1

Nuevos Biomarcadores en Oncología. Dr. Luis Miguel De Sande González. Servicio de Oncología Médica Hospital de León. 24 de abril de

3

4 The role of biomarkers in the diagnostic and therapeutic strategy of cancer is constantly expanding

5 Cell.2000

6 Cell.2011

7 J Pathol 2010; 220: 231–243 Number of unique somatic mutations catalogued in human cancers The mutation data were obtained from the Wellcome Trust Sanger Institute Cata- logue Of Somatic Mutations In Cancer (COSMIC) website

8 Science How Many Genes Are Subtly Mutated in a Typical Human Cancer? In common solid tumors such as those derived from the colon, breast, brain, or pancreas, an average of 33 to 66 genes display subtle somatic mutations that would be expected to alter their protein products.

9 How Many Genes Are Subtly Mutated in a Typical Human Cancer? About 95% of these mutations are single-base substitutions (such as C>G), whereas the remainder are deletions or insertions of one or a few bases (such as CTT>CT) Single-Base Substitutions (SBS) small insertions and deletions (indels) Science

10 Testing conventional markers Histological grade Estrogen receptor and progesterone receptor Ki-67 HER2

11 Prognostic genetic platforms: molecular phenotypes and translation to the clinic MammaPrint Oncotype DX Prosigna EndoPredict

12 HER2

13

14

15 EGFR In our setting, mutations are present in 10–16 % of patients with advanced NSCLC [2]. The most common (85–90 %) are deletions in exon 19 and point mutations in exon 21.

16 Gefitinib Erlotinib Afatinib

Reordenamiento ALK Primer receptor TKs identificado Asociado a linfomas anaplásicos t(2;5) Incidencia en Ca Pulmón 2-7% Asociado a pts no fumadores ALK y EGFR tienden a ser excluyentes (no coexisten) 17

18 Several ALK inhibitors are in clinical development, although only crizotinib is licensed in Europe at the moment. This oral drug, with activity against ALK, c-MET and ROS1, demonstrated significant benefit in terms of progression-free survival (PFS) versus pemetrexed or docetaxel chemotherapy in a phase III study Crizotinib

19

20

21 Which other biomarkers are currently of interest? KRAS mutation ROS1 translocation BRAF mutation HER2 mutation

22

Molecular Biomarkers of Primary and Acquired Resistance to T-Cell-Mediated Immunotherapy in Cancer 23

Molecular Biomarkers of Primary and Acquired Resistance to T-Cell-Mediated Immunotherapy in Cancer 24

25 Molecular Biomarkers of Primary and Acquired Resistance to T-Cell-Mediated Immunotherapy in Cancer

26 This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes

27 In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely. Patients with colorectal carcinoma (CRC) must be tested for molecular biomarkers that predict the response to specific treatments, as this is essential for developing personalize medicine, thereby avoiding the use of inappropriate therapy associated with undesirable effects and costs.

28 Gene expression signatures in localised disease The Oncotype Dx genetic signature was initially validated with data from the QUASAR study [4], The ColoPrint validation sets have also been extended in a pooled analysis of several series containing 227 stage II T3 patients with MSI [8]. Despite this progress, the recommendation level for using these genetic signatures when deciding on adjuvant chemotherapy in stage II is low.

29 All patients with metastatic CRC being considered for anti-EGFR therapy should be tested for KRAS and NRAS status, as this therapy should only be given when no mutations exist in these genes (Level of Evidence Ia) [3]. All patients with metastatic CRC KRAS and NRAS status

30

31

32 ESMO 2013

33 Based on the data available so far, this expert group recommends routinely testing patients with metastatic melanoma for BRAF mutation status, as the result affects the subsequent therapeutic management of these patients.

34 BRAF pathway has become a target of interest for molecular therapy

35

36

37

38

39 CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value

40 Kurman RJ, Shih I-M. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016;186:733–47.

41 Kurman RJ, Shih I-M. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016;186:733–47.

42 Kurman RJ, Shih I-M. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016;186:733–47.

43

44

45 Vergote I, Leamon CP. Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors. Ther Adv Med Oncol. 2015;7:206–18 Folate receptor Folate is essential for nucleotide synthesis and DNA replication It is extensively expressed on ovarian cancer cells (80%) Farletuzumab is a humanised monoclonal antibody (IgG) that binds to the folate receptor a subunit (FRa)

46 Vergote I, Leamon CP. Vintafolide: a novel targeted therapy for the treatment of folate receptor expressing tumors. Ther Adv Med Oncol. 2015;7:206–18 Folate receptor antibody–drug conjugate mirvetuximab soravtansine (IMGN853) IMGN853 at a dose of 6.0 mg/kg showed a manageable safety profile

47

48

49

50 19 Feb Angelini Farmacéutica lanza AVARIC para tratar el dolor irruptivo oncológico AVARIC, comprimidos sublinguales para para el tratamiento del dolor irruptivo en pacientes con cáncer

51