Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
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Oncologia di precisione
Roma, 24 - 25 maggio 2019
Farmacogenetica germinale
Giuseppe Toffoli, MD
CRO – IRCCS, Aviano
Roma 24-25 maggio 2019
Adverse Drug Reactions
in pharmacological treatment
Over 2 millions ADRs yearly in US, 100,000
resulting in death (Inst Med, Nat Acad Press, 2000)
They are estimated to cost £1 billion in UK
(Pirmohamed, Br Med J, 2004), and $4 billion annually in
the US (Lazarou J et al, JAMA, 1998)
A revision of 4,158 patients treated for mCRC in the US in 2014 pointed out
that about 90% developed at least one ADR after the first cycle (66%>1 AE
category) with a significant economic burden mainly related to severe
hematological AE related to chemotherapy (Latremouille et al, J Med Economics,
2016)
Roma 24-25 maggio 2019
https://www.pharmgkb.org/
https://cpicpgx.org/guidelines/
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29° CONGRESSO NAZIONALE SOCIETA' ITALIANA
di CHEMIOTERAPIA, TRIESTE 23-24 NOV. 2018
“Pharmacogenetics” in
PubMed
Roma 24-25 maggio 2019
Gene-drug interactions currently
included in the PGx guidelines
for oncology
•TPMT/ 6-mercaptopurine
•UGT1A1*28/ irinotecan
•DPYD/ fluoropyrimidines
•CYP2D6/ tamoxifen
Roma 24-25 maggio 2019
This prospective clinical study shows no association between endoxifen
concentrations or CYP2D6 genotypes and clinical outcome in 662
patients with early-stage breast cancer receiving adjuvant tamoxifen
Sanchez-Spitman A et al., J Clin Oncol, 2019
Implementazione
farmacogenetica
1.NELLA RICERCA CLINICA
2. NELLA PRATICA CLINICA
3. FARMACOECONOMIA
Roma 24-25 maggio 2019
Phase 1b studies based on the
patient genotype for re-definition
of Maximun Tolerated Dose (MTD)
Exon 1 2 3 4 5
5’ 3’
-53 (TA)nTAA (UGT1A1*28)
•Registrative phase 1 studies for
FOLFIRI regimen did not take patients
genotype into account
•A re-definiton of proper irinotecan
dose for *1/*1 or *1/*28 patients by
genotype is requested
Roma 24-25 maggio 2019
Phase 1bPhase
studies based
I clinical trial ofon the Protocol design
irinotecan:
patient genotype for re-definition
of MTD: the study design
Eligible mCRC patients
Genotyping for UGT1A1 *28
Stratification into two groups
GROUP 1:
UGT1A1 *1/*1 GROUP 2:
WILD TYPE PTS
IRI dose escalation UGT1A1 *1/*28
HETEROZYGOUS PTS
IRI dose escalation
Patients with *28/*28 genotype excluded.
Clinical and pharmacokinetic monitoring
Roma 24-25 maggio 2019
Phase 1b studies based on the
patient genotype for re-definition
of MTD: the results
Therapy *1/*1 genotype, *1/*28genotype,
Dose (mg/m2) Dose (mg/m2)
FOLFIRI,
180 180 Ducreux et al, J Clin Oncol, 1999
standard dose
FOLFIRI 370 310 Toffoli et al, J Clin Oncol , 2010
FOLFIRI plus
310 260 Toffoli et al, Clin Cancer Res, 2017
BEVACIZUMAB
Roma 24-25 maggio 2019The interaction with bevacizumab
is unlikely to be related to a PK interaction
The stratification of patients
in FOLFIRI or FOLFIRI plus
bevacizumab regimens
according to UGT1A1*28
genotype led to a higher
MTD both in UGT1A1*1/*28
and UGT1A1*1/*1 patients.
