© 2001 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 30, 80-84,
2001
© 2001 Oxford University Press
Is Her2 of Value in Identifying Patients Who Particularly Benefit From Anthracyclines During Adjuvant Therapy? A Qualified Yes.
Correspondence to: Peter Ravdin, M.D., Ph.D., Division of Oncology, The University of Texas Health Sciences Center, San Antonio, 7703 Floyd Curl Dr., Rm. 5.214S, San Antonio, TX 78229 (e-mail: pmravdin{at}aol.com).
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ABSTRACT |
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Data from several large adjuvant breast cancer chemotherapy trials suggest that anthracycline-based chemotherapies relative to non-anthracycline-based adjuvant therapies are particularly effective in patients whose tumors overexpress Her2. Most trials show some evidence of this effect, but the interaction generally has not been confirmed statistically, perhaps because the trials are underpowered. In addition, there have been a multiplicity of Her2 immunohistochemistry techniques used in these studies, which are clearly not of equivalent utility in detecting this effect. Thus, while there is good evidence that further work in this area will be of value, at this time the results are inconclusive and not ready for clinical application.
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INTRODUCTION |
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In this article, I will argue for and review the clinical trial evidence for the value of Her2 overexpression to identify breast cancer patients who particularly benefit from the inclusion of anthracyclines in adjuvant therapy.
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DEALING WITH COUNTERARGUMENTS |
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The problem areas for my argument include 1) questions about the methodologies for measuring Her2 overexpression, 2) the apparent discordance between the possible ability of Her2 to select patients who particularly benefit from anthracyclines in adjuvant therapy and its apparent lack of predictive value for selecting patients likely to benefit from anthracycline-based therapy in metastatic disease, 3) the lack of a clear mechanism by which Her2 overexpression should lead to particular anthracycline sensitivity, and 4) some clinical studies (underpowered) that do not support the predictive value of Her2 in anthracycline-based adjuvant therapy.
The weakest element is that there are a number of techniques for detecting and scoring Her2 overexpression in breast tissue samples. At present, nearly all of the work on the predictive value of Her2 has been done using immunohistochemistry (IHC). Clearly, not all immunohistochemical techniques are equivalent; they differ in primary and secondary antibodies used, antigen retrieval methods used, scoring and interpretation of overexpression, and so forth. This complicates the clinical use of Her2 information, as is beautifully illustrated in some of the studies I will review, in which, for patients from the same clinical study, one immunohistochemical technique seems to be predictive of particular benefit of anthracycline-based adjuvant therapy, whereas another Her2 IHC technique used on the same samples was not predictive.
A second counterargument against the use of Her2 for predicting adjuvant benefit of anthracyclines is that Her2 is not a recognized predictor of treatment benefit of anthracyclines in metastatic disease. This is an important point, with most studies not finding Her2 to be a predictor of response to anthracycline-based therapy in metastatic disease. It should be noted that most of the studies in which there was no correlation were quite small [fewer than 100 patients; e.g., studies with only 54 (1), 23 (2), 103 (3), and 60 cases (4)] and, thus, had a very modest statistical power to find correlation between Her2 overexpression and response. To counter this argument, it must be argued that the tumor cells are in a different state when they are part of a macroscopic tumor mass compared with when they are part of a micrometastatic tumor burden. The observation of response in metastatic disease depends on the effects on cell kill as balanced against tumor growth. By promoting rapid regrowth, a marker like Her2 can obscure the benefit conferred by an agent in metastatic disease. Perhaps this effect of rapid regrowth is less prominent in the adjuvant setting. There are some clinical lines of evidence that such a differential effect may occur. For example, in the overview analysis (5), there are repeated trends toward substantially more benefit from adjuvant chemotherapy in estrogen receptor-negative versus estrogen receptor-positive patients, although estrogen receptor status is not an accepted predictor of response to chemotherapy in metastatic disease.
