Comparison of central laboratory assessments of ER, PR, HER2, and Ki67 by IHC/FISH and the corresponding mRNAs (ESR1, PGR, ERBB2, and MKi67) by RT-qPCR on an automated, broadly deployed diagnostic platform

Wu, Na; Wong, Wai P.; Ho, Kenneth; Chu, Victor C.; Rizo, Annaliza; Davenport, Simon; Kelly, Devon D.; Makar, Rosemary; Jassem, Jacek; Duchnowska, Renata; Biernat, Wojciech; Radecka, Barbara; Fujita, Tomoyuki; Klein, J.; Stonecypher, Mark; Ohta, Shoichiro; Hartmut, Juhl; Weidler, Jodi; Bates, Michael; Press, Michael F.

doi:10.1007/s10549-018-4889-5

Cited by 44 publications

(80 citation statements)

References 24 publications

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“… 32 In this study we underscore the significance of central Ki67 counting, which was poorly correlated with the local assessment of the marker's expression, but was found to be highly correlated with the independent automated analysis. Based on these findings and in agreement with previously published literature, 48 , 49 central Ki67 assessment should be considered as the optimal option in clinical and translational studies exploring biomarkers in BC. At the same time, digital image analysis based on this and other studies 50 could potentially become the new standard, greatly improving turnover times while simultaneously providing robust results and circumventing the known shortcomings of Ki67 assessment.…”

Section: Discussionsupporting

confidence: 85%

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

et al. 2021

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Background Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. Methods Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. Results Central Ki67 counting had excellent correlation with the results of digital image analysis ( r = 0.814), but not with the diagnostic samples ( r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HR adj ) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HR adj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HR adj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (p interaction 0.04). Conclusion Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

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Section: Discussionsupporting

confidence: 85%

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

et al. 2021

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“…Our data over the past 2 years supports higher concordance (94%) between these methods for unselected breast cancer samples. 11–13 In this study of 2018 ASCO/CAP ISH group 4 breast cancers that are difficult to classify by conventional testing, most samples also showed RT-qPCR and QIF results close to positive/negative cut points. In contrast in breast carcinomas without equivocal results by conventional testing, both RT-qPCR and QIF showed a wider range in scores further from positive/negative cut points.…”

Section: Discussionmentioning

confidence: 64%

Quantitative assessments and clinical outcomes in HER2 equivocal 2018 ASCO/CAP ISH group 4 breast cancer

et al. 2019

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We quantified human epidermal growth factor receptor 2 (HER2) RNA and protein expression in 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) in situ hybridization (ISH) group 4 ( HER2/centromeric probe 17 ( CEP17 ) ratio <2.0, average HER2 copy number ≥4.0 and <6.0, and 2013 ASCO/CAP ISH equivocal) breast cancers. Breast cancers in 2018 ASCO/CAP ISH group 4 between 2014 and 2017 were identified from the Yale archives. Sixty-three patients (34 with HER2 immunohistochemistry (IHC) 0/1+ and 29 with HER2 IHC 2+) were included. We compared patient characteristics, systemic treatments, and outcomes. We assessed HER2 by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and quantitative immunofluorescence (QIF). Among ISH group 4 cancers, higher HER2 mRNA ( P < 0.0001) but similar HER2 protein levels were observed in IHC 2+ compared to IHC 0/1+ cancers. The distribution of RT-qPCR and QIF scores were independent of fluorescence in situ hybridization (FISH) ratio/copy number. Concordance between HER2 RT-qPCR and QIF was 69.8% ( r = 0.52). Among 29 patients with IHC2+ results, 16 were HER2 positive by RT-qPCR and 12 were HER2 positive by QIF. Systemic treatment, recurrence, and survival outcomes were comparable among ISH group 4 cancers regardless of IHC 0/1+ or 2+ results. ISH group 4 cancers appear to form a distinct group with intermediate levels of RNA/protein expression, close to positive/negative cut points. Therefore, adjudication into positive or negative categories may not be meaningful. Our results support the 2018 ASCO / CAP recommendation to refrain from routine additional testing of these samples. Additional outcome information after trastuzumab treatment for patients in this special group might help to guide treatment decisions in these patients.

