Maxime Rémond

Peutz-Jeghers syndrome (PJS) is a very rare autosomal dominant disorder associated with an increased risk of gastrointestinal and gynecological cancers. However, risk estimates vary widely, due to the small size and retrospective nature of most studies, which may introduce recruitment bias. Accurate data are needed to improve cancer screening. The aim of this study was to estimate cancer risks in a large cohort of PJS patients. A total of 161 patients were included, half of whom were prospectively monitored as part of a surveillance network. This makes it one of the largest cohorts of PJS patients to date. We estimated age-dependent cancer risks using the Genotype Restricted Likelihood (GRL) method to correct for ascertainment bias. Standardized mortality ratios (SMRs) were calculated to assess mortality. PJS patients showed an increased risk of cancer, particularly early-onset cancers (cumulative risk before age 70: 18.1% in men, 36.8% in women). This resulted in excess mortality, especially among young women. The most frequent cancers were breast, lung, and cervical cancers. Small bowel was the site with the highest relative risk. Although the risk of pancreatic adenocarcinoma (PDAC) was elevated, it was much lower than had been reported previously (relative risk at age 50: 11.8). Degenerated intraductal papillary mucinous neoplasms (IPMN) may contribute to the risk of PDAC in PJS, while this carcinogenesis pathway accounts for only 10% of PDACs overall. We report an unexpectedly high risk of lung adenocarcinoma, calling into question the relevance of lung cancer screening in PJS.

Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early‐onset pancreatic cancer (EOPC, defined by an age at diagnosis 50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence‐free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I‐III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal‐like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.

Malignant PEComas are an extremely rare subtype of soft tissue sarcomas. Here, we report the case of a man presenting with a perirectal PEComa and liver metastasis. Since the tumor harbored a tumor mutational burden of 23/Mb and a programmed death-ligand 1 tumor positivity score of 50%, the patient was treated with pembrolizumab as a second line of systemic therapy, in combination with everolimus. This combined therapy led to a near-complete response of the primary tumor and a partial response of the metastasis. Radioembolization of the liver metastasis was performed due to isolated liver progression, and the pelvic tumor was treated by radiotherapy because of pelvic symptoms. The disease is still stable after 13 months of pembrolizumab plus everolimus and multimodal treatment. This case shows that malignant PEComas can display molecular features associated with sensitivity to checkpoint inhibitors. The use of checkpoint inhibitors may be a relevant therapeutic strategy in these patients. It is also the first report on selective internal radiation therapy in PEComas.