timing of surgery with regard to the menstrual cycle in women with primary breast cancer

BREAST CANCER MANAGEMENT 0039-6109/99 $8.00 + .OO

TIMING OF SURGERY WITH REGARD TO THE MENSTRUAL

CYCLE IN WOMEN WITH PRIMARY BREAST CANCER Rajendra A. Badwe, MD, MS, Indraneel Mittra, PhD,

and Rohini Havaldar, BSc, DCM

HORMONE LEVELS DURING THE MENSTRUAL CYCLE

The menstrual cycle is a rhythmic preparation for extrusion of ovum and subsequent pregnancy if the ovum is fertilized. The cycle is under the influence of the hypothalamic gonadotrophins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), that regulate the release of the sex steroid hormones estrogen and progesterone from ovarian interstitium. Estrogen and progesterone in turn prime ovarian follicles and induce ovulation (Fig. 1). Levels of all four hormones are low for the first 4 or 5 days after the first day of menstrual flow. This is the early period of follicular development. Estrogen levels gradually rise during the next 3 to 4 days and peak rapidly by the twelfth day, one day before the LH and FSH peak. Ovulation occurs 24 to 36 hours after the LH peak, on approximately the fourteenth day of the menstrual cycle. The second peak of estrogen levels occurs about one week after ovulation and is opposed by a progesterone peak. Progesterone also increases slightly in concentration corres- ponding to the LH surge. Hence estrogen remains unopposed during the follicular phase, up to day 12; during the rest of the cycle, progesterone opposes the effects of estrogen.70

THE FIRST REPORTS

The effect of the timing of surgery during the menstrual cycle on breast cancer mortality has been debated since the first report by Hrushesky et a1.32 In

From the Clinical Research Secretariat (RH), Breast Unit (RAB, IM, RH), Tata Memorial Centre, Parel, Mumbai, India

SURGICAL CLINICS OF NORTH AMERICA

VOLUME 79 * NUMBER 5 OCTOBER 1999 1047

1048 BADWE et a1

Figure 1. Variation in serum concentration of gonadotrophins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) and sex steroid hormones (estrogen [ER] and progesterone [PgR]) during the menstrual cycle. Day 0 is the first day of the last menstrual period, and day 14 coincides with ovulation.

1989, They reported on the timing of surgery during the menstrual cycle in 41 women with operable breast cancer. Ten-year survival was 95% for the 22 women whose tumors were excised during the periovulatory period (7 to 20 days after the first day of menstruation), and 79% for the 19 women whose tumors were resected during the perimenstrual period (within 7 days before or after the first day of menstruation, days 0 to 6 and 21 to 36 of the menstrual cycle). The investigators’ selection of intervals was based on murine experiments. Ratajczak et a149 had found that the timing of the resection of transplantable breast tumors within the murine estrous cycle influenced the incidence of lung metastases and mortality. Resection of tumors during the proestrous phase was associated with a two and half times better survival rate than resection during the metestrous phase. The proestrous phase in mice is characterized by a surge in the levels of luteinizing and follicle-stimulating hormones with a background of progesterone and estrogen. The proestrous phase in mice corresponds approximately to the periovulatory period (7 days on either side of putative time of ovulation, that is, 7 to 20 days after the first day of menstruation) in the human menstrual cycle. The late luteal phase in mice was also associated with the highest level of splenocyte natural killer (NK) cell activity and interleukin-2 (IL- 2) production.

