Trastuzumab plus capecitabine with or without pertuzumab in patients with HER2-positive MBC whose disease has progressed
during or following trastuzumab-based therapy for first-line metastatic disease: A multicenter, randomized, two-arm, phase
II study (PHEREXA). -- Munoz-Mateu et al. 29 (15): TPS118 -- ASCO Meeting Abstracts
Advertisement
Journal of Clinical Oncology, 2011 ASCO Annual Meeting Abstracts Part 1.
Vol 29, No 15_suppl (May 20 Supplement), 2011: TPS118
Trastuzumab plus capecitabine with or without pertuzumab in patients with HER2-positive MBC whose disease has progressed during
or following trastuzumab-based therapy for first-line metastatic disease: A multicenter, randomized, two-arm, phase II study
(PHEREXA).
M. Munoz-Mateu,
A. Urruticoechea,
R. Separovic,
J. Erfán,
T. D. Bachelot,
N. Kovalenko,
E. Staroslawska,
C. Veyret,
O. Pribylova,
D. L. Ciule,
J. Ratnayake,
K. Mayne and
Hospital Clinico de Barcelona, Barcelona, S Breast Cancer Unit, Institut Catalán d'Oncología, Barcelona, S University
Hospital for Tumors, Zagreb, C Jósa András Oktató Kórház, Nyíregyháza, H Centre Leon Berard, Lyon, F Grand
H?pital de Charleroi, Charleroi, B Stavropol Regional Clinical Oncology Dispensary, Stavropol, R Centrum Onkologii
Ziemi Lubelskiej, Lublin, P Pándy Kálmán Kórház, Gyula, H Department of Medical Oncology, Henri Becquerel Center,
Rouen, F Department of Oncology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague,
Prague, Czech R Spitalul Clinic Judetean de Urgenta Cluj-Napoca, Cluj-Napoca, R Roche Products Limited, Welwyn,
United Kingdom
Background: Pertuzumab (P) is a promising new anti-HER2 antibody which has shown both activity and good tolerability when combined with
trastuzumab (H) in patients with HER2-positive breast cancer. Capecitabine (X) in combination with H has been shown to be
more efficacious than X alone as second-line treatment of patients with HER2-positive metastatic breast cancer (MBC). The
PHEREXA study is designed to investigate the potential benefit of administering P and H combined with X in patients with HER2-positive
MBC whose disease has progressed during or following H-based therapy for first-line MBC. Methods: In this multicenter, open-label, Phase II trial (NCT
), patients are randomized 1:1 to Arm A (H: 8 mg/kg loading dose followed by a 6 mg/ X: 1250 mg/m2 twice daily for 14d q3w) or Arm B (H: 8 mg/kg loading dose followed by a 6 mg/ X: 1000 mg/m2 twice daily for 14d; P: 840 mg loading dose and 420 mg thereafter q3w). Enrolment began in January 2010 and 450 patients
are to be recruited from ~130 sites in 19 countries. Eligible patients must have HER2-positive MBC (fluorescence or chromogenic
in situ hybridization-positive and/or immunohistochemistry 3+), which has progressed during or following H-based therapy for
first-line MBC, prior taxane, and left ventricular ejection fraction (LVEF) 50% at baseline. Exclusion criteria include prior treatment with X or P, concurrent immunotherapy or hormonal anticancer therapy,
and history of LVEF decline to &50% during prior H-based therapy. The primary endpoint is progression-free survival (PFS;
independent assessment). Secondary endpoints include overall survival, PFS (investigator assessment), safety/tolerability.
It is planned that a panel of biomarkers including HER 1, 2 and 3 receptor status and downstream markers will be analysed.
