bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relationship between quantitative HER2 gene expression by the 21-gene RT-PCR assay and adjuvant trastuzumab (H) benefit in NCCTG (Alliance) N9831.
Authors: Perez Edith A. , Butler Steven M , Dueck Amylou C. , Baehner Frederick L. , Jamshidian Farid , Cherbavaz Diana B. , Thompson E Aubrey , Shak Steven , Kaufman Peter Andrew , Davidson Nancy E. , Gralow Julie , Asmann Yan W , Ballman Karla V. 
Published: March 2020

520 Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2+ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg<10.7, equiv 10.7 to <11.5, and pos ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (>10% + cells = +), 91% for RT-PCR vs central FISH (≥2.0 = pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P=0.057). In hormone receptor pos pts (local IHC) the association was significant (P=0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC+ or FISH+ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. [Table: see text]
Combination trastuzumab and chemotherapy to induce immunity to multiple tumor antigens in patients with HER2-positive metastatic breast cancer: NCCTG (Alliance) studies N0337 and N98-32-52.
Authors: Clynes Raphael , Knutson Keith L. , Ballman Karla V. , Erskine Courtney L. , Norton Nadine , Sumrall Susan V. , Northfelt Donald W. , Tan Winston , Calfa Carmen Julia , Pegram Mark D. , Perez Edith A. 
Published: March 2020

521 Background: The addition of trastuzumab to chemotherapy improves responses to therapy and extends survival among patients with metastatic HER2 breast cancer. Several mechanisms have been proposed for the activity of this combination therapy. Trastuzumab, specifically, is thought to activate NK cells and blunt HER2 signaling. Prior work from us has shown that combination trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy. Despite that, it remains unclear whether the immunity that was induced was due to complexing of non-tumor derived HER2 or antigen derived from the tumor site. In the present work, we addressed this question by assessing if combination therapy induced epitope spreading to tumor antigens other than HER2. Methods: Pre-and post-treatment sera were obtained from 56 women enrolled in 2 NCCTG clinical trials, N0337 and 98-32-52. IgG antibodies to HER2 intracellular domain (HER2), p53, IGFBP2, CEA and tetanus toxoid (TT) were examined using ELISAs. Sera from an age-matched group (N=56) of controls and 12 patients treated in the adjuvant setting were also examined. Results: Prior to therapy, metastatic patients had higher IgG levels (≥ 2-fold) to p53 and HER2 but not CEA, IGFBP2 and TT, relative to the controls. Similarly, adjuvant patients had elevated IgGs to multiple tumor antigens prior to therapy, relative to controls. Following therapy, levels of IgG to IGFBP2, HER2, and p53 increased in 81% of metastatic patients, with mean increases of 3.2 (±0.6 sem), 6.2 (±2.7) and 2.7 (±0.7) fold, respectively (p<0.05). Levels of antibodies to TT and CEA were not elevated by treatment. In contrast, IgGs were not increased in adjuvant patients; consistent with the idea that immunity depends on the presence of threshold levels of antigens. Conclusions: These results show that combination treatment induces adaptive immunity to antigens released by tumor and that metastatic patients remain capable of responding immunologically to their cancer. Thus, in metastatic breast cancer patients, combination trastuzumab and chemotherapy may behave as a vaccine.
Generation of adaptive HER2-specific immunity in HER2 breast cancer patients by addition of trastuzumab to chemotherapy in the adjuvant setting: NCCTG (Alliance) study N9831.
Authors: Knutson Keith L. , Perez Edith A. , Ballman Karla V. , Erskine Courtney L. , Fox Nicholas , McCarl Christie-Ann , Norton Nadine , Sumrall Susan V. , Northfelt Donald W. , Tan Winston , Calfa Carmen Julia , Pegram Mark D. , Clynes Raphael 
Published: March 2020

