Dr. Harding on the Prevalence of TSC1/2 Mutations in GI Cancer

James J. Harding, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the prevalence of TSC1 and TSC2 mutations in gastrointestinal (GI) cancer, and the need to develop a standard-of-care treatment for patients with these genetic alterations.

TSC1 and TSC2 mutations are tumor suppressor genes, and these mutations can appear in patients with various solid tumors, Harding begins. Within GI cancer, approximately 5% to 6% of patients harbor TSC1 or TSC2 mutations, Harding explains. Prevalent tumor types that can possess these mutations include hepatobiliary cancer, small bowel ampullary cancer, and other tumors of the gut, Harding adds.

Beyond the TSC1 and TSC2 mutations themselves, many of GI solid rely on mTOR signaling, Harding continues, adding that it is more challenging to identify patients with aberrant mTOR signaling. Although TSC1 and TSC2mutations are relatively rare, they do occur in the GI cancer patient population, Harding explains.

Moreover, from a histologic standpoint, there currently is not a standard treatment approach for patients with GI cancer harboring TSC1 or TSC2 mutations, Harding says. However, there has been a hypothesis that TSC1 and TSC2 loss would drive the mTOR pathway, and precision medicine techniques could allow for the targeting of that pathway. Unfortunately, first-generation mTOR inhibitors failed to demonstrate efficacy in this subset of patients, Harding notes.

Investigators have observed some activity with mTOR inhibitor in malignant perivascular epithelioid cell tumor, which is heavily dependent on mTOR signaling, Harding says. However, more investigation is needed to see if next-generation mTOR inhibitors could be a viable option for patients with TSC1 and TSC2 mutations, Harding continues.

One trial exploring this possibility is the phase 2 PRECISION 1 basket trial (NCT05103358), which is evaluating nab-sirolimus (ABI-009) for adult and adolescent patients with malignant solid tumors harboring TSC1 or TSC2 mutations.