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Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization.

Kao KJ, Chang KM, Hsu HC, Huang AT - BMC Cancer (2011)

Bottom Line: Adjuvant chemotherapy did not provide any survival benefit in early stages of subtype V patients.When molecular subtypes were correlated with recurrence risk predicted by genes of Oncotype and MammaPrint predictors, a significant degree of heterogeneity within the same risk group was noted.Our results indicate that the molecular subtypes established in this study can be utilized for customization of breast cancer treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Research, Koo Foundation SYS Cancer Center, Taipei, Taiwan. kuojang.kao@gmail.com

ABSTRACT

Background: Optimizing treatment through microarray-based molecular subtyping is a promising method to address the problem of heterogeneity in breast cancer; however, current application is restricted to prediction of distant recurrence risk. This study investigated whether breast cancer molecular subtyping according to its global intrinsic biology could be used for treatment customization.

Methods: Gene expression profiling was conducted on fresh frozen breast cancer tissue collected from 327 patients in conjunction with thoroughly documented clinical data. A method of molecular subtyping based on 783 probe-sets was established and validated. Statistical analysis was performed to correlate molecular subtypes with survival outcome and adjuvant chemotherapy regimens. Heterogeneity of molecular subtypes within groups sharing the same distant recurrence risk predicted by genes of the Oncotype and MammaPrint predictors was studied.

Results: We identified six molecular subtypes of breast cancer demonstrating distinctive molecular and clinical characteristics. These six subtypes showed similarities and significant differences from the Perou-Sørlie intrinsic types. Subtype I breast cancer was in concordance with chemosensitive basal-like intrinsic type. Adjuvant chemotherapy of lower intensity with CMF yielded survival outcome similar to those of CAF in this subtype. Subtype IV breast cancer was positive for ER with a full-range expression of HER2, responding poorly to CMF; however, this subtype showed excellent survival when treated with CAF. Reduced expression of a gene associated with methotrexate sensitivity in subtype IV was the likely reason for poor response to methotrexate. All subtype V breast cancer was positive for ER and had excellent long-term survival with hormonal therapy alone following surgery and/or radiation therapy. Adjuvant chemotherapy did not provide any survival benefit in early stages of subtype V patients. Subtype V was consistent with a unique subset of luminal A intrinsic type. When molecular subtypes were correlated with recurrence risk predicted by genes of Oncotype and MammaPrint predictors, a significant degree of heterogeneity within the same risk group was noted. This heterogeneity was distributed over several subtypes, suggesting that patients in the same risk groups require different treatment approaches.

Conclusions: Our results indicate that the molecular subtypes established in this study can be utilized for customization of breast cancer treatment.

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Related in: MedlinePlus

Comparison of survival outcome between patients with molecular subtype IV breast cancer treated with CMF and CAF. Detailed comparisons of pertinent clinical parameters between these two treatment groups are summarized in Table 4. The numbers in parentheses represent the number of events. P values were determined by log-rank test. The upper panel is metastasis-free survival curves and the lower panel is overall survival curves.
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Figure 5: Comparison of survival outcome between patients with molecular subtype IV breast cancer treated with CMF and CAF. Detailed comparisons of pertinent clinical parameters between these two treatment groups are summarized in Table 4. The numbers in parentheses represent the number of events. P values were determined by log-rank test. The upper panel is metastasis-free survival curves and the lower panel is overall survival curves.

Mentions: The breast cancer samples included in this study covered the period of transition of adjuvant chemotherapy regimen from CMF to CAF and to taxane-based regimens. These archival samples provided an opportunity to examine how breast cancer subtypes might have responded differentially to CMF and CAF regimens of adjuvant chemotherapy. The results of this study show that the change from methotrexate to doxorubicin had a major impact on the survival of patients with subtype IV breast cancer (Figure 5). None of the pertinent clinical factors between these two groups of patients showed a significant difference except for the N stage. The N stage was higher in the CAF group (Table 4). In spite of the higher N stage, significantly better metastasis-free and overall survival was observed for subtype IV patients treated with CAF than with CMF (Figure 5). For other molecular subtypes, we did not find significant differences in survival between groups receiving treatment with CAF or CMF (Additional file 1, Table S5). The small sample size did not allow us to draw firm conclusions regarding survival in molecular subtypes other than subtype IV.


Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization.

