Limits...
Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer.

Sonnenblick A, Brohée S, Fumagalli D, Vincent D, Venet D, Ignatiadis M, Salgado R, Van den Eynden G, Rothé F, Desmedt C, Neven P, Loibl S, Denkert C, Joensuu H, Loi S, Sirtaine N, Kellokumpu-Lehtinen PL, Piccart M, Sotiriou C - BMC Med (2015)

Bottom Line: Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways.We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02).These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02).

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.

ABSTRACT

Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance.

Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting.

Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation.

Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.

No MeSH data available.


Related in: MedlinePlus

The pSTAT3-GS has predictive significance in the independent randomized FinHer dataset. a–i Kaplan–Meier curves and forest plots of signature status assessed in the FinHer dataset. Patients with pSTAT3-GS low (a, d, g) and pSTAT3-GS high (b, e, h) status according to trastuzumab treatment in all patients (up), ER-negative only (middle), or ER-positive only (down). Forest plots according to pSTAT3-GS status in all patients (c), ER- negative only (f), or ER-positive only (i). The plots indicate Cox regression hazard ratios and 95 % confidence intervals for trastuzumab benefit for DDFS
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4522972&req=5

Fig2: The pSTAT3-GS has predictive significance in the independent randomized FinHer dataset. a–i Kaplan–Meier curves and forest plots of signature status assessed in the FinHer dataset. Patients with pSTAT3-GS low (a, d, g) and pSTAT3-GS high (b, e, h) status according to trastuzumab treatment in all patients (up), ER-negative only (middle), or ER-positive only (down). Forest plots according to pSTAT3-GS status in all patients (c), ER- negative only (f), or ER-positive only (i). The plots indicate Cox regression hazard ratios and 95 % confidence intervals for trastuzumab benefit for DDFS

Mentions: These observations were further validated in an independent dataset of patients treated in the prospective FinHer trial, in which patients were randomized to trastuzumab in the adjuvant setting (Additional file 3: Table S1B, CONSORT diagram S1). In this validation series, high pSTAT3-GS was associated with a lack of benefit from trastuzumab in the ER-negative subgroup when compared to low pSTAT3-GS (DDFS, P = 0.01; Fig. 2). Cox univariate and multivariable analysis of the pSTAT3-GS in the FinHer study confirmed – with a significant interaction test of P = 0.02 (Table 1) – that the pSTAT3-GS could provide independent predictive information for patients with ER-negative breast cancer who had been treated with trastuzumab. Overall, our data suggest that pSTAT3 pathway activation is predictive for trastuzumab resistance in HER2-positive/ER-negative breast cancer.Fig. 2


Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer.

Sonnenblick A, Brohée S, Fumagalli D, Vincent D, Venet D, Ignatiadis M, Salgado R, Van den Eynden G, Rothé F, Desmedt C, Neven P, Loibl S, Denkert C, Joensuu H, Loi S, Sirtaine N, Kellokumpu-Lehtinen PL, Piccart M, Sotiriou C - BMC Med (2015)

The pSTAT3-GS has predictive significance in the independent randomized FinHer dataset. a–i Kaplan–Meier curves and forest plots of signature status assessed in the FinHer dataset. Patients with pSTAT3-GS low (a, d, g) and pSTAT3-GS high (b, e, h) status according to trastuzumab treatment in all patients (up), ER-negative only (middle), or ER-positive only (down). Forest plots according to pSTAT3-GS status in all patients (c), ER- negative only (f), or ER-positive only (i). The plots indicate Cox regression hazard ratios and 95 % confidence intervals for trastuzumab benefit for DDFS
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522972&req=5

Fig2: The pSTAT3-GS has predictive significance in the independent randomized FinHer dataset. a–i Kaplan–Meier curves and forest plots of signature status assessed in the FinHer dataset. Patients with pSTAT3-GS low (a, d, g) and pSTAT3-GS high (b, e, h) status according to trastuzumab treatment in all patients (up), ER-negative only (middle), or ER-positive only (down). Forest plots according to pSTAT3-GS status in all patients (c), ER- negative only (f), or ER-positive only (i). The plots indicate Cox regression hazard ratios and 95 % confidence intervals for trastuzumab benefit for DDFS
Mentions: These observations were further validated in an independent dataset of patients treated in the prospective FinHer trial, in which patients were randomized to trastuzumab in the adjuvant setting (Additional file 3: Table S1B, CONSORT diagram S1). In this validation series, high pSTAT3-GS was associated with a lack of benefit from trastuzumab in the ER-negative subgroup when compared to low pSTAT3-GS (DDFS, P = 0.01; Fig. 2). Cox univariate and multivariable analysis of the pSTAT3-GS in the FinHer study confirmed – with a significant interaction test of P = 0.02 (Table 1) – that the pSTAT3-GS could provide independent predictive information for patients with ER-negative breast cancer who had been treated with trastuzumab. Overall, our data suggest that pSTAT3 pathway activation is predictive for trastuzumab resistance in HER2-positive/ER-negative breast cancer.Fig. 2

Bottom Line: Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways.We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02).These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02).

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.

ABSTRACT

Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance.

Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting.

Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation.

Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.

No MeSH data available.


Related in: MedlinePlus