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. 2022 Sep 12;24(1):61.
doi: 10.1186/s13058-022-01556-6.

Relationship between ER expression by IHC or mRNA with Ki67 response to aromatase inhibition: a POETIC study

Elena Lopez-Knowles  1   2 , Simone Detre  3 , Margaret Hills  3 , Eugene F Schuster  4   3 , Maggie C U Cheang  5 , Holly Tovey  5 , Lucy S Kilburn  5 , Judith M Bliss  5 , John Robertson  6 , Elizabeth Mallon  7 , Anthony Skene  8 , Abigail Evans  9 , Ian Smith  10 , Mitch Dowsett  4   3
Affiliations

Relationship between ER expression by IHC or mRNA with Ki67 response to aromatase inhibition: a POETIC study

Elena Lopez-Knowles et al. Breast Cancer Res. .

Abstract

Background: In clinical practice, oestrogen receptor (ER) analysis is almost entirely by immunohistochemistry (IHC). ASCO/CAP recommends cut-offs of < 1% (negative) and 1-10% (low) cells positive. There is uncertainty whether patients with ER low tumours benefit from endocrine therapy. We aimed to assess IHC and mRNA cut-points for ER versus biological response of primary breast cancer to 2 weeks' aromatase inhibitor treatment as measured by change in Ki67.

Methods: Cases were selected from the aromatase inhibitor treatment group of POETIC. We selected the 15% with the poorest Ki67 response (PR, < 40% Ki67 suppression, n = 230) and a random 30% of the remainder categorised as intermediate (IR, 40-79% Ki67 suppression, n = 150) and good-responders (GR, ≥ 80% Ki67 suppression, n = 230) from HER2 - group. All HER2 + cases available were selected irrespective of their response category (n = 317). ER expression was measured by IHC and qPCR.

Results: ER IHC was available from 515 HER2 - and 186 HER2 + tumours and ER qPCR from 367 HER2 - and 171 HER2 + tumours. Ninety-one percentage of patients with ER IHC < 10% were PRs with similar rates in HER2 - and HER2 + cases. At or above ER IHC 10% substantial numbers of patients showed IR or GR. Similar proportions of patients were defined by cut-points of ER IHC < 10% and ER mRNA < 5 units. In addition, loss of PgR expression altered ER anti-proliferation response with 92% of PgR - cases with ER IHC < 40% being PRs.

Conclusions: There was little responsiveness at IHC < 10% and no distinction between < 1% and 1-10% cells positive. Similar separation of PRs from IR/GRs was achieved by IHC and mRNA.

Keywords: Aromatase inhibitors; Breast cancer; ESR1; Ki67; PgR.

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Conflict of interest statement

M.C.U.C. has a patent for Breast Cancer Classifier: US Patent No. 9,631,239 with royalties paid and receive research funding from NanoString Technologies and veracyte advisory role. MD receives honoraria from Myriad Genetics and is a consultant and advisory board member of GTx, Radius Health, Orion Pharma, Lilly, Agile and Astrazeneca, has received funding from Pfizer (Inst) and Radius Health (Inst) and has been paid expenses from Pfizer and Myriad Genetics. JMB reports grants from Cancer Research UK, during the conduct of the study; grants from Medivation; grants and non-financial support from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, and Roche, outside the submitted work. LK reports grants from Cancer Research UK, during the conduct of the study. HT received salary from Bayer. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
ER IHC in relation to Ki67 residual % (Ki67 at surgery*100/baseline) by HER2 status. Scatterplots of ER IHC measured in baseline tissue in relation to Ki67 in the overall population (A), HER2 − (B) and HER2 + (C) (original numbers, n = 701) and percentage of patients in Ki67 response categories (PR, IR, GR) in the overall population (D), HER2 − (E) and HER2 + (F) distributed into ER IHC subgroups (HER2 − GR and IR are multiplied by 3.3; derived numbers, n = 1441.6). Red is PR, Black is IR and Green is GR
Fig. 2
Fig. 2
ER IHC in relation to Ki67 residual % (Ki67 at surgery*100/baseline) by PgR status. Scatterplots of ER IHC measured in baseline tissue in relation to Ki67 in the overall population (A), PgR − (B) and PgR + (C) (original numbers, n = 701) and percentage of patients in Ki67 response categories (PR, IR, GR) in the overall population (D), PgR − (E) and PgR + (F) distributed into ER IHC subgroups (HER2 − GR and IR are multiplied by 3.3; derived numbers, n = 1441.6). Red is PR, Black is IR and Green is GR
Fig. 3
Fig. 3
ER qPCR in relation to Ki67 residual % (Ki67 at surgery*100/baseline) by HER2 status. Scatterplots of ER qPCR measured in baseline tissue in relation to Ki67 in the overall population (A), HER2 − (B) and HER2 + (C) (original numbers, n = 538) and percentage of patients in Ki67 response categories (PR, IR, GR) in the overall population (D), HER2 − (E) and HER2 + (F) distributed into ER qPCR subgroups (HER2 − GR and IR are multiplied by 3.3; derived numbers, n = 1085.4). Red is PR, black is IR and green is GR
Fig. 4
Fig. 4
ER qPCR in relation to Ki67 residual % (Ki67 at surgery*100/baseline) by PgR status. Scatterplots of ER qPCR measured in baseline tissue in relation to Ki67 in the overall population (A), PgR − (B) and PgR + (C) (original numbers, n = 538) and percentage of patients in Ki67 response categories (PR, IR, GR) in the overall population (D), PgR − (E) and PgR + (F) distributed into ER qPCR subgroups (HER2 − GR and IR are multiplied by 3.3; derived numbers, n = 1085.4). Red is PR, black is IR and green is GR
Fig. 5
Fig. 5
ER IHC and qPCR. A Scatterplot of Log10 ER qPCR in relation to ER IHC percentage measured in baseline tissue (original numbers, n = 538). B Boxplot of Log10 ER qPCR divided into 3 ER IHC categories: < 1%, ≥ 1 to 10% and ≥ 10% (original numbers n = 538)
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