Combination of the proliferation marker cyclin A, histological grade, and estrogen receptor status in a new variable with high prognostic impact in breast cancer

Strand, Carina; Ahlin, Cecilia; Bendahl, Pär‐Ola; Fjällskog, Marie-Louise; Hedenfalk, Ingrid; Malmström, Per; Fernö, Mårten

doi:10.1007/s10549-011-1386-5

Cited by 13 publications

(17 citation statements)

References 30 publications

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“…In multiple studies, overexpression of cyclin A has been associated with worse prognosis in breast cancer, but the data are not consistent 5 28 29. According to a recent study, cyclin A was a prognostic factor for DMFS in the ER+ subgroups only 29. Cyclin A showed substantial correlation with a shorter period to first relapse and to survival from the time of diagnosis 28.…”

Section: Discussionmentioning

confidence: 98%

Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases

et al. 2015

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Section: Discussionmentioning

confidence: 98%

Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases

et al. 2015

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“…The level of agreement between the two readers was good (correlation coefficient 0.91 between estimated proportions and kappa value 0.77 when applying the cut-off defined below to both series), and results from only one of the readers was chosen for further analysis. Data on cyclin A and Ki67 was already available and assessments and reasons for exclusion have been described previously [34,40]. For cyclin A 200 cells were counted manually by two investigators.…”

Section: Methodsmentioning

confidence: 99%

“…Cyclin B1 regulates onset of mitosis, and high levels of cyclin B1 in breast cancers has in several studies been shown to be a negative prognostic marker [30–33]. High levels of the S-phase specific cyclin A, is also associated with a worse outcome in breast cancer [34–36]. …”

Section: Introductionmentioning

confidence: 99%

The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer

et al. 2013

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Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off ≥10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95%CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95%CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95%CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95%CI: 1.1-6.7), and cyclin A (HR=2.7, 95%CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.

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“…Ki67 is the marker of proliferation most widely used (Goldhirsch et al 2011; De Azambuja et al 2007; Urruticoechea et al 2005; Dowsett et al 2011; Luporsi et al 2012), but the role of other markers, such as cyclin A (Bukholm et al 2001; Michalides et al 2002; Kuhling et al 2003; Baldini et al 2006; Ahlin et al 2009; Strand et al 2012) and phosphohistone H3 (Skaland et al 2007), remains under debate. Furthermore, global gene expression analyses have shown that proliferation-associated genes seem to be among the most important for dividing patients into groups with different prognosis, especially in ER-positive and histological grade 2 breast cancers (Sotiriou et al 2006; Ivshina et al 2006; Teschendorff et al 2007; Desmedt et al 2008).…”

Section: Introductionmentioning

confidence: 99%

The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer

et al. 2013

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BackgroundThe aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naïve breast cancer patients.Methods/designIn the present study, including 1,854 patients, Ki67 was used in the index (KiGE), since it is the generally accepted proliferation marker in clinical routine. The low KiGE-group was defined as histological grade 1 patients and grade 2 patients which were ER-positive and had low Ki67 expression. All other patients made up the high KiGE-group. The KiGE-index separated patients into two groups with different prognosis. In multivariate analysis, KiGE was significantly associated with disease-free survival, when adjusted for age at diagnosis, tumor size and adjuvant endocrine treatment (hazard ratio: 3.5, 95% confidence interval: 2.6–4.7, P<0.0001).DiscussionWe have confirmed a prognostic index based on a proliferation marker (Ki67), histological grade, and ER for identification of a low-risk group of patients with N0/N1 primary breast cancer. For this low-risk group constituting 57% of the patients, with a five-year distant disease-free survival of 92%, adjuvant chemotherapy will have limited effect and may be avoided.

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Combination of the proliferation marker cyclin A, histological grade, and estrogen receptor status in a new variable with high prognostic impact in breast cancer

Cited by 13 publications

References 30 publications

Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases

Expression of proliferation markers Ki67, cyclin A, geminin and aurora-kinase A in primary breast carcinomas and corresponding distant metastases

The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer

The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer

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