bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted sequencing in a phase III trial of luminal breast cancer: Identification of novel targets.
Authors: Bartlett John , Kalatskaya Irina , Yousif Fouad , Bayani Jane , Trinh Quang M , Heisler Lawrence , Timms Lee , Lee Shawna , Buchner Nicholas , Milacic Marija , Rothfels Karen , Crozier Cheryl , Drake Camilla , Hasenburg Annette , Kieback Dirk G , Rea Daniel , McPherson John , Boutros Paul Christopher , Stein Lincoln D 
Published: September 2018

505 Background: The International Cancer Genome Consortium and The Cancer Genome Atlas have had a global transformative impact on our understanding of cancer. These programs have mapped the genomic landscape of common and rare tumors setting the scene for a comprehensive change in the approach to cancer diagnosis and treatment. However, the task remains incomplete until these mutational events are linked to clinical outcomes in the context of current therapeutic intervention to drive future stratified medicine approaches. Methods: We performed targeted sequencing in patients from the Tamoxifen Exemestane Adjuvant Multicentre trial. DNA was extracted and a 101 gene panel analysed using a novel mutation calling pipeline. Both a priori and machine learning analyses were performed using distant recurrence free survival as the primary endpoint. Results: In 1,491 successfully analyzed samples 1,070 (71.76%) samples exhibited at least one single nucleotide mutation (range 0-94, 1.828+/-0.133, mean+/-s.e.). 98/101 genes were mutated in at least one patient. Only variants in PIK3CA, TP53, MLL3, CDH1 were detected in 5% or more of samples. Twenty genes were associated with increased risk of recurrence in multivariate analyses corrected for clinic-pathological variables, 50% of these genes were involved in transcriptional regulation or RNA/protein processing. In a multivariate analysis, two combined signalling modules were independently prognostic for residual risk following hormone therapy (HRvalidation 3.10 95%CI 1.78-5.40 and HRvalidation 2.70 95%CI 1.57-4.64). Conclusions: We successfully performed a signalling pathway-based targeted sequencing analysis within predefined signalling modules. In supervised and unsupervised analyses we identified multiple signalling cassettes linked to poor outcome in patients with ER+ve breast cancers treated with modern endocrine therapy in the context of a phase III clinical trial. These results identify novel candidates as targets to treat endocrine refractory breast cancers.
The plasma lipidome in castration-resistant prostate cancer.
Authors: Horvath Lisa , Lin Hui-Ming , Mahon Kate Lynette , Weir Jacquelyn , Mundra Piyushkumar , Spielman Calan , Briscoe Karen P. , Gurney Howard , Mallesara Girish , Marx Gavin M. , Stockler Martin R. , Parton Robert , Hoy Andrew , Daly Roger J. , Meikle Peter 
Published: September 2018

5055 Background: Biomarker studies of metastatic castration-resistant prostate cancer (CRPC) have mainly focused on changes in the cancer, however, the host environment and its interactions with cancer is increasingly important, especially given the increasing association of PC outcomes and obesity. We sought associations between the plasma lipidome and clinical outcome in CRPC. Methods: Plasma samples were obtained from a Phase 1 discovery cohort of 96 CRPC patients before and after the first cycle of docetaxel chemotherapy. Lipidomic profiling of the plasma samples was performed by liquid chromatography and electrospray ionisation-tandem mass spectrometry. Results were subsequently assessed in a Phase 2 validation cohort of 63 CRPC patients. Results: Lipidomic profiling detected 323 lipid species in plasma samples from the Phase 1 cohort. Patients could be classified into two subgroups with significant survival differences according to their baseline lipidomic profiles (median overall survival 13.7 vs 21.7 months; HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The baseline levels of 46 lipids were individually prognostic (p < 0.01) and predominantly sphingolipids. A prognostic three-lipid signature was derived (ceramide (d18:1/24:1), sphingomyelin (d18:2/16:0), phosphatidylcholine (16:0/16:0)) (11.7 versus 21.7 months, p = 0.00001; HR 2.94, 95% CI 1.80-4.81, p = 0.00002). The signature was associated with shorter overall survival in the Phase 2 cohort (HR 4.78, 95% CI 2.06-11.1, p = 0.0003), and was an independent prognostic factor when modeled with clinicopathological factors and metabolic characteristics (BMI, cholesterol and triacylglycerol). The AUC of ROC analysis of 12 month survival for a clinicopathological model (AUC 0.70, 95% CI 0.54-0.87, p = 0.03) was enhanced by the addition of the 3-lipid signature (AUC 0.73, 95% CI 0.57-0.89, p = 0.01). Conclusions: Our study is the first to comprehensively profile the plasma lipidome of men with CRPC using cutting-edge lipidomic profiling technology, to identify a plasma lipid signature that can reproducibly predict outcome in CRPC and can improve on clinicopathological models. Therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.
Association of androgen receptor (AR) status in plasma DNA with outcome on enzalutamide (enza) or abiraterone (abi) for castration resistant prostate cancer (CRPC).
Authors: Conteduca Vincenza , Wetterskog Daniel , Sharabiani Mansour Taghavi Azar , Jayaram Anuradha , Salvi Samanta , Romanel Alessandro , Lolli Cristian , Casadio Valentina , Gurioli Giorgia , Amadori Dino , Gasi Tandefelt Delila , Wingate Anna , Dearnaley David P. , Demichelis Francesca , De Giorgi Ugo , González-Billalabeitia Enrique , Attard Gerhardt 
Published: September 2018