Another argument against Her2 as a marker of anthracycline responsiveness in adjuvant therapy is that why overexpression of Her2 would be associated with anthracycline sensitivity is not yet well understood. There are a number of plausible explanations, but none as yet has been demonstrated convincingly. These explanations range from possible association of Her2 overexpression with topoisomerase II (the target enzyme for anthracyclines) expression (6,7) to a number of other ideas on how Her2 overexpression may activate other pathways that might render the breast cancer cells more sensitive to chemotherapy.
One additional important counterargument that can be used to deflate "negative studies" in which Her2 is not found to be a statistically significant predictor is that nearly all of the studies of the predictive significance of Her2 are dramatically underpowered to find the kind of effects that they are trying to detect. As a general rule of thumb, in comparison with a two-arm trial comparing two treatment regimens, a study looking for interactions between a marker and treatment will need four times as many patients. Statistical power is further weakened by the fact that Her2 overexpression is found in only 20%–30% of breast tumors. Estimates can be made of how many patients are needed to detect statistically significant interactions, and these estimates suggest that more than 1000 patients are needed. Thus, it might be expected that, even with a real interaction between Her2 and anthracyclines, many studies would not be able to demonstrate this interaction with statistical confidence. Only one study of the interaction between Her2 and anthracycline-based adjuvant therapy has included more than 1000 patients.
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CLINICAL TRIAL EVIDENCE |
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As reviewed below, a picture emerges in which most studies show that subsets of patients whose tumors overexpress Her2 derive particular benefit from anthracyclines. These studies will be reviewed as four different sets of studies: the initial hypothesis generation studies, the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials, two major Cooperative Group studies, and other smaller studies.
First to be reviewed is the Cancer and Leukemia Group B (CALGB) trial that launched a special interest in this area. The second set of trials contains the biologic correlative studies on NSABP B-11 and B-15. These trials are among the largest trials and used exactly the same methodology; thus, to some extent, they cross-validate each other. The third tier of trials contains large trials with more than 500 patients: the Southwest Oncology Group (SWOG)/Intergroup study and a European Consortium study. These two studies used methodologies that, to some extent, were similar to those of the CALGB and NSABP. In addition, by using more than one methodology for Her2 IHC, these two studies attempted to evaluate how generalizable these methodologies are. Finally, in a fourth tier, a review will be presented for the four trials, which supply some relatively weak data from studies of fewer than 400 patients, and with other important nonidealities. Tables 1–3
summarize some of the information from the larger prospective studies.
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Initial (Hypothesis-Generating) Results of the CALGB
The first major block of clinical evidence that Her2 might identify a subset of patients particularly likely to benefit from anthracycline-based chemotherapy came from work on specimens from CALGB 8541 (8). In this study, patients with lymph node-positive breast cancer were randomly assigned to receive one of three dose levels of cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF). An initial cohort of 397 cases (of 1572 from the trial) was analyzed. A polyclonal serum was used as the primary antibody for the IHC, and Her2 expression was scored as a continuous variable. In this first cohort of patients, it was noted that the highest dose CAF was of particular value for patients with Her2-overexpressing tumors.
A second cohort of patients was then analyzed. This subset included mostly patients who were entered in the latter half of the patient accrual when estrogen receptor-positive patients were given tamoxifen. In addition, the Her2 IHC analysis was performed differently in the second cohort in this study than it was in the first cohort. In the second cohort, Her2 expression was determined using the monoclonal CB11 rather than the polyclonal antisera. The initial analysis of the second cohort of patients (without inclusion of the first cohort) did not confirm the interaction between Her2 and anthracycline dose seen in the first cohort.
The data were then combined and analyzed as a 992-patient set (9). A special weighting also was made to adjust for some of the imbalances between the cohorts. In this third combined analysis, a statistically significant interaction between anthracycline dose and Her2 expression was noted. This interaction conferred particular benefit for the higher dose of CAF (what we now consider the standard dose) on patients whose tumors overexpress Her2.
The CALGB study has some important weaknesses. Special statistical weightings were made to balance the two cohorts. Different methodologies were used in the two cohorts for the Her2 IHC. The study and its analysis were retrospective and exploratory in character and subject to the biases of such analyses. Thus, this study might be viewed as useful for hypothesis generation; studies more prospective in character are necessary to validate and extend these hypotheses.
