Abstract
The management of advanced stage nonsmall cell lung cancer (NSCLC) has been altered by the recognition of histology-based treatment and the use of targeted therapy. Whilst outcomes have improved with adenocarcinoma, treatment options are still limited in advanced stage squamous cell lung cancer. With advances in the molecular characterization of squamous cell cancers (SCCs), new potential targets have been identified. In this review, we discuss the role of histology in the treatment of NSCLC, cytotoxic chemotherapy, existing targeted therapies, the new molecular subsets and novel inhibitors in squamous cell lung carcinoma, and the emerging role of immune checkpoint inhibitors. Based on the results of two recent studies, nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been approved by the US Food and Drug Administration (FDA) in the treatment of squamous cell NSCLC in the second-line setting. Well-designed biomarker driven studies are needed to accelerate the development and approval of novel therapies for patients with lung SCC.
Introduction
Lung cancer is the leading cause of cancer death worldwide. Squamous cell cancer (SCC) accounts for 25–30% of lung cancers, having been displaced over the past few decades by adenocarcinoma as the most common type of nonsmall cell lung cancer (NSCLC) [Dela Cruz et al. 2011]. This is attributed to the fact that smoking is more strongly associated with squamous and small cell cancer than with adenocarcinoma, coupled with declining smoking rates. Although the treatment of advanced stage adenocarcinoma has seen impressive progress with the use of molecular therapies targeting epidermal growth factor receptor (EGFR) gene mutations (erlotinib, gefitinib, afatinib) and anaplastic lymphoma kinase (ALK) gene translocation (crizotinib, ceritinib), treatment in lung SCC has not seen the same advances and options are still limited.
With advances in the molecular characterization of SCCs, new potential targets have been identified. In this review, we discuss the role of histology in the treatment of NSCLC, cytotoxic chemotherapy, existing targeted therapies, and the new molecular subsets and novel inhibitors in squamous cell lung carcinoma.
Pathology
The classification of lung cancers has seen some changes in recent years. In the World Health Organization (WHO) 2004 classification, squamous, adenocarcinoma and large cell carcinomas were regarded together as nonsmall cell carcinomas, but in 2011, an international panel of experts suggested that they should be looked at as specific entities, given their differences in molecular profiles and treatment (see below) [Travis et al. 2011].
The diagnosis of SCC is usually made on histopathology and sometimes immunohistochemistry (IHC) is required. On histology, SCC is characterized by the presence of keratinization, pearl formation and intercellular bridges. It is further divided into four variants: papillary; clear cell (abundant clear cytoplasm); small cell (small cells with NSCLC characteristics and focal squamous differentiation); and basaloid (with prominent peripheral palisading of nuclei). SCC has a highly consistent immunoprofile, tending to be p63, CK5, CK6, 34BE12 positive, and TTF1 and napsin A negative, compared with the immunoheterogeneity seen in adenocarcinomas. In differentiating between lung SCC and adenocarcinoma, an IHC panel of TTF1, p63, CK5 and 6 has up to 100% accuracy [Rekhtman et al. 2011; Kim et al. 2013c]. p40, an antibody that recognizes ΔNp63 (a p63 isoform that is specific for squamous/basal cells), has been found to have equivalent sensitivity and superior specificity to p63 [Bishop et al. 2012].
Molecular testing
Unlike in adenocarcinomas, where testing for EGFR mutations and ALK translocations have become part of routine management, the role of molecular profiling in SCC is less well established. Activating EGFR mutations are usually seen in <5% of resected pure SCC lung [Rekhtman et al. 2012] and ALK translocations have only been seen in case reports [Alrifai et al. 2013; Boch et al. 2013]. Even so, some believe that despite the low rates of EGFR mutations, testing should be considered given that there are agents with established benefits available for these patients [Miyamae et al. 2011]. The College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) have suggested that, in the setting of limited tumor samples such as biopsies or cytology where an adenocarcinoma component cannot be completely excluded, testing for EGFR mutation and ALK rearrangement may be performed in cases showing squamous or small cell histology with clinical criteria such as young age or lack of smoking history [Lindeman et al. 2013].
