrew J. 
Published: May 2019

5062 Background: Patients with advanced prostate cancer (PC) frequently harbor pathogenic or likely pathogenic (P/LP) germline variants (GVs) in mismatch repair (MMR) and homologous repair (HR) enzymes which have clinical and treatment implications. However, whether the prevalence of such GVs differ by race, ethnicity, family history, or age is unknown in men with PC. Methods: This is a retrospective analysis of germline DNA from men with PC in the United States, tested by Invitae. Baseline characteristics including self-identified race, ethnicity, family history (FH), and age were recorded. Race and ethnicity were analyzed by 3 cohorts: non-Ashkenazi Caucasian Americans (CA), non-Ashkenazi African Americans (AA), and Ashkenazi Jewish Americans (AJ). Chi-square testing was performed to identify significant differences across these categories between the three cohorts, with respect to combined and individual pathogenic MMR (MSH2/6, MLH1, PMS2, and MUTYH) and HR genes (BRCA1/2, ATM, CHEK2, RAD51D, and PALB2). Results: 3057 men were included in the final analysis: 2248 (74%) men were CA, 229 (7%) were AA, and 210 (7%) were AJ. Of these, 2665 (87%) men had a FH of PC and 463 (15%) had a P/LP GV. In addition, 1068 (35%) were found to have a variant of uncertain significance, and 35 (1.6%) had the HOXB13 G84E variant. There were no significant differences in the overall prevalence of MMR (CA 1.5% vs AA 0.9% vs AJ 1.4%, p = 0.89) or HR genes (CA 7.8% vs AA 7.9% vs AJ 10.5%, p = 0.37) by race/ethnicity. With respect to individual genes, AJ had a higher prevalence of pathogenic BRCA1 alterations (AJ 3.3% vs CA 0.8% vs AA 1.7%, p = 0.0034) and CHEK2 alterations (AJ 4.3% vs CA 2.8% vs AA 0.4%, p = 0.02). There were no significant differences in the prevalence of individual or specific classes of GVs between those with or without a self-reported FH of prostate or breast/ovarian cancers. There was also no association between prevalence of HR genes and age at germline testing (p = 0.40). Conclusions: This national study found that the overall prevalence of pathogenic GVs in MMR and HR genes do not differ by race, ethnicity, or age at the time of testing, and suggests that all men with advanced prostate cancer should be offered germline testing.
CALGB 90203 (Alliance): Radical prostatectomy (RP) with or without neoadjuvant chemohormonal therapy (CHT) in men with clinically localized, high-risk prostate cancer (CLHRPC).
Authors: Eastham James Andrew , Heller Glenn , Halabi Susan , Monk Paul , Clinton Steven K. , Szmulewitz Russell Zelig , Coleman Jonathan , Gleave Martin , Evans Christopher P. , Hillman David W. , Beltran Himisha , Taplin Mary-Ellen , Hahn Olwen Mary , Parsons J Kellogg , Small Eric Jay , Mohler James , Morris Michael J. 
Published: May 2019

5079 Background: Neoadjuvant CHT followed by RP did not increase 3-year biochemical progression free-survival (bPFS) compared to RP alone in men with CLHRPC. However, there is evidence that bPFS and overall survival over time was improved. In the current analysis we assessed whether CHT followed by RP improved pathological specimen features compared to RP alone. Methods: CALGB 90203 (Alliance) is a Phase III study which randomly assigned, in a 1:1 fashion, men with CLHRPC [biopsy Gleason Grade Group (GGG) 4 or 5 or Kattan pre-op nomogram bPFS < 60%] to RP alone or RP plus neoadjuvant CHT [androgen deprivation plus docetaxel (75 mg/m2 every 3 weeks for 6 cycles)]. We conducted an exploratory analysis comparing histologic findings, determined at the treating center, in the RP specimens of men receiving CHT plus RP and men treated with RP alone. We used the Chi-square test, with P-values adjusted by the Holm method for multiple comparisons. Results: A total of 788 men (median age, 62; range: 32-83 years) were randomized, with 738 ultimately undergoing RP. There was no difference in pathologic GGG (Table). Men treated with neoadjuvant CHT had a lower pathologic T-stage and lower likelihood of having seminal vesicle invasion (SVI), positive pelvic lymph nodes, or positive surgical margins (SM) (Table). Conclusions: Most pathologic features in the RP specimen were improved in men receiving neoadjuvant CHT compared to RP alone. The relationship between pathologic changes and the development of metastasis and survival require further analysis. RP pathologic outcomes. Summary statistics are calculated for the number of patients with non-missing data for each characteristic. Clinical trial information: NCT00430183. [Table: see text]
Impact of the extent of resection on primary breast angiosarcoma survival.
Authors: Mitin Timur , McClelland Shearwood , Hatfield Jess , Degnin Catherine , Chen Yiyi 
Published: May 2019

