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© 2001 American Society for Clinical Oncology Influence of Endocrine-Related Factors on Response to Perioperative Chemotherapy for Patients With Node-Negative Breast CancerByFrom the European Institute of Oncology, Milan; Oncologia Medica e Fondazione Beretta, Spedali Civili, Brescia, Italy; International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute and Frontier Science and Technology Research Foundation, Boston, MA; Australian Cancer Society, and University of Sydney, Sydney; Anti-Cancer Council of Victoria, University of Melbourne, Melbourne, Australia; International Breast Cancer Study Group Coordinating Center, and Institute of Medical Oncology, Inselspital, Bern; Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Ospedale Civico, Lugano, Switzerland; Western Swedish Breast Cancer Study Group, Sahlgrenska University Hospital, Göteborg, Sweden; Institute of Oncology, Ljubljana, Slovenia; Hospital de la Seguridad Social, Madrid, Spain; and Groote Schuure Hospital, Cape Town, South Africa. Address reprint requests to Marco Colleoni, MD, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; email: marco.colleoni{at}ieo.it
PURPOSE: We investigated tumor- and patient-related features that might influence the response to perioperative chemotherapy (PeCT) compared with no adjuvant therapy for patients with node-negative breast cancer.
PATIENTS AND METHODS: A total of 1,275 patients were randomized to either no adjuvant treatment (427 patients) or PeCT (848 patients). The following variables thought to have prognostic significance were evaluated: grade, tumor size, estrogen (ER) and progesterone receptor (PgR) content (absent; low, 1 to 9 fmol/mg cytosol protein; or positive, RESULTS: The 10-year DFS percentage for 692 premenopausal patients did not significantly differ between the PeCT and no-adjuvant-treatment groups: 61% and 59%, respectively (relative risk [RR], 0.95; 95% confidence interval [CI], 0.75 to 1.20; P = .70). No predictive factors were identified. For 583 postmenopausal patients, 10-year DFS percentages for the groups were 63% and 58%, respectively (RR, 0.75; 95% CI, 0.58 to 0.93; P = .03). The absence of expression of ER, PgR, or both ER and PgR was the most important factor predicting improved outcome with PeCT among postmenopausal patients. The 10-year DFS percentages were 85% and 53% for the steroid hormone receptor–absent cohort of treated and untreated patients, respectively (RR, 0.18; 95% CI, 0.06 to 0.49; P = .0009). CONCLUSION: The role of PeCT should be explored for patients whose primary tumors do not express steroid hormone receptors, because it is likely that early initiation of treatment is exclusively relevant for such patients.
THERE IS A biologic rationale for initiation of chemotherapy as close as possible to the surgical removal of a macroscopic tumor. Surgical trauma and removal of the primary tumor may lead to an increased number of circulating tumor cells1,2 and to an accelerated growth of micrometastases.3 Moreover, tissue trauma is known to enhance biologic processes, which stimulate wound healing4 and may induce tumor progression.5 The results of a meta-analysis of trials on perioperative chemotherapy (PeCT) showed that early initiation of chemotherapy reduced the risk of relapse by 11%.6 Data on treatment effect according to several important predictive features, such as c-erbB-2, steroid hormone receptor expression, or grading, were not reported. We recently reported a relationship between early initiation of adjuvant chemotherapy and estrogen receptor (ER) expression.7 Premenopausal patients with node-positive breast cancer and no ER expression in their tumors had an improved outcome associated with early initiation of prolonged systemic chemotherapy. The 10-year disease-free survival (DFS) rate was 60% for the early initiation group (84 patients who commenced chemotherapy within 21 days of surgery), compared with 34% for the conventionally timed initiation group (142 patients who commenced chemotherapy 22 to 42 days after surgery; relative risk [RR], 0.49; 95% confidence interval [CI], 0.33 to 0.72; P = .0003). An objective of the current analysis was to verify whether the lack of steroid hormone receptors is correlated with a better response to a single perioperative course of chemotherapy compared with no adjuvant treatment for patients with node-negative disease. There is controversy about whether overexpression of c-erbB-2 in tumor cells predicts reduced response to cyclophosphamide, methotrexate, and fluorouracil (CMF)–based adjuvant systemic treatment8 but not to anthracycline-containing regimens.9,10 We therefore included c-erbB-2 as a factor in the current analysis.8 Between 1981 and 1985, the International (formerly Ludwig) Breast Cancer Study Group conducted a randomized clinical trial, Trial V, to evaluate the timing and duration of adjuvant therapy for women with operable breast cancer.11 A total of 1,275 breast cancer patients with node-negative disease were stratified by menopausal status and randomized to receive CMF perioperative chemotherapy (PeCT) or no adjuvant treatment. At a median follow-up of 42 months, a reduced risk of relapse was observed favoring the PeCT group.11 The current analysis was conducted at a median follow-up of 13.5 years, with the specific aim of identifying predictive factors for PeCT response.
