Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer.
BACKGROUND
Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy.


METHODS
Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival.


RESULTS
A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression.


CONCLUSIONS
ALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells.


BACKGROUND
ACTRN12605000588695.
Muhammad
M
Alamgeer
Vinod
V
Ganju
Beena
B
Kumar
Jane
J
Fox
Stewart
S
Hart
Michelle
M
White
Marion
M
Harris
John
J
Stuckey
Zdenka
Z
Prodanovic
Michal Elisabeth
ME
Schneider-Kolsky
D Neil
DN
Watkins
D000080924:Aldehyde Dehydrogenase 1 Family; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D000077143:Docetaxel; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
D000080924:Aldehyde Dehydrogenase 1 Family; D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D005472:Fluorouracil; D007527:Isoenzymes; D019394:Ki-67 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D050697:Retinal Dehydrogenase; D043823:Taxoids; C510223:ALDH1A1 protein, human