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Originally published as JCO Early Release 10.1200/JCO.2005.10.910 on February 28 2005 © 2005 American Society of Clinical Oncology.
HER2 or Not HER2: That Is the QuestionDana-Farber Cancer Institute, and Brigham & Women’s Hospital, Harvard Medical School, Boston, MA It is becoming increasingly apparent that the long-appreciated clinical heterogeneity in breast cancer arises in large part from intrinsic biologic heterogeneity within the tumor.1-3 In other words, there is more than one type of breast cancer. Different tumor types are not merely arbitrarily defined subsets, but rather different diseases. Underlying this revised taxonomy are different identifiable growth factors and receptors, reflecting the different molecular and cellular features of these distinct tumor types. Hormone receptor-positive and -negative breast cancer and human epidermal growth factor receptor 2 (HER2) -positive and -negative breast cancer are as different from one another as pneumococcal and staphylococcal pneumonia or acute myeloid leukemia and acute lymphoblastic leukemia. The preliminary but provocative results from the preoperative treatment of HER2-positive breast cancer using chemotherapy with or without trastuzumab, reported in this issue by Buzdar et al,4 provide the opportunity to reflect on the challenges clinicians and clinical researchers face in acknowledging and responding to the biologic heterogeneity of breast cancer. In particular, these findings have led us to imagine a time, probably not far from now, when different breast cancers are treated along distinctive pathways that target their intrinsic biologic features. At a minimum, it is likely that treatment will vary depending on hormone receptor expression and HER2 expression and that other novel molecular targets will be identified in years to come. The dilemma that will confront clinically oriented thinking is that many recent lessons regarding optimal breast cancer therapy have been derived from treating patients without prior selection of tumors based on biology. It is not clear how such lessons will apply to biologically defined classes of breast tumors. The trial from the M.D. Anderson Cancer Center randomly assigned women with HER2-positive, operable breast cancer to either preoperative chemotherapy alone or to chemotherapy and trastuzumab. There was a substantial improvement in pathologic complete response (pCR) rate with trastuzumab-based therapy.4 The chosen end point of pCR has been widely used in preoperative treatment trials because of the reproducibility of the measurement and because it may be a surrogate for long-term treatment outcomes.5 It is not all that surprising that trastuzumab improved pCR because randomized trials in the metastatic setting have demonstrated that trastuzumab-based treatment substantially increases response rate, progression-free survival, and overall survival for patients with HER2-positive breast cancer compared with chemotherapy alone. It is critical to articulate what the M.D. Anderson data do not tell us about a standard approach to breast cancer therapy. The study, with approximately 20 patients per arm, is too small to demonstrate with confidence the safety of preoperative trastuzumab administered with or without anthracycline-based chemotherapy. In particular, the study cannot exclude the possibility of clinically important risks of heart failure. The study was not designed to demonstrate, nor did it report, whether trastuzumab would improve long-term results, such as recurrence-free or overall survival, and we await the data from the many randomized trials in the adjuvant setting to define such benefits. The study does not suggest that trastuzumab-based treatment facilitates breast-conserving surgery; the rates of mastectomy were the same in each treatment arm, at approximately 55%, based on the high clinical response rate. For all these reasons, the use of preoperative trastuzumab remains an investigational approach for HER2-overexpressing, early-stage breast cancer. Notwithstanding these limitations, this small trial confirms previous reports of preoperative trastuzumab-based treatment in early-stage breast cancer.6,7 Moreover, the M.D. Anderson data suggest that it may not be too soon to begin to anticipate the era when HER2-positive breast cancer (20% to 25% of all cases) is treated as a separate disorder, and then to assess the implications for how we will care for the remaining three quarters of breast cancer patients. Consider first the impact of winnowing the HER2-positive breast cancer cases out of the pool of unselected tumors. HER2 overexpression is widely appreciated to have an adverse impact on prognosis8 and is associated with relative resistance to many standard therapies. HER2-positive patients have traditionally constituted a disproportionate number of breast cancer recurrences and, for that reason, a disproportionate number of events in the historical literature from clinical trials. It is apparent that all breast cancer patients will seem to have an improved prognosis if new treatments arrive that prevent recurrence of HER2-positive disease. Women with HER2-positive breast cancer will obviously fare better, and all other women would seem to gain as these aggressive tumors, with greater intrinsic risk of recurrence, are withdrawn from the pool of unselected cases. This effect is similar to the Will Rogers phenomenon described for stage migration.9 Because the absolute benefits of adjuvant therapy are strongly influenced by the risk of tumor recurrence, the general improvement in prognosis will seem to diminish the gains associated with adjuvant chemotherapy and even endocrine therapy among women whose tumors