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FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features.

Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, Goodfellow PJ, Pollock PM - PLoS ONE (2012)

Bottom Line: KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors.In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045).In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

ABSTRACT
Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466); KRAS (87/464); CTNNB1 (88/454) and PIK3CA (104/464). KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045). In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.

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Potential utility of FGFR2 mutation status as an adverse prognostic factor to affect clinical decision-making.The decision tree is adapted from 2011 National Comprehensive Cancer Network guidelines using FIGO 2009 staging. BT = brachytherapy; RT = radiation therapy.
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pone-0030801-g003: Potential utility of FGFR2 mutation status as an adverse prognostic factor to affect clinical decision-making.The decision tree is adapted from 2011 National Comprehensive Cancer Network guidelines using FIGO 2009 staging. BT = brachytherapy; RT = radiation therapy.

Mentions: Our finding that FGFR2 mutation is an independent prognostic marker in patients with early stage endometrioid endometrial cancer suggests that FGFR2 mutation testing could ultimately prove useful in the management of endometrial cancer. Current National Comprehensive Cancer Network (NCCN) guidelines for endometrioid endometrial cancer confined to the uterus recommends more aggressive adjuvant therapy as tumor grade and tumor stage increases, and also where multiple adverse prognostic indicators are present, including lymphovascular space involvement. We envisage that the mutation status of FGFR2 could be used to inform clinical decision making in a similar way to a poorly differentiated histology. Specifically, the presence of an FGFR2 mutation and absence of a KRAS mutation would stratify a patient as having high-risk disease, resulting in a recommendation for more aggressive therapy (See Figure 3).


FGFR2 point mutations in 466 endometrioid endometrial tumors: relationship with MSI, KRAS, PIK3CA, CTNNB1 mutations and clinicopathological features.

Byron SA, Gartside M, Powell MA, Wellens CL, Gao F, Mutch DG, Goodfellow PJ, Pollock PM - PLoS ONE (2012)

Potential utility of FGFR2 mutation status as an adverse prognostic factor to affect clinical decision-making.The decision tree is adapted from 2011 National Comprehensive Cancer Network guidelines using FIGO 2009 staging. BT = brachytherapy; RT = radiation therapy.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285611&req=5

pone-0030801-g003: Potential utility of FGFR2 mutation status as an adverse prognostic factor to affect clinical decision-making.The decision tree is adapted from 2011 National Comprehensive Cancer Network guidelines using FIGO 2009 staging. BT = brachytherapy; RT = radiation therapy.
Mentions: Our finding that FGFR2 mutation is an independent prognostic marker in patients with early stage endometrioid endometrial cancer suggests that FGFR2 mutation testing could ultimately prove useful in the management of endometrial cancer. Current National Comprehensive Cancer Network (NCCN) guidelines for endometrioid endometrial cancer confined to the uterus recommends more aggressive adjuvant therapy as tumor grade and tumor stage increases, and also where multiple adverse prognostic indicators are present, including lymphovascular space involvement. We envisage that the mutation status of FGFR2 could be used to inform clinical decision making in a similar way to a poorly differentiated histology. Specifically, the presence of an FGFR2 mutation and absence of a KRAS mutation would stratify a patient as having high-risk disease, resulting in a recommendation for more aggressive therapy (See Figure 3).

Bottom Line: KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors.In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045).In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology.

View Article: PubMed Central - PubMed

Affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

ABSTRACT
Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466); KRAS (87/464); CTNNB1 (88/454) and PIK3CA (104/464). KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045). In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.

Show MeSH
Related in: MedlinePlus