- Email: [email protected]
Can sensitivity to cytotoxic chemotherapy be predicted by biomarkers?
symposium article
Annals of Oncology 23 (Supplement 10): x189–x192, 2012 doi:10.1093/annonc/mds309
Can sensitivity to cytotoxic chemotherapy be predicted by biomarkers? E. Felip* & P. Martinez Vall d’Hebron University Hospital, Department of Medical Oncology, Barcelona, Spain
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with <15% of patients surviving beyond 5 years [1]. Chemotherapy remains a key component of treatment in both the adjuvant and metastatic settings. Newer targeted therapies have demonstrated activity for advanced disease. However, many patients fail to achieve benefit with such treatments. Personalizing therapy to select those patients most likely to benefit promises to limit toxic effects and to maximize efficacy. A predictive biomarker is a patient or tumor characteristic that separates a population in regards to the outcome when using a particular treatment. To date, several molecular analyses and biomarkers have been studied. We review here the main predictive biomarkers to chemotherapy in both the adjuvant and the advanced settings. In order to establish a methodological review of predictive biomarkers to chemotherapy in NSCLC patients, we have grouped them into six main categories: DNA synthesis/repair genes, cell cycle regulators, class III Beta-tubulin, signal transduction pathways, gene expression profiling and microRNAs.
DNA synthesis/repair genes excision repair cross-complementation group 1
Excision repair cross-complementation group 1 (ERCC1) is a protein involved in the nucleotide excision repair pathway and interstrand cross-link repair pathway which has a key role in restoring DNA from platinum damage. Its value as a predictive biomarker in the adjuvant setting was analyzed in the IALT trial in which ERCC1 expression was assessed by immunohistochemistry (IHC). Adjuvant chemotherapy, when compared with observation, substantially prolonged survival
among patients with ERCC1-negative tumors (adjusted hazard ratio [HR] for death: 0.65; 95% confidence interval [CI], 0.50 to 0.86; P = 0.002) but not among patients with ERCC1positive tumors (adjusted HR for death: 1.14; 95% CI 0.84 to 1.55; P = 0.40). Retrospective validation studies of ERCC1 expression as a predictive biomarker are expected shortly from the LACE-Bio project. Additionally, the International Tailored Chemotherapy Adjuvant Trial (ITACA) and the Tailored Post Surgical Therapy in Early-Stage NSCLC (TASTE) trials are ongoing randomized studies that prospectively validate the role of ERCC1 expression in the adjuvant setting. In the ITACA trial, patients with completely resected stage II–III NSCLC are treated with either a cisplatin-based doublet or a tailored treatment based on ERCC1 and TS levels. In the experimental arm, patients receive cisplatin–pemetrexed (low ERCC1, low TS), cisplatin–gemcitabine (low ERCC1, high TS), pemetrexed (high ERCC1, low TS) or a taxane (high ERCC1, high TS). In the TASTE trial, patients with non-squamous stage II–IIIA NSCLC are randomized to standard cisplatin–pemetrexed chemotherapy or to a customized arm (erlotinib for epidermal growth factor receptor (EGFR)-mutated patients, cisplatin– pemetrexed in EGFR wild-type/ERCC1-low patients or observation in EGFR wild-type/ERCC1-high/undetermined patients). In advanced NSCLC patients, several retrospective analyses demonstrated that high ERCC1 expression in the tumors, determined by RT-PCR or by IHC, was associated with poor response to platinum-based chemotherapy and shorter survival [2, 3]. In a Spanish Lung Cancer Group (SLCG) prospective trial in advanced disease, customized chemotherapy based on ERCC1 expression levels determined by RT–PCR compared with a standard chemotherapy resulted in a higher response rate but did not increase the length of survival [4]. Taken together, all these results are encouraging but further validation is needed before ERCC1 expression
*Correspondence to: Dr E. Felip; E-mail: [email protected]
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
overview
Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF ARIZONA on June 5, 2015
Non-small-cell lung cancer is the leading cause of cancer-related death worldwide with poor outcomes, even when a curative treatment approach is feasible. Chemotherapy remains a useful option for the majority of patients with advanced or relapsed disease as well as having a substantial role in the adjuvant setting. Identifying predictive biomarkers would enable us to better select those patients more likely to benefit from chemotherapy while avoiding toxic effects in those patients not deriving benefit from chemotherapy. Although the use of biomarkers to select chemotherapy is not the standard approach, several potential biomarkers have been identified and a few prospective trials are ongoing. We review here the most-studied biomarkers for chemotherapy. Key words: biomarkers, chemotherapy, NSCLC, predictive, prognostic
