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10.1245/ASO.2004.02.019
Annals of Surgical Oncology 11:818-828 (2004)
© 2004 Society of Surgical Oncology
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EDUCATIONAL REVIEW

Models of Breast Cancer Growth and Investigations of Adjuvant Surgical Oophorectomy

Richard R. Love, MD and John E. Niederhuber, MD

From the Department of Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin.

Correspondence: Address correspondence and reprint requests to: Richard R. Love, MD, Department of Medicine (RRL) and Surgery (JEN), University of Wisconsin School of Medicine, 610 Walnut St., 256 WARF Bldg., Madison, WI 53726–2397; Fax: 608-263-4497; E-mail: rrlove{at}facstaff.wisc.edu

ABSTRACT

Clinical observations of the natural history of breast cancer and its response to a variety of therapeutic interventions have contributed to changing concepts about the growth and metastatic spread of this disease. Increased attention has been given to tumor cell dormancy and the occurrence of greatly delayed metastatic disease development, which has been important to rethinking therapy. Although gene profiling of breast tumors recently has highlighted the importance of individual tumor characteristics in patients’ prognosis, considerable data also support the concept of breast cancer as a problem of macro- and microenvironmental regulatory imbalance and dynamic chaos. Observations of unexpectedly large survival benefits from adjuvant surgical oophorectomy done in the luteal phase of the menstrual cycle in premenopausal women are consistent with an interpretation that extratumoral interactions in the host environment are important in prognosis. These observations also suggest that a treatment paradigm shift from an exclusive focus on cell kill and specific tumor cell molecular targets to one focused also on broad host regulatory control may be useful. Clinical trials and laboratory mechanistic investigations based on these data and observations can determine the potential impact of therapeutic interventions targeting host system macro and micro tumor cell environments.

Key Words: Oophorectomy • Breast cancer • Host • Regulation

During the last two decades, a focus of western medicine has been in the development and use of systemic adjuvant chemotherapies for operable breast cancer. Although this emphasis has led to improved outcomes, an increasing body of laboratory and, recently, clinical trial data support the concept that hormonal therapies (using the term broadly) can be dramatically effective. Additionally, these clinical observations of hormonal interventions have been the impetus for development of more comprehensive biological and mathematical models of breast cancer growth and progression. Together, these new response data and growth models suggest that a genuine paradigm shift should occur in our view of breast cancer. Suggested is a shift from one of an autonomous disease whose only successful treatment can follow from efficient tumor cell kill or targeting of specific cell pathways to one of a dynamic process, the course of which can be significantly altered by timely systemic environmental interventions.1 We review selected data that justify such a paradigm shift, and suggest a specific progesterone trigger hypothesis and a research portfolio to investigate observations of the major impact on survival of perioperative adjuvant surgical oophorectomy done in the luteal phase of the menstrual cycle.

CRITICAL OBSERVATION ON THE NATURAL HISTORY OF BREAST CANCER

The significance and unifying explanations for several old and recent observations about the behavior of tumors in patients have provided an impetus and basis for a more nuanced interpretation of the natural history of breast cancer. Clinicians have long been convinced that the disease course is remarkably extended in some patients with breast cancers, more frequently than for most other solid tumors. Whereas cure is a reasonable word to use in discussing the likely status in an apparently disease-free patient >5 years after resection of a primary lung or colorectal cancer tumor, this is not true in breast cancer. Careful, long-term follow-up of patients demonstrates recurrence of breast cancer >20 years after initial surgical treatment—even three or four decades after the original cancer diagnosis and treatment.2 Older case reports of late disease recurrences have been open to criticisms that the development of second cancers had not been convincingly ruled out. Newer reports, however, present credible documentation that such is the case.3 These cases have encouraged more serious consideration of the possibility that some breast cancers, at some periods in their natural history, do not grow at all. From this hypothesis, questions follow about what we do know about rates of breast cancer growth, both in general and over time for individual tumors; what the patterns of growth are in populations; and what might influence these patterns. Among recent provocative clinical observations on these issues are the following:



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  		   FIG. 1. Age-specific incidence rates of breast cancer by the joint status of estrogen and progesterone receptors (ER/PR). Estimated from Danish national data, plotted in a log-log scale. (Adapted from Yasui Y, Potter JD. The shape of age-incidence curves of female breast cancer by hormone-receptor status. Cancer Causes Control 1999;10:431–7; Fig. 1.)
 
