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Clinical Trial
. 2025 Aug;213(1):51-61.
doi: 10.1007/s10549-025-07749-9. Epub 2025 Jun 23.

Adjunctive statistical standardization of quantitated adjuvant HER2 and ultra-low HER2 in Canadian Cancer Trials Group MA.27 trial of exemestane versus anastrozole

Judith-Anne W Chapman  1 , Jane Bayani  2   3 , Sandip SenGupta  3   4 , John M S Bartlett  5 , Tammy Piper  5 , Mary Anne Quintayo  2 , Shakeel Virk  6 , Paul E Goss  7 , James N Ingle  8 , Matthew J Ellis  9 , George W Sledge  10 , G Thomas Budd  11 , Manuela Rabaglio  12 , Rafat H Ansari  13 , Richard Tozer  14 , David P D'Souza  15 , Haji Chalchal  16 , Silvana Spadafora  17 , Vered Stearns  18 , Edith A Perez  19 , Karen A Gelmon  20 , Timothy J Whelan  14 , Catherine Elliott  6 , Lois E Shepherd  6 , Bingshu E Chen  6 , Karen J Taylor  5
Affiliations
Clinical Trial

Adjunctive statistical standardization of quantitated adjuvant HER2 and ultra-low HER2 in Canadian Cancer Trials Group MA.27 trial of exemestane versus anastrozole

Judith-Anne W Chapman et al. Breast Cancer Res Treat. 2025 Aug.

Abstract

Purpose: Statistically standardized estrogen receptor (ER) and progesterone receptor (PgR) differentiated prognosis. Here we examined statistically standardized human epidermal growth receptor 2 (HER2).

Methods: CCTG MA.27 (NCT00066573) was an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER + and/or PgR + tumors. We centrally quantitated machine-image immunohistochemical HER2, defined American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) dual-probe FISH HER2/CEP17 categories, determined ultra-low HER2 (IHC 0 with (0,10%] 1 + stain), and standardized HER2 to mean 0, standard deviation 1. Univariate distant disease-free survival (DDFS) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions 2-sided Wald tests had nominal significance p < 0.05.

Results: Of 7576 women, 2900 had ER results; 2726, PgR; 2680, HER2; and 2325, ER/PgR/HER2 for multivariable investigations. ASCO/CAP categorization significantly differentiated univariate DDFS (p = 0.01), although not values of IHC 0 (N = 864) and ultra-low HER2 (N = 1143). Statistical standardization did not differentiate univariate DDFS (p = 0.08-0.27); however, (natural logarithm-) standardized values ≤ - 1.0 (ultra-low 1 + /2 + /3 + HSCORE, or % + , < 0.1) were similar to > 1.0 (HSCORE > 19; % + > 14). Neither ASCO/CAP, nor statistically standardized, ER (p = 0.65-0.94) or HER2 (p = 0.20-0.97) were associated with DDFS in models with PgR; higher PgR had better DDFS (p ≤ .003).

Conclusions: ASCO/CAP categories significantly differentiated DDFS, while statistical standardization did not. Patients with ultra-low HER2 and IHC 0 without stain had similar 5-year DDFS, while standardization indicated similar prognosis for very low 1 + /2 + /3 + and highest HER2 stain. We caution about assessment of ultra-low, or very low, HER2 due to HER2 assay dynamic range.

Keywords: Breast cancer; ER; HER2; PgR; Standardized biomarkers; Ultra-low HER2.

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Conflict of interest statement

