Chemoprevention in Patients with Peutz-Jeghers Syndrome: Lessons Learned

Justin de Brabander, Ferry A L M Eskens, Susanne E Korsse, Evelien Dekker, Pieter Dewint, Monique E van Leerdam, Susanne van Eeden, Heinz-Josef Klümpen, Justin de Brabander, Ferry A L M Eskens, Susanne E Korsse, Evelien Dekker, Pieter Dewint, Monique E van Leerdam, Susanne van Eeden, Heinz-Josef Klümpen

Abstract

Lessons learned: Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible.

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated.

Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts.

Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized.

Conclusion: Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

Trial registration: ClinicalTrials.gov NCT01178151.

©AlphaMed Press; the data published online to support this summary is the property of the authors.

Figures

Figure 1.
Figure 1.
A Peutz‐Jeghers polyp of the small intestine with arborizing smooth muscle fibers and non‐neoplastic epithelium.

References

    1. van Lier MG, Wagner A, Mathus‐Vliegen EM et al., High cancer risk in Peutz‐Jeghers syndrome: A systematic review and surveillance recommendations. Am J Gastroenterol 2010;105:1258–1264; author reply 1265.
    1. Jenne DE, Reimann H, Nezu J et al. Peutz‐Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 1998;18:38–43.
    1. Korsse SE, Peppelenbosch MP, van Veelen W. Targeting LKB1 signaling in cancer. Biochim Biophys Acta 2013;1835:194–210.
    1. van Veelen W, Korsse SE, van de Laar L et al. The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. Oncogene 2011;30:2289–2303.
    1. Wei C, Amos CI, Zhang N et al. Suppression of Peutz‐Jeghers polyposis by targeting mammalian target of rapamycin signaling. Clin Cancer Res 2008;14:1167–1171.
    1. Shackelford DB, Vasquez DS, Corbeil J et al. mTOR and HIF‐1alpha‐mediated tumor metabolism in an LKB1 mouse model of Peutz‐Jeghers syndrome. Proc Natl Acad Sci U S A 2009;106:11137–11142.
    1. Franz DN, Leonard J, Tudor C et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006;59:490–498.
    1. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006;5:671–688.
    1. Klumpen HJ, Queiroz KC, Spek CA et al. mTOR inhibitor treatment of pancreatic cancer in a patient with Peutz‐Jeghers syndrome. J Clin Oncol 2011;29:e150–e153.
    1. Yee KW, Schittenhelm M, O'Farrell AM et al. Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD‐positive leukemic cells. Blood 2004;104:4202–4209.
    1. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: A double‐blind, randomised, placebo‐controlled phase III trial. Lancet 2008;372:449–456.
    1. Cuzick J. Preventive therapy for cancer. Lancet Oncol 2017;18:e472–e482.
    1. Squarize CH, Castilho RM, Gutkind JS. Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin. Cancer Res 2008;68:7066–7072.
    1. Kuwada SK, Burt R. A rationale for mTOR inhibitors as chemoprevention agents in Peutz‐Jeghers syndrome. Fam Cancer 2011;10:469–472.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner