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Journal of Clinical Oncology, Vol 26, No 20 (July 10), 2008: pp. 3351-3357 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0111 Increased EGFR Gene Copy Number Detected by Fluorescent In Situ Hybridization Predicts Outcome in Non–Small-Cell Lung Cancer Patients Treated With Cetuximab and Chemotherapy
From the Southwest Oncology Group, San Antonio; M.D. Anderson Cancer Center, Houston, TX; University of Colorado Cancer Center, Aurora, CO; University of Kansas Cancer Center, Kansas City, KS; and the University of California Davis Cancer Center, Davis, CA Corresponding author: Fred R. Hirsch, MD, PhD, University of Colorado Cancer Center, E 17th Ave, Aurora, CO 80010; e-mail: Fred.Hirsch{at}UCHSC.edu
Purpose Epidermal growth factor receptor (EGFR) gene copy number detected by fluorescent in situ hybridization (FISH) has proven to be useful for selection of non–small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors. Here, we evaluate EGFR FISH as a predictive marker in NSCLC patients receiving the EGFR monoclonal antibody inhibitor cetuximab plus chemotherapy. Patients and Methods Two hundred twenty-nine chemotherapy-naive patients with advanced-stage NSCLC were enrolled onto a phase II selection trial evaluating sequential or concurrent chemotherapy (paclitaxel plus carboplatin) with cetuximab.
Results EGFR FISH was assessable in 76 patients with available tumor tissue and classified as positive (four or more gene copies per cell in Conclusion These results are the first to suggest that EGFR FISH is a predictive factor for selection of NSCLC patients for cetuximab plus chemotherapy. Prospective validation of these findings is warranted.
Lung cancer is the most frequent cause of cancer death.1 The overall prognosis remains poor, with 15% of patients surviving 5 years.2 Gefitinib and erlotinib, which are tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR), provide objective response in 8% to 15% of patients with advanced non–small-cell lung cancer (NSCLC) progressing after initial chemotherapy. In a randomized, placebo-controlled, phase III study, erlotinib improved survival in NSCLC patients previously treated with chemotherapy.3 Despite independent activity of chemotherapy and EGFR TKIs in NSCLC, the addition of gefitinib or erlotinib to chemotherapy failed to improve survival in four large randomized trials when compared with chemotherapy alone.4-7 After these results, interest in identifying predictive biomarkers to EGFR TKIs intensified. EGFR pathway analysis of NSCLC cell lines and patient tumor tissue has described predictive value for several potential biomarkers of EGFR TKI activity, including EGFR protein expression by immunohistochemistry, EGFR gene copy number by fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization, EGFR activating mutations, as well as KRAS mutations, p-MAPK, and p-AKT.8 EGFR mutations, which typically predict rapid objective response to EGFR TKIs, are most frequent in never-smokers and more common in those patients with clinical characteristics associated with response (ie, patients with adenocarcinomas, Asian race, and female sex). Certain EGFR mutations, such as deletions in exon 19, associate with high response rate and prolonged survival after EGFR TKIs, whereas point mutations in exon 20 (T790) associate with acquired resistance.8 High EGFR gene copy number has been consistently associated with a favorable outcome after EGFR TKI therapy, whereas KRAS mutations are consistently associated with a poor outcome.9-14 The role of the EGFR-targeting monoclonal antibodies in the therapy of NSCLC has not yet been clarified. Cetuximab (Erbitux; Bristol-Myers Squibb Co, New York, NY/ImClone Systems Inc, New York, NY), a chimerized antibody of the immunoglobulin G1 subclass, has proven efficacy in colorectal cancer15 and head and neck cancer.16,17 In NSCLC, a phase II study in pretreated advanced-stage patients showed a response rate of 4.5%, but disease control rates (DCRs) and overall survival were comparable to that achieved with pemetrexed, docetaxel, and erlotinib in similar groups of patients.18 Early phase II trials and randomized phase II trials of cetuximab plus concurrent chemotherapy versus chemotherapy alone in unselected chemotherapy-naive advanced NSCLC patients favored the combination.19-21 In view of previous phase III studies showing no benefit of concurrent EGFR TKI plus chemotherapy combinations over chemotherapy alone, the Southwest Oncology Group (SWOG) sought to study cetuximab in a randomized phase II selection design, comparing sequential versus concurrent cetuximab and paclitaxel-carboplatin chemotherapy (S0342), to select the most appropriate regimen to test against chemotherapy alone in the phase III setting. Preliminary clinical data from S0342 demonstrated comparable response rates and progression-free survival (PFS) and overall survival data in both arms of the study.22 Here, for the first time to our knowledge, we report that EGFR gene copy number detected by FISH predicts outcomes in patients with advanced-stage NSCLC receiving these cetuximab plus chemotherapy combinations.