522 Background: In the adjuvant setting, patients with HER2 breast cancer treated with trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy in patients with HER2+ metastatic breast cancer. It remained unclear from those studies, however, whether the HER2-specific immunity played a role and if antibody immunity was associated with improved disease free survival in the adjuvant setting. In the present study, we addressed these questions by analyzing sera samples from a subset of patients enrolled in the NCCTG adjuvant trial, N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and post-treatment initiation sera were obtained from 50 women enrolled in N9831 (22 Arm A; 14 Arm B, and 14 Arm C). Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and presented as an index (>0.2 was considered a positive response). Results: Prior to therapy, across all three arms, N9831 patients had similar mean HER2 IgG levels (0.19 units in Arm A, 0.14 in Arm B, and 0.23 in Arm C, P=0.85). Following treatment, the mean levels of antibodies increased in Arm B to 0.35 units and in Arm C to 0.56 units and were higher (p<0.001) than in Arm A where levels did not increase. The proportion of patients who demonstrated antibody immunity increased by 9% in Arm A, 50% in Arm B and 28% in Arm C (P=0.026). Although the event rate was low in this cohort, Cox modeling suggested that larger increases in antibodies were associated with improved disease free survival (HR=0.23; p=0.04). Conclusions: These results show that the increased antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant and results from the inclusion of trastuzumab. The findings may have important implications for improving treatment outcomes in patients treated with trastuzumab.
ACOSOG Z1041 (Alliance): Cardiac events (CE) among those receiving neoadjuvant anthracyclines (A) and taxanes with trastuzumab (T) for HER2+ breast cancer.
Authors: Ewer Michael , Suman Vera J. , Buzdar Aman , McCall Linda Mackie , Meric-Bernstam Funda , Leitch A. Marilyn , Ellis Matthew James , Boughey Judy Caroline , Unzeitig Gary Walter , Royce Melanie , Hunt Kelly 
Published: March 2020

526 Background: Z1041 randomized women with HER2+ operable breast cancer to: FEC → P+T (Arm 1) or P+T → FEC+T (Arm 2). Treatment administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4; paclitaxel 80 mg/m2weekly x 12 and T 4 mg/kg once then 2 mg/kg weekly x 11. T was to continue q3 weeks post-op for 40 weeks. A secondary aim was to examine the cardiotoxicity (CE). Methods: Ejection fraction (EF) was measured at baseline (BL), between regimens (wk 12), prior to surgery (wk 24) and PRN. Eligibility: BL EF ≥ 55%. CEs included decline in EF of > 15%, or >10% points to a value < LLN. Reversibility was adjudicated by blinded investigators as reversible (R: recovery of EF to ≤ 5% below BL), partially reversible (PR: recovery of > 10% points from nadir, but ≤ 5% points below BL), indeterminate (IN: no additional EF data), or irreversible (IRR:follow-up EF studies showed no improvement). Results: Of the 280 patients (Arm 1: 138) who began treatment, 15 pts (Arm 1: 10; Arm 2: 5) did not receive T. The number of weeks of T was 13 (range: 1-18) in Arm 1 and 24 (range: 1-31) in Arm 2. Changes in EF and severe treatment related cardiac toxicities prior to surgery (sx) are tabled below. There were 271 pts (Arm 1: 131) who had post-BL EFs. Prior to sx, there were 11 CE (8.3%) in Arm 1 and 13 CE (9.2%) in Arm 2. CEs were R in 12 pts (Arm 1: 5; Arm 2: 7); PR in 6 pts (Arm 1: 4; Arm 2: 2); IN in 4 pts (Arm 1: 2; Arm 2: 3) and IRR in 1 Arm 2 pt. Conclusions: The number of CE events in arms 1 and 2 showed no significant difference; greater scatter was observed in arm 2 patients. While concern for late cardiac events makes ongoing cardiac surveillance prudent due to A, concomitant use of A and T appear to not be associated with increased cardiac risk. Clinical trial information: NCT00513292. [Table: see text]
The prognostic role of androgen receptor in early-stage breast cancer patients: A meta-analysis.
Authors: Bozovic-Spasojevic Ivana , Zardavas Dimitrios , De Azambuja Evandro , Ameye Lieveke , Sotiriou Christos , Piccart-Gebhart Martine J. , Paesmans Marianne 
Published: March 2020

