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Imaging, Diagnosis, Prognosis |
Authors' Affiliations: 1 Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università "Federico II"; 2 Cattedra di Oncologia Medica, Seconda Universita degli Studi di Napoli, Napoli, Italy; 3 The Breast Center at Baylor College of Medicine and The Methodist Hospital; 4 Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas; and 5 Divisione di Oncologia Medica, Ospedale "G. Rummo," Benevento, Italy
Requests for reprints: Michele De Laurentiis, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università "Federico II," via Sergio Pansini, 5, 80131 Napoli, Italy. Phone: 39-81-7464286; Fax: 39-81-2290150; E-mail: michele.delaurentiis{at}unina.it.
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Abstract |
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Experimental Design: Studies have been identified by searching the Medline, Embase, and American Society of Clinical Oncology abstract databases. Selection criteria were (a) metastatic breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). For each study, the relative risk for treatment failure for HER-2-positive over HER-2-negative patients with 95% confidence interval was calculated as an estimate of the predictive effect of HER-2. Pooled estimates of the relative risk were computed by the Mantel-Haenszel method.
Results: Twelve studies (n = 2,379 patients) were included in the meta-analysis. The overall relative risk was 1.42 (95% confidence interval, 1.32-1.52; P < 0.00001; test for heterogeneity = 0.380). For studies involving tamoxifen, the pooled relative risk was 1.33 (95% confidence interval, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97); for studies involving other hormonal drugs, a pooled relative risk of 1.49 (95% confidence interval, 1.36-1.64; P < 0.00001; test for heterogeneity = 0.08) was estimated. A second meta-analysis limited to tumors that were either estrogen receptor positive, estrogen receptor unknown, or estrogen receptor negative/progesterone receptor positive yielded comparable results.
Conclusions: HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment. This effect holds in the subgroup of patients with positive or unknown steroid receptors.
Overexpression of HER-2, generally due to gene amplification, is found in 20% to 30% of human breast cancers and it has been postulated that this overexpression may modulate the clinical sensitivity of tumors to endocrine treatments. However, clinical studies have yielded conflicting results in both adjuvant and metastatic settings.
In particular, in the metastatic setting, several groups have identified a correlation between HER-2 overexpression and a lower response rate to endocrine treatment (12–21), whereas others have not (22–26). Instances of conflicting results may be related to the lack of a standardized methodology for HER-2 analysis, to flawed experimental designs, but also to the low statistical power of the single studies.
We have conducted a meta-analysis of the pertinent published studies in an attempt to gain insights into the association between HER-2 and response to different types of endocrine therapy in metastatic breast cancer.
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Methods |
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Study identification. Studies were identified by a computerized search of the Medline (1966-2002), Cancerlit (1966-2002), and Embase (1990-2002) databases using the following text words: "breast cancer and (c-erbB-2 or c-erbB2 or Neu or HER2)." A computerized search of the Proceedings of the Annual Meetings of the American Society of Clinical Oncology held between 1998 and 2002 was run to identify relevant studies published in abstract form. Lastly, all review articles and all cross-referenced studies from retrieved articles were screened for pertinent articles.
Selection criteria. To be included in the meta-analysis, retrieved studies had to fulfill the following simple inclusion criteria: (a) advanced breast cancer, (b) endocrine therapy (any line of treatment), and (c) evaluation of HER-2 expression (any method). Studies meeting these criteria were excluded from the analysis if any of the following cases occurred: (a) the response rate stratified by HER-2 status was neither reported in nor derivable from the original article and the principal investigator refused or was unable to provide this information on request and (b) the article was an earlier report of data updated in a subsequent article to be included in the meta-analysis.
Data extraction. Data were independently extracted from each report by G.A. and E.M., who were blinded to each other, using a data recording form developed for this purpose. After extraction, data were reviewed and compared by M.D.L. Instances of disagreement between the two data extractors were resolved by consultation. When needed, additional information about a specific study was gathered by directly querying the principal investigator.
