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

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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.

authors

  • Chapman, Judith-Anne W
  • Bayani, Jane
  • SenGupta, Sandip
  • Bartlett, John MS
  • Piper, Tammy
  • Quintayo, Mary Anne
  • Virk, Shakeel
  • Goss, Paul E
  • Ingle, James N
  • Ellis, Matthew J
  • Sledge, George W
  • Budd, G Thomas
  • Rabaglio, Manuela
  • Ansari, Rafat H
  • Tozer, Richard
  • D'Souza, David P
  • Chalchal, Haji
  • Spadafora, Silvana
  • Stearns, Vered
  • Perez, Edith A
  • Gelmon, Karen A
  • Whelan, Timothy
  • Elliott, Catherine
  • Shepherd, Lois E
  • Chen, Bingshu E
  • Taylor, Karen J

publication date

  • June 23, 2025