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Originally published as JCO Early Release 10.1200/JCO.2004.01.904 on February 23 2004 © 2004 American Society of Clinical Oncology.
Toward Customized Trastuzumab in HER-2/neu-Overexpressing Non-Small-Cell Lung CancersInstitut Català d'Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain Amplification or overexpression of the HER-2/neu gene in breast cancer is associated with aggressive behavior and resistance to systemic and local radiation therapies.1 The phosphatidylinositol 3-kinase (PI3K) and Akt is the signaling cascade that results from HER-3 heterodimerization with overexpressed HER-2/neu receptors in breast cancer cells, promoting cell survival and enhanced tumor aggressiveness.1,2 Trastuzumab is a recombinant DNA-derived monoclonal antibody that selectively binds to p185HER2, the protein product of the extracellular human epidermal growth factor oncogene, HER-2/neu, and HER-2/neu expression is a predictor of trastuzumab response. Trastuzumab was approved by the US Food and Drug Administration for the treatment of metastatic breast cancer, based on superior survival compared to conventional therapy.3,4 Until recently, the role of trastuzumab and HER-2/neu expression in lung cancer has been largely marginalized. In this issue of the Journal of Clinical Oncology, Langer et al5 present evidence as to the feasibility of combining chemotherapy and trastuzumab in advanced non–small-cell lung cancer (NSCLC). A seminal study showed that HER-2/neu mRNA expression, quantified by Northern blotting in twenty NSCLC cell lines, was a predictor of intrinsic multidrug resistance.6 More recently, Bunn et al7 found that synergy between trastuzumab and cisplatin or gemcitabine was even greater in HER-2/neu-positive NSCLC cell lines than in breast cancer cell lines. Breast cancer cell lines overexpressed HER-2/neu because of gene amplification, but that gene amplification occurred infrequently in NSCLC cell lines. Only the Calu-3 cell line had true gene amplification. The greatest growth inhibition with trastuzumab was seen in cell lines expressing high levels of HER-2/neu.7,8 One of the problems faced by clinical investigators in using trastuzumab for NSCLC patients is to define that a patient is HER-2/neu-positive. Traditionally, HER-2/neu status has been assessed by at least one of the three following methods: immunohistochemistry (IHC), ranking as negative, 1+, 2+, or 3+; fluorescence in situ hybridization (FISH), reflecting positivity or negativity; enzyme-linked immunoabsorbent assay (ELISA), where a HER-2/neu serum concentration > 15 ng/mL is considered positive.3 Several studies have demonstrated that women with metastatic breast cancer that is HER-2/neu 3+ by IHC or demonstrate gene amplification by FISH obtain the greatest benefit from trastuzumab.9,10 Various studies in whole tissue or tissue microarray sections of NSCLC have demonstrated that HER-2/neu overexpression by IHC using the US Food and Drug Administration-approved HercepTest (Dako Corp, Carpinteria, CA) is consistent with the level of overexpression detected in breast cancers (19% to 30%; 2+ or 3+)11-14. The majority of NSCLC cases with HER-2/neu abnormalities are adenocarcinomas. HER-2/neu true gene amplification (average ratio of HER-2/neu gene to chromosome 17 copy numbers > 2) occurred substantially less frequently in NSCLC (ranging from 2% to 22%)13–15 than in breast cancer. A recent meta-analysis involving more than 4,500 NSCLC patients showed that patients not expressing HER-2/neu had better survival than those overexpressing HER-2/neu, with a hazard ratio of 1.46.16 NSCLC patients with HercepTest 3+ tumors or gene amplification account for only 11% of all patients and also show significantly shorter survival.13 Trastuzumab targets this small subgroup of patients, where benefit can be expected to be greatest. However, the majority of NSCLC patients with HercepTest 2+ may not be good candidates for trastuzumab treatment. Furthermore, it is well documented that HER-2/neu receptor may be overexpressed in the absence of gene amplification. In addition, the reliable assessment of HER-2/neu status is a prerequisite for successful individualized trastuzumab therapy. Very little data exist on HER-2/neu mRNA evaluation. Measurement of HER-2/neu mRNA transcripts by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR), based on TaqMan methodology, detected transcript levels above normal in 47% of NSCLCs.15 Quantitative RT-PCR is used to examine transcripts in several genes that can predict therapeutic response or resistance.17 Elevated levels of HER-2/neu mRNA levels range from moderate to very high. At the high end of this spectrum, Pellegrini et al15 identified cases with high levels of gene amplification accompanied by extremely elevated mRNA and protein overexpression. RT-PCR makes mRNA quantitation more precise and reproducible,18 and should be used as a screening test for trastuzumab treatment. Other authors have found the same frequencies of elevated HER-2/neu mRNA expression (35%) and similar frequencies of high EGFR expression, indicating that transcript assessment could be much more accurate than the interpretation of IHC positivity.19 The ELISA evaluates the extracellular domain of HER-2/neu, which is shed into blood by tumor cells, and could therefore be used for monitoring trastuzumab efficacy.