The hypothesis that the timing of breast cancer surgery during the menstrual cycle might affect outcome was subsequently refined by Badwe et a17 who suggested that resection of tumor during the phase of unopposed estrogen may be deleterious for survival. The authors compared the survival of 75 women on whom surgery was performed during days 3 through 12 of the menstrual cycle, when estrogen is unopposed, with that of 174 women who had resection during the remainder of the menstrual cycle (days 0 through 2, and 13 through 32). The overall survival rate at 10 years was 54% for the women whose breast

TIMING OF SURGERY WITH REGARD TO THE MENSTRUAL CYCLE 1049

cancer was resected during the unopposed estrogen phase compared with 84% for the other women ( P < 0.001). On multivariate analysis, the number of metastatic lymph nodes, timing of surgery, histologic type, and patient’s age were significant determinants of survival. Subsequently, Senie et a15‘j analyzed the results of patients whose breast cancers were resected during the follicular or luteal phase of the menstrual cycle, respectively. For patients whose tumor was excised during the follicular phase, disease-free survival was 57% (n = 141), compared with 71% (n = 142) for women whose tumor was excised during the luteal phase ( P < 0.02). They also analyzed the survival rates after assessing outcomes according to Hrushesky’s intervals, but the results obtained were contrary to those determined by Hrushesky’s group.

THE HYPOTHESIS

The hypothesis that the timing of surgery during the menstrual cycle can affect survival in breast cancer carries two distinct postulates. The first is that the hormonal milieu in the host can modulate the metastatic potential of breast cancer. The second is that events at the time of surgery can influence survival. It may be worthwhile to examine the evidence for and against each of these postulates and then decide whether a prospective randomized study is justified.

HORMONES AND BREAST CANCER SURVIVAL: CLINICAL EVIDENCE

A deleterious effect of unopposed estrogen on survival in breast cancer patients was deduced from the poor survival rates of perimenopausal women with breast cancer.7, 12, 38 The natural cessation of ovarian function is associated with repeated anovulatory cycles before a true postmenopausal state is reached. During these anovulatory cycles, estrogen is unopposed much more frequently than in premenopausal women, and the levels of unopposed estrogen in these women are much higher than in postmenopausal women.

If unopposed estrogen is responsible for the deleterious effect on survival, then the effect should be evident whenever women experience this state. In premenopausal women estrogen is unopposed during the follicular phase of the menstrual cycle, days 3 through 12 (see Fig. 1). A meta-analysis (using a fixed- effect model) of the 37 published studies* that allowed comparison of surgery during the unopposed estrogenic phase with surgery during the opposed estrogenic phase showed a relative reduction (RR) of 15% with confidence intervals (CI) k 4 (2P = 0.0003) (Fig. 2) in favor of women operated on during the luteal phase. The test for trend according to year of publication is not statistically significant, and the test for heterogeneity is significant (P < 0.001). In 38, 67, 69 of these 37 studies, the circulating serum progesterone and estrogen levels were measured one or two days before and after surgery. All three studies indicated that circulating progesterone was protective against metastasis and death. The overall relative reduction was up to 53% ? 32 (2P < 0.001). The test of heterogeneity and trend was not statistically significant ( P > 0.2) (Fig. 3).

Perimenopausal and postmenopausal women are more likely to have unopposed estrogen than premenopausal women. In premenopasual women, at least

“References 4, 5, 13-16, 19, 25-27, 30, 32, 33, 35, 37, 39, 40, 43, 44, 46-48, 51, 53, 55-60, 63, 65-69, 71

1050 BADWE et a1

BADWE 1 HRUSHESKEY GELBER POWLES 1 POWLES 2 VILLE SAINSBURY RACETH SENIE LOW BADWE 2 STEWART SICURDSSON CNANT MARQUES NATHAN SPRAl-r STONELAKE CORDER S M D VERONESI JACER SAUERBREI KROMAN WOBBES MINCKWITZ D'EREDITA HOLLI KUREBAYASHI TSUCHIYA LEVINE CHANG VANEK COLDHIRSCH MONDINI ZHANC CALLIES

OVERALL e 1

Figure 2. Meta-analysis of 37 studies dealing with timing of surgery during the menstrual cycle. Information content of the study (squares), which is proportional to the variance (observed-expected) of value of events for that study. Ninety-five percent confidence intervals (CI) (lines). Overall effect and its 95% CI (diamond). n = 10,476. Odds red n: 15% +. 8. 2P = 0.0003. Results from two distinct cohorts of patients (1 and 2). (Data from references 4, 5, 13-16, 19, 25-27, 30, 32, 33, 35, 37, 39, 40, 43, 44, 46-48, 51, 53, 55-60, 63, 65-69, and 71 .)