Information about the type endocrine therapy administered was collected for almost all the studies. Two main groups were created: the tamoxifen group, which included trials that used tamoxifen, and the no tamoxifen group, which included trials using all other kinds of hormonal treatment. When the drug used was not specified, the study was included in the no tamoxifen group.
End point for analysis. Treatment failure was chosen as a clinically meaningful end point of the meta-analysis. It was defined as progression of the disease within 6 months of treatment onset. In fact, there is a general acceptance that endocrine therapy-induced stabilization of advanced breast cancer lasting 
6 months should be deemed a therapeutic achievement (clinical benefit) because it results in a survival comparable with that of partial responding patients (27).
Statistical analysis. The risk of treatment failure was taken as a measure of the resistance of the disease to the hormonal therapy. The correlation between HER-2 expression and treatment failure rate within each single study was expressed as relative risk (RR) for treatment failure of HER-2-positive over HER-2-negative patients. Thus, a RR equal to 1 indicates a lack of association between HER-2 status and treatment failure rate; a RR higher than 1 corresponds to a direct correlation between treatment failure rate and HER-2-positive status (i.e., a tendency of HER-2-positive patients to have a higher rate of treatment failure), an inverse correlation being indicated by a RR lower than 1 (i.e., a tendency of HER-2-positive patients to have a lower rate of treatment failure).
A pooled estimate (meta-analysis) of the RRs of the individual studies was computed by a fixed effect model according to Mantel and Haenszel (28). Homogeneity assumption was checked by a 
2 test with a df equal to the number of analyzed studies minus 1.
A sensitivity analysis was carried out by recalculating the pooled RR estimate for different subgroups of studies based on relevant clinical features. This analysis serves to determine whether the pooled estimates are stable or whether they depend on some features of the studies included in the meta-analysis. Consequently, it shows whether the overall result would be affected by a change in the meta-analysis selection criteria.
An estimate of the potential publication bias was carried out by plotting the single study RR on a log-scale against respective SE (funnel plot). A simulation was also carried out by recalculating the overall RR after the inclusion of increasing numbers of simulated negative trials. This serves to evaluate how many potentially unpublished negative trials would be necessary to make the overall results nonstatistically significant.
Quality score. A quality score was assigned to each study based on the sample size. Three clusters of studies were identified: those with <90 patients (score 0), those with 90 to 200 (score 1), and those with >200 patients (score 2). It was necessary to assign this quality score because the assumption underlying the use of the Mantel-Haenszel pooled estimator may not hold for studies with a very low number of patients. Because of its subjective nature, however, the quality score was not used to weigh further the contribution of each study to the meta-analysis. The quality score was used as a stratification factor in the sensitivity analysis to evaluate whether the pooled results of the meta-analysis are independent of the size of the studies included.
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Results |
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Steroid receptor information. Steroid receptor information was available for most studies in the meta-analysis (Table 3) for a total of 2,288 of 2,385 (95.9%) patients (2,379 of whom evaluable for the meta-analysis). Among these, 1,368 (59.8%) were ER positive, 357 (15.6%) were either ER positive or progesterone receptor (PgR) positive, and 368 (16.1%) had unknown ER status. The study by Berns et al. (14) did not report steroid receptor information for the 126 patients with HER-2 status evaluation; however, it was assumed that the proportion of ER-positive patients was approximately superimposable to that of the whole study population (ER positive: 193 of 259 = 59%). Two small studies (17, 19) lacked clear information about steroid receptor status. However, given the selection criteria of these studies, it is reasonable to assume that ER-positive patients represent a vast proportion of subjects in this series.
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The RR of treatment failure was calculated for each study in the meta-analysis. The data of the 2,379 patients were first analyzed globally. Single-study RRs ranged from 1.06 to 3.81. Overall, the estimated pooled RR for all the studies was 1.42 [95% confidence interval (95% CI), 1.32-1.52], showing a highly significant correlation between HER-2 positivity and treatment failure (P < 0.00001; Fig. 1). The result of the test forheterogeneity (P = 0.380) shows that the differences among single-study figures may be explained by chance andconfirms the appropriateness of pooling the data. Interestingly, the correlation between HER-2 positivity and treatment failure is maintained regardless of the type of endocrine therapy administered. The RR was 1.33 (95% CI, 1.20-1.48; P < 0.00001; test for heterogeneity = 0.97) for studies involving tamoxifen (tamoxifen group) and 1.49 (95% CI, 1.36-1.64; P < 0.00001) for studies regarding other endocrine agents (no tamoxifen group), respectively. However, in this latter group, the effect of HER-2 as regard to tumor responsiveness showed a trend to heterogeneity although not significant (test for heterogeneity = 0.08; Fig. 1).