are HER2 negative. Unless accounted for, another consequence of the improvement in overall prognosis will be a diminution of the statistical power of ongoing clinical trials whose analytic assumptions estimated rates of recurrence from unselected pools of patients. Such a rising tide should also prompt reconsideration of many established principles in current adjuvant therapy because it is not clear how these principles apply to HER2-negative breast cancer once the HER2-positive patients are removed. Consider the following specific treatment issues. DOES CHEMOTHERAPY ADD TO ENDOCRINE THERAPY FOR HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE BREAST CANCER? Randomized clinical trials, such as NSABP B-20, have suggested that even low-risk patients benefit from chemotherapy in addition to endocrine therapy with tamoxifen, although the effect of chemotherapy on ovarian function in premenopausal women confounds the interpretation of these studies. Current treatment guidelines from the National Comprehensive Cancer Network and the National Cancer Institute in the United States suggest consideration of chemotherapy for women with tumors greater than 1 cm or with node-positive breast cancer, regardless of hormone receptor status.10 Many but not all retrospective analyses suggest that HER2-positive tumors are more resistant to endocrine therapy, particularly with antiestrogens, than HER2-negative tumors, likely because of interactions between estrogen receptor (ER) and HER211 and because of the quantitatively lower levels of hormone receptor expression seen among those HER2-positive tumors that coexpress ER.12 It is easy to imagine that the additive benefits of chemotherapy with hormonal treatment are found principally in women whose tumors are HER2 positive. The data from Intergroup Trial 010013 are illustrative in this regard. This randomized trial of tamoxifen alone compared with chemotherapy with cyclophosphamide, doxorubicin, fluorouracil, and tamoxifen showed a survival advantage for administering chemotherapy to postmenopausal women with node-positive, hormone receptor–positive tumors13; however, preliminary findings suggest that the significant differences in recurrence favoring the addition of cyclophosphamide, doxorubicin, and fluorouracil to tamoxifen are noted particularly in women whose tumors were HER2 positive.14 ANTHRACYCLINE-BASED ADJUVANT CHEMOTHERAPY The Early Breast Cancer Trialists’ Collaborative Group (Oxford overview, 2000, unpublished data) continues to demonstrate a survival advantage for anthracycline-based chemotherapy over nonanthracycline-based treatment. Multiple retrospective analyses from randomized trials have demonstrated consistently that HER2 expression is a predictive marker for benefit from anthracycline-based adjuvant chemotherapy.15,16 By contrast, the benefit and, thus, the necessity of anthracycline-based treatment over nonanthracycline treatment in HER2-negative breast cancer have been difficult to establish. TAXANE-BASED AND DOSE-DENSE CHEMOTHERAPY The significance of HER2 status in predicting benefit for adjuvant chemotherapy, including taxanes or dose-dense scheduling, has been inadequately studied. However, there are hints in the literature that HER2 status may be important in affecting outcomes with these treatment strategies as well. The relative gains achieved with sequential addition of paclitaxel to anthracycline-based chemotherapy or with dose-dense treatment over standard chemotherapy scheduling are more pronounced among patients with ER-negative tumors than ER-positive tumors.17,18 Given the inverse correlation between HER2 status and ER status, it seems reasonable to anticipate that there is more gain achieved with addition of taxanes or dose-dense treatment among women with HER2-positive tumors than HER2-negative tumors. One randomized trial compared results using standard schedule fluorouracil, epirubicin, and cyclophosphamide (FEC) every 21 days versus dose-dense FEC every 14 days, and showed a trend towards an advantage for dose-dense therapy among HER2-overexpressing patients.19 OPTIMAL ENDOCRINE THERAPY IN POSTMENOPAUSAL PATIENTS Historically, 5 years of tamoxifen therapy has been the standard recommendation for adjuvant endocrine therapy. Recent results from clinical trials using aromatase inhibitors in postmenopausal women with early-stage breast cancer have suggested that these agents may be superior to tamoxifen as primary therapy for reducing tumor recurrence20 and that the sequential use of an aromatase inhibitor after 2 to 321 or 5 years22 of tamoxifen may be superior to treatment with 5 years of tamoxifen alone. Trials of preoperative endocrine therapy using either tamoxifen or an aromatase inhibitor,23,24 as well as other studies of treatment for advanced breast cancer,25 have suggested that HER2-positive tumors are relatively resistant to tamoxifen but may have greater sensitivity to estrogen deprivation with aromatase inhibitors. Similarly, the optimal duration of tamoxifen may differ in HER2-positive tumors. Retrospective analyses of a randomized trial that compared 2 years of tamoxifen therapy with 5 years of tamoxifen therapy indicate that, although patients with HER2-negative tumors derived substantial benefit from 5 years of tamoxifen treatment, the prolonged therapy beyond 2 years was not of benefit to women whose tumors were HER2 positive.26 Finally, recent genomic methods used to predict recurrence risk in women treated with adjuvant tamoxifen weigh heavily on HER2 overexpression as an adverse contributor to a recurrence score.27 Thus, there is the suggestion that the relative benefits of endocrine strategies may differ in HER2-negative and HER2-positive tumors. DISCUSSION We would argue that