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Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer.

Toi M, Sperinde J, Huang W, Saji S, Winslow J, Jin X, Tan Y, Ohno S, Nakamura S, Iwata H, Masuda N, Aogi K, Morita S, Petropoulos C, Bates M - BMC Cancer (2010)

Bottom Line: Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses.Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group.These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Medicine, Kyoto University, Kyoto, Japan. toi@kuhp.kyoto-u.ac.jp

ABSTRACT

Background: We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC.

Methods: HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses.

Results: Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group.

Conclusions: These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.

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Related in: MedlinePlus

Kaplan-Meier curve of OS by HER2 expression subgroup.
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Figure 2: Kaplan-Meier curve of OS by HER2 expression subgroup.

Mentions: As a whole, two-year survival rate of the cohort was 60.8% (95% C.I., 48.4 - 73.2%). In the univariate analyses, patients were classified into four subgroups defined by the 25th, 50th, and 75th percentiles for each of the three variables, H2T, H2D, and their ratio H2D/H2T, in order to examine the assumption of linearity for the continuous variables used in the subsequent Cox regression analysis. A significant difference in OS was found between the four subgroups with respect to H2T (Log rank test, p = 0.003; Figure 2), but not for the others (p = 0.371 and p = 0.573). The 25th, 50th, and 75th percentiles for the log-transformed values of H2T were 1.41, 1.80, and 2.25, respectively. The patients' characteristics by H2T subgroup (< the median value of H2T: n = 37 v.s. • the median value of H2T: n = 37) is summarized in Table 1. Higher proportion of patients with greater H2T value than its median value had IHC 2+ or 3+ (p < 0.001) and higher HER2 score on repeat testing (p < 0.001). No significant difference in OS was found between the IHC subgroups (log-rank test: p = 0.610). Table 2 summarizes the other univariate analyses for OS. Figure 3 shows the hazard function plots estimated in the four H2T subgroups. The subgroups with the 25% highest and lowest H2T values had substantially lower risk of death than the middle two subgroups. These univariate analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. As shown in Table 3, this parabolic relationship was also confirmed by the Cox regression analysis using the categorized variable of H2T (compared with the reference subgroup having higher 50%-75% H2T, HR of the 25% highest = 0.25, p = 0.019, 95%CI: 0.08-0.77; HR of the 25%-50% = 0.79, p = 0.610, 95%CI: 0.32-1.97; HR of the 25% lowest = 0.12, p = 0.004, 95%CI: 0.03-0.51), which also shows that hormone receptor status (HR = 0.18, p = 0.014, 95%CI: 0.04-0.71) and brain metastases (HR = 0.07, p < 0.001, 95%CI: 0.02-0.24) were significant prognostic factors. Thus, the best multivariate model contained three variables, H2T, progesterone receptor status, and brain metastases.


Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer.

Toi M, Sperinde J, Huang W, Saji S, Winslow J, Jin X, Tan Y, Ohno S, Nakamura S, Iwata H, Masuda N, Aogi K, Morita S, Petropoulos C, Bates M - BMC Cancer (2010)

Kaplan-Meier curve of OS by HER2 expression subgroup.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837013&req=5

Figure 2: Kaplan-Meier curve of OS by HER2 expression subgroup.
Mentions: As a whole, two-year survival rate of the cohort was 60.8% (95% C.I., 48.4 - 73.2%). In the univariate analyses, patients were classified into four subgroups defined by the 25th, 50th, and 75th percentiles for each of the three variables, H2T, H2D, and their ratio H2D/H2T, in order to examine the assumption of linearity for the continuous variables used in the subsequent Cox regression analysis. A significant difference in OS was found between the four subgroups with respect to H2T (Log rank test, p = 0.003; Figure 2), but not for the others (p = 0.371 and p = 0.573). The 25th, 50th, and 75th percentiles for the log-transformed values of H2T were 1.41, 1.80, and 2.25, respectively. The patients' characteristics by H2T subgroup (< the median value of H2T: n = 37 v.s. • the median value of H2T: n = 37) is summarized in Table 1. Higher proportion of patients with greater H2T value than its median value had IHC 2+ or 3+ (p < 0.001) and higher HER2 score on repeat testing (p < 0.001). No significant difference in OS was found between the IHC subgroups (log-rank test: p = 0.610). Table 2 summarizes the other univariate analyses for OS. Figure 3 shows the hazard function plots estimated in the four H2T subgroups. The subgroups with the 25% highest and lowest H2T values had substantially lower risk of death than the middle two subgroups. These univariate analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. As shown in Table 3, this parabolic relationship was also confirmed by the Cox regression analysis using the categorized variable of H2T (compared with the reference subgroup having higher 50%-75% H2T, HR of the 25% highest = 0.25, p = 0.019, 95%CI: 0.08-0.77; HR of the 25%-50% = 0.79, p = 0.610, 95%CI: 0.32-1.97; HR of the 25% lowest = 0.12, p = 0.004, 95%CI: 0.03-0.51), which also shows that hormone receptor status (HR = 0.18, p = 0.014, 95%CI: 0.04-0.71) and brain metastases (HR = 0.07, p < 0.001, 95%CI: 0.02-0.24) were significant prognostic factors. Thus, the best multivariate model contained three variables, H2T, progesterone receptor status, and brain metastases.

Bottom Line: Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses.Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group.These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Faculty of Medicine, Kyoto University, Kyoto, Japan. toi@kuhp.kyoto-u.ac.jp

ABSTRACT

Background: We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC.

Methods: HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses.

Results: Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group.

Conclusions: These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.

Show MeSH
Related in: MedlinePlus