Taken together these observations suggest that (1) rates of breast cancer growth vary from zero to high levels, at least at times in magnitudes independent of tumor clone size; and (2) changes in these rates (both major increases and decreases to zero) for preclinical and clinical tumors are profoundly influenced by macro- or microenvironment or by host factors and are not solely a consequence of the inherent biology of the tumor clone.

MODELS OF BREAST CANCER GROWTH AND METASTASES

Over the last 25 years, most of the American adjuvant treatment clinical trials have been driven by and based on a continuous growth model, with modifications for Gompertzian kinetics and resistance and have presumed log cell kill.17–20 Recent positive results of a dose-intense adjuvant therapy program has lent further support to the usefulness of this model.21,22

Animal studies in the 1970s suggested the likelihood of changing kinetics of tumor growth, particularly in model metastases after removal of a primary tumor.23 In interpreting these studies, emphasis was on the increases in growth kinetics in secondary lesions, as opposed to the apparent suppressant effect of the primary tumor on these metastases. Interestingly, a single dose of chemotherapy before surgical removal of a primary murine mammary tumor prevents the increase in labeling indices of metastases.24 In 1990, Meltzer25 focused attention on some of the clinical observations noted above, particularly the occurrence of late metastases, bringing prominence to the concept of tumor dormancy. Over the last decade, authors have grounded models in laboratory observations about new metastatic tumor angiogenesis.4,26 In considering the implications of such models, authors first focused on usual adjuvant chemotherapy, but also began considering the implications for primary surgery timing.4 Initially Schipper et al.1 framed their considerations about models for breast cancer growth more broadly, but highlighted the view that tumors were growing in complex systems at the edge of chaos, exquisitely sensitive to "trivial degrees of perturbations." More recently Baum et al.27 called attention to mathematical models that describe this "dynamic chaos" as it operates with micrometastatic tumor angiogenesis. As these mathematical models, in combination with clinical and laboratory data, have been presented and highlighted, the development of individual gene profiling of breast tumors has thrown the emphasis of treatment back on characteristics and abnormalities of the individual tumor and away from macro- or microenvironmental host factors and has targeted patients bearing certain tumor features for treatment.28

Broadly then, as framed by Schipper et al.1, the debate and models concern the extent to which, in particular, breast cancer is viewed either as a morphologic entity characterized by autonomous behavior or as a process characterized by regulatory imbalance and dynamic instability. If viewed as the former, at least when so profiled in studies of tumor genetics, then "killing the last tumor cell," as the recently reported dose-intense chemotherapy study has emphasized, is one strategy.21,22 If instead, or perhaps also, the challenges and possibilities in breast cancer treatment follow from viewing the problem as the latter (i.e., a host-environment regulatory issue), then how can these models and data direct our interventional efforts? In particular, what evidence exists that the host environment can be manipulated in ways to influence long-term outcome for a patient?

Adjuvant Surgical Oophorectomy as a Useful Regulatory Treatment
Surgical oophorectomy as adjuvant therapy for breast cancer, now a century old, can provide a dramatic example of an effective host-environment and not solely specific tumor regulatory treatment.29,30 As one kind of adjuvant hormonal therapy for breast cancer, surgical oophorectomy has been believed to confer some level of benefit for the last decade. In 1992, however, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) published data from a meta-analysis of several older clinical trials of both adjuvant surgical and radiation oophorectomy. Based on the absence of clear long-term benefits from most of these meta-analysis—included trials individually, the prevailing opinion then was that adjuvant oophorectomy had but transient favorable effects on disease-free survival.31 The conclusion of the EBCTCG meta-analysis (i.e., adjuvant oophorectomy has long-term, disease-free and overall survival benefits of magnitudes similar to those achieved by usual adjuvant chemotherapy regimens) has been more widely accepted in the last decade. At the time the results of this study were published, given the selected patient data available in the analysis, this was seen more as a hypothesis. Since then, several clinical trials have been carried out evaluating medical and surgical adjuvant ovarian function-suppression or oophorectomy, which have supported the original EBCTCG conclusion (Table 1).32–40 Increasingly it has been accepted that for premenopausal patients whose tumors show evidence of hormone receptors, adjuvant oophorectomy (i.e., ovarian ablation, or some type of ovarian function-suppression) appears comparable in efficacy to usual chemotherapy programs, and that this should be a standard therapeutic option.41,42