the identification of patients with HER2-positive tumors and their removal from the unselected pool of breast cancer patients will have profound implications for understanding the value and necessity of many standard therapies for breast cancer. Limited retrospective studies are inadequate to change important principles of therapy. Because of vagaries in HER2 testing, the small numbers of patients in the HER2-positive cohorts, and the power limitations of tests for interaction between clinical subsets, it is impossible to establish with confidence the true role of HER2 status in defining adjuvant treatment at present.28 However, these retrospective analyses question the extrapolation of treatment principles derived from unselected patient populations into patient cohorts defined by virtue of the biologic features of their tumors. They also underscore the importance of redefining therapeutic maxims in HER2-negative patient cohorts through prospective clinical trials. Buzdar et al4 have given us, with their initial report of preoperative trastuzumab therapy, a reminder that the need for such trials is on us. The challenge for clinical investigators and clinicians is to stop seeking one treatment for all types of breast cancer. It will be hard to develop studies that adequately analyze HER2 status and treatment outcome. If we do not make that effort, it will be even harder to explain to patients with HER2-negative breast cancer how our treatment paradigms apply to them. Authors’ Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Eric P Winer, Genentech. Honoraria: Eric P Winer, Genentech. Research Funding: Harold J Burstein, Genentech; Eric P Winer, AstraZeneca, Genentech, GlaxoSmithKline, Pfizer, Roche. For a detailed description of these 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 of Information for Contributors found in the front of every issue. REFERENCES 1. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumors. Nature 406:747-752, 2000[CrossRef][Medline]
2. Sotiriou C, Neo SY, McShane LM, et al: Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 100:10393-10398, 2003
3. Wang ZC, Lin M, Wei LJ, et al: Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers. Cancer Res 64:64-71, 2004 4. Buzdar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2–positive operable breast cancer. J Clin Oncol 23:10.1200/JCO.2005.07.032 5. Schwartz GF, Hortobagyi GN: Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26-28, 2003, Philadelphia, Pennsylvania. Cancer 100:2512-2532, 2004[CrossRef][Medline]
6. Burstein HJ, Harris LN, Gelman R, et al: Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: A pilot study. J Clin Oncol 21:46-53, 2003 7. Harris L, Burstein HJ, Gelman R, et al: Preoperative trastuzumab and vinorelbine is a highly active, well tolerated regimen for HER2 3+/FISH+ stage II/III breast cancer. Proc Am Soc Clin Oncol 22:22, 2003 (abstr 86)
8. Slamon DJ, Clark GM, Wong WG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987 9. Feinstein AR, Sosin DM, Wells CK: The Will Rogers phenomenon: Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 312:1604-1608, 1985[Abstract] 10. National Institutes of Health Consensus Development Conference Statement: Adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst Monogr 30:5-15, 2001
11. Schiff R, Massarweh S, Shou J, et al: Breast cancer endocrine resistance: How growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 9:447S-454S, 2003 (suppl 1)
12. Konecny G, Pauletti G, Pegram M, et al: Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J Natl Cancer Inst 95:142-153, 2003 13. Albain K, Green S, Ravdin P, et al: Overall survival after cyclophosphamide, Adriamycin, 5-FU, and tamoxifen (CAFT) is superior to T alone in postmenopausal, receptor (+), node (+) breast cancer: New findings from phase III Southwest Oncology Group Intergroup Trial S8814 (INT-0100). Proc Am Soc Clin Oncol 20:24a, 2001 (abstr 94) 14. Albain K, Barlow W, O’Malley F, et al: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III Intergroup trial 0100 (SWOG-8814). Proceedings of the 27th San Antonio Breast Cancer Symposium, 2004. Available at: http://www.abstracts2view.com/sabcs/
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17. Henderson IC, Berry DA, Demetri G, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003
18. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 19. Venturini M, Aitini E, Del Mastro L, et al: Phase III adjuvant trial comparing standard versus accelerated FEC regimen in early breast cancer patients: Results from GONO-MIG1 study. Breast Cancer Res Treat 82:S9, 2003 (suppl 1, abstr 12) 20. Baum M, Buzdar A, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer 98:1802-1810, 2003[CrossRef][Medline]
21. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004
22. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793-1802, 2003
23. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808-3816, 2001 24. Smith IE, Dowsett MD: Comparison of anastrozole versus tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in postmenopausal women: The IMPACT trial. Breast Cancer Res Treat 82:S6, 2003 (suppl 1, abstr 1)
25. Pritchard KI: Use of ErbB-1 and ErbB-2 to select endocrine therapy for breast cancer: Will it play in Peoria? J Clin Oncol 19:3795-3797, 2001
26. Stal O, Borg A, Ferno M, et al: ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer. Ann Oncol 11:1545-1550, 2000 27. Paik S, Shak S, Tang G, et al: Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. Breast Cancer Res Treat 88:S15, 2004 (suppl 1, abstr 24)[CrossRef] 28. Valagussa P: HER2 status: A statistician’s view. Ann Oncol 12:S29-S34, 2001 (suppl 1) Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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