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An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer.

Lee HE, Kim JH, Kim YJ, Choi SY, Kim SW, Kang E, Chung IY, Kim IA, Kim EJ, Choi Y, Ryu HS, Park SY - Br. J. Cancer (2011)

Bottom Line: The proportions of putative CSCs with CD44+/CD24- or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST.Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Seoul National University Hospital, 28 Yeongon-dong, Jongno-gu, Seoul 110-744, Korea.

ABSTRACT

Background: The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer.

Methods: Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST with the regimen of doxorubicin plus docetaxel (AD) (n=50) or doxorubicin plus cyclophosphamide (AC) (n=42) and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24- or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.

Results: A higher proportion of CD44+/CD24- tumour cells and ALDH1 positivity in pre-chemotherapy tissue was correlated with higher histologic grade, oestrogen receptor (ER) negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24- and ALDH1+ tumour cells were significantly increased after PST. The cases with increased CD44+/CD24- tumour cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumour cell population after PST were associated with ER negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.

Conclusion: The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumour progression, emphasising the need for targeting of CSCs in the breast cancer therapeutics.

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Related in: MedlinePlus

Disease-free survivals according to changes of the putative CSC population after primary systemic therapy. Patients with increased proportions of CD44+/CD24− (A) and ALDH1+ (B) tumour cells showed significantly poorer DFS than the other patients in total. In the subgroup analyses by primary systemic therapy (PST) regimen (AD or AC regimen), the patients with the increase of CD44+/CD24− tumour cell populations tended to have shorter DFS times than the remaining patients irrespective of PST regimen (C and E). With regard to the changes of ALDH1+ tumour cell populations in the subgroup analyses by PST regimen (D and F), the survival difference was much greater in the subgroup receiving AC regimen (F), but not in the subgroup treated by AD regimen (D). AD=doxorubicin plus docetaxel; AC=doxorubicin plus cyclophosphamide.
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fig4: Disease-free survivals according to changes of the putative CSC population after primary systemic therapy. Patients with increased proportions of CD44+/CD24− (A) and ALDH1+ (B) tumour cells showed significantly poorer DFS than the other patients in total. In the subgroup analyses by primary systemic therapy (PST) regimen (AD or AC regimen), the patients with the increase of CD44+/CD24− tumour cell populations tended to have shorter DFS times than the remaining patients irrespective of PST regimen (C and E). With regard to the changes of ALDH1+ tumour cell populations in the subgroup analyses by PST regimen (D and F), the survival difference was much greater in the subgroup receiving AC regimen (F), but not in the subgroup treated by AD regimen (D). AD=doxorubicin plus docetaxel; AC=doxorubicin plus cyclophosphamide.

Mentions: We also investigated the relationships of the changes of CD44+/CD24− and ALDH1+ tumour cell population after PST with DFS. At the time of the analysis, the median follow-up was 3 years (range, 1–7 years). There were four (4%) loco-regional recurrences as first events and seven (8%) distant metastases. In Kaplan–Meier survival analyses, the patients with increased CD44+/CD24− and ALDH1+ tumour cell populations had a significantly shorter DFS times than the remaining patients (P=0.043 and 0.041, respectively) (Figures 4A and B). Subgroup analyses by the PST regimen revealed that the survival difference was much greater in the patients receiving AC regimen between the group with increased ALDH+ tumour cell population after PST and the remaining group (P<0.001). On the other hand, there was no survival difference between the two groups in patients treated with AD regimen. With regard to the changes of CD44+/CD24− tumour cell populations, the patients with the increase of CD44+/CD24− tumour cell populations tended to have shorter DFS times than the remaining patients irrespective of PST regimen, although they were not statistically significant (Figures 4C–F). In multivariate analysis, ypT stage (ypT0-2 vs ypT3-4; HR, 4.82; 95% CI: 1.28–18.18; P=0.020) was identified as an independent predictor for DFS. However, the changes of CD44+/CD24− and ALDH1+ tumour cell populations did not remain as independent prognostic factors.


An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer.

