Affiliations of authors: R. R. Love, Department of Medicine, Section of Medical Oncology, University of Wisconsin School of Medicine, Madison; N. B. Duc, N. V. Dinh, Hospital K, National Cancer Institute, Hanoi, Vietnam; T.-Z. Shen, People's Hospital of Haimen City, Haimen, Jiangsu, China; T. C. Havighurst, Department of Biostatistics and Medical Informatics, University of Wisconsin; D. C. Allred, Department of Pathology, Baylor College of Medicine, Houston, TX; D. L. DeMets, Department of Biostatistics and Medical Informatics, University of Wisconsin.
Correspondence to: Richard R. Love, M.D., M.S., 610 Walnut St., 256 WARF, Madison, WI 53705 (email: rrlove{at}facstaff.wisc.edu).
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ABSTRACT |
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INTRODUCTION |
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In this historical context, we began a prospective randomized controlled trial of surgical oophorectomy and tamoxifen adjuvant therapy in Vietnamese and Chinese premenopausal women in 1993. The first results of the study show a highly statistically significant benefit in DFS and a nominally statistically significant benefit in OS from the adjuvant treatment (23). In our trial, we recorded the date of the last menstrual period (LMP) before oophorectomy surgery, which in the majority of our study patients was done under the same anesthesia as mastectomy. Patients were diagnosed with breast cancer by aspiration cytology alone and, thus, mastectomy was the only breast surgical procedure they underwent. We report here the results of an exploratory evaluation of the impact of oophorectomy performed during the follicular or luteal phase of the menstrual cycle, as defined by Badwe et al. (13,16), on the DFS and OS of patients in this randomized clinical trial.
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SUBJECTS AND METHODS |
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The main initial results, study design, treatments, quality control, definitions, estrogen and progesterone receptor protein evaluation methods, and the histologic subtyping and grading for the trial, from which a subset of patients is reported upon here, have been published (23). Briefly, from April 7, 1993, through June 30, 1999, 662 Vietnamese and 47 Chinese premenopausal women (defined as those with at least one menstrual period in the last 12 months) with operable breast cancer [TumorNodeMetastasis stages II through IIIA (24)] were recruited into a randomized clinical trial of mastectomy with adjuvant surgical oophorectomy and tamoxifen (20 mg by mouth per day) for 5 years versus mastectomy alone. In the mastectomy-alone group, subsequent oophorectomy and tamoxifen treatment were recommended for those who developed metastatic cancer.
All estrogen receptor (ER) studies were done 27 years after surgery on paraffin-embedded tissues available for two thirds of study patients (23). Each participant gave written informed consent. The study was reviewed and approved by an institutional review board at the University of Wisconsin, by the Office for Protection of Research Risk of the U.S. National Institutes of Health, by the Scientific and Technical Council of the Ministry of Health of Vietnam, and by institutional review committees in China. A data monitoring committee of five experts from North America periodically reviewed the overall trial conduct and the primary, secondary, and safety results.
Statistical Methods
The results reported here are from exploratory post hoc analyses of subsets of trial participants as defined in Fig. 1. The chi-square (
2) test and the Wilcoxon test were used to analyze differences in categoric and ordinal baseline variables, respectively (25). Univariate and multivariate analyses for DFS and OS used a log-rank test and the Cox proportional hazards model (26,27). The model did not differ substantially from proportional hazards. DFS and OS curves were calculated using KaplanMeier methods (28). All computations were performed with SAS software (version 6.12; SAS Institute, Cary, NC). All P values were calculated with two-sided tests of significance.
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RESULTS |
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In this study, patients were randomly assigned to receive adjuvant therapy with oophorectomy and tamoxifen or observation after primary surgical treatment with mastectomy (Fig. 1). Of the 709 patients who enrolled in the study, 89 patients were excluded from the primary analyses reported here because they entered the study after having undergone a mastectomy within the previous 2 months, they were without data on individual cycle length, or the estimates of the date of their last menstrual period were considered unreliable. Of the remaining 611 patients, 46 (7.5%) reported a first day of their last menstrual period more than 42 days before mastectomy with or without oophorectomy (Fig. 1
), and 97 (15.9%) reported a last menstrual period more than 28 but less than 43 days from the date of the surgeries. These data are consistent with those showing that 12% and 31% of subjects were older than 48 years and older than 45 years, respectively, when they entered the study and thus were at risk for perimenopausal anovulatory cycles. We assumed that a majority of the 46 patients with more than 42 days since their last menstrual period were anovulatory and, therefore, we excluded them from the primary analyses.