symposium article (IHC, RT–PCR or other) can be recommended as a clinically useful biomarker in the adjuvant or advanced setting. MutS homologue 2
breast cancer gene 1
Breast cancer gene 1 (BRCA1) is a protein with a central role in DNA repair which is also involved in cell cycle dynamics [8]. High BRCA1 levels have been associated with platinum resistance in several models [9]. In resected NSCLC patients, high BRCA1 mRNA levels by qRT-PCR seem to be a worse prognostic biomarker in chemotherapy-naïve patients [10]. Based on this finding, the SLCG is carrying out a prospective phase III randomized trial to evaluate BRCA1 levels, assessed by qRT-PCR, as a predictive biomarker to address the use of adjuvant chemotherapy in completely resected stage II–III NSCLC patients [11]. In the control arm, patients receive cisplatin–docetaxel (Taxotere) and in the customized arm, patients with high BRCA1 expression receive adjuvant docetaxel alone, those with low expression receive cisplatin– gemcitabine and those with intermediate expression receive cisplatin–docetaxel. ribonucleotide reductase messenger 1
Ribonucleotide reductase messenger 1 (RRM1) is a regulator of ribonucleotide reductase, an enzyme important in the ribonucleotide synthesis and DNA repair. High RRM1 expression by qRT-PCR has been shown to correlate with lower response rates and shorter survival in patients with locally advanced NSCLC treated with gemcitabine-based chemotherapy [12]. Its predictive value in customizing chemotherapy was analyzed in a prospective phase II study in which chemotherapy was chosen according to ERCC1 and RRM1 mRNA levels [13]. Patients were allocated to carboplatin–gemcitabine (low RRM1, low ERCC1), docetaxel– gemcitabine (low RRM1, high ERCC1), carboplatin–docetaxel (high RRM1, low ERCC1) or docetaxel–vinorelbine (high RRM1, high ERCC1). The overall response rate was 44% and median survival was 13.3 months, which suggests that customized chemotherapy based on RRM1 and ERCC1 levels is feasible and might improve the outcome in advanced
x | Felip and Martinez
NSCLC patients. Whether RRM1 is predictive in the adjuvant chemotherapy context is now being explored in the SWOG 0720 trial. In that study, patients with resected T2N0M0 or tumors >2 cm are allocated to either adjuvant cisplatin– gemcitabine (low ERCC1 or low RRM1) or observation (high ERCC1 and high RRM1). thymidylate synthase
Thymidylate synthase (TS) is an important enzyme in the DNA replication and repair mechanisms, and it is also the main target of pemetrexed. The fact that TS expression level is higher in squamous cell carcinoma than in non-squamous cell carcinoma is one potential explanation for the sub-histologicassociated pemetrexed activity in NSCLC [14, 15]. The predictive value of TS in resected NSCLC is being studied in the ITACA trial.
cell cycle regulators p27
As a member of the cyclin-dependent kinase inhibitory family, its main activity consists in regulating progression from G1 to the S phase of the cell cycle. In completed resected patients, an important association between p27 expression and benefit from adjuvant chemotherapy was observed in the IALT-Bio program [16]. Benefit derived from adjuvant chemotherapy was restricted to p27-negative tumors (HR 0.66, 95% CI 0.50 to 0.88; P = 0.006) [17]. p53
The tumor suppressor gene p53 play a role in cell cycle, apoptosis induction and genome stability. In the JBR.10 trial, patients with high p53 expression derived benefit from adjuvant chemotherapy (HR 0.54, 95% CI 0.32 to 0.92; P = 0.02) whereas patients with low p53 expression did not. In contrast, p53 mutations were not a predictive factor for adjuvant chemotherapy benefit [18]. The predictive value of p53 expression and mutational status was also studied as part of the LACE-Bio program; where no significant interaction among p53 expression or p53 mutations and treatment was found [19]. Bax
Bax is a proapoptotic factor that is activated by p53 [20]. Bax expression was studied in the IALT-Bio program. Bax expression showed a trend toward an association between increasing levels and higher sensitivity to adjuvant chemotherapy (HR 1.08, 0.83 and 0.68; for groups with low, medium and high Bax expression; P = 0.06) [21]. Bax expression was also evaluated in a pooled analysis of IALT and JBR.10 patients. In these analyses, Bax-positive patients derived benefit from adjuvant chemotherapy in comparison to observation (HR 0.72, 95% CI 0.56 to 0.91; P = 0.007)[22].