Lee HE, Kim JH, Kim YJ, Choi SY, Kim SW, Kang E, Chung IY, Kim IA, Kim EJ, Choi Y, Ryu HS, Park SY - Br. J. Cancer (2011)

Disease-free survivals according to changes of the putative CSC population after primary systemic therapy. Patients with increased proportions of CD44+/CD24− (A) and ALDH1+ (B) tumour cells showed significantly poorer DFS than the other patients in total. In the subgroup analyses by primary systemic therapy (PST) regimen (AD or AC regimen), the patients with the increase of CD44+/CD24− tumour cell populations tended to have shorter DFS times than the remaining patients irrespective of PST regimen (C and E). With regard to the changes of ALDH1+ tumour cell populations in the subgroup analyses by PST regimen (D and F), the survival difference was much greater in the subgroup receiving AC regimen (F), but not in the subgroup treated by AD regimen (D). AD=doxorubicin plus docetaxel; AC=doxorubicin plus cyclophosphamide.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111169&req=5

fig4: Disease-free survivals according to changes of the putative CSC population after primary systemic therapy. Patients with increased proportions of CD44+/CD24− (A) and ALDH1+ (B) tumour cells showed significantly poorer DFS than the other patients in total. In the subgroup analyses by primary systemic therapy (PST) regimen (AD or AC regimen), the patients with the increase of CD44+/CD24− tumour cell populations tended to have shorter DFS times than the remaining patients irrespective of PST regimen (C and E). With regard to the changes of ALDH1+ tumour cell populations in the subgroup analyses by PST regimen (D and F), the survival difference was much greater in the subgroup receiving AC regimen (F), but not in the subgroup treated by AD regimen (D). AD=doxorubicin plus docetaxel; AC=doxorubicin plus cyclophosphamide.
Mentions: We also investigated the relationships of the changes of CD44+/CD24− and ALDH1+ tumour cell population after PST with DFS. At the time of the analysis, the median follow-up was 3 years (range, 1–7 years). There were four (4%) loco-regional recurrences as first events and seven (8%) distant metastases. In Kaplan–Meier survival analyses, the patients with increased CD44+/CD24− and ALDH1+ tumour cell populations had a significantly shorter DFS times than the remaining patients (P=0.043 and 0.041, respectively) (Figures 4A and B). Subgroup analyses by the PST regimen revealed that the survival difference was much greater in the patients receiving AC regimen between the group with increased ALDH+ tumour cell population after PST and the remaining group (P<0.001). On the other hand, there was no survival difference between the two groups in patients treated with AD regimen. With regard to the changes of CD44+/CD24− tumour cell populations, the patients with the increase of CD44+/CD24− tumour cell populations tended to have shorter DFS times than the remaining patients irrespective of PST regimen, although they were not statistically significant (Figures 4C–F). In multivariate analysis, ypT stage (ypT0-2 vs ypT3-4; HR, 4.82; 95% CI: 1.28–18.18; P=0.020) was identified as an independent predictor for DFS. However, the changes of CD44+/CD24− and ALDH1+ tumour cell populations did not remain as independent prognostic factors.

Bottom Line: The proportions of putative CSCs with CD44+/CD24- or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST.Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Seoul National University Hospital, 28 Yeongon-dong, Jongno-gu, Seoul 110-744, Korea.

ABSTRACT

Background: The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer.

Methods: Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST with the regimen of doxorubicin plus docetaxel (AD) (n=50) or doxorubicin plus cyclophosphamide (AC) (n=42) and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24- or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.

Results: A higher proportion of CD44+/CD24- tumour cells and ALDH1 positivity in pre-chemotherapy tissue was correlated with higher histologic grade, oestrogen receptor (ER) negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24- and ALDH1+ tumour cells were significantly increased after PST. The cases with increased CD44+/CD24- tumour cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumour cell population after PST were associated with ER negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.

Conclusion: The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumour progression, emphasising the need for targeting of CSCs in the breast cancer therapeutics.

Show MeSH
Related in: MedlinePlus