BADWE

VILLE

WOBBES

-m- I

I I

Figure 3. Meta-analysis of studies based on actual estimation of serum progesterone concentration. Information content of the study (squares), which is proportional to the variance (observed-expected) of value of events for that study. Ninety-five percent confidence intervals (CI) (lines). Overall effect and its 95% CI (diamond). n = 388. Odds red n: 53% f 32. 2P < 0.001, (Data from references 8, 67, and 69.)

50% of the time, estrogen will be opposed by progesterone. A meta-analysis of 22 published studies examined the effect of menopausal status or age at diagnosis on s~ rv iva l .~ Fifteen of the 22 studies revealed better survival in premenopausal (or women under age 50), and 7 showed equivocal results. The overall collated evidence showed a significantly higher survival rate among premenopausal women (odds ratio [OR] = 0.76, CI = 0.74 to 0.78, 2P < 0.0000001) with an odds reduction of 24% f 1.

In postmenopausal women, the source of estrogen is the enzyme aromatase in body fat, which converts precursors of estrogen into active hormoneJs Obese women produce more estrogen than thin women.62 Hence, if unopposed estrogen is deleterious for survival of breast cancer, thin women should experience a better breast cancer survival rate than obese women. A meta-analysis of 18 studies6 addressing obesity and breast cancer survival supported a quantitative inverse relationship between them. In 12 studies, nonobese women had better survival rates than obese women; 6 studies showed equivocal results. None of the studies showed that obese women had better survival rates than thin women. The relative reduction for thin women was 35.6 +- 3.7, 2P < 0.000001.

HORMONES AND BREAST CANCER SURVIVAL: LABORATORY EVIDENCE

Metastasis is a cascade of sequential steps involving multiple tumor /host interactions. Metastasis involves the migration of tumor cells from their primary site to a distant site, in adequate numbers to establish a colony. The first process of migration requires the digestion of surrounding tissue by tumor cells to gain access to lymphatic and blood vessels. Proteases bestow this invasive ability upon tumor cells. At least two proteases are known to be modulated by estrogen in vitro. CathepsinssO and u P A ~ ~ are upregulated in breast cancer cells by estrogen, and the ability of the primary tumor to secrete these two proteases has an inverse correlation with survival in breast cancer.34, 50 Saad et alS2 recently re-

1052 BADWE et a1

ported an increased expression of cathepsin L and matrix metalloproteinase (MMP-9 and MMP-2), and downregulation of tissue inhibitors of metalloprotei- nases TIMP-1 and TIMP-2 in tumors excised during the follicular phase of the menstrual cycle. The invasive ability of the primary tumor was pathologically evaluated by the presence of vascular and lymphatic invasion (LVI). The incidence of LVI has been found to correlate strongly with the unopposed estrogenic phase in premenopausal women2 and has a direct correlation with obesity as assessed by body eight.^ Tumor cells under the influence of estrogen secrete proteases, thus increasing their invasive ability. The products of digestion by protease would usurp ionic calcium as the result of pH changes; this usurpation would reduce the binding capacity of calcium dependent E cadherin,6l allowing cells to gain access to lymphatic and vascular channels and be carried to distant sites. Many other prognostic factors of operable breast cancer have also been shown to be unfavorably modulated by estrogen. These include epidermal growth factor (EGF)42 and cyclin D,' which induce proliferation of tumor cells and allow them to nestle at distant sites.

