Genetics-guided therapy in neuroendocrine carcinoma: response to BRAF- and MEK-inhibitors
Keywords:
neuroendocrine carcinoma, neuroendocrine neoplasm, BRAF-mutation, BRAF-inhibitors, targeted therapy, small-molecule targeted drug
Abstract
Background: Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation.
Methods: This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1st, 2018 and December 31st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy.
Results: We screened 48 patients diagnosed with NEC between January 1st, 2018 and December 31st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months.
Conclusions: BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.
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References
1. Raphael MJ, Chan DL, Law C, Singh S. Principles of diagnosis and management of neuroendocrine tumours. CMAJ. 2017;189:E398–404. doi: 10.1503/cmaj.160771
2. Rizen EN, Phan AT. Neuroendocrine tumors: a relevant clinical update. Curr Oncol Rep. 2022;24:703–14. doi: 10.1007/s11912-022-01217-z
3. Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol. 2022;33:115–54. doi: 10.1007/s12022-022-09708-2
4. Rinke A, Ambrosini V, Dromain C, Garcia-Carbonero R, Haji A, Koumarianou A, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for colorectal neuroendocrine tumours. J Neuroendocrinol. 2023;35:e13309. doi: 10.1111/jne.13309
5. Sorbye H, Grande E, Pavel M, Tesselaar M, Fazio N, Reed NS, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma. J Neuroendocrinol. 2023;35:e13249. doi: 10.1111/jne.13249
6. Regionala cancercentrum i samverkan. Nationellt vårdprogram för neuroendokrina buktumörer; version 3.0. [Internet]. Stockholm: Regionala cancercentrum i samverkan; 2021. Available from: https://kunskapsbanken.cancercentrum.se/diagnoser/neuroendokrina-buktumorer/vardprogram/bakgrund-och-orsaker/#chapter-4-10-Neuroendokrin-cancer-NEC [cited 5 March 2024].
7. Mollazadegan K, Welin S, Crona J. Systemic treatment of gastroenteropancreatic neuroendocrine carcinoma. Curr Treat Options Oncol. 2021;22:68. doi: 10.1007/s11864-021-00866-9
8. Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF mutated melanoma and beyond. Nat Rev Cancer. 2014;14:455–67. doi: 10.1038/nrc3760
9. Santarpia L, Lippman SL, El-Naggar AK. Targeting the mitogen-activated protein kinase RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103–19. doi: 10.1517/14728222.2011.645805
10. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011;2:135–64. doi: 10.18632/oncotarget.240
11. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54. doi: 10.1038/nature00766
12. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation [Internet]. US Food Drug Adm. 2022; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid [cited 16 January 2024].
13. Vranic S, Basu GD, Hall DW, Gatalica Z. Tumor-type agnostic, targeted therapies: BRAF inhibitors join the group. Acta Med Acad. 2022;51:217–31. doi: 10.5644/ama2006-124.392
14. Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33:4023–31. doi: 10.1200/JCO.2015.63.2471
15. Venizelos A, Elvebakken H, Perren A, Nikolaienko O, Deng W, Lothe IMB, et al. The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2021;29:1–14. doi: 10.1530/ERC-21-0152
16. STROBE [Internet]. STROBE. Available from: https://www.strobe-statement.org/ [cited 23 January 2024].
17. OncoKBTM – MSK’s precision oncology knowledge base [Internet]. OncoKBTM. Available from: https://www.oncokb.org/ [cited 22 February 2024].
