Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Customizing systemic therapy in patients with advanced non-small cell lung cancer:

Customizing systemic therapy in patients with advanced non-small cell lung cancer: Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Customizing systemic therapy in patients with (2011) 3(4) 207218 DOI: 10.1177/ advanced non-small cell lung cancer ! The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/ ´ ´ A. M. Sadowska, V. Nowe, A. Janssens, E. Boeykens, W. A. De Backer and P. R. Germonpre journalsPermissions.nav Abstract: Lung cancer is the leading cause of cancer deaths worldwide. Standard chemo- therapy has been shown to improve quality of life and has a modest influence on overall survival. This modest improvement in survival is partly due to the choice of chemotherapy regimens that have been based on prognostic factors such as age, performance status and comorbidities of the patient. This underlines the importance of developing a more personalized therapy for patients with non-small cell lung cancer. Such an approach may reduce the var- iation in how individual patients respond to medications by tailoring therapies to their genetic profile. In this review we focus on several aspects of customized therapy, looking not only at patient characteristics but also to tumor histology and specific tumor biomarkers. Keywords: bevacizumab, histology, non-small cell lung cancer, pemetrexed, personalized therapy, tyrosine kinase inhibitors Correspondence to: Introduction such a personalized treatment should be based A. M. Sadowska, MD, PhD Lung cancer is the leading cause of cancer- on patient and/or tumor characteristics, which Dept of Respiratory Medicine, University related deaths in Western countries, with non- together provide prognostic and/or predictive Hospital Antwerp, small-cell lung cancer (NSCLC) accounting for information. This information should then facil- Wilrijkstraat 10, 2650 Antwerp, Belgium more than 85% of primary lung cancers. itate the selection of appropriate systemic treat- a_m_sadowska@ Importantly, the majority of lung cancers are ment for an individual patient by avoiding yahoo.co.uk metastasized at the time of diagnosis, making unnecessary, less effective or more toxic treat- V. Nowe´, MD, PhD A. Janssens, MD them illegible for curative treatment by either ments (Figure 1). E. Boeykens, MD surgery or radiotherapy. W. A. De Backer, MD, PhD There are three considerations to produce a P. R. Germonpre´, MD, PhD Systemic treatment with either chemotherapy or successful molecularly targeted biological treat- Department of Pulmonary biologic therapy is the key component for the ment. First, the oncogenic target controlling Medicine, Antwerp University Hospital and treatment of patients with disseminated cancer growth and survival must be identified; University of Antwerp, NSCLC. Indeed, chemotherapy in addition to second, an effective therapy targeting this onco- Belgium supportive care has been shown to improve qual- genic target needs to be made available; and, ity of life, control symptoms and overall survival third, a biomarker that predicts a favorable out- (i.e. 10% increase in the 1-year survival rate) in come of the targeted therapy needs to be patients with advanced NSCLC [Non-small Cell identified. Lung Cancer Collaborative Group, 1995]. However these improvements are modest Recently, advances have been made to elucidate (response rates 30% for first-line treatment molecular pathways that play a role in NSCLC and 10% for second-line treatment, with 2 carcinogenesis and that may also correlate with month increase in median overall survival), indi- clinical response. Many biomarkers are suggested cating that many NSCLC patients fail to respond to have both prognostic and predictive proper- to ‘standard’ chemotherapy. In part, this is due to ties; however, randomized clinical trials and the fact that until recently the choice of chemo- meta-analyses are necessary to determine the therapy regimens was based mainly on either the usefulness of a given marker in clinical setting age, performance status (PS) and comorbidities (Figure 2). To date, the only biomarkers, which of the patient or on the physician’s experience have been tested or validated in large phase III and patient’s preferences. These facts underline trials, are tumor histology and the presence of an the importance of developing a more personal- activating epidermal growth factor receptor ized therapy for patients with NSCLC. Ideally, (EGFR) mutation. http://tam.sagepub.com 207 Therapeutic Advances in Medical Oncology 3 (4) Patient Tumor characteristics Avoid -histology -unnecessary treatment -genetic alterations -ineffective treatment -gene expression -toxic treatment -protein expression Prognostic information � adequate treatment Personalized treatment Predictive information � sensitivity to treatment � treatment related toxicity Patient characteristics Society -germ-line genetics -better use available (i.e. SNPs, …) resources -cytokines -reduce cost of care Figure 1. Development of personalized therapy for non-small cell lung cancer. Many biomarkers have both prognostic and predictive properties  RCT and/or meta- analyses are required to determine the clinical usefulness of a marker Open label Retrospective Double-blind analysis randomized Small numbers Non-stratified Placebo-controlled Single arm Adequately powered Prospective analysis Stratified by biomarker status Figure 2. Many biomarkers have both prognostic and predictive properties. Randomized controlled trials and/ or meta-analyses are required to determine their clinical usefulness. Clinical patient-based treatment decisions confirmed that PS is a very important prognostic factor, while age and gender were other indepen- Age, performance and comorbidities dent significant variables [Sculier et al. 2008]. In a The choice of chemotherapy regimens until number of trials, the presence of comorbidities recently was based on prognostic factors such as was also found to be associated with poorer sur- age, PS and comorbidities of the patient. vival [Lee et al. 2011; Irisa et al. 2010]. Nevertheless, NSCLC patients with a poorer The retrospective analysis of the large PS, older age, or the presence of comorbidities International Staging Committee database derive a similar survival benefit from 208 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. chemotherapy as patients without these poor while pemetrexed had a superior survival in the prognostic factors, but they experience signifi- nonsquamous subgroup [Hanna et al. 2004]. cantly more toxicities [Davidoff et al. 2010; Gronberg et al. 2010; Asmis et al. 2008; Weiss A preplanned subgroup analysis in the first-line et al. 2006; Lilenbaum et al. 2005; Langer et al. study confirmed that the effect on survival of 2002]. In other words, age, PS and the presence pemetrexed-containing chemotherapy is signifi- of comorbidities may predict for tolerability and cantly different in patients with nonsquamous toxicity, but not for survival benefits associated NSCLC and patients with squamous cell carci- with single-agent or platinum-based noma. In patients with adenocarcinoma and chemotherapy. large-cell carcinoma, the overall survival was superior in the cisplatin plus pemetrexed arm, while in patients with squamous cell carcinoma Pemetrexed there was a significant improvement in survival Pemetrexed is a multitargeted antifolate inhibitor with cisplatin plus gemcitabine. The overall sur- of thymidilate syntethase (TS) dihydrofolate vival for a fourth group, consisting of all of those reductase and glycinamide ribonucleotide patients in whom a generic cytological diagnosis formyl transferase [Hong et al. 2010; Shih et al. of NSCLC without further subtype classification 1998]. was made (NOS or ‘not otherwise specified’), did Several trials studied the role pemetrexed as a not show a significant difference between the two first- or second-line treatment in patients with arms. [Scagliotti et al. 2008] advanced NSCLC. The results of these phase Similar results were found in the pemetrexed III trials are summarized in Table 1. In summary, maintenance trial: the improvements in progres- there was no difference between first-line peme- sion-free survival and overall survival were con- trexed plus cisplatin and cisplatin plus gemcita- fined to patients with nonsquamous histology. bine with regard to progression-free survival and In patients with squamous cell cancer, the pro- median overall survival [Scagliotti et al. 2008]. gression-free survival and overall survival was Similarly, pemetrexed was not inferior to doce- similar in the pemetrexed and the placebo arms taxel when given as second-line treatment [Ciuleanu et al. 2009]. The hazard ratios (HRs) [Hanna et al. 2004]. Recently, pemetrexed was also compared with placebo in the maintenance for overall survival according to tumor histology or ‘early second line’ following four cycles of first- are summarized in Table 2. line platinum-based chemotherapy. The use of pemetrexed in this maintenance setting resulted Resistance to pemetrexed in cancer cell lines has in a significantly longer progression-free survival been shown to be due to upregulation of TS and overall survival [Ciuleanu et al. 2009]. [Sigmond et al. 2003]. Pemetrexed in combina- tion with cisplatin was first licensed for the treat- A retrospective analysis of the trial comparing ment of malignant pleural mesothelioma pemetrexed with docetaxel in previously treated [Vogelzang et al. 2003]. Recently, low TS protein NSCLC patients found a significant treatment- levels were found to be predictive of improved by-histology interaction. Docetaxel resulted in a time-to-progression and overall survival in better survival in the squamous cell subgroup, patients with mesothelioma treated with Table 1. Pemetrexed in the treatment of non-small cell lung cancer. Data from Scagliotti et al., [2008], Hanna et al., [2004], and Ciuleanu et al., [2009]. st nd 1 line: 2 line: Maintenance Cis-Gem Cis-Pem Doc Pern Plac Pern Median PFS 5.1 m 4.8 m 2.9 m 2.9 m 2.0 m 4.0 m HR 1.04 HR 0.97 HR 0.60* Median OS 10.3 m 10.3 m 7.9 m 8.3 m 10.6 m 13.4 m HR 0.99 HR 0.99 HR 0.79* HR, hazard ratio; PFS, progression-free survival; OS, overall survival; Cis-Gem, cisplatin plus gemcitabine; Doc, docetaxel; Pem, pemetrexed; Plac, placebo; m, months; *p< 0.05. http://tam.sagepub.com 209 Therapeutic Advances in Medical Oncology 3 (4) Table 2. Pemetrexed and non-small cell lung cancer histology: squamous versus non-squamous. Data shown as hazard ratio. Data from Ciuleanu et al., [2009]. st nd Histology 1 line: Cis-Pem 2 line: Maintenance: vs. Cis-Gem Pern vs. Doc Pern vs. Plac Non-squamous 0.81* 0.78* 0.70* Squamous 1.23 1.56* 1.07 Cis-Gem, cisplatin plus gemcitabine; Pem, pemetrexed; Plac, placebo; *p< 0.05. pemetrexed-based chemotherapy [Righi et al. anti-angiogenic effects [Hanahan and Weinberg, 2010]. Similarly, the observed treatment-by-his- 2000], but it normalizes the tumor vasculature tology interaction for pemetrexed in NSCLC has thereby improving the drug delivery to the been related to differences in TS expression in tumor [Jain, 2001]. Indeed, several trials have the different histologic subtypes. In chemother- shown the beneficial effects of adding bevacizu- apy-naive patients, the baseline expression of TS mab to standard chemotherapy in a variety of is significantly higher in squamous cell carcinoma tumors [Willett et al. 2007, 2004; Sandler et al. compared to adenocarcinoma [Ceppi et al. 2006]. 