Declarations. Competing interests: Jane Bayani: Honoraria: Thermo Fisher Scientific, NanoString Technologies. Research Funding: Thermo Fisher Scientific. Patents, Royalties, Other Intellectual Property: Invention Disclosure Name: A Molecular Classifier for Personalized Risk Stratification for Patients with Prostate Cancer (Inst), Patent (applied): A Molecular Classifier for Personalized Risk Stratification for Patients with Prostate Cancer (Invention Title), PCT International Application No.: PCT/CA2021/050837, International Filing Date: June 18, 2021 (Inst), Patent (applied): 95-Gene Signature of Residual Risk Following Endocrine Treatment in Early Breast Cancer (Patent Title), National Phase Application, Patent application number 3007118 (Country of Filing: Canada—Patent Application Date: 06/01/18); 15/781,939 (USA—06/06/18) (Inst), Patent (granted): 95-Gene Signature of Residual Risk Following Endocrine Treatment in Early Breast Cancer (Patent Title), National Phase Application, Patent number: 2016368696 (Country: Australia, Date: March 10, 2022); 2016800813945 (China, March 18, 2022); 3387168 (Europe, May 12, 2022); 7043404 (Japan, March 18, 2022) (Inst). John M.S. Bartlett: Leadership: MedcomXchange. Honoraria: bioTheranostics, MedcomXchange. Consulting or Advisory Role: Insight Genetics, BioNTech, bioTheranostics, RNA Diagnostics, Pfizer, oncoXchange, Herbert Smith Freehills Paris, OncoCyte, Ontario Institute for Cancer Research, AstraZeneca, Cerca Biotech, Tempus. Research Funding: NanoString Technologies, Stratifyer GmbH, Genoptix, Thermo Fisher Scientific, Agendia, bioTheranostics, Exact Sciences. Patents, Royalties, Other Intellectual Property: Invention Disclosure Name: A Molecular Classifier for Personalized Risk Stratification for Patients with Prostate Cancer, Date: 21/08/2019 (Inst), John Bartlett currently has three granted patents: -CIN4 predicts benefit from anthracycline (Invention Title), National Phase Application, Patent number: 11214836 (Country: United States, Date: January 4, 2022); 3169815 (Europe, Dec. 23, 2020) -Targeting the Histone Pathway to Detect and Overcome Anthracycline Resistance (IP Title), National Phase Application, Patent number: 2016800728463 (Country: China, Date: Aug. 27, 2021); 11,015,226 (United States, May 25, 2021); 3359508 (Europe, Sept. 9, 2020) -Gene Signature of Residual Risk Following Endocrine Treatment in Early Breast Cancer (Patent Title), National Phase Application, Patent number: 2016368696 (Country: Australia, Date: Mar. 10, 2022); 2016800813945 (China, Mar. 18, 2022); 3387168 (Europe, May 12, 2022); 7043404 (Japan, Mar. 18, 2022) (Inst), John Bartlett currently has six pending patents: -CIN4 predicts benefit from anthracycline, National Phase Application, (Canada, Jan. 11, 2017) -Systems, Devices and Methods for Constructing and Using a Biomarker, National Phase Application, 15/328,108 (United States, Jan. 23, 2017); 15824751.0 (Europe, Jan. 12, 2017); (Canada, Jan. 12, 2017)—Targeting the Histone Pathway to Detect and Overcome Anthracycline Resistance (IP Title), National Phase Application, PCT/CA2016/000247, Patent Application #: 3000858 (Country of filing: Canada—Patent Application Date: Apr. 4, 2018)—Immune Gene Signature Predicts Anthracycline Benefit, PCT (international application), PCT/CA2016/000305, Filing date: Dec. 7, 2016—Gene Signature of Residual Risk Following Endocrine Treatment in Early Breast Cancer (Patent Title), National Phase Application, Patent application number 3007118 (Country of Filing: Canada—Patent Application Date: 06/01/18); 15/781,939 (USA—06/06/18)—A Molecular Classifier for Personalized Risk Stratification for Patients with Prostate Cancer (Invention Title), PCT International Application No.: PCT/CA2021/050837, International Filing Date: June 18, 2021 (Inst). Travel, Accommodations, Expenses: bioTheranostics. Matthew J. Ellis: Employment: AstraZeneca. Patents, Royalties, Other Intellectual Property: Royalties from Veracyte from the PAM50 patent for Prosigna. George W. Sledge: Employment: Caris Life Sciences. Leadership: Syndax, Caris Life Sciences. Stock and Other Ownership Interests: Syndax, Caris Life Sciences. Consulting or Advisory Role: Syndax. Travel, Accommodations, Expenses: Caris Life Sciences. G. Thomas Budd: Honoraria: Gilead Sciences, AADi. Consulting or Advisory Role: Genentech/Roche. Speakers’ Bureau: Deciphera. Research Funding: Genentech/Roche (Inst), TRACON Pharma (Inst), Daiichi Sankyo/Lilly (Inst), Ambrx (Inst), Ayala Pharmaceuticals (Inst), Salarius Pharmaceuticals (Inst), CytomX Therapeutics, Criterium (Inst). Open Payments Link: https://openpaymentsdata.cms.gov/physician/774695 . David P. D’Souza: Honoraria: Tersera. Consulting or Advisory Role: Knight Pharmaceuticals, Merck. Travel, Accommodations, Expenses: Tersera. Silvana Spadafora: Honoraria: AstraZeneca, Novartis. Vered Stearns: Research Funding: AbbVie (Inst), Pfizer (Inst), Novartis (Inst), Puma Biotechnology (Inst), Biocept (Inst), QUE Oncology (Inst). Other Relationship: AstraZeneca. Uncompensated Relationships: Foundation Medicine (Inst). Edith A. Perez: Employment: Genentech, Bolt Biotherapeutics. Leadership: Bolt Biotherapeutics. Stock and Other Ownership Interests: Genentech/Roche. Consulting or Advisory Role: Seagen, Puma Biotechnology, Daiichi Sankyo. Karen A. Gelmon: Honoraria: AstraZeneca, Merck Sharp & Dohme, Seagen, Novartis Canada Pharmaceuticals Inc, Pfizer, Lilly, Gilead Sciences. Consulting or Advisory Role: Pfizer, Novartis, AstraZeneca, Merck, Lilly, Roche, Mylan, Ayala Pharmaceuticals, Gilead Sciences. Research Funding: Pfizer (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst). Expert Testimony: Genentech. Timothy J. Whelan: Research Funding: Exact Sciences (Inst). No other potential conflicts of interest were reported.

References

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