Targeted Toxic Therapy: Identifying Platinum Resistance

1
Targeted Toxic TherapyIdentifying Platinum
Resistance

• Boone Goodgame, M.D.
• Washington University School of Medicine, St.
  Louis.

2
Introduction

• Platinum based doublets are standard for patients
  with advanced NSCLC and good performance status.
• 40-60 of patients NSCLC progress during
  platinum based therapy, while some have excellent
  responses.
• Schiller, Harrington et al. N Engl J Med, 2002
• Platinum doublets have a marginally increased RR
  (17) vs third generation non-platinum doublets
  but OS is not improved.
• D'Addario, Pintilie et al. J Clin Oncol, 2005

3
Key Clinical Question

• Which patients are most likely to benefit from
  these effective therapies, and which patients
  should be offered alternatives?

4
Overview

• Fundamentals of platinum based DNA damage and
  repair.
• Identifying platinum resistant NSCLC patients.
• BRCA1
• ERCC1
• Germline polymorphisms
• Tumor expression by mRNA
• Immunohistochemistry
• Polymorphisms in ERCC2 XRCC1

5
The DNA repair paradox

• Decreased DNA repair capacity increases cancer
  susceptibility and cancer aggressiveness.
• Decreased DNA repair capacity increases
  susceptibility to platinums.

6
Mechanism of platinum DNA damage

• DNA damage is the primary mechanism of platinum
  cytotoxicity
• Three different types of lesions
• Monoadducts
• intrastrand crosslinks
• interstrand crosslinks
• Rabik and Dolan Cancer Treat Rev, 2006

7
Fundamentals of DNA Repair

• Base excision repair (BER)
• e.g. excision of uracil and replace with thymine
• Mismatch repair
• excision of incorrectly paired nucleotides
• Nucleotide excision repair (NER)
• Essential NER independent of transcription
• Transcription coupled NER
• Homologous Recombination Repair (HRR)
• Repair of double strand breaks

8
Essential NER

• recognition of damage
• incision of DNA
• excision of oligonucleotides (25 30
  nucleotides)
• Friedberg Nat Rev Cancer, 2001

9
Transcription coupled NER
10
Excision Repair System

• Rosell, Cobo et al. Lung Cancer, 2005

11
Clinically important mediators of DNA repair for
platinum based damage

• Essential NER
• DNA unwinding ERCC2 (XPD)
• Incision of DNA ERCC1 (XPF)
• Transcription coupled NER
• BRCA1
• Base Excision Repair
• XRCC1

12
General mechanisms of platinum resistance

• Detoxification
• Inhibitors of apoptosis
• DNA methylation
• Changes in influx/efflux
• Increased DNA repair capacity
• Rabik and Dolan Cancer Treat Rev, 2006

13
Increased DNA repair capacity increases
resistance to platinums in multiple malignancies

• Ovarian Platinum resistance correlates with
  elevated expression of XPA, XPB, ERCC1 in
  patient tumors.
• Gastric correlation between cisplatin resistance
  and ERCC1 mRNA levels.
• Testicular cancer (very responsive to cisplatin)
  has low levels of XPA and ERCC1-XPF.
• In breast and ovarian cell lines BRCA1 expression
  increases platinum radiation resistance.
• Rabik and Dolan Cancer Treat Rev, 2006

14
Established mediators of platinum resistance in
NSCLC

• BRCA1
• ERCC1
• Germline polymorphisms
• Tumor expression by mRNA
• Immunohistochemistry
• Polymorphisms in ERCC2 XRCC1

15
BRCA1

• In a breast cancer cell line low BRCA1 mRNA
  expression increased sensitivity to cisplatin and
  etoposide, but increased resistance to paclitaxel
  and vincristine.
• In a BRCA1-negative cell line, reconstitution of
  wild-type BRCA1 led to a a 20-fold increase in
  cisplatin resistance and, in contrast, in a
  100010 000-fold increase in sensitivity to
  antimicrotubule drugs.
• Low BRCA1 mRNA levels in sporadic breast cancer
  were associated with a higher frequency of
  distant metastases.
• Taron, Rosell et al. Hum Mol Genet, 2004

16
BRCA1 mRNA expression levels and survival in
NSCLC patients treated with neo-adjuvant
gemcitabine cisplatin.

• Total 55 pts Bottom N15, Middle28, Top12
  p0.01
• Taron, Rosell et al. Hum Mol Genet, 2004

