• 6/1/2007
  • web-based article
  • Arlene A. Forastiere et al.
  • Journal of Clinical Oncology, Vol 25, No 16 (June 1), 2007

Squamous cell cancer of the head and neck (HNSCC) would seem to be the ideal malignancy for epidermal growth factor receptor (EGFR) inhibition either with antibodies or small molecule tyrosine kinase (TK) inhibitors. EGFR protein is overexpressed in more than 90% of tumors relative to normal tissue, and high expression is associated with poor disease control.1-3 Data from preclinical models show at least additive effects of the two classes of EGFR inhibitors when combined with cisplatin,4,5 providing rationale for combination therapy. To date, cetuximab has been studied in recurrent HNSCC in combination with cisplatin6 and platinum plus fluorouracil (FU)7 as first-line treatment for recurrence and in the setting of platinum refractory disease,8,9 whereas the small molecule TK inhibitors have been tested as single agents in the second- or third-line setting.10-12 The optimal timing of EGFR inhibitors in the palliation of patients with disease recurrence has not been well defined. HNSCC has the theoretical advantage of providing easily accessible tumor for biopsy, which could facilitate study of the putative effects of molecularly targeted therapies on the complex signaling pathways downstream of the EGFR. Such correlative tissue studies are needed to elucidate EGFR pathway tumor biology and identify predictive markers for better patient selection for these costly therapies. This issue of the Journal of Clinical Oncology contains five articles that provide some insights into these questions and the results of an analysis of the impact of radiotherapy (RT) plus EGFR antibody therapy on quality of life (QoL).

QoL is a complex measure, particularly for those not immersed in this field, seemingly with its own terminology, variety of tools, and myriad statistical tests. However, the importance of QoL cannot be underestimated for patients with head and neck cancer. As multimodality therapies are intensified, consideration of QoL in therapeutic decision-making, and in formulating standards of care, is of paramount importance. This issue of JCO contains a report of QoL assessments13 that were performed as part of the prospective comparison of RT alone to RT plus concurrent cetuximab in patients with locally advanced HNSCC published by Bonner et al.14 Significant improvements in overall survival and local-regional recurrence-free survival were observed for patients in the cetuximab treatment group without an apparent increase in toxicity. The current paper bolsters those findings through the use of two validated questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Quality of Life Questionnaire, Head and Neck Module) that address symptom burden and its effect on physical and functional well-being, emotional, and social interactions. No significant differences were found between the two treatments in QoL at baseline or during the course of treatment out to 12 months. In both groups, QoL declined during treatment, with the greatest impact on function due to fatigue, loss of appetite, swallowing difficulty, and sensory problems, and then improved by 8 to 12 months. The authors interpreted this as a positive result.

This pattern of decline and then return to baseline by about 12 months confirms data from other head and neck trials as does the observed correlation between global health/QoL and survival. Because a significant difference in local-regional control was reported in the primary paper, one might have postulated that the symptom burden of uncontrolled disease would result in a worse QOL for patients in the control group. In other words, the real goal and indication of a positive outcome should be an improvement in QOL for patients receiving the treatment that afforded them significantly longer survival and disease control, in this case RT plus cetuximab. It is not clear whether the occurrence of more dropouts over time among controls (RT alone) obscured this effect or the questionnaires used were not sensitive enough to detect differences between the treatment groups (not just within treatment groups). The conclusion that QOL was not worse for patients receiving RT plus cetuximab than for those treated with RT alone is, unfortunately, not very satisfying. As advances are made in multimodality therapies, we should seek improvements in QoL that parallel improvements in survival.

Two therapeutic trials are reported in this issue.15,16 Vermorken et al tested single-agent cetuximab in a multicenter phase II trial enrolling 103 patients with recurrent/metastatic HNSCC that had progressed on platinum-based chemotherapy. In a two-part design, patients were first treated with cetuximab alone until disease progression, and then they were offered continuation of cetuximab with the addition of platinum. The objective response rate (complete plus partial response) for treatment with cetuximab alone was 13% (95% CI, 7 to 21), the disease control rate (complete plus partial plus stable response) was 46% (95% CI, 36 to 56), and the median time to progression (TTP) was 70 days. Of these 103 patients, 53 proceeded to the second part of the trial and received cetuximab plus platinum. No objective responses were observed, the disease control rate was 26% (95% CI, 15 to 40), and the median TTP was 50 days.