Patients with advanced NSCLC not previously treated with chemotherapy or radiotherapy were randomly assigned either to receive paclitaxel 225 mg/m2 and carboplatin (area under the curve = 6) every 3 weeks plus concurrent cetuximab 400 mg/m2 by 2-hour infusion on day 1 in week 1 and, thereafter, 250 mg/m2 by 1-hour infusion weekly for four cycles followed by maintenance cetuximab or to receive sequential paclitaxel plus carboplatin for four cycles followed by cetuximab (Fig 1). Treatment was continued until progressive disease or unacceptable toxicity. After progressive disease, patients were treated at investigator discretion. No data regarding second-line therapy were collected. Eligible patients were required to have stage IIIB (pleural infusion) or stage IV disease without brain metastases, a performance status of 0 to 1, and adequate organ function. The primary end point was survival. All patients had signed informed consent.
EGFR Gene Copy Number Analysis by FISH Available tissue samples were submitted to the SWOG tumor bank at the University of Colorado Cancer Center and evaluated for tumor content. Formalin-fixed, paraffin-embedded tissue sections were stained with hematoxylin and eosin, and a quality control assessment of the tumor tissue was made before FISH analysis was performed to ensure that sufficient material was available.
FISH analysis was performed as previously described.9,10 Tumors with four or more copies of the EGFR gene in
Statistical Design
Two hundred twenty-nine patients were enrolled onto the S0342 clinical trial. Seventy-six patients gave informed consent for correlative science participation (S9925 master correlative science protocol) and had assessable tumor tissue. Patient characteristics were similar between the overall study group and patients with EGFR FISH analysis performed (Table 1). Of the 76 patients in whom EGFR FISH testing was performed, 46 patients (61%) had adenocarcinoma, 17 patients (22%) had squamous cell carcinoma, and the rest of patients had NSCLC not otherwise specified or other NSCLC histologies. Ten patients (13%) had stage IIIB disease, and 66 patients (87%) had stage IV disease. Forty patients were treated in the concurrent arm, and 36 patients were treated in the sequential arm. Smoking status assessment showed 83% ever-smokers (current and former, 67% of females and 97.5% of males, P = .0004); 17% of patients were never-smokers (Table 1).