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  		TABLE 1. Key studies evaluating ovarian ablation, suppression and chemotherapy adjuvant treatments
 
How does oophorectomy exert its favorable regulatory effects? The usual interpretation has been that, with the prominent reductions in estrogenic hormones after ovarian suppression or oophorectomy, critical growth factors for specific tumor cells are removed and, for some tumors, the balance of growth and apoptosis favors the latter. This biologic effect in tumors was thought to be temporary, however. Thus, when long-term benefits were suggested by the EBCTCG meta-analysis, reconsideration of the likely growth pattern became necessary. The intermediate-term effects of medical ovarian suppression of limited duration (2 to 3 years) have forced reconsideration of the growth consequences of disrupting ovarian function.39 This reconsideration has been stimulated by the observation that the timing of surgical oophorectomy during the menstrual cycle appears to markedly influence long-term outcomes.30 These observations have broadened the discussion of the impact of adjuvant oophorectomy.

ADJUVANT SURGICAL OOPHORECTOMY BY MENSTRUAL CYCLE PHASE

As a secondary analysis, in a study we conducted of adjuvant surgical oophorectomy and tamoxifen, we evaluated the association of the timing of the surgical oophorectomy in the menstrual cycle and outcomes.30,40 The circumstances and details of this analysis and the results in various subgroups are critical to the credibility of a hypothesis that perioperative systemic regulation can profoundly influence long-term outcomes in women with all types of breast cancer.

In this trial, we investigated a hypothesis put forth by Badwe et al.43 that luteal phase breast surgery was associated with improved outcomes. We obtained data on the dates of last menstrual period before surgeries. Although these data were unconfirmed by observers or blood hormone studies, they appear reliable. The patients in this trial of adjuvant oophorectomy and tamoxifen had fine needle aspiration cytology alone before surgery and no chemotherapy. In previous studies, multiple biopsies and operations, mammography, and adjuvant therapies have confounded assessments of the timing of breast surgery. In the observation group treated with mastectomy only, we found timing of surgery in the follicular versus the luteal phases of the menstrual cycle had no observable impact on outcomes.30 In contrast, patients receiving adjuvant oophorectomy simultaneously with (immediately before) mastectomy operated on in the follicular phase of the menstrual cycle had poorer disease-free and overall survival than patients operated on in the luteal phase (Fig. 2). If subsets of estrogen receptor-positive and estrogen receptor-negative and progesterone receptor-positive and progesterone receptor-negative patients treated with adjuvant oophorectomy plus tamoxifen are examined, differences of borderline statistical significance are seen in disease-free and overall survival, all favoring patients in the luteal phase (Figs. 3–6GoGoGo).



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  		FIG. 2. Kaplan-Meier curves for disease-free survival (DFS) (A) and overall survival (OS) (B) in patients with operable breast cancer who were randomly assigned to mastectomy and oophorectomy on the same day, followed by tamoxifen therapy daily begun within 7 days. Patients in the follicular phase (n = 118) (solid line) were defined as those reporting a last menstrual period 1 to 14 days from the time of mastectomy. Patients in the luteal phase (n = 158) (dotted line) were defined as those reporting a last menstrual period 15 to 42 days from the time of surgery. (From Love RR, Duc NB, Dinh NV, et al. Mastectomy and oophorectomy by menstrual cycle phase in operable breast cancer. J Natl Cancer Inst 2002;94:662–9. Fig. 2.)