18. RECIST 1.1 – RECIST [Internet]. Available from: https://recist.eortc.org/recist-1-1-2/ [cited 23 January 2024].
19. Ricco G, Seminerio R, Andrini E, Malvi D, Gruppioni E, Altimari A, et al. BRAF V600E-mutated large cell neuroendocrine carcinoma responding to targeted therapy: a case report and review of the literature. Anticancer Drugs. 2023;34:1076. doi: 10.1097/CAD.0000000000001508
20. Burkart J, Owen D, Shah MH, Abdel-Misih SRZ, Roychowdhury S, Wesolowski R, et al. Targeting BRAF mutations in high-grade neuroendocrine carcinoma of the colon. J Natl Compr Canc Netw. 2018;16:1035–40. doi: 10.6004/jnccn.2018.7043
21. Chae YK, Tamragouri KB, Chung J, Lin X, Miller V, Ali SM, et al. Large-cell neuroendocrine carcinoma of the lung: a focused analysis of BRAF alterations and case report of a BRAF non-V600–mutated tumor responding to targeted therapy. JCO Precis Oncol. 2018;1–12. doi: 10.1200/PO.17.00150
22. Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, et al. BRAFV600E mutations in high grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov. 2016;6:594–600. doi: 10.1158/2159-8290.CD-15-1192
23. Imperiale A, Latgé A, Schaff-Wendling F, Goichot B, Kurtz JE, Malouf GG. Metabolic response to BRAF-MEK combination therapy in cecal neuroendocrine carcinoma with BRAFV600E mutation and refractory lactic acidosis. Clin Nucl Med. 2018;43:698. doi: 10.1097/RLU.0000000000002231
24. Owaki S, Mori Y, Nakai S, Maeda H, Imazu M, Tomita Y, et al. BRAF V600E-mutated colorectal neuroendocrine carcinoma effectively treated with a chemotherapy protocol for BRAF-mutated metastatic colorectal cancer: a case report. Intern Med Tokyo Jpn. 2023. doi: 10.2169/internalmedicine.2870-23
25. Dizdar L, Werner TA, Drusenheimer JC, Möhlendick B, Raba K, Boeck I, et al. BRAFV600E mutation: a promising target in colorectal neuroendocrine carcinoma. Int J Cancer. 2019;144:1379–90. doi: 10.1002/ijc.31828
26. Galarza Fortuna GM, Dvir K. Circulating tumor DNA: where are we now? A mini review of the literature. World J Clin Oncol. 2020;11:723–31. doi: 10.5306/wjco.v11.i9.723
27. Hasenleithner SO, Speicher MR. A clinician’s handbook for using ctDNA throughout the patient journey. Mol Cancer. 2022;21:81. doi: 10.1186/s12943-022-01551-7
28. Zakka K, Nagy R, Drusbosky L, Akce M, Wu C, Alese OB, et al. Blood-based next-generation sequencing analysis of neuroendocrine neoplasms. Oncotarget. 2020;11:1749–57. doi: 10.18632/oncotarget.27588
29. Shah D, Lamarca A, Valle JW, McNamara MG. The potential role of liquid biopsies in advancing the understanding of neuroendocrine neoplasms. J Clin Med. 2021;10:403. doi: 10.3390/jcm10030403
30. Fedorenko IV, Paraiso KHT, Smalley KSM. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011;82:201–9. doi: 10.1016/j.bcp.2011.05.015
31. Shan KS, Rehman TU, Ivanov S, Domingo G, Raez LE. Molecular targeting of the BRAF proto-oncogene/mitogen-activated protein kinase (MAPK) pathway across cancers. Int J Mol Sci. 2024;25:624. doi: 10.3390/ijms25010624
32. Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med. 2019;381:1632–43. doi: 10.1056/NEJMoa1908075
33. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3. doi: 10.1038/nature10868
34. Capdevila J, Arqués O, Hernández Mora JR, Matito J, Caratù G, Mancuso FM, et al. Epigenetic EGFR gene repression confers sensitivity to therapeutic BRAFV600E blockade in colon neuroendocrine carcinomas. Clin Cancer Res. 2020;26:902–9. doi: 10.1158/1078-0432.CCR-19-1266
