Tissue microarrays for comparing molecular features with proliferation activity in breast cancer

Ruiz, Christian; Seibt, Silvia; Kuraya, Khawla Al; Siraj, Abdul K.; Mirlacher, Martina; Schraml, Peter; Maurer, Robert; Spichtin, Hanspeter; Torhorst, J.; Popovska, S; Simon, Ronald; Sauter, Guido

doi:10.1002/ijc.21581

Cited by 100 publications

(113 citation statements)

References 39 publications

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“…18 We chose tissue microarray as it is less time consuming, allows assessments of large numbers of tumors on a single slide, and as earlier studies have shown a good agreement of Ki67 quantification between tissue microarray and large section. 31,32 Our findings support the use of Ki67 as a reproducible, easily assessed marker of proliferation. Another advantage with Ki67 is that paraffin-embedded material can be used, whereas multigene assays need fresh frozen tissue, 11,12,[14][15][16] with the exception of the 21-gene Recurrence Score.…”

Section: Discussionsupporting

confidence: 73%

The prognostic value of Ki67 is dependent on estrogen receptor status and histological grade in premenopausal patients with node-negative breast cancer

et al. 2010

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The aim of this study was to evaluate the prognostic value of Ki67 in relation to established prognostic factors in lymph node-negative breast cancer, and furthermore, whether the prognostic impact was dependent on estrogen receptor (ER) status and histological grade. In 200 premenopausal patients, with 5 years of follow-up, Ki67 was determined on tissue microarrays. In univariate analysis, Ki67 (r20 vs 420%) was a prognostic factor for distant disease-free survival (hazard ratio: 2.7, 95% confidence interval: 1.3-5.4, P ¼ 0.005) and overall survival (hazard ratio: 4.9, 95% confidence interval: 1.7-14, P ¼ 0.003). When stratifying for ER status and histological grade, Ki67 was a significant prognostic factor for distant disease-free survival and overall survival only in the ER-positive group, and only in patients with histological grade 2, respectively. In multivariate analysis, human epidermal growth factor receptor 2 and age were independent prognostic factors for distant disease-free survival, whereas Ki67, histological grade, and tumor size were not. Ki67 was, however, an independent prognostic factor in the 87% of the patients who had not received adjuvant medical treatment. Agreement between the three readers was very good (j-values: 0.83-0.88). Furthermore, Ki67 was a significant prognostic factor for all three investigators (hazard ratio: 2.7-3.2). This study shows that Ki67 is a prognostic factor in node-negative breast cancer. It is noteworthy that the prognostic information of Ki67 is restricted to ER-positive patients, and to patients with histological grade 2. Taken together, Ki67, as an easily assessed and reproducible proliferation factor, may be an alternative or complement to histological grade as a prognostic tool and for selection of adjuvant treatment.

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Section: Discussionsupporting

confidence: 73%

The prognostic value of Ki67 is dependent on estrogen receptor status and histological grade in premenopausal patients with node-negative breast cancer

et al. 2010

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“…A fraction of 50% to 60% analyzable cancers was expected based on previous analyses of the same TMA. 40,41 Analysis failure was due to lack of tissue spots in the TMA section (9%), lack of tumor cells in the tissue spot (21%), and lack of FISH signals in the tissue spot (13%) because of insufficient probe penetration. Although the number of FISH interpretable tissue spots can be increased by repeated FISH analysis using more stringent tissue pretreatment conditions, we did not do so in order to avoid a bias that might arise from repeated analyses of some but not all spots.…”

Section: P Deletion Frequencymentioning

confidence: 99%

“…Association with amplifications of HER2, CCND1 and MYC HER2, CCND1 and MYC amplification results were available from a previous study. 40 In total, FISH results on both 8p deletions and amplification of HER2, CCND1 and MYC were available in subsets of 1,046 (HER2), 792 (MYC) and 1,147 (CCND1) cancers. There was a positive association between 8p deletion and amplification of HER2, CCND1, and MYC.…”

Section: P Deletion Frequencymentioning

confidence: 99%

“…40 A total of 556 tumors harboring 8p deletions averaged a Ki67 Labeling Index (Ki67LI) of 32.9 § 0.6, while the average Ki67LI was 25.8 § 0.6 in 518 cancers without 8p deletion (P < 0.0001, Prognostic role Data on raw survival were available from 1,246 cancers with interpretable 8p FISH results. Presence of 8p deletion was linked to shortened overall survival if all cancers were jointly analyzed (P < 0.0001, Fig.…”