No untoward safety signals have yet been identified. There are currently 58 patients randomized in the study (as of 13 January
J Clin Oncol (Meeting Abstracts)vol. 29 no. 15_suppl
? Meeting Abstract
AdvertisementAdvertisement问天奇迹，S6版本。求战士最强PK加点法！ HS混龙套+大天套+火龙盾。全部15的会员装备。满点不到1W2。_百度知道
问天奇迹，S6版本。求战士最强PK加点法！ HS混龙套+大天套+火龙盾。全部15的会员装备。满点不到1W2。
提问者采纳
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1w2点觉得好久给我分吧！
第一点；敏1500；必要的话敏可以在加高一点；智1500；好的话给我分哦
提问者评价
谢谢了，这样智力太少了。
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出门在外也不愁Published in final edited form as: doi:
PMCID: PMC3172680NIHMSID: NIHMS305078Genome-Wide Analysis Identifies a Quantitative Trait Locus in the MHC Class II Region Associated with Generalized Vitiligo Age of Onset,1,2 ,1,3 ,1,2,4 ,1 ,1 ,1 ,5 ,6 ,6 ,7 ,8 ,9 ,8 ,10 ,10 ,11 ,11 ,11 ,12 ,12 ,13 and
1,22 Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado, USA3 Department of Dermatology, University of Colorado Denver School of Medicine, Aurora, Colorado, USA4 Barbara Davis Center for Childhood Diabetes, University of Colorado Denver School of Medicine, Aurora, Colorado, USA5 Division of Basic Medical Sciences, St George’s, University of London, London, UK6 Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA7 Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida, USA8 Department of Human Metabolism, School of Medicine, University of Sheffield, Sheffield, UK9 Department of Dermatology, Royal Hallamshire Hospital, Sheffield, UK10 Laboratorio Fisiopatologia Cutanea, Istituto Dermatologico San Gallicano, Rome, Italy11 Centre de Référence des Maladies Rares de la Peau, Department of Dermatology, Hô pital St-André, Bordeaux, France12 Department of Dermatology, Ghent University Hospital, Ghent, Belgium13 Lumiderm, Madrid, SpainCorrespondence: Richard A. Spritz, Human Medical Genetics Program, University of Colorado Denver, Aurora, Colorado 80045, USA. Email:
The publisher's final edited version of this article is available free at See other articles in PMC that
the published article.Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10-BTNL2 (rs7758128; P = 8.14×10−11), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se.Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas (). Moreover, generalized vitiligo is epidemiologically associated with increased risk of several other autoimmune diseases, both in patients and their close relatives (; ), suggesting that these autoimmune diseases involve shared susceptibility genes. Twin and epidemiological studies indicate that generalized vitiligo is a complex disease involving multiple genetic and environmental susceptibility factors, and genetic linkage, candidate gene, and recent genome-wide association studies have implicated a number of genes in vitiligo susceptibility (; , ; ; ). Most of these genes encode immunoregulatory proteins, and many have also been implicated in susceptibility to some of the other autoimmune diseases that are epidemiologically associated with generalized vitiligo.In addition to vitiligo susceptibility per se, variation in vitiligo age of onset also involves a genetic component. Vitiligo age of onset is correlated among affected relatives (), and mean age of onset is significantly earlier in multiplex families (21.5±15.0 years) than among sporadic cases (24.2±16.2 years) (). Furthermore, patients with early disease onset tend to have more affected relatives and more extensive disease involvement (). In this study, using MENDEL 7.0 (), we calculated heritability of vitiligo age of onset as 0.45 in 184 multiplex families.We previously described a genome-wide association study of generalized vitiligo susceptibility in whites of European descent, in which we identified a number of loci that contribute to disease susceptibility (, ; ). These included major association signals in the major histocompatibility complex (MHC) class I and class II regions and at least 11 non-MHC loci. Here, we have specifically addressed vitiligo age of onset as a heritable trait distinct from disease susceptibility per se, re-analyzing our previous genome-wide data set by coding patients’ self-reported age of disease onset as a quantitative trait, testing for association genome-wide, and then re-testing significant association signals in an independent replication cohort. These analyses identified a quantitative trait locus in the MHC class II region that contributes significantly to generalized vitiligo age of onset, thus illustrating that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility.Genome-wide scanConsidering all 2,016 cases in the present study, the mean vitiligo age-of-onset was 24.45 24.84 for males (634 cases) and 24.27 for females (1,382 cases) (). After excluding some cases and markers by applying stringent quality control filters (), we tested association of 520,460 autosomal and X-chromosomal single-nucleotide polymorphisms (SNPs) with generalized vitiligo age of onset in 1,339 unrelated cases () () by linear regression, considering P<5×10−8 as the criterion for genome-wide significance (). A quantile– quantile plot of the genome-wide P-values () generally fit the null expectation, except at the extreme of the tail where observed P-values departed from expectation. The overall genomic inflation factor () was 1.007, indicating minimal inflation of the genome-wide statistics because of population stratification.Genome-wide association results for generalized vitiligo age of onsetSummary description of the patients with generalized vitiligo used in this studyAs shown in
