Prognostic relevance and putative histogenetic role of cytokeratin 7 and MUC5AC expression in Crohn’s disease-associated small bowel carcinoma

Most Crohn’s disease-associated small bowel carcinomas (CrD-SBCs) are diagnosed in advanced stage and have poor prognosis. To improve diagnosis and therapy, a better knowledge of tumour precancerous lesions, histotypes and prognostic factors is needed. We investigated histologically and immunohistochemically 52 CrD-SBCs and 51 small bowel carcinomas unrelated to inflammatory disease, together with their tumour-associated mucosa, looking for Crohn-selective changes. Histologic patterns and phenotypic markers potentially predictive of CrD-SBC histogenesis and prognosis were analysed. Cytokeratin 7 or MUC5AC-positive metaplastic changes were found in about half of investigated CrD-SBCs, significantly more frequently than in CrD-unrelated SBCs. They correlated with metaplastic changes of their associated mucosa, while being absent in normal ileal mucosa. Histologic patterns suggestive for progression of some cytokeratin 7 and/or MUC5AC-positive metaplastic lesions into cancer of the same phenotype were also observed. Patient survival analyses showed that tumour cytokeratin 7 or MUC5AC expression and non-cohesive histotype were adverse prognostic factors at univariable analysis, while cytokeratin 7 and non-cohesive histotype were also found to predict worse survival in stage- and age-inclusive multivariable analyses. Besides conventional dysplasia, hyperplasia-like non-conventional lesions were observed in CrD-SBC-associated mucosa, with patterns suggestive for a histogenetic link with adjacent cancer. In conclusion the cytokeratin 7 and/or MUC5AC-positive metaplastic foci and the non-conventional growths may have a role in cancer histogenesis, while tumour cytokeratin 7 and non-cohesive histotype may also predict poor patient survival. Present findings are worth being considered in future prospective histogenetic and clinical studies.

Phase I study of rucaparib and irinotecan in advanced solid tumors with homologous recombination deficiency (HRD) mutations.

3513 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for multiple tumor types with HRD mutations. In efforts to prolong durations of response, combination treatments of PARPi and chemotherapy are being explored. However, expected overlapping toxicities have previously limited the tolerability of PARPi-chemotherapy combinations. Preclinical studies suggest that the inhibition of PARP will prevent the repair of topoisomerase induced DNA strand breaks. In this Phase I trial, we test whether pulse dosing and alternate treatment schedules of rucaparib and irinotecan are safe and tolerable. Methods: Rucaparib and irinotecan were dose escalated in a 3+3 design. Patients with advanced solid tumors and somatic or germline known or suspected pathogenic mutations in HRD were accepted on trial. 15 patients have been enrolled in 3 cohorts and treated with rucaparib 400 mg BID (days 1-7) and irinotecan 65 mg/m2 (cohort 1) or 100 mg/m2 (cohort 2) every 2 weeks or 100 mg/m2 every 3 weeks (cohort 2i). Results: Tumor types on trial are heterogeneous and include pancreatic ductal adenocarcinoma (PDAC: 3), cholangiocarcinoma, neuroendocrine carcinoma of the pancreas, ovarian cancer/primary peritoneal carcinoma (3), prostate cancer, small bowel carcinoma, squamous cell carcinoma of the tonsil, testicular cancer, triple negative breast cancer, and urothelial carcinoma. 14/15 patients had 3+ prior lines of therapy. Mutation types include: 7 ATM, 3 BRCA1, 3 BRCA2, 1 CHEK2, and 1 PALB2. All patients were previously exposed to platinum chemotherapies; 8/15 had progressive disease while on platinum. 5/15 patients had prior PARPi with progression. There were 3 DLT events, all of which were related to grade 3 or 4 neutropenia. Of the 13 patients evaluable for response, there was one confirmed partial response (PR). 5 patients have remained on study for longer than 6 months and 3 patients with ATM mutations have remained on study for longer than one year (primary peritoneal cancer, small bowel carcinoma, PNET). 4/5 patients with clinical benefit had prior platinum progression and 1/5 had previously progressed on a PARPi. Our current recommended phase 2 dose is rucaparib 400 mg BID days 1-7 and irinotecan 100 mg/m2 every 3 weeks. Conclusions: The pulse dosing schedule of rucaparib and irinotecan has allowed for long term tolerability and exposure to both agents with encouraging efficacy in patients with ATM mutations. Further testing of PARPi and topoisomerase inhibitors at this schedule in patients with ATM mutations is planned. Clinical trial information: NCT03318445 .

Separation of Low- Versus High-grade Crohn’s Disease-associated Small Bowel Carcinomas is Improved by Invasive Front Prognostic Marker Analysis

Background and Aims Crohn’s disease-associated small bowel carcinoma is a rare event, usually reported to have a severe prognosis. However, in previous investigations we have found a minority of cases displaying a relatively favourable behaviour, thus outlining the need to improve the histopathological prediction of Crohn’s disease-associated small bowel carcinoma prognosis. Methods As in recent studies on colorectal cancer, a substantial improvement in prognostic evaluations has been provided by the histological analysis of the tumour invasive front; we therefore systematically analysed the tumour budding and poorly differentiated clusters in the invasive front of 47 Crohn’s disease-associated small bowel carcinomas collected through the Small Bowel Cancer Italian Consortium. Results Both tumour budding and poorly differentiated cluster analyses proved highly effective in prognostic evaluation of Crohn’s disease-associated small bowel carcinomas. In addition, they retained prognostic value when combined with two other parameters, i.e. glandular histology and stage I/II, both known to predict a relatively favourable small bowel carcinoma behaviour. In particular, association of tumour budding and poorly differentiated clusters in a combined invasive front score allowed identification of a minor subset of cancers [12/47, 25%] characterised by combined invasive front low grade coupled with a glandular histology and a low stage [I or II] and showing no cancer-related death during a median follow-up of 73.5 months. Conclusions The improved distinction of lower- from higher-grade Crohn’s disease-associated small bowel carcinomas provided by invasive front analysis should be of potential help in choosing appropriate therapy for these rare and frequently ominous neoplasms.