2006]. Large-cell carcinomas, when considered as a single group of tumors, have a median TS The initial randomized phase II trial evaluating expression comparable with squamous cell the role of bevacizumab in patients with cancer, and higher than in adenocarcinoma. advanced or recurrent NSCLC demonstrated However, the TS expression in large-cell carcino- that addition of bevacizumab (high dose) to car- mas differs according to their immunohistochem- boplatin and paclitaxel resulted in higher ical profile: in large-cell carcinomas expressing response rates (31.5% versus 18.8%, respectively) markers of squamous cell differentiation (i.e. and longer time-to-progression (7.4 months with p63) the TS levels were significantly higher bevacizumab versus 4.2 months for chemotherapy than in those expressing markers of adenocarci- alone). However, an alarming rate (9%) of life- noma (i.e. TTF-1). Thus, the expression of TS threatening pulmonary bleeding was observed in in large-cell carcinoma may resemble that of ade- the bevacizumab-treated patients. This life-threa- nocarcinomas or squamous cell carcinomas tening pulmonary hemorrhage was found to be [Monica et al. 2009]. These findings may explain associated with squamous cell histology (four of why the HRs for overall survival are consistently the six cases occurred in patients with squamous in favor of the pemetrexed-treated adenocarci- cell histology), tumor necrosis and cavitation, noma patients, but vary for the large-cell and and disease location close to major blood vessels ‘NOS’ subgroups (Table 3). [Johnson et al. 2004]. In summary, it may be concluded that in As a result of these safety concerns observed in patients with nonsquamous NSCLC, peme- the phase II trials, the subsequent phase III trials trexed-containing treatments are superior to excluded patients with tumors with a predomi- gemcitabine- or docetaxel-containing treatments. nant squamous component. The rates of grade Furthermore, these results should warrant a pro- 3 pulmonary hemorrhage in the bevacizumab spective study that is specifically designed to eval- plus chemotherapy arms of these phase III trials uate TS-expression as a more reliable marker to in patients with nonsquamous cell NSCLC were select those patients most likely to benefit from <2% [Reck et al. 2009; Sandler et al. 2006]. cisplatin plus pemetrexed therapy. The ECOG-trial showed that the addition of bev- Bevacizumab acizumab to paclitaxel plus carboplatin resulted Bevacizumab is a monoclonal vascular endothe- in a significant increase in progression-free sur- lial growth factor (VEGF) antibody binding vival (6.2 versus 4.5 months; HR 0.66) and over- directly to VEGF and removing it from the envi- all survival (12.3 months versus 10.3 months; HR ronment [Presta et al. 1997]. It is not considered 0.79) [Sandler et al. 2006]. The AVAiL trial con- cytotoxic bearing in mind it has mostly firmed progression-free survival of bevacizumab 210 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. Table 3. Pemetrexed and non-small cell lung cancer histology: squamous versus adenocarcinoma, large-cell carcinoma and not other specified types. Data shown as hazard ratio. Data from Scagliotti et al., [2008] and Ciuleanu et al., [2009]. st nd Histology 1 line: Cis-Pem 2 line: Pern Maintenance: vs. Cis-Gem vs. Doc Pern vs. Plac Non-squamous 0.81* 0.78* 0.70* Adenocarcinoma 0.84* 0.92 0.73* Large cell 0.67 0.27* 0.98 NOS 1.08 0.57 0.61* Squamous 1.23 1.56* 1.07 Cis-Gem, cisplatin plus gemcitabine; Doc, docetaxel; Pem, pemetrexed; Plac, placebo; NOS, not otherwise specified; *p< 0.05 when combined with cisplatin plus gemcitabine with higher frequency in women, nonsmokers, (HR 0.75). However, in the AVAiL trial the pro- adenocarcinoma, and in patients of Asian eth- gression-free survival benefit did not translate nicity, thus explaining the higher response rates into a significant overall survival benefit. This to treatment with EGFR-TKIs in these patient lack of overall survival benefit has been attributed groups [Pao et al. 2004]. Importantly, the con- to the use of efficacious second-line therapies stitutive EGFR activation caused by these muta- [Reck et al. 2010]. tions causes oncogene addiction to the EGFR pathway. This means that de-induction of Thus, by using nonsquamous histology as a bio- mutant EGFR expression leads to dramatic marker for selecting patients eligible for bevaci- regression of tumors suggesting the need for zumab treatment, undue toxicity could be persistent mutant EGFR activity for continued avoided without compromising the antitumoral tumor survival [Herbst et al. 2008]. effects. These EGFR mutations were also found to be a favorable prognostic factor for survival in Tumor biomarker-based treatment decisions advanced NSCLC patients treated with chemo- therapy with or without concomitant EGFR-TKI EGFR tyrosine kinase inhibitors treatment [Eberhard et al. 2005]. EGFR belongs to a family of four related trans- membrane receptors, namely EGFR (HER1), The presence of the activating mutation in exons HER2, HER3 and HER4. It regulates important 19 and 21 of the EGFR results in an activation of processes including proliferation, apoptosis, the Akt and STAT pathways without having an angiogenesis and invasion. As EGFR is fre- effect on ERK/MAP signaling. It has been sug- quently expressed in NSCLC [Rusch et al. gested that EGFR-TKIs affect wild-type and 1997], it has been an important target for the mutant cells differently. Namely, gefinitib triggers development of new agents. The EGFR tyrosine apoptosis in cell-lined harboring EGFR exon 19 kinase inhibitors (TKIs), erlotinib and gefitinib, or 21 mutations that results in complete or partial have been extensively studied in NSCLC. response. On the other hand, it induces G1 arrest in EGFR wild-type cells that leads to stable dis- Even with the first clinical trials of EGFR-TKIs, ease [Pao and Miller, 2005]. it was observed that female patients, nonsmo- kers, patients of Asian ethnicity and patients Recently, several trials have examined the poten- with adenocarcinomas had a greater response tial role of EGFR-TKIs in the first-line treatment rate following treatment with EGFR-TKIs. of patients with tumors with activating mutations However, it has now been demonstrated that the EGFR-TKI sensitivity is associated with on the EGFR [Mitsudomi et al. 2010; Maemondo the presence of activating mutations in the tyro- et al. 2010]. These trials all showed that the pres- sine kinase domain of EGFR in the NSCLC ence of EGFR mutation is a strong predictive tumor and not with these clinical characteristics marker for improved response rate and improved per se [Rosell et al. 2009; Lynch et al. 2004; Paez progression free survival with EGFR-TKI versus et al. 2004]. However, these mutations occur chemotherapy (Table 4). The IPASS trial, which http://tam.sagepub.com 211 Therapeutic Advances in Medical Oncology 3 (4) Table 4. Progression-free survival and response rate in epidermal growth factor receptor (EGFR) mutation positive patients following first-line treatment. Data from Mitsudomi et al. [2009] and Makato et al. [2010]. Progression-free survival (months) Response rate Chemotherapy EGFR-TKI Chemotherapy EGFR-TKI Mitsudomi et al. [2009] 6.3 9.3 32.2% 62.1% Cisplatin-docetaxel versus gefinitib Makato etal. [2010] 5.5 10.4 30.7% 73.7% Carboplatin-paclitaxel versus gefinitib TKI, tyrosine kinase inhibitor. Table 5. First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) versus chemother- apy: IPASS trial. The presence of EGFR mutation is a strong predictive marker for response rate and progres- sion-free survival (PFS). Data from Mok et al. [2009]. EGFR wild type EGFR-mutationþ Gefitinib Carbo/Pacli Gefitinib Carbo/Pacli Response rate 1% 23%* 71%* 47% PFS 1.5 m 5.5 m* 9.6 m* 6.3 m HR2.85* HR 0.48* OS MST 12 m MST 20 m HR1.38 HR0.78 Carbo, carboplatin; HR, hazard ratio; MST, musculoskeletal toxicity; OS: Overall Survival; Pacli, paclitaxel; *p< 0.05. also included patients without activating EGFR Erlotinib has also been shown to prolong survival mutations, demonstrated that the presence of an in patients with NSCLC after failure of first-line EGFR mutation is associated with a higher or second-line chemotherapy [Shepherd et al. response rate to chemotherapy and is a favorable 2005]. In this trial, the presence of an EGFR prognostic factor regardless of treatment (Table 5). mutation was shown to increase the responsive- ness to erlotinib, but it is not indicative of a sur- Similar findings were reported in the SATURN vival benefit as the overall survival benefit was trial, which explored the role of erlotinib in main- also observed in the EGRF wild-type patients tenance or early second-line settings immediately [Tsao et al. 2005]. after completion of the initial course of platinum- based chemotherapy. In unselected patients, Inhibition of other oncogenic drivers such as median progression-free survival was significantly anaplastic lymphoma kinase longer with erlotinib than with placebo (12.3 A number of specific genetic lesions (i.e. KRAS, versus 11.1 weeks respectively; HR 0.71; ALK, BRAF, MET, PGDFR, PIK3CA, HER2) p< 0.0001). Moreover, in patients with tumors driving tumor proliferation have been identified harboring an EGFR mutation, erlotinib as main- in primary lung adenocarcinomas. Inhibition of tenance treatment resulted in a dramatic increase these oncogenic drivers in NSCLC patients har- in progression-free survival (HR 0.10; boring these mutated pathways is a logical candi- p< 0.0001). However, patients with tumors with wild-type EGFR also seemed to derive a date for future targeted treatments. So far, the most promising results have been observed with benefit from erlotinib maintenance as the overall survival was significantly improved in these the inhibition of anaplastic lymphoma kinase patients (HR 0.77; p< 0.05) [Cappuzzo et al. (ALK) in patients with NSCLC with EML4- 2010]. ALK translocation. 212 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. ALK is an oncogene that induces cell transfor- reduces the accumulation of genetic aberrations mation in vitro and in vivo. Translocation of ALK that are thought to contribute to a tumors malig- results in an abnormal fusion gene, usually with nant potential and therefore the risk of relapse its counterpart in lung cancer, echinoderm after definitive treatment. This study is in accor- dance with the results of the International microtubule-associated protein-like 4 (ELM4). Adjuvant Lung Cancer Biology Trial (IALT- The translocation produces an ongoing activation Bio) [Olaussen et al. 2006] that showed better of an intercellular tyrosine kinase, which then survival in patients with ERCC1 positive leads to proliferation and cancer propagation tumors (p¼ 0.009). In contrast to these studies, [Horn and Pao, 2009]. In some lung cancers, Rosell and colleagues showed that ERCC1 over- this will be the sole driver of their existence because the ALK translocation is so dominant expression was related to worse prognosis. Their study, however, did not reach a statistical [Soda et al. 2008, 2007]. Treatment of patients with ALK rearrangements with crizotinib, an significance of p> 0.05 [Rosell et al. 2007]. inhibitor of the ALK tyrosine kinase, results in Nevertheless, the analysis of patients with response rates in excess of 50% and estimated advanced disease treated with cisplatin and gem- probability of 6-month progression-free survival citabine showed that low expression of ERRC1 of more than 70% [Kwak et al. 2010]. was associated with longer survival [Lord et al. 2002]. ALK rearrangements and EGFR mutations seem to be usually mutually exclusive while mainly Ribonucleotide reductase messenger 1 (RRM1) occurring