NSABP Studies of the Predictive Character of Her2
The strongest of the studies supporting the use of Her2 to select patients who might particularly benefit from anthracycline-based chemotherapy come from the NSABP. The first of their studies was based on NSABP B-11 (10). In this trial, lymph node-positive, steroid hormone receptor-negative patients were randomly assigned to receive either melphalan, doxorubicin, and 5-fluorouracil (PAF) or melphalan and 5-fluorouracil (PF). The NSABP studies have used as antibodies for primary staining a cocktail of a monoclonal MAb-1 and p-Ab1 polyclonal sera. Cases were scored as positive if greater than 1% of the cells were stained. Tumor samples from 638 patients were analyzed. Her2 overexpression was observed in 38% of the cases. The mean time of follow-up was 13.5 years.
The patients with Her2-positive tumors received a higher degree of benefit from PAF than from PF. The improved outcome for Her2-positive patients was reflected in a relative risk (RR) of relapse, which in the Her2-positive patients was 0.60 (95% confidence interval [CI] = 0.42 to 0.82; P = .002), and survival was 0.66 (95% CI = 0.47 to 0.92; P = .01). Statistically significant improvements were not seen for patients with Her2-negative tumors with disease-free survival (DFS) showing an RR of relapse of 0.96 (95% CI = 0.75 to 1.23; P = ns); and an RR for survival of 0.90 (95% CI = 0.69 to 1.19; P = ns). A statistically significant interaction between doxorubicin treatment and erbB-2 overexpression was demonstrated for DFS (P = .02), with a trend for such an interaction demonstrated for survival, although this did not reach conventional statistical significance (P = .15). The authors of this manuscript concluded that their data supported the hypothesis of a preferential benefit from doxorubicin in patients with Her2-positive breast cancer.
This study was followed by a second NSABP study (11) that used the same techniques (the same antibody mixture for the IHC and the same scoring criteria). This study had a similar result but was less convincing than the B-11 study. The second NSABP study was based on NSABP B-15, in which lymph node-positive patients were randomly assigned to received doxorubicin and cyclophosphamide (AC); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); or AC followed by CMF. It was hypothesized that AC would be superior to CMF, particularly in the patients whose tumors overexpress Her2. Immunohistochemical Her2 determinations were performed on 1355 cases treated from the AC or CMF arms of the study. Twenty-nine percent of the patients had overexpression of Her2. Trends toward improved outcome for Her2-positive patients treated with the AC arm relative to the CMF arm were seen with an RR of relapse of 0.84 (95% CI = 0.65 to 1.07; P = .15) and with an RR for survival of 0.82 (95% CI = 0.63 to 1.06; P = .13). Trends toward a better outcome of the AC arm versus the CMF arm were not seen for patients with erbB-2-negative tumors for DFS, with an RR of relapse of 1.02 (95% CI = 0.86 to 1.20; P = .84) or an RR for survival of 1.07 (95% CI = 0.88 to 1.30; P = .51). A borderline statistically significant interaction between doxorubicin treatment and erbB-2 overexpression was demonstrated for DFS (P = .19), with a trend for such an interaction demonstrated for survival (P = .11). The authors of this manuscript concluded that the results supported a preference for AC over CMF in patients whose tumors overexpress Her2.
Two Large Cooperative Group Studies Addressing This Issue
Analysis of Her2 in the European consortium trial of epirubicin-containing chemotherapy versus CMF. A European consortium has reported the results of their analyses (12,13) of the predictive value of Her2 as determined by IHC in a randomized phase III study in lymph node-positive patients comparing 1) CMF, 2) epirubicin (60 mg/m2)/cyclophosphamide (EC), and 3) epirubicin (100 mg/m2)/cyclophosphamide (HEC). The analysis of Her2 by IHC was performed only for the patients who were in the CMF and HEC arms. The median follow-up was 50 months. Samples from 481 patients were analyzed. Two different antibody cocktails were used. The first study used 4D5 and/or CB11, apparently on different samples. The second study used a mixture of antibodies similar to those used by the NSABP (a cocktail of the MAb-1 and the pAb-1 polyclonal serum). Cases were scored as positive if greater than or equal to 1% of the cells scored as positive. For the first and the second studies, 12% and 18% of the cases scored as positive, respectively.