The main study sample had 565 patients who reported a last menstrual period 42 or fewer days before surgery (Fig. 1). For further analyses, the patients who were randomly assigned to receive oophorectomy and tamoxifen were segregated into three study subsets. Subset 1 contained 98 patients who, on the basis of available ER data, were ER-positive. Subset 2 contained 90 patients who, on the basis of available ER data, were ER-negative (Fig. 1
). Subset 3 contained 180 patients who were younger than 45 years and who reported a last menstrual period less than 36 days before the surgeries (Fig. 1
). For subset 3, we assumed that these criteria would lead to the inclusion of very few anovulatory women (in contrast with the situation for the main study samples, in which modest percentages of anovulatory women were likely to be included). The median follow-up time was 3.6 years (range = 10 days through 8 years, 3 months), with the status unknown for longer than 6 months for fewer than 5% of the patients.
There was no statistically significant difference between the 565 patients with a reported last menstrual period at 42 or fewer days before the surgery and the 144 patients who entered the study but who were not included in the analyses regarding age, weight, pathologic tumor size, percentage of patients with pathologically positive axillary nodes, numbers of positive axillary nodes, or percentage of patients with histologic grade III tumors. For the prognostic factors listed in Table 1, the population of patients with hormone receptor data did not statistically significantly differ from the population without these data.
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Principal Findings
To determine whether surgery during a particular menstrual cycle phase was associated with differences in the DFS or OS of the main study samples, we performed univariate proportional hazard analyses. Table 2 shows that the DFS and OS were similar for patients in the observation arm regardless of phase of the menstrual cycle. Compared with patients in the observation arm, patients treated with oophorectomy and tamoxifen benefited from this adjuvant treatment; however, the magnitude of the benefit for DFS was statistically significant only for those treated during the luteal phase of the menstrual cycle (RR [risk ratio] = 0.45; 95% CI = 0.28 to 0.73; P = .001). Compared with patients treated with oophorectomy and tamoxifen during the follicular phase of the menstrual cycle, those in the same arm treated during the luteal phase of the menstrual cycle had a statistically significant benefit for DFS (RR = 0.54; 95% CI = 0.32 to 0.96; P = .02) and for OS (RR = 0.53; 95% CI = 0.30 to 0.95; P = .03) (Table 2
).
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To further investigate the association of menstrual cycle phase and response to adjuvant oophorectomy, we performed KaplanMeier analysis of the DFS and OS for the main study sample. As shown in Fig. 2, among patients in the mastectomy only arm there was no statistically significant difference in DFS and OS for those who had surgery during the follicular phase of the menstrual cycle versus those who had surgery during the luteal phase. There was a statistically significant benefit in DFS for patients in the oophorectomy and tamoxifen arm who had surgery during the luteal phase compared with patients in the observation arm who had surgery during the luteal phase (P = .001) and a benefit for oophorectomy/tamoxifen patients who had surgery during the follicular phase compared with follicular phase observation arm patients (P = .016 for DFS) (data not shown). KaplanMeier estimates showed that patients in the oophorectomy and tamoxifen arm who had surgery during the luteal phase of the menstrual cycle had a statistically significant benefit compared with patients who had surgery during the follicular phase (P = .02 for DFS and P = .03 for OS) (Fig. 3
).
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In subset 1, patients with ER-positive cancers in the oophorectomy and tamoxifen arm who had surgery during the luteal phase of the menstrual cycle had better DFS than those who had surgery during the follicular phase (P = .04) (Fig. 4 and Table 2
). In subset 2, patients with ER-negative cancers in the oophorectomy and tamoxifen arm who had surgery during the luteal phase of the menstrual cycle had better DFS (P = .04) and OS (P = .02) than did those who had surgery during the follicular phase (Fig. 4
and Table 2
).
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DISCUSSION |
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In this study, using definitions of follicular and luteal phase derived from the reported date of the last menstrual period as surrogates to classify women with different hormonal conditions at the time of mastectomy and oophorectomy surgeries is clearly imperfect. Badwe et al. (29) found that, without blood hormone studies, at least 16% of premenopausal women are misclassified on the basis of reported menstrual cycle history. In our study, there may be a substantial anovulatory population (with unopposed but lower than follicular-phase estrogen levels) and a follicular population (with the follicular phase lasting longer than 14 days) included in the luteal phase groups in the main study samples. When the analysis was restricted to patients 44 years old and younger with a luteal phase of 1535 days since the last menstrual periodcircumstances likely to decrease the number of women with anovulatory, nonprogesterone-producing cycles included in the luteal phase groupthe differences in the outcomes between the groups in the luteal and follicular phases increased (Fig. 6 and Table 2
). The absence of hormone receptor data for one third of patients in the entire study led to small numbers in the hormone-receptor-positive and hormone-receptor-negative subsets. The study samples description (Fig. 1
) shows that the study sample subsets 1, 2, and 3, on whom data are reported, are selected groups for whom the initial study randomization cannot provide assurances regarding selection bias.