online, the five top-ranked SNPs genome-wide (based on P-values) were all located at chromosome 6p21.3 in the MHC class II region. SNP rs7758128, located near c6orf10-BTNL2, exceeded the criterion for genome-wide significance (P= 5.98×10−9), and three nearby SNPs showed suggestive association: rs (P= 1.48×10−6), rs (P= 1.09×10−7), and rs (P= 1.48×10−6). One additional MHC class II region SNP, rs532098, located &#x kb distal to the others, in the vicinity of HLA-DRB1-DQA1, also showed suggestive evidence of association (P= 2.03×10−6).To more accurately assess the influence of these five SNPs on vitiligo age of onset, we applied Cox proportional hazards models () to test the multiplicative effect of each SNP on the hazard. As shown in
online, Cox models yielded results very similar to the genome-wide linear regression results, with P-values of 6.24×10−9, 1.44×10−6, 9.82×10−8, 1.44×10−6, and 5.12×10−6 for SNPs rs7758128, rs, rs, rs, and rs532098, respectively.As shown in , these five SNPs derive from a prominent association peak for generalized vitiligo age of onset in the MHC class II region, which corresponds closely to a highly significant association peak for generalized vitiligo susceptibility (, and ). In contrast, there was no association signal for vitiligo age of onset in the MHC class I region that is similarly strongly associated with vitiligo susceptibility (), indicating that the MHC class II region has a specific influence on vitiligo age of onset, whereas the class I region does not.Major histocompatibility complex association results from genome-wide analyses of generalized vitiligo age of onset and susceptibilityThe SNPs rs7758128, rs, rs, and rs span 37.8 kb within one block of strong linkage disequilibrium, whereas rs532098, over 200 kb distal, is not in linkage disequilibrium with the other four SNPs ( online). To determine which of these five SNPs exert independent effects on the age of onset, and to test whether family history of vitiligo, co-occurrence of other concomitant autoimmune disorders, and gender might also contribute to vitiligo age of onset, we included these eight variables in a Cox model, utilizing L1 penalized (lasso) estimation and a small L2 penalty () to identify variables with the strongest effects on the age of onset. Under the optimal value of &#x0031= 5.04 and &#x0032= 0.01, three variables (SNP rs7758128, SNP rs532098, and family history) showed non-zero coefficients. Accordingly, we re-tested association of rs7758128 and rs532098 with the age of onset in both linear regression analysis and in a Cox model adjusted for family history. As shown in , incorporating family history as a covariate slightly improved the linear regression and the Cox model P-values for rs7758128, P= 3.22×10−9 and P= 4.92×10−9, respectively, whereas for rs532098 the P-values were slightly worse, P= 1.56×10−5 and P= 1.30× 10−5, respectively. Together, these results indicate that SNPs rs7758128 and rs532098 may exert independent effects on vitiligo age of onset, and may partially explain the previously observed association between vitiligo age of onset and positive family history ().Loci with strongest association with generalized vitiligo age of onsetReplication analysisTo test the replication of association of rs7758128 and rs532098 with vitiligo age of onset, we genotyped these two SNPs in an independent cohort of 677 European-derived white generalized vitiligo patients () (). As shown in , for rs7758128 we confirmed association with vitiligo age of onset in the replication cohort (linear regression P= 2.05×10−3; Cox model P= 0.014). Furthermore, the meta-analysis of rs7758128 in the genome-wide and replication data sets yielded highly significant P-values (linear regression P= 8.14×10−11; Cox model P= 1.36× 10−9), with a hazard ratio of 1.50 per A allele. For rs532098, we observed the same effect direction in the replication cohort, although the P-values were only marginal (linear regression P= 0.081; Cox model P= 0.044) and the combined P-values did not achieve genome-wide significance (linear regression P= 1.83×10−5; Cox model P= 4.23×10−6).Our findings show that variation in the MHC class II region, best represented by rs7758128 in the vicinity of BTNL2, is strongly associated with generalized vitiligo age of onset. In contrast, other loci that are associated with generalized vitiligo susceptibility (, ; ), including variation in the MHC class I region, are not associated with disease age of onset ( online). These findings thus indicate that different loci have differing roles in vitiligo susceptibility versus vitiligo age of onset.Penalized regression analysis suggested that MHC class II SNPs rs7758128 and rs532098 may contribute independently to vitiligo age of onset, although replication