class III beta-tubulin Microtubules are essential in cell dynamics and mitosis. Taxanes and vinca alkaloids disrupt normal microtubule function and cause mitosis arrest, which results in apoptosis. Class III beta-tubulin may mediate resistance to taxanes [23]. The value of class III beta-tubulin as a predictive factor was
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MutS homologue 2 (MSH2) is a protein which has a role in initiating DNA repair process in response to cisplatin-induced DNA damages [5]. Its predictive value with the use of adjuvant chemotherapy was studied within the IALT-Bio program [6]. In the low-MSH2 group, assessed by IHC, there was a trend toward improving overall survival with adjuvant chemotherapy when compared with observation (adjusted HR for death: 0.76; 95% CI 0.59 to 0.97; P = 0.03). In the high MSH2 group, there was no difference in the overall survival rate between the adjuvant chemotherapy arm and the observation arm. The effect of combining MSH2 and ERCC1 or p27 expression was also explored. In the combined low MSH2/low ERCC1 subgroup, the magnitude of the overall survival improvement with the use of adjuvant chemotherapy was greater than with any other low-expression marker alone (adjusted HR for death: 0.65; 95% CI 0.47 to 0.91; P = 0.01). In patients with advanced NSCLC, low MSH2 expression detected by IHC predicts response to oxaliplatin-based chemotherapy (response rate 38% versus 0%, P = 0.04) [7].
Annals of Oncology
Annals of Oncology
analyzed in a study in advanced NSCLC patients in which class III beta-tubulin levels were measured by qRT-PCR. In patients with low beta-tubulin levels, carboplatin/paclitaxel yielded a higher response rate than did cisplatin/vinorelbine or cisplatin/gemcitabine [24].
signal transduction pathways KRAS
EGFR
EGFR mutations. The effect of EGFR mutation on patients with early-stage NSCLC receiving adjuvant chemotherapy has been reported from patients enrolled in the JBR.10 study. The presence of sensitizing mutations resulted in relatively greater benefit in patients receiving adjuvant chemotherapy (HR 0.44, 95% CI 0.11 to 1.70, P = 0.22) compared with wild-type patients (HR 0.78, 95% CI 0.58 to 1.06, P = 0.12), but this quantitative difference was not significant (interaction P = 0.50) [30]. EGFR expression. The effect of EGFR gene copy number on patients with early-stage NSCLC receiving adjuvant chemotherapy has also been studied in the JBR.10 study [30]. High EGFR copy was neither significantly prognostic nor predictive, although quantitatively it was associated with greater benefit from adjuvant chemotherapy. In the FLEX trial, the value of an EGFR IHC score as a predictive biomarker for the addition of cetuximab to chemotherapy has been analyzed [31]. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy/cetuximab group than in the chemotherapy alone group (median 12.0 versus 9.6 months, HR 0.73, 0.58–0.93; P = 0.011), with no meaningful increase in side effects. There was no survival benefit for patients in the low
Volume 23 | Supplement 10 | September 2012
EGFR expression group (median 9.8 months versus 10.3 months; HR 0.99, 0.84–1.16; P = 0.88). gene expression profiling The multigene expression technologies have the potential of interrogating thousand of genes simultaneously. Several different platforms and analysis tools are available what makes signatures and genes vary one from another and make reproducibility more difficult. A 15-gene signature as a predictor of benefit from adjuvant chemotherapy was defined from patients enrolled in the JBR.10 study [32]. This signature separated patients into high-risk and low-risk subgroup and correlated with survival. In the high-risk group, treatment with vinorelbine/cisplatin conferred significant survival benefit compared to observation alone (HR 0.33, 0.17–0.63; P = 0.0005) but low-risk patients did not (HR 3.67, 1.22–11.06, P = 0.01). Further validation studies are needed before implementation of theses signatures in clinical practice.
microRNAs (miRNAs) miRNAs are short ribonucleic acid (RNA) molecules of 20 to 22 nucleotides involved in post-transcriptional regulation that bind to complementary sequences on target messenger RNA transcripts resulting in translational repression or target degradation and gene silencing, thus makes miRNAs be related to cell growth, differentiation and survival. In the IALT-Bio project expression of miR-21, miR-29b, miR-34a-b-c, miR-155 and let-7a were analyzed [33]. Expression of these miRNAs, alone or combined, was not predictive for benefit from adjuvant chemotherapy.
conclusion Individualized therapy in patients with NSCLC on the basis of predictive biomarkers has the potential to improve outcomes The identification of EGFR mutations and ALK translocations in NSCLC patients has defined particular populations with different treatment options. Whether a similar approach could be make for patients receiving chemotherapy remains unanswered. At present, several predictive biomarkers have been purposed and their validation in prospective trials is needed. Technical issues are relevant; several methods have been used and its standardization needs to be performed before its implementation in the clinic. Nevertheless, all these results are encouraging and results from ongoing and future trials will better define the useful of biomarkers to predict benefit derived from chemotherapy.
disclosure The authors have declared no conflicts of interest.
references 1. Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10–30. 2. Ceppi P, Volante M, Novello S et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 2006; 17: 1818–1825.