521 Background: The widely accepted standard of care in treating primary breast angiosarcoma involves surgical resection, often followed by adjuvant therapy (radiation and/or chemotherapy). The rarity of this disease has precluded large-scale analyses. The question regarding the impact of resection extent on survival has yet to be examined on a nationwide scale. Methods: The National Cancer Data Base (NCDB) from 2004-2014 identified primary breast angiosarcoma patients throughout the United States having undergone surgical resection. The extent of resection (mastectomy versus lumpectomy) was adjusted for several variables (including patient age, race, income, primary payer for care, tumor size, adjuvant therapies, and medical comorbidities) to assess its impact on breast angiosarcoma-related mortality. Results: Over this eleven-year span, 826 resected primary breast angiosarcoma patients were identified in the United States. Mastectomy was by far the most common surgical modality for primary breast angiosarcoma (86% of patients). Increasing tumor size was predictive for mastectomy over lumpectomy (p < 0.0001), and for involvement of adjuvant radiation therapy (p = 0.001). The extent of surgical resection was inversely predictive of radiation usage (p = 0.017). However, surgical modality was not significantly predictive of breast angiosarcoma-related mortality. Conclusions: Despite the frequent preference of mastectomy for primary breast angiosarcoma treatment (more than 6 of every 7 patients), there is no survival benefit of mastectomy versus lumpectomy. This lack of benefit should be discussed with patients, given the reduced operative morbidity of lumpectomy versus mastectomy. The Class IIB evidence provided from this analysis represents the highest level of evidence to-date governing management of this disease.
Effect of tart cherry on aromatase inhibitor-induced arthralgia (AIA) in nonmetastatic hormone-positive breast cancer patients: A randomized double-blind placebo-controlled trial.
Authors: Shenouda Mina , Tirona Maria R. B. Tria 
Published: May 2019

525 Background: Aromatase inhibitors (AI) are the standard treatment for hormone receptor‐positive breast cancer in postmenopausal women. About half of patients (pts) taking AI suffer from AIA which can be severe enough to cause noncompliance. Suboptimal AI adherence is associated with decreased disease-free and overall survival, suggesting that improving adherence will lead to improved breast cancer outcomes. Effective interventions for AIA are still limited. In clinical trials, tart cherry (TC) showed beneficial effect on musculoskeletal pain associated with osteoarthritis, gout, and strenuous exercise. The flavonoids and anthocyanins in TC reportedly exert an anti-inflammatory effect that may lessen adverse effects of estrogen deficiency. This trial aimed to investigate whether TC can reduce AIA in non-metastatic hormone positive breast cancer (NMHPBC) pts. Methods: This is a randomized, placebo-controlled, double-blind trial. Eligible Pts with NMHPBC on AI for at least 4 weeks were randomized to TC concentrate (equivalent to 50 tart cherries) versus placebo (P) [syrup] in a 1:1 model. Pts were instructed to take 1 Oz of TC or P in 8 Oz water daily for 6 weeks, and to document their pain intensity at baseline, weekly and at study completion in a diary using a Visual Analog Scale (VAS), with 0 mm indicating no pain, and 100 mm indicating highest pain. Results: 60 pts were enrolled from May 2016 to August 2018. 2 pts did not complete the study due to diarrhea. 10 pts were non-compliant. 48 pts were included in the final analysis. TC group (23 pts) had 34.7% mean decrease in pain compared to 1.4% in P group (25 pts). This difference was statistically significant (Mann-Whitney U Test P = 0.034). Conclusions: Tart cherry can significantly improve AIA in non-metastatic breast cancer patients.
Breast cancer-specific survival outcomes among patients based on 21-gene recurrence score.
Authors: Swenson Wade T. , Mallick Shantanu 
Published: May 2019

