Exploration of Targeted Anti-tumor Therapy

		RT-PCR	Total
NGS	BRAF mutated	12	2	14
BRAF wild-type	0	15	15
Total	12	17	29

Declarations

Author contributions

PC, LA and CT designed the study; MM, AG, MG, EG, AA collected data and organized the database; MM, PJ, MG, EG performed the experiments; PC, PJ, AA, CT analyzed and interpreted data; PC performed the statistical analysis and wrote the first draft of the manuscript; All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

The study was approved by Internal Review Board of the Hospital Clinic of Barcelona (Barcelona, Spain; HCB/2017/0097).

Consent to participate

The informed consent to participate in the study was obtained from all participants.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Vogenberg FR, Isaacson Barash C, Pursel M. Personalized medicine: part 1: evolution and development into theranostics. P T. 2010;35:560–76. [PubMed] [PMC]

Seyhan AA, Carini C. Are innovation and new technologies in precision medicine paving a new era in patients centric care? J Transl Med. 2019;17:114. [DOI] [PubMed] [PMC]

Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. Nature. 2007;445:851–7. [DOI] [PubMed]

Rebecca VW, Sondak VK, Smalley KSM. A brief history of melanoma: from mummies to mutations. Melanoma Res. 2012;22:114–22. [DOI] [PubMed] [PMC]

González-Cao M, Rodón J, Karachaliou N, Sánchez J, Santarpia M, Viteri S, et al. Other targeted drugs in melanoma. Ann Transl Med. 2015;3:266. [DOI] [PubMed] [PMC]

Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res. 2003;63:3883–5. [PubMed]

Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. [DOI] [PubMed] [PMC]

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] [PubMed]

The Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–96. [DOI] [PubMed] [PMC]

10.

Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell. 2015;28:370–83. [DOI] [PubMed] [PMC]

11.

Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548:234–8. [DOI] [PubMed] [PMC]

12.

Zaman A, Wu W, Bivona TG. Targeting oncogenic BRAF: past, present, and future. Cancers. 2019;11:E1197. [DOI] [PubMed] [PMC]

13.

Michielin O, van Akkooi A, Ascierto P, Dummer R, Keilholz U; ESMO Guidelines Committee. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30:1884–901. [DOI] [PubMed]

14.

van Krieken JH, Normanno N, Blackhall F, Boone E, Botti G, Carneiro F, et al. Guideline on the requirements of external quality assessment programs in molecular pathology. Virchows Arch. 2013;462:27–37. [DOI] [PubMed]

15.

Jennings LJ, Arcila ME, Corless C, Kamel-Reid S, Lubin IM, Pfeifer J, et al. Guidelines for validation of next-generation sequencing-based oncology panels. J Mol Diagn. 2017;19:341–65. [DOI] [PubMed] [PMC]

16.

Gargis AS, Kalman L, Bick DP, da Silva C, Dimmock DP, Funke BH, et al. Good laboratory practice for clinical next-generation sequencing informatics pipelines. Nat Biotechnol. 2015;33:689–93. [DOI] [PubMed] [PMC]

17.

Bisschop C, ter Elst A, Bosman LJ, Platteel I, Jalving M, van den Berg A, et al. Rapid BRAF mutation tests in patients with advanced melanoma: comparison of immunohistochemistry, Droplet Digital PCR, and the Idylla Mutation Platform. Melanoma Res. 2018;28:96–104. [DOI] [PubMed] [PMC]

18.

Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74. [DOI] [PubMed]

19.

Carter J, Tseng LH, Zheng G, Dudley J, Illei P, Gocke CD, et al. Non-p.V600E BRAF mutations are common using a more sensitive and broad detection tool. Am J Clin Pathol. 2015;144:620–8. [DOI] [PubMed]

20.

Reiman A, Kikuchi H, Scocchia D, Smith P, Tsang YW, Snead D, et al. Validation of an NGS mutation detection panel for melanoma. BMC Cancer. 2017;17:150. [DOI] [PubMed] [PMC]

21.