528 Background: Androgen receptor (AR) expression has been observed in ~70% of breast cancer (BC) patients, but its prognostic role is not established yet. To assess this we performed a meta-analysis of studies that evaluated the impact of AR on disease free survival (DFS) and/or on overall survival (OS) in early stage BC. Methods: Published studies were identified by an electronic search on PubMed using the MeSH terms "breast neoplasm" and "androgen receptor" (up to June 2012). Identified studies were assessed against the following criteria for inclusion in the analysis: early stage BC and reported results of AR status in correlation with clinical outcome. We report combined HRs with 95% confidence intervals (CI) using AR negative patients as reference. Results: Twenty studies were eligible for the meta-analysis out of 493 initially identified and 12 among them, including 6,525 patients, were considered as evaluable (i.e., reporting enough information to allow aggregation of results). AR positivity was associated with lower risk of relapse in all breast cancer patients, and better overall survival in both univariate (U) and multivariate (M) analysis. AR prognostic impact in different subtypes was also assessed (see Table). Conclusions: Our analysis demonstrated that AR delivers prognostic information overall, serving as a positive prognostic factor in early stage BC. Further studies are needed to delineate its prognostic impact within the different subtypes of the disease. [Table: see text]
Relative effectiveness of letrozole alone or in sequence with tamoxifen for patients diagnosed with invasive lobular carcinoma.
Authors: Metzger Filho Otto , Giobbie-Hurder Anita , Mallon Elizabeth A , Viale Giuseppe , Winer Eric P. , Thurlimann Beat J. K. , Gelber Richard D. , Regan Meredith M. , Colleoni Marco , Ejlertsen Bent , Bonnefoi Herve , Forbes John F. , Neven Patrick , Wardley Andrew M. , Lang Istvan , Smith Ian E. , Price Karen N. , Coates Alan S. , Goldhirsch Aron ,   International Breast Cancer Study Group
Published: March 2020

529 Background: BIG 1-98 is a randomized, phase III study that compares five years of tamoxifen (tam) or letrozole (let), (monotherapy arms), or their sequences (tam-let or let-tam) in post-menopausal women with ER+ early BC. In the monotherapy arms, the magnitude of benefit of adjuvant let compared with tam varies by histology (greater in invasive lobular carcinoma (ILC) than invasive ductal carcinoma (IDC)). In this analysis we investigate the magnitude of benefit of let compared to tam-let and let-tam according to histology (IDC and ILC) at 96 months of median follow-up. Methods: There were 4,634 patients enrolled in the let, tam-let and let-tam arms of BIG-98. This analysis includes patients with centrally-reviewed histological subtype (n=4,223); classified as classic ILC or IDC (n=3,790); and with centrally reviewed ER, PgR and Ki67 (n=3,212). Results: The 8-year DFS and OS univariate estimates (±SE) for IDC and ILC are presented in the Table. When correcting for classic clinicopathological variables, treatment assignment was not a significant predictor of DFS and OS. Conclusions: We observed a trend toward greater magnitude of benefit in favor of let monotherapy for ILC than IDC. In the ILC subset, improvements for both DFS and OS were seen for let when compared to tam-let or let-tam, though not statistically significant. This may be due to the reduced number of ILC patients across subgroups. The present analysis is consistent with previous data from the monotherapy arms where let was associated with better DFS and OS than tam for ILC, and suggests that let might be the preferred upfront regimen for patients diagnosed with ILC. Clinical trial information: NCT00004205. [Table: see text]
Expression of enhancer of zeste homologue 2, correlated with HIF-1α, to refine relapse risk and predict poor outcome for breast cancer.
Authors: Dong Min , Fan XinJuan , Chen Zhan-Hong , Li Xing , Wang Tian tian , Chen Jie , Lin Qu , Wen Jing-Yun , Ma Xiao-Kun , Wei Li , Ruan Dan-Yun , Lin Ze-Xiao , Liu Quentin , Wan XiangBo , Wu Xiang-Yuan 
Published: March 2020

