Alice Boilève

Cancer cells accommodate multiple genetic and epigenetic alterations that initially activate intrinsic (cell-autonomous) and extrinsic (immune-mediated) oncosuppressive mechanisms. Only once these barriers to oncogenesis have been overcome can malignant growth proceed unrestrained. Tetraploidization can contribute to oncogenesis because hyperploid cells are genomically unstable. We report that hyperploid cancer cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. Hyperploid, calreticulin-exposing cancer cells readily proliferated in immunodeficient mice and conserved their increased DNA content. In contrast, hyperploid cells injected into immunocompetent mice generated tumors only after a delay, and such tumors exhibited reduced DNA content, endoplasmic reticulum stress, and calreticulin exposure. Our results unveil an immunosurveillance system that imposes immunoselection against hyperploidy in carcinogen- and oncogene-induced cancers.

LBA3504 Background: We have reported that neoadjuvant chemotherapy (NACT) with FOLFIRINOX followed by chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ACT) significantly improved outcomes in patients (pts) with locally advanced rectal cancer (LARC) compared with pts who received standard CRT, surgery, and ACT. We now report the primary and secondary endpoints with mature follow-up (F/U). Methods: PRODIGE 23 is a phase III randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, T location, and T extramural spread. Arm A pts received preoperative CRT (50 Gy, 2 Gy/fr; 25 fr + capecitabine), surgery, then ACT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX, then the same preoperative CRT, surgery and 3 mos of ACT, mFOLFOX6 or capecitabine. From 6/2012 to 6/2017, pts were randomly assigned in Arm A (n=230) and B (n=231) by 35 participating centers. Analysis was performed on intent-to-treat population. For survival outcomes, HR and 95% CI were estimated by a stratified Cox proportional hazard (PH) model. However, we observed non-PH. So we used the restricted mean survival time (RMST) to evaluate the treatment effect (Liang F & al Ann Oncol 2018, Pak K & al JAMA Oncol 2017). Results: With a median F/U of 82.2 mos, death was reported for 55 pts in arm A and 42 in Arm B. All survival endpoints were better for Arm B vs Arm A. The absolute increase in 5-year survival were 7.6% for Disease-Free Survival (DFS), 6.9% for Overall Survival (OS), 9.9% for Metastasis-Free Survival (MFS), and 5.7% for Cancer Specific Survival (CSS) in Arm B compared to Arm A. Survival results at 7 years are presented in the Table. 7-year cumulative incidence of locoregional relapses are 5.3% in arm B vs 8.1% in arm A (p= 0.38). Conclusions: NACT with mFOLFIRINOX followed by CRT, surgery, and ACT significantly improved all outcomes, including OS in pts with LARC vs those who received standard CRT, surgery, and ACT. Clinical trial information: NCT01804790 . [Table: see text]

<h3>Background</h3> <i>Microphthalmia Transcription Factor</i> (<i>MITF</i>)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring <i>TFE3</i>/<i>TFEB</i> translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. <h3>Patients and methods</h3> This multicenter retrospective study identified patients with <i>MITF</i> family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. <h3>Results</h3> Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1–22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1–40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (<i>PBRM1</i> and <i>BRD8</i>) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of <i>BRD8</i> mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10^{− 6}). <h3>Conclusions</h3> <i>MITF</i> family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.