The design for Trial V has been previously described.11 Briefly, Trial V for node-negative patients evaluated whether the administration of perioperative cyclophosphamide (400 mg/m2 intravenously [IV] days 1 and 8), methotrexate (40 mg/m2 IV days 1 and 8), fluorouracil (600 mg/m2 IV days 1 and 8), leucovorin (15 mg IV 24 hours after day 1 and 15 mg orally 24 hours after day 8) commenced within 36 hours after mastectomy significantly improved DFS compared with no adjuvant treatment. From 1981 through 1985, a total of 1,275 eligible breast cancer patients with node-negative disease were stratified by menopausal status and randomized, 427 to the no-treatment group and 848 to the PeCT group.
Follow-up data as of June 1999 were used for these analyses. Median follow-up was 13.5 years. DFS was defined as the interval from randomization to relapse, the appearance of a second primary cancer (including a contralateral breast cancer), or death, whichever occurred first. DFS curves were estimated by the Kaplan-Meier method.12 Log-rank tests were used to test for differences between the DFS curves.13 Cox proportional hazards regression models were used to provide analyses adjusted for a variety of covariates and to test for interactions between the effect of PeCT and covariates.14 Covariates considered for the multiple regression models included grade, assessed by central review (1, 2, and 3); tumor size (
A total of 1,275 eligible patients from the International Breast Cancer Study Group Trial V were included in the analysis. The patient characteristics are presented in Table 1. Six hundred ninety-two (54%) of the patients were premenopausal, and 583 (46%) were postmenopausal at the time of study entry. Figure 1 shows the Kaplan-Meier plots of DFS for the PeCT group compared with the no-adjuvant-treatment group for the entire study cohort.
Among 692 premenopausal patients, 10-year DFS rates were 61% for the PeCT group and 59% for the no-adjuvant-treatment group (multivariate RR, 0.95; 95% CI, 0.75 to 1.20; P = .70) (Fig 2A). No significant differences in DFS between PeCT and no adjuvant treatment were observed in the univariate or multivariate analyses according to baseline characteristics (Table 2). Figure 2B shows the DFS curves for PeCT and no-adjuvant-treatment groups for premenopausal patients with ER-absent tumors, and Fig 2C shows the DFS curves for those with ER expression in the primary tumor.
Among 583 postmenopausal patients, 10-year DFS rates were 63% for the PeCT group and 58% for the no-adjuvant-treatment group (multivariate RR, 0.75; 95% CI, 0.58 to 0.97; P = .03) (Fig 3A). In both the univariate and multivariate analyses, the most important predictive factor for postmenopausal patients was the absence of expression of ER, PgR, or both (Table 3). Postmenopausal patients with ER-absent tumors who received PeCT had a higher 10-year DFS rate than untreated patients (80% v 45%; RR, 0.25; 95% CI, 0.11 to 0.56; P = .0007) (Fig 3B). Similarly, postmenopausal patients with PgR-absent tumors who received PeCT had a higher 10-year DFS rate than untreated patients (70% v 52%; RR, 0.53; 95% CI, 0.34 to 0.84; P = .005). Moreover, postmenopausal patients with both ER-absent and PgR-absent tumors who received PeCT had a higher 10-year DFS rate than untreated patients (85% v 53%; RR, 0.18; 95% CI, 0.06 to 0.49; P = .0009). In contrast, no treatment difference was found for patients with tumors expressing steroid hormone receptors. Figure 3C shows the results for tumors with ER-expression.
