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Predictive value of phosphorylated mammalian target of rapamycin for disease-free survival in breast cancer patients receiving neoadjuvant chemotherapy.

Wang S, Sun Y, He A, Zheng C, Zheng X - Oncol Lett (2014)

Bottom Line: It was found that the expression of p-mTOR and p-4E-BP1 was downregulated following NAC.The decrease in mTOR expression following NAC was found to positively correlate with HER2 expression and the reduction of tumor sizes.In conclusion, NAC was found to decrease the expression levels of p-mTOR and p-4E-BP1.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China.

ABSTRACT
The mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) pathway plays a critical role in cell growth, survival and angiogenesis, and has been demonstrated to correlate with human epidermal growth factor receptor 2 (HER2) status. Neoadjuvant chemotherapy (NAC), also known as preoperative therapy, is now well established in the treatment of inoperable locally advanced and inflammatory breast cancer. In vitro study has shown that mTOR inhibitors, together with cytotoxic agents, exhibit tumor cell killing activity. A number of non-randomized studies in HER2-positive trastuzumab-resistant metastatic breast cancer have revealed the antitumor activity of mTOR inhibitors when used together with standard chemotherapy plus trastuzumab. In the present study, the expression levels of phosphorylated (p)-mTOR and p-4E-BP1 were analyzed in breast cancer patients prior to and following NAC, to determine whether p-mTOR and p-4E-BP1 affect the response to NAC and the subsequent survival. Formalin-fixed, paraffin-embedded tissues representing matched pairs of core biopsy (pre-NAC) and surgical specimen (post-NAC) from 83 patients with invasive ductal carcinomas were collected. Immunohistochemistry was performed to evaluate the expression of p-mTOR and p-4E-BP1 using a semi-quantitative scoring system by two pathologists. It was found that the expression of p-mTOR and p-4E-BP1 was downregulated following NAC. The decrease in mTOR expression following NAC was found to positively correlate with HER2 expression and the reduction of tumor sizes. The high expression of p-mTOR and p-4E-BP1 in pre-NAC specimens was associated with poor disease-free survival (DFS). Furthermore, the high expression of p-mTOR in post-NAC specimens was associated with poor DFS, regardless of whether the expression was high or low in the pre-NAC specimens. In conclusion, NAC was found to decrease the expression levels of p-mTOR and p-4E-BP1. The p-mTOR expression post-NAC may potentially serve as a predictor for DFS. However, further study is required to clarify the mechanism and to evaluate the predictive value of the phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathway in NAC.

No MeSH data available.


Related in: MedlinePlus

Kaplan-Meier survival analyses of disease-free survival in different patient groups. (A-D) Tumors with high or low expression levels of p-mTOR and p-4E-BP1 pre- and post-NAC. (E and F) Tumors with high or low expression of mTOR post-NAC, in groups A and B. High levels of p-mTOR and p-4E-BP1 expression pre-NAC were found to correlate with a poor DFS, and a high expression of p-mTOR post-NACwas found to be significantly associated with a poor DFS. High expression of p-mTOR post-NAC was found to correlate with a poor DFS, regardless its expression pre-NAC. Group A, high expression of p-mTOR pre-NAC; group B, low expression of p-mTOR pre-NAC; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1; NAC, neoadjuvant; DFS, disease-free survival.
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f4-ol-08-06-2642: Kaplan-Meier survival analyses of disease-free survival in different patient groups. (A-D) Tumors with high or low expression levels of p-mTOR and p-4E-BP1 pre- and post-NAC. (E and F) Tumors with high or low expression of mTOR post-NAC, in groups A and B. High levels of p-mTOR and p-4E-BP1 expression pre-NAC were found to correlate with a poor DFS, and a high expression of p-mTOR post-NACwas found to be significantly associated with a poor DFS. High expression of p-mTOR post-NAC was found to correlate with a poor DFS, regardless its expression pre-NAC. Group A, high expression of p-mTOR pre-NAC; group B, low expression of p-mTOR pre-NAC; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1; NAC, neoadjuvant; DFS, disease-free survival.

