Leitlinienkonformer Einsatz von uPA/PAI-1 und Ki-67 beim primären Mammakarzinom zum möglichen Verzicht auf adjuvante Chemotherapie bei Niedrigrisikopatientinnen: Beobachtetes rezidivfreies Überleben im Vergleich zur Vorhersage mittels Adjuvant Online!

552 Background: Use of multi-gene real-time PCR (RT-PCR) based assays e.g. Recurrence Score (RS) and single markers (grade, uPA/PAI-1, ER/PR, HER2, KI-67) is currently controversially discussed in early BC. Here, we present the final WSG-planB trial correlation analysis of risk assessment tools and first prospective comparison of independent central pathology IHC/FISH assessment and RT-PCR for single markers. Methods: Plan B trial (n=2,448 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2- BC). RS has been used as selection criterion for cht omission in HR+ BC (if RS<11 in pN0 or pN1). uPA/PAI-1 was optionally obtained. Grade, ER/PR, HER2 (IHC/FISH), Ki-67 were evaluated by the independent trial pathologist in all tumors. Results: From 04/09 to 11/11, 3196 patients have been recruited and 2448 randomized. RS distribution in 2551 HR+ tumors: 0-11 (18%), 12-25 (60%), >25 (22%). In 354 pN0-1 patients, cht was omitted based on low risk RS (88% compliance). Central grade for n=3038 and IHC/FISH results are currently available in n=1476. Moderately significant correlations were only found between RS and both central grade (rs=0.313; p<0.001) as well as Ki-67 (rs=0.374; p<0.001) and a weak one for uPA/PAI-1, particularly due to poor correlations within the RS group <26. In 1476 locally HER2- cases, n=9 were found as 3+ and/or FISH+ by central analysis. In 6 HR+/HER2+ cases, RS revealed 2 positive, 2 equivocal and 2 negative results. In 7 cases positive for HER2 by RT-PCR central pathology revealed 4 negative results. 24 locally HR+ cases are assessed as HR- in central pathology (2%). Among these, 6 were ER positive by RT-PCR. Final correlation analyses will be presented at the meeting. Conclusions: These first prospective data demonstrate that high-risk status according to RS is predictive of high risk by other factors, but the converse is not true. Regarding controversial HER2 and HR status by RT-PCR and IHC/FISH, we found few cases with false-negative or positive RT-PCR results in HER2- BC by local pathology. However, these discrepancies could potentially have a substantial impact on clinical patient management.

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A novel machine learning-derived decision tree including uPA/PAI-1 for breast cancer care

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-1065 ◽

2019 ◽

Vol 57 (6) ◽

pp. 901-910 ◽

Cited By ~ 1

Author(s):

Nathalie Reix ◽

Massimo Lodi ◽

Stéphane Jankowski ◽

Sébastien Molière ◽

Elisabeth Luporsi ◽

...

Keyword(s):

Breast Cancer ◽

Machine Learning ◽

Decision Tree ◽

Tumor Grade ◽

Added Value ◽

Routine Practice ◽

Final Decision ◽

Ki 67 ◽

Estrogen Receptor Positive ◽

Pai 1

Abstract Background uPA and PAI-1 are breast cancer biomarkers that evaluate the benefit of chemotherapy (CT) for HER2-negative, estrogen receptor-positive, low or intermediate grade patients. Our objectives were to observe clinical routine use of uPA/PAI-1 and to build a new therapeutic decision tree integrating uPA/PAI-1. Methods We observed the concordance between CT indications proposed by a canonical decision tree representative of French practices (not including uPA/PAI-1) and actual CT prescriptions decided by a medical board which included uPA/PAI-1. We used a method of machine learning for the analysis of concordant and non-concordant CT prescriptions to generate a novel scheme for CT indications. Results We observed a concordance rate of 71% between indications proposed by the canonical decision tree and actual prescriptions. Discrepancies were due to CT contraindications, high tumor grade and uPA/PAI-1 level. Altogether, uPA/PAI-1 were a decisive factor for the final decision in 17% of cases by avoiding CT prescription in two-thirds of cases and inducing CT in other cases. Remarkably, we noted that in routine practice, elevated uPA/PAI-1 levels seem not to be considered as a sufficient indication for CT for N≤3, Ki 67≤30% tumors, but are considered in association with at least one additional marker such as Ki 67>14%, vascular invasion and ER-H score <150. Conclusions This study highlights that in the routine clinical practice uPA/PAI-1 are never used as the sole indication for CT. Combined with other routinely used biomarkers, uPA/PAI-1 present an added value to orientate the therapeutic choice.

