bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER family protein expression and activation predicts response to combination T-DM1/pertuzumab in HER2+ patients in the I-SPY 2 TRIAL.
Authors: Wulfkuhle Julia Dianne , Wolf Denise M. , Yau Christina , Gallagher Rosa Isela , Brown Swigart Lamorna , Hirst Gillian L. , Yee Douglas , Pohlmann Paula Raffin , Elias Anthony D. , Moulder Stacy L. , Tripathy Debu , DeMichele Angela , Esserman Laura , Berry Donald A. , van 't Veer Laura , Petricoin Emanuel ,   I-SPY 2 Investigators
Published: May 2019

3133 Background: T-DM1 (T), a conjugate of the anti-HER2 therapeutic antibody trastuzumab and the microtubule assembly inhibitor emtansine, was administered in combination with pertuzumab (P), an anti-HER2 therapeutic antibody, to HER2+ breast cancer patients in the I-SPY 2 TRIAL, and graduated in all HER2+ subtypes. Pre-specified biomarker analysis was performed to identify candidate biomarkers associated with pCR within the HER family and cell proliferation pathways in patients treated with T+P. We hypothesized that quantitative measurement and activation of HER2 and activation of its major dimerization partner, EGFR would predict response to T+P. Methods: In the T+P treatment arm, 49 had RPPA and pCR data. 40 RPPA endpoints including 14 total/phospho-proteins in the HER family were assessed for association with pCR using logistic regression (likelihood ratio test; p < 0.05). Analysis was also performed adjusting for HR status and within HR subsets. Markers were analyzed individually; multiple comparison correction (Benjamini-Hochberg) was applied to all p-values. Our statistics are descriptive and do not adjust for multiplicities of other biomarkers outside this study. Results: Of the endpoints tested, only quantitative total HER2 expression, phospho-HER2 (Y1248 and Y877), phospho-EGFR (Y1173 and Y1068), and phospho-SHC Y317 had a positive association with response in the population as a whole, and in a model adjusting for HR status (BH p < 0.05). In HR subset analysis, these 5 analytes had uncorrected p < 0.05 regardless of HR subtype but only survived p-value correction in HR+ tumors. Conclusions: Quantitative measurement of HER2 protein positively associates with response to T+P in patients already identified as HER2+ by central IHC and FISH testing. Activation of HER2 and its dimerization partner, EGFR, also associate with response to T+P in HR+ patients. While our results need to be validated in larger prospective trials, they indicate that new approaches to measure more quantitatively the amount and activation state of HER2 and activated EGFR may more effectively identify patients that respond to HER2 targeted therapies than HER2 IHC and FISH alone.
A prognostic 10-miRNA risk score (10-miRNA RS) in predicting neoadjuvant chemotherapy sensitivity of luminal breast cancer.
Authors: Gong Chang , Tan Luyuan , You Na , Chen Kai , Tan Weige , Tian Zhenluan , Zhong Wenjing , Lin Wanyi , Yu Zhigang , Li Zhihua , Zheng Wenbo , Liu Qiang , Song Erwei 
Published: May 2019