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KRAS is a member of the RAS family, with an intrinsic GTPase activity. KRAS activation results in cell growth, differentiation and survival. KRAS mutations are present in up to 30% of lung adenocarcinomas. In the adjuvant setting, the KRAS wild-type status was predictive of the benefit of adjuvant chemotherapy in a sub-analyses performed in the JBR.10 trial (HR 0.69, 95% CI 0.49 to 0.97; P = 0.03) [18]. Patients with KRAS mutations derived no benefit from the use of adjuvant chemotherapy compared with observation (HR 0.95, 95% CI 0.53 to 1.71; P = 0.87). However, the P value for interaction was not significant. A similar trend was observed in the CALGB9633 for patients with wild-type KRAS allocated to adjuvant carboplatin–paclitaxel (HR 0.69) but again without statistical significance [25]. In a pooled analysis of KRAS mutations in the LACE-Bio project, the KRAS mutation status predicted no benefit from adjuvant chemotherapy [26]. In patients with advanced NSCLC, a large phase III trial has demonstrated overall survival benefit with the addition of cetuximab [27]. The value of KRAS status in NSCLC is not established, when compared with colorectal cancer patients, where the use of cetuximab is restricted to wild-type KRAS patients. In the BMS099 study, which compared platinun– taxane-based chemotherapy alone or plus cetuximab in advanced NSCLC, the presence of KRAS mutations was not associated with a lack of benefit from cetuximab [28, 29].
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in patients with resected non-small cell lung cancer (NSCLC). Ann Oncol 2010; 21, S8:130. Selvakumaran M, Lin HK, Miyashita T et al. Immediate early up-regulation of bax expression by pp53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. Oncogene 1994; 9: 1791–1798. Brambilla E, Dunant A, Filipits M et al. Prognosis and predictive role of alterations of the p53–bax-bcl2 pathway of apoptosis in the IALT (International Adjuvant Lung Cancer Trial). Lung Cancer 2005; 49: pS3; s10. Brambilla E, Bourredjem A, Lantejoul S et al. Bax expression as a predictive marker of survival benefit in non-small cell lung carcinoma treated by adjuvant cisplatin-based chemotherapy. Chicago Multidisciplinary Symp Thoracic Oncol, 2010. Seve P, Lai R, Ding K et al. Class III beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer: analysis of NCIC JBR.10. Clin Cancer Res 2007; 13: 994–999. Rosell R, Scagliotti G, Danenberg KD et al. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Oncogene 2003; 22: 3548–3553. Capelleti M, Wang X, Gu L et al. Impact of KRAS mutations on adjuvant carboplatin/paclitaxel in surgically resected stage IB NCSLC: CALGB 9633. J Clin Oncol 2010; 28: 15S: abstract 7008. Tsao M, Hainaut P, Bourredjem A et al. LACE-Bio pooled analysis of the prognosis and predictive value of KRAS mutation in completely resected nonsmall cell lung cancer (NSCLC). Ann Oncol 2010; 21: 63–67. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009; 373: 1525–1531. Lynch TJ, Patel T, Dreisbach L et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010; 28: 911–917. Khambata-Ford S, Harbison CT, Hart LL et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 918–927. Tsao MS, Sakurada A, Ding K et al. Prognostic and predictive value of epidermal growth factor receptor tyrosine kinase domain mutation status and gene copy number for adjuvant chemotherapy in non-small cell lung cancer. J Thorac Oncol 2011; 6: 139–147. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. New England J Med 2009; 361: 947–957. Pirker R, Pereira JR, von Pawel J et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-smallcell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 33–42. Zhu CQ, Ding K, Strumpf D et al. Prognostic and predictive gene signature for adjuvant chemotherapy in resected non-small-cell lung cancer. J Clin Oncol 2010; 28: 4417–4424. Voortman J, Goto A, Mendiboure J et al. MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. Cancer Res 70: 8288–8298.