Kao KJ, Chang KM, Hsu HC, Huang AT - BMC Cancer (2011)

Comparison of survival outcome between patients with molecular subtype IV breast cancer treated with CMF and CAF. Detailed comparisons of pertinent clinical parameters between these two treatment groups are summarized in Table 4. The numbers in parentheses represent the number of events. P values were determined by log-rank test. The upper panel is metastasis-free survival curves and the lower panel is overall survival curves.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094326&req=5

Figure 5: Comparison of survival outcome between patients with molecular subtype IV breast cancer treated with CMF and CAF. Detailed comparisons of pertinent clinical parameters between these two treatment groups are summarized in Table 4. The numbers in parentheses represent the number of events. P values were determined by log-rank test. The upper panel is metastasis-free survival curves and the lower panel is overall survival curves.
Mentions: The breast cancer samples included in this study covered the period of transition of adjuvant chemotherapy regimen from CMF to CAF and to taxane-based regimens. These archival samples provided an opportunity to examine how breast cancer subtypes might have responded differentially to CMF and CAF regimens of adjuvant chemotherapy. The results of this study show that the change from methotrexate to doxorubicin had a major impact on the survival of patients with subtype IV breast cancer (Figure 5). None of the pertinent clinical factors between these two groups of patients showed a significant difference except for the N stage. The N stage was higher in the CAF group (Table 4). In spite of the higher N stage, significantly better metastasis-free and overall survival was observed for subtype IV patients treated with CAF than with CMF (Figure 5). For other molecular subtypes, we did not find significant differences in survival between groups receiving treatment with CAF or CMF (Additional file 1, Table S5). The small sample size did not allow us to draw firm conclusions regarding survival in molecular subtypes other than subtype IV.

Bottom Line: Adjuvant chemotherapy did not provide any survival benefit in early stages of subtype V patients.When molecular subtypes were correlated with recurrence risk predicted by genes of Oncotype and MammaPrint predictors, a significant degree of heterogeneity within the same risk group was noted.Our results indicate that the molecular subtypes established in this study can be utilized for customization of breast cancer treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Research, Koo Foundation SYS Cancer Center, Taipei, Taiwan. kuojang.kao@gmail.com

ABSTRACT

Background: Optimizing treatment through microarray-based molecular subtyping is a promising method to address the problem of heterogeneity in breast cancer; however, current application is restricted to prediction of distant recurrence risk. This study investigated whether breast cancer molecular subtyping according to its global intrinsic biology could be used for treatment customization.

Methods: Gene expression profiling was conducted on fresh frozen breast cancer tissue collected from 327 patients in conjunction with thoroughly documented clinical data. A method of molecular subtyping based on 783 probe-sets was established and validated. Statistical analysis was performed to correlate molecular subtypes with survival outcome and adjuvant chemotherapy regimens. Heterogeneity of molecular subtypes within groups sharing the same distant recurrence risk predicted by genes of the Oncotype and MammaPrint predictors was studied.

Results: We identified six molecular subtypes of breast cancer demonstrating distinctive molecular and clinical characteristics. These six subtypes showed similarities and significant differences from the Perou-Sørlie intrinsic types. Subtype I breast cancer was in concordance with chemosensitive basal-like intrinsic type. Adjuvant chemotherapy of lower intensity with CMF yielded survival outcome similar to those of CAF in this subtype. Subtype IV breast cancer was positive for ER with a full-range expression of HER2, responding poorly to CMF; however, this subtype showed excellent survival when treated with CAF. Reduced expression of a gene associated with methotrexate sensitivity in subtype IV was the likely reason for poor response to methotrexate. All subtype V breast cancer was positive for ER and had excellent long-term survival with hormonal therapy alone following surgery and/or radiation therapy. Adjuvant chemotherapy did not provide any survival benefit in early stages of subtype V patients. Subtype V was consistent with a unique subset of luminal A intrinsic type. When molecular subtypes were correlated with recurrence risk predicted by genes of Oncotype and MammaPrint predictors, a significant degree of heterogeneity within the same risk group was noted. This heterogeneity was distributed over several subtypes, suggesting that patients in the same risk groups require different treatment approaches.

Conclusions: Our results indicate that the molecular subtypes established in this study can be utilized for customization of breast cancer treatment.

Show MeSH
Related in: MedlinePlus