Cytotoxic chemotherapy
Historically patients with advanced stage NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 were treated in the first-line setting with a platinum doublet. Outcomes according to different chemotherapy treatments were comparable with overall response rates (ORR) of 17–21% and median overall survival (OS) of 7.4–8.1 months [Schiller et al. 2002]. Patients with ECOG PS of 3–4 should be managed with best supportive care [National Comprehensive Cancer Network (NCCN) guidelines].
Differences in efficacy based on histology were appreciated following the results of a phase III study that compared the combinations of cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with advanced stage NSCLC. In the overall patient population, the median OS was similar in both treatment groups at 10.3 months [hazard ratio (HR) 0.94; 95% confidence interval (CI) 0.84–1.05]. In the nonsquamous subset treated with cisplatin/pemetrexed versus cisplatin/gemcitabine, the median OS was 11.8 versus 10.4 months (HR 0.81; 95% CI 0.70–0.94), whereas in the SCC subset the OS was 9.4 versus 10.8 months (HR 1.23; 95% CI 1.00–1.51) [Scagliotti et al. 2008]. One hypothesis for the ineffectiveness of pemetrexed in SCC is that higher levels of thymidylate synthetase are expressed in SCC [Ceppi et al. 2006]. Given the difference in efficacy according to histology, cisplatin and pemetrexed is the optimal regimen for patients with nonsquamous NSCLC, whereas platinum combined with paclitaxel, docetaxel, gemcitabine or vinorelbine remains the standard option for advanced stage lung SCC (NCCN guidelines).
Newer agents are also coming into the picture: nab-paclitaxel has shown promising results in SCC. Preclinical studies showed that this albumin-bound form of paclitaxel might reach the tumor environment better than standard solvent-based (sb) paclitaxel. A phase III trial compared weekly nab-paclitaxel with carboplatin versus 3-weekly sb-paclitaxel with carboplatin. In the SCC subset, there was a significant improvement in ORR of 41% versus 24% in the nab-paclitaxel arm compared with sb-paclitaxel, whereas no difference in ORR was seen in the adenocarcinoma subset [Socinski et al. 2012]. However, in a more recent randomized phase II study of first-line nab-paclitaxel/carboplatin versus carboplatin/gemcitabine in Chinese patients with advanced lung SCC, no differences in ORR, progression-free survival (PFS) or OS were seen, but significantly more leucopenia and neutropenia were observed in nab-paclitaxel arm [Yang et al. 2014]. A phase III study of maintenance nab-paclitaxel after nab-paclitaxel/carboplatin induction therapy in advanced SCC lung is ongoing [ClinicalTrials.gov identifier: NCT02027428].
In the second-line setting, docetaxel and erlotinib have been used for patients whose disease has progressed after first-line therapy. Pemetrexed has been compared with docetaxel in the second-line setting and in the overall population, clinical outcomes (ORR, PFS and OS) were equivalent [Hanna et al. 2004]. However post hoc analysis revealed in patients with squamous cell histology, pemetrexed was less active than docetaxel with a shorter OS (HR 1.56) and PFS (HR 1.4) [Scagliotti et al. 2009]. Treatment selection in the second-line setting is primarily based on side effect profile and patient preferences (National Comprehensive Cancer Network(NCCN) guidelines).
Epidermal growth factor receptor (EGFR) targeted agents
EGFR, a transmembrane receptor tyrosine kinase that plays a key role in carcinogenesis, is overexpressed in 40–80% of NSCLC [Hirsch et al. 2003]. Somatic activating mutations in EGFR occur in exons 18–21 (exons encoding the kinase domain). This results in increased kinase activity leading to the downstream activation of proliferative and anti-apoptotic signaling pathways. EGFR mutations are more frequent among East Asians, never smokers, females and adenocarcinoma histologic subtypes [Shigematsu and Gazdar, 2006].
