Published Ahead of Print on February 21, 2012 as 10.1200/JCO.2011.37.7879 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.37.

7879

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COMMENTS AND CONTROVERSIES

Is Adjuvant Chemotherapy Useful for Women With Luminal A Breast Cancer?

Alan S. Coates, International Breast Cancer Study Group and University of Sydney, Sydney, New South Wales, Australia Marco Colleoni, International Breast Cancer Study Group and European Institute of Oncology, Milan, Italy Aron Goldhirsch, International Breast Cancer Study Group and European Institute of Oncology, Milan, Italy; and Swiss Center for Breast Health, St Anna Clinic, Lugano, Switzerland

Cytotoxic chemotherapy is, on average, benecial in delaying relapse and prolonging survival for women with early breast cancer.1 Thus, there is a motivation to prescribe it freely to all or nearly all such women. Guidelines from the 2000 National Institutes of Health Consensus Development Conference stated that because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status2(p5) and that at the present time, there are no convincing data to support the use of any known biologic factor in selecting a specic adjuvant chemotherapy regimen in breast cancer.2(p7,8) These recommendations clearly took no account of potential heterogeneity of tumor biology, which has been extensively studied in the interim. Each year sees clearer demonstration that breast cancer is a heterogeneous disease. However, contemporary guidelines from the USNationalComprehensiveCancerNetworkpersistinadvisingchemotherapy for all patients with node-positive invasive breast cancer.3 A classication of breast cancer based on gene array proles of the disease has been proposed for a better understanding of its biology.4-7 The subtypes identied differ in terms of epidemiology,8,9 natural history,10,11 and response to various therapies.12-14 The panel at the recent St Gallen Consensus Conference accepted the principle of using intrinsic tumor subtype as a basis for identifying patients for whom each type of therapy is most likely to be benecial and, conversely, those for whom a particular treatment may be futile.15 The panel also recognized that gene array analysis would not be possible in all patients in the immediate future and accepted the pragmatic approximation5 of dening intrinsic subtypes using immunohistochemical and in situ hybridization technology as reasonable in current practice. This classication provides a convenient shorthand description of the factors agreed on by earlier St Gallen Consensus panels as indicating the likely efcacy of specic therapy modalities. It has been many years since we recommended tamoxifen for patients whose tumors lack estrogen receptor (ER). Likewise (although less securely), we avoid anti human epidermal growth factor receptor 2 (HER2) therapies for patients whose tumors lack the appropriate target of overexpressed or amplied HER2. Can we identify a group of patients who are optimally treated without cytotoxics? Direct trials of this question have until now failed to recruit adequate numbers.16 Ongoing studies in dened populaJournal of Clinical Oncology, Vol 30, 2012

tions may result in direct evidence in the near future. The TailoRx (Trial Assigning IndividuaLized Options for Treatment) study has completed accrual of node-negative patients with intermediate OncotypeDX (Genomic Health, Redwood City, CA) recurrence scores (RSs) randomly assigned to treatment with endocrine therapy alone or endocrine therapy plus chemotherapy. This is an important trial, although it is perhaps a pity that the RS levels adopted for denition of low, intermediate, and high risk do not match those recommended in clinical practice. The recently activated SWOG (Southwest Oncology Group) S1007 trial RxPONDER (Treatment for Positive Node, Endocrine Responsive Breast Cancer) aims to extend the assessment to node-positive disease and determine the effect of endocrine therapy versus endocrine therapy plus chemotherapy in patients with node-positive breast cancer who do not have high RSs. Like TailoRx, this is an important study, but results cannot be expected for some years. Similarly, the MINDACT (Microarray in NodeNegative Disease May Avoid Chemotherapy) trial17 has completed enrollment, randomly assigning chemotherapy to those in whom there is discrepancy of opinion regarding the need for chemotherapy between clinical assessment using the Adjuvant! Online program18 and the 70-gene assay developed at the Netherlands Cancer Institute.19 This trial chiey aims to detect a patient group with risk so low that even if the proportional benet of the addition of chemotherapy were the same, the absolute benet would be judged insufcient to justify the addition of chemotherapy. No published studies have explicitly used luminal A subtype as an eligibility or stratication criterion. However, the characteristics of luminal A disease high expression of ER, low proliferation, and no amplication or overexpression of HER2 oncogeneare well documented and were accepted by the 2011 St Gallen panel as adequately dening the subtype for clinical purposes.15 Retrospective analysis of the effect of therapy for patients so dened has been possible in several completed trials, some of which were prospectively stratied for degree of ER expression. There is strong evidence from these studies that chemotherapy does not add benet when compared with endocrine therapy alone in dened subgroups resembling and including luminal A disease. Thus, the IBCSG (International Breast Cancer Study Group) IX trial in postmenopausal women with node-negative disease found no benet of adding cyclophosphamide, methotrexate, and uorouracil chemotherapy in the prospective stratum with
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Coates, Colleoni, and Goldhirsch