The final results from the Eastern Cooperative Oncology Group 2598 study5 reported in this issue show the feasibility of combining trastuzumab with paclitaxel and carboplatin in 56 advanced NSCLC patients with HER-2/neu 1+ to 3+ tumors, good performance status, and a left ventricular ejection fraction Trastuzumab resistance remains to be elucidated. Several lines of evidence indicate that there is crosstalk between the heterodimers of HER-2/neu, HER-3, and the PI3K/Akt pathway (a key factor in chemoresistance).1 Akt is constitutively active in more than 90% of NSCLC cell lines. Overexpression of insulin-like growth factor-1 (IGF-1) receptor has been reported to abrogate the antitumor effect of trastuzumab.23 Simultaneous blockade of either the IGF-1 receptor or PI3K restored sensitivity to trastuzumab.24 One mechanism for aberrant activation of Akt is the loss of the tumor suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (PTEN).24 Loss of PTEN expression is as a result of PTEN promoter hypermethylation in more than 30% of glioblastomas,25 gastric cancers,26 and NSCLCs.27 Recently, frequent methylation of the suppressors of cytokine signaling has been observed in NSCLC, leading to upregulation of signal transducers and activators of transcription.28 Collectively, there are multiple signaling pathways that can abrogate trastuzumab efficacy. Many uncertainties remain in the use of trastuzumab in NSCLC. However, moving on to large phase III trials is not the best way to proceed. It seems that the next logical step should be to consolidate customized trastuzumab strategies by selecting patients with high HER-2/neu transcripts as a target group for chemotherapy plus trastuzumab. Since HER-2/neu transcripts are present in all cases and elevated in approximately 40%, more restrictive criteria for high mRNA levels should be implemented. Perhaps only a quarter of patients with the highest HER-2/neu transcripts should be selected as candidates for trastuzumab treatment, and among these patients, those coexpressing high levels of IGF-1 receptor should perhaps be ruled out. Genetic markers of trastuzumab resistance should be investigated. Serum DNA methylation of PTEN or suppressors of cytokine signaling and Western blot of Akt in peripheral blood lymphocytes can shed some light on trastuzumab resistance, and should be examined as well. While gene amplification by FISH is definitely a good predictor in breast cancer, it is not useful in NSCLC. However, transcript analysis by RT-PCR merits being examined in both breast cancer and NSCLC. New studies should focus on testing these principles and selecting patients according to HER-2/neu transcript levels, in order to correctly identify the proportion of NSCLC patients in whom survival can be substantially improved. Finally, the ultimate goal is to integrate customized chemotherapy and targeted therapies by identifying different subsets of patients that will respond to different antisignaling molecules. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Bacus SS, Altomare DA, Lyass L, et al: AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival. Oncogene 21:3532–3540, 2002[CrossRef][Medline] 2. Chen JS, Lan K, Hung MC: Strategies to target HER2/neu overexpression for cancer therapy. Drug Resist Updat 6:129–136, 2003[CrossRef][Medline]
3. Ferrone M, Motl SE: Trastuzumab for the treatment of non-small-cell lung cancer. Ann Pharmacother 37:1904–1908, 2003
4. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792, 2001
5. Langer CJ, Stephenson P, Thor A, et al: Trastuzumab in the treatment of advanced non–small-cell lung cancer: Is there a role? Focus on Eastern Cooperative Oncology Group Study 2598. J Clin Oncol 22:1180–1187, 2004
6. Tsai CM, Chang KT, Perng RP, et al: Correlation of intrinsic chemoresistance of non-small-cell lung cancer cell lines with HER-2/neu gene expression but not with ras gene mutations. J Natl Cancer Inst 85:897–901, 1993
7. Bunn PA Jr, Helfrich B, Soriano AF, et al: Expression of Her-2/neu in human lung cancer cell lines by immunohistochemistry and fluorescence in situ hybridization and its relationship to in vitro cytotoxicity by trastuzumab and chemotherapeutic agents. Clin Cancer Res 7:3239–3250, 2001 8. Hirsch FR, Helfrich B, Franklin WA, et al: Preclinical studies of gemcitabine and trastuzumab in breast and lung cancer cell lines. Clin Breast Cancer 3:S12–S16, 2002 (suppl 1)