Mentions: In order to assess the differential survival with respect to pre- and post-NAC expression, as well as the expression change following NAC for the two markers, Kaplan-Meier survival analyses were performed. ROC curve analyses were used to dichotomize the expression scores into high and low expression groups. The cut-off values were obtained from the highest combined sensitivity and specificity at the endpoint of DFS, and were as follows: p-mTOR, 8 and p-4E-BP1, 9 for pre-NAC; and p-mTOR, 7 and p-4E-BP1, 5 for post-NAC. A high expression of p-mTOR and p-4E-BP1 was found to significantly correlate with poor DFS pre-NAC (Fig. 4A and B, log-rank, P=0.013 for p-mTOR and P=0.025 for p-4E-BP1). The expression of p-4E-BP1 post-NAC was not significantly correlated with DFS (Fig. 4D). By contrast, the high expression of p-mTOR in post-NAC samples had a significant association with poor DFS compared with the pre-NAC samples (Fig. 4C, log-rank, P<0.001). It was also examined whether the expression changes of the factors correlate with DFS. Changes in expression of the two factors were dichotomized as up- or downregulated, but no significant correlation was found. In order to identify the predictive value of mTOR post-NAC, patients with high p-mTOR expression pre-NAC were defined as group A, while those with low p-mTOR expression pre-NAC were defined as group B. Next, the p-mTOR expression was compared between groups A and B post-NAC. High expression of p-mTOR post-NAC was found to correlate with poor DFS, regardless of whether the patients were in group A or B (P=0.043 for group A and P=0.006 for group B). Finally, multivariate Cox regression analysis was performed taking into account p-mTOR and p-4E-BP1 expression pre-NAC, p-mTOR expression post-NAC and other clinicopathological features, including tumor grade, receptor status, tumor stage pre-NAC and axillary metastasis. Post-NAC expression of p-mTOR was identified as the only significant factor, with its high expression associated with a hazard ratio of 3.073 (95% confidence interval, 1.4–6.8; P=0.006).


Predictive value of phosphorylated mammalian target of rapamycin for disease-free survival in breast cancer patients receiving neoadjuvant chemotherapy.

Wang S, Sun Y, He A, Zheng C, Zheng X - Oncol Lett (2014)

Kaplan-Meier survival analyses of disease-free survival in different patient groups. (A-D) Tumors with high or low expression levels of p-mTOR and p-4E-BP1 pre- and post-NAC. (E and F) Tumors with high or low expression of mTOR post-NAC, in groups A and B. High levels of p-mTOR and p-4E-BP1 expression pre-NAC were found to correlate with a poor DFS, and a high expression of p-mTOR post-NACwas found to be significantly associated with a poor DFS. High expression of p-mTOR post-NAC was found to correlate with a poor DFS, regardless its expression pre-NAC. Group A, high expression of p-mTOR pre-NAC; group B, low expression of p-mTOR pre-NAC; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1; NAC, neoadjuvant; DFS, disease-free survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214504&req=5

