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Successful control of heavily pretreated metastatic gastric cancer with the mTOR inhibitor everolimus (RAD001) in a patient with PIK3CA mutation and pS6 overexpression.

Park JH, Ryu MH, Park YS, Park SR, Na YS, Rhoo BY, Kang YK - BMC Cancer (2015)

Bottom Line: Everolimus was re-tried as salvage chemotherapy (re-treatment), and the patient achieved stable disease for 1 year until his death.After two cycles of everolimus re-treatment, the overexpression of pS6 became nearly absent in follow-up IHC staining.Everolimus monotherapy was satisfactory in a patient with refractory metastatic GC harboring PIK3CA and pS6 aberrations.

View Article: PubMed Central - PubMed

Affiliation: Departments of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea. irvineusa@hanmail.net.

ABSTRACT

Background: Everolimus (RAD001) is an orally administered mTOR inhibitor that is well known for its antitumor efficacy and that has been approved for the treatment of several solid tumors, including renal cell carcinoma. In gastric cancer (GC), despite previous preclinical and phase I/II studies suggesting the promising efficacy of everolimus in previously treated AGC, more recent trials revealed that only certain subsets of patients might benefit from treatment with everolimus.

Case presentation: A 26-year-old man with metastatic gastric cancer with multiple liver lesions was treated with everolimus after failure of 1st-line and 2nd-line chemotherapy. A durable partial response was achieved for over 2 years. After progression from initial everolimus treatment, sequential cytotoxic chemotherapies were tried but failed rapidly. Everolimus was re-tried as salvage chemotherapy (re-treatment), and the patient achieved stable disease for 1 year until his death. Subsequent mutational analysis and immunohistochemical (IHC) staining with the tumor tissues just before re-treatment with everolimus revealed a PIK3CA hotspot mutation and pS6 overexpression in the primary tumor. After two cycles of everolimus re-treatment, the overexpression of pS6 became nearly absent in follow-up IHC staining.

Conclusions: Everolimus monotherapy was satisfactory in a patient with refractory metastatic GC harboring PIK3CA and pS6 aberrations. These molecular alterations might be potential biomarkers that can predict the treatment response of everolimus, particularly in the terms of durable disease control. This case suggests and emphasizes that close evaluation of biomarkers in tumor tissue may be essential for identifying highly favorable groups among various subpopulations with AGC.

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Immunohistochemical (IHC) staining for pS6 (serine 235/236 and serine 240/244) and PTEN was performed just before and during the everolimus re-treatment. All photographs were taken at 200 X magnification. Before everolimus re-treatment, the tumor cells exhibited strong positivity for pS6 in more than 50% of the tumor, whereas PTEN was weakly positive in tumor cells compared with the internal controls of endothelial cells (A). After 2 months of everolimus re-treatment, the tumor cells in the follow-up biopsy were completely negative for pS6. However, the intensity of PTEN was notably increased in all tumor cells (B).
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Fig3: Immunohistochemical (IHC) staining for pS6 (serine 235/236 and serine 240/244) and PTEN was performed just before and during the everolimus re-treatment. All photographs were taken at 200 X magnification. Before everolimus re-treatment, the tumor cells exhibited strong positivity for pS6 in more than 50% of the tumor, whereas PTEN was weakly positive in tumor cells compared with the internal controls of endothelial cells (A). After 2 months of everolimus re-treatment, the tumor cells in the follow-up biopsy were completely negative for pS6. However, the intensity of PTEN was notably increased in all tumor cells (B).

Mentions: Before re-treatment with everolimus, according to results from our previous retrospective data [8], we investigated the mutation of the PIK3CA gene in the tumor tissue obtained just before re-treatment of everolimus. DNA was amplified using oligonucleotide primers specific for mutational hotspots in exons 9 and 20 of human PIK3CA. The mutational analysis revealed one of the classical activating PIK3CA hotspot mutations: E545K in exon 9 (Figure 2). In addition, we performed immunohistochemical (IHC) staining for pS6 at serine 235/236 (pS6Ser235/236, 1:150 dilution, rabbit monoclonal, Cell Signaling Techmology) and at serine 240/244 (pS6Ser240/244, 1:200 dilution, rabbit polyclonal, Cell Signaling Technology) and PTEN (1:50 dilution, rabbit monoclonal, Cell Signaling Technology) with tumor tissues obtained just before and 2 months after re-treatment with everolimus. The tumor cells were strongly positive for pS6 in more than 50% of the tumor, and PTEN was weakly positive in tumor cells relative to the internal controls of endothelial cells (Figure 3A). From January 2012 to February 2013, during the re-treatment with 10 mg everolimus daily, we evaluated the tumor every 2 months by APCT and observed stationary state of liver metastasis. After two months of everolimus re-treatment, the patient underwent follow-up endoscopic biopsy and IHC staining for pS6 and PTEN. Strikingly, the tumor cells in the follow-up biopsy were completely negative for pS6, whereas the intensity of PTEN was notably increased in all tumor cells (Figure 3B). As a result of re-treatment with everolimus, this patient was able to maintain stable disease for more than 1 year but unfortunately died in March 2013 (Figure 4).Figure 2


Successful control of heavily pretreated metastatic gastric cancer with the mTOR inhibitor everolimus (RAD001) in a patient with PIK3CA mutation and pS6 overexpression.