ER-positive disease,20 whereas in the corresponding premenopausal study IBCSG VIII, no benet of chemotherapy was seen among patients whose tumors had high expression of ER21 or low proliferation as measured by Ki67 labeling index.22 Recent analysis of patients from these two trials showed no benet of chemotherapy in the subset with high endocrine receptor, negative HER2, and low Ki67,23 corresponding to the surrogate denition of luminal A disease.24 Retrospective analysis of the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-20 trial in patients with node-negative disease found no benet of adding chemotherapy to tamoxifen except among those with the highest levels of RS as measured by OncotypeDX.25 Similarly, among postmenopausal women with node-positive disease, SWOG 881426 demonstrated no benet of the addition of cyclophosphamide, doxorubicin, and uorouracil chemotherapy to tamoxifen for those with high ER levels and negative HER2 (ie, those fullling the surrogate denition of luminal A disease) and specically for those with low or intermediate RS (ie, predominantly those with selectively higher ER, lower proliferation, HER2-negative tumors), which would include virtually all patients with luminal A disease. Conforti et al27 found that chemotherapy benet was predicted both by ER expression and a clinicopathologic approximation to intrinsic subtype. Berry et al28 found that the efcacy of anthracycline-based chemotherapy was markedly higher among patients with ER-negative disease. However, in a joint analysis of the BCIRG (Breast Cancer International Research Group) 001 and PACS (French Adjuvant Study Group) 01 trials, Andre et al29 found no association between ER expression and the additional efcacy of a taxane. BCIRG 001 and PACS 01 enrolled patients with strongly node-positive disease (median, three positive nodes), and therefore, patients with luminal B disease may have contributed to the overall result. This possibility is directly supported by the analysis by Penault-Llorca et al30 of the PACS 01 trial, in which the additional benet of taxane among patients with ER-positive disease was conned to those with higher proliferation as measured by Ki67 expression. In premenopausal women, the interpretation of the efcacy of chemotherapy is complicated by its endocrine effect in suppressing ovarian function, because chemotherapy-induced amenorrhea is associated with superior outcome.31-34 This effect may also explain the counterintuitive benet of higher-dose chemotherapy seen in the IBCSG 15-95 trial35 among patients with ER-positive disease and in similar patients in the Dutch high-dose therapy trial.36 Use of chemotherapy in premenopausal women based on its ability to induce amenorrhea could be regarded as an unusually toxic and unpleasant form of ovarian suppression. In young women with ERpositive disease, chemotherapy may also be poorly efcacious, because chemotherapy-induced amenorrhea is uncommon among patients age younger than 35 years.37 The lack of efcacy of neoadjuvant chemotherapy in patients with ER-positive disease is additional evidence of heterogeneity of response to chemotherapy based on ER level.38 Among patients with high ER expression, no case of pathologic complete remission has been observed at the European Institute of Oncology.39 It may be argued that because even a few patients may benet, all should receive chemotherapy. This ignores the potential harm of exposing a large majority to the toxic (occasionally fatal) adverse effects of chemotherapy to no purpose. There is a natural tendency within each oncology subspecialty to a bias toward its own treatment modality. In the case of medical
2
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oncology, there may be a further perverse economic incentive toward the administration of intravenous therapy in those countries in which reimbursement for such therapy provides substantial practice income. There is a long-established practice of recommending chemotherapy for patients with higher disease burden. Although tumor bulk per se is not included in the OncotypeDX RS (which was developed in patients with node-negative disease), higher RSs have on average been observed among patients with increasing tumor burden as evidenced by node involvement.26,40 Nevertheless, not all patients with nodepositive disease have high RSs, and the SWOG 8814 study suggests that chemotherapy has little if anything to offer to those with low or intermediate RSs. Thus, by this measure, it is tumor biology, not tumor bulk, that denes chemotherapy utility. A popular method for assessing the risk of recurrence and benet of endocrine therapy and chemotherapy is Adjuvant! Online.18 However, the algorithm it uses is based on historical trials with variable selection procedures, in which the comparator groups may not have received adequate endocrine therapy. In the specic subgroup of immunohistochemically dened luminal A disease under discussion, there is empirical evidence that Adjuvant! Online is unreliable. Among premenopausal patients with receptor-positive disease treated with ovarian suppression and tamoxifen, excellent outcomes were observed, and no additional benet of chemotherapy could be demonstrated.16 When tested against these prospective data from IBCSG 11-93 trial, Adjuvant! Online was found to grossly overestimate the benet of chemotherapy.41 Similar excellent outcomes were observed among premenopausal patients in the Austrian study ABCSG (Austrian Breast and Colorectal Cancer Study Group) 1242 who received endocrine therapy including ovarian suppression without chemotherapy. The SOFT (Suppression of Ovarian Function Trial) study has recently completed accrual and will eventually provide more information on the benet of ovarian suppression in addition to tamoxifen in premenopausal patients.43 We are aware that a parallel contribution44 to Journal of Clinical Oncology may argue a different position. It has also been reported that the unpublished draft of the most recent Oxford Overview of chemotherapy trials has failed to distinguish a group of patients who do not benet from chemotherapy. Until this claim has been subjected to peer review, it is premature to comment in detail, but we note that the simultaneous allowance for age, hormone receptor status, tumor proliferation, and adequacy of concomitant endocrine therapy is difcult in the overview setting, because subgroups are predominantly considered using one or at most two features at a time. In stressing the homogenized totality of the evidence, there is, we believe, a risk that real differences based on biologically dened subtypes will be submerged. The overview remains a blunt instrument for investigation of subset effects. In fact, the totality of the randomized evidence available for the biologically based luminal A subtype provides no signal that chemotherapy provides benet over and above that obtained with optimal endocrine therapy alone. What should we therefore conclude in the interim, before results are available from larger prospective trials? One approach would be to continue to regard breast cancer as an essentially homogeneous entity until prospective evidence forces a deviation from this position. We reject this approach and prefer instead to accept the evolving evidence of biologic heterogeneity. Taken together, the evidence strongly suggests that there exists, and that we can dene, a group of women with early breast cancer for whom the benet of adding chemotherapy to
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Comments and Controversies

