The difficult decision-making process for using or not using adjuvant chemotherapy in premenopausal endocrine-responsive breast cancer patients

Abstract

Available adjuvant treatments for premenopausal endocrine-responsive breast cancer patients include chemotherapy, tamoxifen and luteinizing hormone-releasing hormone (LH-RH) agonists. In women younger than 50 years and estrogen receptor-positive (ER+) tumors, adjuvant polychemotherapy is associated with an annual reduction in mortality of 31% [standard error (SE) = 0.10]. In this subgroup of patients, tamoxifen is also very effective with an annual reduction in mortality ranging from 39% (SE = 0.12) in women younger than 40 years to 24% in women aged 40–49 years [1.Early Breast Cancer Trialists' Collaborative Group Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 365: 1687-1717Abstract Full Text Full Text PDF PubMed Scopus (6420) Google Scholar]. A recent meta-analysis showed that LH-RH agonists did not significantly reduce death after recurrence neither when used as the only systemic treatment [17.8% relative reduction, 95% confidence interval (CI) -52.8 to 42.9; P = 0.49] nor when added to tamoxifen (15.9%; 95% CI -40.7 to 19.4; P = 0.33) or to chemotherapy (12.9%; 95% CI -26.5 to 3.2; P = 0.11) [2.LHRH-agonists in Early Breast Cancer Overview group Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone receptor positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials.Lancet. 2007; 369: 1711-1723Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. Trends observed in this meta-analysis are consistent with data from the USA Intergroup 0101 trial showing a benefit with the addition of LH-RH agonist after chemotherapy only in women younger than 40 years, supporting the hypothesis that ovarian suppression may be of benefit in younger women not achieving this with chemotherapy [3.Davidson N.E. O'Neill A.M. Vukov A.M. et al.Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer. Results from INT 0101 (E5188).J Clin Oncol. 2005; 23: 5973-5982Crossref PubMed Scopus (206) Google Scholar]. A controversial issue is whether both endocrine and chemotherapy treatments are necessary or whether endocrine therapy alone may be enough in premenopausal women with endocrine-responsive cancers. In women younger than 50 years with ER+ tumors, the addition of combination chemotherapy to tamoxifen achieved a highly significant death rate ratio of 0.65 (SE = 0.10) compared with tamoxifen alone [1.Early Breast Cancer Trialists' Collaborative Group Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 365: 1687-1717Abstract Full Text Full Text PDF PubMed Scopus (6420) Google Scholar]. Since these data can be considered as strong evidence for using both chemotherapy and endocrine therapy in premenopausal endocrine-responsive breast cancer patients, it may be surprising that the question about to give or not to give chemotherapy still arises. The main limits of the meta-analysis results are the difficulty to generalize them for all patients: the ‘average’ results could not properly fit all patients. In order to maximize the benefit and minimize toxic effects of adjuvant treatments, oncologists attempt to ‘individualize’ treatment taking into account both patient and tumor characteristics. The best way for treatment ‘individualization’ should be based on good, reliable predictors of benefit (or resistance) for any drug, allowing the oncologist to give the right drug to the right patient. Unfortunately, such predictors are not yet completely available in breast cancer. Even for endocrine therapy, only the total absence of ER and progesterone (PgR) are informative, ruling out benefit from endocrine therapy. However, the presence of even strong expression of ER and/or PgR is associated with no more than 60% probability of objective response or clinical benefit [4.Osborne C.K. Yochmowitz M.G. Knight W.A. McGuire W.L. The value of estrogen and progesterone receptors in the treatment of breast cancer.Cancer. 1980; 46: 2884-2888Crossref PubMed Scopus (649) Google Scholar, 5.Ellis M.J. Coop A. Singht B. et al.Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial.J Clin Oncol. 2001; 19: 3808-3816Crossref PubMed Scopus (1026) Google Scholar]. The numbers are very similar for HER2 expression/amplification and response to trastuzumab [6.Vogel C.L. Cobleigh M.A. Tripathy D. et al.Efficacy and safety of trastuzumab as a single agent in first-line treatment for HER2-overexpressing metastatic breast cancer.J Clin Oncol. 