3139 Background: The 10-miRNA risk score is a prognostic 10-gene expression signature specifically developed in luminal breast cancer associated with relapse-free survival. Since high-risk patients identified by10-miRNA RS had worse prognosis but better outcome with chemotherapy than low-risk patients (Gong C et al, EBioMedicine. 2016), this model may facilitate personalized therapy-decision making for luminal breast cancer patients. Therefore, we seek to validate whether high-risk group are more sensitive to chemotherapy than low-risk group by assessing the predictive value of 10-miRNA RS for pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC). Methods: The 10-miRNA gene expression and clinicopathological data were prospectively gathered from 251 pretreated biopsy-diagnosed luminal breast cancer patients from 4 breast cancer centers. Formalin-fixed paraffin-embedded tissues from basal line biopsy were used for the detection of 10-miRNA expression to calculate the RS. The correlation between pCR and the 10-miRNA RS classification were identified. Results: In this prospective, multicenter study, the overall pCR rate was 13.6% (34/251). The 10-miRNA RS of the pCR group was significantly higher than the non-pCR group ( P = 0.015). Fifty-one percent of patients were classified as low-risk according to the 10-miRNA RS classification and 49% as high-risk with a RS cut-off point of 2.144. The 10-miRNA RS classification was associated with a pCR rate of 9.4% in the low-risk group and 17.8% in the high-risk group ( P = 0.041). The correlation between the pCR and the 10-miRNA RS classification was significant in subgroup analysis stratified by molecular subtypes (8% vs. 13.2% in luminal B1; 14.7% vs. 30.1% in luminal B2; no pCR was observed in all 13 luminal A subtype). In multivariate analysis, the 10-miRNA RS remained significantly associated with pCR and independent from subtype, ki67 and other clinicopathological characteristics. Conclusions: 10-miRNA RS clearly defined that high-risk patients are more sensitive to chemotherapy which leads to a higher pCR rate in NAC patients. Thus, 10-miRNA RS is not only a prognostic factor but an effective method in determining whether a patient would undergo surgery or receive NAC prior to surgery. Clinical trial information: ChiCTR-DDD-17013651.
Vascular endothelial growth factor A (VEGF-A) amplification and long-term response to ramucirumab (ram) in metastatic gastric cancer (mGC): The VERA study.
Authors: Raimondi Alessandra , Gasparini Patrizia , Lonardi Sara , Corallo Salvatore , Fornaro Lorenzo , Laterza Maria Maddalena , Di Salvatore Mariantonietta , Giommoni Elisa , Lotesoriere Claudio , Murgioni Sabina , Saggio Serena , Martinetti Antonia , Niger Monica , Antista Maria , Pupa Serenella , De Braud Filippo G. , Di Bartolomeo Maria , Sozzi Gabriella , Morano Federica , Pietrantonio Filippo 
Published: May 2019

3143 Background: The anti-VEGFR-2 monoclonal antibody ram, alone or with paclitaxel, is a cornerstone of second-line treatment of mGC. Even if about half patients do not benefit from ram, no predictive biomarkers have been identified so far. In TCGA, VEGF-A amplification was found in 7% of cases, almost exclusively in chromosomal instability subtype. We hypothesize that VEGF-A amplification in tumor cells could lead to autocrine/paracrine stimulation of tumor growth beside angiogenesis, potentially identifying a patients’ subgroup with exceptional responses to ram. Methods: VERA was a multicentric, prospective study based on a translational hypothesis. mGC patients were included according to the following criteria: 1) complete (CR) or partial response (PR) to single-agent ram; 2) >6 months PFS to single-agent ram; 3) >10 months PFS to paclitaxel+ram. According to a Fleming single-stage design, hypothesizing a prevalence of VEGF-A amplification of 1% and 15% among all-comers and exceptional responders, 20 exceptional responders were required to reject the null hypothesis of low prevalence of VEGF-A amplification, with alpha- and beta- errors of 0.05 and 0.10, respectively. VEGF-A amplification (defined as >10% tumor cells with ≥10 VEGF-A copies, variably sized signal clusters or a ratio of VEGF-A gene to centromere of ≥2) was centrally assessed through fluorescent in situ hybridization on pre-treatment FFPE tumor tissue. Results: At 7 Italian Centers, we included 20 patients satisfying the 1st (n=1), 2nd (n=2), or 3rd (n=17) criterion. Clinical-pathological features were: M/F, 11/9; median age 63 years; gastric/GEJ, 17/3; intestinal/diffuse, 14/6, HER2+/HER2-, 4/16. Median PFS and overall survival to ram-based treatment were 15.6 and 25.7 months, with best response: CR/PR/SD, 0/10/10. VERA met its primary endpoint, revealing 3/20 (15%) tumors with VEGF-A amplification (1 case presenting big clusters, 1 small clusters and 1 with >10% tumor cells with ≥10 VEGF-A copies). Conclusions: Validation analyses of first- and second-line randomized trials could confirm VEGF-A amplification as a biomarker of long-term response to ram-based treatment in mGC patients, advancing treatment personalization.
Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC).
Authors: Iveson Timothy , Sobrero Alberto F. , Yoshino Takayuki , Sougklakos Ioannis , Ou Fang-Shu , Meyers Jeffery P. , Shi Qian , Saunders Mark P. , Labianca Roberto , Yamanaka Takeharu , Boukovinas Ioannis , Hollander Niels Henrik , Torri Valter , Yamazaki Kentaro , Georgoulias Vassilis , Lonardi Sara , Harkin Andrea , Rosati Gerardo , Paul James ,   on behalf of the IDEA Collaboration
Published: May 2019