A total of 84 specimens from 76 S0342 patients were investigated for FISH analysis. Discrepancies between the first and second readers were found in nine specimens (10.7%), which is within the expected range of discrepancies for the laboratory (5% to 15%). Increased EGFR gene copy number (FISH positive) was present in 45 patient specimens (59.2%), whereas 31 specimens (40.7%) were FISH negative. Twenty-five (62.5%) of 40 patients were FISH positive in the concurrent treatment arm, and 20 (55.5%) of 36 patients in the sequential treatment arm were FISH positive. Treatment results for all 229 patients enrolled onto the S0342 trial were similar between the concurrent and sequential arms, with no difference in overall response rate (34% v 31%, respectively), stable disease rate (34% v 39%, respectively), DCR (68% v 69%, respectively), median PFS (4 months in both arms), or median overall survival (11 v 10 months, respectively).21 Outcomes were similar between the overall patient population and patients assessed for EGFR FISH. The median survival time was 10.5 months for all of the patients in the study (N = 209) and 11 months in patients assessed for EGFR FISH (n = 76; P = .29). There was a statistically insignificant trend for association of smoking status and EGFR FISH status (P = .35). Study results according to FISH status and treatment arms are listed in Table 2. Among the S0342 patients assessed by EGFR FISH, the median survival time was 15 months compared with 7 months for patients with a positive versus negative test, respectively (HR = 0.58, P = .046; Fig 2). One-year survival rate was 58% for FISH-positive patients and 32% for FISH-negative patients. FISH-positive patients had a superior survival in both treatment arms, although the difference was only significant in the concurrent arm. In the concurrent arm (Fig 3), the median survival time was 16 months for FISH-positive patients compared with 8 months for FISH-negative patients (HR = 0.43, P = .03), whereas in the sequential treatment arm (Fig 4), the median survival time was 15 months for FISH-positive patients compared with 7 months for the FISH-negative patients (HR = 0.83, P = .65). The 1-year survival rate was 64% v 20% in the concurrent arm and 50% v 44% in the sequential arm for FISH-positive and FISH-negative patients, respectively.
Median PFS time was significantly longer (6 months) in the FISH-positive group compared with the FISH-negative group (3 months; HR = 0.45; P = .0011; Fig 2). A significant difference in PFS was seen between FISH-positive and FISH-negative patients in each of the treatment arms (concurrent arm: 5 v 3 months, respectively; HR = 0.45; P = .02; sequential arm: 6 v 3 months, respectively; HR = 0.46; P = .03; data not shown). The overall response rate (complete plus partial response) was 37% (n = 27) for the 73 response assessable patients in the EGFR FISH group, 36% in the concurrent arm, and 38% in the sequential arm. One patient in the sequential arm showed improvement from stable disease to partial response during the cetuximab maintenance treatment. (Two patients improved from stable disease to partial response on the concurrent arm during cetuximab maintenance.) The DCR (objective response + stable disease) was 70% (51 of 73 patients; 69% in the concurrent arm and 71% in the sequential arm), which was not significantly different from the overall study population. Within the FISH-positive group (both treatment arms), the overall response rate was 45% (19 of 42 patients) compared with 26% in the FISH-negative group (eight of 31 patients), but the difference was not significant (P = .14). The DCR was significantly higher in FISH-positive patients (81%) than in FISH-negative patients (55%; P = .02). When analyzed within treatment arms, both response rate and DCR were numerically but not statistically higher in the FISH-positive versus FISH-negative subgroup (concurrent arm: response rate, 42% v 27%; DCR, 79% v 53%, respectively; sequential arm: response rate, 50% v 25%; DCR, 83% v 56%, respectively). Altogether, 47 patients received poststudy therapy, including 17 of 31 patients in the FISH-negative group (four patients received EGFR TKI) and 30 of 45 patients in the FISH-positive group (six patients received EGFR TKI). There was no imbalance between the groups regarding poststudy therapy. A multivariate Cox regression model including treatment arm and EGFR FISH status revealed a significant effect for EGFR FISH status in favor of FISH positivity (P = .049) even when adjusting for treatment arm. The effect of treatment arm was not significant (P = .42). A test for interaction between FISH and treatment arm was not significant (P = .25). The role of smoking status was analyzed in a multivariate Cox model. In a model that included FISH status, smoking status (current/former v never) did not represent a significant addition (P = .79).