EGFR inhibitors include the small molecule EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, afatinib and dacomitinib, and EGFR-targeted monoclonal antibodies cetuximab and necitumumab. EGFR inhibitors have had limited efficacy in lung SCC. In a randomized phase III study of erlotinib versus placebo in patients with pretreated NSCLC, no difference in OS was seen in the SCC subset [Shepherd et al. 2005]. In a phase III study of second line gefitinib versus docetaxel in patients with NSCLC, OS was similar in the SCC subset as well [Kim et al. 2008]. Preliminary data from a phase III study of second-line afatinib versus erlotinib in advanced stage lung SCC showed a PFS of 2.4 versus 1.9 months (HR 0.82; 95% CI 0.68–1.0; p = 0.043) and a disease control rate of 45.7% versus 36.8% (p = 0.02), respectively. These patients were not selected on EGFR mutation status but on squamous cell histology [Goss et al. 2014] (Table 1).
Selected studies of targeted agents in advanced stage NSCLC.
ADC, adenocarcinoma; CI, confidence interval; CTLA-4, cytotoxic T-lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; HR, hazard ratio; ir, immune-related; NSCLC, nonsmall cell lung cancer; ORR, overall response rate; OS, overall survival; PARP, poly (ADP-ribose) polymerase-1; PD-1, programmed death-1; PD-L1, programmed death ligand 1; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors; SCC, squamous cancer cell; TKI, tyrosine kinase inhibitor.
In a retrospective pooled analysis comparing the outcomes in patients with lung SCC with EGFR mutations versus adenocarcinoma with EGFR mutations in patients treated with gefitinib, the ORR was 36% versus 69%, respectively, and the PFS was 3.1 months versus 9.4 months, respectively [Shukuya et al. 2011]. In a study of patients with lung SCC treated with an EGFR TKI, the ORR was higher in those with EGFR mutations compared with EGFR wild type at 25% and 9%, respectively, [Hata et al. 2013].
The EGFR monoclonal antibody cetuximab has shown marginal improvements in OS benefit (HR 0.871; 95% CI 0.762–0.996; p = 0.044) when combined with cisplatin and vinorelbine in EGFR-expressing NSCLC [Pirker et al. 2009]. In a subset analysis, a borderline survival benefit (HR 0.80; 95% CI 0.64–1.00) was seen in the lung SCC cohort when treated with cetuximab and chemotherapy. Preliminary data from a phase III study of cisplatin/gemcitabine, with or without necitumumab, in patients with advanced stage lung SCC, reported that the addition of necitumumab resulted in a modest improvement in OS (9.9–11.5 months; HR 0.84; 95% CI 0.74–0.96) and PFS (5.5–5.7 months; HR 0.85; 95% CI 0.74–0.98) [Thatcher et al. 2014]. These benefits, although small, represent development in the treatment of advanced stage lung SCC, a disease where little progress has been made previously. In addition future analysis may identify a subgroup of patients that derive greater benefit with the addition of necitumumab to chemotherapy.
Anti-angiogenic agents
Anti-angiogenic agents, including monoclonal antibodies and TKIs, have been studied in lung SCC. Bevacizumab, the anti-vascular endothelial growth factor (VEGF) agent that inhibits tumor angiogenesis, was initially studied in combination with chemotherapy in all histological subtypes in a phase II trial [Johnson et al. 2004]. However, 31% of SCC patients treated with bevacizumab developed pulmonary hemorrhage. In view of these safety issues, bevacizumab is not used in SCC. In subsequent pivotal studies, SCC was excluded and survival benefits were seen when bevacizumab was combined with chemotherapy. Bevacizumab is currently approved only in patients with nonsquamous NSCLC [Sandler et al. 2006].
Ramucirumab is a monoclonal antibody that specifically binds to the extracellular domain of VEGF receptor 2. A phase III study of ramucirumab and docetaxel versus docetaxel showed an improvement in OS and PFS with ramucirumab and docetaxel in the overall patient population. In the lung SCC cohort, while improvement in PFS was seen, there was no OS benefit [Garon et al. 2012]. The addition of VEGF receptor TKIs to chemotherapy has had no impact on OS [Herbst et al. 2010; De Boer et al. 2011, Tan et al. 2015] and in some studies, it has been associated with an increased risk of hemoptysis and mortality [Scagliotti and Govindan, 2010; Scagliotti et al. 2012].