 


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  		FIG. 3. Kaplan-Meier curves for disease-free survival (DFS) (A) (n = 98) and overall survival (OS) (B) (n = 98) in a subset of patients with estrogen receptor-positive breast cancer who were randomly assigned to mastectomy and oophorectomy on the same day, followed by tamoxifen therapy daily begun within 7 days. Follicular phase and luteal phase definitions as for Figure 2. (From Love RR, Duc NB, Dinh NV, et al. Mastectomy and oophorectomy by menstrual cycle phase in operable breast cancer. J Natl Cancer Inst 2002;94:662–9; Fig. 4A.)

 


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  		FIG. 4. Kaplan-Meier curves for disease-free survival (DFS) (A) (n = 116) and overall survival (OS) (B) (n = 116) in a subset of patients with progesterone receptor-positive breast cancer who were randomly assigned to mastectomy and oophorectomy on the same day, followed by tamoxifen therapy daily begun within 7 days. Follicular phase and luteal phase definitions as for Figure 2.

 


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  		FIG. 5. Kaplan-Meier curves for disease-free survival (DFS) (A) (n = 90) and overall survival (OS) (B) (n = 90) in a subset of patients with estrogen receptor-negative breast cancer who were randomly assigned to mastectomy and oophorectomy on the same day, followed by tamoxifen therapy daily begun within 7 days. Follicular phase and luteal phase definitions as for Figure 2. (From Love RR, Duc NB, Dinh NV, et al. Mastectomy and oophorectomy by menstrual cycle phase in operable breast cancer. J Natl Cancer Inst 2002;94:662–9; Fig. 4B.)

 


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  		FIG. 6. Kaplan-Meier curves for disease-free survival (DFS) (A) (n = 71) and overall survival (OS) (B) (n = 71) in a subset of patients with progesterone receptor-negative breast cancer who were randomly assigned to mastectomy and oophorectomy on the same day, followed by tamoxifen therapy daily begun within 7 days. Follicular phase and luteal phase definitions as for Figure 2.

 
Subset analyses that exclude patients over the age of 44 years and with longer menstrual cycles suggest that differences in favor of luteal phase surgery are greater in younger women (Fig. 7). Younger women and women reporting shorter (<36 days) menstrual cycles were considered less likely to be having anovulatory menstrual cycles and, therefore, more likely to be producing increased blood levels of progesterone. Figure 8 shows no differences in outcome according to the phase of the menstrual cycle at surgery in a similarly defined sample of women <45 years of age treated with mastectomy alone. The figures indicate that the survival experience of women operated on in the follicular phase of their menstrual cycles is essentially no different from that of women receiving no adjuvant therapy. Figure 9 shows, as expected, significant levels of benefit from luteal phase oophorectomy and mastectomy in the highest risk axillary node-positive patients.



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  		FIG. 7. Kaplan-Meier curves for disease-free survival (DFS) (n = 180) (A) and overall survival (OS) (B) (n = 180) for a subset of patients 44 years of age or younger with operable breast cancer who were randomly assigned to mastectomy and oophorectomy on the same day, followed by tamoxifen therapy daily begun within 7 days. Patients in the follicular phase (solid line) were defined as those reporting a last menstrual period 1 to 14 days from the time of mastectomy. Patients in the luteal phase (dotted line) were defined as those reporting a last menstrual period 15 to 35 days from the time of surgery. (From Love RR, Duc NB, Dinh NV, et al. Mastectomy and oophorectomy by menstrual cycle phase in operable breast cancer. J Natl Cancer Inst 2002;94:662–9; Fig 6.)

 


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  		FIG. 8. Kaplan-Meier curves for disease-free survival (DFS) (n = 186) (A) and overall survival (OS) (B) (n = 186) in a subset of patients younger than 45 years with operable breast cancer who were randomly assigned to mastectomy and observation. Patients in the follicular phase (solid line) were defined as those reporting a last menstrual period 1 to 14 days from the time of mastectomy. Patients in the luteal phase patient (dotted line) were defined as those reporting a last menstrual period 15 to 35 days from the time of surgery. (From Love RR, Duc NB, Dinh NV, et al. Mastectomy and oophorectomy by menstrual cycle phase in operable breast cancer. J Natl Cancer Inst 2002;94:662–9; Fig. 5.)

