Tumor BRCA1, RRM1 and RRM2 mRNA Expression Levels and Clinical Response to First-Line Gemcitabine plus Docetaxel in Non-Small-Cell Lung Cancer Patients

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Abstract

Background

Overexpression of RRM1 and RRM2 has been associated with gemcitabine resistance. BRCA1 overexpression increases sensitivity to paclitaxel and docetaxel. We have retrospectively examined the effect of RRM1, RRM2 and BRCA1 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients.

Methodology and Principal Findings

Tumor samples were collected from 102 chemotherapy-naïve advanced NSCLC patients treated with gemcitabine plus docetaxel as part of a randomized trial. RRM1, RRM2 and BRCA1 mRNA levels were assessed by quantitative PCR and correlated with response, time to progression and survival. As BRCA1 levels increased, the probability of response increased (Odds Ratio [OR], 1.09: p = 0.01) and the risk of progression decreased (hazard ratio [HR], 0.99; p = 0.36). As RRM1 and RRM2 levels increased, the probability of response decreased (RRM1: OR, 0.97; p = 0.82; RRM2: OR, 0.94; p<0.0001) and the risk of progression increased (RRM1: HR, 1.02; p = 0.001; RRM2: HR, 1.005; p = 0.01). An interaction observed between BRCA1 and RRM1 allowed patients to be classified in three risk groups according to combinations of gene expression levels, with times to progression of 10.13, 4.17 and 2.30 months ( p = 0.001). Low BRCA1 expression was the only factor significantly associated with longer time to progression in 31 patients receiving cisplatin-based second-line therapy.

Conclusions

The mRNA expression of BRCA1, RRM1 and RRM2 is potentially a useful tool for selecting NSCLC patients for individualized chemotherapy and warrants further investigation in prospective studies.

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Most cited references 28

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Cancer statistics, 2007.

Ahmedin Jemal, Rebecca Siegel, Elizabeth Ward … (2007)

Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. This report considers incidence data through 2003 and mortality data through 2004. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007. Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 0.3% per year in women; and a 13.6% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.

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First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.

Lecia V. Sequist, Renato G. Martins, David Spigel … (2008)

Somatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non-small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms. Chemotherapy-naïve patients with advanced NSCLC with >or= 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate. Ninety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification. First-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.

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RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites.

Bijan Sobhian, Genze Shao, Dana R. Lilli … (2007)

Mutations affecting the BRCT domains of the breast cancer-associated tumor suppressor BRCA1 disrupt the recruitment of this protein to DNA double-strand breaks (DSBs). The molecular structures at DSBs recognized by BRCA1 are presently unknown. We report the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (BRCA1-associated ring domain protein 1) E3 ligase and the deubiquitinating enzyme (DUB) BRCC36 to MDC1-gammaH2AX-dependent lysine(6)- and lysine(63)-linked ubiquitin polymers at DSBs. These events are required for cell cycle checkpoint and repair responses to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of DSBs.

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Author and article information

Contributors

: Role: Editor

Journal

Journal ID (nlm-ta): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2008

Publication date (Electronic): 11 November 2008

Volume: 3

Issue: 11

Affiliations

[1 ]“Theagenion” Cancer Hospital of Thessaloniki, Thessaloniki, Greece

[2 ]Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Greece

[3 ]Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, Badalona, Barcelona, Spain

[4 ]Pangaea Biotech, USP Dexeus University, C/Sabino Arana 5, Barcelona, Spain

[5 ]Department of Medical Oncology, University General Hospital of Heraklion, Crete, Greece

[6 ]Department of Pathology, University General Hospital of Heraklion, Crete, Greece

[7 ]University of Alcala de Henares, Alcala de Henares, Spain

[8 ]Autonomous University of Madrid, Madrid, Spain

Karolinska Institutet, Sweden

Author notes

* E-mail: rrosell@ 123456ico.scs.es (RR); georgsec@ 123456med.uoc.gr (JS)

Conceived and designed the experiments: VG JS. Performed the experiments: CP PM MT DM MT. Contributed reagents/materials/analysis tools: IB DM AK. Wrote the paper: MSR RR. Supervised the Laboratory work: MT. Evaluation of the samples: AK ES. Performed the statistical analyses: MSR JJS.

Article

Publisher ID: 08-PONE-RA-04917R2

DOI: 10.1371/journal.pone.0003695

PMC ID: 2579656

PubMed ID: 19002265

SO-VID: b4b29367-7945-4e8d-814a-8c2a40a9ab28

Copyright statement: Boukovinas et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Tumor BRCA1, RRM1 and RRM2 mRNA Expression Levels and Clinical Response to First-Line Gemcitabine plus Docetaxel in Non-Small-Cell Lung Cancer Patients

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Abstract

Background

Methodology and Principal Findings

Conclusions

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PLOS: COVID-19 pandemic

Most cited references 28

Cancer statistics, 2007.

First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.

RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites.

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