C-erbB-2 overexpression was assessed in the primary tumor for 401 (58%) of the premenopausal patients and 359 (62%) of the postmenopausal patients. For both premenopausal and postmenopausal patients evaluated separately, a slight detrimental effect of PeCT was suggested for the c-erbB-2–positive group, compared with a slight beneficial effect of PeCT for the c-erbB-2–negative group. The tests for interaction of c-erbB-2–overexpression and effect of PeCT were, however, not statistically significant (P = .08 for premenopausal; P = .93 for postmenopausal). The three-way interaction that evaluated whether the changes in effect of PeCT on DFS rates according to c-erbB-2 were different for premenopausal compared with postmenopausal patients was not statistically significant (P = .60). In Cox models that controlled for treatment, grade, tumor size, c-erbB-2 status, ER, PgR, and age, we examined the interactions between the magnitude of the PeCT effect and the steroid hormone receptor status for premenopausal and postmenopausal patients separately (Table 4). For the premenopausal cohort, there was a statistically significant interaction between treatment effect and PgR-absent status. PeCT was worse than no treatment for patients with tumors that did not express any PgR but better than no treatment for those with some expression of PgR. For the postmenopausal women, there was a positive interaction between treatment effect and ER-absent status. The effect of PeCT was larger for patients with ER-absent tumors than for those with ER expression. The three-way interactions among menopausal status, treatment effect, and hormone receptor status (ER-absent, PgR-absent, or both absent) were each also statistically significant (P= .006, P = .009, and P = .01, respectively), which demonstrated that the effect of PeCT within cohorts defined by steroid hormone receptor content of the primary tumor was different according to menopausal status.
The results of this study lead to the hypothesis that the factors associated with response to adjuvant chemotherapy for breast cancer are different for premenopausal and postmenopausal patients and that these factors are related to the potential endocrine susceptibility for tumor-cell proliferation and response. A previous report on this randomized clinical trial described treatment response according to pathologic features of the primary tumor at a median follow-up of 5 years.15 The current report, at a median follow-up of 13.5 years, focuses on differences in response to the perioperative single cycle according to menopausal status that might be associated with the substantial differences in the endocrine environment between these two age groups. Steroid hormone receptor content of breast cancer is considered to be an important factor for predicting responsiveness to endocrine therapies. However, the relevance of steroid hormone receptor content as a predictive factor for response to chemotherapy was dismissed many years ago after contradictory findings in advanced disease.16,17 Our observations provide strong support for the hypothesis that endocrine factors related to both menopausal status and steroid hormone receptor status, considered together, play a key role in influencing response to chemotherapy. Estrogens are essential for the growth of the normal mammary gland and most ER-positive mammary carcinomas.18,19 It is well known that chemotherapy exerts some of its effect via an endocrine mechanism in premenopausal women with ER-positive tumors. In a recent report, a better outcome was observed in patients with ER-positive tumors who achieved amenorrhea after adjuvant chemotherapy.20 As already shown,21,22 a duration of chemotherapy sufficient to produce ovarian function suppression is required to improve outcome for these patients. For patients with endocrine-nonresponsive breast cancer, chemotherapy is effective mainly through direct cytotoxicity on tumor cells, which, if sensitive, fail to repair the induced damage. Ovarian functioning might interfere with the effects of chemotherapy in premenopausal patients with ER-negative tumors. There is a significant controversy about the role of estrogens in influencing growth and proliferation of ER-absent cells. Some data indicate that 17 beta-estradiol stimulates the clonogenic growth of human breast tumor cell lines independent of the ER status of the cells.23 Alternatively, there are reports that 17 beta-estradiol powerfully inhibits cell proliferation in ER-negative breast carcinoma cell lines.24 Furthermore, estradiol-induced microtubule disruption seems to be independent of estradiol binding to receptors.25 Thus either inhibition of estrogen production or its excessive production could theoretically lead to tumor proliferation in patients with hormone receptor–negative