17
ERCC1 (Excision repair cross-complementing 1)

• Essential component of NER
• Assessed by
• Functional germ-line polymorphisms
• Expression levels by mRNA
• Expressional levels by IHC

18
Polymorphisms of ERCC1 and survival in cisplatin
treated NSCLC.

• C118T does not change the encoded amino acid but
  does affect transcription levels.
• Two studies correlated with survival in advanced
  NSCLC treated with cisplatin doublets.
• 109 patients 50 wild type survivals were 16
  months vs 9 months with either 1 or 2 alleles
  (p0.0058)
• 62 patients 18 wild type survivals were 9.7
  months and gt18 months (p0.04)
• Ryu, Hong et al. Lung Cancer, 2004
• Isla, Sarries et al. Ann Oncol, 2004

19
Polymorphisms of ERCC1 and survival in cisplatin
treated NSCLC.

• A third study found no correlation with C118T
  survival
• 128 patients, 21 wild type, survivals were 18
  months 13 months (p0.41)
• A separate polymorphism C8092A was associated
  with survival in this study
• 13 months vs 22 months (p0.006).
• Zhou, Gurubhagavatula et al. Clin Cancer Res,
  2004

20
ERCC1 mRNA levels in advanced NSCLC treated with
gemcitabine-cisplatin.

• 56 patients with advanced NSCLC.
• Low vs high ERCC1 mRNA
• RR 52 and 36 (p NS), MS 15 months and 5
  months (P lt 0.001)
• Lord, Brabender et al. Clin
• Cancer Res, 2002

21

• Rosell, et.al. ASCO 2005

22

• Rosell, et.al. ASCO 2005

23
ERCC1 mRNA levels in resected NSCLC

• 51 resected tumors, no chemotherapy
• no correlation between ERCC1 levels and stage
  higher ERCC1 in adenocarcinomas
• Simon, Sharma et al. Chest, 2005

24
ERCC1 by immunohistochemistry in resected NSCLC

• 761 patients from the IALT trial who had tissue
  available
• 1867 patients with completely resected stages
  I-III NSCLC randomized to observation or
  cisplatin plus etoposide or vinorelbine.
• Immunostaining with monoclonal antibody to ERCC1
  interpreted by two blinded pathologists.
• Score calculated by multiplying intensity of
  staining with proportion of positive nuclei.
• Median score defined high vs low ERCC1
  expression.
• Olaussen, Dunant et al. N Engl J Med, 2006

25
ERCC1 in IALT Results

• ERCC1 was more likely to be positive
  in Squamous cell carcinoma Age gt 55
• For the study population as a whole, ERCC1 had no
  prognostic value.
• Olaussen, Dunant et al. N Engl J Med, 2006

26

• Olaussen, Dunant et al. N Engl J Med, 2006

27
Polymorphisms in ERCC2 and XRCC1

• Highly conserved SNPs that likely affect DNA
  repair activity.
• ERCC2 (Asp312Asn) and XRCC1 (Arg 399Gln)
  retrospectively evaluated in 103 NSCLC patients
  treated with platinum based doublets.
• Gurubhagavatula, Liu et al. J Clin Oncol, 2004

28
The Utility of DNA Repair Gene Polymorphisms in
Predicting Outcomes in Patients with Advanced
NSCLC Receiving Systemic Chemotherapy
29
Objectives

• Aim 1
• To validate the differential efficacy (disease
  control) of a platinum based doublet in advanced
  NSCLC and polymorphisms in XPD and XRCC
• Aim 2
• To assess the impact of polymorphisms in XPD and
  XRCC in patients with advanced NSCLC receiving a
  non platinum doublet
• Aim 3
• To correlate the tissue ERCC expression and the
  differential efficacy (disease control) of a
  platinum based doublet in advanced NSCLC

30
Summary

• Decreased DNA repair capacity increases malignant
  potential but also increases sensitivity to
  platinum agents.
• BRCA1 expression conveys platinum resistance but
  susceptibility to anti-microtubule drugs.
• ERCC1 expression by mRNA or IHC predicts platinum
  sensitivity in NSCLC.
• SNPs in ERCC2 XRCC1 may provide a non-invasive
  means of identifying platinum resistance.

31
References

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