5060 Background: There is an urgent need to identify biomarkers to guide personalized therapy in CRPC. We aimed to clinically qualify the association of AR status in plasma DNA with worse outcome in pre- and post-docetaxel (doc) CRPC. Methods: We used droplet digital (dd)PCR to assess AR copy number (CN) and mutations (mut) (2105T > A (p.L702H) and 2632A > G (p.T878A) status in plasma DNA from 171 patients (pts) treated with abi/enza in biomarker protocols at 2 institutions. The aim to evaluate plasma AR was defined after sample collection but prior to analysis. Results: We first optimised multiplex ddPCR to accurately define AR status and identified an AR CN cutpoint = 2.01 as having the greatest likelihood to split pts into 2 prognostic groups. We confirmed a strong agreement between ddPCR and NGS for quantitating AR CN and mut allelic frequency (Bland-Altman test: mean difference -0.02 95%CI -2.45 to 2.41; mean difference -0.01 95%CI -0.015 to 0.016 respectively). AR CN gain was observed in 10 (14%) pre- and 33 (34%) postdoc pts and associated with a worse OS (HR 3.98 95%CI 1.74-9.10 p < 0.001; HR 3.81 95%CI 2.28-6.37 p < 0.001 respectively), PFS (HR 2.18 95%CI 1.08-4.39 p = 0.03; HR 1.95 95%CI 1.23-3.11 p = 0.01 respectively) and PSA decline ≥50% (OR 4.7 95%CI 1.17-19.17 p = 0.035; OR 5.0 95%CI 1.70-14.91 p = 0.003 respectively). AR mut were observed in 8 (11%) postdoc but no pre-doc abi-treated pts and also associated with worse OS (HR 3.26 95%CI 1.47-not reached p = 0.004). There was no interaction between AR and doc status (p = 0.83 for OS, p = 0.99 for PFS). Multivariate analysis, adjusting for AR CN and mut, previous doc, double stranded DNA concentration, LDH, confirmed AR status was independently associated with OS (HR 3.77 95%CI 2.42-5.88 p < 0.001 and HR 2.76 95%CI 1.26-6.07 p = 0.011 for AR CN and mut respectively) and PFS (HR 1.96 95% CI 1.32-2.93 p = 0.001). Conclusions: Plasma AR status assessment using multiplex ddPCR identifies CRPC with worse outcome to enza/abi in pre/postdoc CRPC. Additional clinical qualification is available from the PREMIERE study (Grande et al;ASCO2017;Abstract#). Prospective evaluation of treatment decisions based on plasma AR is now required.
A secondary analysis of PSA response in NRG Oncology/RTOG 9902: A phase III trial of adjuvant chemotherapy with androgen suppression and radiation for high-risk prostate cancer (CaP).
Authors: Mihalcik Stephen Andrew , Regan Meredith M. , Rosenthal Seth A. , Bubley Glenn J. , Pienta Kenneth J. , Gomella Leonard G. , Grignon David A. , Hartford Alan C , Morginstin Mark S. , Michalski Jeff M. , Rajan Raghu , McDonald Andrew Michael , Dominello Michael M. , Atkins James Norman , Jones Christopher U , Moughan Jennifer , Sandler Howard M. , Kaplan Irving D. 
Published: September 2018

