XXV Corso Nazionale TSLB: evoluzione o ri(e)voluzione?

Transcription

1 XXV Corso Nazionale TSLB: evoluzione o ri(e)voluzione? Marcatori predittivi di efficacia nel carcinoma del colon: DESTRO verso SINISTRO conta? Dott. Matteo Clavarezza S.C. Oncologia Medica

2

3 RAS metastatic BRAF metastatic MSI adjuvant/metastatic

4 Continuum Mutation Profile in CRC Loree JM, et al. Clin Cancer Res 2018

5 Continuum Mutation Profile in CRC Loree JM, et al. Clin Cancer Res 2018

6 Courtesy by Antoniotti C. Genomic markers in mcrc What guidelines recommend to test The most updated molecular puzzle Van Cutsem et al, Ann Oncol 2016 Sepulveda et al, J Clin Oncol 2017

7 RAS

8 RIGHT vs LEFT RAS WT: CT + Ab-EGFR vs CT Overall Survival (months) PRIME (N=416) CHEMO + Ab-EGFR CHEMO HR (CI95%) CRYSTAL (N=364) CHEMO + Ab-EGFR CHEMO HR, p RIGHT HR 0.87 ( ) HR 1.08, p 0.76 LEFT HR 0.73 ( ) HR 0.65, p 0.002

9 RIGHT vs LEFT: Ab-EGFR vs BEVA RAS WT Overall Survival (months) CALGB (N=474) CHEMO + Ab-EGFR CHEMO + BEVACIZUMAB HR, p FIRE-3 (N=394) CHEMO + Ab-EGFR CHEMO + BEVACIZUMAB HR, p PEAK (N=143) CHEMO + Ab-EGFR CHEMO + BEVACIZUMAB HR (CI95%) RIGHT HR 1.36, p HR 1.44, p HR 0.45 ( ) LEFT HR 0.77, p HR 0.63, p HR 0.84 ( )

10 Cremolini C, et al. Nature Reviews 2017

11

12 Cremolini et al, Ann Oncol 2017 PRESSING panel: results Primary resistant pts Sensitive pts PRESSING panel alterations are more frequent: Resistant vs sensitive pts, p<0.001 Right-sided vs left-sided tumors, p=0.030 PRESSING panel: predictive accuracy of 75.3%

13 HER2 status in CRC Salem ME, et al. Oncotarget 2017

14 Sartore Bianchi A, et al. Lancet Oncol 2016 Trastuzumab plus Lapatinib KRAS WT and HER2+ pretreated mcrc (n=27) Response Rate: 30%

15 BRAF

16 % BRAF mutation by CRC side Salem ME, et al. Oncotarget 2017

17 % MSI by CRC side Salem ME, et al. Oncotarget 2017 Loree JM, et al. Clin Cancer Res 2018

18 Taieb J, et al. J Natl Cancer Inst 2017 MSI is often associated with BRAF MUT Stage III CRC (n=4411) ALL MSS 89% MSI 11%

19 Gavin PG, et al. Clin Cancer Res 2012 BRAF MUT: poor prognosis (V600E) Right colon Peritoneal metastasis MSI RAS WT

20 Cremolini C, et al. Lancet Oncol 2015 BRAF MUT mcrc The triplet chemo plus Bevacizumab 18 months 12 months

21 No Ab-EGFR efficacy in BRAF MUT Pietrantonio F, et al. Eur J Cancer 2015

22

23 Courtesy by Antoniotti C. Not All BRAF MUT are equal BRAF non-v600 mutations Prevalence: 2% Young Male Left colon/rectum No peritoneal mts MSS RAS mut* *some coexist with RAS mutations Jones et al, J Clin Oncol 2017; Cremolini et al, Ann Oncol 2015

24 MSI

25 Sargent D, et al. J Clin Oncol 2010 Predictive Value of MMR Adjuvant CRC 5FU Stage II Stage III dmmr pmmr

26 Dudley JC et al, Clin Cancer Res 2016:

27 Le DT, et al. New Engl J Med 2015; 372: PD-1 Blockade in dmmr Tumors PEMBROLIZUMAB

28

29

30 Overman MJ, et al. Lancet Oncol 2017; 18: PFS OS

31 Conclusions Actually, for clinicians, the definition of LEFT or RIGHT side of the primary tumor is exclusively anatomical LEFT/RIGHT side of the primary tumor combined with MSI, RAS, BRAF status must be assessed to evaluate prognosis and to choose the best systemic treatment in CRC LEFT COLON and RAS WT/BRAF WT: optimal selection for high sensibility to ANTI-EGFR monoclonal antibodies plus chemotherapy BRAF MUT: more frequent in the RIGHT COLON, bad prognosis, requires intensive treatment, clinical trials about triplet biological therapy are ongoing, rare non-v600e mutations in the LEFT COLON with good prognosis MSI: more frequent in the RIGHT COLON, good prognosis in the adjuvant setting, no adjuvant chemotherapy in high-risk Stage II, select patients for immunotherapy with anti-pd1