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P178 Prospective comparison of uPA/PAI-1, Ki-67 based molecular classification, Recurrence Score and clinical–pathological characteristics in hormone-receptor (HR) positive primary breast cancer: Pilot phase of the randomized WSG PlanB trial

The Breast ◽

10.1016/s0960-9776(11)70120-5 ◽

2011 ◽

Vol 20 ◽

pp. S38

Author(s):

C. Liedtke ◽

O. Gluz ◽

H. Kreipe ◽

T. Degenhardt ◽

R. Kates ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Primary Breast Cancer ◽

Recurrence Score ◽

Molecular Classification ◽

Pilot Phase ◽

Ki 67 ◽

Pathological Characteristics ◽

Prospective Comparison ◽

Pai 1

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Genes overexpressed in cerebral arteries following salt-induced hypertensive disease are regulated by angiotensin II, JunB, and CREB

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00913.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. H1075-H1085 ◽

Cited By ~ 13

Author(s):

Patricia Rose ◽

Jeffrey Bond ◽

Scott Tighe ◽

Michael J. Toth ◽

Theresa L. Wellman ◽

...

Keyword(s):

Angiotensin Ii ◽

Cerebral Arteries ◽

Plasminogen Activator Inhibitor ◽

Fisher Exact Test ◽

Mrna Levels ◽

Ang Ii ◽

Plasminogen Activator Inhibitor 1 ◽

Hypertensive Disease ◽

Ki 67 ◽

Pai 1

Although changes in gene expression are necessary for arterial remodeling during hypertension, the genes altered and their mechanisms of regulation remain uncertain. The goal of this study was to identify cerebral artery genes altered by hypertension and define signaling pathways important in their regulation. Intact cerebral arteries from Dahl salt-sensitive normotensive and hypertensive high-salt (HS) rats were examined by immunostaining, revealing an increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of the proliferative marker Ki-67 in arteries from hypertensive animals. Arterial RNA analyzed by microarray and validated with RT-quantitative PCR revealed that jun family member junB and matricellular genes plasminogen activator inhibitor-1 (PAI-1) and osteopontin (OPN) were significantly overexpressed in HS arteries. Fisher exact test and annotation-based gene subsets showed that genes upregulated by Jun and Ca2+/cAMP-response element-binding protein (CREB) were overrepresented. A model of cultured rat cerebrovascular smooth muscle cells was used to test the hypothesis that angiotensin II (ANG II), JunB, and CREB are important in the regulation of genes identified in the rat hypertension model. ANG II induced a transient induction of junB and a delayed induction of PAI-1 and OPN mRNA levels, which were reduced by ERK inhibition with U-0126. Silencing junB using small-interfering RNA reduced mRNA levels of OPN but not PAI-1. The silencing of CREB reduced PAI-1 induction by ANG II but enhanced the transcription of OPN. Together, these results suggest that salt-induced hypertensive disease promotes changes in matricellular genes that are stimulated by ANG II, regulated by ERK, and selectively regulated by JunB and CREB.

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Remodeling of the adventitia during coronary arteriogenesis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00478.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. H31-H40 ◽

Cited By ~ 57

Author(s):

Wei-Jun Cai ◽

Sophie Koltai ◽

Elisabeth Kocsis ◽

Dimitri Scholz ◽

Sawa Kostin ◽

...

Keyword(s):

Elastic Fiber ◽

Tissue Type ◽

Active Growth ◽

Ki 67 ◽

Chronic Occlusion ◽

Type Plasminogen Activator ◽

Collateral Vessels ◽

Myocyte Damage ◽

Endothelial Nitric Oxide ◽

Pai 1

We studied the role of the adventitia in adaptive arteriogenesis during the phase of active growth of coronary collateral vessels (CV) induced by chronic occlusion of the left circumflex coronary artery in canine hearts. We used electron microscopy and immunoconfocal (IF) labeling for bFGF, matrix metalloproteinase (MMP)-2, MMP-9, tissue-type plasminogen activator (tPA), its inhibitor (PAI-1), fibronectin (FN), and Ki-67. Proliferation of smooth muscle cells and adventitial fibroblasts was evident. Quantitative IF showed that adventitial MMP-2, MMP-9, and FN were 9.2-, 7.5-, and 8.6-fold, bFGF was 5.1-fold, and PAI-1 was 3.4-fold higher in CV than in normal vessels (NV). The number of fibroblasts was 5-fold elevated in CV, but the elastic fiber content was 25-fold greater in NV than in CV. Perivascular myocyte damage and induction of endothelial nitric oxide synthase in peri-CV capillaries indicate expansion of CV. It was concluded that adventitial activation is associated with the development of CV through cell proliferation, production of growth factors, and induction of extracellular proteolysis thereby contributing to remodeling during adaptive arteriogenesis.

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