Under the influence of unopposed estrogen, not only do tumors manifest increased ability to invade and proliferate, but the host environment is also permissive. The NK cell activity is at its lowest level during the follicular phase of the menstrual cycle.29

EVENTS AT THE TIME OF SURGERY AND SURVIVAL: CLINICAL EVIDENCE

The conclusion that the hormonal milieu during the menstrual cycle might influence outcome depends on the assumption that events at the time of surgery can affect the long-term survival of breast cancer. Data from randomized trials, modelling studies, and the laboratory suggest that the event of surgery itself influences the onset or autonomy of distant micrometa~tases.~ In sharp contrast with rigorous testing of radiation therapy and chemotherapy that has been undertaken in randomized trials,I7 the effect of surgery on survival has never been tested. The best experiment to test the surgical dissemination/autonomy (SDA) hypothesis would be to compare surgery with no surgery, but such a trial would be unethical.

Randomized trials of screening offer the next best opportunity to test the SDA hypothesis. In these trials, the event of surgery is delayed in the control group by about 18 to 24 months (lead-time), compared with the screened group; hence, the first few years of follow-up should offer a comparison between surgery and natural progression in vivo. Because the majority of patients in both groups eventually undergo surgery, a comparison can be made between early surgery and late surgery. The conventional theoryZ1 holds that the event of surgery does not influence the natural history of cancer and that metastasis is determined by the presence of unrecognized micrometastases before diagnosis. The conventional theory would predict identical numbers of deaths for the first several years in both groups. On the other hand, if dissemination/autonomy were to occur at the time of surgery, it would lead to excess deaths in the screened group during the first few years. A meta-analysis18 of annual cumulative mortality of all the published screening trials in breast cancer revealed that there is indeed an excess mortality in the screened group during the first few years. In women above the age of 50, the excess mortality in the screened group was seen only during the first year, but in younger women it persisted for the first 7 years after randomization (Table 1). An excess mortality in the screened


Table 1. META-ANALYSIS OF DATA FROM SCREENING TRIALS FOR BREASTCANCER

Ratio of Average Cumulative Mortality:

Screened versus Control

y after Randomization Age < 50 y Age > 50 y

1 2 3 4 5 6 7 8 9

10

1.67 1.05 1.88 1.31 1.22 1.15 1.02 0.98 0.92 0.90

1.62 0.69 0.76 0.77 0.66 0.65 0.69 0.67 0.67 0.68

Ratio of cumulative mortality in screening versus control by years of randomization showing excess deaths in screened group up to seventh year in women younger than 50 years and for the first year in women older than 50 years. (Datafrom Elwood JM, Cox B, Richardson AK The effectiveness of breast cancer screening by mammography in younger women. Online J Curr Clin Trials. Doc 32, 1993.)

group was evident in both of the randomized trials of screening for lung cancerz4, 36 beyond 6 years of follow-up. In the United Kingdom colon cancer screening trial,"I the group that received biennial screening for occult blood in stool experienced excess deaths compared with the control group during the first 10 years. All the published screening data thus suggest that early surgical intervention has a detrimental prognostic effect on the natural history of cancer in the first few years. A careful analysis of the breast cancer screening data reveals that the ultimate reduction in deaths from breast cancer is the net effect of early excess mortality in the screened group (a comparison of surgery versus no surgery) and later saving of lives (a comparison of early surgery versus late surgery).

Modelling studies have also challenged the conventional theory of biological pre-determinism and have led to the alternative paradigm of the importance of events at the time of surgery. Conventional belief assumes that the presence of pre-existing micrometastases is related to the size of tumor at diagnosis. Early diagnosis improves survival if patients can be treated before the onset of micrometastases. Those who harbor micrometastases have smaller volume (younger) occult disease if diagnosed early than if diagnosed later. If this is true, then patients with T1 tumors (< 2 cm) should enjoy a lead-time equivalent to the transition from T1 to T2 (2 to 5 cm). This, however, could not be demonstrated in a study from the United Kingdomlo based on breast cancer data from the King's/Cambridge trial and from Guy's Hospital. Data for breast cancer patients from Tata Memorial Centre, Parel, Mumbai, India, showed similar results.