Toffoli et al, Clin Cancer Res, 2017
Roma 24-25 maggio 2019Nuove strategie per la farmacogenetica: varianti rare
85 su 95 pts (89%) patients with G3-5 toxicity
are not carriers of any of the 3 DPYD SNPs
(*2A, *13, 2846A>T)
Rare and novel variants
can significantly
contribute to inter-
patients variability
Kozyra et al., Genetics in Medicine 2016
Roma 24-25 maggio 2019Preliminary Results II-DPYD novel and rare variants
Functional Freq
Variant Rs Location Observed Toxicity
Consequences ExAC_NFE
c.G345C p.M115I rs377169736 Exon5 Missense 0,0001 G4 Non Hematologic
c.G481A p.E161K / Exon5 Missense / Splice / G4 Hematologic
c.C800T p.T267I / Exon 8 Missense / Splice / G3 Non Hematologic
c.G958A p.G320R / Exon9 Missense / Splice / G4 Hematologic
c.A1110G p.I370M / Exon 10 Missense / Splice / G4 Non Hematologic
c.C1579T p.P527S / Exon13 Missense / Splice / G3 Non Hematologic
c.A2137G p.N713D rs773407491 Exon 17 Missense 0.000008247 G4 Non Hematologic
c.*431A>G / UTR3 / / G4 Hematologic
c .-416A>G / Upstream / / G4 Non Hematologic
G345C C800T G9858A
A110G G481A A1110G C1579T A2137G *431A>G
5’UTR 3’UTR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23PARADIGM SHIFT IN CANCER THERAPY
Knowledge of tumor dependencies and immunologic vulnerabilities
CRO
AVIANOExploratory research of new genetic markers of treatment sensitivity:
the immunogenetic approach
Immunosystem
PGx studies
Int. J. Mol. Sci. 2017, 18, 1366; doi:10.3390/ijms18071366 Roma 24-25 maggio 2019Significant associations between
HLA-G 3’UTR haplotypes and G3-4 toxicities
Immunogenetic germline variants can interact with the effect of chemotherapy and
identify profiles of pateints at high risk of severe
Garziera et al., Int. J. Mol. Sci. 2017, 18, 1366Immunogenetic Biomarker of Biochemical
Recurrence in Locally Advanced Prostate Cancer
after Radiotherapy.
rs4143815-PDL1 and 10-year Biochemical Recurrence (BCR)
549 Cancer
Prostate patients
treated with
Radiotherapy
*
*
Int J Mol Sci. 2019 Apr 27;20(9) C. Zanusso C. ……and G.Toffoli *months
Roma 24-25 maggio 2019SNPs on TGF-β PATHWAY SCORE
predicts Overall Survival
SNPs significantly associated with OS and involved in TGF-β pathway:
230 ovarian cancer pts treated
with Platinum-based therapy
Score legend
0-2 unfavorable genotypes
3 unfavorable genotypes
4 unfavorable genotypes
5 unfavorable genotypes
Log-rank test 6 unfavorable genotypes
7-8 unfavorable genotypes
(months) FSC Unpublished dataBRCA mutations and treatment of ovarian
cancer
OC of BRCA origin are more sensitive to platinum
based chemotherapy than sporadic OC cases
Pegylated liposomal doxorubicin is active in
BRCAm OC (Kaye SB et al. J. Clin. Oncol. 2012)
PARP inhibitors are active in BRACAm OCImplementazione
farmacogenetica
1.NELLA RICERCA CLINICA
2. NELLA PRATICA CLINICA
3. FARMACOECONOMIA
Roma 24-25 maggio 2019UGT1A1-Irinotecan
Exon 1 2 3 4 5
5’ 3’
-53 (TA)nTAA (UGT1A1*28)
An impaired SN38 detoxification by
an UGT1A1*28 polymorphic form
increases the risk of acute severe
toxicity
*1/*1 or *1/*28 patients have
lower toxicity than *28/*28
Roma 24-25 maggio 2019Our hypothesis external validation in collaboration with Universitè Laval-Quebec
UGT1A HAPLOTYPES
UGT1A1 UGT1A7 UGT1A9
*93 *60 *28 *2 *4 *22 Allelic
frequency
I *1 *1 *1 G T *22 34.2%
II *93 *60 *28 T C *1 23.2%
III *1 *1 *1 G T *1 14.4%
IV *1 *60 *1 G T *1 4.6%
others 23.0%
OUR RESULTS ON HAPLOTYPE II (as reported by us,
all “defective” UGT1A allelesWERE REPLICATED IN
AN INDEPENDENT COHORT OF 167 CANADIAN
mCRC PATIENTS TREATED WITH FOLFIRI- BASED
REGIMENS.
