Abstract:
PURPOSE:Ki-67 has been clinically validated for risk assessment in breast cancer, but the analytical validation and cutpoint-definition remain a challenge. Intraclass correlation coefficients (ICCs) are a statistical parameter for Ki-67 interobserver performance. However, the maximum degree of variance among pathologists allowed for meaningful biomarker results has not been defined. METHODS:Different amounts of variance were added to central pathology Ki-67 data (n = 9069) from three cohorts (IBCSGVIII + IX, BIG1-98, GeparTrio) by simulation of 4500 evaluations for each cohort, which were grouped by ICCs, ranging from excellent (ICC = 0.9) to poor concordance (ICC = 0.1). Endpoints were disease-free survival (DFS) and pathological complete response (pCR, GeparTrio). RESULTS:Ki-67 was a significant continuous prognostic marker for DFS over a wide range of cutpoints between 8% and 30% in all three cohorts. In our modelling approach, Ki-67 was a stable prognostic marker despite increased interpathologist variance. Even for a poor ICC of 0.5, one or more significant Ki-67 cutoffs were detected in 86.8% (GeparTrio), 92.4% (IBCSGVIII + IX) and 100% of analyses (BIG1-98). Similarly, in GeparTrio, even with an extremely low ICC of 0.2, 99.6% of analyses were significant for pCR. CONCLUSIONS:Our study shows that Ki-67 is a continuous marker which is extremely robust to pathologist variation. Even if only 50% of variance is attributable to true Ki-67-based proliferation (ICC = 0.5), this information is sufficient to obtain statistically significant differences in clinical cohorts. This stable performance explains the observation that many Ki-67 studies achieve significant results despite relevant interobserver variance and points to a high clinical validity of this biomarker. For clinical decisions based on analysis of individual patient data, ongoing efforts to further reduce interobserver variability, including ring trials and standardized guidelines as well as image analysis approaches, should be continued.
journal_name
Breast Cancer Res Treatjournal_title
Breast cancer research and treatmentauthors
Denkert C,Budczies J,Regan MM,Loibl S,Dell'Orto P,von Minckwitz G,Mastropasqua MG,Solbach C,Thürlimann B,Mehta K,Blohmer JU,Colleoni M,Müller V,Klauschen F,Ataseven B,Engels K,Kammler R,Pfitzner BM,Dietel M,Faschingdoi
10.1007/s10549-018-05112-9subject
Has Abstractpub_date
2019-08-01 00:00:00pages
557-568issue
3eissn
0167-6806issn
1573-7217pii
10.1007/s10549-018-05112-9journal_volume
176pub_type
杂志文章abstract::A potential advantage of primary over adjuvant chemotherapy in breast cancer survival had been proposed on theoretical grounds. In 1994, early results of the S6-trial comparing primary chemotherapy vs. adjuvant chemotherapy for operable breast cancer in 390 premenopausal patients had shown significant improvement in s...
journal_title:Breast cancer research and treatment
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Breast cancer research and treatment
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journal_title:Breast cancer research and treatment
pub_type: 历史文章,杂志文章
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/BF01805980
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journal_title:Breast cancer research and treatment
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doi:10.1007/s10549-009-0413-2
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1023/a:1005990806919
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abstract:PURPOSE:Whether young age at diagnosis of breast cancer is an independent risk factor for death remains controversial, and the question whether young age should be considered in treatment decisions is still to be answered. METHODS:From a population-based cohort of 22,017 women with breast cancer, all women <35 years (...
journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-016-3983-9
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1023/a:1006123721205
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-011-1398-1
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
doi:10.1007/s10549-019-05481-9
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章,评审
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pub_type: 杂志文章
doi:10.1007/s10549-019-05347-0
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pub_type: 杂志文章,评审
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章
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journal_title:Breast cancer research and treatment
pub_type: 杂志文章,多中心研究
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journal_title:Breast cancer research and treatment
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