35. Nakano M, Shimada Y, Matsumoto Y, Saiki T, Zhou Q, Sasaki K, et al. Efficacy of BRAF inhibitor and anti-EGFR antibody in colorectal neuroendocrine carcinoma. Clin J. Gastroenterol. 2022;15:413–8. doi: 10.1007/s12328-022-01599-4
36. Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keilholz U. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up††Approved by the ESMO Guidelines Committee: February 2002, last update September 2019. Ann Oncol. 2019;30:1884–901. doi: 10.1093/annonc/mdz411
2. Rizen EN, Phan AT. Neuroendocrine tumors: a relevant clinical update. Curr Oncol Rep. 2022;24:703–14. doi: 10.1007/s11912-022-01217-z
3. Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol. 2022;33:115–54. doi: 10.1007/s12022-022-09708-2
4. Rinke A, Ambrosini V, Dromain C, Garcia-Carbonero R, Haji A, Koumarianou A, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for colorectal neuroendocrine tumours. J Neuroendocrinol. 2023;35:e13309. doi: 10.1111/jne.13309
5. Sorbye H, Grande E, Pavel M, Tesselaar M, Fazio N, Reed NS, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma. J Neuroendocrinol. 2023;35:e13249. doi: 10.1111/jne.13249
6. Regionala cancercentrum i samverkan. Nationellt vårdprogram för neuroendokrina buktumörer; version 3.0. [Internet]. Stockholm: Regionala cancercentrum i samverkan; 2021. Available from: https://kunskapsbanken.cancercentrum.se/diagnoser/neuroendokrina-buktumorer/vardprogram/bakgrund-och-orsaker/#chapter-4-10-Neuroendokrin-cancer-NEC [cited 5 March 2024].
7. Mollazadegan K, Welin S, Crona J. Systemic treatment of gastroenteropancreatic neuroendocrine carcinoma. Curr Treat Options Oncol. 2021;22:68. doi: 10.1007/s11864-021-00866-9
8. Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF mutated melanoma and beyond. Nat Rev Cancer. 2014;14:455–67. doi: 10.1038/nrc3760
9. Santarpia L, Lippman SL, El-Naggar AK. Targeting the mitogen-activated protein kinase RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103–19. doi: 10.1517/14728222.2011.645805
10. Chappell WH, Steelman LS, Long JM, Kempf RC, Abrams SL, Franklin RA, et al. Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget 2011;2:135–64. doi: 10.18632/oncotarget.240
11. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54. doi: 10.1038/nature00766
12. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation [Internet]. US Food Drug Adm. 2022; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid [cited 16 January 2024].
13. Vranic S, Basu GD, Hall DW, Gatalica Z. Tumor-type agnostic, targeted therapies: BRAF inhibitors join the group. Acta Med Acad. 2022;51:217–31. doi: 10.5644/ama2006-124.392
14. Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, et al. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33:4023–31. doi: 10.1200/JCO.2015.63.2471
15. Venizelos A, Elvebakken H, Perren A, Nikolaienko O, Deng W, Lothe IMB, et al. The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2021;29:1–14. doi: 10.1530/ERC-21-0152
16. STROBE [Internet]. STROBE. Available from: https://www.strobe-statement.org/ [cited 23 January 2024].
17. OncoKBTM – MSK’s precision oncology knowledge base [Internet]. OncoKBTM. Available from: https://www.oncokb.org/ [cited 22 February 2024].