New molecular targets and pathways
Recent molecular characterization of SCC lung has revealed new candidates that are potential therapeutic targets. Molecular targets identified include amplification of the fibroblast growth factor receptor 1 (FGFR1) gene, FGFR fusions, discoidin death receptor 2 (DDR2) gene mutations, and PI3KCA gene amplifications and mutations [Kim et al. 2013b]. Using comprehensive genomic analysis, The Cancer Genome Atlas (TCGA) group found that 96% of SCCs contain mutations in genes that may have oncogenic or tumour suppressor activity. Recurrent somatic gene mutations have been reported, including TP53 (81% of SCC samples), MLL2 (20%), PIK3CA (16%) and CDKN2A (15%) [Hammerman et al. 2012]. A similar range of genetic alterations was described in East Asian patients with lung SCC, including TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2 and PIK3CA [Kim et al. 2014].
FGFR inhibitors
The FGFR family of tyrosine kinases com-prises four members, FGFR1–4, which mediate tumorigenesis via the MAPK and PI3K pathways. Aberrant FGFR signaling in solid tumors can occur through gene amplification, mutations, translocation, alternative splicing and isoform switching [Dienstmann et al. 2014]. FGFR1 amplification was initially described to be oncogenic in lung SCC with a frequency of 21% [Weiss et al. 2010] and is associated with smoking [Kim et al. 2013a]. FGFR1 amplification was first reported to be associated with a worse outcome by Kim and colleagues, but a recent meta-analysis found no association [Jiang et al. 2015]. Discrepancies in the frequency of FGFR1 amplification and prognostic outcomes could be attributed to differences in sample size and methodology used to detect FGFR1 amplification. As differences in defining FGFR1 amplification may have clinical implications on patient selection for treatment, it is of great importance to standardize the criteria for FGFR1 amplification [Seo et al. 2014].
Preliminary results from early phase studies of the pan-FGFR TKIs AZD4547 and BGJ398 in FGFR1 amplified lung SCC have reported an ORR of 8 and 16%, respectively [Paik et al. 2014; Nogova et al. 2014]. In a phase I/II study of lucitanib, an FGFR1-2, VEGFR1–3 and PDGFR TKI, in patients with pretreated solid tumors harboring FGF-aberrant pathways or considered angiogenesis-sensitive, promising activity (ORR 50%) was seen in patients with breast cancer; however, minimal responses were reported in patients with NSCLC [Soria et al. 2014] (Table 1).
Recent studies have reported that FGFR1, FGFR2 and FGFR3 gene rearrangements are oncogenic drivers in multiple solid tumor types including NSCLC, with a role in tumor initiation and maintenance [Wu et al. 2013]; 2.7% of lung SCCs harbored FGFR2 or FGFR3 fusions in the TCGA study. In another study, FGFR3 fusions were found in 1.4% of East Asian patients with SCC [Hammerman et al. 2012; Kim et al. 2014]. Recently, the frequency of FGFR1–3 fusions was reported to be 1.3% in patients with NSCLC, and more likely in lung SCC (3.5%) than lung adenocarcinoma (0.6%). FGFR fusions were associated with smoking and larger tumors. While multiple fusion partners of FGFR have been reported, only one fusion partner for FGFR1 and FGFR3 fusion has been identified in lung SCC, namely BAG4-FGFR1 and FGFR3-TACC3 [Wang et al. 2014]. Studies of FGFR inhibitors are ongoing in patients with lung SCC harboring alterations in the FGFR pathway [ClinicalTrials.gov identifier: NCT01795768, NCT01861197, NCT02109016, NCT01004224].
Point mutations in FGFR2 and FGFR3 encoding the extracellular and kinase domains have been reported in lung SCC at a frequency of 3% each. Preclinical studies have demonstrated these mutations induce cellular transformation. In addition, mutations in the extracellular domains of FGFR2 resulted in constitutive FGFR dimerization. In the same study, a patient with an oral SCC harboring FGFR2 mutation responded to pazopanib, a multi TKI including the FGFR family, providing a rationale for conducting studies of FGFR TKIs in lung and oral SCC with FGFR2 or FGFR3 mutations [Liao et al. 2013].