538 Background: Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior for breast cancer. In vitro, hypoxia-inducible factor 1 alpha (HIF-1α) transcriptionally activates EZH2 and promotes breast tumor initiating cells progression. Here, we characterized the clinicopathological effect of HIF-1α and EZH2 in breast cancer patients. Methods: Tumor specimens from 410 luminal subtype breast cancer patients were used to construct tissue microarray. EZH2 and HIF-1α level were examined by immunohistochemistry staining and Western blot analysis. With the 5-year follow up, the prognostic effect of EZH2 was subjected to multivariate analysis. Results: EZH2 and HIF-1α were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with high histological grade (P=0.030), lymphatic invasion (P=0.025), HER2 overexpression (P=0.005) and hypoxic condition (P<0.001). Forced expression of EZH2 predicted a poor 5-year overall survival (OS, 74.8% vs. 93.4%, P=0.001), disease-free survival (DFS, 72.2% vs. 88.6%, P=0.031), local failure-free survival (LFFS, 95.7% vs. 97.9%, P=0.045) and distant metastasis-free survival (DMFS, 75.4% vs. 90.5%, P=0.039). However, the prognostic effect of HIF-1α was not detected for breast cancer. Cox multivariate analysis confirmed that EZH2 was an independent prognostic factor for OS, DFS and LFFS. Moreover, a positive correlation was detected between EZH2 and HIF-1α (r=0.299, P<0.001). Importantly, tumors with HIF-1α and EZH2 co-overexpression were correlated with a worsened OS (P=0.007). Conclusions: EZH2 was an independent negative prognostic biomarker for luminal subtype breast cancer. Targeting HIF-1α transcriptionally regulated EZH2 pathway might be of benefit in the treatment of luminal subtype of breast cancer.
Factors predicting endoxifen levels in breast cancer patients taking standard-dose tamoxifen and following dose escalation.
Authors: Fox Peter , Gao Bo , Balakrishnar Bavanthi , Menzies Alexander M , Yeap Shang Heng , Ali Sayed Sahanawaz , Gebski Val , Provan Pamela , Coulter Sally , Liddle Christopher , Hui Rina , Kefford Richard , Lynch Jodi , Wilcken Nicholas , Balleine Rosemary L , Gurney Howard 
Published: March 2020

543 Background: Tamoxifen (TAM) is transformed via CYP2D6 to its major active metabolite endoxifen (Endox). Recent data suggest that 15nM Endox may be a therapeutic threshold for breast cancer . This study identified predictors of achieving specified Endox target levels (15nM and 30nM) on standard dose TAM, and following dose escalation. Methods: Baseline Endox was measured in 122 breast cancer pts on TAM 20mg pd. Pts with baseline Endox <30nM underwent incremental dose escalation to a maximum of 60mg pd until Endox reached 30nM or dose limiting toxicity. Clinical data were collected and CYP2D6 genotype was used to specify extensive, intermediate or poor metabolizer categories (EM, IM, PM). Multiple regression analyses examined associations between Endox and potential predictive factors. Results: Baseline Endox ranged from 3.1-72.2nM (mean 27.6nM). In 19% (n=23), baseline Endox was below 15nM and 62% (n=76) were below 30nM. Low baseline Endox was associated with CYP2D6 genotype (IM or PM, p<0.001) and younger age (p=0.02). Following dose escalation, 96% (n=117) attained an Endox level of 15nM and 76% (n=93) reached 30nM. Baseline Endox level was the only variable independently associated with achieving both targets (p=0.02, p<0.001 respectively). CYP2D6 genotype did not independently predict attainment of Endox targets following dose escalation (p>0.4). The ratio of Endox to its precursor N-desmethylTAM, an indicator of CYP2D6 activity, was stable with dose escalation, suggesting that CYP2D6 was not saturated. Conclusions: Although IM/PM predict for low Endox on 20mg TAM, only low baseline Endox predicted failure to achieve both 15nM and 30nM targets following dose escalation. These results suggest a role for Endox level monitoring to determine optimal TAM dose. Clinical trial information: NCT01075802. [Table: see text]
Phase III placebo controlled double blind randomized trial of radiation therapy for stage 2B-4A cervical cancer with immunomodulator Z-100: JGOG-DT101 study.
Authors: Fujiwara Keiichi , Ohashi Yasuo , Ochiai Kazunori , Noda Kiichiro 
Published: March 2020

