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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 overall survival between subtype I patients treated with CAF and CMF adjuvant chemotherapy. Clinical variables including age at diagnosis, TNM stages, positive lymph node number, nuclear grade, hormonal therapy and post-op radiation were compared between these two treatment groups. There were no significant differences (Additional file 1, Table S6). The results of this small sample size study are supported by a recent report on two large-scale clinical trials [32].
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Figure 7: Comparison of overall survival between subtype I patients treated with CAF and CMF adjuvant chemotherapy. Clinical variables including age at diagnosis, TNM stages, positive lymph node number, nuclear grade, hormonal therapy and post-op radiation were compared between these two treatment groups. There were no significant differences (Additional file 1, Table S6). The results of this small sample size study are supported by a recent report on two large-scale clinical trials [32].

Mentions: As mentioned earlier, subtype I breast cancer was essentially the same as the basal-like intrinsic type (Figure 4), and this subtype of breast cancer is known to be chemosensitive [30]. The five and ten year survival rates of patients with basal-like breast cancer who did not receive adjuvant chemotherapy were 64% and 44%, respectively [24]. This is consistent with the fact that basal-like breast cancer has aggressive clinical course and poor survival without adjuvant chemotherapy [31]. When we studied the survival of patients with subtype I breast cancer following CMF or CAF adjuvant chemotherapy, it was noticed that both groups had good long-term survival outcome based on the results from a limited number of patients (Figure 7). This suggests that subtype I breast cancer responds well to CMF adjuvant chemotherapy, and this finding is supported by a recent study of two large randomized clinical trials in which patients with node negative basal-like breast cancer were sensitive and responsive to CMF adjuvant chemotherapy and had good long-term survival following treatment [32]. Adjuvant chemotherapy is therefore critical for the long-term survival of patients with early stage subtype I breast cancer. The use of less toxic CMF could be as effective as CAF and deserves further study.


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 overall survival between subtype I patients treated with CAF and CMF adjuvant chemotherapy. Clinical variables including age at diagnosis, TNM stages, positive lymph node number, nuclear grade, hormonal therapy and post-op radiation were compared between these two treatment groups. There were no significant differences (Additional file 1, Table S6). The results of this small sample size study are supported by a recent report on two large-scale clinical trials [32].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Comparison of overall survival between subtype I patients treated with CAF and CMF adjuvant chemotherapy. Clinical variables including age at diagnosis, TNM stages, positive lymph node number, nuclear grade, hormonal therapy and post-op radiation were compared between these two treatment groups. There were no significant differences (Additional file 1, Table S6). The results of this small sample size study are supported by a recent report on two large-scale clinical trials [32].
Mentions: As mentioned earlier, subtype I breast cancer was essentially the same as the basal-like intrinsic type (Figure 4), and this subtype of breast cancer is known to be chemosensitive [30]. The five and ten year survival rates of patients with basal-like breast cancer who did not receive adjuvant chemotherapy were 64% and 44%, respectively [24]. This is consistent with the fact that basal-like breast cancer has aggressive clinical course and poor survival without adjuvant chemotherapy [31]. When we studied the survival of patients with subtype I breast cancer following CMF or CAF adjuvant chemotherapy, it was noticed that both groups had good long-term survival outcome based on the results from a limited number of patients (Figure 7). This suggests that subtype I breast cancer responds well to CMF adjuvant chemotherapy, and this finding is supported by a recent study of two large randomized clinical trials in which patients with node negative basal-like breast cancer were sensitive and responsive to CMF adjuvant chemotherapy and had good long-term survival following treatment [32]. Adjuvant chemotherapy is therefore critical for the long-term survival of patients with early stage subtype I breast cancer. The use of less toxic CMF could be as effective as CAF and deserves further study.

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