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Editorials

Histology Matters: Individualizing Treatment in Non-Small Cell Lung Cancer

Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

Correspondence: Joel W. Neal, M.D., Massachusetts General Hospital Cancer Center, 55 Fruit Street, Lawrence House 221, Boston, Massachusetts 02114, USA. Telephone: 617-724-4000; Fax: 617-724-3166; e-mail: jwneal{at}partners.org

Received December 4, 2009; accepted for publication December 6, 2009; first published online in THE ONCOLOGIST Express on January 19, 2010.

Disclosures: Joel W. Neal: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the author or independent peer reviewers.

A critical advance in the treatment of advanced non-small cell lung cancer (NSCLC) over the last 20 years has been the development of tolerable platinum-based chemotherapy doublets [1]. Despite this, the estimated survival time of patients is still only slightly >12 months in the best large, randomized clinical trials [2, 3], and only 6 months for the general population with newly diagnosed advanced NSCLC [4]. Interestingly, a recent analysis of the Surveillance, Epidemiology, and End Results data from 1990–2005 does demonstrate a significant but modest improvement in the treatment of stage IV lung cancer over the last 15 years, with 1-year survival rates improving by 6% and 2-year survival rates improving by 3%. Within this recent analysis, it is clear that different histologic subtypes of NSCLC have had differential improvements. Patients with adenocarcinoma histology have seen an 8% improvement in their 1-year survival rate, from 15% to 23%, even in an era before the clinical significance of histology was recognized. Much of this benefit was achieved during the 2002–2005 period, in which erlotinib, gefitinib, and pemetrexed were approved, and during that period the observed survival duration for patients with the adenocarcinoma and squamous cell histologic subtypes diverged for the first time in history. With multiple new treatments that appear safer and more effective in patients with adenocarcinoma, this difference is likely to widen in the coming years. It is clear that histology is critical in choosing the appropriate therapy for NSCLC patients. In this editorial, specific treatment implications for each histological subtype are addressed. Going forward, it is likely that improved molecular testing will augment and even replace histologic classification alone.

For patients with adenocarcinoma, treatment options have grown dramatically over the last few years. First-line treatment consists of four to six cycles of a platinum-containing chemotherapy doublet, plus bevacizumab for eligible patients. The incorporation of pemetrexed into bevacizumab-containing first-line regimens appears to be safe and effective [5], and a randomized phase III comparison of the benchmark regimen of carboplatin, paclitaxel, and bevacizumab with carboplatin, pemetrexed, and bevacizumab is ongoing. For patients with adenocarcinoma known to have an epidermal growth factor receptor (EGFR) mutation, first-line tyrosine kinase inhibitor therapy should be considered based on the recent Iressa® Pan-Asia Study (IPASS), which demonstrated better progression-free survival and quality of life in patients with an EGFR mutation treated with gefitinib as compared with chemotherapy [6]. However, identification of a KRAS mutation in the tumor strongly predicts resistance to this therapy, and it should be avoided in patients with known KRAS mutations [7, 8]. In the second-line setting, an overall survival benefit favoring both pemetrexed and erlotinib has been observed from the strategy of "switch maintenance": giving a noncrossresistant therapy before symptomatic or radiographic progression [3, 9]. Based on these data, the U.S. Food and Drug Administration (FDA) recently approved pemetrexed as maintenance therapy for patients with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. This strategy is likely to be most beneficial for individuals in whom symptomatic progression of disease may preclude later treatment, but does have the theoretical downside of depriving patients of a treatment-free interval following first-line therapy.

Unfortunately, patients with squamous cell histology have relatively fewer options outside the scope of a clinical trial. For these patients, platinum-based doublet chemotherapy is still the mainstay of treatment. Although gemcitabine plus cisplatin was compared directly with pemetrexed plus cisplatin and appeared to have a more favorable response rate in patients with squamous cell histology [10], all non-pemetrexed containing chemotherapy doublets are probably similarly effective in squamous cell tumors. Regarding the role of targeted therapy, the monoclonal EGFR antibody cetuximab has a survival benefit in combination with cisplatin and vinorelbine, but not with carboplatin and paclitaxel [11, 12]. In the First-Line Trial for Patients with EGFR-Expressing Advanced NSCLC (FLEX), this improvement in survival appeared to be driven in part by a trend toward benefit in the 33% of enrolled patients with squamous tumors (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.64–1.00), as compared with adenocarcinoma patients, who have a smaller degree of benefit (HR, 0.95; 95% CI, 0.77–1.15). Therefore, a first-line regimen with cetuximab may be considered for patients with squamous cell histology. Following first-line treatment, the strategy of switch maintenance to erlotinib also appears to retain a progression-free survival benefit even in patients with squamous histology, but whether this is also true of overall survival has not yet been reported [9]. For second-line treatment and beyond, many other chemotherapy agents, except for pemetrexed, appear to have modest and equivalent activity in NSCLC patients regardless of histology. Of these, both erlotinib and docetaxel are FDA approved.

