Lo sviluppo di resistenze:
impatto clinico e strategie terapeutiche
Marzia Del Re
UO Farmacologia clinica e Farmacogenetica
Azienda Ospedaliero Universitaria Pisana
Griffin R, Ramirez RA. Ochsner J. 2017;17(4):388-392
Molecular classification and treatment options in NSCLC
EGFR mutant NSCLC
EGFR-dependent and independent mechanisms of resistance
Lim, et al. Cancer Treatment Reviews (2018) 65, 1–10 Wu and Shih. Molecular Cancer (2018) 17:38
Mechanisms of resistance to 1 st /2 nd vs 3 rd EGFR-TKIs
Oxnard GR, et al. JAMA Oncol 2018;4(11):1527-1534 Del Re M, et al. Expert Rev Mol Diagn. 2014;14(4):453-68
Mechanisms of resistance to 1 st /2 nd vs 3 rd EGFR-TKIs
PD - 1
st/2
ndEGFR-TKIs
Del Re M, et al. Oncotarget. 2017;8(8):13611-13619 Oxnard GR, et al. JAMA Oncol 2018;4(11):1527-1534
Challenges of acquired resistance
• Detect the driver alteration and stop it
• Track resistance
• Best sequence to »drive» resistance
Longitudinal
analysis of ctDNA dynamics reveals distinct patterns of resistance
mechanisms
Tsui DWY, et al. EMBO Molecular Medicine (2018) 10, e7945
Girard N. Future Oncol. 2018 May;14(11):1117-1132
Optimizing outcomes in EGFR mutation-positive NSCLC: which TKI and when?
Not all EGFR TKIs are equal: activity against EGFR mutations
Girard N. Future Oncol. 2018 May;14(11):1117-1132
Longitudinal monitoring of mutant NSCLC patients
Del Re M, et al. BMC Cancer (2019) 19:410
Acquired resistance to osimertinib from the AURA Trial
Oxnard GR, et al. JAMA Oncol. doi:10.1001/jamaoncol.2018.2969
TTD in patients with or without T790M loss Resistance in patients with short vs long TTD
Plasma analysis reveals global copy number
changes and ctDNA
dynamics in patients with histological transformation to SCLC
Tsui DWY, et al. EMBO Molecular Medicine (2018) 10, e7945
ALK mutant NSCLC
Childress M.A, et al. Mol Cancer Res 2018. DOI: 10.1158/1541-7786.MCR-18-0171. Gainor JF, et al. Cancer Discov. 2016 October ; 6(10): 1118–1133.
Not all ALK TKIs are equal: activity against ALK translocations and mutations
Acquired resistance in EGFR and ALK NSCLC
Lin et al. Cancer Discov. (2017) 7(2):137-155 Dagogo-Jack I, et al. JCO Precis Oncol. 2018; doi: 10.1200/PO.17.00160.
Plasma ALK and mutation kinetics during treatment
Ibiayi Dagogo-Jack, et al. JCO Precis Oncol. 2018; DOI:10.1200/PO.17.00160
Which tool do we have?
Potential of Liquid Biopsies in Precision Medicine
Mutations as
Biomarkers Monitoring
Tumors
Tracking
Resistance
Applications of Liquid Biopsy in Precision Medicine: CHALLENGES
• Biology and tissue of origin is not fully elucidated
(anatomic barriers to ctDNA release)
• The proportion of ctDNA in blood can be extremely low, which requires super-
sensitive technologies to detect mutations of allelic frequencies as low as 0.1%
• Heterogeneity
Bettegowda C, et al. Sci Transl Med. 2014;6(224):224ra24
Sensitivity analysis of CSF ctDNA and plasma ctDNA
De Mattos-Arruda L, et al. Nat Commun. 2015;6:8839
Cerebrospinal fluid cfDNA to longitudinally monitor tumor burden in leptomeningeal metastasis
Zhe ng M M , e t al . J T ho rac O nc o l. 2019 M ay ;14(5) :924 -932
ESMO 2018 – modified by Abbosh, et al. Nature 2017 545:446-453