tumors. A single course of chemotherapy administered immediately after surgery might induce an initial decrease of estradiol production26 followed by a rebound of ovarian estradiol production27 in premenopausal patients, with subsequent increased proliferation of ER-absent and/or PgR-absent tumor cells. Two possible mechanisms might be suggested to explain the absence of PeCT effect in premenopausal patients with ER-absent disease. Friedl and Jordan28 showed that ER-negative tumors would grow faster by reducing cell loss in immune mice in the presence of treatment with estrogen. In addition, estrogens enhance endothelial cell activities both in vitro and in vivo,29,30 which suggests a stimulation of angiogenesis. Therefore, a longer duration of chemotherapy is required for premenopausal patients with ER-negative tumors as has been demonstrated.21,22 For postmenopausal patients, only a minimal interference on estrogen production can be hypothesized (eg, adrenal suppression and recovery as a result of cytotoxics and steroids, which are frequently used as antiemetics). This might explain the significantly improved outcome seen in the PeCT-treated cohort of postmenopausal patients with ER-negative tumors. Although the breast cancer overview found only modest effects of chemotherapy for postmenopausal women,31 the majority of these patients had ER-positive tumors, and many of the trials compared chemotherapy plus tamoxifen versus tamoxifen alone for this endocrine-responsive disease. Even when one looks only at the results for the ER-negative cohort of postmenopausal patients in the overview, one sees that the majority received concurrent chemotherapy and tamoxifen, which blunts the effectiveness of chemotherapy alone. In the overview, the magnitude of the effect of chemotherapy without tamoxifen for postmenopausal women with ER-negative tumors is substantial and even larger than that observed for chemotherapy among premenopausal women.32,33 Historically, patients have been classified as having ER-negative disease when there was less than 10 fmol/mg of cytosol protein or when less than 10% of positive cells were immunohistochemically stained.34 However, a recently reported study by Harvey et al35 indicated that the prognosis of patients treated with adjuvant endocrine therapy was better for those with tumors expressing as few as 1% of cells immunohistochemically stained compared with those with no expression of ER. Therefore, the absence of any expression of steroid hormone receptors should be the cutoff for defining a cohort of patients with tumors that are nonresponsive to endocrine therapy. We recently published results indicating a relationship between early initiation of prolonged adjuvant chemotherapy and outcome for premenopausal patients with ER-absent tumors.7 Among patients with ER-absent tumors, the 10-year DFS rate was 60% for the early initiation group, compared with 34% for the conventionally timed initiation. This difference remained statistically significant in a Cox multiple regression analysis that controlled for study group, number of positive nodes, tumor size, age, vessel invasion, and institution. Conversely, early initiation of chemotherapy did not significantly improve DFS for patients with tumors expressing ER. In a separate pilot project that included 117 patients treated with preoperative chemotherapy, we also observed a significantly higher response rate for patients with tumors that did not express ER and PgR compared with the other tumors (82% v 56%; P = .03). Pathologic complete remission rates were also different in the two groups (22% v 7%; P = .04).36 These results, as well as the results of the current study, support the hypothesis that tumors that do not express both ER and PgR might represent a different clinical entity in terms of chemotherapy responsiveness, as already hypothesized in the past.36 Although the method used for ER and PgR assessment (ligand-binding assay) may have influenced the results, there is a good correlation between the immunohistochemical (IHC) staining and ligand-binding assay in a majority of studies.37,38 Thus it is likely that the conclusions of this study would have been similar with IHC analysis. The IHC assay is more sensitive, which increases the likelihood of accurately identifying an endocrine unresponsive status, for which response to PeCT in postmenopausal patients might have been even larger than reported here. We conclude that, in contrast to what is observed in premenopausal patients, a single course of adjuvant PeCT is highly effective for postmenopausal women with node-negative, endocrine-nonresponsive tumors. We hypothesize that chemotherapy responsiveness might be strictly related to the ER and PgR expression of the primary tumor and to the endocrine environment (menopause).