highly effective endocrine therapy is vanishingly small or nonexistent. Our patients deserve to benet from the emerging knowledge of tumor biology and treatment strategies tailored for dened subtypes. Addendum: January 2012 Since this article was submitted in June 2011, the most recent Early Breast Cancer Trialists Collaborative Group overview of chemotherapy studies has been published.45 As foreshadowed in our commentary, this overview nds that proportional risk reductions [from chemotherapy] were little affected by age, nodal status, tumor diameter or differentiation (moderate or poor; few were well differentiated), ER status, or tamoxifen use and that information was lacking about tumor gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both.45 Thus, our thesis that there exists within breast cancer a biologic subgroup, broadly synonymous with the luminal A subtype, that does not derive benet from the addition of chemotherapy to optimal adjuvant endocrine therapy is neither supported nor refuted by the overview, which is simply unable to test it.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: Alan S. Coates, Roche, Takeda Pharmaceuticals
AUTHOR CONTRIBUTIONS

Manuscript writing: All authors Final approval of manuscript: All authors

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40. Dowsett M, Cuzick J, Wale C, et al: Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: A TransATAC study. J Clin Oncol 28:1829-1834, 2010 41. Paridaens RJ, Gelber S, Cole BF, et al: Adjuvant! Online estimation of chemotherapy effectiveness when added to ovarian function suppression plus tamoxifen for premenopausal women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 123:303-310, 2010 42. Gnant M, Mlineritsch B, Schippinger W, et al: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679-691, 2009 43. Puhalla S, Brufsky A, Davidson N: Adjuvant endocrine therapy for premenopausal women with breast cancer. Breast 18:S122S130, 2009 (suppl 3) 44. Hayes DF: Targeting adjuvant chemotherapy: A good idea that needs to be proven! J Clin Oncol doi:10.1200/JCO.2011.38.4529 45. Early Breast Cancer Trialists Collaborative Group: Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet [epub ahead of print on December 5, 2011]

DOI: 10.1200/JCO.2011.37.7879; published online ahead of print at www.jco.org on February 21, 2012

Acknowledgment We thank Richard D. Gelber, PhD, and Shari Gelber, MS, MSW, for their assistance in discussions of the topic.

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