2002; 20: 719-726Crossref PubMed Scopus (2740) Google Scholar]. For the prediction of the benefit of chemotherapy, the picture is even more complicated with no validated tools to select patients most likely to respond to the commonly used chemotherapeutic drugs. The lack of predictors of chemotherapy sensitivity could lead some oncologists to inappropriately use the presence or absence of hormone receptors in the decision making for adjuvant chemotherapy, disregarding the biological mean of hormone receptors, i.e. that they are the target of endocrine therapy and not the target of chemotherapy. Although women with estrogen receptor-negative (ER-) breast cancer benefit more from chemotherapy, as compared with women with ER+ disease [7.Berry D.A. Cirrincione C. Henderson I.C. et al.Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer.JAMA. 2006; 295: 1658-1667Crossref PubMed Scopus (624) Google Scholar], this latter group of patients do benefit from chemotherapy, especially if they are younger than 50 years [1.Early Breast Cancer Trialists' Collaborative Group Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.Lancet. 2005; 365: 1687-1717Abstract Full Text Full Text PDF PubMed Scopus (6420) Google Scholar]. The ER+ breast cancer population is very heterogeneous [8.Fan C. Oh D.S. Wessels L. et al.Concordance among gene-expression-based predictors for breast cancer.N Engl J Med. 2006; 355: 560-569Crossref PubMed Scopus (1097) Google Scholar], and the benefit of adjuvant endocrine therapy is greater when the expression of ER is strong as compared with low expression [9.FL Baehner LA Habel CP Quesenberry. Quantitative RT-PCR analysis of ER and PR by Oncotype Dx indicates distinct and different associations with prognosis and prediction of tamoxifen benefit29th Annual San Antonio Breast Cancer SymposiumSan Antonio, TX1417December, 2006 (Abstr 45)Google Scholar, 10.Dowsett M. Allred C. Knox J. et al.Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial.J Clin Oncol. 2008; 7: 1059-1065Crossref Scopus (376) Google Scholar]. As a consequence, it could be hypothesized that in highly endocrine responsive breast cancer, endocrine therapy alone may be sufficient thus avoiding adjuvant chemotherapy also in premenopausal women [11.Goldhirsch A. Wood W.C. Gelber R.D. et al.Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007.Ann Oncol. 2007; 18: 1133-1144Abstract Full Text Full Text PDF PubMed Scopus (833) Google Scholar]. Recent data, however, indicate that the benefit of modern adjuvant chemotherapy regimens, such as those including docetaxel, in patients with high expression of ER (>80%) is similar to that obtained in patients with ER- tumors. The hazard ratio for death in patients treated with docetaxel-containing chemotherapy, as compared with those not receiving docetaxel, was 0.57 (95% CI 0.37 to 0.88) in patients with ER >80% and 0.58 (95% CI 0.41 to 0.80) in patients with ER- tumors [12.Andre F. Broglio K. Roche H. et al.Estrogen receptor expression and efficacy of docetaxel in early breast cancer: a pooled analysis of 3490 patients included in two randomized trials.J Clin Oncol. 2007; 25 (2007 ASCO Annual Meeting Proceedings): 537Crossref Google Scholar]. The data reported above indicate that the presence of hormone receptors, even if highly expressed, is not a reliable predictor of chemotherapy resistance and should not be a reason to rule out a potential benefit of chemotherapy when added to endocrine therapy. The uncertainty about the tumor and patients' characteristics to be considered in making the decision about the use of adjuvant chemotherapy may lead to adopt very different strategy in the same patient among different oncologists. The paper of Regan et al. [13.MM Regan O Pagani B Walley. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?Ann Oncol. Advance Access published on March 5, 2008; doi:10.1093/annonc/mdn037Google Scholar] in this issue of Annals of Oncology describes patient- and tumor-related factors used in the decision-making process of whether or not to give chemotherapy in premenopausal endocrine-responsive patients who entered the phase III Tamoxifen and Exemestane Trial (TEXT). TEXT investigates the role of aromatase inhibitors compared with tamoxifen in premenopausal endocrine-responsive early breast cancer patients receiving ovarian function suppression. The decision of whether or not to use chemotherapy was determined not by the trial but by the center for each individual patient, thus providing the