18. RECIST 1.1 – RECIST [Internet]. Available from: https://recist.eortc.org/recist-1-1-2/ [cited 23 January 2024].
19. Ricco G, Seminerio R, Andrini E, Malvi D, Gruppioni E, Altimari A, et al. BRAF V600E-mutated large cell neuroendocrine carcinoma responding to targeted therapy: a case report and review of the literature. Anticancer Drugs. 2023;34:1076. doi: 10.1097/CAD.0000000000001508
20. Burkart J, Owen D, Shah MH, Abdel-Misih SRZ, Roychowdhury S, Wesolowski R, et al. Targeting BRAF mutations in high-grade neuroendocrine carcinoma of the colon. J Natl Compr Canc Netw. 2018;16:1035–40. doi: 10.6004/jnccn.2018.7043
21. Chae YK, Tamragouri KB, Chung J, Lin X, Miller V, Ali SM, et al. Large-cell neuroendocrine carcinoma of the lung: a focused analysis of BRAF alterations and case report of a BRAF non-V600–mutated tumor responding to targeted therapy. JCO Precis Oncol. 2018;1–12. doi: 10.1200/PO.17.00150
22. Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, et al. BRAFV600E mutations in high grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov. 2016;6:594–600. doi: 10.1158/2159-8290.CD-15-1192
23. Imperiale A, Latgé A, Schaff-Wendling F, Goichot B, Kurtz JE, Malouf GG. Metabolic response to BRAF-MEK combination therapy in cecal neuroendocrine carcinoma with BRAFV600E mutation and refractory lactic acidosis. Clin Nucl Med. 2018;43:698. doi: 10.1097/RLU.0000000000002231
24. Owaki S, Mori Y, Nakai S, Maeda H, Imazu M, Tomita Y, et al. BRAF V600E-mutated colorectal neuroendocrine carcinoma effectively treated with a chemotherapy protocol for BRAF-mutated metastatic colorectal cancer: a case report. Intern Med Tokyo Jpn. 2023. doi: 10.2169/internalmedicine.2870-23
25. Dizdar L, Werner TA, Drusenheimer JC, Möhlendick B, Raba K, Boeck I, et al. BRAFV600E mutation: a promising target in colorectal neuroendocrine carcinoma. Int J Cancer. 2019;144:1379–90. doi: 10.1002/ijc.31828
26. Galarza Fortuna GM, Dvir K. Circulating tumor DNA: where are we now? A mini review of the literature. World J Clin Oncol. 2020;11:723–31. doi: 10.5306/wjco.v11.i9.723
27. Hasenleithner SO, Speicher MR. A clinician’s handbook for using ctDNA throughout the patient journey. Mol Cancer. 2022;21:81. doi: 10.1186/s12943-022-01551-7
28. Zakka K, Nagy R, Drusbosky L, Akce M, Wu C, Alese OB, et al. Blood-based next-generation sequencing analysis of neuroendocrine neoplasms. Oncotarget. 2020;11:1749–57. doi: 10.18632/oncotarget.27588
29. Shah D, Lamarca A, Valle JW, McNamara MG. The potential role of liquid biopsies in advancing the understanding of neuroendocrine neoplasms. J Clin Med. 2021;10:403. doi: 10.3390/jcm10030403
30. Fedorenko IV, Paraiso KHT, Smalley KSM. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011;82:201–9. doi: 10.1016/j.bcp.2011.05.015
31. Shan KS, Rehman TU, Ivanov S, Domingo G, Raez LE. Molecular targeting of the BRAF proto-oncogene/mitogen-activated protein kinase (MAPK) pathway across cancers. Int J Mol Sci. 2024;25:624. doi: 10.3390/ijms25010624
32. Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med. 2019;381:1632–43. doi: 10.1056/NEJMoa1908075
33. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100–3. doi: 10.1038/nature10868
34. Capdevila J, Arqués O, Hernández Mora JR, Matito J, Caratù G, Mancuso FM, et al. Epigenetic EGFR gene repression confers sensitivity to therapeutic BRAFV600E blockade in colon neuroendocrine carcinomas. Clin Cancer Res. 2020;26:902–9. doi: 10.1158/1078-0432.CCR-19-1266
35. Nakano M, Shimada Y, Matsumoto Y, Saiki T, Zhou Q, Sasaki K, et al. Efficacy of BRAF inhibitor and anti-EGFR antibody in colorectal neuroendocrine carcinoma. Clin J. Gastroenterol. 2022;15:413–8. doi: 10.1007/s12328-022-01599-4
36. Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keilholz U. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up††Approved by the ESMO Guidelines Committee: February 2002, last update September 2019. Ann Oncol. 2019;30:1884–901. doi: 10.1093/annonc/mdz411
Published
2024-04-09
How to Cite
Falkman L., Sundin A., Skogseid B., Botling J., Bernardo Y., Wallin G., Zhang L., Welin S., Lase I., Mollazadegan K., & Crona J. (2024). Genetics-guided therapy in neuroendocrine carcinoma: response to BRAF- and MEK-inhibitors. Upsala Journal of Medical Sciences, 129(S1), e10660. https://doi.org/10.48101/ujms.v129.10660
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