Purpose
We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).
Experimental Design
We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for six months or longer. Non-responders were defined as those with disease progression during the first three months of therapy. Fisher's exact test assessed the association between mutation status in mTOR pathway genes and treatment response.
Results
Mutations in MTOR, TSC1 or TSC2 were more common in responders, 12 (28%) of 43, than non-responders, 4 (11%) of 36 (p=0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than non-responders, 2(6%), (p=0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1 or TSC2 compared to 4 (11%) of 36 non-responders (p=0.03). Eight additional genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.
Conclusion
In this cohort of mRCC patients, mutations in MTOR, TSC1 or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (31 of 43, 72%) had no mTOR pathway mutation identified.
In the last decade, important advances have been made in the treatment of metastatic prostate cancer, resulting in a better understanding of the biology underlying the disease, and in the approval of several therapeutic agents such as immunotherapy, new generation antiandrogens, cytotoxic chemotherapies, and radiopharmaceuticals. All these recent advances have been incorporated in clinical guidelines and a critical analysis of the data available should be important to help the decision-making process. In addition, the incorporation of well established therapies in early disease stages have demonstrated a robust overall survival gain for patients with castration-sensitive metastatic prostate cancer. However, no predictive biomarkers of response are available and the selection of the best therapeutic option is still challenging depending on clinical and pathological factors. Many questions related to the optimal sequencing of agents, or comparison of its efficacy remain unanswered.
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