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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

Median values with interquartile ranges of mammalian target of rapamycin changes in groups A and B. Patients whose tumor sizes diminished by <1 cm, showed no change or increased were defined as group A, while patients whose tumor sizes diminished by >1 cm or achieved pathological complete response were defined as group B. The Mann-Whitney U test was used to determine significant differences between groups A and B (P=0.033). The decreased p-mTOR expression was more significant in patients whose tumor size had decreased by >1 cm or who had achieved a complete pathological response.p-mTOR, phosphorylated-mammalian target of rapamycin.
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f3-ol-08-06-2642: Median values with interquartile ranges of mammalian target of rapamycin changes in groups A and B. Patients whose tumor sizes diminished by <1 cm, showed no change or increased were defined as group A, while patients whose tumor sizes diminished by >1 cm or achieved pathological complete response were defined as group B. The Mann-Whitney U test was used to determine significant differences between groups A and B (P=0.033). The decreased p-mTOR expression was more significant in patients whose tumor size had decreased by >1 cm or who had achieved a complete pathological response.p-mTOR, phosphorylated-mammalian target of rapamycin.

Mentions: Pre-NAC expression, post-NAC expression and the expression change following NAC of p-mTOR and p-4E-BP1 was evaluated to identify correlations with patient or tumor characteristics, including patient age at diagnosis, tumor grade and stage, estrogen receptor status, and HER2 status of tumors from core biopsy at diagnosis, as well as the tumor stage and presence of axillary metastases from resection pathology. Spearman’s ρ analyses were performed, and not only did the expression of p-mTOR and p-4E-BP1 in pre-NAC samples correlate with HER2 [ρ coefficient, 0.181 (P=0.05) for p-mTOR; ρ coefficient, 0.193 (P=0.04) for p-4E-BP1], which is consistent with the previous study, but the change of mTOR expression was also found to significantly correlate with HER2 (ρ coefficient, 0.275; P=0.006). Next, the changes of p-mTOR in HER2-positive and -negative groups were compared, and the expression of mTOR was found to decrease significantly following treatment with NAC in the HER2-positive group. The changes of p-mTOR expression had median values of 4 in the HER2-positive group and 1 in HER2-negative group. The Mann-Whitney U test was used to assess the differences between the two groups, and a P-value of 0.041 was obtained, suggesting some degree of cross-talk between the PI3K/Akt/mTOR-related pathways and HER2. The expression of p-mTOR and p-4E-BP1 pre- and post-NAC was also evaluated, as well as the expression change of the two factors to identify correlations with tumor size. Therefore, patients were classified into different groups according to tumor size; patients with tumors that had diminished by <1 cm, showed no change, or had increased were defined as group A, while patients whose tumor sizes had diminished by >1 cm, or patients who had achieved PCR were defined as group B. The only significant correlation was found between the expression change of mTOR and diminishing tumor size. The median values of expression change of mTOR were 2 in group A and 6 in group B (Fig. 3). The Mann-Whitney U test showed a significant difference between groups A and B (P=0.033). No significant correlations were found between the two factors and other clinicopathological features.


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)

Median values with interquartile ranges of mammalian target of rapamycin changes in groups A and B. Patients whose tumor sizes diminished by <1 cm, showed no change or increased were defined as group A, while patients whose tumor sizes diminished by >1 cm or achieved pathological complete response were defined as group B. The Mann-Whitney U test was used to determine significant differences between groups A and B (P=0.033). The decreased p-mTOR expression was more significant in patients whose tumor size had decreased by >1 cm or who had achieved a complete pathological response.p-mTOR, phosphorylated-mammalian target of rapamycin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3-ol-08-06-2642: Median values with interquartile ranges of mammalian target of rapamycin changes in groups A and B. Patients whose tumor sizes diminished by <1 cm, showed no change or increased were defined as group A, while patients whose tumor sizes diminished by >1 cm or achieved pathological complete response were defined as group B. The Mann-Whitney U test was used to determine significant differences between groups A and B (P=0.033). The decreased p-mTOR expression was more significant in patients whose tumor size had decreased by >1 cm or who had achieved a complete pathological response.p-mTOR, phosphorylated-mammalian target of rapamycin.
Mentions: Pre-NAC expression, post-NAC expression and the expression change following NAC of p-mTOR and p-4E-BP1 was evaluated to identify correlations with patient or tumor characteristics, including patient age at diagnosis, tumor grade and stage, estrogen receptor status, and HER2 status of tumors from core biopsy at diagnosis, as well as the tumor stage and presence of axillary metastases from resection pathology. Spearman’s ρ analyses were performed, and not only did the expression of p-mTOR and p-4E-BP1 in pre-NAC samples correlate with HER2 [ρ coefficient, 0.181 (P=0.05) for p-mTOR; ρ coefficient, 0.193 (P=0.04) for p-4E-BP1], which is consistent with the previous study, but the change of mTOR expression was also found to significantly correlate with HER2 (ρ coefficient, 0.275; P=0.006). Next, the changes of p-mTOR in HER2-positive and -negative groups were compared, and the expression of mTOR was found to decrease significantly following treatment with NAC in the HER2-positive group. The changes of p-mTOR expression had median values of 4 in the HER2-positive group and 1 in HER2-negative group. The Mann-Whitney U test was used to assess the differences between the two groups, and a P-value of 0.041 was obtained, suggesting some degree of cross-talk between the PI3K/Akt/mTOR-related pathways and HER2. The expression of p-mTOR and p-4E-BP1 pre- and post-NAC was also evaluated, as well as the expression change of the two factors to identify correlations with tumor size. Therefore, patients were classified into different groups according to tumor size; patients with tumors that had diminished by <1 cm, showed no change, or had increased were defined as group A, while patients whose tumor sizes had diminished by >1 cm, or patients who had achieved PCR were defined as group B. The only significant correlation was found between the expression change of mTOR and diminishing tumor size. The median values of expression change of mTOR were 2 in group A and 6 in group B (Fig. 3). The Mann-Whitney U test showed a significant difference between groups A and B (P=0.033). No significant correlations were found between the two factors and other clinicopathological features.

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