9. Burstein HJ, Harris LN, Gelman R, et al: Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxurubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: A pilot study. J Clin Oncol 21:46–53, 2003
10. Vogel CL, Cobleigh MA, Tripathy D, et al: Efficacy and safety of trastuzumab as a single agent in first line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726, 2002 11. Scheurle D, Jahanzeb M, Aronsohn RS, et al: HER-2/neu expression in archival non-small cell lung carcinomas using FDA-approved Hercep test. Anticancer Res 20:2091–2096, 2000[Medline] 12. Nakamura H, Saji H, Ogata A, et al: Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer. Int J Cancer 103:61–66, 2003[CrossRef][Medline] 13. Tan D, Deeb G, Wang J, et al: HER-2/neu protein expression and gene alteration in stage I-IIIA non-small cell lung cancer: A study of 140 cases using a combination of high throughput tissue microarray, immunohistochemistry, and fluorescent in situ hybridization. Diagn Mol Pathol 12:201–211, 2003[CrossRef][Medline] 14. Hirsch FR, Scagliotti GV, Langer CJ, et al: Epidermal growth factor family of receptors in preneoplasia and lung cancer: Perspectives for targeted therapies. Lung Cancer 41:S29–S42, 2003 (suppl 1)
15. Pellegrini C, Falleni M, Marchetti A, et al: HER-2/Neu alterations in non-small cell lung cancer: A comprehensive evaluation by real time reverse transcription-PCR, fluorescence in situ hybridization, and immunohistochemistry. Clin Cancer Res 9:3645–3652, 2003 16. Meert AP, Martin B, Paesmans M, et al: The role of HER-2/neu expression on the survival of patients with lung cancer: A systematic review of the literature. Br J Cancer 89:959–965, 2003[CrossRef][Medline] 17. Rosell R, Scagliotti G, Danenberg KD, et al: Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Oncogene 22:3548–3553, 2003[CrossRef][Medline] 18. Juhasz A, Frankel P, Cheng C, et al: Quantification of chemotherapeutic target gene mRNA expression in human breast cancer biopsies: Comparison of real-time reverse transcription-PCR vs. relative quantification reverse transcription-PCR utilizing DNA sequencer analysis of PCR products. J Clin Lab Anal 17:184–194, 2003[CrossRef][Medline]
19. Brabender J, Danenberg KD, Metzger R, et al: Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival. Clin Cancer Res 7:1850–1855, 2001
20. Gatzemeier U, Groth G, Butts C, et al: Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol 15:19–27, 2004
21. Feldman AM, Lorell BH, Reis SE: Trastuzumab in the treatment of metastatic breast cancer: Anticancer therapy versus cardiotoxicity. Circulation 102:272–274, 2000 22. Mangi AA, Noiseux N, Kong D, et al: Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9:1195–1201, 2003[CrossRef][Medline] 23. Bacus SS, Beresford PJ, Yarden Y, et al: The use of predicting factors and surrogate markers in patients' cancer biopsies treated with targeted antibodies to ErbB receptors and ErbB tyrosine kinase inhibitors. Proc Am Soc Clin Oncol 22:848, 2003 (abstr 3408) 24. Bianco R, Shin I, Ritter CA, et al: Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22:2812–2822, 2003[CrossRef][Medline] 25. Baeza N, Weller M, Yonekawa Y, et al: PTEN methylation and expression in glioblastomas. Acta Neuropathol 106:479–485, 2003[CrossRef][Medline] 26. Kang YH, Lee HS, Kim WH: Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest 82:285–291, 2002[CrossRef][Medline]
27. Soria JC, Lee HY, Lee JI, et al: Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 8:1178–1184, 2002
28. He B, You L, Uematsu K, et al: SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci U S A 100:14133–14138, 2003
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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45%. Standard doses of paclitaxel and carboplatin were administered every 3 weeks, with a trastuzumab loading dose followed by maintenance trastuzumab every 3 weeks. Patients could continue receiving maintenance trastuzumab therapy for up to 1 year. The overall response rate was 24.5%, median survival was 10.1 months, and 1-year survival rate was 42%. No exacerbation of hematologic toxicity was reported, and asymptomatic reduction of left ventricular ejection fraction occurred in 7% of patients. Langer et al
