Akt/mTOR Pathways Activated in Synovial Sarcoma, Linked to Poorer Outcome

The Akt/mammalian target of rapamycin (mTOR) pathway is often activated in patients with synovial sarcoma, and activation of the pathway is associated with worse outcomes, according to a new study conducted in Japan.

Akt/mTOR, downstream of PI3K, “is regarded as oncogenic and has the potential to be a therapeutic target,” wrote authors led by Nokitaka Setsu, MD, PhD, of Kyushu University in Fukuoka, Japan. “The prognostic impact of the activation of this pathway, however, remains to be clarified.”

In the new study, the investigators analyzed clinicopathologic data and phosphorylation status of samples from 112 patients with synovial sarcoma. Twenty-four samples were frozen and 120 were formalin-fixed, paraffin-embedded samples. The results of the study were published in the October 1 issue of Cancer.

The investigators looked for activation of a number of pathways and proteins in the samples. Akt was activated in 76.5% of the samples, and mTOR was activated in 67.6% of samples. The eukaryotic translation initiation factor 4E binding protein (4E-BP1) was activated in 59.6% of samples, and the S6 ribosomal protein was activated in 42.6% of the samples. Positive phosphorylated mTOR and 4E-BP1 were correlated with higher mitotic activity, and phosphorylated 4E-BP1 was linked to higher rates of necrosis.

Survival data were available for 108 patients; the 5-year overall survival (OS) rate in that cohort was 62%. Phosphorylated mTOR was correlated with poorer OS (P = .0016), as was phosphorylated 4E-BP1 (P = .007). On multivariate analysis, however, only positive pAkt test results were correlated with any change in survival, and in that case only event-free survival was shorter. Positive p-mTor showed a trend toward poorer OS, though it did not reach significance (P = .0593).

Twenty-seven of the patients received adjuvant chemotherapy, usually doxorubicin and ifosfamide. “Patients who had pAkt-positive tumors tended to show better responses (P = .0486), but not other molecules were correlated with responses to chemotherapy,” the researchers wrote. Also on multivariate analysis, the study showed that frequent mitosis (P = .0108) was a poor prognostic risk factor for OS, while male sex, visceral location, large tumor size, and frequent mitosis were all poor indicators for event-free survival.

Targeting these pathways could yield clinical benefit for patients with synovial sarcomas. In earlier clinical trials, the mTOR inhibitor ridaforolimus produced significantly prolonged progression-free survival in patients with soft-tissue sarcomas, though no difference in OS was found. Pazopanib also may act by suppressing the Akt pathway, according to results from a trial of soft-tissue sarcoma patients.

“These findings support the validity of molecular therapy targeting this pathway in patients with synovial sarcoma,” the authors concluded.