of rs532098 association with vitiligo age of onset was only marginally significant. Linear regression analyses indicated that rs7758128 accounts for 2.5% of the variance of vitiligo age of onset, rs532098 accounts for 1.5%, and both SNPs together account for 3.4% of the variance of vitiligo age of onset. The early age-of-onset-associated alleles of these two SNPs are also associated with increased disease susceptibility (), and the associated allele of rs532098 is in strong linkage disequilibrium with HLA-DR4, which we previously showed is associated with both vitiligo susceptibility and early disease onset ().To determine which HLA class II haplotypes include the SNP alleles that affect vitiligo age of onset, we analyzed class II alleles and SNP data from 74 previously reported vitiligo trios () and 37 CEPH (Centre d’Etude du Polymorphisme Humain) trios (). This analysis showed that the A allele of rs7758128 that is associated with earlier vitiligo age of onset is exclusively located on the HLA class II haplotype DRB1*1301-DQA1*0103-DQB1*0603, although the majority of this haplotype (0.61) carry the C allele.As shown in , the 27-kb rs7758128/rs/ rs/rs SNP cluster that is associated with vitiligo age of onset is located in close proximity to only one known gene, BTNL2, which encodes an immunoglobulin superfamily membrane protein implicated in T-cell activation, and one predicted gene of unknown function, c6orf10. The c6orf10/BTNL2 gene region has been associated with susceptibility to many other autoimmune diseases, including type 1 diabetes (; ), rheumatoid arthritis (; ), systemic lupus erythematosus (), ulcerative colitis (), psoriasis (), and Graves’ disease (), as well as with sarcoidosis ().Biological evidence indicates that variation in the HLA class I region (specifically, HLA-A*0201) may contribute to disease susceptibility by mediating ongoing immune surveillance against malignant melanomas (and thus recognition of melanocytes) by the immune system (; ). In contrast, association of the MHC class II region with both disease susceptibility and disease age of onset suggests that variation in this region might mediate response to environmental triggers encountered over the course of the life of genetically susceptible individuals.SubjectsThe discovery cohort comprised 1,339 unrelated generalized vitiligo patients and the replication cohort 677 additional unrelated patients, all of European white origin (). The age of onset was by self-report. All study participants provided written informed consent, and the study was approved by each institutional review board and was conducted according to the Declaration of Helsinki Principles.Genotyping and quality controlDNA preparation, genome-wide genotyping using the Illumina 610-Quad BeadChip (Illumina, San Diego, CA) and replication genotyping using the Sequnom MassArray iPLEX system (Sequenom, San Diego, CA), and quality control filtering of the data have been described previously ().Statistical analysesFor both the genome-wide and replication analyses, linear regression analyses were performed using PLINK (), considering the age of onset as a quantitative trait. To control for population stratification, we performed principal component analysis in the 1,339 discovery phase cases using EIGENSOFT (), using a subset of 21,642 independent SNPs, and included the three significant principal components (Tracy–Widom P&#x) detected as continuous covariates in the linear regression analyses. We applied a Cox proportional hazards model () to the five top-ranked SNPs from the genome-wide scan and the two SNPs in the replication analysis using STATA 10 (). To obtain combined linear regression P-values, we performed meta-analysis using the inverse variance-weighted method (). To obtain combined Cox model P-values, we specified genome-wide scan and replication data as different strata in the Cox model. We used L1 penalized (lasso) estimation with a small L2 penalty in a Cox proporational hazards model to determine those variables exhibiting the strongest effects on age-of-onset, using cross-validation to calculate the global optimal value of the tuning parameter &#x003 ().PHASE (), version 2.1.1, was used to determine which HLA class II haplotypes include the SNP alleles that affect vitiligo age of onset. Linkage disequilibrium was calculated using Haploview () version 4.1.2(2.8M, pdf)This study was supported by grants AR45584 and AR056292 from the National Institutes of Health. We thank the University of Colorado Denver Microarray Core and the Washington University St Louis Genotyping Core, Janelle Noble, and Henry Erlich for CEPH HLA genotype data, and the memberships of Vitiligo Support International, the Vitiligo Society, the National Vitiligo Foundation, the American Vitiligo Research Foundation, and Associazione Ricerca Informazione per la Vitiligine for their participation.MHCmajor histocompatibility complexSNPsingle-nucleotide polymorphism CONFLICT OF INTERESTThe authors state no conflict of interest. is linked to the online version of the paper at Alkhateeb A, Fain PR, Thody A, et al.
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