 


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  		FIG. 9. Kaplan-Meier curves for disease-free survival (DFS) (n = 142) (A) and overall survival (OS) (B) (n = 142) in a subset of patients with axillary node-positive operable breast cancer who were randomly assigned to mastectomy and oophorectomy on the same day, followed by tamoxifen therapy begun within 7 days. Follicular phase and luteal phase definitions are as for Figure 2.

 
Whereas these analyses on the relation of last menstrual period to outcomes were secondary ones and the results of significance testing must be considered nominal, the methods are rigorous, most trial participants were included in these analyses, and no evidence of selection bias in the main study exists. In fact, conservative biasing, if anything, is seen against the results found and shown.44 Specifically, the definitions of follicular and luteal phases we used led to larger numbers of luteal cases, many of whom were actually in follicular or anovulatory phases. Thus, the follicular phase main sample (Fig. 2 results) is likely composed of all physiologically follicular cases, whereas the luteal phase main sample includes both luteal and follicular or anovulatory cases.

The four groups in the main study sample—mastectomy-alone luteal phase results (not shown), mastectomy-alone follicular phase results (not shown), mastectomy and oophorectomy luteal phase results (Fig. 2), mastectomy and oophorectomy follicular phase results (Fig. 2)—did not differ in prognostic factors30 (Table 1). Statistical differences by menstrual cycle phase were seen only for the patients treated by mastectomy and oophorectomy. These four main study groups were defined by a prerandomization variable: the first day of the last menstrual period and, thus, these groups should not be subject to selection bias. Statistical tests applied to these groups, therefore, are valid because of the randomization. Multivariate analyses provided further assurances that the results from the four main study groups were not explained by subtle differences in prognostic factors. Data from this study are internally concordant: the four intervention or menstrual cycle phase comparisons present a consistent picture; different definitions of the follicular and luteal phases of the menstrual cycle give qualitatively similar results; the strength of the apparent benefit for patients with surgical oophorectomy during the luteal phase (and not for patients having mastectomy only) increases when likely anovulatory patients (>44 years) are excluded (Figs. 7, 8Go); and the luteal phase benefit is strongly apparent in an axillary node-positive subset (Fig. 9).

These data from a clinical trial are startling in two major respects: First, they suggest a long-term impact from a regulatory change or difference imposed at the time any primary breast tumor is removed. In regularly cycling women (Fig. 7), the 5-year, disease-free survival difference by menstrual cycle phase approaches 30%. This is a relative risk reduction of 0.62 (luteal vs. follicular oophorectomy), a magnitude exceeding that suggested for any adjuvant therapy for breast cancer. Second, this apparent regulatory effect, which first reflects ovarian hormonal level changes, is not confined to estrogen- or progesterone-positive, tumor-bearing patients; hormone receptor-negative, tumor-bearing patients appear to be similarly benefited by luteal phase oophorectomy (Figs. 5 and 6Go). Indeed, the major beneficial levels from luteal phase surgery, seen in Figures 7 and 9Go, further reflect this apparent global benefit.

Mechanisms, Models, and Implications for Breast Cancer Therapies
In support of a major role for regulatory factors in growth of breast cancer, data from adjuvant oophorectomy during the luteal phase are compelling because they come from a clinical trial of treatment in women, the differences found are so great, and the data internally are concordant. Suggesting possible molecular and signaling mechanisms that could account for the differences observed is not difficult: a myriad of pathways appear to be involved in the full spectrum of tumor shedding, arrest, tissue migration, and initiated and sustained growth of micrometastases, which can be influenced by the abrupt changes in ovarian hormone levels after surgical oophorectomy.45 Whereas systemic changes can be critical, those that have a specific impact on the microenvironments of small metastases may be most critical; recent data emphasize the interrelationships of tumors and their immediate environments.46 In usual circumstances, malignant cells dominate these microenvironments. We hypothesize that the signaling following a luteal phase oophorectomy interrupts this process and keeps micrometastases dormant or kills them. More specifically, we propose a progesterone trigger hypothesis (Fig. 10). Our hypothesis is based on the underlying observations that the half-life of progesterone is short (i.e., 20 to 30 minutes) and that progesterone levels control systemic levels of other critical humeral and cytokine factors (e.g., vascular endothelial growth factor).47,48 These changes in downstream factors cause breast cancer micrometastases to die—an extreme progesterone withdrawal response. Additionally, micrometastases can be particularly vulnerable to such macro- and microenvironmental changes because of the removal of the primary (parent) tumor immediately after the oophorectomy,23,24 which can partially explain the observation about luteal phase oophorectomy. In a murine melanoma model, Vantyghem et al.49 reported that the estrous cycle led to marked differences in organ-specific metastases. Increasing support is given that stromas reciprocally promote tumor growth and development.50 What is striking about the observation of the effects of luteal oophorectomy is the suggestion that systemic acute changes or regulation can have such major long-term consequences. Adjuvant chemotherapy programs have subacute courses, and hormonal therapies have been considered to exact their benefits in proportion to their duration and through direct effects on sensitive tumor cells themselves.