in patients with the same clinical char- is the regulatory component of ribonucleotide acteristics, namely younger patients, never or reductase that assists with DNA synthesis and light smokers and adenocarcinomas. repair. Moreover, it is the predominant target of Interestingly, the group of patients with ALK nucleoside analogue, gemcitabine. Analysis of rearrangements tends to have a slightly higher patients with advanced NSCLC treated with proportion of males compared with those who cisplatin-containing combinations or nonplati- num doublets showed a longer median survival have EGFR mutations. Importantly, patients in a group with low RRM1 expression (13.7 with ALK rearrangements do not respond to months) versus a group with high RRM1 EGFR-TKI treatment [Shaw et al. 2009]. expression (3.6 months). Moreover, median Cisplatin-based therapy and DNA repair survival was significantly longer in the group systems treated with cisplatin plus gemcitabine who Cisplatin and carboplatin are used as standard had lower levels of both RMM1 and ERCC1 chemotherapy for solid tumors. The mecha- expression than other subgroups. Therefore, it nism of action is based on the formation of cis- has been suggested that RRM1 expression is a platin-DNA adducts leading to apoptosis. predictive marker of survival in gemcitabine Removal of these adducts, leading to chemoresis- plus cisplatin-treated patients [Rosell et al. tance, is mainly carried out by the nucleotide 2004]. excision repair system. Breast cancer type 1 susceptibility protein Excision repair cross-complementation group 1 (BRCA1) plays a central role in DNA repair as (ERCC 1) is a rate-limiting protein in the NER a component of multiple repair pathways. and ICL-R pathways, which works by recogniz- Furthermore, BRCA1 is a potential regulator of ing and removing platinum adducts and by mitotic spindle assembly as it is found to be colo- repairing interstrand DNA crosslinks. Its prog- calized with beta-tubulin to the microtubules nostic effect was assessed in a study by Simon of the mitotic spindle [Coate et al. 2009; and colleagues in chemotherapy-naı ¨ve patients Lafarge et al. 2001]. The increased expression with resected NSCLC [Simon et al. 2005]. of BRCA1 appears to be an unfavorable prognos- Namely, there was a statistically significant differ- tic factor as it is correlated with decreased overall ence in median survival for patients with ERCC1 survival in chemotherapy-naı ¨ve patients with expression >50 (94.6 months) compared with NSCLC after surgery [Rosell et al. 2007]. <50 (35.5 months) (p¼ 0.01). Multivariate anal- ysis revealed that high ERCC1 expression inde- In preclinical models, upregulation of BRCA1 pendently predicted longer survival. They also has been linked to platinum resistance and sensi- suggested that an intact DNA repair mechanism tivity to antimicrotubule drugs such as taxanes http://tam.sagepub.com 213 Therapeutic Advances in Medical Oncology 3 (4) and vinca alkaloids [Rosell et al. 2004]. This dif- Median overall survival was 11 months in the ferential sensitivity to different chemotherapeutic lowest BRCA1 expression treated with gemcita- agents according to the BRCA1 expression levels bine plus cisplatin and 2-year survival was makes BRCA1 an interesting candidate marker 41.2%, comparable with the median survival to customize chemotherapy treatment in and 2-year survival obtained with cisplatin and NSCLC. This concept has been tested in a gemcitabine in a recent large phase III trial phase II trial where nonsquamous cell carcinoma [Scagliotti et al. 2008]. Meanwhile, in patients patients were allocated to different treatments with the highest BRCA expression treated with based on the EGFR mutation status and docetaxel alone, median survival was 11 months BRCA1 mRNA expression levels. Treatment (similar to the survival obtained in a large phase algorithm is shown in Figure 3. In this trial, the III trial in patients treated with cisplatin plus influence of receptor- associated protein 80 (RAP either docetaxel or vinorelbine) [Fossella et al. 80) expression was also examined as RAP 80 has 2003]. The survival of patients with low been shown to act upstream of BRCA1 and be BRCA1 expression decreased as RAP 80 expres- required for the accumulation of BRCA1 to sites sion increased, confirming that RAP80 can of DNA breaks [Rosell et al. 2007; Wang et al. replace the BRCA1 DNA repair function in 2007]. cells lacking BRCA (Table 6). RNA & DNA extraction from tumor EGFR mutation + Erlotinib BRCA1 mRNA expression in EGFR WT* Low Intermediate High Cisplatin + Cisplatin + Docetaxel Gemcitabine Docetaxel monotherapy Figure 3. Customized treatment of non-small cell lung cancer based on epidermal growth factor receptor (EGFR) mutation and BRCA1 mRNA expression. WT, wild type. Table 6. Customized treatment of non-small cell lung cancer based on epidermal growth factor receptor mutations and BRCA1 mRNA expression. Correlation of BRCA1 and RAP80 expression with median survival. Purple circle, cisplatingemcitabine; green circle, cisplatindocetaxel; red, docetaxel monotherapy. Data from Rosell et al. [2007]. RAP80 mRNA Low Intermediate High BRCA1 mRN Low NR 8 m 7 m Intermediate 5 m 13 m 16 m High 6 m 12 m 11 m m, months. 214 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. Thus, this trial showed that chemotherapy cus- help us guide treatment choices. In patients with tomized according to BRCA1 expression levels is squamous cell cancers, treatment with bevacizu- associated with encouraging overall survival, and mab leads to life-threatening toxicity. that RAP80 could play a crucial modulating Furthermore, squamous cell tumors appear to effect in this model of customized chemotherapy. be more or less resistant to pemetrexed-contain- The concept of customizing chemotherapy treat- ing chemotherapy. Thus, by restricting treatment ment based on BRCA1 and RAP80 expression with bevacizumab and pemetrexed to patients levels is now being tested in a prospective ran- with nonsquamous NSCLC it should be possible domized phase III trial. to obtain better clinical outcomes (i.e. better tol- erability and/or survival). The presence of an activating EGFR mutation predicts for a better Conclusions response rate and progression-free survival with The newer systemic therapies for NSCLC are EGFR-TKI treatment compared with first-line directed towards specific targets but their efficacy chemotherapy regimens. In the maintenance will be strongly influenced by inherent tumor het- and second-line treatment trials with erlotinib, erogeneity and the multiple robust and compen- an overall survival benefit was also observed in satory signaling pathways involved in tumor patients with wild-type EGFR [Cappuzzo et al. homeostasis [Thomson et al. 2008; Amit et al. 2010]. Thus, EGFR-TKI treatment is a valid 2007]. Therefore, identification of genotypes choice for first-line treatment in patients with that respond better to specific therapies, thus actually adjusting the therapies to the genetic such an EGFR mutation. However, this does profile of the patients, remains an important not mean that treatment with EGFR-TKIs and interesting issue. should be restricted to patients with EGFR muta- tions: in patients with wild-type EGFR, erlotinib The recent advances in our understanding of can be considered for second- or third-line treat- NSCLC tumor biology and the mechanisms of ment (Table 7). action of various systemic treatments have led to the first steps towards personalized treatment These first steps towards personalized medicine of patients with NSCLC. A number of potential represent a shift in the management of NSCLC. selection factors for customizing systemic treat- Indeed, NSCLC should no longer be viewed as ment in advanced NSCLC are summarized in one common generic tumor but rather as a col- Figure 4. At present, only tumor histology and lection of more rare tumors with differing biolog- EGFR-mutation status have been validated in ical behaviors and different sensitivities to various phase III trials as predictive markers, which can systemic treatments. NSCLC TNM-stage Tumor Histology characteristics Tumor biomarkers Performance status Patient Age and comorbidities characteristics “common cancer” Patient biomarkers Toxicities Patient preference Treatment administration Doctor Experience with drug preference “collection of cancer” Figure 4. Potential selection factors for customizing systemic treatment in advanced non-small cell lung cancer (NSCLC). Moving from thinking of NSCLC as a single entity towards customized treatment of a collec- tion of tumors grouped under the term NSCLC. http://tam.sagepub.com 215 Therapeutic Advances in Medical Oncology 3 (4) Table 7. Selection factors for customizing systemic treatment in advanced non-small cell lung cancer. Category Drug Selection factor Effect Tumor histology EGFR-TKI Adeno Improved response rate Pemetrexed Nonsquamous Exclusion non-benefiting pts Bevacizumab Non-Squamous Safety concerns in squamous Molecular tumor EGFR-TKI EGFR-mutation Improved PFS biomarkers Pemetrexed Low TS expression Selection of benefiting pts Gemcitabine Low RRM1 Selection of benefiting pts Platinum ERCC1.BRCA1, RAP80 Improved RR, PFS and/or OS EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; PFS, progression-free survival; OS, overall survi- val; pts, patients; RR, response rate; TS, thymidilate syntethase; RRM1; ribonucleotide reductase messenger 1. patients with advanced non-small-cell lung cancer. J Funding Clin Oncol 28: 21912197. This research received no specific grant from any funding agency in the public, commercial, or not- Eberhard, D.A., Johnson, B.E., Amler, L.C., Goddard, A.D., Heldens, S.L., Herbst, R.S. et al. for-profit sectors. (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic Conflict of interest statement indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in The authors declare no conflict of interest in pre- combination with erlotinib. J Clin Oncol paring this manuscript. 23: 59005909. Fossella, F., Pereira, J.R., von Pawel, J., Pluzanska, A., Gorbounova, V., Kaukel, E. et al. (2003) Randomized, References multinational, phase III study of docetaxel plus plati- Amit, I., Wides, R. and Yarden, Y. (2007) Evolvable num combinations versus vinorelbine plus cisplatin for signaling networks of receptor tyrosine kinases: rele- advanced non-small-cell lung cancer: the TAX 326 vance of robustness to malignancy and to cancer study group. J Clin Oncol 21: 30163024. therapy. Mol Syst Biol 3: 151. Gronberg, B.H., Sundstrom, S., Kaasa, S., Bremnes, Asmis, T.R., Ding, K., Seymour, L., Shepherd, F.A., R.M., Flotten, O., Amundsen, T. et al. (2010) Leighl, N.B., Winton, T.L. et al. (2008) Age and Influence of comorbidity on survival, toxicity and comorbidity as independent prognostic factors in the health-related quality of life in patients with advanced treatment of non small-cell lung cancer: a review of non-small-cell lung cancer receiving platinum-doublet National Cancer Institute of Canada Clinical Trials chemotherapy. Eur J Cancer 46: 22252234. Group trials. J Clin Oncol 26(1): 5459. Hanahan, D. and Weinberg, R.A. (2000) The hall- Cappuzzo, F., Ciuleanu, T., Stelmakh, L., Cicenas, S., marks of cancer. Cell 100: 5770. Szczesna, A., Juhasz, E. et al. (2010) Erlotinib as Hanna, N., Shepherd, F.A., Fossella, F.V., Pereira, maintenance treatment in advanced non-small-cell J.R., De Marinis, F., von Pawel, J. et al. (2004) lung cancer: a multicentre, randomised, placebo-con- Randomized phase III trial of pemetrexed versus doc- trolled phase 3 study. Lancet Oncol 11: 521529. etaxel in patients with non-small-cell lung cancer pre- Ceppi, P., Volante, M., Saviozzi, S., Rapa, I., Novello, viously treated with chemotherapy. J Clin Oncol S., Cambieri, A. et al. (2006) Squamous cell carci- 22: 15891597. noma of the lung compared with other histotypes Herbst, R.S., Heymach, J.V. and Lippman, S.M. shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107: 15891596. (2008) Lung cancer. N Engl J Med 359: 13671380. Hong, J., Kyung, S.Y., Lee, S.P., Park, J.W., Jung, Ciuleanu, T., Brodowicz, T., Zielinski, C., Kim, J.H., S.H., Lee, J.I. et al. (2010) Pemetrexed versus gefitinib Krzakowski, M., Laack, E. et al. (2009) Maintenance pemetrexed plus best supportive care versus placebo versus erlotinib in previously treated patients with non- plus best supportive care for non-small-cell lung small cell lung cancer. Korean J Intern Med cancer: a randomised, double-blind, phase 3 study. 