Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom

 
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
Oncologia di precisione
Roma, 24 - 25 maggio 2019

Farmacogenetica germinale

Giuseppe Toffoli, MD
CRO – IRCCS, Aviano

                            Roma 24-25 maggio 2019
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
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
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
https://www.pharmgkb.org/
                                            https://cpicpgx.org/guidelines/

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29° CONGRESSO NAZIONALE SOCIETA' ITALIANA
di CHEMIOTERAPIA, TRIESTE 23-24 NOV. 2018
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
“Pharmacogenetics” in
      PubMed

                  Roma 24-25 maggio 2019
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
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
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
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
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
Implementazione
       farmacogenetica

1.NELLA RICERCA CLINICA

2. NELLA PRATICA CLINICA

3. FARMACOECONOMIA

                           Roma 24-25 maggio 2019
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
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
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
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
Oncologia di precisione - Roma, 24 - 25 maggio 2019 CRO - IRCCS, Aviano Roma 24-25 maggio 2019 - Aiom
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 2019
The 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 2019
Nuove 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 2019
Preliminary 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 23
PARADIGM SHIFT IN CANCER THERAPY

Knowledge of tumor dependencies and immunologic vulnerabilities

                                                              CRO
                                                              AVIANO
Exploratory 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 2019
Significant 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, 1366
Immunogenetic 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 2019
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

                                                                       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 data
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
Implementazione
       farmacogenetica

1.NELLA RICERCA CLINICA

2. NELLA PRATICA CLINICA

3. FARMACOECONOMIA

                           Roma 24-25 maggio 2019
UGT1A1-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 2019
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%

                                                              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 2019
DPYD-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 2019
DPYD pharmacogenetics

                                       DPYD*2A
                             DPYD*13
      c. 1236 G>A / Hap B3

                                  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

                                 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 2019
Henricks et al, Pharmacogenomics, 2015             DPWG
                                         pharmacogenomics
                                           recommendations

                                         Roma 24-25 maggio 2019
FP 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 2019
Raccomandazioni
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
AVIANO
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
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
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.
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 Favaretto
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