S0342 is the first study to report that increased EGFR gene copy number by FISH predicts clinical outcomes after cetuximab-based therapy in patients with NSCLC. We previously reported that EGFR FISH portends a poor prognosis in NSCLC and is a reliable marker for prediction of clinical outcome after treatment with an EGFR TKI (ie, gefitinib),9-11,23 and others have reported the predictive value of EGFR FISH for erlotinib.12 Although these EGFR TKIs are well established in the treatment of NSCLC, to date, the biologic activity of cetuximab in this tumor type has remained poorly defined. Therefore, our results, although requiring prospective validation, are provocative because they are indicative of a clinical effect of this EGFR-targeting monoclonal antibody, which is associated with inhibition of the biologic target. Moreover, our results suggest that the addition of cetuximab to chemotherapy may reverse the underlying poor prognosis associated with EGFR FISH positivity, similar to the effects of trastuzumab plus chemotherapy in HER-2 FISH-positive breast cancer patients.24 In S0342, FISH-positive patients achieved a remarkable overall survival time (median, 15 months) when compared with the FISH-negative group (median, 7 months). In FISH-positive patients, the median PFS time was 6 months (v 3 months for the FISH-negative patients), and the objective response rate was 45% (v 26% for the FISH-negative patients). Furthermore, more than half of the patients in our study (59%) tested positive by FISH, increasing the potential clinical importance of our findings. Although this FISH-positive rate of 59% may seem somewhat high, it is not unexpected considering the underlying patient population within this cooperative group study (ie, primarily adenocarcinoma [61%] and almost one-half female [47%]). In another recent study from our group, the FISH-positive rate was 54%.13 Previously, several single-arm and randomized phase II trials combining cetuximab with chemotherapy in advanced NSCLC patients suggested higher response rates and longer survival times than might be expected for chemotherapy alone.19-21 Subsequently, several randomized phase III trials of chemotherapy alone versus chemotherapy plus cetuximab were initiated. The results of our study suggest that these all-comer trial designs may prove to be suboptimal for demonstrating the efficacy of cetuximab-chemotherapy combinations. Preliminary data from one of these phase III trials (study 099) reported that the primary end point of prolongation in disease-free survival was not met, although all end points favored the cetuximab-containing arm.25 Unfortunately, the study had no prespecified biomarker analysis. Because our study indicates that EGFR FISH-positive patients derive considerable benefit from a chemotherapy-cetuximab combination, as defined by response rate, PFS, and overall survival, it is possible, but unproven, that benefit from cetuximab was diluted out by an undefined EGFR FISH-negative population. In support of this explanation are the preliminary results of a more recent phase III trial of chemotherapy with or without cetuximab (FLEX), in which patient eligibility required positive EGFR protein expression by immunohistochemistry. Using this approach, the primary end point of improved survival was achieved.25a We hypothesize that prospective trials using EGFR FISH analysis to select patients with NSCLC for cetuximab-based therapy will optimize clinical benefit from this agent. Testing this approach in other cancers is also appealing, including head and neck cancer, where positive results for cetuximab-based therapy are reported and FISH positivity is associated with poor outcome in the absence of EGFR-targeted therapy.16,17,26,27 Our results suggest that there may be inherent differences that distinguish cetuximab-chemotherapy combinations from EGFR TKI combination therapies. Four large randomized phase III trials comparing chemotherapy alone with chemotherapy plus an EGFR TKI showed no benefit for the combination.4-7 Potential explanations for lack of benefit include nonselection of patients for a predictive biomarker and a negative interaction between concurrently administered chemotherapy and EGFR TKIs.28 These results led SWOG to conduct the current randomized phase II trial evaluating cetuximab plus chemotherapy administered either concurrently or sequentially in a pick-the-winner design for subsequent phase III testing against chemotherapy alone. Outcomes were favorable in