25: 294300. Lancet 374: 14321440. Horn, L. and Pao, W. (2009) EML4-ALK: honing in Coate, L.E., John, T., Tsao, M.S. and Shepherd, F.A. on a new target in non-small-cell lung cancer. J Clin (2009) Molecular predictive and prognostic markers in Oncol 27: 42324235. non-small-cell lung cancer. Lancet Oncol Irisa, K., Masago, K., Togashi, Y., Fujita, S., Hatachi, 10: 10011010. Y., Fukuhara, A. et al. (2010) Significance of Davidoff, A.J., Tang, M., Seal, B. and Edelman, M.J. pretreatment comorbidities in elderly patients (2010) Chemotherapy and survival benefit in elderly with advanced non-small-cell lung cancer treated 216 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. with chemotherapy or epidermal growth factor lung cancer harbouring mutations of the epidermal receptor-tyrosine kinase inhibitor. Med Oncol, growth factor receptor (WJTOG3405): an open label, in press. randomised phase 3 trial. Lancet Oncol 11: 121128. Jain, R.K. (2001) Normalizing tumor vasculature with Mitsudomi et al. (2009). anti-angiogenic therapy: a new paradigm for combi- Mok et al. (2009). nation therapy. Nat Med 7: 987989. Monica, V., Scagliotti, G.V., Ceppi, P., Righi, L., Johnson, D.H., Fehrenbacher, L., Novotny, W.F., Cambieri, A., Lo Iacono, M. et al. (2009) Differential Herbst, R.S., Nemunaitis, J.J., Jablons, D.M. et al. Thymidylate Synthase Expression in Different Variants (2004) Randomized phase II trial comparing bevaci- of Large-Cell Carcinoma of the Lung. Clin Cancer Res zumab plus carboplatin and paclitaxel with carboplatin 15: 75477552. and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. J Clin Oncol 22: 21842191. (1995) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual Kwak, E.L., Bang, Y.J., Camidge, D.R., Shaw, A.T., patients from 52 randomised clinical trials. Br Med J Solomon, B., Maki, R.G. et al. (2010) Anaplastic 311: 899909. lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363: 16931703. Olaussen, K.A., Dunant, A., Fouret, P., Brambilla, E., Andre, F., Haddad, V. et al. (2006) DNA repair by Lafarge, S., Sylvain, V., Ferrara, M. and Bignon, Y.J. ERCC1 in non-small-cell lung cancer and cisplatin- (2001) Inhibition of BRCA1 leads to increased che- based adjuvant chemotherapy. N Engl J Med moresistance to microtubule-interfering agents, an 355: 983991. effect that involves the JNK pathway. Oncogene 20: 65976606. Paez, J.G., Janne, P.A., Lee, J.C., Tracy, S., Greulich, H., Gabriel, S. et al. (2004) EGFR mutations in lung Langer, C.J., Manola, J., Bernardo, P., Kugler, J.W., cancer: correlation with clinical response to gefitinib Bonomi, P., Cella, D. et al. (2002) Cisplatin-based therapy. Science 304: 14971500. therapy for elderly patients with advanced non-small- cell lung cancer: implications of Eastern Cooperative Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, Oncology Group 5592, a randomized trial. J Natl K., Sarkaria, I. et al. (2004) EGF receptor gene Cancer Inst 94: 173181. mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors Lee, L., Cheung, W.Y., Atkinson, E. and to gefitinib and erlotinib. Proc Natl Acad Sci U S A Krzyzanowska, M.K. (2011) Impact of comorbidity on 101: 1330613311. chemotherapy use and outcomes in solid tumors: a systematic review. J Clin Oncol 29: 106117. Pao, W. and Miller, V.A. (2005) Epidermal growth factor receptor mutations, small-molecule kinase Lilenbaum, R.C., Herndon II, J.E., List, M.A., Desch, inhibitors, and non-small-cell lung cancer: current C., Watson, D.M., Miller, A.A. et al. (2005) knowledge and future directions. J Clin Oncol Single-agent versus combination chemotherapy in 23: 25562568. advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol Presta, L.G., Chen, H., O’Connor, S.J., Chisholm, V., 23: 190196. Meng, Y.G., Krummen, L. et al. (1997) Humanization of an anti-vascular endothelial growth factor mono- Lord, R.V., Brabender, J., Gandara, D., Alberola, V., clonal antibody for the therapy of solid tumors and Camps, C., Domine, M. et al. (2002) Low ERCC1 other disorders. Cancer Res 57: 45934599. expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small Reck, M., von Pawel, J., Zatloukal, P., Ramlau, R., cell lung cancer. Clin Cancer Res 8: 22862291. Gorbounova, V., Hirsh, V. et al. (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or Lynch, T.J., Bell, D.W., Sordella, R., bevacizumab as first-line therapy for nonsquamous Gurubhagavatula, S., Okimoto, R.A., Brannigan, B.W. non-small-cell lung cancer: AVAil. J Clin Oncol et al. (2004) Activating mutations in the epidermal 27: 12271234. growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med Reck, M., von Pawel, J., Zatloukal, P., Ramlau, R., 350: 21292139. Gorbounova, V., Hirsh, V. et al. (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or pla- Makato et al. (2010). cebo as first-line therapy for nonsquamous non-small- Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, cell lung cancer: results from a randomised phase III S., Oizumi, S., Isobe, H. et al. (2010) Gefitinib or trial (AVAiL). Ann Oncol 21: 18041809. chemotherapy for non-small-cell lung cancer with Righi, L., Papotti, M.G., Ceppi, P., Bille, A., Bacillo, mutated EGFR. N Engl J Med 362: 23802388. E., Molinaro, L. et al. (2010) Thymidylate synthase Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., but not excision repair cross-complementation group 1 Okamoto, I., Tsurutani, J. et al. (2010) Gefitinib versus tumor expression predicts outcome in patients with cisplatin plus docetaxel in patients with non-small-cell malignant pleural mesothelioma treated with http://tam.sagepub.com 217 Therapeutic Advances in Medical Oncology 3 (4) pemetrexed-based chemotherapy. J Clin Oncol resistance to the multitargeted antifolate Pemetrexed 28: 15341539. (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Rosell, R., Danenberg, K.D., Alberola, V., Bepler, G., Biochem Pharmacol 66: 431438. Sanchez, J.J., Camps, C. et al. (2004) Ribonucleotide reductase messenger RNA expression and survival Simon, G.R., Sharma, S., Cantor, A., Smith, P. and in gemcitabine/cisplatin-treated advanced non-small Bepler, G. (2005) ERCC1 expression is a predictor of cell lung cancer patients. Clin Cancer Res survival in resected patients with non-small cell lung 10: 13181325. cancer. Chest 127: 978983. Rosell, R., Moran, T., Queralt, C., Porta, R., Soda, M., Choi, Y.L., Enomoto, M., Takada, S., Cardenal, F., Camps, C. et al. (2009) Screening for Yamashita, Y., Ishikawa, S. et al. (2007) epidermal growth factor receptor mutations in lung Identification of the transforming EML4-ALK fusion cancer. N Engl J Med 361: 958967. gene in non-small-cell lung cancer. Nature 448: 561566. Rosell, R., Skrzypski, M., Jassem, E., Taron, M., Bartolucci, R., Sanchez, J.J. et al. (2007) BRCA1: a Soda, M., Takada, S., Takeuchi, K., Choi, Y.L., novel prognostic factor in resected non-small-cell lung Enomoto, M., Ueno, T. et al. (2008) A mouse model cancer. PLoS One 2: e1129. for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 105: 1989319897. Rusch, V., Klimstra, D., Venkatraman, E., Pisters, P.W., Langenfeld, J. and Dmitrovsky, E. (1997) Thomson, S., Petti, F., Sujka-Kwok, I., Epstein, D. Overexpression of the epidermal growth factor recep- and Haley, J.D. (2008) Kinase switching in mesench- tor and its ligand transforming growth factor alpha is ymal-like non-small cell lung cancer lines contributes frequent in resectable non-small cell lung cancer but to EGFR inhibitor resistance through pathway redun- does not predict tumor progression. Clin Cancer Res dancy. Clin Exp Metastasis 25: 843854. 3: 515522. Tsao, M.S., Sakurada, A., Cutz, J.C., Zhu, C.Q., Sandler, A., Gray, R., Perry, M.C., Brahmer, J., Kamel-Reid, S., Squire, J. et al. (2005) Erlotinib in Schiller, J.H., Dowlati, A. et al. (2006) Paclitaxel-car- lung cancer - molecular and clinical predictors of out- boplatin alone or with bevacizumab for non-small-cell come. N Engl J Med 353: 133144. lung cancer. N Engl J Med 355: 25422550. Vogelzang, N.J., Rusthoven, J.J., Symanowski, J., Scagliotti, G.V., Parikh, P., von Pawel, J., Biesma, B., Denham, C., Kaukel, E., Ruffie, P. et al. (2003) Vansteenkiste, J., Manegold, C. et al. (2008) Phase III Phase III study of pemetrexed in combination study comparing cisplatin plus gemcitabine with cis- with cisplatin versus cisplatin alone in patients platin plus pemetrexed in chemotherapy-naive patients with malignant pleural mesothelioma. J Clin Oncol with advanced-stage non-small-cell lung cancer. J Clin 21: 26362644. Oncol 26: 35433551. Wang, B., Matsuoka, S., Ballif, B.A., Zhang, D., Sculier, J.P., Chansky, K., Crowley, J.J., Van Smogorzewska, A., Gygi, S.P. et al. (2007) Abraxas Meerbeeck, J. and Goldstraw, P. (2008) The impact of and RAP80 form a BRCA1 protein complex required additional prognostic factors on survival and their for the DNA damage response. Science relationship with the anatomical extent of disease 316: 11941198. expressed by the 6th Edition of the TNM Weiss, G.J., Langer, C., Rosell, R., Hanna, N., Classification of Malignant Tumors and the proposals Shepherd, F., Einhorn, L.H. et al. (2006) for the 7th Edition. J Thorac Oncol 3: 457466. Elderly patients benefit from second-line cytotoxic Shaw, A.T., Yeap, B.Y., Mino-Kenudson, M., chemotherapy: a subset analysis of a randomized Digumarthy, S.R., Costa, D.B., Heist, R.S. et al. phase III trial of pemetrexed compared with (2009) Clinical features and outcome of patients with docetaxel in patients with previously treated non-small-cell lung cancer who harbor EML4-ALK. J advanced non-small-cell lung cancer. J Clin Oncol Clin Oncol 27: 42474253. 24: 44054411. Shepherd, F.A., Rodrigues Pereira, J., Ciuleanu, T., Willett, C.G., Boucher, Y., di Tomaso, E., Duda, Tan, E.H., Hirsh, V., Thongprasert, S. et al. (2005) D.G., Munn, L.L., Tong, R.T. et al. (2004) Direct Erlotinib in previously treated non-small-cell lung evidence that the VEGF-specific antibody bevacizu- cancer. N Engl J Med 353: 123132. mab has antivascular effects in human rectal cancer. Nat Med 10: 145147. Shih, C., Habeck, L.L., Mendelsohn, L.G., Chen, V.J. and Schultz, R.M. (1998) Multiple folate enzyme Willett, C.G., Duda, D.G., di Tomaso, E., Boucher, inhibition: mechanism of a novel pyrrolopyrimidine- Y., Czito, B.G., Vujaskovic, Z. et al. (2007) Complete based antifolate LY231514 (MTA). Adv Enzyme Regul pathological response to bevacizumab and chemora- 38: 135152. diation in advanced rectal cancer. Nat Clin Pract Oncol Visit SAGE journals online http://tam.sagepub.com 4: 316321. Sigmond, J., Backus, H.H., Wouters, D., Temmink, O.H., Jansen, G. and Peters, G.J. (2003) Induction of 218 http://tam.sagepub.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

Customizing systemic therapy in patients with advanced non-small cell lung cancer:

Loading next page...