5078 Background: RTOG 9902 was a randomized controlled trial of the addition of adjuvant chemotherapy (CT; paclitaxel, oral etoposide, and estramustine x4 cycles) to 24 mo of androgen suppression (AS) and radiation (RT) for patients (pts) with high-risk CaP., beginning with an initial 4 mo of AS; RT began after 2 mo. 9902 accrued 397 pts and closed early due to excess toxicity. At a median follow-up of 9.2 years, there was no benefit to CT, but it is hypothesized that a subset analysis by post-RT PSA identifies pts that benefit from treatment intensification with CT. Methods: Post-RT PSA status was dichotomized at > 0.2 ng/mL within 1 mo of RT. Landmark analysis redefined starting times for disease-free survival (DFS), time to distant metastasis (TDM) and overall survival (OS) at 16 weeks post-RT (36 weeks post-randomization) when CT was planned to complete. Pts were excluded if they did not get RT or assigned CT, or experienced DFS events/lost to follow-up < 36 wks post-randomization. Hazard ratios (HR), 95% confidence intervals (CI), and PSA-by-treatment interaction were estimated by Cox or competing-risks regression. Results: 333 pts were analyzed: 190 without and 143 with CT. 37% of pts had a post-RT PSA ≤0.2, 34% > 0.2, and 29% no recorded PSA in the defined interval. CT was associated with improved DFS for pts with PSA > 0.2 (HR 0.59, 0.38-0.91), but not for those with PSA ≤0.2 (HR 0.94, 0.60-1.46; interaction p = 0.13). This association, for those with PSA > 0.2, persisted in those pts who received the full course of CT and trended in the same direction for pts receiving 1-3 cycles. CT was associated with a trend toward improved TDM in the PSA > 0.2 group (HR 0.56, 0.23-1.35) and not in the PSA≤0.2 group (HR 1.31, 0.36-4.70), based on 32 pts with metastases. OS did not show the same pattern (PSA > 0.2: HR 0.98, 0.55-1.77; PSA≤0.2: HR 0.57, 0.29-1.13). Conclusions: This analysis suggests that men with high-risk CaP and suboptimal response to AS+RT, as identified by post-RT PSA > 0.2, may benefit from adjuvant CT. Prospective trials using contemporary CT (e.g. docetaxel) will help optimize treatment for these men. NRG-GU002, recently activated, is addressing this issue.
SWOG S0221 updated: Randomized comparison of chemotherapy schedules in breast cancer adjuvant therapy.
Authors: Budd G. Thomas , Barlow William E. , Moore Halle C. F. , Hobday Timothy J. , Stewart James A. , Isaacs Claudine , Salim Muhammad , Cho Jonathan K. , Rinn Kristine , Albain Kathy S. , Chew Helen K. , Burton Gary Von , Moore Timothy David , Srkalovic Gordan , McGregor Bradley Alexander , Flaherty Lawrence E. , Livingston Robert B. , Lew Danika L , Gralow Julie , Hortobagyi Gabriel N. 
Published: September 2018

521 Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P<0.001) than the HER2-positive or ER/PR+/HER2- subsets, with 5 year DFS of 75% vs 83% and 84%, respectively. While we previously found in the triple negative subset that the arm using q 2 weeks for both AC and paclitaxel was marginally superior, the differences among the arms are no longer significant for DFS (p=0.12) or OS (p=0.11). Among the 578 pts assigned ACx4 and randomized to Pw v P2 there were no overall differences in DFS (p=0.70) or OS (p=0.63) after 4.4 years median follow-up. Conclusions: There were no significant differences in DFS or OS between any of the schedules with extended follow-up in the original cohort and no difference in outcome by paclitaxel schedule for the 578 additional patients in the revised protocol. Either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564.
Non-adherence behaviors among young women on adjuvant endocrine therapy for breast cancer.
Authors: Wassermann Johanna , Gelber Shari I. , Rosenberg Shoshana M. , Ruddy Kathryn Jean , Tamimi Rulla M. , Schapira Lidia , Borges Virginia F. , Come Steven E. , Partridge Ann H. 
Published: September 2018