3501 Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p < .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.
Re-evaluating disease-free survival (DFS) as an endpoint versus overall survival (OS) in adjuvant colon cancer (CC) trials with chemotherapy +/- biologics: An updated surrogacy analysis based on 18,886 patients (pts) from the Accent database.
Authors: Shi Qian , De Gramont Aimery , Dixon Jesse G. , Yin Jun , Van Cutsem Eric , Taieb Julien , Alberts Steven R , Wolmark Norman , Schmoll Hans-Joachim hans-joachim , Saltz Leonard B. , Goldberg Richard M. , Kerr Rachel , Lonardi Sara , Yoshino Takayuki , Yothers Greg , Grothey Axel , Andre Thierry , Salem Mohamed E. ,   Adjuvant Colon Cancer ENd PoinTs (ACCENT) Group
Published: May 2019

3502 Background: DFS with 3 years median follow-up (3yDFS) was validated as a surrogate for OS with 5 years median follow-up (5yOS) in adjuvant chemotherapy CC trials prior. Recent data showed improved survival after recurrence and OS, over time, in pts who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS, as well as the optimal follow-up of OS to aid its utility in future adjuvant trials is needed. Methods: Individual patient data from 8 randomized adjuvant studies conducted from 1998-2009 were included; 3 trials tested anti-VEGF or anti-EGFR agents. Trial-level surrogacy examining the correlation of treatment effect estimates (i.e. hazard ratios) of 3yDFS and 5y to 8yOS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models. For the R2, a value closer to 1 indicates a stronger correlation. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80 and neither < 0.7, with lower-bound 95% Confidence Interval (CI) > 0.60. The rank correlation coefficient (ρ) quantified the individual-level surrogacy. Results: Total of 18,886 pts were analyzed, with median age 60, 54% male, 83% stage III, 59% > 12 nodes examined. Median follow-up for survival ranged from 5 to 10 years across trials. Trial level correlation between 3yDFS and OS remained strong (R2WLS ≥0.74; R2Copula ≥ 0.89) and increased as the median follow-up of OS extended longer (see table). Analyses limited to stage III pts and/or trials tested biologics showed consistent results. Conclusions: 3yDFS remains a validated surrogate endpoint for 5yOS in adjuvant trials in CC pts per prespecified criteria. The correlation was strengthened with more than 6 years of follow-up for OS. [Table: see text]
FOxTROT: an international randomised controlled trial in 1052 patients (pts) evaluating neoadjuvant chemotherapy (NAC) for colon cancer.
Authors: Seymour Matthew T. , Morton Dion ,   on behalf of the International FOxTROT Trial Investigators
Published: May 2019