 
/lp/sage/customizing-systemic-therapy-in-patients-with-advanced-non-small-cell-0RLnQb3CLe
Publisher
SAGE
Copyright
Copyright © 2022 by SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
ISSN
1758-8340
eISSN
1758-8359
DOI
10.1177/1758834011409000
Publisher site
See Article on Publisher Site

Abstract

Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Customizing systemic therapy in patients with (2011) 3(4) 207218 DOI: 10.1177/ advanced non-small cell lung cancer ! The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/ ´ ´ A. M. Sadowska, V. Nowe, A. Janssens, E. Boeykens, W. A. De Backer and P. R. Germonpre journalsPermissions.nav Abstract: Lung cancer is the leading cause of cancer deaths worldwide. Standard chemo- therapy has been shown to improve quality of life and has a modest influence on overall survival. This modest improvement in survival is partly due to the choice of chemotherapy regimens that have been based on prognostic factors such as age, performance status and comorbidities of the patient. This underlines the importance of developing a more personalized therapy for patients with non-small cell lung cancer. Such an approach may reduce the var- iation in how individual patients respond to medications by tailoring therapies to their genetic profile. In this review we focus on several aspects of customized therapy, looking not only at patient characteristics but also to tumor histology and specific tumor biomarkers. Keywords: bevacizumab, histology, non-small cell lung cancer, pemetrexed, personalized therapy, tyrosine kinase inhibitors Correspondence to: Introduction such a personalized treatment should be based A. M. Sadowska, MD, PhD Lung cancer is the leading cause of cancer- on patient and/or tumor characteristics, which Dept of Respiratory Medicine, University related deaths in Western countries, with non- together provide prognostic and/or predictive Hospital Antwerp, small-cell lung cancer (NSCLC) accounting for information. This information should then facil- Wilrijkstraat 10, 2650 Antwerp, Belgium more than 85% of primary lung cancers. itate the selection of appropriate systemic treat- a_m_sadowska@ Importantly, the majority of lung cancers are ment for an individual patient by avoiding yahoo.co.uk metastasized at the time of diagnosis, making unnecessary, less effective or more toxic treat- V. Nowe´, MD, PhD A. Janssens, MD them illegible for curative treatment by either ments (Figure 1). E. Boeykens, MD surgery or radiotherapy. W. A. De Backer, MD, PhD There are three considerations to produce a P. R. Germonpre´, MD, PhD Systemic treatment with either chemotherapy or successful molecularly targeted biological treat- Department of Pulmonary biologic therapy is the key component for the ment. First, the oncogenic target controlling Medicine, Antwerp University Hospital and treatment of patients with disseminated cancer growth and survival must be identified; University of Antwerp, NSCLC. Indeed, chemotherapy in addition to second, an effective therapy targeting this onco- Belgium supportive care has been shown to improve qual- genic target needs to be made available; and, ity of life, control symptoms and overall survival third, a biomarker that predicts a favorable out- (i.e. 10% increase in the 1-year survival rate) in come of the targeted therapy needs to be patients with advanced NSCLC [Non-small Cell identified. Lung Cancer Collaborative Group, 1995]. However these improvements are modest Recently, advances have been made to elucidate (response rates 30% for first-line treatment molecular pathways that play a role in NSCLC and 10% for second-line treatment, with 2 carcinogenesis and that may also correlate with month increase in median overall survival), indi- clinical response. Many biomarkers are suggested cating that many NSCLC patients fail to respond to have both prognostic and predictive proper- to ‘standard’ chemotherapy. In part, this is due to ties; however, randomized clinical trials and the fact that until recently the choice of chemo- meta-analyses are necessary to determine the therapy regimens was based mainly on either the usefulness of a given marker in clinical setting age, performance status (PS) and comorbidities (Figure 2). To date, the only biomarkers, which of the patient or on the physician’s experience have been tested or validated in large phase III and patient’s preferences. These facts underline trials, are tumor histology and the presence of an the importance of developing a more personal- activating epidermal growth factor receptor ized therapy for patients with NSCLC. Ideally, (EGFR) mutation. http://tam.sagepub.com 207 Therapeutic Advances in Medical Oncology 3 (4) Patient Tumor characteristics Avoid -histology -unnecessary treatment -genetic alterations -ineffective treatment -gene expression -toxic treatment -protein expression Prognostic information � adequate treatment Personalized treatment Predictive information � sensitivity to treatment � treatment related toxicity Patient characteristics Society -germ-line genetics -better use available (i.e. SNPs, …) resources -cytokines -reduce cost of care Figure 1. Development of personalized therapy for non-small cell lung cancer. Many biomarkers have both prognostic and predictive properties  RCT and/or meta- analyses are required to determine the clinical usefulness of a marker Open label Retrospective Double-blind analysis randomized Small numbers Non-stratified Placebo-controlled Single arm Adequately powered Prospective analysis Stratified by biomarker status Figure 2. Many biomarkers have both prognostic and predictive properties. Randomized controlled trials and/ or meta-analyses are required to determine their clinical usefulness. Clinical patient-based treatment decisions confirmed that PS is a very important prognostic factor, while age and gender were other indepen- Age, performance and comorbidities dent significant variables [Sculier et al. 2008]. In a The choice of chemotherapy regimens until number of trials, the presence of comorbidities recently was based on prognostic factors such as was also found to be associated with poorer sur- age, PS and comorbidities of the patient. vival [Lee et al. 2011; Irisa et al. 2010]. Nevertheless, NSCLC patients with a poorer The retrospective analysis of the large PS, older age, or the presence of comorbidities International Staging Committee database derive a similar survival benefit from 208 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. chemotherapy as patients without these poor while pemetrexed had a superior survival in the prognostic factors, but they experience signifi- nonsquamous subgroup [Hanna et al. 2004]. cantly more toxicities [Davidoff et al. 2010; Gronberg et al. 2010; Asmis et al. 2008; Weiss A preplanned subgroup analysis in the first-line et al. 2006; Lilenbaum et al. 2005; Langer et al. study confirmed that the effect on survival of 2002]. In other words, age, PS and the presence pemetrexed-containing chemotherapy is signifi- of comorbidities may predict for tolerability and cantly different in patients with nonsquamous toxicity, but not for survival benefits associated NSCLC and patients with squamous cell carci- with single-agent or platinum-based noma. In patients with adenocarcinoma and chemotherapy. large-cell carcinoma, the overall survival was superior in the cisplatin plus pemetrexed arm, while in patients with squamous cell carcinoma Pemetrexed there was a significant improvement in survival Pemetrexed is a multitargeted antifolate inhibitor with cisplatin plus gemcitabine. The overall sur- of thymidilate syntethase (TS) dihydrofolate vival for a fourth group, consisting of all of those reductase and glycinamide ribonucleotide patients in whom a generic cytological diagnosis formyl transferase [Hong et al. 2010; Shih et al. of NSCLC without further subtype classification 1998]. was made (NOS or ‘not otherwise specified’), did Several trials studied the role pemetrexed as a not show a significant difference between the two first- or second-line treatment in patients with arms. [Scagliotti et al. 2008] advanced NSCLC. The results of these phase Similar results were found in the pemetrexed III trials are summarized in Table 1. In summary, maintenance trial: the improvements in progres- there was no difference between first-line peme- sion-free survival and overall survival were con- trexed plus cisplatin and cisplatin plus gemcita- fined to patients with nonsquamous histology. bine with regard to progression-free survival and In patients with squamous cell cancer, the pro- median overall survival [Scagliotti et al. 2008]. gression-free survival and overall survival was Similarly, pemetrexed was not inferior to doce- similar in the pemetrexed and the placebo arms taxel when given as second-line treatment [Ciuleanu et al. 2009]. The hazard ratios (HRs) [Hanna et al. 2004]. Recently, pemetrexed was also compared with placebo in the maintenance for overall survival according to tumor histology or ‘early second line’ following four cycles of first- are summarized in Table 2. line platinum-based chemotherapy. The use of pemetrexed in this maintenance setting resulted Resistance to pemetrexed in cancer cell lines has in a significantly longer progression-free survival been shown to be due to upregulation of TS and overall survival [Ciuleanu et al. 2009]. [Sigmond et al. 2003]. Pemetrexed in combina- tion with cisplatin was first licensed for the treat- A retrospective analysis of the trial comparing ment of malignant pleural mesothelioma pemetrexed with docetaxel in previously treated [Vogelzang et al. 2003]. Recently, low TS protein NSCLC patients found a significant treatment- levels were found to be predictive of improved by-histology interaction. Docetaxel resulted in a time-to-progression and overall survival in better survival in the squamous cell subgroup, patients with mesothelioma treated with Table 1. Pemetrexed in the treatment of non-small cell lung cancer. Data from Scagliotti et al., [2008], Hanna et al., [2004], and Ciuleanu et al., [2009]. st nd 1 line: 2 line: Maintenance Cis-Gem Cis-Pem Doc Pern Plac Pern Median PFS 5.1 m 4.8 m 2.9 m 2.9 m 2.0 m 4.0 m HR 1.04 HR 0.97 HR 0.60* Median OS 10.3 m 10.3 m 7.9 m 8.3 m 10.6 m 13.4 m HR 0.99 HR 0.99 HR 0.79* HR, hazard ratio; PFS, progression-free survival; OS, overall survival; Cis-Gem, cisplatin plus gemcitabine; Doc, docetaxel; Pem, pemetrexed; Plac, placebo; m, months; *p< 0.05. http://tam.sagepub.com 209 Therapeutic Advances in Medical Oncology 3 (4) Table 2. Pemetrexed and non-small cell lung cancer histology: squamous versus non-squamous. Data shown as hazard ratio. Data from Ciuleanu et al., [2009]. st nd Histology 1 line: Cis-Pem 2 line: Maintenance: vs. Cis-Gem Pern vs. Doc Pern vs. Plac Non-squamous 0.81* 0.78* 0.70* Squamous 1.23 1.56* 1.07 Cis-Gem, cisplatin plus gemcitabine; Pem, pemetrexed; Plac, placebo; *p< 0.05. pemetrexed-based chemotherapy [Righi et al. anti-angiogenic effects [Hanahan and Weinberg, 2010]. Similarly, the observed treatment-by-his- 2000], but it normalizes the tumor vasculature tology interaction for pemetrexed in NSCLC has thereby improving the drug delivery to the been related to differences in TS expression in tumor [Jain, 2001]. Indeed, several trials have the different histologic subtypes. In chemother- shown the beneficial effects of adding bevacizu- apy-naive patients, the baseline expression of TS mab to standard chemotherapy in a variety of is significantly higher in squamous cell carcinoma tumors [Willett et al. 2007, 2004; Sandler et al. compared to adenocarcinoma [Ceppi et al. 2006]. 