Background
SMAD4, a tumor suppressor gene, is inactivated or deleted in 60–90% of pancreatic adenocarcinomas (PDA). Loss of SMAD4 allows tumor progression by limiting cell cycle arrest and apoptosis and increasing metastases. SMAD4 deficient PDA cells are resistant to radiotherapy by upregulating autophagy, a cell survival mechanism that counteracts apoptotic mechanisms and allows intracellular recycling of macromolecules and organelles. Hydroxychloroquine (HCQ) is an orally available autophagy inhibitor with an established toxicity profile. We studied whether HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation.
Methods
We retrospectively analyzed the SMAD4 status of PDA patients enrolled in two prospective clinical trials evaluating administration of preoperative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine/nab-paclitaxel +/- HCQ evaluated Evans Grade histopathologic response (NCT01978184). Immunohistochemistry of resected specimens for SMAD4 was previously performed. Patients not treated at the max HCQ dose (n = 5), not resected (n = 2) or with SMAD4 staining unavailable were excluded (n = 10). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher’s exact test and log-rank test were used to assess response and survival.
Results
52 patients receiving HCQ with neoadjuvant chemotherapy were studied. 25 of these patients had SMAD4 loss (48%). 76% of HCQ treated patients with SMAD4 loss obtained a histopathologic response ≥ 2A, compared to only 37% with SMAD4 intact (p = 0.006). In contrast with prevailing views, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact, p = 0.18).
Conclusions
The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship between SMAD4, autophagy and treatment outcomes in PDA is warranted.