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3. Azuma K, Komohara Y, Sasada T et al. Excision repair cross-complementation group 1 predicts progression-free and overall survival in non-small cell lung cancer patients treated with platinum-based chemotherapy. Cancer Sci 2007; 98: 1336–1343. 4. Cobo M, Isla D, Massuti B et al. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in nonsmall-cell lung cancer. J Clin Oncol 2007; 25: 2747–2754. 5. Duckett DR, Drummond JT, Murchie AI et al. Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. Proc Natl Acad Sci USA 1996; 93: 6443–6447. 6. Kamal NS, Soria JC, Mendiboure J et al. MutS homologue 2 and the long-term benefit of adjuvant chemotherapy in lung cancer. Clin Cancer Res 2010; 16: 1206–1215. 7. Scartozzi M, Franciosi V, Campanini N et al. Mismatch repair system (MMR) status correlates with response and survival in non-small cell lung cancer (NSCLC) patients. Lung Cancer 2006; 53: 103–109. 8. Murphy CG, Moynahan ME. BRCA gene structure and function in tumor suppression: a repair-centric perspective. Cancer J 2010; 16: 39–47. 9. Husain A, He G, Venkatraman ES et al. BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res 1998; 58: 1120–1123. 10. Rosell R, Skrzypski M, Jassem E et al. BRCA1: a novel prognostic factor in resected non-small-cell lung cancer. PLoS One 2007; 2: e1129. 11. Cobo M, Massuti B, Morán T et al. Spanish customized adjuvant trial (SCAT) based on BRCA1 mRNA levels. J Clin Oncol 2008; 26, 15S: abstract 7533 12. Bepler G, Kusmartseva I, Sharma S et al. RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 2006; 24: 4731–4737. 13. Simon G, Sharma A, Li X et al. Feasibility and efficacy of molecular analysisdirected individualized therapy in advanced non-small-cell lung cancer. J Clin Oncol 2007; 25: 2741–2746. 14. Scagliotti GV, Parikh P, von Pawel J et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26: 3543–3551. 15. Ceppi P, Volante M, Saviozzi S et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 2006; 107: 1589–1596. 16. Filipits M, Pirker R, Dunant A et al. Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the International Adjuvant Lung Cancer Trial Biologic Program. J Clin Oncol 2007; 25: 2735–2740. 17. Pirker R, Rousseau D, Paris E et al. Cross-validation and pooled analyses of the putative prognostic/predictive biomarkers p27, p16, and cyclin E in IALT, ANITA, JBR10 and CALGB 9633. Chicago Multidisciplinary Symp Thoracic Oncol 2010. 18. Tsao MS, Aviel-Ronen S, Ding K et al. Prognostic and predictive importance of pp53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J Clin Oncol 2007; 25: 5240–5247. 19. Graziano S, Paris E, Ma X et al. LACE-Bio pooles analysis of the prognostic and predictive value of p53 mutations and expression by inmunohistochemistry (IHC)
Annals of Oncology
Annals of Oncology 23 (Supplement 10): x189–x192, 2012 doi:10.1093/annonc/mds309
Can sensitivity to cytotoxic chemotherapy be predicted by biomarkers? E. Felip* & P. Martinez Vall d’Hebron University Hospital, Department of Medical Oncology, Barcelona, Spain
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with <15% of patients surviving beyond 5 years [1]. Chemotherapy remains a key component of treatment in both the adjuvant and metastatic settings. Newer targeted therapies have demonstrated activity for advanced disease. However, many patients fail to achieve benefit with such treatments. Personalizing therapy to select those patients most likely to benefit promises to limit toxic effects and to maximize efficacy. A predictive biomarker is a patient or tumor characteristic that separates a population in regards to the outcome when using a particular treatment. To date, several molecular analyses and biomarkers have been studied. We review here the main predictive biomarkers to chemotherapy in both the adjuvant and the advanced settings. In order to establish a methodological review of predictive biomarkers to chemotherapy in NSCLC patients, we have grouped them into six main categories: DNA synthesis/repair genes, cell cycle regulators, class III Beta-tubulin, signal transduction pathways, gene expression profiling and microRNAs.