PI3K signaling pathway inhibitors
The PI3K/AKT/mTOR signaling pathway plays a crucial role in cancer cell survival and proliferation. Dysregulation in the PI3K signaling pathway may be due to mutations or amplification of PIK3CA (the gene that codes for the catalytic subunit of PI3K, located on chromosome 3q), mutations in AKT, or mutations in PTEN (which negatively regulates the pathway via the dephosphorylation of PIP3) [Beck et al. 2014]. In the TCGA paper, one of the components of the PI3K/AKT pathway was altered in 47% of tumors [Hammerman et al. 2012]. This is concordant with other literature, in which PI3KCA copy number gains occur in 33–43% of lung SCCs, at a higher frequency than activating PI3KCA mutations (3.6–7.1%) [Drilon et al. 2012]. Mutations of PIK3CA tend to occur at exons 9 and 20, which code for the helicase and kinase domains of PI3K and cause constitutive activation. PTEN mutations are seen in 10.2% and AKT1 mutations in 1.1–7.1%; AKT mutations are commonly an activating point mutation E17K. These were all in much higher proportions than lung adenocarcinomas [Drilon et al. 2012]. While lung adenocarcinomas with PIK3CA gains tend to have other mutations, SCCs with PIK3CA gains do not, indicating that it may play a pivotal role in the pathogenesis of SCC [Yamamoto et al. 2008].
There are a number of drugs targeting this pathway currently in development, including pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors and dual PI3K/mTOR inhibitors [Beck et al. 2014]. A randomized phase II study of docetaxel and PX-866, a pan-isoform inhibitor of PI3K, versus docetaxel alone in molecularly unselected pretreated patients with NSCLC reported ORRs of 6% and 0%, respectively [Levy et al. 2014]. Studies of PIK3CA inhibitors in NSCLC as monotherapy or in combination with chemotherapy are ongoing [ClinicalTrials.gov identifier: NCT01493843, NCT01297491, NCT01737502].
Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors
PARP is a family of proteins important in DNA repair. PARP-1, the most studied in the family, accounts for more than 90% of cellular PARP activity [Dantzer et al. 1999] and is a critical regulator of the DNA base excision repair (BER) and single-strand break (SSB) repair pathways [Rouleau et al. 2010]. PARP-1 mRNA expression is higher in multiple cancers, including lung SCC [Ossovskaya et al. 2010]. Inhibition of PARP1 results in accumulation of SSBs with subsequent double-strand breaks and eventual cell death.
Iniparib (BSI-201) was previously thought to be a PARP inhibitor, but has subsequently been shown to be nonselective modifier of cysteine-containing proteins [Liu et al. 2012]. In a randomized phase II trial of patients with lung SCC, the addition of iniparib to cisplatin/gemcitabine versus chemotherapy alone showed a marginal improvement in PFS and OS [Novello et al. 2014]. In a confirmatory phase III study (ECLIPSE) in patients with lung SCC, the addition of iniparib to carboplatin/gemcitabine did not meet the primary endpoint of OS compared with chemotherapy alone [Spigel et al. 2013] and its development has been discontinued. A study of maintenance olaparib, another PARP inhibitor, in lung SCC is currently underway [ClinicalTrials.gov identifier: NCT01788332].
Immunotherapy
Lung tumorigenesis is not only dependent on genetic aberrants within cancer cells but also on interactions with the immune system [Hanahan and Weinberg, 2011]. Although NSCLC has historically been thought to be a nonimmunogenic tumor, the development of a new generation of cancer vaccines and immune modulators has created great interest in using immunotherapy in NSCLC. With regards to cancer vaccines, several key phase III trials reported negative results in the adjuvant (melanoma associated antigen A3 vaccine) [GlaxoSmithKline, 2014] and locally advanced setting (tecemotide and belagenpumatucel-L vaccines) [Butts et al. 2014; Giaconne et al. 2013].
Immune checkpoint or co-inhibitory molecules, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), function in a normal physiological state to protect against autoimmunity [Pardoll, 2012]. Effector T cells are primed and activated upon interaction with antigen presenting cells. The activated T cells then express CTLA-4 which in turn downregulates the T-cell response, thus preventing autoimmunity. Ipilimumab, a humanized monoclonal antibody that binds to CTLA-4, reduces the inhibition of T-cell activation by CTLA-4. In addition, inhibition of CTLA-4 also reduces regulatory T-cell mediated immunosuppression, resulting in enhanced antitumor activity [Zielinski et al. 2013].
