Joshi et al. Page 18

FOLFIRINOX is an effective regimen for pancreatic cancer, but its utility is limited by toxicities. Joshi and colleagues hypothesized that nab-paclitaxel may result in less toxicity when substituted for oxaliplatin and, therefore, assessed the combination of 5-fluorouracil/leucovorin, irinotecan, and nab-paclitaxel (FOLFIRABRAX) in patients with advanced gastrointestinal cancer. Given previous data suggesting a relationship between UGT1A1 genotyp. and exposure to SN-38, the active metabolite of irinotecan, the authors utilized UGT1A1 genotype-guided dosing for this trial. FOLFIRABRAX was tolerable in patients with UGT1A1*1*1 and UGT1A1*1*28 genotypes and led to a lower rate of severe neuropathy than FOLFIRINOX. Responses were observed in multiple cancer subtypes; in particular, 34% of patients with pancreatic cancer showed a complete or partial response. Randomized studies comparing FOLFIRINOX and FOLFIRABRAX, especially regarding their safety and efficacy, are warranted.

Lee et al. Page 25

Inhibitors of the progesterone receptor (PR) have not been tested in patients with early-stage breast cancer, despite preclinical data supporting this strategy. Lee and colleagues assessed telapristone acetate (TPA) in a presurgical window trial of 61 women with breast cancer. TPA reduced tumor proliferation compared with placebo specifically in premenopausal women. Gene expression analysis revealed enrichment of genes relating to mitosis, cell cycle, and chromatin modification in responders, as well as downregulation of interferon signaling. These results justify further assessment of PR inhibitors, particularly in premenopausal women with breast cancer.

Sharma et al. Page 61

Current treatment options for patients with advanced urothelial carcinoma (UC) are limited, as chemotherap. only provides modest survival benefits. Immunotherapy has emerged as a new treatment strategy for UC, albeit with a high rate of recurrence. Sharma and colleagues conducted a phase II trial assessing tremelimumab, a CTLA-4 targeting monoclonal antibody, in UC. An objective response rate of 18.8% was observed, and tremelimumab was generally well tolerated. Further study of this agent, especially in combination with anti-PD-1/PD-L1 treatment, is warranted for patients with UC.

Mota Reyes et al. Page 220

While the overall prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor, neoadjuvant therapy (neoTx) has improved the prognosis for patients with locally advanced disease. Mota Reyes and colleagues characterized the tumor microenvironments of PDAC treated with neoTx compared to surgery alone. Overall, neoTx treatment remodeled the tumor microenvironment to a more anti-tumor millieu: Tregs and myeloid derived suppressor cells were decreased, and the proportion of CD8+ T cells, NK cells, and M1 macrophages were increased. Furthermore, neoTx reduced stromal activation and neural invasion in tumors. As PDAC has, typically, been considered to be immunologically “cold,” this work highlights the possibility of combining neoTx with immunotherapy in patients with PDAC.