The results were suggestive of a positive interaction between Her2 expression and anthracyclines for the first methodology but not for the second. The adjusted hazard ratios for the event-free survival comparison of HEC versus CMF were as follows: Her-2 positive, 0.33 (95% CI = 0.09 to 1.27; P = .08); and Her-2 negative, 1.16 (95% CI = 0.71 to 1.90; P = .56). The P value of the interaction test was .10. When Her2 was evaluated by MAb-1 + pAb-1 antibodies, the adjusted hazard ratios for the same comparison were as follows: Her-2 positive, 1.06 (95% CI = 0.45 to 2.52; P = .90); and Her-2 negative, 0.99 (95% CI = 0.58 to 1.68; P = .97). The P value for the interaction test was .84. The authors rationalized the negative result with the second methodology as being as a result of 1) the low sample size and low statistical power and 2) the fact that the concordance of expression of Her2 by IHC and FISH (fluorescence in situ hybridization) was 92% for the first methodology but only 68% for the second. This suggests that the first methodology might be measuring something more tightly coupled to Her2 gene amplification than the second. Taken together, the results of this study are both encouraging (in one instance, the results supported the hypothesis) and discouraging. The results highlight that all Her2 methodologies are not equivalent and that some may be inferior and inadequate to be used to predict anthracycline sensitivity. It is particularly disappointing that the antibody cocktail used with success by the NSABP was not predictive in the hands of this second set of investigators.
Analysis of Her2 by the SWOG in specimens from adjuvant breast cancer trial S8814. Specimens (746 cases of the 1558 on study) have been analyzed from the adjuvant therapy trial S8814 (14). In this trial, postmenopausal estrogen receptor-positive women were randomly assigned to receive either tamoxifen for 5 years or chemohormonal therapy with six cycles of CAF and tamoxifen for 5 years (either starting it concurrently with the chemotherapy or after completion of the chemotherapy). For the purposes of the Her2 study, the treatment arms were collapsed to two: tamoxifen alone versus tamoxifen plus CAF.
IHC was performed in two separate studies using different IHC techniques. In the first study, MAb-1 (the same monoclonal antibody as that used by the NSABP) was used with the same interpretation of Her2 overexpression (any cells with definite membrane staining). This study showed clear trends for an interaction between Her2 overexpression and benefit from CAF. In this study, chemoendocrine therapy was superior to tamoxifen-alone therapy in the Her2-positive patients, with an RR for relapse of 0.53 (95% CI = 0.30 to 0.95; P = .03) and an RR for survival of 0.44 (95% CI = 0.24 to 0.83; P = .009). The chemoendocrine therapy arm was not superior in the patients whose tumors do not overexpress Her2, with RRs for DFS and overall survival (OS) of 0.85 and 0.96, respectively, neither of which reached statistical significance. In this underpowered study, the test for interaction between treatment and Her2 expression showed weak trends (0.24 and 0.10 for DFS and OS, respectively) but did not reach the level of conventional statistical significance.
In a second study using the monoclonal antibody CB11, no suggestion of predictive power for DFS or OS was seen (see Tables 2 and 3
). In this study, there were no differences that reached statistical significance in the apparent efficacy of treatment with chemoendocrine therapy versus treatment with tamoxifen therapy in patients whose tumors either do or do not overexpress Her2. This is a disappointment, and in some ways it leads to the same conclusion as the European study—that details of the methodologies used are important.