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“…Alternative methods to immunohistochemical Ki-67 assessments, such as mRNA-based analyses, were recommended in recent studies, as inter-laboratory reproducibility with ICC values of 0.980–0.998 revealed the excellent agreement of quantitative measurements for Ki-67 levels measured using MammaTyper 13,32 . Another recent mRNA-based study assessing Ki-67 levels with STRAT4 showed a good correlation with Ki-67 immunohistochemistry at a 30% cut-off 36 . However, the clinical utility, particularly in the intermediate range, has not yet been confirmed.…”

Section: Discussionmentioning

confidence: 89%

Ki-67 assessment in early breast cancer: SAKK28/12 validation study on the IBCSG VIII and IBCSG IX cohort

Varga

Jochum

et al. 2019

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The assessment of Ki-67 in early-stage breast cancer has become an important diagnostic tool in planning adjuvant therapy, particularly for the administration of additional chemotherapy to hormone-responsive patients. An accurate determination of the Ki-67 index is of the utmost importance; however, the reproducibility is currently unsatisfactory. In this study, we addressed the predictive/prognostic value of Ki-67 index assessed by using the most reproducible methods, which were identified in the pilot phase. Paraffin blocks obtained from patients with moderately differentiated, estrogen receptor (ER)-positive early-stage breast cancer in Switzerland, who were originally randomized to the treatment arms with and without chemotherapy in the IBCSG VIII-IX trials, were retrieved. Of these 344 randomized patients, we identified 158 patients (82 treated with and 76 treated without chemotherapy) for whom sufficient tumour tissue was available. The presence of Ki-67 was assessed visually by counting 2000 cells at the periphery (A) and estimating the number of positive cells in five different peripheral regions (C), which was determined to be the most reproducible method identified the pilot phase. The prognostic and predictive value was assessed by calculating the breast cancer-free interval (BCFI) and overall survival (OS) rate. Ki-67 was considered a numerical and categorical variable when different cut-off values were used (10%, 14%, 20% and 30%). An mRNA-based subtyping by using the MammaTyper kit with the application of a 20% Ki-67 immunohistochemistry (IHC) cut-off equivalent was also performed. 158 of 344 randomized patients could be included in the Ki-67 analysis. The mean Ki-67 values obtained by using the two methods differed (A: 21.32% and C: 16.07%). Ki-67 assessed by using method A with a cut-off of 10% was a predictive marker for OS, as the hazard ratio (>10% vs. <=10%) in patients with chemotherapy was 0.48 with a 95% confidence interval of [0.19–1.19]. Further, the HR of patients treated without chemotherapy was 3.72 with a 95% confidence interval of [1.16–11.96] (pinteraction=0.007). Higher Ki-67 index was not associated with outcome and using the 10% Ki-67 cut-off there was an opposite association for patients with and without chemotherapy. Ki-67 assessments with IHC significantly correlated with MammaTyper results (p=0.002). The exact counting method (A) performed via a light-microscope revealed the predictive value of Ki-67 assessment with a 10% cut-off value. Further analyses employing image analyses and/or mRNA-based-assessments in larger populations are warranted.

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Comparison of central laboratory assessments of ER, PR, HER2, and Ki67 by IHC/FISH and the corresponding mRNAs (ESR1, PGR, ERBB2, and MKi67) by RT-qPCR on an automated, broadly deployed diagnostic platform

Cited by 44 publications

References 24 publications

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

Quantitative assessments and clinical outcomes in HER2 equivocal 2018 ASCO/CAP ISH group 4 breast cancer

Ki-67 assessment in early breast cancer: SAKK28/12 validation study on the IBCSG VIII and IBCSG IX cohort

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