Mesothelioma Powerpoint Targeted Toxic Therapy
Targeted Toxic Therapy:
Identifying Platinum Resistance
Boone Goodgame, M.D.
Washington University School of Medicine, St. Louis.
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}
Key Clinical Question:
• Which patients are most likely to benefit from these effective therapies, and which patients should be offered alternatives?
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
The DNA repair paradox
• Decreased DNA repair capacity increases cancer susceptibility and cancer aggressiveness.
• Decreased DNA repair capacity increases susceptibility to platinums.
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}
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
Essential NER
• recognition of damage
• incision of DNA
• excision of oligonucleotides (25 – 30 nucleotides)
{Friedberg; Nat Rev Cancer, 2001}
Transcription coupled NER
Excision Repair System
{Rosell, Cobo et al.; Lung Cancer, 2005}
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
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}
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}
Established mediators of platinum resistance in NSCLC
• BRCA1
• ERCC1
– Germline polymorphisms
– Tumor expression by mRNA
– Immunohistochemistry
• Polymorphisms in ERCC2 & XRCC1
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 1000–10 000-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}
BRCA1 mRNA expression levels and survival in NSCLC patients treated with neo-adjuvant gemcitabine & cisplatin.
• Total 55 pts; Bottom: N=15, Middle=28, Top=12; p=0.01
{Taron, Rosell et al.; Hum Mol Genet, 2004}
ERCC1 (Excision repair cross-complementing 1)
• Essential component of NER
• Assessed by:
– Functional germ-line polymorphisms
– Expression levels by mRNA
– Expressional levels by IHC
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 (p=0.0058)
– 62 patients; 18% wild type; survivals were 9.7 months and >18 months (p=0.04)
{Ryu, Hong et al.; Lung Cancer, 2004}
{Isla, Sarries et al.; Ann Oncol, 2004}
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 (p=0.41)
• A separate polymorphism C8092A was associated with survival in this study
– 13 months vs 22 months (p=0.006).
{Zhou, Gurubhagavatula et al.; Clin Cancer Res, 2004}
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 < 0.001)
{Lord, Brabender et al.; Clin
Cancer Res, 2002}
{Rosell, et.al.; ASCO; 2005}
{Rosell, et.al.; ASCO; 2005}
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}
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}
ERCC1 in IALT Results
• ERCC1 was more likely to be positive in:
Squamous cell carcinoma
Age > 55
• For the study population as a whole, ERCC1 had no prognostic value.
• {Olaussen, Dunant et al.; N Engl J Med, 2006}
{Olaussen, Dunant et al.; N Engl J Med, 2006}
Polymorphisms in ERCC2 and XRCC1
• Highly conserved SNP’s 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}
The Utility of DNA Repair Gene Polymorphisms in Predicting Outcomes in Patients with Advanced NSCLC Receiving Systemic Chemotherapy
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
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.
• SNP’s in ERCC2 & XRCC1 may provide a non-invasive means of identifying platinum resistance.
References
1. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-8, 2002
2. D'Addario G, Pintilie M, Leighl NB, et al: Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 23:2926-36, 2005
3. Rabik CA, Dolan ME: Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev, 2006
4. Friedberg EC: How nucleotide excision repair protects against cancer. Nat Rev Cancer 1:22-33, 2001
5. Rosell R, Cobo M, Isla D, et al: Applications of genomics in NSCLC. Lung Cancer 50 Suppl 2:S33-40, 2005
6. Husain A, He G, Venkatraman ES, et al: BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 58:1120-3, 1998
7. Taron M, Rosell R, Felip E, et al: BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer. Hum Mol Genet 13:2443-9, 2004
8. Ryu JS, Hong YC, Han HS, et al: Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 44:311-6, 2004
9. Isla D, Sarries C, Rosell R, et al: Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol 15:1194-203, 2004
10. Zhou W, Gurubhagavatula S, Liu G, et al: Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res 10:4939-43, 2004
11. Lord RV, Brabender J, Gandara D, et al: Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 8:2286-91, 2002
12. Simon GR, Sharma S, Cantor A, et al: ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest 127:978-83, 2005
13. Olaussen KA, Dunant A, Fouret P, et al: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983-91, 2006
14. Gurubhagavatula S, Liu G, Park S, et al: XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol 22:2594-601, 2004
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