The diagnosis of bronchioloalveolar carcinoma (BAC), a less invasive subtype of NSCLC adenocarcinoma characterized by well-differentiated cells growing along pulmonary septae, may also imply a particular treatment strategy. This type of NSCLC may be enriched for mutations in the EGFR tyrosine kinase domain, which are strongly associated with response to EGFR tyrosine kinase inhibitor (TKI) treatment. However, there is variability in histology and molecular status even within this NSCLC subtype. In a series of 111 adenocarcinoma patients from our institution, EGFR mutations were observed in 47% of patients with nonmucinous BACs, but patients with the mucinous form of BAC never had an EGFR mutation, and six of seven actually had a KRAS mutation [13]. These data suggest that patients with nonmucinous BAC have a reasonable chance of responding to "empiric" EGFR TKI therapy, but that TKI treatment should probably be avoided in patients with mucinous BAC unless the molecular status is known.

In summary, an increasing array of therapeutic options is becoming available for patients with advanced NSCLC (Table 1). As part of the growing effort to individualize therapy, histologic subtype must now be incorporated into treatment decisions. It is essential to obtain an adequate sample of tissue at the time of initial diagnosis for both histologic confirmation and molecular testing, preferably via surgical specimens, core biopsies, or serial fine-needle aspiration samples. Adequate tissue availability may be the key to identifying the most appropriate treatment for each patient, improving the chances of finding an effective therapy as early as possible in a patient's treatment. It is likely that the differential histological response to newer therapies actually reflects underlying differences in the molecular characteristics of the tumor. In fact, the lack of highly reproducible inter-pathologist agreement in the identification of squamous cell histology by H+E slides alone [14] may be improved by H + immunohistochemical staining for molecular markers such as TTF1, TP63, and others to classify tumors that otherwise do not appear histologically distinct [15]. Eventually, specific molecular testing for perturbations in genes like EGFR, KRAS, ALK, thymidylate synthase, and others will augment, and may even supplant, the role of histology in predicting responses to particular therapies.

	REFERENCES

Top References

1. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311:899–909.[Abstract/Free Full Text]
2. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550.[Abstract/Free Full Text]
3. Ciuleanu T, Brodowicz T, Zielinski C et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 2009;374:1432–1440.[CrossRef][Medline]
4. NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: A systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol 2008;26:4617–4625.[Abstract/Free Full Text]
5. Patel JD, Hensing TA, Rademaker A et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol 2009;27:3284–3289.[Abstract/Free Full Text]
6. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947–957.[Abstract/Free Full Text]
7. Han SW, Kim TY, Jeon YK et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 2006;12:2538–2544.[Abstract/Free Full Text]
8. Massarelli E, Varella-Garcia M, Tang X et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 2007;13:2890–2896.[Abstract/Free Full Text]
9. Cappuzzo F, Coudert B, Wierzbicki R et al. Efficacy and safety of erlotinib as first-line maintenance in NSCLC following non-progression with chemotherapy: results from the phase III SATURN study [abstract A282.281]. J Thorac Oncol 2009;4(suppl 1):S289.
10. Scagliotti GV, Parikh P, von Pawel J et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543–3551.[Abstract/Free Full Text]
11. Pirker R, Pereira JR, Szczesna A et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label randomised phase III trial. Lancet 2009;373:1525–1531.[CrossRef][Medline]
12. Lynch TJ, Patel T, Dreisbach L et al. Overall survival (OS) results from the phase III trial BMS 099: Cetuximab +/- taxane/carboplatin as 1st line treatment for advanced NSCLC. J Thorac Oncol 2008;3:S305.
13. Finberg KE, Sequist LV, Joshi VA et al. Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. J Mol Diagn 2007;9:320–326.[Abstract/Free Full Text]
14. Grilley-Olson JE, Hayes DN, Qaqish BF et al. Diagnostic reproducibility of squamous cell carcinoma (SC) in the era of histology-directed non-small cell lung cancer (NSCLC) chemotherapy: A large prospective study [abstract 8008]. J Clin Oncol 2009;27:15s.[CrossRef]
15. Ring BZ, Seitz RS, Beck RA et al. A novel five-antibody immunohistochemical test for subclassification of lung carcinoma. Mod Pathol 2009;22:1032–1043.[CrossRef][Medline]

This Article Free via Open Access: OA Full Text (PDF) OA All Versions of this Article: theoncologist.2009-0306v1 theoncologist.2009-0306v2 15/1/3    most recent eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Neal, J. W. PubMed PubMed Citation Articles by Neal, J. W.