526 Background: Young age at diagnosis (dx) is a predictor of worse prognosis in patients (pts) with luminal breast cancer (BC). Poorer adherence to endocrine therapy (ET) among younger women may contribute to this disparity. Aim: To assess non-adherent behaviors and associated factors among young women with stage 1-3 hormone receptor (HR)+ BC taking ET. Methods: This study is a part of a multi-center, prospective cohort of pts with dx of BC at or under age 40. On a survey 30 months after dx, among pts reporting taking ET, adherence was measured using a 3-item Likert-type scale (Do you ever forget to take your ET? If you feel worse when you take your ET, do you stop taking it? Did you take your ET exactly as directed by your doctor?). Pts reporting any non-adherent behavior during the last 3 months were classified as non-adherers. Variables with a p-value <0.20 were included in a multivariate logistic model. Results: Among361 pts eligible for this analysis, 174 (48%) reported some non-adherent behaviors in the last 3 months; 56 (16%) moderate or greater non-adherent behaviors. None of the studied variables was associated with non-adherent behaviors (table). Conclusions: Non-adherent behaviors to ET are present in almost half of the young women with HR+ BC. Further analyses of explanatory factors and impact of non-adherence are required to understand and potentially improve this problem. [Table: see text]
Endocrine therapy non-persistence in young women with early-stage breast cancer.
Authors: Rosenberg Shoshana M. , Gelber Shari I. , Ruddy Kathryn Jean , Tamimi Rulla , Wasserman Johanna , Schapira Lidia , Borges Virginia F. , Come Steven E. , Meyer Meghan E , Partridge Ann H. 
Published: September 2018

531 Background: The greatest age disparity in early stage breast cancer (BC) outcomes is in young women with hormone receptor positive (HR+) BC. While differences in biology may play a role, understanding the role of non-persistence (early discontinuation) with endocrine therapy (ET) is critical given the demonstrated efficacy of ET in this population. Methods: As part of a prospective cohort that enrolled women with BC diagnosed (dx) at age ≤40 between 2006-2016, we identified women with HR+, Stage I-III BC. Socio-demographic and treatment information, fertility concerns and confidence with the ET treatment decision were assessed by survey within 1 yr of dx. Medical record review was used to ascertain stage and HR status. Women who initiated ET but did not report taking tamoxifen or an aromatase inhibitor at 3 yrs post-diagnosis (or last follow-up if <3 yrs) were classified as non-persistent. Chi-square tests were used to compare categorical variables between persisters and non-persisters and stepwise multivariable regression to evaluate predictors of non-persistence. Results: In 538 women who initiated ET, median age at dx was 36; 10% were non-persistent. Discontinuation of ET was more likely in those who were less confident with their ET decision compared to those who were more confident (25/179, 14% vs 18/263, 7%, p=0.01). A greater proportion of women concerned about fertility discontinued vs. women not concerned (29/213,14% vs 25/319, 8%, p=0.03), and fertility concerns were associated with non-persistence in multi-variable analyses (OR: 1.85, 95% CI 1.05-3.26, p=0.03). Age at dx, race, education, employment, financial comfort, marital status, parity, stage, chemotherapy and local therapy were not associated with non-persistence. Conclusions: A significant minority of women with HR+ BC discontinued ET within 3 yrs. The association between fertility concerns expressed soon after dx and non-persistence underscores a need to address psychosocial issues that can impact treatment decisions in young women. Strategies to reduce decisional conflict and increasing confidence with the choice to take ET, may influence persistence. Future work will evaluate the contribution of other factors (eg symptom burden) to non-persistence.
The performance of the 21-gene assay standard cutpoints of 18 and 31 in HR+, HER2- invasive breast cancer (BC), while waiting for TAILORx mid-range recurrence score results.
Authors: Miller Dave P. , Petkov Valentina I. , Shak Steven 
Published: September 2018