Smaller Studies or Studies With Other Non-Idealities
There are studies with important weaknesses that have addressed the question of whether Her2 expression might predict the benefit of anthracycline-based therapy. A Spanish study (15) (with only 141 patients) that compared CMF with FAC found that FAC was superior to CMF in patients whose tumors overexpress Her2 but that FAC was equivalent to CMF in patients whose tumors do not overexpress Her2. This study is so small and underpowered as to not contribute strongly to the testing of the hypothesis. A small German study (16) with 144 patients randomly assigned to receive either high-intensity epirubicin or a more standard epirubicin dose intensity has reported on the effects of Her2 expression. In this study, both those patients whose tumors did and those patients whose tumors did not overexpress Her2 appeared to benefit from therapy, so the authors concluded that Her2 expression was not predictive of the benefit of dose intensification of an anthracycline. In reality, this study is so small as not to address this question with any real statistical power. An Italian study (17) (with 266 patients) that randomly assigned patients to receive either CMF or single-agent epirubicin had the same weakness of too few patients to have reasonable statistical power to investigate an interaction between treatment and Her2 expression. In this study, the DFS was equal in the two arms, with a trend toward epirubicin being more effective than CMF in patients whose tumors overexpress Her2 and less effective in the patients whose tumors do not overexpress Her2, but the study was so small that these trends did not reach statistical significance.
European Organization for Research and Treatment of Cancer (EORTC) trial 10854 compared the value of a single cycle of perioperative FAC to no further therapy. This study (18) made available Her2 determinations on 441 patients. Also, in this study, DFS was improved by FAC in the patients whose tumors do not overexpress Her2 (4-year DFS 85% versus 78%; P = .05) and also in the patients whose tumors overexpress Her2 (90% versus 77%; P = .17). The hazard of relapse seemed to be reduced to a greater extent in the patients with Her2-overexpressing tumors, but this study did not do a formal statistical test to demonstrate this interaction. This study, while in some ways supportive of the concept of an interaction between anthracycline responsiveness and Her2 expression, did not demonstrate this effect formally and, because of its design (a single perioperative cycle of therapy), may not be directly comparable with the studies of multiple cycles of therapy. A second analysis of these cases for these effects on local recurrence rates found no interaction between treatment effectiveness and Her2 expression, but this study (19) had so few events as to not have any power to demonstrate this interaction.
Of course, adjuvant phase II studies without a control group that received a non-anthracycline-based treatment plan cannot be used to address the question of the interaction between treatment effectiveness and Her2 expression because the effects of Her2 on prognosis cannot be distinguished from its effects on the efficacy of therapy (20,21).
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CONCLUSIONS |
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Taken together, the evidence provides tantalizing but as yet inconclusive evidence that Her2 overexpression can be used to identify patients with early breast cancer who will particularly benefit from anthracyclines. In the four major studies with at least some element of prospective character (the two NSABP studies, the European study, and the SWOG study), in most instances much (all?) of the apparent additional benefit of anthracyclines was seen in the subset of patients whose tumors overexpress Her2. Yet these studies demonstrate the inconclusive nature of the current evidence as well. In general, the studies are vastly underpowered, so effects that seem obvious to the eye do not reach statistical significance. In addition, the European and SWOG studies demonstrate the importance of the techniques used, with some Her2 IHC techniques seeming to be inferior methods for the detection of the interaction.
The road forward is obvious and, hopefully, will confirm the observation that anthracyclines seem to confer additional benefit in patients whose tumors overexpress Her2.
Better standardization of IHC Her2 methodologies among studies would seem important in the research studies. Ideally, methodologies should be used that have been approved for routine clinical evaluation of patient samples, so that the results, if truly predictive, can be brought quickly into clinical use with confidence in the methodology.
Whether other measures of Her2 have value for the prediction of treatment effects should be explored. For example, the use of FISH has led to better predictions than the use of IHC as to which patients are most likely to benefit from Herceptin. Perhaps FISH will be a better test for prediction of anthracycline sensitivity in adjuvant therapy.
Larger and better statistically powered studies are crucial; the ideal would be large studies based on large clinical trials testing anthracycline- and non-anthracycline-based adjuvant therapies. The value of meta-analyses in this field is problematic not only because of the variance in treatments among the trials but because of the multiplicity of the IHC methods used.
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