Section: Association With Cell Proliferationmentioning

confidence: 99%

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8p deletion is strongly linked to poor prognosis in breast cancer

Lebok

Mittenzwei

Kluth

et al. 2015

Cancer Biology & Therapy

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Deletions of chromosome 8p occur frequently in breast cancers, but analyses of its clinical relevance have been limited to small patient cohorts and provided controversial results. A tissue microarray with 2,197 breast cancers was thus analyzed by fluorescence in-situ hybridization using an 8p21 probe in combination with a centromere 8 reference probe. 8p deletions were found in 50% of carcinomas with no special type, 67% of papillary, 28% of tubular, 37% of lobular cancers and 56% of cancers with medullary features. Deletions were always heterozygous. 8p deletion was significantly linked to advanced tumor stage (P < 0.0001), high-grade (P < 0.0001), high tumor cell proliferation (Ki67 Labeling Index; P < 0.0001), and shortened overall survival (P < 0.0001). For example, 8p deletion was seen in 32% of 290 grade 1, 43% of 438 grade 2, and 65% of 427 grade 3 cancers. In addition, 8p deletions were strongly linked to amplification of MYC (P < 0.0001), HER2 (P < 0.0001), and CCND1 (p D 0.001), but inversely associated with ER receptor expression (p D 0.0001). Remarkably, 46.5% of 8p-deleted cancers harbored amplification of at least one of the analyzed genes as compared to 27.5% amplifications in 8p-non-deleted cancers (P < 0.0001). In conclusion, 8p deletion characterizes a subset of particularly aggressive breast cancers. As 8p deletions are easy to analyze, this feature appears to be highly suited for future DNA based prognostic breast cancer panels. The strong link of 8p deletion with various gene amplifications raises the possibility of a role for regulating genomic stability.

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“…In addition, expected associations with molecular markers including TP53 positivity were also demonstrated. 35 A study on urothelial carcinoma similarly showed that the proliferation index can be accurately and reliably measured using a tissue microarray with a single core per tumor. 36 However, there are no published studies comparing Ki67 indices on whole sections vs tissue microarrays in breast cancer.…”

Section: Lp Feeley Et Almentioning

confidence: 99%

Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information

et al. 2014

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The objectives of this study were to determine the prognostic significance of subgrouping estrogen receptor (ER)-positive breast tumors into low-and high-risk luminal categories using Ki67 index, TP53, or progesterone receptor (PR) status. The study group comprised 540 patients with lymph node negative, invasive breast carcinoma. Luminal A subtype was defined as being ER positive, HER2 negative, and Ki67 low (o14% cells positive) and luminal B subtype as being ER positive, HER2 negative, and Ki67 high (Z14% cells positive). Luminal tumors were also subgrouped into risk categories based on the PR and TP53 status. Survival analysis was performed. Patients with luminal B tumors (n ¼ 173) had significantly worse disease-free survival compared to those with luminal A tumors (n ¼ 186) (log rank P-value ¼ 0.0164; univariate Cox regression relative risk 2.00; 95% CI, 1.12-3.58; P ¼ 0.0187). Luminal subtype remained an independent prognostic indicator on multivariate analysis including traditional prognostic factors (relative risk 2.12; 95% CI, 1.16-3.88; P ¼ 0.0151). Using TP53 status or PR negativity rather than Ki67 to classify ER-positive luminal tumors gave similar outcome results to those obtained using the proliferation index. However, it was a combination of the three markers, which proved the most powerful prognostically. Ki67 index, TP53 status, or PR negativity can be used to segregate ERpositive, HER2-negative tumors into prognostically meaningful subgroups with significantly different clinical outcomes. These biomarkers particularly in combination may potentially be used clinically to guide patient management.

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Tissue microarrays for comparing molecular features with proliferation activity in breast cancer

Cited by 100 publications

References 39 publications

The prognostic value of Ki67 is dependent on estrogen receptor status and histological grade in premenopausal patients with node-negative breast cancer

The prognostic value of Ki67 is dependent on estrogen receptor status and histological grade in premenopausal patients with node-negative breast cancer

8p deletion is strongly linked to poor prognosis in breast cancer

Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information

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