Lévesque E, Bélanger AS, Harvey M, Couture F, Jonker D,Innocenti F, Cecchin E, Toffoli G, and Guillemette C
J Pharmacol and Exp Ther, 2013 Roma 24-25 maggio 2019DPYD-Fluoropyrimidines
5-FU for 40 Yrs
•FL are the mainstay of many
5-FU bolus
chemotherapeutic schemes in different
5-FU infusion
– 24 hrs combination for different pathologies
– 48 hrs and settings
– 46 hrs
– 120 hrs
– ∞ hrs
LV + 5-FU
5-FU + LV •10 to 26% of patients experiencing
5-FU + Lev acute severe or life-threatening toxicity
5-FU + everything
even in monotherapy regimens (Twelves. N. Engl.
…………… J. Med., 352, 2005)
Roma 24-25 maggio 2019DPYD pharmacogenetics
DPYD*2A
DPYD*13
c. 1236 G>A / Hap B3
Roma 24-25 maggio 2019Clinical validity of a DPYD-based pharmacogenetic test to
predict severe toxicity to fluoropyrimidines.
Toffoli G, Giodini L, Buonadonna A, Berretta M, De Paoli A, Scalone S, Miolo G, Mini E, Nobili S, Lonardi S, Pella N,
Lo Re G, Montico M, Roncato R, Dreussi E, Gagno S, Cecchin E.
603 solid cancer patients treated with FL-based regimen
Clinical End-Point: Severe (≥G3) or lethal toxicity related to FL administration
Total Toxicity1 G≥3
N
Genotype n (%) OR 95% CI² p³
DPYD-rs3918290
• Frontline genotyping could have allowed the
(*2A)
identification of 10 patients at risk for severe
GG toxicity591 87 death (14.7)
and 1 toxic (11.6% of 1severe toxic
4
AG events)12 8 (66.7) 12.6 2.9-51.0 0.003
DPYD-rs67376798
(2846 A>T)
• The patient with toxic death was compound
heterozygous for DPYD*2A, and DPYD*13 and
was treated in an adjuvant regimen for gastric
AA cancer583 92 (15.8) 14
AT 5 3 (60.0) 7.8 1.5-41.8 0.048
Roma 24-25 maggio 2019Henricks et al, Pharmacogenomics, 2015 DPWG
pharmacogenomics
recommendations
Roma 24-25 maggio 2019FP dose reduction in DPYD*2A patients-
Henricks LM et al., Int J Cancer, 2019 is the treatment still effective?
40 heterozygous DPYD*2A carriers,
treated with a ~50% reduced FP
dose, were identified. A matched pair-
analysis was performed in which for
each DPYD*2A carrier a DPYD*2A
wild-type patient was identified.
DPYD*2A genotype-guided
dosing appears to have no
negative effect on
effectiveness of FP-based
chemotherapy, while resulting
in significantly improved
patient safety.
Roma 24-25 maggio 2019Raccomandazioni
Farmaco Gene Polimorf SIF-AIOM CPIC DPWG
Irinotecano UGT1A1 *28 *28/*28: ridurre la dose del 30%; Nessuna linea guida presente *”28/*28: ridurre la dose del 30%;
*1/*28: 100% della dose *1/*28: 100% della dose
Fluoropirim DPYD *2A, PM (allele variante/allele PM (allele variante/allele Sulla base del “gene activity score”
*13, variante): selezionare un farmaco variante): selezionare un riduzione dal 25% al /75%
c.2846 A>T, alternativo; farmaco alternativo;
HapB3 (solo Allele *2A e *13 in combinazione
per CPIC e IM (*1/allele variante): riduzione IM: (*1/allele variante): omozigosi selezionare un farmaco
DPWG) dose del 50%; . riduzione dose del 50%. alternativo
Tiopurine TPMT Es. *2, *3A, PM: riduzione dose del 90% e PM (allele variante/allele PM (allele variante/allele variante):
*3B, *3C titolare successivamente in base a variante): riduzione dose del riduzione dose del 90% o selezionare un
tollerabilità. 90%, 3 somministrazioni a farmaco alternativo ;
settimana;
IM(*1/allele variante): riduzione dose
IM (*1/allele variante): del 50% o selezionare un farmaco
IM: riduzione dose del 50% . riduzione dose del 30-50%. alternativo.