Park JH, Ryu MH, Park YS, Park SR, Na YS, Rhoo BY, Kang YK - BMC Cancer (2015)

Immunohistochemical (IHC) staining for pS6 (serine 235/236 and serine 240/244) and PTEN was performed just before and during the everolimus re-treatment. All photographs were taken at 200 X magnification. Before everolimus re-treatment, the tumor cells exhibited strong positivity for pS6 in more than 50% of the tumor, whereas PTEN was weakly positive in tumor cells compared with the internal controls of endothelial cells (A). After 2 months of everolimus re-treatment, the tumor cells in the follow-up biopsy were completely negative for pS6. However, the intensity of PTEN was notably increased in all tumor cells (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4374284&req=5

Fig3: Immunohistochemical (IHC) staining for pS6 (serine 235/236 and serine 240/244) and PTEN was performed just before and during the everolimus re-treatment. All photographs were taken at 200 X magnification. Before everolimus re-treatment, the tumor cells exhibited strong positivity for pS6 in more than 50% of the tumor, whereas PTEN was weakly positive in tumor cells compared with the internal controls of endothelial cells (A). After 2 months of everolimus re-treatment, the tumor cells in the follow-up biopsy were completely negative for pS6. However, the intensity of PTEN was notably increased in all tumor cells (B).
Mentions: Before re-treatment with everolimus, according to results from our previous retrospective data [8], we investigated the mutation of the PIK3CA gene in the tumor tissue obtained just before re-treatment of everolimus. DNA was amplified using oligonucleotide primers specific for mutational hotspots in exons 9 and 20 of human PIK3CA. The mutational analysis revealed one of the classical activating PIK3CA hotspot mutations: E545K in exon 9 (Figure 2). In addition, we performed immunohistochemical (IHC) staining for pS6 at serine 235/236 (pS6Ser235/236, 1:150 dilution, rabbit monoclonal, Cell Signaling Techmology) and at serine 240/244 (pS6Ser240/244, 1:200 dilution, rabbit polyclonal, Cell Signaling Technology) and PTEN (1:50 dilution, rabbit monoclonal, Cell Signaling Technology) with tumor tissues obtained just before and 2 months after re-treatment with everolimus. The tumor cells were strongly positive for pS6 in more than 50% of the tumor, and PTEN was weakly positive in tumor cells relative to the internal controls of endothelial cells (Figure 3A). From January 2012 to February 2013, during the re-treatment with 10 mg everolimus daily, we evaluated the tumor every 2 months by APCT and observed stationary state of liver metastasis. After two months of everolimus re-treatment, the patient underwent follow-up endoscopic biopsy and IHC staining for pS6 and PTEN. Strikingly, the tumor cells in the follow-up biopsy were completely negative for pS6, whereas the intensity of PTEN was notably increased in all tumor cells (Figure 3B). As a result of re-treatment with everolimus, this patient was able to maintain stable disease for more than 1 year but unfortunately died in March 2013 (Figure 4).Figure 2

Bottom Line: Everolimus was re-tried as salvage chemotherapy (re-treatment), and the patient achieved stable disease for 1 year until his death.After two cycles of everolimus re-treatment, the overexpression of pS6 became nearly absent in follow-up IHC staining.Everolimus monotherapy was satisfactory in a patient with refractory metastatic GC harboring PIK3CA and pS6 aberrations.

View Article: PubMed Central - PubMed

Affiliation: Departments of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea. irvineusa@hanmail.net.

ABSTRACT

Background: Everolimus (RAD001) is an orally administered mTOR inhibitor that is well known for its antitumor efficacy and that has been approved for the treatment of several solid tumors, including renal cell carcinoma. In gastric cancer (GC), despite previous preclinical and phase I/II studies suggesting the promising efficacy of everolimus in previously treated AGC, more recent trials revealed that only certain subsets of patients might benefit from treatment with everolimus.

Case presentation: A 26-year-old man with metastatic gastric cancer with multiple liver lesions was treated with everolimus after failure of 1st-line and 2nd-line chemotherapy. A durable partial response was achieved for over 2 years. After progression from initial everolimus treatment, sequential cytotoxic chemotherapies were tried but failed rapidly. Everolimus was re-tried as salvage chemotherapy (re-treatment), and the patient achieved stable disease for 1 year until his death. Subsequent mutational analysis and immunohistochemical (IHC) staining with the tumor tissues just before re-treatment with everolimus revealed a PIK3CA hotspot mutation and pS6 overexpression in the primary tumor. After two cycles of everolimus re-treatment, the overexpression of pS6 became nearly absent in follow-up IHC staining.

Conclusions: Everolimus monotherapy was satisfactory in a patient with refractory metastatic GC harboring PIK3CA and pS6 aberrations. These molecular alterations might be potential biomarkers that can predict the treatment response of everolimus, particularly in the terms of durable disease control. This case suggests and emphasizes that close evaluation of biomarkers in tumor tissue may be essential for identifying highly favorable groups among various subpopulations with AGC.

Show MeSH
Related in: MedlinePlus