DNA synthesis/repair genes excision repair cross-complementation group 1
Excision repair cross-complementation group 1 (ERCC1) is a protein involved in the nucleotide excision repair pathway and interstrand cross-link repair pathway which has a key role in restoring DNA from platinum damage. Its value as a predictive biomarker in the adjuvant setting was analyzed in the IALT trial in which ERCC1 expression was assessed by immunohistochemistry (IHC). Adjuvant chemotherapy, when compared with observation, substantially prolonged survival
among patients with ERCC1-negative tumors (adjusted hazard ratio [HR] for death: 0.65; 95% confidence interval [CI], 0.50 to 0.86; P = 0.002) but not among patients with ERCC1positive tumors (adjusted HR for death: 1.14; 95% CI 0.84 to 1.55; P = 0.40). Retrospective validation studies of ERCC1 expression as a predictive biomarker are expected shortly from the LACE-Bio project. Additionally, the International Tailored Chemotherapy Adjuvant Trial (ITACA) and the Tailored Post Surgical Therapy in Early-Stage NSCLC (TASTE) trials are ongoing randomized studies that prospectively validate the role of ERCC1 expression in the adjuvant setting. In the ITACA trial, patients with completely resected stage II–III NSCLC are treated with either a cisplatin-based doublet or a tailored treatment based on ERCC1 and TS levels. In the experimental arm, patients receive cisplatin–pemetrexed (low ERCC1, low TS), cisplatin–gemcitabine (low ERCC1, high TS), pemetrexed (high ERCC1, low TS) or a taxane (high ERCC1, high TS). In the TASTE trial, patients with non-squamous stage II–IIIA NSCLC are randomized to standard cisplatin–pemetrexed chemotherapy or to a customized arm (erlotinib for epidermal growth factor receptor (EGFR)-mutated patients, cisplatin– pemetrexed in EGFR wild-type/ERCC1-low patients or observation in EGFR wild-type/ERCC1-high/undetermined patients). In advanced NSCLC patients, several retrospective analyses demonstrated that high ERCC1 expression in the tumors, determined by RT-PCR or by IHC, was associated with poor response to platinum-based chemotherapy and shorter survival [2, 3]. In a Spanish Lung Cancer Group (SLCG) prospective trial in advanced disease, customized chemotherapy based on ERCC1 expression levels determined by RT–PCR compared with a standard chemotherapy resulted in a higher response rate but did not increase the length of survival [4]. Taken together, all these results are encouraging but further validation is needed before ERCC1 expression
*Correspondence to: Dr E. Felip; E-mail: [email protected]
© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
symposium article
overview
Downloaded from http://annonc.oxfordjournals.org/ at UNIVERSITY OF ARIZONA on June 5, 2015
Non-small-cell lung cancer is the leading cause of cancer-related death worldwide with poor outcomes, even when a curative treatment approach is feasible. Chemotherapy remains a useful option for the majority of patients with advanced or relapsed disease as well as having a substantial role in the adjuvant setting. Identifying predictive biomarkers would enable us to better select those patients more likely to benefit from chemotherapy while avoiding toxic effects in those patients not deriving benefit from chemotherapy. Although the use of biomarkers to select chemotherapy is not the standard approach, several potential biomarkers have been identified and a few prospective trials are ongoing. We review here the most-studied biomarkers for chemotherapy. Key words: biomarkers, chemotherapy, NSCLC, predictive, prognostic
symposium article (IHC, RT–PCR or other) can be recommended as a clinically useful biomarker in the adjuvant or advanced setting. MutS homologue 2
breast cancer gene 1
Breast cancer gene 1 (BRCA1) is a protein with a central role in DNA repair which is also involved in cell cycle dynamics [8]. High BRCA1 levels have been associated with platinum resistance in several models [9]. In resected NSCLC patients, high BRCA1 mRNA levels by qRT-PCR seem to be a worse prognostic biomarker in chemotherapy-naïve patients [10]. Based on this finding, the SLCG is carrying out a prospective phase III randomized trial to evaluate BRCA1 levels, assessed by qRT-PCR, as a predictive biomarker to address the use of adjuvant chemotherapy in completely resected stage II–III NSCLC patients [11]. In the control arm, patients receive cisplatin–docetaxel (Taxotere) and in the customized arm, patients with high BRCA1 expression receive adjuvant docetaxel alone, those with low expression receive cisplatin– gemcitabine and those with intermediate expression receive cisplatin–docetaxel. ribonucleotide reductase messenger 1
Ribonucleotide reductase messenger 1 (RRM1) is a regulator of ribonucleotide reductase, an enzyme important in the ribonucleotide synthesis and DNA repair. High RRM1 expression by qRT-PCR has been shown to correlate with lower response rates and shorter survival in patients with locally advanced NSCLC treated with gemcitabine-based chemotherapy [12]. Its predictive value in customizing chemotherapy was analyzed in a prospective phase II study in which chemotherapy was chosen according to ERCC1 and RRM1 mRNA levels [13]. Patients were allocated to carboplatin–gemcitabine (low RRM1, low ERCC1), docetaxel– gemcitabine (low RRM1, high ERCC1), carboplatin–docetaxel (high RRM1, low ERCC1) or docetaxel–vinorelbine (high RRM1, high ERCC1). The overall response rate was 44% and median survival was 13.3 months, which suggests that customized chemotherapy based on RRM1 and ERCC1 levels is feasible and might improve the outcome in advanced
x | Felip and Martinez
NSCLC patients. Whether RRM1 is predictive in the adjuvant chemotherapy context is now being explored in the SWOG 0720 trial. In that study, patients with resected T2N0M0 or tumors >2 cm are allocated to either adjuvant cisplatin– gemcitabine (low ERCC1 or low RRM1) or observation (high ERCC1 and high RRM1). thymidylate synthase
Thymidylate synthase (TS) is an important enzyme in the DNA replication and repair mechanisms, and it is also the main target of pemetrexed. The fact that TS expression level is higher in squamous cell carcinoma than in non-squamous cell carcinoma is one potential explanation for the sub-histologicassociated pemetrexed activity in NSCLC [14, 15]. The predictive value of TS in resected NSCLC is being studied in the ITACA trial.