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Discussion |
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To address the latter issue, we conducted a meta-analysis of the published studies to obtain an overall pooled estimate of the association between HER-2 overexpression and treatment failure rate. We found a significant direct correlation between HER-2 overexpression and the risk of disease progression while on endocrine treatment. Furthermore, we showed a lack of statistical heterogeneity among studies, which suggests that contradictory results were related to chance.
Although many trials addressing the relationship between endocrine resistance and HER-2 expression/amplification have been conducted in the adjuvant setting (30–35), in the present study, we decided to include only studies involving the metastatic setting. In the adjuvant trials, individual response is impossible to categorize; thus, the use of aggregated data to estimate treatment failure and treatment success rather than raw data from the single individual would have been not appropriate (36).
Because of the difference in biological activity between tamoxifen and other types of endocrine therapy, such as aromatase inhibitors and steroidal pure antiestrogens (such as fulvestrant), it has been suggested that the use of the latest, unlike tamoxifen, may overcome resistance of HER-2-positive tumors. A recent randomized trial of neoadjuvant therapy (37) showed that, in the subset of ER-positive, epidermal growth factor receptor–positive, and/or HER-2-positive, letrozole was significantly more effective than tamoxifen. However, in more conventional treatment settings (adjuvant and/or metastatic), this finding has not been confirmed yet. In a large randomized trial of first-line hormone therapy for metastatic breast cancer that is included in the present meta-analysis (21), patients with normal serum HER-2 receiving letrozole showed a significantly greater objective response rate and clinical benefit and longer time to progression and time to treatment failure than patients receiving tamoxifen. However, in patients with elevated serum HER-2, there was no significant difference between letrozole and tamoxifen in objective response rate and clinical benefit, although a strong trend favoring longer duration of response with letrozole was observed. Whether letrozole or any other form of endocrine treatment could be better than tamoxifen in the HER-2-positive group of patients cannot be assessed by this meta-analysis. The heterogeneity of treatments among the included studies makes it difficult to extrapolate any firm conclusion about this issue. Nevertheless, the vast majority of the patients in the no tamoxifen group received letrozole and the vast majority of patients in the tamoxifen group received tamoxifen or another selective ER modulator. Our results suggest that, overall, endocrine therapy is less effective in patients with a HER-2-positive tumor and that the increased risk of treatment failure for HER-2-positive breast cancer may hold irrespective of the drug administered at least in the metastatic setting.
Some methodologic issues of our work are worth of discussion. The present study is a meta-analysis of nonrandomized observational trials. In general, randomization provides a more unbiased estimate because it controls for potential unknown confounders, and it should be the preferred approach whenever possible. In some research settings, however, randomized trials are rarely, if ever, feasible (i.e., translational studies in oncology). However, also for observational studies, pooled estimates are by far superior to the usual assessment of consistency constituted by tallies of the percentage of positive, negative, and null studies. Indeed, the meta-analytic method applied to this setting has produced very informative data (38, 39). The overt clinical heterogeneity of the patient populations included in this study could be considered a potential problem in interpreting the results of the present analyses. There is, in fact, a substantial diversity in the studies in terms of HER-2 status evaluation technique, drug used, and line of treatment. However, despite this clinical heterogeneity, there is no statistical heterogeneity among the study results. This shows that it is entirely appropriate to use an overall estimate of the effect of HER-2 expression and suggests that the clinical variability could rather be considered a strength of our results. Indeed, a great variability among studies is equivalent to adding "noise" to the analysis, which very unlikely would convert a null result into a positive finding; rather, it is more likely that a positive correlation between HER-2 overexpression and treatment resistance would be masked or weakened by this "noise." Furthermore, as suggested by the sensitivity analysis, the correlation is fairly stable among subgroups of studies, thereby suggesting that it may be a general feature of breast tumor responsiveness to endocrine treatment across different clinical situations. Another potential problem of meta-analysis of published studies is the tendency to inflate "positive" results because of a general inclination for "negative" studies (i.e., studies that do not confirm the research hypothesis) to be underrepresented in the literature. However, the "funnel" analysis combined with a simulation procedure indicated that this bias, although theoretically possible, should be negligible in the setting of our meta-analysis.