f4-ol-08-06-2642: Kaplan-Meier survival analyses of disease-free survival in different patient groups. (A-D) Tumors with high or low expression levels of p-mTOR and p-4E-BP1 pre- and post-NAC. (E and F) Tumors with high or low expression of mTOR post-NAC, in groups A and B. High levels of p-mTOR and p-4E-BP1 expression pre-NAC were found to correlate with a poor DFS, and a high expression of p-mTOR post-NACwas found to be significantly associated with a poor DFS. High expression of p-mTOR post-NAC was found to correlate with a poor DFS, regardless its expression pre-NAC. Group A, high expression of p-mTOR pre-NAC; group B, low expression of p-mTOR pre-NAC; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1; NAC, neoadjuvant; DFS, disease-free survival.
Mentions: In order to assess the differential survival with respect to pre- and post-NAC expression, as well as the expression change following NAC for the two markers, Kaplan-Meier survival analyses were performed. ROC curve analyses were used to dichotomize the expression scores into high and low expression groups. The cut-off values were obtained from the highest combined sensitivity and specificity at the endpoint of DFS, and were as follows: p-mTOR, 8 and p-4E-BP1, 9 for pre-NAC; and p-mTOR, 7 and p-4E-BP1, 5 for post-NAC. A high expression of p-mTOR and p-4E-BP1 was found to significantly correlate with poor DFS pre-NAC (Fig. 4A and B, log-rank, P=0.013 for p-mTOR and P=0.025 for p-4E-BP1). The expression of p-4E-BP1 post-NAC was not significantly correlated with DFS (Fig. 4D). By contrast, the high expression of p-mTOR in post-NAC samples had a significant association with poor DFS compared with the pre-NAC samples (Fig. 4C, log-rank, P<0.001). It was also examined whether the expression changes of the factors correlate with DFS. Changes in expression of the two factors were dichotomized as up- or downregulated, but no significant correlation was found. In order to identify the predictive value of mTOR post-NAC, patients with high p-mTOR expression pre-NAC were defined as group A, while those with low p-mTOR expression pre-NAC were defined as group B. Next, the p-mTOR expression was compared between groups A and B post-NAC. High expression of p-mTOR post-NAC was found to correlate with poor DFS, regardless of whether the patients were in group A or B (P=0.043 for group A and P=0.006 for group B). Finally, multivariate Cox regression analysis was performed taking into account p-mTOR and p-4E-BP1 expression pre-NAC, p-mTOR expression post-NAC and other clinicopathological features, including tumor grade, receptor status, tumor stage pre-NAC and axillary metastasis. Post-NAC expression of p-mTOR was identified as the only significant factor, with its high expression associated with a hazard ratio of 3.073 (95% confidence interval, 1.4–6.8; P=0.006).

Bottom Line: It was found that the expression of p-mTOR and p-4E-BP1 was downregulated following NAC.The decrease in mTOR expression following NAC was found to positively correlate with HER2 expression and the reduction of tumor sizes.In conclusion, NAC was found to decrease the expression levels of p-mTOR and p-4E-BP1.

View Article: PubMed Central - PubMed

Affiliation: Department of Breast Surgery, First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China.

ABSTRACT
The mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) pathway plays a critical role in cell growth, survival and angiogenesis, and has been demonstrated to correlate with human epidermal growth factor receptor 2 (HER2) status. Neoadjuvant chemotherapy (NAC), also known as preoperative therapy, is now well established in the treatment of inoperable locally advanced and inflammatory breast cancer. In vitro study has shown that mTOR inhibitors, together with cytotoxic agents, exhibit tumor cell killing activity. A number of non-randomized studies in HER2-positive trastuzumab-resistant metastatic breast cancer have revealed the antitumor activity of mTOR inhibitors when used together with standard chemotherapy plus trastuzumab. In the present study, the expression levels of phosphorylated (p)-mTOR and p-4E-BP1 were analyzed in breast cancer patients prior to and following NAC, to determine whether p-mTOR and p-4E-BP1 affect the response to NAC and the subsequent survival. Formalin-fixed, paraffin-embedded tissues representing matched pairs of core biopsy (pre-NAC) and surgical specimen (post-NAC) from 83 patients with invasive ductal carcinomas were collected. Immunohistochemistry was performed to evaluate the expression of p-mTOR and p-4E-BP1 using a semi-quantitative scoring system by two pathologists. It was found that the expression of p-mTOR and p-4E-BP1 was downregulated following NAC. The decrease in mTOR expression following NAC was found to positively correlate with HER2 expression and the reduction of tumor sizes. The high expression of p-mTOR and p-4E-BP1 in pre-NAC specimens was associated with poor disease-free survival (DFS). Furthermore, the high expression of p-mTOR in post-NAC specimens was associated with poor DFS, regardless of whether the expression was high or low in the pre-NAC specimens. In conclusion, NAC was found to decrease the expression levels of p-mTOR and p-4E-BP1. The p-mTOR expression post-NAC may potentially serve as a predictor for DFS. However, further study is required to clarify the mechanism and to evaluate the predictive value of the phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathway in NAC.

No MeSH data available.


Related in: MedlinePlus