3504 Background: NAC is well established in many solid tumours but has not undergone large-scale evaluation in colon cancer. Methods: Pts had operable, non-obstructed colon cancer; CT-predicted stage T3-4, N0-2, M0, and were fit for FOLFOX and surgery. They were randomised 2:1 to the novel sequence (6 wk FOLFOX NAC, then surgery, then 18 wk FOLFOX) or control (surgery then 24 wk FOLFOX). RAS-wt pts allocated to the novel arm could optionally be sub-randomized 1:1 to ± panitumumab (pan) during the NAC phase. Two "dealer’s choices" allowed total chemo duration 12 wk instead of 24 (in older/low-risk pts) and OxCap in place of FOLFOX (except in pts randomized ± pan). Primary endpoint is freedom from recurrent or persistent disease after 2 yrs, by ITT. Secondary endpoints include safety, histological stage, completeness of resection, OS. Results: 1052 pts were randomised, Jun 2008-Dec 2016, at 85 centres in UK, Denmark and Sweden. Conclusions: NAC was well tolerated and safe, with no increase in perioperative morbidity and a trend toward fewer serious postoperative complications. Evidence of histological regression was seen in 59% pts after NAC, including some pCRs. This resulted in marked histological downstaging and a halving of the rate of incomplete resections. We observed an improvement in 2-yr failure rate (HR=0.77), but this fell short of statistical significance (p=0.11). NAC for colon cancer improves surgical outcomes and can now be considered as a treatment option; longer follow-up and further trials are required to confirm the long-term benefits, refine its use and optimise case selection. Clinical trial information: 87163246. [Table: see text]
NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—First experimental arm (EA) initial results.
Authors: George Thomas J. , Yothers Greg , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Lucas Peter C. , Gollub Marc Jeffrey , Hall William Adrian , Kachnic Lisa A. , Vijayvergia Namrata , Wolmark Norman 
Published: May 2019

3505 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of hypotheses in a consistent high-risk pt population with correlative biomarkers. Primary endpoint (EP) and available secondary EPs from the first EA using veliparib (a PARPi) are reported. NCT02921256. Methods: Stage II/III pts with LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX (x 4mo) → chemoRT (cape with 50.4Gy +/- veliparib 400mg PO BID) → surgery 8-12 wks later. Primary EP: 4 point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α = 0.10 and 80% power. NAR compared by linear model controlling for stratification and possibly other factors. Secondary EPs: OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, and SSS. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 10/2016 - 2/2018, 178 pts were randomized (88 control, 90 veliparib). Baseline characteristics were balanced except for candidate for SSS at entry (39% control, 61% veliparib). 140 pts were evaluable for NAR (72 control, 68 veliparib). Mean NAR was 12.6 control (95% CI: 9.8–15.3) vs 13.7 for veliparib (CI: 10.2–17.2). Controlling for stratification (p = 0.69) or stratification and candidate for SSS (p = 0.78), NAR difference was not significant. pCR = 21.6% vs 33.8% (p = 0.14); cCR = 28.2% vs 33.3% (p = 0.60); and SSS = 52.5% vs 59.3% (p = 0.43). Most common grade 3/4 AEs were diarrhea and cytopenias. The EA had two deaths (cardiac arrest [FOLFOX]; enterocolitis [chemoRT]). Conclusions: Veliparib added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie. Clinical trial information: NCT02921256.
Final results and OS of the randomized phase II VOLFI trial (AIO- KRK0109): mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer (mCRC).
Authors: Geissler Michael , Riera-Knorrenschild Jorge , Martens Uwe Marc , Held Swantje , Greeve Jobst , Florschütz Axel , Ettrich Thomas Jens , Kanzler Stephan , Tannapfel Andrea , Heinemann Volker , Reinacher-Schick Anke C. , Seufferlein Thomas , Wessendorf Swen , Modest Dominik Paul 
Published: May 2019