2006]. Large-cell carcinomas, when considered as a single group of tumors, have a median TS The initial randomized phase II trial evaluating expression comparable with squamous cell the role of bevacizumab in patients with cancer, and higher than in adenocarcinoma. advanced or recurrent NSCLC demonstrated However, the TS expression in large-cell carcino- that addition of bevacizumab (high dose) to car- mas differs according to their immunohistochem- boplatin and paclitaxel resulted in higher ical profile: in large-cell carcinomas expressing response rates (31.5% versus 18.8%, respectively) markers of squamous cell differentiation (i.e. and longer time-to-progression (7.4 months with p63) the TS levels were significantly higher bevacizumab versus 4.2 months for chemotherapy than in those expressing markers of adenocarci- alone). However, an alarming rate (9%) of life- noma (i.e. TTF-1). Thus, the expression of TS threatening pulmonary bleeding was observed in in large-cell carcinoma may resemble that of ade- the bevacizumab-treated patients. This life-threa- nocarcinomas or squamous cell carcinomas tening pulmonary hemorrhage was found to be [Monica et al. 2009]. These findings may explain associated with squamous cell histology (four of why the HRs for overall survival are consistently the six cases occurred in patients with squamous in favor of the pemetrexed-treated adenocarci- cell histology), tumor necrosis and cavitation, noma patients, but vary for the large-cell and and disease location close to major blood vessels ‘NOS’ subgroups (Table 3). [Johnson et al. 2004]. In summary, it may be concluded that in As a result of these safety concerns observed in patients with nonsquamous NSCLC, peme- the phase II trials, the subsequent phase III trials trexed-containing treatments are superior to excluded patients with tumors with a predomi- gemcitabine- or docetaxel-containing treatments. nant squamous component. The rates of grade Furthermore, these results should warrant a pro- 3 pulmonary hemorrhage in the bevacizumab spective study that is specifically designed to eval- plus chemotherapy arms of these phase III trials uate TS-expression as a more reliable marker to in patients with nonsquamous cell NSCLC were select those patients most likely to benefit from <2% [Reck et al. 2009; Sandler et al. 2006]. cisplatin plus pemetrexed therapy. The ECOG-trial showed that the addition of bev- Bevacizumab acizumab to paclitaxel plus carboplatin resulted Bevacizumab is a monoclonal vascular endothe- in a significant increase in progression-free sur- lial growth factor (VEGF) antibody binding vival (6.2 versus 4.5 months; HR 0.66) and over- directly to VEGF and removing it from the envi- all survival (12.3 months versus 10.3 months; HR ronment [Presta et al. 1997]. It is not considered 0.79) [Sandler et al. 2006]. The AVAiL trial con- cytotoxic bearing in mind it has mostly firmed progression-free survival of bevacizumab 210 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. Table 3. Pemetrexed and non-small cell lung cancer histology: squamous versus adenocarcinoma, large-cell carcinoma and not other specified types. Data shown as hazard ratio. Data from Scagliotti et al., [2008] and Ciuleanu et al., [2009]. st nd Histology 1 line: Cis-Pem 2 line: Pern Maintenance: vs. Cis-Gem vs. Doc Pern vs. Plac Non-squamous 0.81* 0.78* 0.70* Adenocarcinoma 0.84* 0.92 0.73* Large cell 0.67 0.27* 0.98 NOS 1.08 0.57 0.61* Squamous 1.23 1.56* 1.07 Cis-Gem, cisplatin plus gemcitabine; Doc, docetaxel; Pem, pemetrexed; Plac, placebo; NOS, not otherwise specified; *p< 0.05 when combined with cisplatin plus gemcitabine with higher frequency in women, nonsmokers, (HR 0.75). However, in the AVAiL trial the pro- adenocarcinoma, and in patients of Asian eth- gression-free survival benefit did not translate nicity, thus explaining the higher response rates into a significant overall survival benefit. This to treatment with EGFR-TKIs in these patient lack of overall survival benefit has been attributed groups [Pao et al. 2004]. Importantly, the con- to the use of efficacious second-line therapies stitutive EGFR activation caused by these muta- [Reck et al. 2010]. tions causes oncogene addiction to the EGFR pathway. This means that de-induction of Thus, by using nonsquamous histology as a bio- mutant EGFR expression leads to dramatic marker for selecting patients eligible for bevaci- regression of tumors suggesting the need for zumab treatment, undue toxicity could be persistent mutant EGFR activity for continued avoided without compromising the antitumoral tumor survival [Herbst et al. 2008]. effects. These EGFR mutations were also found to be a favorable prognostic factor for survival in Tumor biomarker-based treatment decisions advanced NSCLC patients treated with chemo- therapy with or without concomitant EGFR-TKI EGFR tyrosine kinase inhibitors treatment [Eberhard et al. 2005]. EGFR belongs to a family of four related trans- membrane receptors, namely EGFR (HER1), The presence of the activating mutation in exons HER2, HER3 and HER4. It regulates important 19 and 21 of the EGFR results in an activation of processes including proliferation, apoptosis, the Akt and STAT pathways without having an angiogenesis and invasion. As EGFR is fre- effect on ERK/MAP signaling. It has been sug- quently expressed in NSCLC [Rusch et al. gested that EGFR-TKIs affect wild-type and 1997], it has been an important target for the mutant cells differently. Namely, gefinitib triggers development of new agents. The EGFR tyrosine apoptosis in cell-lined harboring EGFR exon 19 kinase inhibitors (TKIs), erlotinib and gefitinib, or 21 mutations that results in complete or partial have been extensively studied in NSCLC. response. On the other hand, it induces G1 arrest in EGFR wild-type cells that leads to stable dis- Even with the first clinical trials of EGFR-TKIs, ease [Pao and Miller, 2005]. it was observed that female patients, nonsmo- kers, patients of Asian ethnicity and patients Recently, several trials have examined the poten- with adenocarcinomas had a greater response tial role of EGFR-TKIs in the first-line treatment rate following treatment with EGFR-TKIs. of patients with tumors with activating mutations However, it has now been demonstrated that the EGFR-TKI sensitivity is associated with on the EGFR [Mitsudomi et al. 2010; Maemondo the presence of activating mutations in the tyro- et al. 2010]. These trials all showed that the pres- sine kinase domain of EGFR in the NSCLC ence of EGFR mutation is a strong predictive tumor and not with these clinical characteristics marker for improved response rate and improved per se [Rosell et al. 2009; Lynch et al. 2004; Paez progression free survival with EGFR-TKI versus et al. 2004]. However, these mutations occur chemotherapy (Table 4). The IPASS trial, which http://tam.sagepub.com 211 Therapeutic Advances in Medical Oncology 3 (4) Table 4. Progression-free survival and response rate in epidermal growth factor receptor (EGFR) mutation positive patients following first-line treatment. Data from Mitsudomi et al. [2009] and Makato et al. [2010]. Progression-free survival (months) Response rate Chemotherapy EGFR-TKI Chemotherapy EGFR-TKI Mitsudomi et al. [2009] 6.3 9.3 32.2% 62.1% Cisplatin-docetaxel versus gefinitib Makato etal. [2010] 5.5 10.4 30.7% 73.7% Carboplatin-paclitaxel versus gefinitib TKI, tyrosine kinase inhibitor. Table 5. First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) versus chemother- apy: IPASS trial. The presence of EGFR mutation is a strong predictive marker for response rate and progres- sion-free survival (PFS). Data from Mok et al. [2009]. EGFR wild type EGFR-mutationþ Gefitinib Carbo/Pacli Gefitinib Carbo/Pacli Response rate 1% 23%* 71%* 47% PFS 1.5 m 5.5 m* 9.6 m* 6.3 m HR2.85* HR 0.48* OS MST 12 m MST 20 m HR1.38 HR0.78 Carbo, carboplatin; HR, hazard ratio; MST, musculoskeletal toxicity; OS: Overall Survival; Pacli, paclitaxel; *p< 0.05. also included patients without activating EGFR Erlotinib has also been shown to prolong survival mutations, demonstrated that the presence of an in patients with NSCLC after failure of first-line EGFR mutation is associated with a higher or second-line chemotherapy [Shepherd et al. response rate to chemotherapy and is a favorable 2005]. In this trial, the presence of an EGFR prognostic factor regardless of treatment (Table 5). mutation was shown to increase the responsive- ness to erlotinib, but it is not indicative of a sur- Similar findings were reported in the SATURN vival benefit as the overall survival benefit was trial, which explored the role of erlotinib in main- also observed in the EGRF wild-type patients tenance or early second-line settings immediately [Tsao et al. 2005]. after completion of the initial course of platinum- based chemotherapy. In unselected patients, Inhibition of other oncogenic drivers such as median progression-free survival was significantly anaplastic lymphoma kinase longer with erlotinib than with placebo (12.3 A number of specific genetic lesions (i.e. KRAS, versus 11.1 weeks respectively; HR 0.71; ALK, BRAF, MET, PGDFR, PIK3CA, HER2) p< 0.0001). Moreover, in patients with tumors driving tumor proliferation have been identified harboring an EGFR mutation, erlotinib as main- in primary lung adenocarcinomas. Inhibition of tenance treatment resulted in a dramatic increase these oncogenic drivers in NSCLC patients har- in progression-free survival (HR 0.10; boring these mutated pathways is a logical candi- p< 0.0001). However, patients with tumors with wild-type EGFR also seemed to derive a date for future targeted treatments. So far, the most promising results have been observed with benefit from erlotinib maintenance as the overall survival was significantly improved in these the inhibition of anaplastic lymphoma kinase patients (HR 0.77; p< 0.05) [Cappuzzo et al. (ALK) in patients with NSCLC with EML4- 2010]. ALK translocation. 212 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. ALK is an oncogene that induces cell transfor- reduces the accumulation of genetic aberrations mation in vitro and in vivo. Translocation of ALK that are thought to contribute to a tumors malig- results in an abnormal fusion gene, usually with nant potential and therefore the risk of relapse its counterpart in lung cancer, echinoderm after definitive treatment. This study is in accor- dance with the results of the International microtubule-associated protein-like 4 (ELM4). Adjuvant Lung Cancer Biology Trial (IALT- The translocation produces an ongoing activation Bio) [Olaussen et al. 2006] that showed better of an intercellular tyrosine kinase, which then survival in patients with ERCC1 positive leads to proliferation and cancer propagation tumors (p¼ 0.009). In contrast to these studies, [Horn and Pao, 2009]. In some lung cancers, Rosell and colleagues showed that ERCC1 over- this will be the sole driver of their existence because the ALK translocation is so dominant expression was related to worse prognosis. Their study, however, did not reach a statistical [Soda et al. 2008, 2007]. Treatment of patients with ALK rearrangements with crizotinib, an significance of p> 0.05 [Rosell et al. 2007]. inhibitor of the ALK tyrosine kinase, results in Nevertheless, the analysis of patients with response rates in excess of 50% and estimated advanced disease treated with cisplatin and gem- probability of 6-month progression-free survival citabine showed that low expression of ERRC1 of more than 70% [Kwak et al. 2010]. was associated with longer survival [Lord et al. 2002]. ALK rearrangements and EGFR mutations seem to be usually mutually exclusive while mainly Ribonucleotide reductase messenger 1 (RRM1) occurring in patients with the same