5506 Background: We previously reported that the lower dose (0.2 μg) of immunomodulator Z-100 showed better overall survival (OS) compared to higher dose (40 μg) in patients with locally advanced cervical cancer who received radiation therapy (RT). Therefore, we conducted a placebo controlled double-blind randomized trial to elucidate the role of additive immunotherapy in standard RT. Methods: Patients of stages 2B to 4A squamous cell carcinoma of the uterine cervix, who were scheduled to receive standard RT with or without platinum-based chemotherapy, were eligible. Z-100 at 0.2 μg (Z) or placebo (P) was given subcutaneously twice a week during the RT, followed by maintenance therapy by administering either Z or P once every two weeks. Therapy was continued until disease progression or termination of the trial in2011. Primary endpoint was OS, secondary endpoints were recurrent-free survival (RFS), response rate (RR), and safety. Sample size was calculated by assuming 5-year survival rates (5YSR) as 60% in Arm Z and 38-44% for Arm P, (hazard ratio HR: 0.526-0.625), and was determined to be 120 patients in each arm. Results: Between 2004 and 2006, 249 patients were randomized. Total of 244 patients were eligible for safety analysis, and 243 patients were eligible for survival analysis. In Arm Z, 29 deaths were reported, and in Arm P, 42. 5YSR was 75.7% (95%CI: 66.4-82.8%) for Arm Z and 65.8 % (95%CI: 56.2-73.8%) for Arm P; HR was 0.646 (95%CI: 0.400-1.043). Survival benefit in Arm Z was observed regardless of chemoradiation or radiation alone. There were no differences between arms in terms of RR and RFS, and side effects. Neoplasms, including benign cases, observed were 4 in Arm Z, and 13 in Arm P. Conclusions: Immunomodulator Z-100, used as an adjuvant therapy after radiation, showed clinically significant improvement of OS in locally advanced cervical cancer, although the statistical power was less than anticipated because survival rates were unexpectedly higher than expected for both arms. Further exploration of Z-100 is warranted. Clinical trial information: C000000221.
Prognostic relevance of gene signatures in high-grade serous ovarian carcinoma.
Authors: Konecny Gottfried E. , Wang Chen , Winterhoff Boris , Dering Judy , Ginther Charles , Chen Hsiao-Wang , Hamidi Habib , Podratz Karl C. , Cliby William , Dowdy Sean Christopher , Haluska Paul , Hartmann Lynn C. , Kalli Kimberly , Goode Ellen L. , Slamon Dennis J. 
Published: March 2020

5510 Background: Transcriptional profiling of ovarian cancers has proven to be complex. As such it has been difficult to validate existing signatures across studies. Cancer Genome Atlas (TCGA) researchers have identified four molecular subtypes of high-grade serous ovarian cancer (HGSOC). However, survival duration did not differ significantly for the TCGA subtypes. Potential limitations of the TCGA data include short clinical follow-up (45% were alive at the time of last follow-up) and the need to unify gene expression measures from multiple platforms. Methods: Clinically annotated stage-II–IV HGSOC samples (n = 175) with >70% tumor cell content were profiled using the Agilent Whole Human Genome 4 x 44K chip. To identify subtypes non-negative matrix factorization (NMF) of mRNA expression was performed using ~2000 genes with the highest variability across patients. In parallel differentially expressed genes were identified using the Rosetta Similarity Search Tool as well as analysis of variance based on genes known to be involved in epithelial to mesenchymal transition. Results: Median follow-up time was 35 months (range, 0–202 months, 12% were alive at the time of last follow-up). NMF clustering confirmed four HGSOC subtypes (immunoreactive, differentiated, proliferative, and mesenchymal) on the basis of gene content in the clusters. Pathway signatures with therapeutic potential were identified for individual or multiple subtypes. Survival differed significantly between the four molecular subgroups in univariate (Hazard Ratio [HR] 2.4, 95% CI 1.5-4.1, p = 0.007) and multivariate (HR 2.3, 95% CI 1.3-4.0, p = 0.003) analyses when accounting for age, stage, grade, and postoperative residual tumor. Using the supervised clustering approach two distinct molecular subtypes of HGSOC based on epithelial and mesenchymal gene expression signatures were identified with significantly different survival outcomes. Conclusions: Here we independently validate and expand upon the molecular TCGA classification of HGSOC. The potential of these two prognostic classifiers may lie in their ability to recognize categories of patients that are more likely to respond to particular therapies.