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/
BACKGROUND
29° CONGRESSO NAZIONALE SOCIETA' ITALIANA di CHEMIOTERAPIA, TRIESTE 23-24 NOV. 2018
“Pharmacogenetics” in PubMed
Roma 24-25 maggio 2019
•TPMT/ 6-mercaptopurine
•UGT1A1*28/ irinotecan
•DPYD/ fluoropyrimidines
•CYP2D6/ tamoxifen
Gene-drug interactions currently included in the PGx guidelines for oncology
Roma 24-25 maggio 2019
Sanchez-Spitman A et al., J Clin Oncol, 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
1 . N E L L A R I C E R C A C L I N I C A
2 . N E L L A P R A T I C A C L I N I C A
3 . F A R M A C O E C O N O M I A
Implementazione farmacogenetica
Roma 24-25 maggio 2019
Phase 1b studies based on the patient genotype for re-definition of Maximun Tolerated Dose (MTD)
•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
5’ 3’ 2 3 4 Exon 1
-53 (TA)nTAA (UGT1A1*28)
5
Roma 24-25 maggio 2019
Genotyping for UGT1A1 *28
Stratification into two groups
GROUP 1:
UGT1A1 *1/*1
WILD TYPE PTS GROUP 2:
UGT1A1 *1/*28
HETEROZYGOUS PTS
Phase I clinical trial of irinotecan: Protocol design
Eligible mCRC patients
Patients with *28/*28 genotype excluded.
Phase 1b studies based on the patient genotype for re-definition of MTD: the study design
IRI dose escalation
IRI dose escalation
Clinical and pharmacokinetic monitoring
Roma 24-25 maggio 2019
*1/*28genotype, Dose (mg/m2)
Phase 1b studies based on the patient genotype for re-definition of MTD: the results
Therapy
FOLFIRI, standard dose
FOLFIRI
FOLFIRI plus BEVACIZUMAB
*1/*1 genotype, Dose (mg/m2)
180
370
310
180
310
260
Ducreux et al, J Clin Oncol, 1999
Toffoli et al, J Clin Oncol , 2010
Toffoli et al, Clin Cancer Res, 2017
Roma 24-25 maggio 2019
The interaction with bevacizumab is unlikely to be related to a PK interaction
Roma 24-25 maggio 2019
Toffoli et al, Clin Cancer Res, 2017
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.
85 su 95 pts (89%) patients with G3-5 toxicity are not carriers of any of the 3 DPYD SNPs (*2A, *13, 2846A>T)
Roma 24-25 maggio 2019
Nuove strategie per la farmacogenetica: varianti rare
Kozyra et al., Genetics in Medicine 2016
Rare and novel variants can significantly
contribute to inter-patients variability
Preliminary Results II-DPYD novel and rare variants
Variant Rs Location Functional
Consequences Freq
ExAC_NFE Observed Toxicity
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
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
5’UTR 3’UTR
A110G A1110G *431A>G C1579T A2137G G481A
G9858A G345C C800T
PARADIGM SHIFT IN CANCER THERAPY
Knowledge of tumor dependencies and immunologic vulnerabilities
CRO AVIANO
Int. J. Mol. Sci. 2017, 18, 1366; doi:10.3390/ijms18071366
PGx studies
Immunosystem
Exploratory research of new genetic markers of treatment sensitivity: the immunogenetic approach
Roma 24-25 maggio 2019
Significant associations between HLA-G 3’UTR haplotypes and G3-4 toxicities
Garziera et al., Int. J. Mol. Sci. 2017, 18, 1366
Immunogenetic germline variants can interact with the effect of chemotherapy and identify profiles of pateints at high risk of severe
rs4143815-PDL1 and 10-year Biochemical Recurrence (BCR)
Immunogenetic Biomarker of Biochemical Recurrence in Locally Advanced Prostate Cancer after Radiotherapy.
Roma 24-25 maggio 2019
Int J Mol Sci. 2019 Apr 27;20(9) C. Zanusso C. ……and G.Toffoli
549 Cancer Prostate patients treated with Radiotherapy
*
*
*months
SNPs 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
FSC Unpublished data
Score legend
0-2 unfavorable genotypes
3 unfavorable genotypes
4 unfavorable genotypes
5 unfavorable genotypes
6 unfavorable genotypes
7-8 unfavorable genotypes
Log-rank test
(months)
BRCA 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 OC
1 . N E L L A R I C E R C A C L I N I C A
2 . N E L L A P R A T I C A C L I N I C A
3 . F A R M A C O E C O N O M I A
Implementazione farmacogenetica
Roma 24-25 maggio 2019
UGT1A1-Irinotecan
5’ 3’ 2 3 4 Exon 1
-53 (TA)nTAA (UGT1A1*28)
5
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 2019
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.
Our 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%
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 2019
DPYD-Fluoropyrimidines
5-FU bolus
5-FU infusion
– 24 hrs
– 48 hrs
– 46 hrs
– 120 hrs
– ∞ hrs
LV + 5-FU
5-FU + LV
5-FU + Lev
5-FU + everything
……………
5-FU for 40 Yrs •FL are the mainstay of many chemotherapeutic schemes in different combination for different pathologies and settings •10 to 26% of patients experiencing acute severe or life-threatening toxicity even in monotherapy regimens (Twelves. N. Engl.