Van Haele M, Vander Borght S, Ceulemans A, Wieërs M, Metsu S, Sagaert X, et al. Rapid clinical mutational testing of KRAS, BRAF and EGFR: a prospective comparative analysis of the Idylla technique with high-throughput next-generation sequencing. J Clin Pathol. 2020;73:35–41. [DOI] [PubMed]

22.

Melchior L, Grauslund M, Bellosillo B, Montagut C, Torres E, Moragón E, et al. Multi-center evaluation of the novel fully-automated PCR-based IdyllaTM BRAF mutation test on formalin-fixed paraffin-embedded tissue of malignant melanoma. Exp Mol Pathol. 2015;99:485–91. [DOI] [PubMed]

23.

Tomizuka T, Namikawa K, Higashi T. Characteristics of melanoma in Japan: a nationwide registry analysis 2011–2013. Melanoma Res. 2017;27:492–7. [DOI] [PubMed]

24.

Schadendorf D, Fisher DE, Garbe C, Gershenwald JE, Grob JJ, Halpern A, et al. Melanoma. Nat Rev Dis Primer. 2015;1:15003.

25.

Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251–63. [DOI] [PubMed] [PMC]

26.

Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome landscapes of major melanoma subtypes. Nature. 2017;545:175–80. [DOI] [PubMed]

27.

Zhu ML, Zhou L, Sadri N. Comparison of targeted next generation sequencing (NGS) versus isolated BRAF V600E analysis in patients with metastatic melanoma. Virchows Arch. 2018;473:371–7. [DOI] [PubMed]

28.

Giardina T, Robinson C, Grieu-Iacopetta F, Millward M, Iacopetta B, Spagnolo D, et al. Implementation of next generation sequencing technology for somatic mutation detection in routine laboratory practice. Pathology (Phila). 2018;50:389–401. [DOI]

29.

de Unamuno Bustos B, Murria Estal R, Pérez Simó G, de Juan Jimenez I, Escutia Muñoz B, Rodríguez Serna M, et al. Towards personalized medicine in melanoma: implementation of a clinical next-generation sequencing panel. Sci Rep. 2017;7:495. [DOI] [PubMed] [PMC]

30.

Read J, Wadt KAW, Hayward NK. Melanoma genetics. J Med Genet. 2016;53:1–14. [DOI] [PubMed]

31.

Jakob JA, Bassett RL, Ng CS, Curry JL, Joseph RW, Alvarado GC, et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer. 2012;118:4014–23. [DOI] [PubMed] [PMC]

32.

Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327–34. [DOI] [PubMed] [PMC]

33.

Dumaz N, Jouenne F, Delyon J, Mourah S, Bensussan A, Lebbé C. Atypical BRAF and NRAS mutations in mucosal melanoma. Cancers. 2019;11:E1133. [DOI] [PubMed] [PMC]

34.

Siroy AE, Boland GM, Milton DR, Roszik J, Frankian S, Malke J, et al. Beyond BRAFV600: clinical mutation panel testing by next-generation sequencing in advanced melanoma. J Invest Dermatol. 2015;135:508–15. [DOI] [PubMed] [PMC]

35.

Li CH, Haider S, Shiah YJ, Thai K, Boutros PC. Sex differences in cancer driver genes and biomarkers. Cancer Res. 2018;78:5527–37. [DOI] [PubMed]

36.

Gupta S, Artomov M, Goggins W, Daly M, Tsao H. Gender disparity and mutation burden in metastatic melanoma. J Natl Cancer Inst. 2015;107:djv221. [DOI] [PubMed] [PMC]

37.

Matthijs G, Souche E, Alders M, Corveleyn A, Eck S, Feenstra I, et al. Guidelines for diagnostic next-generation sequencing. Eur J Hum Genet. 2016;24:2–5. [DOI] [PubMed] [PMC]