537 Background: The Recurrence Score (RS) was shown in NSABP B-20 to predict chemotherapy (CT) benefit for RS ≥31 and no CT benefit for RS <18. The TAILORx results for RS <11 (NEJM 2015) reported excellent outcomes with no opportunity for CT to add additional benefit. As we await TAILORx results for RS 11-25, we characterized BC specific mortality (BCSM) for RS groups (cutoffs of 11, 18, 25, and 31) in the population-based SEER study of pts treated based on RS. Methods: RS results were provided to SEER registries per their methods (npj Breast Cancer 2016). Pts diagnosed (Jan 2004 - Dec 2012) with N0 HR+ HER2- negative BC, and no prior malignancy were eligible. BCSM estimates by CT use were computed using standard cutpoints of 18 and 31 and TAILORx cutpoints of 11 and 25. Results: Among 49,681 with a RS, 9,486 (19%) had RS <11, 17,988 (36%) had RS 11-17, 14,541 (29%) had RS 18-25, 3,805 (8%) had RS 26-30, and 3,861 (8%) had RS ≥31. Reported CT use and 5-y BCSM increased with increasing RS. For pts with both RS <11 and RS 11-17, CT use was uncommon and 5-y BCSM was low regardless of CT use. For pts with RS 18-25, CT use was more common and the 5-y BCSM was about 1% regardless of CT use. For pts with RS of 26-30 or ≥31, CT was common, and lower 5-y BCSM was observed with CT reported yes than with CT reported no or unknown. Conclusions: Pts in real-world clinical practice with RS <11, consistent with TAILORx, and pts with RS 11-17 have low 5-y BCSM with limited CT use, supporting hormonal therapy alone for pts with RS <18. The high end of the TAILORx mid-range (18-25) also showed good 5-y BCSM both with and without CT, highlighting the importance of the randomized results of TAILORx. [Table: see text]
Recent time trends in chemotherapy use and oncologists' chemotherapy recommendations for early-stage, hormone receptor-positive breast cancer.
Authors: Kurian Allison W. , Bondarenko Irina , Jagsi Reshma , McLeod Chandler , Hawley Sarah T. , Hamilton Ann S. , Ward Kevin C. , Katz Steven J. 
Published: September 2018

541 Background: Advances in tumor genomic profiling enable increasingly precise estimates of the benefit of adjuvant chemotherapy in early-stage breast cancer. However, little is known about how chemotherapy use, medical oncologists’ (MO) perspectives and recommendations have changed in recent years, particularly in key clinical subgroups such as node-negative and node-positive. Methods: We surveyed 5,080 women (70% response rate), newly diagnosed with breast cancer in 2013-2015 and accrued through two population-based SEER registries (Georgia and Los Angeles), about their MOs’ chemotherapy recommendations and whether they received chemotherapy. Using patient report, we identified 470 attending MOs and surveyed them (n=310, 66% response) about approaches to chemotherapy recommendation, using node-negative and node-positive case scenarios. We evaluated factors associated with chemotherapy receipt over time using multi-level logistic regression. Results: The analytic sample was 2,926 patients with stages I-II, estrogen receptor-positive, HER2-negative breast cancer. Chemotherapy use declined to 21% from 34% during the study period (2013-2015, p<.001). For node-positive patients, chemotherapy use declined to 64% from 81% and for node-negative/micrometastasis patients to 14% from 27%. Based on patient report, MOs’ recommendations for chemotherapy declined during the study period to 32% from 45% (p<.001). Recommendations reported by MOs were generally guideline-concordant. MOs were much more likely to order tumor genomic profiling when patient preferences were discordant with recommendations [67%, standard error (SE) 3% versus 18% (SE 2%) without discordance], and they adjusted chemotherapy recommendations based on patient preferences and genomic profiling results. Conclusions: For both node-negative/micrometastasis and node-positive patients, chemotherapy receipt and oncologists’ recommendations for chemotherapy declined markedly in recent years. The results of ongoing clinical trials of genomic profiling will be essential to confirm the quality of this approach to breast cancer care. Funded by NCI P01CA163233.