clinical char- is the regulatory component of ribonucleotide acteristics, namely younger patients, never or reductase that assists with DNA synthesis and light smokers and adenocarcinomas. repair. Moreover, it is the predominant target of Interestingly, the group of patients with ALK nucleoside analogue, gemcitabine. Analysis of rearrangements tends to have a slightly higher patients with advanced NSCLC treated with proportion of males compared with those who cisplatin-containing combinations or nonplati- num doublets showed a longer median survival have EGFR mutations. Importantly, patients in a group with low RRM1 expression (13.7 with ALK rearrangements do not respond to months) versus a group with high RRM1 EGFR-TKI treatment [Shaw et al. 2009]. expression (3.6 months). Moreover, median Cisplatin-based therapy and DNA repair survival was significantly longer in the group systems treated with cisplatin plus gemcitabine who Cisplatin and carboplatin are used as standard had lower levels of both RMM1 and ERCC1 chemotherapy for solid tumors. The mecha- expression than other subgroups. Therefore, it nism of action is based on the formation of cis- has been suggested that RRM1 expression is a platin-DNA adducts leading to apoptosis. predictive marker of survival in gemcitabine Removal of these adducts, leading to chemoresis- plus cisplatin-treated patients [Rosell et al. tance, is mainly carried out by the nucleotide 2004]. excision repair system. Breast cancer type 1 susceptibility protein Excision repair cross-complementation group 1 (BRCA1) plays a central role in DNA repair as (ERCC 1) is a rate-limiting protein in the NER a component of multiple repair pathways. and ICL-R pathways, which works by recogniz- Furthermore, BRCA1 is a potential regulator of ing and removing platinum adducts and by mitotic spindle assembly as it is found to be colo- repairing interstrand DNA crosslinks. Its prog- calized with beta-tubulin to the microtubules nostic effect was assessed in a study by Simon of the mitotic spindle [Coate et al. 2009; and colleagues in chemotherapy-naı ¨ve patients Lafarge et al. 2001]. The increased expression with resected NSCLC [Simon et al. 2005]. of BRCA1 appears to be an unfavorable prognos- Namely, there was a statistically significant differ- tic factor as it is correlated with decreased overall ence in median survival for patients with ERCC1 survival in chemotherapy-naı ¨ve patients with expression >50 (94.6 months) compared with NSCLC after surgery [Rosell et al. 2007]. <50 (35.5 months) (p¼ 0.01). Multivariate anal- ysis revealed that high ERCC1 expression inde- In preclinical models, upregulation of BRCA1 pendently predicted longer survival. They also has been linked to platinum resistance and sensi- suggested that an intact DNA repair mechanism tivity to antimicrotubule drugs such as taxanes http://tam.sagepub.com 213 Therapeutic Advances in Medical Oncology 3 (4) and vinca alkaloids [Rosell et al. 2004]. This dif- Median overall survival was 11 months in the ferential sensitivity to different chemotherapeutic lowest BRCA1 expression treated with gemcita- agents according to the BRCA1 expression levels bine plus cisplatin and 2-year survival was makes BRCA1 an interesting candidate marker 41.2%, comparable with the median survival to customize chemotherapy treatment in and 2-year survival obtained with cisplatin and NSCLC. This concept has been tested in a gemcitabine in a recent large phase III trial phase II trial where nonsquamous cell carcinoma [Scagliotti et al. 2008]. Meanwhile, in patients patients were allocated to different treatments with the highest BRCA expression treated with based on the EGFR mutation status and docetaxel alone, median survival was 11 months BRCA1 mRNA expression levels. Treatment (similar to the survival obtained in a large phase algorithm is shown in Figure 3. In this trial, the III trial in patients treated with cisplatin plus influence of receptor- associated protein 80 (RAP either docetaxel or vinorelbine) [Fossella et al. 80) expression was also examined as RAP 80 has 2003]. The survival of patients with low been shown to act upstream of BRCA1 and be BRCA1 expression decreased as RAP 80 expres- required for the accumulation of BRCA1 to sites sion increased, confirming that RAP80 can of DNA breaks [Rosell et al. 2007; Wang et al. replace the BRCA1 DNA repair function in 2007]. cells lacking BRCA (Table 6). RNA & DNA extraction from tumor EGFR mutation + Erlotinib BRCA1 mRNA expression in EGFR WT* Low Intermediate High Cisplatin + Cisplatin + Docetaxel Gemcitabine Docetaxel monotherapy Figure 3. Customized treatment of non-small cell lung cancer based on epidermal growth factor receptor (EGFR) mutation and BRCA1 mRNA expression. WT, wild type. Table 6. Customized treatment of non-small cell lung cancer based on epidermal growth factor receptor mutations and BRCA1 mRNA expression. Correlation of BRCA1 and RAP80 expression with median survival. Purple circle, cisplatingemcitabine; green circle, cisplatindocetaxel; red, docetaxel monotherapy. Data from Rosell et al. [2007]. RAP80 mRNA Low Intermediate High BRCA1 mRN Low NR 8 m 7 m Intermediate 5 m 13 m 16 m High 6 m 12 m 11 m m, months. 214 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. Thus, this trial showed that chemotherapy cus- help us guide treatment choices. In patients with tomized according to BRCA1 expression levels is squamous cell cancers, treatment with bevacizu- associated with encouraging overall survival, and mab leads to life-threatening toxicity. that RAP80 could play a crucial modulating Furthermore, squamous cell tumors appear to effect in this model of customized chemotherapy. be more or less resistant to pemetrexed-contain- The concept of customizing chemotherapy treat- ing chemotherapy. Thus, by restricting treatment ment based on BRCA1 and RAP80 expression with bevacizumab and pemetrexed to patients levels is now being tested in a prospective ran- with nonsquamous NSCLC it should be possible domized phase III trial. to obtain better clinical outcomes (i.e. better tol- erability and/or survival). The presence of an activating EGFR mutation predicts for a better Conclusions response rate and progression-free survival with The newer systemic therapies for NSCLC are EGFR-TKI treatment compared with first-line directed towards specific targets but their efficacy chemotherapy regimens. In the maintenance will be strongly influenced by inherent tumor het- and second-line treatment trials with erlotinib, erogeneity and the multiple robust and compen- an overall survival benefit was also observed in satory signaling pathways involved in tumor patients with wild-type EGFR [Cappuzzo et al. homeostasis [Thomson et al. 2008; Amit et al. 2010]. Thus, EGFR-TKI treatment is a valid 2007]. Therefore, identification of genotypes choice for first-line treatment in patients with that respond better to specific therapies, thus actually adjusting the therapies to the genetic such an EGFR mutation. However, this does profile of the patients, remains an important not mean that treatment with EGFR-TKIs and interesting issue. should be restricted to patients with EGFR muta- tions: in patients with wild-type EGFR, erlotinib The recent advances in our understanding of can be considered for second- or third-line treat- NSCLC tumor biology and the mechanisms of ment (Table 7). action of various systemic treatments have led to the first steps towards personalized treatment These first steps towards personalized medicine of patients with NSCLC. A number of potential represent a shift in the management of NSCLC. selection factors for customizing systemic treat- Indeed, NSCLC should no longer be viewed as ment in advanced NSCLC are summarized in one common generic tumor but rather as a col- Figure 4. At present, only tumor histology and lection of more rare tumors with differing biolog- EGFR-mutation status have been validated in ical behaviors and different sensitivities to various phase III trials as predictive markers, which can systemic treatments. NSCLC TNM-stage Tumor Histology characteristics Tumor biomarkers Performance status Patient Age and comorbidities characteristics “common cancer” Patient biomarkers Toxicities Patient preference Treatment administration Doctor Experience with drug preference “collection of cancer” Figure 4. Potential selection factors for customizing systemic treatment in advanced non-small cell lung cancer (NSCLC). Moving from thinking of NSCLC as a single entity towards customized treatment of a collec- tion of tumors grouped under the term NSCLC. http://tam.sagepub.com 215 Therapeutic Advances in Medical Oncology 3 (4) Table 7. Selection factors for customizing systemic treatment in advanced non-small cell lung cancer. Category Drug Selection factor Effect Tumor histology EGFR-TKI Adeno Improved response rate Pemetrexed Nonsquamous Exclusion non-benefiting pts Bevacizumab Non-Squamous Safety concerns in squamous Molecular tumor EGFR-TKI EGFR-mutation Improved PFS biomarkers Pemetrexed Low TS expression Selection of benefiting pts Gemcitabine Low RRM1 Selection of benefiting pts Platinum ERCC1.BRCA1, RAP80 Improved RR, PFS and/or OS EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; PFS, progression-free survival; OS, overall survi- val; pts, patients; RR, response rate; TS, thymidilate syntethase; RRM1; ribonucleotide reductase messenger 1. patients with advanced non-small-cell lung cancer. J Funding Clin Oncol 28: 21912197. This research received no specific grant from any funding agency in the public, commercial, or not- Eberhard, D.A., Johnson, B.E., Amler, L.C., Goddard, A.D., Heldens, S.L., Herbst, R.S. et al. for-profit sectors. (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic Conflict of interest statement indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in The authors declare no conflict of interest in pre- combination with erlotinib. J Clin Oncol paring this manuscript. 23: 59005909. Fossella, F., Pereira, J.R., von Pawel, J., Pluzanska, A., Gorbounova, V., Kaukel, E. et al. (2003) Randomized, References multinational, phase III study of docetaxel plus plati- Amit, I., Wides, R. and Yarden, Y. (2007) Evolvable num combinations versus vinorelbine plus cisplatin for signaling networks of receptor tyrosine kinases: rele- advanced non-small-cell lung cancer: the TAX 326 vance of robustness to malignancy and to cancer study group. J Clin Oncol 21: 30163024. therapy. Mol Syst Biol 3: 151. Gronberg, B.H., Sundstrom, S., Kaasa, S., Bremnes, Asmis, T.R., Ding, K., Seymour, L., Shepherd, F.A., R.M., Flotten, O., Amundsen, T. et al. (2010) Leighl, N.B., Winton, T.L. et al. (2008) Age and Influence of comorbidity on survival, toxicity and comorbidity as independent prognostic factors in the health-related quality of life in patients with advanced treatment of non small-cell lung cancer: a review of non-small-cell lung cancer receiving platinum-doublet National Cancer Institute of Canada Clinical Trials chemotherapy. Eur J Cancer 46: 22252234. Group trials. J Clin Oncol 26(1): 5459. Hanahan, D. and Weinberg, R.A. (2000) The hall- Cappuzzo, F., Ciuleanu, T., Stelmakh, L., Cicenas, S., marks of cancer. Cell 100: 5770. Szczesna, A., Juhasz, E. et al. (2010) Erlotinib as Hanna, N., Shepherd, F.A., Fossella, F.V., Pereira, maintenance treatment in advanced non-small-cell J.R., De Marinis, F., von Pawel, J. et al. (2004) lung cancer: a multicentre, randomised, placebo-con- Randomized phase III trial of pemetrexed versus doc- trolled phase 3 study. Lancet Oncol 11: 521529. etaxel in patients with non-small-cell lung cancer pre- Ceppi, P., Volante, M., Saviozzi, S., Rapa, I., Novello, viously treated with chemotherapy. J Clin Oncol S., Cambieri, A. et al. (2006) Squamous cell carci- 22: 15891597. noma of the lung compared with other histotypes Herbst, R.S., Heymach, J.V. and Lippman, S.M. shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107: 15891596. (2008) Lung cancer. N Engl J Med 359: 13671380. Hong, J., Kyung, S.Y., Lee, S.P., Park, J.W., Jung, Ciuleanu, T., Brodowicz, T., Zielinski, C., Kim, J.H., S.H., Lee, J.I. et al. (2010) Pemetrexed versus gefitinib Krzakowski, M., Laack, E. et al. (2009) Maintenance pemetrexed plus best supportive care versus placebo versus erlotinib in previously treated patients with non- plus best supportive care for non-small-cell lung small cell lung cancer. Korean J Intern Med cancer: a randomised, double-blind, phase 3 study. 