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- Alvarez, Mariano J., et al.
(author)
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A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 979-989
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Journal article (peer-reviewed)abstract
- We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
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| 2. |
- Clift, A. K., et al.
(author)
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Incidence of Second Primary Malignancies in Patients with Neuroendocrine Tumours
- 2015
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In: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 102:1-2, s. 26-32
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Journal article (peer-reviewed)abstract
- Background: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. Methods: This was a retrospective review of our institutional prospectively maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. Results: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n = 6), breast and renal carcinomas (both n = 5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small-bowel NET patients were comparable (15.7 vs. 19.6%, p = 0.78). A personyear methodology was used to compare observed numbers of SPM against expected values generated from age-and sex-specific incidence tables, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous subset (SIR 2.732, CI 1.177-5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241-0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044-1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238-30.474). Conclusions: Our data support the use of colonoscopy in the diagnostic work-up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted. (C) 2015 S. Karger AG, Basel
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| 4. |
- Carlsen, Esben Andreas, et al.
(author)
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Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3 : a multicenter cohort study
- 2019
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In: Endocrine-Related Cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 26:2, s. 227-239
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Journal article (peer-reviewed)abstract
- Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 >= 55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.
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