According to the American Society of Clinical Oncology Expert Panel on Tumor Markers, which proposed a tumor marker utility grading system (40), most of the studies in this meta-analysis can be regarded as level III studies (14, 16, 18–22, 24, 26); a few are level IV (13, 17, 23). The latter, which may correspond to those assigned a quality score of 0 in our work, did not affect the overall meta-analytic result as shown by the sensitivity analysis. Consequently, it can be argued that the correlation observed between HER-2 overexpression and a lower response to endocrine therapy approaches level I of evidence. However, the reported correlation should not to be regarded as a certain causal association. Because the analyzed trials did not include a control arm (i.e., an arm in which the therapeutic intervention was not administered), we cannot assess whether our results derive from resistance to endocrine therapy or simply from more aggressive biological behavior of HER-2-positive tumors. However, the consistency of our results across different settings (i.e., adjuvant, neoadjuvant, and metastatic) and the biological plausibility of our hypothesis support the role of HER-2 in the development of endocrine resistance in human breast cancer.
Because of the lack of a control arm without therapeutic intervention, the benefit ratio (i.e., the ratio of the benefit from treatment between groups of patients characterized by different status of the hypothetical predictive factor) could not be assessed (41). Furthermore, although a clear-cut association between HER-2 positivity and treatment emerges from our analysis, the variability of the studies may have reduced the strength of the effect by adding noise to the pooled analysis. Therefore, although we show a >40% increase of the risk of treatment failure for HER-2-positive advanced breast cancer, it may not allow an accurate evaluation of the predictive strength of the marker. Predictive strength should more appropriately be evaluated in the scenario of randomized trials of adjuvant therapy.
Increasing evidences from preclinical models show that the cross-talk between tyrosine kinase receptors and ER may be crucial for the development of the endocrine resistance. Other downstream molecules, such as the coregulator AIB1 or the protein actMap-kinase (42–44), are implicated in this cross-talk and might play an important role in determining response to endocrine therapy. A recent study (45) in patients receiving tamoxifen adjuvant therapy suggests that HER-2 is associated with resistance only in tumors that also express high levels of AIB1, an ER coactivator that is turned on by HER-2 signaling. Thus, measuring only HER-2 may provide only part of the information and may cause some variability in small clinical trials.
From a clinical standpoint, our meta-analysis shows that, for metastatic breast cancer, the results of all published studies are consistent with an association between HER-2 overexpression and higher rates of failure of endocrine treatment. These results may have direct clinical implications. Indeed, endocrine therapy alone should not be considered a first-choice treatment for patients with ER-positive/HER-2-positive metastatic breast tumors; rather, the treatment strategy for such patients should prefer chemotherapy alone or in combination with trastuzumab. Alternatively, the combination of endocrine therapy with trastuzumab may potentially overcome the partial resistance of such tumors to hormonal manipulations. This latter strategy has been proven effective in preclinical models (8) and randomized trials investigating it in the clinical setting are expected to deliver results in 2005. Finally, the exploitation of endocrine agents, such as the "pure" antiestrogen fulvestrant, the antiproliferative action of which in vitro is not affected by HER-2 status (46), may be useful. However, clinical data demonstrating its efficacy in this specific context are still lacking. Better designed clinical trials able to answer to these new challenging biological questions are required to further clarify mechanism of endocrine resistance and to investigate alternatives treatment strategies designed to prevent resistance.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 12/13/04; revised 4/ 7/05; accepted 4/14/05.
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