Promising activity of ipilimumab has been reported in a phase II study in which patients with advanced stage NSCLC were randomized to receive six cycles of chemotherapy alone (control), chemotherapy concurrent with ipilimumab from cycles 1 to 4 (concurrent) or chemotherapy with the addition of ipilimumab from cycles 3 to 6 (phased). The primary endpoint was immune-related PFS (irPFS), which takes into account the immune-related response criteria. In the concurrent and phased treatment arms, the irPFS was 5.5 versus 4.6 months (HR 0.81; p = 0.13) and 5.7 versus 4.6 months (HR 0.72; p = 0.05), respectively. On subset analysis, the irPFS in the phased cohort was longer in patients with squamous histology (HR 0.55) than in patients with nonsquamous histology (HR 0.82; 95% CI 0.52–1.28) [Lynch et al. 2012]. To confirm these encouraging subset results, a larger phase III trial is being conducted in patients with squamous subtype NSCLC [ClinicalTrials.gov identifier: NCT01285609].
Another immune checkpoint molecule is PD-1, a receptor found on T and B lymphocytes, natural killer (NK) cells and T regulatory cells. Upon ligation with the ligand PD-L1, PD-1 is activated in T cells, resulting in the downregulation of effector T cell function. In this way, PD-1/PD-L1 regulates T cell activity in peripheral tissues during an inflammatory response [Chen et al. 2012]. PD-1 is upregulated in tumor infiltrating lymphocytes (TILs), while many tumors have increased PD-L1 expression. By this mechanism, tumors can induce T-cell anergy and also avoid the processing of tumor antigens by antigen-presenting cell (APCs) that lead to recognition [Dong et al. 2002; Chen et al. 2012].
Inhibitors of PD-1 include PD-L1 antibodies such as nivolumab (BMS936558), lambrolizumab (MK-3475) and pidilizumab (CT-011), while PD-L1 inhibitors include MPDL3280A, BMS-936559, and MEDI4736 [Sundar et al. 2014]. Early phase studies of both PD-1 inhibitors and PD-L1 inhibitors have reported ORRs of 8–23% and durable disease stabilization in heavily pretreated NSCLC. No discernable difference in outcomes was seen between SCC and non-SCC histologic subtypes [Brahmer et al. 2012; Herbst et al. 2014; Garon et al. 2014] (Table 1). Initial results from a phase II study of nivolumab in pretreated SCC cell lung (Checkmate-017) have shown an ORR of 15%, an OS of 8.2 months and a 1-year survival of 41%. These results are highly promising, as 65% of patients had already received 3 or more prior lines of therapy [Rizvi et al. 2015]. More recently a phase III study of nivolumab versus docetaxel in previously treated patients with advanced or metastatic lung SCC (Checkmate-063) was stopped early as an independent Data Monitoring Committee concluded the study met its endpoint of improved OS, with an OS of 9.2 months versus 6 months (HR 0.59; 95% CI 0.44–0.79). Based on the results of CheckMate-017 and CheckMate-063, the US Food and Drug Administration (FDA) has granted a new indication for nivolumab in the treatment of squamous cell NSCLC with progression on or after platinum-based chemotherapy [Bristol-Myers Squibb, 2015].
Conclusion
Unlike the therapeutic success seen in patients with advanced lung adenocarcinoma with the use of molecular targeted therapy, no specific targeted therapy is currently established in lung SCC. The combination of a platinum agent (cisplatin or carboplatin) with either gemcitabine, vinorelbine or a taxane remains the standard first-line treatment in lung SCC. Based on promising results from early phase studies, immune checkpoint inhibitors herald a new therapeutic paradigm, and given the lack of new effective therapies in lung SCC, results from randomized confirmatory studies in SCC are eagerly awaited. One of the main obstacles to improvement in outcomes has been the lack of a predictive biomarker that could identify patients who would benefit from treatment. The identification of novel targets by comprehensive genomic analysis and the use of well-designed biomarker driven studies [Malik et al. 2014] will play a role in accelerating the development and approval of novel therapies for patients with lung SCC.
Footnotes
Acknowledgements
R.A.S. is supported by the National Research Foundation, Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Conflict of interest statement
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.