537 Background: The 21-gene recurrence assay predicts cancer recurrence rates and benefit from adjuvant chemotherapy among patients with hormone-receptor-positive breast cancer. The National Cancer Institute and Genomic Health collaborated to provide Recurrence Score (RS) results to complement data from 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Program. Methods: Using the SEER database with linked RS results, a cohort of female breast cancer patients, age greater than 20 years, was identified by RS (low: < 18, intermediate: 18-30, high: > 30) diagnosed between the years 2004 and 2007. A retrospective analysis was conducted to determine eight-year breast cancer-specific survival rates based on RS and other variables. Results: 10,318 patients were identified in the cohort. 5,194 had a low risk RS; 4,282 had an intermediate risk RS; 872 had a high risk RS. Histologic subtypes were: 7,459 infiltrating ductal carcinoma, 941 mixed infiltrating and lobular carcinoma, 933 lobular carcinoma, 327 mixed infiltrating ductal and other histology, 244 mucinous adenocarcinoma, 101 tubular adenocarcinoma, 45 mixed lobular and other histology, 268 other histologies. 644 low risk RS patients received chemotherapy (12.4%); 1,608 intermediate risk RS patients received chemotherapy (37.8%); 593 high risk patients received chemotherapy (68.0%). The eight-year breast cancer-specific survival rates (with 95% confidence intervals) among low risk RS patients without known chemotherapy administration was 98.9% (98.5, 99.2), and 98.4% (97.0, 99.1) with chemotherapy; intermediate risk RS patients without known chemotherapy was 97.0% (96.2, 97.6), and 96.9% (95.9, 97.7) with chemotherapy; high risk RS patients without known chemotherapy was 89.7% (85.4, 92.8), and 92.9% (90.4, 94.7) with chemotherapy. Conclusions: Among a large cohort of patients identified in a population-based cancer registry between 2004 and 2007, there was no statistically significant difference in eight-year breast cancer-specific survival rates among those who received chemotherapy and those who did not, regardless of RS risk group.
Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy: A Breast International Group (BIG) 1-98 sub-analyses.
Authors: Leone Jose Pablo , Cole Bernard F. , Regan Meredith M. , Thurlimann Beat J. K. , Coates Alan S. , Goldhirsch Aron , Di Leo Angelo , Colleoni Marco , Luis Ines Maria Vaz Duarte , Lin Nancy U. 
Published: May 2019

538 Background: Endocrine therapy resistance is a major cause of distant recurrence (DR) in HR+ breast cancer. Currently, no data exists evaluating differences in clinical behavior after DR between patients (pts) treated in the adjuvant setting with different endocrine therapy regimens. The aim of this study was to analyze post-DR survival of pts treated on BIG 1-98. Methods: BIG 1-98 compared 5 years of adjuvant treatment between 4 arms: tamoxifen (T), letrozole (L), T followed by L (TL) and L followed by T (LT). After 8.1 years median follow-up (follow-up through 2010), 911 (T n = 302, L n = 285, TL n = 170, LT n = 154) of 8010 pts had DR as site of first recurrence. Univariate and multivariable Cox analyses were performed to determine features associated with post-DR survival. With 661 total observed deaths, statistical power was 0.8 to detect a hazard ratio (HaR) > 1.24 at the 2-sided 0.05 level of significance. Results: Median follow up time after DR was 59 months (IQR: 29-88). Among all pts with DR, 38.1% were ≥ 65 years at study enrollment, 61.9% had tumor size > 2 cm, 69.7% were node positive. Neo/adjuvant chemotherapy was administered to 35.6% of pts. There was no difference in post-DR survival by treatment arm (median survival: T 20.8, L 17.9, TL 17.3, LT 20.8 months; p = 0.21). In multivariable analysis, older pts (HaR 1.36; p = 0.0002), tumors > 2cm (HaR 1.2; p = 0.04), ≥ 4 positive nodes (HaR 1.32; p = 0.05) and PR- tumors (HaR 1.28; p = 0.001) had significantly worse post-DR survival. Endocrine treatment arm, type of surgery, radiotherapy and neo/adjuvant chemotherapy were not associated with post-DR survival in the multivariate model. Conclusions: Treatment with adjuvant T, L or their sequence were not associated with differences in survival after DR. We observed significant differences in survival by primary tumor size, nodal and PR status, which suggest that traditional high-risk features remain prognostic in the metastatic setting. Clinical trial information: NCT00004205.
Distinct mutational landscape between HR+ and HR- HER2+ early-stage breast cancer patients.
Authors: Chen Bo , Liao Ning , Zhang Guo-Chun , Wang Yulei , Chen Xiaoqing , Guo Liping , Cao Li , Mok Hsiaopei , Ren Chong-Yang , Li Kai , Jia Minghan , Li Cheukfai , Wen Ling-Zhu , Lin Jiali , Wei Guangnan , Hou Ting , Lizaso Analyn , Liu Jing , Balch Charles M. 
Published: May 2019