Tamoxifene CYP2D6 varianti, PM: incremento di dose; evitare PM: selezionare PM: selezionare un’alternativa (inibitori
delezione la cosomministrazione di farmaci un’alternativa (inibitori aromatasi);
gene, inibitori di CYP2D6 ; aromatasi);
duplicazion IM: selezionare un’alternativa (inibitori
e gene IM: evitare la IM: selezionare un’alternativa aromatasi) .
cosomministrazione di farmaci (inibitori aromatasi) o
inibitori di CYP2D6. aumentare il dosaggio del
100%;
PM, IM Evitare la
29° CONGRESSO NAZIONALE SOCIETA' ITALIANA cosomministrazione di
di CHEMIOTERAPIA, TRIESTE 23-24 NOV. 2018 farmaci inibitori del CYP2D6.Spreading of UGT1A1*28 pre-emptive genotyping to increase irinotecan safety is still
limited. The definition of the cost consequences of patients genotype is one of the
pending issues. A survey of the toxicity associated costs in 243 FOLFIRI treated mCRC
Roma 24-25 maggio 2019
CRO
AVIANOThe genotype for DPYD risk variants in colorectal cancer patients
and the related toxicity management costs in clinical practice
Analysis on 550 patients from everyday clinical practice
4-SNP Panel
Status n aMean (Euros) 95% CI
Non-carriers 513 817 779-854
Carriers (at least 1 allele) 37 2,972 2,456-3,505 pFUTURE PERSPECTIVES DRG represents the basis for hospital payment systems in many western countries. The introduction of DRG-based payment has been claimed to reduce the quality of care in many European countries because high-cost outlier cases are not properly taken into account. PGx profiling for the DRG-based reimbursement system could deliver a more precise and efficient care that could be ultimately functional to save costs.
Coordinated by Leiden University-Prof HJ Guchelaar
PAESI
BASSI
AUSTRIA ITALIA
GRECIA UK
SLOVENIA SPAGNA
http://upgx.eu/Acknowledgements
Experimental and Clinical Pharmacology
CRO U-Pgx European
Director Giuseppe Toffoli AVIANO
van der Wouden CH, Cambon-Thomsen A, Cecchin E, Cheung K,
Pgx group: Dávila-Fajardo CL, Deneer VH, Dolžan V, Ingelman-Sundberg M,
Erika Cecchin Jönsson S, Karlsson MO, Kriek M, Mitropoulou C, Patrinos GP,
Francesco Angelini, Alessia Bignucolo, Francesco Comello, Pirmohamed M, Samwald M, Schaeffeler E, Schwab M,
Lisa Dal Cin, Chiara Dalle Fratte, Elena De Mattia, Tania Di Steinberger D, Stingl J, Sunder-Plassmann G, Toffoli G, Turner
Raimo, Eva Dreussi, Fabrizio Ecca, Marica Garziera, Michela RM, van Rhenen MH, Swen JJ
Guardascione , Silvia Mezzalira, Loredana Romanato,
Rossana Roncato, Franca Sartor Univ of Padova- Istituto Oncologico Veneto
Quebec University- Prof Chantal Guillemette Univ di Trieste- Burlo Garofolo- Prof G De Corti, Prof G Stocco
Univ of Florence- Prof E Mini, Dr S Nobili
University of Chapel Hill- Prof Federico Innocenti Hospital San Filippo Neri –Roma- Dr. M D’Andrea
Hospital Ca Foncello- Treviso- Dr. A FavarettoYou can also read