cell cycle regulators p27
As a member of the cyclin-dependent kinase inhibitory family, its main activity consists in regulating progression from G1 to the S phase of the cell cycle. In completed resected patients, an important association between p27 expression and benefit from adjuvant chemotherapy was observed in the IALT-Bio program [16]. Benefit derived from adjuvant chemotherapy was restricted to p27-negative tumors (HR 0.66, 95% CI 0.50 to 0.88; P = 0.006) [17]. p53
The tumor suppressor gene p53 play a role in cell cycle, apoptosis induction and genome stability. In the JBR.10 trial, patients with high p53 expression derived benefit from adjuvant chemotherapy (HR 0.54, 95% CI 0.32 to 0.92; P = 0.02) whereas patients with low p53 expression did not. In contrast, p53 mutations were not a predictive factor for adjuvant chemotherapy benefit [18]. The predictive value of p53 expression and mutational status was also studied as part of the LACE-Bio program; where no significant interaction among p53 expression or p53 mutations and treatment was found [19]. Bax
Bax is a proapoptotic factor that is activated by p53 [20]. Bax expression was studied in the IALT-Bio program. Bax expression showed a trend toward an association between increasing levels and higher sensitivity to adjuvant chemotherapy (HR 1.08, 0.83 and 0.68; for groups with low, medium and high Bax expression; P = 0.06) [21]. Bax expression was also evaluated in a pooled analysis of IALT and JBR.10 patients. In these analyses, Bax-positive patients derived benefit from adjuvant chemotherapy in comparison to observation (HR 0.72, 95% CI 0.56 to 0.91; P = 0.007)[22].
class III beta-tubulin Microtubules are essential in cell dynamics and mitosis. Taxanes and vinca alkaloids disrupt normal microtubule function and cause mitosis arrest, which results in apoptosis. Class III beta-tubulin may mediate resistance to taxanes [23]. The value of class III beta-tubulin as a predictive factor was
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MutS homologue 2 (MSH2) is a protein which has a role in initiating DNA repair process in response to cisplatin-induced DNA damages [5]. Its predictive value with the use of adjuvant chemotherapy was studied within the IALT-Bio program [6]. In the low-MSH2 group, assessed by IHC, there was a trend toward improving overall survival with adjuvant chemotherapy when compared with observation (adjusted HR for death: 0.76; 95% CI 0.59 to 0.97; P = 0.03). In the high MSH2 group, there was no difference in the overall survival rate between the adjuvant chemotherapy arm and the observation arm. The effect of combining MSH2 and ERCC1 or p27 expression was also explored. In the combined low MSH2/low ERCC1 subgroup, the magnitude of the overall survival improvement with the use of adjuvant chemotherapy was greater than with any other low-expression marker alone (adjusted HR for death: 0.65; 95% CI 0.47 to 0.91; P = 0.01). In patients with advanced NSCLC, low MSH2 expression detected by IHC predicts response to oxaliplatin-based chemotherapy (response rate 38% versus 0%, P = 0.04) [7].