both arms, meeting prespecified criteria for further study.22 A comparison of the concurrent versus sequential arms of S0342 in FISH-positive patients showed that, although similar results were achieved overall, survival data were significantly improved only in the concurrent arm. These results suggest considerable benefit for FISH-positive patients whether cetuximab is administered concurrently or sequentially, whereas FISH-negative patients fare poorly with either mode of therapy. Whether similar results could be achieved by using FISH to select patients for EGFR TKI–chemotherapy combinations remains undetermined, but the recently reported results from TRIBUTE suggest otherwise.29,30 In our analysis of EGFR FISH in this large phase III study of chemotherapy with or without erlotinib, response rate was lower (11.6%) in patients receiving chemotherapy plus erlotinib compared with patients receiving chemotherapy plus placebo (29.8%; P = .0495). Additionally, although PFS was higher with the combination, compared with chemotherapy plus placebo, in FISH-positive patients (6.3 v 5.8 months, respectively; P = .043), separation of the Kaplan-Meier curve first began 6 months after completion of chemotherapy. Moreover, in FISH-negative patients, PFS numerically favored patients randomly assigned to placebo compared with erlotinib (6 v 4.6 months, respectively; P = .0895).30 These results suggest a negative interaction between erlotinib and concurrent chemotherapy not seen in the current S0342 analysis of cetuximab plus chemotherapy. Lastly, this report does not address other potential predictive EGFR pathway biomarkers (ie, EGFR mutations, EGFR protein expression, KRAS mutations, and EGFR polymorphisms). Although these studies are underway on available S0342 specimens, the tissue resource remaining after EGFR FISH analysis is more limited. Results will be reported in conjunction with the overall clinical results of S0342. It is notable, however, that the incidence of EGFR FISH positivity in NSCLC populations (35% to 50% in most studies and 59% in the current analysis) is substantially higher than that of EGFR activating mutations in white populations.8,9,11,12 EGFR mutations are typically associated with rapid objective response to EGFR TKIs. However, in the BR.21 study comparing erlotinib with placebo, where the response rate to the EGFR TKI was less than 10%, EGFR mutation alone cannot explain the overall survival benefit, much of which is derived from patients who achieve stable disease.3,12 Furthermore, in TRIBUTE, the presence of EGFR mutation correlated with a better patient outcome independent of the therapy administered, indicating a prognostic association rather than a predictive one.29 In this regard, preclinical studies suggest that response to cetuximab is independent of EGFR mutation status.31 If substantiated in clinical samples, this observation may increase the likelihood that EGFR FISH is preferable for selection of NSCLC patients for cetuximab-containing combinations. In summary, the current study demonstrated improved response, PFS, and overall survival in FISH-positive patients with advanced NSCLC receiving cetuximab-chemotherapy. The median survival time of 15 months in FISH-positive patients is by far the longest survival time achieved in a SWOG trial in this clinical setting and is longer than the median survival time reported with chemotherapy and bevacizumab, which in the United States is considered the current standard of care for patients with advanced NSCLC.32,33 These findings support the hypothesis that EGFR FISH may be broadly applicable for selection of patients for EGFR-targeted therapies. Prospective validation of these results is warranted.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Fred R. Hirsch, AstraZeneca (C), Lilly Oncology (C), Roche (C), Merck Serono (C), Pfizer (C); Roy S. Herbst, ImClone Systems Inc (C), Bristol-Myers Squibb Co (C); Karen Kelly, ImClone Systems Inc (C), Bristol-Myers Squibb Co (C); Paul A. Bunn Jr, ImClone Systems Inc (C), Bristol-Myers Squibb Co (C), AstraZeneca (C), Eli Lilly & Co (C), OSI Pharmaceuticals (C), Genentech (C), Sanofi-Aventis (C) Stock Ownership: None Honoraria: None Research Funding: Fred R. Hirsch, AstraZeneca, Genetech, OSI Pharmaceuticals; Roy S. Herbst, ImClone Systems Inc, Bristol-Myers Squibb Co; David R. Gandara, Bristol-Myers Squibb Co Expert Testimony: None Other Remuneration: None
