The predictive role of phosphatase and tensin homolog (PTEN) loss, phosphoinositol-3 (PI3) kinase (PIK3CA) mutation, and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis

Wang, Yaohui; Liu, Yu; Du, Yueyao; Yin, Wen; Lu, Jinsong

doi:10.1185/03007995.2013.794775

Cited by 48 publications

(36 citation statements)

References 27 publications

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“…PTEN acts as a negative regulator of the PI3K/Akt pathway via the dephosphorylation of PI(3,4,5)P3, and is ultimately involved in regulation of the cell proliferation, apoptosis, cell cycle, migration, cell adhesion, invasion as well as metastasis during cancer progression (34). Downregulation of PTEN leads to activation of the PI3K/AKT signaling pathway, promoting anti-apoptosis and cell proliferation in several cancer cells (34)(35)(36)(37). PTEN was shown to be a direct target gene for miR-494 in malignant-transformed 16HBE and colorectal cancer cells (22,23).…”

Section: Discussionmentioning

confidence: 99%

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

et al. 2015

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Abstract. acts as an oncomiR and is involved in tumor development, progression and metastasis, and confers resistance to chemotherapeutic drugs by targeting a number of molecules in several human cancers. However, the function and underlying molecular mechanism of miR-494 in hepatocellular carcinoma (HCC) has not been totally elucidated. In the present study, we determined the role played by miR-494 in HCC tissues and HCC cell lines using quantitative RT-PCR (RT-qPCR). The results showed that, miR-494 was significantly upregulated in HCC tissues and HCC cell lines. Additionally, a high miR-494 expression positively correlated with tumor differentiation (P<0.01), TNM stage (P<0.01) and lymph node metastasis (P<0.01). Luciferase reporter assays confirmed that miR-494 binds to the 3'-untranslated region (3'-UTR) of the phosphatase and tensin homolog (PTEN) mRNA and represses its translation. Functional analyses indicated that the upregulation of miR-494 promoted cell viability, migration and invasion, decreased cell apoptosis and cell cycle arrest at G1 stage, and conferred sorafenib resistance to HCC cell lines. Underexpression of PTEN by siRNA significantly attenuated the inhibitory effects of anti-miR-494 on the proliferation, migration and invasion of liver cancer cells. Mechanistic investigations revealed that miR-494 suppressed the expression of PTEN but increased the expression of PI3K and p-Akt, which contribute to the promotion of proliferation, migration and invasion, and increased sorafenib resistance to HCC cell lines. These findings suggested that miR-494 is a potential candidate for HCC therapeutics.

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Section: Discussionmentioning

confidence: 99%

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

et al. 2015

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“…6 Activating mutations in the PIK3CA gene and loss of PTEN expression have been proposed as the most important markers of PI3K pathway activation that lead to intrinsic resistance to trastuzumab. 7 However, whereas several clinical studies in the metastatic or neoadjuvant setting demonstrated such an association, 8,9 other studies failed to replicate the association. 10 A recent meta-analysis of published studies failed to confirm the interaction between PIK3CA mutation or PTEN loss and resistance to trastuzumab.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 90%

“…10 A recent meta-analysis of published studies failed to confirm the interaction between PIK3CA mutation or PTEN loss and resistance to trastuzumab. 9 Furthermore, retrospective analyses of the Finland Herceptin (FINHER) 10 and North Central Cancer Treatment Group (NCCTG) N9831 trials, 11 two randomized clinical trials of adjuvant trastuzumab, found no association of PIK3CA mutation (FINHER) or PTEN loss (N9831) with trastuzumab resistance. To test their worth as predictive markers for adjuvant trastuzumab, we have assayed PAM50 intrinsic subtypes and PIK3CA mutations using archived tumor blocks from the NSABP B-31 trial, which tested the worth of adding 1 year of trastuzumab to adjuvant chemotherapy in the treatment of HER2-positive stage III breast cancer.…”

Section: Journal Of Clinical Oncology O R I G I N a L R E P O R T V Omentioning

confidence: 99%

Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial

Pogue–Geile

Song

Jeong

et al. 2015

JCO

103

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Purpose Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) –positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31. Patients and Methods Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point. Results Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64). Conclusion Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting.

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“…PTEN was identified as the only gene of the 8000 tested in which suppression led to trastuzumab resistance [34], and patients with HER2þ tumors and loss of PTEN function are more often resistant to trastuzumab therapy and have shorter survival times [71]. The association of PTEN loss and trastuzumab and lapatinib resistance has also been reported [35,72].…”

Section: Role Of Pi3k/akt/mtor Pathway In Her2þ Breast Cancermentioning

confidence: 98%

Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway

Wilks¹

2015

The Breast

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Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancers and is a marker of aggressive disease. While HER2-targeted therapies have improved outcomes in these tumors, resistance to these agents develops in a large proportion of patients. Determining molecular mechanisms underlying resistance might help improve outcomes for patients with HER2-positive disease by allowing development of strategies to overcome resistance. Activation of signaling pathways involving the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway might contribute to the development of resistance to HER2-targeted therapies. Several inhibitors of this pathway are under investigation in this disease setting and phase 3 data for everolimus in combination with trastuzumab and chemotherapy in trastuzumab-refractory, advanced disease are promising. In this review, molecular mechanisms underlying resistance to HER2-targeted therapies are considered and evidence for strategies to manage resistance is evaluated, including the use of inhibitors of the PI3K/Akt/mTOR pathway.

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The predictive role of phosphatase and tensin homolog (PTEN) loss, phosphoinositol-3 (PI3) kinase (PIK3CA) mutation, and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis

Cited by 48 publications

References 27 publications

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN

Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial

Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway

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