These results should be viewed in context with trials of cetuximab published by Burtness,6 Baselga,8 and Herbst.9 The proof of principle trial was conducted by Burtness et al in the Eastern Cooperative Oncology Group (E5397) in a phase III comparison of cisplatin plus placebo to cisplatin plus cetuximab in the first-line treatment for recurrent/metastatic HNSCC.6 A significant improvement in the objective response rate was observed for the cetuximab plus cisplatin patient group, with 26% versus 10% (P = .03), indicating at least an additive effect of cetuximab. The trial, however, was not adequately powered to demonstrate significant differences in survival end points. The phase II trials reported by Basalga8 and by Herbst9 tested the addition of cetuximab to cisplatin in patients who were refractory to platinum-based combination chemotherapy. Both studies determined an objective response rate of 10% in this population, but whether this tumor shrinkage was due to cetuximab alone or to a reversal of platinum resistance could not be discerned from the study designs. Taken together, those two trials8,9 and that of Vermorken15 yield essentially the same response rate, suggesting that cetuximab monotherapy should be used in the second-line setting and that there is likely no advantage to reintroducing or continuing platinum chemotherapy. Furthermore, this trial provides confirmation of the level of efficacy to be expected from single-agent cetuximab. A contrary point of view, however, is that for the 53 patients in the Vermorken study who initially progressed on single-agent cetuximab and then received cisplatin plus cetuximab, the lack of response with this strategy does not prove that this doublet may not have been beneficial. The decision to treat with the doublet at cross over was presumably related to patient fitness, and this selection bias might have had the effect of excluding patients with the most aggressive disease, perhaps those with the highest amount of EGFR or ligand expression in their tumors.

In contrast to the combination studies reported with cetuximab, the data for erlotinib and gefitinib is from single-agent phase II studies in which the inhibitor was used in the second- or third-line setting.10-12 In this issue of JCO, Siu et al16 report the results of a phase I-II trial of erotinib plus cisplatin as first-line therapy for recurrent HNSCC. Doses of erlotinib 100 mg daily plus cisplatin 75 mg/m2 every 3 weeks were selected for phase II study, though these were not the maximally tolerated doses based on the protocol design. In 44 patients, an objective response rate of 21% (95% CI, 10 to 36), median progression-free survival of 3.3 months, median survival time of 7.9 months, and a 19.5% 1-year survival rate was observed. Previous testing of single-agent erlotinib in 115 chemotherapy refractory patients with HNSCC yielded a 4.3% objective response rate.10 Even though these patient groups are not comparable relative to prior therapies, there seems to be at least an additive effect for the combination, which is similar to the level of efficacy observed with cetuximab plus cisplatin.6

Another pressing issue, as targeted therapeutics come into clinical use, is the identification of outcome predictors. This is not proving easy to do for EGFR-directed therapies in head and neck cancer. Although EGFR contributes to an aggressive and treatment-resistant malignant phenotype when it is highly expressed,1,2,6 a variety of molecular mechanisms may account for this effect. For instance, the EGFR gene may be amplified in HNSCC17,18; excess amounts of ligand may be coexpressed in the same cancers1; a truncated form of EGFR known as EGFRvIII is present in 42% of HNSCC, and this form of EGFR is weakly constitutively phosphorylated in a ligand-independent manner19; and phospho-EGFR may be translocated to the nucleus, where it is believed to function as a transcription factor, and where it is associated with worse outcome in oropharynx cancer.20

Although one would not expect significant clinical effects from EGFR-directed therapy in cancers in which EGFR-dependent signaling was not abundant, the specific manner in which such cancers would be sensitive to or resistant to EGFR targeting might well differ, depending on the mechanism(s) of EGFR activation. Thus, cancers with high ligand expression might be most sensitive to a monoclonal antibody, which competitively inhibits ligand-binding and ligand-dependent EGFR activation. Tumors with extremely high EGFR expression or very high tumor burden might not be adequately saturated with antibody at the current dose and schedule of cetuximab administration. Mutant EGFR that is constitutively active has been shown in the laboratory to be more sensitive to tyrosine kinase inhibitors than to monoclonal antibodies targeting the ligand-binding domain. Little is known about the role of receptor internalization and degradation in the antitumor effect of cetuximab, and how this compares among EGFR isoforms or at different levels of EGFR expression. The possibility that abnormal activation of ras, Akt, and other downstream signal transduction molecules would render cancers resistant to EGFR targeting also has not been sufficiently studied.

It is in this context that the report in this issue of JCO from Agulnik et al21 detailing pharmacodynamic tissue studies from the patients enrolled in their study of erlotinib and cisplatin,16 is particularly welcome. These investigators tested archival and paired tumor specimens and skin biopsies before and after treatment with erlotinib plus cisplatin for EGFR downstream signaling intermediates in the Ras-Raf-MEK-ERK, PI3K/AKT, STAT-3, and NF-kB pathways. Given the low response rate to the regimen and large number of markers analyzed in this study, any positive correlations must be viewed as exploratory and warrant further study in much larger prospective trials. Obtaining paired tumor specimens (pretreatment and on-treatment) is challenging relative to patient acceptance and the costs of tissue acquisition and as illustrated in this trial of 51 patients, only nine paired tumor biopsy specimens and 32 paired skin biopsies were obtained. A decrease in phosphorylated-EGFR in both skin and tumor after 7 days of erlotinib correlated with an increase in TTP and overall survival, suggesting that skin biopsy could serve as a surrogate predictor of likelihood of therapeutic benefit. The most intriguing finding was that patients with high EGFR gene copy number indicative of gene amplification and high polysomy were more likely to respond to treatment and have longer TTP and survival. Data from studies of patients with non–small-cell lung cancer suggest that EGFR gene amplification is a positive predictor for outcome from gefitinib treatment.22

