The outcome of TGFß antagonism in metastatic breast cancer models in vivo reflects a complex balance between tumor-suppressive and pro-progression activities of TGFß

PURPOSE: Transforming growth factor-ßs (TGF-ßs) are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGF-ß pathway are in early phase oncology trials. However, TGF-ßs also have tumor suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored. EXPERIMENTAL DESIGN: A panel of twelve immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGF-ß antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms. RESULTS: Heterogeneous responses to anti-TGF-ß treatment were observed, with 5/12 models (42%) showing suppression of metastasis, 4/12 (33%) showing no response and 3/12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, while stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus the integrated outcome of TGF-ß antagonism depends on a complex balance between enhancing effective anti-tumor immunity and disrupting persistent tumor suppressive effects of TGF-ß on the tumor cell. Applying transcriptomic signatures derived from treatment-naive mouse primary tumors to human breast cancer datasets suggested that breast cancer patients with high-grade, estrogen receptor-negative disease are most likely to benefit from anti-TGF-ß therapy. CONCLUSIONS: Contrary to dogma, tumor suppressive responses to TGF-ß are retained in some advanced metastatic tumors. Safe deployment of TGF-ß antagonists in the clinic will require good predictive biomarkers.

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