Supported in part by Swedish Cancer Society, Australian Cancer Society, Australian New Zealand Breast Cancer Trials Group, Swiss Cancer League, Swiss Group for Clinical Cancer Research, Frontier Science and Technology Research Foundation, and grant no. CA-75362 from the United States National Cancer Institute. We thank the patients, physicians, nurses, and data managers who participated in the International Breast Cancer Study Group trials.
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Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. J Clin Oncol 18 : 584-591, 2000 8. Gusterson BA, Gelber RD, Goldhirsch A, et al: Prognostic importance for c-erbB-2 expression in breast cancer. J Clin Oncol 10: 1049-1056, 1992[Abstract]
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Paik S, Bryant J, Tan-Chiu E, et al: HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92: 1991-1998, 2000 11. Ludwig Breast Cancer Study Group: Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med 320: 491-496, 1989[Abstract] 12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 13. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline] 14. Cox DR: Regression models and life tables. J R Stat Soc B 34: 187-220, 1972
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Neville AM, Bettleheim R, Gelber RD, et al: Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. J Clin Oncol 10: 696-705, 1992 16. Kiang DT, Frenning DH, Goldman AI, et al: Estrogen receptors and responses to chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med 299: 1330-1334, 1978[Abstract] 17. Lippman ME, Allegra JC: Lack of estrogen receptor associated with an increased response rate to cytotoxic chemotherapy in metastatic breast cancer? Recent Results Cancer Res 71: 155-161, 1980[Medline] 18. Dickson RB, Lippman ME: Control of human breast cancer by estrogens, growth factors, and oncogenes, in Lippman ME, Dickson RB (eds): Breast Cancer: Cellular and Molecular Biology. Boston, MA, Kluwer Academic Publishers, 1988, pp 119-165 19. Addeo R, Altucci L, Battista T, et al: A stimulation of human breast cancer MCF-7 cells with estrogen prevents cell cycle arrest by HMG-CoA reductase inhibitors. Biochem Biophys Res Commun 220: 864-870, 1996[Medline] 20. Pagani O, O’Neill A, Castiglione M, et al: Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: Results of the International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 34: 632-640, 1998 21. Ludwig Breast Cancer Study Group: Combination adjuvant chemotherapy for node-positive breast cancer: Inadequacy of a single perioperative cycle. N Engl J Med 319: 677-683, 1988[Abstract] 22. Goldhirsch A, Gelber RD, Castiglione M, et al: The best available adjuvant treatments are within the framework of clinical trials: International (Ludwig) Breast Cancer Study Group. Isr J Med Sci 31: 144-154, 1995[Medline] 23. Hug V, Drewinko B, Hortobagyi GN, et al: Regulation of breast tumor growth by high-dose estrogen is independent of the presence of estrogen receptors. Breast Cancer Res Treat 6: 237-240, 1985[Medline] 24. Yoo JY, Lessor T, Hamburger AW: Inhibition of cell proliferation by 17 beta-estradiol and heregulin beta 1 in estrogen receptor negative human breast carcinoma cell lines. Breast Cancer Res Treat 51: 71-81, 1998[Medline]
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Harvey JM, Clark GM, Osborne CK, et al: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17: 1474-1481, 1999
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Colleoni M, Minchella I, Mazzarol G, et al: Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors. Ann Oncol 11: 1-3, 2000 37. Barnes DM, Harris WH, Smith P, et al: Immunohistochemical determination of oestrogen receptor: Comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 74: 1445-1451, 1996[Medline] 38. Esteban JM, Ahn C, Battifora H, et al: Predictive value of estrogen receptors evaluated by quantitative immunohistochemical analysis in breast cancer. Am J Clin Pathol 102: 9-12, 1994 Submitted March 23, 2001; accepted July 5, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 fmol/mg cytosol protein), c-erbB-2 overexpression, menopausal status, and age. Cox proportional hazards regression models were used to assess the relative influence of these factors to predict the effect of PeCT on disease-free survival (DFS). Median follow-up was 13.5 years. 
1 cm, 