3511 Background: This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. The final primary endpoint was presented at ASCO and ESMO 2018. Now we report for the first time the final results regarding OS and PFS. Methods: Prospective 2:1 randomized, controlled, open label multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Prospective strata were cohort 1: irresectable mCRC (n=65), and cohort 2: chance of secondary resection of metastatic lesions (n=31). Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 87.3% in arm A and 60.6% in arm B (p=0.0041, OR 4.47; 95%-CI 1.614-12.376). Secondary resections of metastases in the ITT population were observed in 33·3% (arm A Pmab) versus 12·1% (arm B) (OR=3.63; 95%-CI 1.13–11.67, p=0·029) and in cohort 2 in 75% (arm A Pmab) versus 36.4% (arm B) (OR=5.25; 95%-CI 1.07–25.8, p=0.05), respectively. Median PFS was similar in the study arms (9.7 mo in both arms, HR 1.071; 95%-CI 0.689-1.665, p=0.76). OS in the ITT population showed a strong trend in favour of the Pmab-containing arm A with a median OS of 35.7 mo compared to 29.8 mo in arm B (HR: 0·67; 95%-CI 0.41-1.11, P=0·12). mOS of cohort 2 was 52.0 mo in arm A versus 41.7 mo in arm B (HR 0.413; 95%-CI 0.15-1.12, p=0.07). Further results regarding to sidedness and BRAF mutational status will be presented. Conclusions: The addition of Pmab to a mFOLFOXIRI regimen in patients with RASwildtype metastatic colorectal cancer significantly improved objective response rate and the rate of secondary resection of metastases. Although PFS was comparable, there was a strong trend towards improved OS in the Pmab arm. Future studies are warranted to confirm this trend towards improved overall survival with this regimen. Clinical trial information: NCT01328171.
Relative contribution of clinical and molecular features to outcome within low and high risk T and N groups in stage III colon cancer (CC).
Authors: Sinicrope Frank A. , Huebner Lucas J. , Laurent-Puig Pierre , Smyrk Thomas C. , Tabernero Josep , Mini Enrico , Goldberg Richard M. , Folprecht Gunnar , Zaanan Aziz , Le Malicot Karine , Shi Qian , Alberts Steven R , Taieb Julien 
Published: May 2019

3520 Background: Duration of adjuvant FOLFOX or CAPOX for stage III CC is being guided by pt stratification into low (T1-3N1) and high (T4 or N2) risk groups based on the IDEA study. We determined the relative contributions of clinical and molecular features for prediction of time-to-recurrence (TTR) and survival after recurrence (SAR) within each risk group. Methods: Stage III CC (N=5,430) from 2 trials of adjuvant FOLFOX ± cetuximab with similar outcome by study arm [NCCTG N0147 (Alliance), PETACC-8] were used. Tumors were analyzed for mismatch repair (dMMR vs pMMR), mutations in KRAS (exon 2) and BRAFV600E. Median pt follow-up was 83.4 months. Relative contributions to predicting outcome were assessed using χ2 (Harrell’s rms) based on multivariable (MV) Cox models. Results: N (50.8%) and T (31.8%) stage were the top two contributors to prediction of TTR which supports risk grouping. High risk (n=2566) vs low risk (n=2774) pts had poorer TTR (HR 2.7, 95% CI, 2.4-3.0) and SAR [HR 1.6 (1.4-1.9)], both p<.0001. TTR: KRAS contributed the most to predicting TTR among high (58.6%) and low (51.1%) risk pts (Table). Contribution of MMR (16%) to predicting TTR was limited to low risk pts. Contribution of BRAFV600E to TTR was nearly 3-fold increased in high vs low risk pts. SAR: BRAFV600E contributed the most to predicting SAR, especially in high vs low risk pts (2-fold increase). Tumor sidedness and performance status (PS) were key contributors to SAR, but not TTR. MV associations: TTR: low risk, KRAS [HR 1.7 (1.4-2.3], MMR [HR 0.55 (.35-.87), gender (M/F) [HR 1.3 (1.0-1.5)], all p<.04]; high risk: BRAF [HR 1.3 (1.1-1.7)], sidedness (R vs L) [HR 1.14 (1.0-1.3)], KRAS [HR 1.4 (1.2-1.6)], all p<.04]. SAR: BRAF, sidedness, PS (all p<.05). Conclusions: KRAS mutation was the strongest predictor of shorter TTR in both risk groups whereas BRAFV600E was the primary driver of SAR, especially in high risk pts. Support: U10CA180821, U10CA180882, U24CA196171; BMS, Pfizer, Sanofi. NCT00079274.[Table: see text]