Expression of organic anion-transporting polypeptide 1A2 and organic cation transporter 6 as a predictor of pathologic response to neoadjuvant chemotherapy in triple negative breast cancer

Abstract

Organic anion-transporting polypeptide 1A2 (OATP1A2) and organic cation transporter 6 (OCT6) are involved in the uptake of taxanes and anthracyclines, respectively. The aim of this study was to evaluate expression levels of OATP1A2 and OCT6 as a predictor of response to neoadjuvant chemotherapy (NAC) in breast cancer. A total of 124 patients who received anthracycline/taxane-based NAC were included. Expression levels of OATP1A2 and OCT6 were immunohistochemically assessed in core needle biopsies obtained prior to NAC. A pathologic good response (pGR) and a pathologic complete response (pCR) were achieved in 24 and 10 % of patients, respectively. In univariate analysis of the entire cohort, negative hormone receptor (HR) status (pGR and pCR, P < 0.001), high Ki-67 level (pGR, P = 0.03; pCR, P = 0.02), triple negative (TN) subtype (pGR, P = 0.001; pCR, P < 0.001), and high OCT6 (pGR, P = 0.003) were associated with the response. In combined analysis, high OATP1A2/high OCT6 level was also a significant factor for pGR (P = 0.001) and pCR (P = 0.001). Two separate multivariate analyses showed that HR status, TN subtype and combined high OATP1A2/high OCT6 level were significant independent predictors. When TN and non-TN tumors were assessed separately in univariate analysis, high Ki-67 level (P = 0.04) were associated with pGR and combined high OATP1A2/high OCT6 level was associated with both pGR (P = 0.005) and pCR (P = 0.03) in the TN group. Multivariate analysis identified the combined high OATP1A2/high OCT6 level as the sole independent predictor of pGR. In the non-TN group, negative HR status (P = 0.03) and positive HER2 status (P = 0.005) were associated with pGR, but HER2 status was the sole independent predictor of pGR. These results suggest that response-associated predictors may differ between the TN and non-TN tumors. Combined high OATP1A2/high OCT6 may be a potential predictor of response to anthracycline/taxane-based chemotherapy in breast cancer, especially in TN tumors.

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology

“…However, increased OATP expression may also make breast tumors more susceptible to chemotherapeutic agents that are transported by that OATP, as was suggested in a study where OATP1B3 expression was associated with improved prognosis in estrogen receptor positive patients only, possibly due to increased uptake of tamoxifen in these patients (Muto et al, 2007). Recently, it has been shown that OATP1A2 expression may predict pathologic response to neoadjuvant chemotherapy in triple-negative breast cancer patients as well (Hashimoto et al, 2014).…”

Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance

“…Thus, it is plausible that its efficacy in breast cancer treatment could be related to the fact that doxorubicin is an excellent OATP1A2 substrate and hence would preferentially accumulate in breast cancer cells due to OATP1A2 overexpression. Indeed, a recent study in breast cancer patients indicated those tumors with high expression of OATP1A2 was an independent predictor of good pathologic response to anthracycline-and taxane-based chemotherapy (Hashimoto et al, 2014). This merits further investigation because these data would suggest that OATPs may be an appropriate drug target when overexpressed in tumor tissues as chemotherapeutic agents that are good Fig.…”

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

“…Interestingly, Miki et al also reported a significant correlation between the expression of OATP1A2 and the nuclear receptor PXR (pregnane X receptor), providing possible insights into the regulation of OATP1A2 expression (61) (14). In the clinical setting, the expression of OATP1A2 combined with another transporter OCT6 in patients with triple-negative breast cancer (which displays no detectable expression for estrogen receptor, progesterone receptor, and Her2/neu and has very poor prognosis) was predictive of response to anthracycline/ taxane-based neoadjuvant chemotherapy (96). Further investigations will be required to evaluate the clinical relevance of these findings in patients with hormone-dependent or triplenegative breast cancers.…”