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  		FIG. 10. Progesterone trigger hypothesis.

 
The breadth of clinical observations, the disease models, and these data on luteal phase oophorectomy seem to suggest that major durable changes in tumor metastases growth occur through other than specific cell kill or targeted therapies. The first peak of recurrences at 2 to 3 years, the premenopausal axillary node-positive recurrence pattern, and data on the perioperative luteal phase intervention suggest that a focus on perioperative first surgical treatment is worthwhile.4,27 Specific clinical trials that seek to replicate the data on luteal phase oophorectomy are warranted. In these studies, besides usual disease-free and overall survival outcomes, evaluation of differences in signaling pathways and, in the adjuvant studies, observation of the rates of recurrences over time will be critical. We propose a portfolio of four clinical trials in breast cancer (Table 2). As shown in this table, these are of modest sizes because the suggested benefits of luteal phase oophorectomy are large. These trials address different practical clinical questions. Trials 1 and 2 differ in looking at patient groups having or not having simultaneous primary breast surgery. Although we were unable to show a benefit associated with menstrual cycle phase in patients treated in our study with mastectomy alone,30 we cannot exclude the possibility of interactive effects of breast and ovarian cancer surgeries. The therapeutic question in trial 1 is of compelling interest to the increasing numbers of young and poorer women in the world needing effective and cost-effective adjuvant therapy for breast cancer. The therapeutic question in trial 2 is more germane to younger women in countries with greater resources who are currently routinely given adjuvant chemotherapy as their initial postsurgical treatment. Trial 3 addresses the provocative data suggesting that luteal phase oophorectomy can act through secondary hormonal effects on angiogenic or cytokine proteins. Finally, trial 4 addresses the practical issue of better, survival-increasing treatment for women with metastatic disease. Whereas the ultimate efficacy of luteal phase ovarian surgery can be in the treatment of micrometastases, which are of obvious importance to patients with clinically evident metastatic disease, demonstrating a salutary effect on survival in patients with evidence of metastatic cancer would be very useful.


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  		TABLE 2. Portfolio of proposed clinical trials in breast cancer evaluating hypotheses about systemic disease regulatory effects of surgical oophorectomy in the luteal phase of the menstrual cycle (Love and Niederhuber)
 
Perhaps, some biologic studies in other solid tumors investigating the changes in angiogenic proteins and cytokines that accompany primary tumor removal under different hormonal conditions should also be considered.

CONCLUSIONS

Laboratory, tumor cell growth modeling, and clinical data suggest that greater consideration should be given to understanding and controlling the internal milieu of patients with breast cancer. Optimal results for patients, particularly those for whom more expensive diagnostic and therapeutic options are not available, may be achievable with timed host-environment interventions. Optimal control of breast cancer appears to involve more than control of the individual tumor.

FOOTNOTES

Supported in part by NIH/NCI CA64339.

Increasing data support the concept of breast cancer as a problem of host regulatory imbalance. Information about surgical oophorectomy done at different times in the menstrual cycle suggest that secondary cytokine effects may have powerful consequences for micrometastases.

Received for publication February 17, 2004. Accepted for publication June 8, 2004.

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