Conception and design: Fred R. Hirsch, Roy S. Herbst, John Crowley, Karen Kelly, Paul A. Bunn Jr, Marileila Varella-Garcia, David R. Gandara Financial support: Fred R. Hirsch, Roy S. Herbst, David R. Gandara Administrative support: Fred R. Hirsch, Roy S. Herbst, Paul A. Bunn Jr, David R. Gandara Provision of study materials or patients: Fred R. Hirsch, Roy S. Herbst, Christine Olsen, Karen Kelly, Wilbur A. Franklin, Paul A. Bunn Jr, Marileila Varella-Garcia, David R. Gandara Collection and assembly of data: Fred R. Hirsch, Roy S. Herbst, Christine Olsen, John Crowley, Wilbur A. Franklin, Paul A. Bunn Jr, Marileila Varella-Garcia, David R. Gandara Data analysis and interpretation: Fred R. Hirsch, Roy S. Herbst, Christine Olsen, Kari Chansky, John Crowley, Karen Kelly, Wilbur A. Franklin, Paul A. Bunn Jr, Marileila Varella-Garcia, David R. Gandara Manuscript writing: Fred R. Hirsch, Roy S. Herbst, Christine Olsen, Kari Chansky, John Crowley, Karen Kelly, Wilbur A. Franklin, Paul A. Bunn Jr, Marileila Varella-Garcia, David R. Gandara Final approval of manuscript: Fred R. Hirsch, Roy S. Herbst, Christine Olsen, Kari Chansky, John Crowley, Karen Kelly, Wilbur A. Franklin, Paul A. Bunn Jr, Marileila Varella-Garcia, David R. Gandara
We thank Sujatha Gajapathy, MS, Kathy Thompsen, BS, and Margaret Skogan, MS (UCCC Cytogenetic Core), for assistance with the FISH analysis and Rafal Dziadziuszko, MD, PhD, and Kelly Lucas, BS, for assistance with specimens’ quality control and data entry.
Supported by the National Cancer Institute Specialized Program for Research Excellence (SPORE) in Lung Cancer Grant No. P50 CA 058187 and the Cancer Center Core Grant No. P30 CA 046934 to the University of Colorado Health Science Center and by Grants No. CA38926 and CA32102 to the Southwest Oncology Group. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Hirsch FR, Varella-Garcia M, Bunn PA Jr: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non–small-cell lung cancer. J Clin Oncol 24:5032-5042, 2006 12. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 13. 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 13:2890-2896, 2007 14. Hirsch FR, Varella-Garcia M, Cappuzzo F, et al: Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small cell lung cancer patients treated with gefitinib. Ann Oncol 18:752-760, 2007 15. Cunningham D, Hummblet Y, Siena VS, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 16. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006 17. Vermorken JB, Trigo J, Hitt R, et al: Open-label, uncontrolled multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum based therapy. J Clin Oncol 25:2171-2177, 2007 18. Hanna N, Lilenbaum R, Ansari R, et al: Phase II trial of cetuximab in patients with previously treated non-small cell lung cancer. J Clin Oncol 24:5253-5258, 2006 19. Rosell R, Ramlau DR, Szczesna M, et al: Randomized phase II study of cetuximab in combination with cisplatin (C) and vinorelbine (V) vs CV alone in the first-line treatment of patients with epidermal growth factor receptor expressing advanced non-small cell lung cancer. 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Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Fluorescence in situ hybridization (FISH) subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in NSCLC. Clin Cancer Res (in press) 31. Mukohara T, Engelman JA, Hanna NH, et al: Differential effects of gefitinib and cetuximab on non-small cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 97:1185-1194, 2005 32. Williamson SK, Crowley J, Lata P, et al: Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small cell lung cancer: Southwest Oncology Group Trial S0003. J Clin Oncol 23:9097-9104, 2005 33. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355:2542-2550, 2006
Submitted August 22, 2007;
accepted April 4, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
40% of the cells or gene amplification) in 59.2%. Response (complete response/partial response) was numerically higher in FISH-positive (45%) versus FISH-negative (26%) patients (P = .14), whereas disease control rate (complete response/partial response plus stable disease) was statistically superior (81% v 55%, respectively; P = .02). Patients with FISH-positive tumors had a median progression-free survival time of 6 months compared with 3 months for FISH-negative patients (P = .0008). Median survival time was 15 months for the FISH-positive group compared with 7 months for patients who were FISH negative. (P = .04). Furthermore, survival favored FISH-positive patients receiving concurrent therapy. 