25: 294300. Lancet 374: 14321440. Horn, L. and Pao, W. (2009) EML4-ALK: honing in Coate, L.E., John, T., Tsao, M.S. and Shepherd, F.A. on a new target in non-small-cell lung cancer. J Clin (2009) Molecular predictive and prognostic markers in Oncol 27: 42324235. non-small-cell lung cancer. Lancet Oncol Irisa, K., Masago, K., Togashi, Y., Fujita, S., Hatachi, 10: 10011010. Y., Fukuhara, A. et al. (2010) Significance of Davidoff, A.J., Tang, M., Seal, B. and Edelman, M.J. pretreatment comorbidities in elderly patients (2010) Chemotherapy and survival benefit in elderly with advanced non-small-cell lung cancer treated 216 http://tam.sagepub.com AM Sadowska, V Nowe´ et al. with chemotherapy or epidermal growth factor lung cancer harbouring mutations of the epidermal receptor-tyrosine kinase inhibitor. Med Oncol, growth factor receptor (WJTOG3405): an open label, in press. randomised phase 3 trial. Lancet Oncol 11: 121128. Jain, R.K. (2001) Normalizing tumor vasculature with Mitsudomi et al. (2009). anti-angiogenic therapy: a new paradigm for combi- Mok et al. (2009). nation therapy. Nat Med 7: 987989. Monica, V., Scagliotti, G.V., Ceppi, P., Righi, L., Johnson, D.H., Fehrenbacher, L., Novotny, W.F., Cambieri, A., Lo Iacono, M. et al. (2009) Differential Herbst, R.S., Nemunaitis, J.J., Jablons, D.M. et al. Thymidylate Synthase Expression in Different Variants (2004) Randomized phase II trial comparing bevaci- of Large-Cell Carcinoma of the Lung. Clin Cancer Res zumab plus carboplatin and paclitaxel with carboplatin 15: 75477552. and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. Non-small Cell Lung Cancer Collaborative Group. J Clin Oncol 22: 21842191. (1995) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual Kwak, E.L., Bang, Y.J., Camidge, D.R., Shaw, A.T., patients from 52 randomised clinical trials. Br Med J Solomon, B., Maki, R.G. et al. (2010) Anaplastic 311: 899909. lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363: 16931703. Olaussen, K.A., Dunant, A., Fouret, P., Brambilla, E., Andre, F., Haddad, V. et al. (2006) DNA repair by Lafarge, S., Sylvain, V., Ferrara, M. and Bignon, Y.J. ERCC1 in non-small-cell lung cancer and cisplatin- (2001) Inhibition of BRCA1 leads to increased che- based adjuvant chemotherapy. N Engl J Med moresistance to microtubule-interfering agents, an 355: 983991. effect that involves the JNK pathway. Oncogene 20: 65976606. Paez, J.G., Janne, P.A., Lee, J.C., Tracy, S., Greulich, H., Gabriel, S. et al. (2004) EGFR mutations in lung Langer, C.J., Manola, J., Bernardo, P., Kugler, J.W., cancer: correlation with clinical response to gefitinib Bonomi, P., Cella, D. et al. (2002) Cisplatin-based therapy. Science 304: 14971500. therapy for elderly patients with advanced non-small- cell lung cancer: implications of Eastern Cooperative Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, Oncology Group 5592, a randomized trial. J Natl K., Sarkaria, I. et al. (2004) EGF receptor gene Cancer Inst 94: 173181. mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors Lee, L., Cheung, W.Y., Atkinson, E. and to gefitinib and erlotinib. Proc Natl Acad Sci U S A Krzyzanowska, M.K. (2011) Impact of comorbidity on 101: 1330613311. chemotherapy use and outcomes in solid tumors: a systematic review. J Clin Oncol 29: 106117. Pao, W. and Miller, V.A. (2005) Epidermal growth factor receptor mutations, small-molecule kinase Lilenbaum, R.C., Herndon II, J.E., List, M.A., Desch, inhibitors, and non-small-cell lung cancer: current C., Watson, D.M., Miller, A.A. et al. (2005) knowledge and future directions. J Clin Oncol Single-agent versus combination chemotherapy in 23: 25562568. advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol Presta, L.G., Chen, H., O’Connor, S.J., Chisholm, V., 23: 190196. Meng, Y.G., Krummen, L. et al. (1997) Humanization of an anti-vascular endothelial growth factor mono- Lord, R.V., Brabender, J., Gandara, D., Alberola, V., clonal antibody for the therapy of solid tumors and Camps, C., Domine, M. et al. (2002) Low ERCC1 other disorders. Cancer Res 57: 45934599. expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small Reck, M., von Pawel, J., Zatloukal, P., Ramlau, R., cell lung cancer. Clin Cancer Res 8: 22862291. Gorbounova, V., Hirsh, V. et al. (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or Lynch, T.J., Bell, D.W., Sordella, R., bevacizumab as first-line therapy for nonsquamous Gurubhagavatula, S., Okimoto, R.A., Brannigan, B.W. non-small-cell lung cancer: AVAil. J Clin Oncol et al. (2004) Activating mutations in the epidermal 27: 12271234. growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med Reck, M., von Pawel, J., Zatloukal, P., Ramlau, R., 350: 21292139. Gorbounova, V., Hirsh, V. et al. (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or pla- Makato et al. (2010). cebo as first-line therapy for nonsquamous non-small- Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, cell lung cancer: results from a randomised phase III S., Oizumi, S., Isobe, H. et al. (2010) Gefitinib or trial (AVAiL). Ann Oncol 21: 18041809. chemotherapy for non-small-cell lung cancer with Righi, L., Papotti, M.G., Ceppi, P., Bille, A., Bacillo, mutated EGFR. N Engl J Med 362: 23802388. E., Molinaro, L. et al. (2010) Thymidylate synthase Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., but not excision repair cross-complementation group 1 Okamoto, I., Tsurutani, J. et al. (2010) Gefitinib versus tumor expression predicts outcome in patients with cisplatin plus docetaxel in patients with non-small-cell malignant pleural mesothelioma treated with http://tam.sagepub.com 217 Therapeutic Advances in Medical Oncology 3 (4) pemetrexed-based chemotherapy. J Clin Oncol resistance to the multitargeted antifolate Pemetrexed 28: 15341539. (ALIMTA) in WiDr human colon cancer cells is associated with thymidylate synthase overexpression. Rosell, R., Danenberg, K.D., Alberola, V., Bepler, G., Biochem Pharmacol 66: 431438. Sanchez, J.J., Camps, C. et al. (2004) Ribonucleotide reductase messenger RNA expression and survival Simon, G.R., Sharma, S., Cantor, A., Smith, P. and in gemcitabine/cisplatin-treated advanced non-small Bepler, G. (2005) ERCC1 expression is a predictor of cell lung cancer patients. Clin Cancer Res survival in resected patients with non-small cell lung 10: 13181325. cancer. Chest 127: 978983. Rosell, R., Moran, T., Queralt, C., Porta, R., Soda, M., Choi, Y.L., Enomoto, M., Takada, S., Cardenal, F., Camps, C. et al. (2009) Screening for Yamashita, Y., Ishikawa, S. et al. (2007) epidermal growth factor receptor mutations in lung Identification of the transforming EML4-ALK fusion cancer. N Engl J Med 361: 958967. gene in non-small-cell lung cancer. Nature 448: 561566. Rosell, R., Skrzypski, M., Jassem, E., Taron, M., Bartolucci, R., Sanchez, J.J. et al. (2007) BRCA1: a Soda, M., Takada, S., Takeuchi, K., Choi, Y.L., novel prognostic factor in resected non-small-cell lung Enomoto, M., Ueno, T. et al. (2008) A mouse model cancer. PLoS One 2: e1129. for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A 105: 1989319897. Rusch, V., Klimstra, D., Venkatraman, E., Pisters, P.W., Langenfeld, J. and Dmitrovsky, E. (1997) Thomson, S., Petti, F., Sujka-Kwok, I., Epstein, D. Overexpression of the epidermal growth factor recep- and Haley, J.D. (2008) Kinase switching in mesench- tor and its ligand transforming growth factor alpha is ymal-like non-small cell lung cancer lines contributes frequent in resectable non-small cell lung cancer but to EGFR inhibitor resistance through pathway redun- does not predict tumor progression. Clin Cancer Res dancy. Clin Exp Metastasis 25: 843854. 3: 515522. Tsao, M.S., Sakurada, A., Cutz, J.C., Zhu, C.Q., Sandler, A., Gray, R., Perry, M.C., Brahmer, J., Kamel-Reid, S., Squire, J. et al. (2005) Erlotinib in Schiller, J.H., Dowlati, A. et al. (2006) Paclitaxel-car- lung cancer - molecular and clinical predictors of out- boplatin alone or with bevacizumab for non-small-cell come. N Engl J Med 353: 133144. lung cancer. N Engl J Med 355: 25422550. Vogelzang, N.J., Rusthoven, J.J., Symanowski, J., Scagliotti, G.V., Parikh, P., von Pawel, J., Biesma, B., Denham, C., Kaukel, E., Ruffie, P. et al. (2003) Vansteenkiste, J., Manegold, C. et al. (2008) Phase III Phase III study of pemetrexed in combination study comparing cisplatin plus gemcitabine with cis- with cisplatin versus cisplatin alone in patients platin plus pemetrexed in chemotherapy-naive patients with malignant pleural mesothelioma. J Clin Oncol with advanced-stage non-small-cell lung cancer. J Clin 21: 26362644. Oncol 26: 35433551. Wang, B., Matsuoka, S., Ballif, B.A., Zhang, D., Sculier, J.P., Chansky, K., Crowley, J.J., Van Smogorzewska, A., Gygi, S.P. et al. (2007) Abraxas Meerbeeck, J. and Goldstraw, P. (2008) The impact of and RAP80 form a BRCA1 protein complex required additional prognostic factors on survival and their for the DNA damage response. Science relationship with the anatomical extent of disease 316: 11941198. expressed by the 6th Edition of the TNM Weiss, G.J., Langer, C., Rosell, R., Hanna, N., Classification of Malignant Tumors and the proposals Shepherd, F., Einhorn, L.H. et al. (2006) for the 7th Edition. J Thorac Oncol 3: 457466. Elderly patients benefit from second-line cytotoxic Shaw, A.T., Yeap, B.Y., Mino-Kenudson, M., chemotherapy: a subset analysis of a randomized Digumarthy, S.R., Costa, D.B., Heist, R.S. et al. phase III trial of pemetrexed compared with (2009) Clinical features and outcome of patients with docetaxel in patients with previously treated non-small-cell lung cancer who harbor EML4-ALK. J advanced non-small-cell lung cancer. J Clin Oncol Clin Oncol 27: 42474253. 24: 44054411. Shepherd, F.A., Rodrigues Pereira, J., Ciuleanu, T., Willett, C.G., Boucher, Y., di Tomaso, E., Duda, Tan, E.H., Hirsh, V., Thongprasert, S. et al. (2005) D.G., Munn, L.L., Tong, R.T. et al. (2004) Direct Erlotinib in previously treated non-small-cell lung evidence that the VEGF-specific antibody bevacizu- cancer. N Engl J Med 353: 123132. mab has antivascular effects in human rectal cancer. Nat Med 10: 145147. Shih, C., Habeck, L.L., Mendelsohn, L.G., Chen, V.J. and Schultz, R.M. (1998) Multiple folate enzyme Willett, C.G., Duda, D.G., di Tomaso, E., Boucher, inhibition: mechanism of a novel pyrrolopyrimidine- Y., Czito, B.G., Vujaskovic, Z. et al. (2007) Complete based antifolate LY231514 (MTA). Adv Enzyme Regul pathological response to bevacizumab and chemora- 38: 135152. diation in advanced rectal cancer. Nat Clin Pract Oncol Visit SAGE journals online http://tam.sagepub.com 4: 316321. Sigmond, J., Backus, H.H., Wouters, D., Temmink, O.H., Jansen, G. and Peters, G.J. (2003) Induction of 218 http://tam.sagepub.com

Journal

Therapeutic Advances in Medical OncologySAGE

Published: Jun 15, 2011

Keywords: bevacizumab; histology; non-small cell lung cancer; pemetrexed; personalized therapy; tyrosine kinase inhibitors

References