title: A standardized method for quantifying proliferation by Ki-67 and cyclin A immunohistochemistry in breast cancer.
abstract: Immunohistochemical analysis of proliferation markers such as Ki-67 and cyclin A is widely used in clinical evaluation as a prognostic factor in breast cancer. The proliferation status of tumors is guiding the decision of whether or not a patient should be treated with chemotherapy because low-proliferative tumors are less sensitive by such treatment. However, the lack of optimal cutoff points and selection of tumor areas hamper its use in clinical practice. This study was performed to compare the Ki-67 and cyclin A expression counted in hot-spot vs average counting based on 5 to 14 random tumor areas in 613 breast carcinomas. We correlated the findings with 10-year follow-up in order to standardize the evaluation of proliferation markers in clinical practice. A significant correlation was found between the percentage of positive cells estimated by Ki-67 and cyclin A both by hot-spot and by average counting. Both methods showed that high expression of Ki-67 and cyclin A is associated with more adverse tumor stage. The cutoff value for Ki-67 for distant metastases was set to 22% and to 15%, using hot-spot and average counting, respectively. For cyclin A, the values were set to 14% and 8% using the respective methods. Survival curves revealed that patients with a high hot-spot proliferation index had a significantly greater risk of shorter tumor-free survival. Our findings suggest that the determination of proliferation markers in breast cancer should be standardized to hot-spot counting and that specific cutoff values for proliferation could be useful as prognostic markers in clinical practice. Moreover, we suggest that expression levels of cyclin A could be used as a complementary marker to estimate the proliferation status in tumors, especially those with "borderline" expression levels of Ki-67, in order to more accurately estimate the proliferations status of the tumors.
authors.affiliation: Department of Pathology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Mu
authors.affiliation: Department of Pathology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
authors.forename: Qingrui
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pathology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Haiqin
authors.initials: H
authors.lastname: Yun
authors.affiliation: Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Stockholm, Sweden.
authors.forename: Pedram
authors.initials: P
authors.lastname: Kharaziha
authors.affiliation: Fudan University Shanghai Cancer Center (FUSCC), Shanghai, PR China.
authors.forename: Ding-Wei
authors.initials: DW
authors.lastname: Ye
authors.affiliation: Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Stockholm, Sweden.
authors.forename: Gert
authors.initials: G
authors.lastname: Auer
authors.affiliation: Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Stockholm, Sweden. Electronic address: svetlana.lagercrantz@ki.se.
authors.forename: Svetlana Bajalica
authors.initials: SB
authors.lastname: Lagercrantz
authors.affiliation: Karolinska Institutet, Department of Oncology-Pathology, Cancer Center Karolinska, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Zetterberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D019925:Cyclin A / Q000032:analysis* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry / Q000295:instrumentation / Q000592:standards; D019394:Ki-67 Antigen / Q000032:analysis* / Q000378:metabolism; D008875:Middle Aged; D008940:Mitotic Index; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000378:metabolism; D012680:Sensitivity and Specificity
chemical_list: D019925:Cyclin A; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen
keywords: Breast cancer; Cyclin A; Hot-spot region; Ki-67; Prognosis; Proliferation marker