J. Med., 352, 2005)
Roma 24-25 maggio 2019
DPYD*2A
DPYD*13 c. 1236 G>A / Hap B3
DPYD pharmacogenetics
Roma 24-25 maggio 2019
Clinical 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
Roma 24-25 maggio 2019
Genotype
Total N
Toxicity1 G≥3
n (%) OR 95% CI² p³
DPYD-rs3918290 (*2A)
GG 591 87 (14.7) 14
AG 12 8 (66.7) 12.6 2.9-51.0 0.003
DPYD-rs67376798 (2846 A>T)
AA 583 92 (15.8) 14
AT 5 3 (60.0) 7.8 1.5-41.8 0.048
• Frontline genotyping could have allowed the
identification of 10 patients at risk for severe toxicity and 1 toxic death (11.6% of severe toxic events)
• The patient with toxic death was compound
heterozygous for DPYD*2A, and DPYD*13 and was treated in an adjuvant regimen for gastric cancer
DPWG pharmacogenomics
recommendations
Henricks et al, Pharmacogenomics, 2015
Roma 24-25 maggio 2019
FP dose reduction in DPYD*2A patients- 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.
Henricks LM et al., Int J Cancer, 2019
Roma 24-25 maggio 2019
Raccomandazioni
29° CONGRESSO NAZIONALE SOCIETA' ITALIANA di CHEMIOTERAPIA, TRIESTE 23-24 NOV. 2018
Farmaco Gene Polimorf SIF-AIOM CPIC DPWG
Irinotecano UGT1A1 *28 *28/*28: ridurre la dose del 30%; *1/*28: 100% della dose
Nessuna linea guida presente *”28/*28: ridurre la dose del 30%; *1/*28: 100% della dose
Fluoropirim DPYD *2A, *13, c.2846 A>T, HapB3 (solo per CPIC e DPWG)
PM (allele variante/allele variante): selezionare un farmaco alternativo; IM (*1/allele variante): riduzione dose del 50%; .
PM (allele variante/allele variante): selezionare un farmaco alternativo; IM: (*1/allele variante): riduzione dose del 50%.
Sulla base del “gene activity score” riduzione dal 25% al /75% Allele *2A e *13 in combinazione omozigosi selezionare un farmaco alternativo
Tiopurine
TPMT Es. *2, *3A, *3B, *3C
PM: riduzione dose del 90% e titolare successivamente in base a tollerabilità. IM: riduzione dose del 50% .
PM (allele variante/allele variante): riduzione dose del 90%, 3 somministrazioni a settimana; IM (*1/allele variante): riduzione dose del 30-50%.
PM (allele variante/allele variante): riduzione dose del 90% o selezionare un farmaco alternativo ; IM(*1/allele variante): riduzione dose del 50% o selezionare un farmaco alternativo.
Tamoxifene CYP2D6 varianti, delezione gene, duplicazione gene
PM: incremento di dose; evitare la cosomministrazione di farmaci inibitori di CYP2D6 ; IM: evitare la cosomministrazione di farmaci inibitori di CYP2D6.
PM: selezionare un’alternativa (inibitori aromatasi); IM: selezionare un’alternativa (inibitori aromatasi) o aumentare il dosaggio del 100%; PM, IM Evitare la cosomministrazione di farmaci inibitori del CYP2D6.
PM: selezionare un’alternativa (inibitori aromatasi); IM: selezionare un’alternativa (inibitori aromatasi) .
CRO
AVIANO
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
The 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
G Toffoli, F Innocenti, J Polesel , E De Mattia, M Guardascione, L Foltran, A Bignucolo, M Berretta, A De Paoli, R Roncato , and E Cecchin; Clin Pharmacol Ther, October 2018, e-pub
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 p<0.0001
GENE ACTIVITY SCORE
2 513 825 785-864 -
1.5 28 2,188 1,683-2,693
1 9 5,414 2,268-8,561 -
0 - - - p<0.0001
Cycle
1 2 3 4 5 6 7 8 9 10 11 12
Pa
tie
nts
(%
)
0
10
20
30
40
Non-carriers
Carriers
B)A)
Cycle
1 2 3 4 5 6 7 8 9 10 11 12
Pa
tie
nts
(%
)
0
5
10
15
20
Carriers
Non-carriers
Most of the costs are related to hospitalization (grade 4 toxicity). The risk of grade 4 toxicity is DPYD allele dependent
HOSP-related tox
Any costly tox
FUTURE 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.
http://upgx.eu/
Coordinated by Leiden University-Prof HJ Guchelaar
PAESI BASSI
ITALIA
UK
SPAGNA SLOVENIA
GRECIA
AUSTRIA
Experimental and Clinical Pharmacology Director Giuseppe Toffoli Pgx group: Erika Cecchin Francesco Angelini, Alessia Bignucolo, Francesco Comello, Lisa Dal Cin, Chiara Dalle Fratte, Elena De Mattia, Tania Di Raimo, Eva Dreussi, Fabrizio Ecca, Marica Garziera, Michela Guardascione , Silvia Mezzalira, Loredana Romanato, Rossana Roncato, Franca Sartor
Quebec University- Prof Chantal Guillemette University of Chapel Hill- Prof Federico Innocenti
Acknowledgements
Univ of Padova- Istituto Oncologico Veneto Univ di Trieste- Burlo Garofolo- Prof G De Corti, Prof G Stocco Univ of Florence- Prof E Mini, Dr S Nobili Hospital San Filippo Neri –Roma- Dr. M D’Andrea Hospital Ca Foncello- Treviso- Dr. A Favaretto
U-Pgx European van der Wouden CH, Cambon-Thomsen A, Cecchin E, Cheung K, Dávila-Fajardo CL, Deneer VH, Dolžan V, Ingelman-Sundberg M, Jönsson S, Karlsson MO, Kriek M, Mitropoulou C, Patrinos GP, Pirmohamed M, Samwald M, Schaeffeler E, Schwab M, Steinberger D, Stingl J, Sunder-Plassmann G, Toffoli G, Turner RM, van Rhenen MH, Swen JJ
CRO
AVIANO