Also in this issue of JCO, Temam et al17 report their finding that EGFR copy number alterations correlate with poor clinical outcome in patients with HNSCC. The investigators studied 134 primary HNSCCs with quantitative real-time polymerase chain reaction (Q-PCR). Aberrant EGFR copy number was identified in 24%—17% with increased copy number and 7% with decreased copy number. The 5-year survival for patients with increased EGFR copy number was only 9%, compared with 71% for those with normal copy number. These results bear comparison to those of Chung et al18 and Freier et al,23 who previously reported on EGFR copy number in HNSCC. Chung et al determined EGFR copy number by fluorescence in situ hybridization (FISH) in 86 patients with HNSCC.18 Tumors were classified as FISH-positive (high polysomy/gene amplification) or FISH-negative (disomy/low polysomy), according to a previously described system used in lung cancer.24 Fifty-eight percent of the tumors were classified as FISH-positive. As in the Temam study, patients in the Chung series with FISH-positive tumors had a worse survival (median survival 20 months compared with 29 months for FISH-negative tumors; P < .01). Differences in the magnitude of the effect may well be related to differences in the patient populations and the methods used to determine gene copy number. Freier et al23 also used FISH and studied a large tissue array. Tumors were scored as EGFR gene amplified if 10% of cells showed eight or more signals or tight clusters of signals of the oncogene probe. The results of Freier at el, with 13% of the cases displaying EGFR gene amplification, more closely resemble the results of the current series, but comparisons are difficult because of the methodologic differences and heterogeneity of cases. Exons 18, 19, and 21 mutations were sought in both the Temam and Chung studies because such mutations are correlated with sensitivity to the tyrosine kinase inhibitors erlotinib and gefinitib in lung cancer. No mutations were found in either study. Work from other laboratories also suggests that such mutations are rare in HNSCC in non-Asian populations.

The use of Q-PCR in assessing gene copy number merits comment. Q-PCR relies on amplification of DNA that is extracted from whole tissue. An obvious concern is dilution of tumor-specific findings by stromal or normal epithelial cells in the tissue specimen. The authors attempted to prevent this problem by using specimens with more than 70% tumor cells, or by microdissecting the tumor free from associated stroma. The primers used were in exon 2 of the EGFR and should not identify EGFRvIII, which has an in-frame deletion of exons 2 to 7. Thus, any contribution of EGFRvIII expression to worse outcome, as predicted by preclinical models,19 would not be detected.

The authors advocate the use of Q-PCR over FISH for several reasons: a larger sample of the tumor will be assayed reducing the impact of intratumoral heterogeneity on the result, the technique is cheaper, and it may be less subject to interobserver variability. However, comparing retrospective series analyzed with different methods will not establish the preferred test for gene amplification, or which test correlates most closely with outcome. Temam et al compared Q-PCR with FISH and immunohistochemistry in 16 of the cases, with a distribution of normal, increased and decreased gene copy number. The correlation between FISH and Q-PCR in this useful but small and highly exploratory experiment was good. Further confirmation of this finding is required before Q-PCR can be assumed to be equivalent or superior to FISH for gene copy number assessment. Although the number of tumors studied here is larger than in the Chung study,18 the ability to control for primary site, tumor stage, smoking history, and treatment effect is limited in a sample this size, and the important prognostic variable of HPV status was not considered at all.

The authors comment on the possibility that the EGFR gene copy number will predict for responsiveness to EGFR-directed therapies. Preclinical experiments have suggested that this will be the case,25 and the findings of Algunik et al in this issue of JCO are consistent with the hypothesis, although they do not confirm it. This remains an important question for study in tandem with ongoing and future trials of EGFR inhibition with monoclonal antibodies, tyrosine kinase inhibitors, and combinations of targeted therapies. The work of Temam et al17 confirms findings of other groups and raises the possibility of using Q-PCR for gene copy number determination. The larger goal of a predictive marker to guide patient selection for EGFR directed therapy however remains elusive.

References:

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Authors:
Arlene A. Forastiere1, Barbara A. Burtness2

Authors’ affiliations:
1. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

2. Fox Chase Cancer Center, Philadelphia, PA