opportunity to investigate what factors are used in the decision-making process of whether or not to give chemotherapy in addition to combined endocrine therapy. The uncertainty still present in such a decision-making process emerges from the study results which showed that geography is one of the major determinants of chemotherapy use. The proportion of patients receiving chemotherapy varied widely according to region, ranging from 64% to 100% of those with node-positive (N+) disease and from 18% to 83% of those with node-negative (N-) disease. In particular, in North American centers where the substitution of ovarian ablation for chemotherapy is not routinely recommended to premenopausal patients [14.Pater J.L. Parulekar W.R. Ovarian ablation as adjuvant therapy for premenopausal women with breast cancer—another step forward.J Natl Cancer Inst. 2003; 24: 1811-1812Crossref Scopus (8) Google Scholar], 52% of N- patients received chemotherapy as compared with 31% of patients from European centers of the Breast International Group. As expected, in the study of Regan et al. [13.MM Regan O Pagani B Walley. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?Ann Oncol. Advance Access published on March 5, 2008; doi:10.1093/annonc/mdn037Google Scholar], other determinants of chemotherapy use were lymph node status (88% of N+ treated versus 46% of N-), patient age, tumor size and grade. It was only partly surprising that other biological factors such as degree of receptor positivity and HER2 status were not determinants of chemotherapy use. These results indicate that clinicians are well aware that some factors such as nodal status, patients age, tumor size and grade are strongly validated as prognostic factors while other factors such as degree of receptor positivity and HER2 status are poorly useful in predicting chemotherapy benefit, being not the target of chemotherapy but the target of endocrine therapy and trastuzumab, respectively. The paper of Regan et al. [13.MM Regan O Pagani B Walley. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy?Ann Oncol. Advance Access published on March 5, 2008; doi:10.1093/annonc/mdn037Google Scholar] indicates that in the absence of strong predictors of chemotherapy sensitivity, the risk of relapse is considered by many clinicians as the primary determinant for using chemotherapy. In order to optimize the decision-making process for using or not using chemotherapy, our goal is to develop predictors of benefit (or resistance) for all drugs used, thus avoiding the use of poorly reliable surrogates. Although this is more complicated than we were hoping for, recent results with the use of gene expression tests are very encouraging. The 21-gene recurrence score seems able to predict benefit of both combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil [15.Paik S. Tang G. Shak S. et al.Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.J Clin Oncol. 2006; 24: 3726-3734Crossref PubMed Scopus (2118) Google Scholar] and combination chemotherapy with cyclophosphamide, doxorubicin and fluorouracil [16.K Albain W Barlow S Shak. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal, node-positive, ER-positive breast cancer (S8814, INT0100)30th Annual San Antonio Breast Cancer SymposiumSan Antonio, TX1316December, 2007 (Abstr 10)Google Scholar] in N- and N+ endocrine-responsive early breast cancer patients receiving tamoxifen. The introduction of gene expression tests is expected to be very useful to help clinicians in choosing whether or not to add chemotherapy to endocrine therapy and in identifying which type of drugs is more likely to be active in each patient [17.Potti A. Dressman H.K. Bild A. et al.Genomic signatures to guide the use of chemotherapeutics.Nat Med. 2006; 12: 1294-1300Crossref PubMed Scopus (490) Google Scholar]. In the future, these tools will avoid that the same patient may receive very different treatment strategies depending on the center where she is referred to. Waiting for the wide diffusion of such new tools, clinicians should continue to consider risk factors as the primary determinants for using chemotherapy in endocrine-responsive premenopausal breast cancer patients and should not forget that hormone receptors, being the targets of endocrine therapy, are not reliable predictors of chemotherapy resistance. The days of ‘one size fits all’ therapy for patients with breast cancer are coming to an end, but the new era of ‘the right size for each patient’ is still a work in progress.