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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

Expression levels of (A) p-mTOR and (B) p-4E-BP1 in matched breast tumor tissues pre- and post-NAC. Left panels show the distribution of the scores of evaluation of the immunohistochemistry pre- and post-NAC. Right panels show the median values (central marker) with interquartile ranges (bars) pre- and post-NAC. The median expression of p-mTOR and p-4E-BP1 were decreased signifcantly following chemotherapy. NAC, neoadjuvant chemotherapy; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1.
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f2-ol-08-06-2642: Expression levels of (A) p-mTOR and (B) p-4E-BP1 in matched breast tumor tissues pre- and post-NAC. Left panels show the distribution of the scores of evaluation of the immunohistochemistry pre- and post-NAC. Right panels show the median values (central marker) with interquartile ranges (bars) pre- and post-NAC. The median expression of p-mTOR and p-4E-BP1 were decreased signifcantly following chemotherapy. NAC, neoadjuvant chemotherapy; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1.

Mentions: The expression of p-mTOR and p-4E-BP1 were examined in the tumors of 83 cases of breast cancer patients. The patients who had achieved pCR were not examined post-NAC. Tumors were obtained from diagnostic biopsies pre-NAC and surgical resections post-NAC. Table I shows the clinical and pathological features of the patient cohort. The staining of p-mTOR was predominantly cytoplasmic, and present in 71/83 cases (85.5%) and 58/83 cases (69.9%) pre-NAC (Fig. 1A) and post-NAC (Fig. 1B), respectively. The p-4E-BP1 was detected in the nucleus and cytoplasm, with positive rates of p-4E-BP1 in 69/83 cases (83.1%) and 58/83 cases (69.9%) pre-NAC (Fig. 1C) and post-NAC (Fig. 1D), respectively. The scores and their distributions are shown in Fig. 2. Scores were lower for p-mTOR (51/83 cases; 61.4%) and p-4E-BP1 (56/83 cases; 67.5%) in post-NAC samples than in the matched pre-NAC samples, indicating a decrease in their expression in response to NAC. Wilcoxon signed-rank test showed significant differences between pre- and post-NAC scores (P<0.001 for p-mTOR and p-4E-BP1). It was also examined whether a correlation exists between the expression of p-mTOR and p-4E-BP1 pre- and post-NAC, as well as for the expression change following treatment (pre-NAC minus post-NAC level). The expression of p-mTOR and p-4E-BP1 were found to significantly correlate with each other in pre-NAC samples (Spearman’s ρ analyses, P=0.004), which is consistent with previous studies (2,32,33). However, the two factors were not found to correlate with each other in post-NAC samples, indicating that chemotherapy may have changed the expression of the two factors to some degree. No significant correlations were found between the changes of p-mTOR and p-4E-BP1 following NAC. As would be expected, the pre- and post-NAC levels were significantly associated with the expression change of the respective factor.


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)

Expression levels of (A) p-mTOR and (B) p-4E-BP1 in matched breast tumor tissues pre- and post-NAC. Left panels show the distribution of the scores of evaluation of the immunohistochemistry pre- and post-NAC. Right panels show the median values (central marker) with interquartile ranges (bars) pre- and post-NAC. The median expression of p-mTOR and p-4E-BP1 were decreased signifcantly following chemotherapy. NAC, neoadjuvant chemotherapy; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2-ol-08-06-2642: Expression levels of (A) p-mTOR and (B) p-4E-BP1 in matched breast tumor tissues pre- and post-NAC. Left panels show the distribution of the scores of evaluation of the immunohistochemistry pre- and post-NAC. Right panels show the median values (central marker) with interquartile ranges (bars) pre- and post-NAC. The median expression of p-mTOR and p-4E-BP1 were decreased signifcantly following chemotherapy. NAC, neoadjuvant chemotherapy; p-mTOR, phosphorylated-mammalian target of rapamycin; p-4E-BP1, phosphorylated-eukaryotic translation initiation factor 4E-binding protein 1.
Mentions: The expression of p-mTOR and p-4E-BP1 were examined in the tumors of 83 cases of breast cancer patients. The patients who had achieved pCR were not examined post-NAC. Tumors were obtained from diagnostic biopsies pre-NAC and surgical resections post-NAC. Table I shows the clinical and pathological features of the patient cohort. The staining of p-mTOR was predominantly cytoplasmic, and present in 71/83 cases (85.5%) and 58/83 cases (69.9%) pre-NAC (Fig. 1A) and post-NAC (Fig. 1B), respectively. The p-4E-BP1 was detected in the nucleus and cytoplasm, with positive rates of p-4E-BP1 in 69/83 cases (83.1%) and 58/83 cases (69.9%) pre-NAC (Fig. 1C) and post-NAC (Fig. 1D), respectively. The scores and their distributions are shown in Fig. 2. Scores were lower for p-mTOR (51/83 cases; 61.4%) and p-4E-BP1 (56/83 cases; 67.5%) in post-NAC samples than in the matched pre-NAC samples, indicating a decrease in their expression in response to NAC. Wilcoxon signed-rank test showed significant differences between pre- and post-NAC scores (P<0.001 for p-mTOR and p-4E-BP1). It was also examined whether a correlation exists between the expression of p-mTOR and p-4E-BP1 pre- and post-NAC, as well as for the expression change following treatment (pre-NAC minus post-NAC level). The expression of p-mTOR and p-4E-BP1 were found to significantly correlate with each other in pre-NAC samples (Spearman’s ρ analyses, P=0.004), which is consistent with previous studies (2,32,33). However, the two factors were not found to correlate with each other in post-NAC samples, indicating that chemotherapy may have changed the expression of the two factors to some degree. No significant correlations were found between the changes of p-mTOR and p-4E-BP1 following NAC. As would be expected, the pre- and post-NAC levels were significantly associated with the expression change of the respective factor.

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