Author(s): Naoki Aomatsu 1 , Masakazu Yashiro 1 , 2 , * , Shinichiro Kashiwagi 1 , Tsutomu Takashima 1 , Tetsuro Ishikawa 1 , Masahiko Ohsawa 3 , Kenichi Wakasa 3 , Kosei Hirakawa 1
Neoadjuvant chemotherapy (NAC) increases the resectability of tumors and decreases the risk of postoperative recurrence; thus resulting in superior long-term survival , . For this reason, NAC is a standard care regimen for patients with various types of carcinomas, including breast cancer . The optimal regimen for NAC in breast cancer involves a combination of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by paclitaxel (PTX). ,  The main aim of NAC is to reduce the size of the primary tumor, increase the likelihood of breast conservation , and allow evaluation of the therapeutic effects that facilitate establishment of therapeutic strategies based on the evaluation results . Recent studies have demonstrated that pathologic complete response (pCR) in primary breast tumors after NAC correlates with improved disease-free survival (DFS) and overall survival (OS) , . NAC for breast cancer has a pCR rate of approximately 30% , ,  and a clinical CR (cCR) rate of approximately 60% . In contrast, NAC is ineffective in approximately half of all patients, and many experience toxicity. Therefore, it would be advantageous to identify patients with chemosensitive tumors before initiating NAC, to avoid potential therapy-related complications and inappropriate delay of surgical treatment.
NAC has numerous advantages, including the use of pathological response data as a surrogate marker for long-term clinical outcome ,  and assessment of responsiveness to NAC that allows the evaluation of potential predictive molecular markers for chemosensitivity. Several biological markers, including the estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67, p21, p53, Bcl, multi-drug-resistant P-glycoprotein, and topoisomerase 2A, have recently been investigated; however, there is no clear correlation between marker expression and chemosensitivity after sequential taxane- and anthracycline-based chemotherapies -, and more useful predictive markers for chemosensitivity need to be clinically identified.
Figure 1. Association between pCR and survival. DFS in pathologic non-responders was significantly (p = 0.01) shorter than that for responders, while OS was not significantly different (p = 0.12). [see PDF for image]
The recent discovery of the hierarchical organization among cancer stem cells (CSCs) and the finding that cancers emerge from their own progenitor stem cells has had important implications in cancer therapy . In addition to being considered the source of tumor initiation and metastasis , , CSCs have been demonstrated to be resistant to chemotherapy, indicating that they are also responsible for tumor recurrence , . In fact, several in vitro studies have shown that CSCs are resistant to PTX, doxorubicin, 5-fluorouracil, and platinum. Recently, Prominin-1 (CD133) has been considered to be a CSC marker in many types of cancers, such as breast -, colorectal , , brain , , prostate , pancreatic , and gastric cancers . In addition, recently, aldehyde dehydrogenase (ALDH) 1 has been identified as a reliable marker for breast CSC marker -.