There are several strengths to the data reported in this study. First, the data were not confounded by oral contraceptive use (none used by our study patients), multiple surgeries, possible effects of mammography (none of the patients had mammography) and, most importantly, unspecified adjuvant therapies. Second, the date of the first day of the last menstrual period was available for all but 89 study subjects (Fig. 1). The four main study sample groups were defined by a pre-randomization variablethe first day of last menstrual period; thus, these groups should not be subject to selection bias. Statistical tests applied to these groups are therefore valid because of the randomization. The results of the multivariable analyses provide further assurances that the results from the main study sample groups are not explained by subtle differences in prognostic factors. Finally, the data from this study are internally concordant: the four intervention/menstrual cycle phase comparisons present a consistent picture (Table 2
); different definitions of the follicular and luteal phases of the menstrual cycle give qualitatively similar results; and the strength of the apparent benefit for patients having surgery during the luteal phase increases when likely anovulatory patients (women 45 years old and older) are excluded.
Our results do not address the impact of menstrual cycle phase at the time of mastectomy surgery in the same way as the results of the previous investigators did (1416). In our study, the possible critical variables are the abrupt lowering of elevated estrogen and particularly progesterone levels as a result of oophorectomy at the time of breast cancer surgery. If the peri-mastectomy state is important, then our results support the Badwe et al. (13) hypothesis. However, it seems more likely that the impact of surgical oophorectomy is influenced by the phase of the menstrual cycle during which the surgery is performed. In normal breast tissue, epithelial cell proliferation and expression of prolactin receptors increase during the luteal phase of the menstrual cycle (30). If such increases also occur in micrometastases, then the rapid lowering of hormonal levels by surgical oophorectomy during the luteal phase may exert a cytocidal effect through a variety of mechanisms (31). In particular, differences in the regulation or levels of angiogenic factors and proteases between luteal and follicular phases may be important (32,33). Rapid changes in hormonal levels may also influence conditions within tissues that affect implantation of micrometastases (34). In this study, the similar levels of benefit of oophorectomy during the luteal phase seen in patients with ER-positive or ER-negative cancers suggest that an exaggerated hormone withdrawal response is not the major mechanism operating.
The results reported here are from post hoc analyses of a trial designed to address other primary objectives and, clearly, further investigations are needed to establish the possible mechanisms and to confirm the findings. The impact of other systemic adjuvant therapies (both chemotherapies and LHRH agonists) may similarly vary with initiation at different times during the menstrual cycle. Furthermore, the timing of the withdrawal of hormone replacement therapy in women found to have breast cancer may influence their long-term prognosis. Our results suggest a paradigm shift in breast cancer treatment from the current emphasis on the type of hormonal therapy used to greater emphasis on the characteristics of the patient and the tumor when hormonal therapy is begun. Because the levels of effect associated with oophorectomy are large, and because having surgery during the luteal phase is easily achieved, it is urgent that rigorous clinical trials be done to determine whether specifically performing definitive breast tumor excision surgery with simultaneous oophorectomy in the luteal rather than the follicular phase of the menstrual cycle is, in fact, beneficial and to investigate the mechanisms through which such observations operate. Studies of the impact of oophorectomy at different times in the menstrual cycle as a treatment for metastatic disease are also indicated by our results. In new trials, blood hormone assessments should be done to specify the biochemical phase of the menstrual cycle at the time of surgery, a protocol being followed in the National Surgical Adjuvant Breast Project/North Central Cancer Treatment Group (NSABP/NCCTG) N9431 (35). Finally, these results may have implications for the timing of therapies, particularly those of primary surgery, for other solid tumors.
In summary, we have found no evidence that the timing of mastectomy influences outcomes in women with operable breast cancer who received no adjuvant systemic therapy. By contrast, we found that women who underwent adjuvant oophorectomy simultaneously with mastectomy surgery during the estimated luteal phase of the menstrual cycle benefited from this treatment to a statistically significantly greater extent than did women who had this surgery during the follicular phase, and that women undergoing mastectomy and oophorectomy and tamoxifen during the follicular phase of the menstrual cycle derived a marginal benefit from the adjuvant hormonal treatment.
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NOTES |
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Tamoxifen (Nolvadex) for this clinical trial was provided at cost by AstraZeneca Pharmaceuticals, Singapore.
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