Annals of Oncology
Annals of Oncology
analyzed in a study in advanced NSCLC patients in which class III beta-tubulin levels were measured by qRT-PCR. In patients with low beta-tubulin levels, carboplatin/paclitaxel yielded a higher response rate than did cisplatin/vinorelbine or cisplatin/gemcitabine [24].
signal transduction pathways KRAS
EGFR
EGFR mutations. The effect of EGFR mutation on patients with early-stage NSCLC receiving adjuvant chemotherapy has been reported from patients enrolled in the JBR.10 study. The presence of sensitizing mutations resulted in relatively greater benefit in patients receiving adjuvant chemotherapy (HR 0.44, 95% CI 0.11 to 1.70, P = 0.22) compared with wild-type patients (HR 0.78, 95% CI 0.58 to 1.06, P = 0.12), but this quantitative difference was not significant (interaction P = 0.50) [30]. EGFR expression. The effect of EGFR gene copy number on patients with early-stage NSCLC receiving adjuvant chemotherapy has also been studied in the JBR.10 study [30]. High EGFR copy was neither significantly prognostic nor predictive, although quantitatively it was associated with greater benefit from adjuvant chemotherapy. In the FLEX trial, the value of an EGFR IHC score as a predictive biomarker for the addition of cetuximab to chemotherapy has been analyzed [31]. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy/cetuximab group than in the chemotherapy alone group (median 12.0 versus 9.6 months, HR 0.73, 0.58–0.93; P = 0.011), with no meaningful increase in side effects. There was no survival benefit for patients in the low
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EGFR expression group (median 9.8 months versus 10.3 months; HR 0.99, 0.84–1.16; P = 0.88). gene expression profiling The multigene expression technologies have the potential of interrogating thousand of genes simultaneously. Several different platforms and analysis tools are available what makes signatures and genes vary one from another and make reproducibility more difficult. A 15-gene signature as a predictor of benefit from adjuvant chemotherapy was defined from patients enrolled in the JBR.10 study [32]. This signature separated patients into high-risk and low-risk subgroup and correlated with survival. In the high-risk group, treatment with vinorelbine/cisplatin conferred significant survival benefit compared to observation alone (HR 0.33, 0.17–0.63; P = 0.0005) but low-risk patients did not (HR 3.67, 1.22–11.06, P = 0.01). Further validation studies are needed before implementation of theses signatures in clinical practice.
microRNAs (miRNAs) miRNAs are short ribonucleic acid (RNA) molecules of 20 to 22 nucleotides involved in post-transcriptional regulation that bind to complementary sequences on target messenger RNA transcripts resulting in translational repression or target degradation and gene silencing, thus makes miRNAs be related to cell growth, differentiation and survival. In the IALT-Bio project expression of miR-21, miR-29b, miR-34a-b-c, miR-155 and let-7a were analyzed [33]. Expression of these miRNAs, alone or combined, was not predictive for benefit from adjuvant chemotherapy.
conclusion Individualized therapy in patients with NSCLC on the basis of predictive biomarkers has the potential to improve outcomes The identification of EGFR mutations and ALK translocations in NSCLC patients has defined particular populations with different treatment options. Whether a similar approach could be make for patients receiving chemotherapy remains unanswered. At present, several predictive biomarkers have been purposed and their validation in prospective trials is needed. Technical issues are relevant; several methods have been used and its standardization needs to be performed before its implementation in the clinic. Nevertheless, all these results are encouraging and results from ongoing and future trials will better define the useful of biomarkers to predict benefit derived from chemotherapy.
disclosure The authors have declared no conflicts of interest.
references 1. Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10–30. 2. Ceppi P, Volante M, Novello S et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol 2006; 17: 1818–1825.
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KRAS is a member of the RAS family, with an intrinsic GTPase activity. KRAS activation results in cell growth, differentiation and survival. KRAS mutations are present in up to 30% of lung adenocarcinomas. In the adjuvant setting, the KRAS wild-type status was predictive of the benefit of adjuvant chemotherapy in a sub-analyses performed in the JBR.10 trial (HR 0.69, 95% CI 0.49 to 0.97; P = 0.03) [18]. Patients with KRAS mutations derived no benefit from the use of adjuvant chemotherapy compared with observation (HR 0.95, 95% CI 0.53 to 1.71; P = 0.87). However, the P value for interaction was not significant. A similar trend was observed in the CALGB9633 for patients with wild-type KRAS allocated to adjuvant carboplatin–paclitaxel (HR 0.69) but again without statistical significance [25]. In a pooled analysis of KRAS mutations in the LACE-Bio project, the KRAS mutation status predicted no benefit from adjuvant chemotherapy [26]. In patients with advanced NSCLC, a large phase III trial has demonstrated overall survival benefit with the addition of cetuximab [27]. The value of KRAS status in NSCLC is not established, when compared with colorectal cancer patients, where the use of cetuximab is restricted to wild-type KRAS patients. In the BMS099 study, which compared platinun– taxane-based chemotherapy alone or plus cetuximab in advanced NSCLC, the presence of KRAS mutations was not associated with a lack of benefit from cetuximab [28, 29].
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