543 Background: HER2 targeted therapy has revolutionized the survival outcomes of early and advanced HER2+ breast cancer (BC). However, among HER2+ patients, the therapeutic response to HER2 inhibitors vary. To understand the molecular mechanism of the variability in therapeutic efficacies, the mutational landscape of HER2+ tumors need to be elucidated. Methods: 107 HER2+ Chinese stage I-III BC patients were included in the study, including 64 HR+ and 43 HR- patients. A majority of the patients were diagnosed with infiltrating ductal carcinoma (99/107). Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes spanning 1.64 MB of the human genome. Results: 1,119 alterations were detected, including 478 single nucleotide variants (SNVs), 14 insertions or deletions, 29 fusions, 593 copy number amplifications (CNA), 2 large genomic rearrangements and 3 CN deletions in 267 genes. Alterations in 99 genes were shared between HR+/HER2+ and HR-/HER2+ tumors; while 123 and 45 genes were only detected in either HR+/HER2+ or HR-/HER2+ tumors, respectively. CNA, splice site and frameshift mutations were significantly more in HR+/HER2+ patients ( p= 0.017). Specifically, CNA in SPOP, CCND1, FGF19, FGF3, FGF4, RNF43, RAD51C, ADGRA4 and MDM4 and various alterations in GATA3 were significantly more among HR+/HER2+ tumors ( p< 0.05). In addition to HER2 amplifications, concurrent fusions in ERBB2 (67%, 4/6), SNVs in ERBB3 (100%, 3/3) and ERBB4 (100%, 1/1) were more likely to be detected in HR+/HER2+ tumors, while concurrent EGFR amplifications were exclusively detected in HR-/HER2+ tumors. The trend of concurrent mutations was consistent with mutation types detected in HER2- tumors based on HR status, wherein EGFR amplifications were more frequent in HR-/HER2- tumors, while SNVs in EGFR, ERBB2, ERBB3 and ERBB4 were more predominant in HR+/HER2- tumors. Based on KEGG pathway analysis, HR+/HER2+ tumors had more frequent alterations in TGFb ( p= 0.007), WNT ( p= 0.002) and homologous recombination ( p= 0.004) pathways than HR-/HER2+ tumors. Furthermore, our data revealed that HR+/HER2+ and HR-/HER2+ patients had comparable TMB ( p= 0.24), with a median TMB of 4.0 mutations/Mb for both. Conclusions: Our study revealed genetic heterogeneity between HR+ and HR- HER2+ tumors. The distinct genetic alterations are potentially relevant in the development of optimal treatment strategies for such patients.
Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial.
Authors: Barcenas Carlos Hernando , Hurvitz Sara A. , Di Palma Jack A. , Bose Ron , Chan Arlene , Chien Amy Jo , Farrell Cindy , Hunt Daniel , McCulloch Leanne , Kupic Amy , Tripathy Debu , Rugo Hope S. 
Published: May 2019

548 Background: CONTROL (clinicaltrials.gov: NCT02400476) is an open-label, sequential-cohort, phase II study investigating the effectiveness of prophylaxis or dose escalation in preventing diarrhea and improving tolerability of neratinib, an irreversible pan-HER tyrosine kinase inhibitor. Neratinib has demonstrated benefit as an extended adjuvant therapy for early-stage HER2+ breast cancer. Various prophylactic agents are being studied in adult patients treated with oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Methods: Patients (n = 485) were enrolled into cohorts investigating antidiarrheal prophylaxis for 1–2 cycles (28 days) with the following agents: loperamide (n = 137); loperamide + budesonide (n = 64); loperamide + colestipol (n = 136); loperamide prn + colestipol (n = 104). An additional cohort assessing loperamide prn + neratinib dose escalation with no mandatory prophylaxis (n = 44) is ongoing. Adverse events were graded according to NCI-CTCAE v4.0. The primary endpoint was incidence of grade ≥3 diarrhea. Data cut-off: 14 Jan 2019. Results: As shown in the table, all prophylactic regimens reduce the incidence of Grade 3 diarrhea and drug discontinuation compared with the prior ExteNET trial [Martin et al. 2017]. The median cumulative duration of Grade 3 or higher diarrhea spanned from 2.0 to 3.5 days across regimens for the entire treatment period. No Grade 4 diarrhea was reported. Conclusions: The addition of budesonide or colestipol to loperamide prophylaxis given for 1–2 cycles reduces the severity and duration of diarrhea in patients treated with neratinib, thereby improving tolerability. Updated data for the dose-escalation cohort will be presented at the meeting. Clinical trial information: NCT02400476. [Table: see text]