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Is HER-2/neu a Predictor of Anthracycline Utility? No.

George W. Sledge, Jr., M.D.

HER-2/neu is important in the natural history of breast cancer. This importance derives from HER-2/neu’s role in tumor growth, invasion, and metastasis (the clinical summation of which is its role as a prognostic factor in early-stage breast cancer) as well as its role as a predictor of response to trastuzumab (Herceptin monoclonal antibody). These roles for HER-2/ neu seem firmly established.

Three recent American cooperative group trials have suggested that patients receiving adriamycin are the most likely to benefit if their tumors overexpress the HER-2/neu glycoprotein. This role of HER-2/neu, as a predictor of anthracycline utility seems promising, and if confirmed clearly would be of importance. But to what extent should we accept the data presented to date?

Problems in Positive Trials

Three trials have reported positive results (Paik, Bryant, Park, et al., 1998; Thor, Berry, Budman, et al., 1998; Ravdin, Green, Albain, et al., 1998). Individually and collectively, however, these trials suffer from potential and actual flaws. All data presented to date utilize immunohistochemical techniques (IHC), and such techniques are well known to suffer from methodological flaws. Even in good hands, the correlation of these techniques with the “gold standard” of fluorescence in situ hybridization (FISH) is only about 80 percent. IHC techniques also have unknown correlations with each other, and all three studies used differing antibodies and techniques. In each case, tissue collection was retrospective. In one of the studies (Thor and colleagues), the antibody utilized was switched mid-study; in another (Paik and colleagues), the IHC technique was done on old slides rather than off paraffin-embedded tissue.

Leaving aside these potential methodological flaws, the analyses of the reported trials leave something to be desired. All three involved retrospective analyses and should therefore be viewed as hypothesis-generating rather than as proof-of-principle studies. In the Cancer and Leukemia Group B (CALGB) trial, an initial analysis reported positive results, a second analysis with a somewhat larger number of patients failed to reach statistical significance, and a third analysis combining the two was once again positive. The data reported by SWOG involved subset analyses involving a truly small number of patients, with broad confidence intervals. Tests for interaction did not reach statistical significance in any of the three trials.

Finally, what are we to make of comparing the available trials? In the first trial reported (CALGB), “high-dose” anthracycline-based therapy was superior to “low-dose” anthracycline-based therapy. The low-dose arm of the CALGB trial, however, utilized the same dose intensity employed in the standard AC arm of NSABP B-11. Are we to believe that the magnitude of difference between AC and CMF in the NSABP trial is equal to the magnitude of difference between that same dose and twice the dose of adriamycin? That seems unlikely.

Problems With Consistency

Though most doxorubicin-based adjuvant trials have reported positive results, at least one epirubicin-based analysis reported no differential benefit for HER-2 positivity (Untch, Konecny, Lebeau, et al., 1998). That study compared a standard-dose epirubicin/cyclophosphamide combination with a dose-intense epirubicin/cyclophosphamide regimen. Only in the HER-2 negative subgroup was there a benefit for the dose-intense regimen, a result that contrasts strikingly with the CALGB results. Given that epirubicin is at least as beneficial in the adjuvant setting as doxorubicin, how could one explain the absence of an HER-2 related benefit?

Similarly, Colozza, Gori, Mosconi, et al. (1999) evaluated the effect of HER-2 status in a trial comparing epirubicin with CMF adjuvant chemotherapy in patients with Stage I or II breast cancer. With a median followup of 5.6 years and 266 patients available for HER-2 status, epirubicin treatment had no significant impact on the outcome of patients with HER-2 positive tumors.

One would expect a consistency of effect across all stages of breast cancer if the HER-2 relationship were real. We would not expect a predictive factor to have a benefit in Stage II breast cancer but not in Stage III or IV breast cancer, yet this is what we are asked to accept for the HER-2/doxorubicin interaction. Numerous trials have examined the effect of HER-2 overexpression on response to preoperative or metastatic anthracycline-based regimens. These trials (summarized in table 1) are inconsistent in their results, and generally fail to demonstrate a positive relation. Although the number of patients entered in these trials was small relative to the numbers of those in adjuvant trials, the number of events is large, since virtually every patient entered was measurable for response.

Biologic Problems

If HER-2 overexpression conferred sensitivity to doxorubicin in the clinic, one would expect that a similar effect might be seen in the laboratory. Pegram and colleagues tested this hypothesis by transfecting four breast cancer cell lines with HER-2 and then exposing them to doxorubicin in vitro. No alteration in chemosensitivity was observed in any of the transfected breast cancer cell lines versus the parent cell lines, nor in a related in vivo nude mouse xenograft model (Pegram, Finn, Arzoo, et al., 1997).

Problems With Extrapolation

The problem with accepting the results seen in the available adjuvant trials mirrors the problem with HER-2 testing in general. Immunohistochemical analysis of HER-2 is only imperfectly correlated with fluorescence in situ hybridization (FISH), and is subject to interobserver reproducibility problems, problems with technique, and problems with tissue preservation. None of the current trials used the same immunohistochemical techniques. How then can we extrapolate the results to clinically available testing kits?

Similarly, proponents of the HER-2/doxorubicin link need to follow through on the logical conclusions of this linkage. Two-thirds to three-quarters of breast cancer patients are HER-2 negative. The same studies suggesting a benefit for doxorubicin in HER-2 positive patients show a lack of added benefit in HER-2 negative patients. Given the overview demonstration of benefit for anthracycline-based regimens in the adjuvant setting, are we really confident that doxorubicin can be omitted in HER-2 negative patients?

Conclusion

Conclusion HER-2/neu testing has many real benefits. These benefits should not blind us to the real concerns surrounding the use of HER-2 as a therapeutic predictor for anthracyclines. We currently lack a solid biologic basis for the proposed linkage. The available positive studies have real uncertainties. There are studies contradicting the linkage in the adjuvant, neo-adjuvant, and metastatic settings. The cumulative weight of these concerns calls the hypothesis into question. Until more solid data emerges, HER-2 should not be accepted as a predictor.

References

Colozza M, Gori S, Mosconi A, et al. erb-B2 expression as a predictor of outcome in a randomized trial comparing adjuvant CMF vs single agent epirubicin in Stage I-II breast cancer (BC) patients. [abstract]. Proc Am Soc Clin Oncol 1999;18:70. Abstract.

Paik S, Bryant J, Park C, Fisher B, Tan-Chiu E, Hyams D, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone-receptor-negative breast cancer. J Natl Cancer Inst 1998;90:1361-70. Abstract.

Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon DJ. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancers cells. Oncogene 1997;15:537-47. Abstract.

Ravdin P, Green S, Albain K, et al. Initial report of the SWOG biological correlative study of c-erbB-2 expression as a predictor of outcome in a trial comparing adjuvant CAF T with tamoxifen (T) alone. [abstract]. Proc Am Soc Clin Oncol 1998;17:97a. Abstract.

Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998;90:1346-60. Abstract.

Untch M, Konecny G, Lebeau A, et al. Dose-intensification (DI) of anthracycline in the adjuvant treatment of high risk breast cancer (HRBC) and c-erbB-2 overexpression. [abstract]. Proc Am Soc Clin Oncol 1998;17:103. Abstract.