Life-table analysis of the Tata Memorial Centre data showed the expected difference in survival between patients with T1 and T2 tumors: relapse-free survival for distant metastases (RFS) at 5 years was 72% for patients with T1 tumors and 52% for those with T2 tumors. Median survival was not determined for women with T1 tumors; it was 7 years for women with T2 tumors (P < 0.0001) (Fig. 4). The time to relapse was the same for T1 and T2 tumors; the difference was in the number of patients with relapse (Fig. 5). There was no

1054 BADWE et a1

1 .o

0.9

0.8

0.7

0.6

0.4.

0.3.

0.1 o'21 0 1 2 3 4 5 6 7 8

Years

Figure 4. Life-table analysis stratified by tumor size. Median survival for patients with T2 ( n = 1660) tumors is 7 y, whereas median survival is not reached in those with T1 (n = 855) tumors. P = 0.000.

demonstrable lag in the onset of relapse in the T1 group. The advantage of lead- time for the estimated post-treatment survival of patients with T1 tumors was not discernible. This lack of difference in the time to relapse was further con- firmed by examining the life-table curves of those who relapsed, which showed a median RFS of 22 months for patients with T1 tumors and 21 months for those with T2 tumors (P = not statistically significant) (Fig. 6). Thus, it is not that smaller tumors recur late and larger tumors recur early, but smaller tumors recur in lesser numbers but over an identical time span as larger tumors. Mueller has drawn a similar conclusion based on Connecticut Tumor Registry

EVENTS AT THE TIME OF SURGERY AND SURVIVAL: LABORATORY EVIDENCE

Laboratory evidence for surgical dissemination of tumor cells has been available since the beginning of this century. Tyzzer@ showed it in animal studies, Fisherz3 in portal vein blood samples from colon cancer patients, and recently, with the greater precision possible through polymerase chain reaction (PCR) technology, surgical dissemination has been demonstrated in prostatezo and breast cancer." From animal experiments Fisher et alZ2 suggest outgrowth of metastasis after the event of surgery and postulate that it may be related to a perturbation of the balance between inhibitory and stimulatory factors elabo- rated by the primary tumor. Folkman et al3I showed that the removal of a


0.2

E w 0.1 m I

0 0 1 2 3 4 5 6

Years

7 8

Figure 5. Half-yearly hazard rates for relapse stratified by tumor size. There is a difference in the magnitude of hazard, but the rate is identical on time scale for patients with T1 (n = 855) and T2 (n = 1660) tumors.

primary Lewis lung carcinoma tumor in mice resulted in the exponential growth of its lung metastases. The presence of primary tumor elaborating angiostatin, which had an antiangiogenic property, suppressed outgrowth of micrometastases.

SUMMARY

There is sufficient evidence to support both the hormonal influence on the outcome of breast cancer surgery and the SDA hypothesis. The SDA model produces a paradigm shift in the understanding of the natural history of breast cancer. It offers opportunities to try modifying a tumor’s biological potential for metastasis (e.g., by tamoxifen, progesterone, antiprotease, or angiostatin) in the neoadjuvant setting. It continues to support the beneficial effects of detection and surgery early in the natural history of disease. It would be worthwhile to plan a trial comparing standard practice (unplanned surgery as the patient enrolls) with surgery during the luteal phase of the menstrual cycle in premenopausal women. Another possibility, based on studies of circulating progesterone, would be to compare primary progesterone treatment (for 4 to 10 days before surgery) with standard practice. Such a trial of primary progesterone is already under way, conducted by the Indian Breast Group. More than 200 patients have enrolled so far. The details of the trial are available from Clinical Research

1056 BADWE et a1

1 .o

0.8

- z z

5

‘z 0.6

0) > m = 0.4

0

.- c

0.2

0

a

1 2 3 4 5 6

Years

Figure 6. Life-table analysis stratified by tumor size for patients who have relapsed. The rate of relapse is similar in both groups (TI [n = 8551 and T2 [n = 16601). P = not significant.

Secretariat, Tata Memorial Centre, Parel, Mumbai, India (e mail: tmho3k2bom2.v- snl.in).

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Address reprint requests to

Rajendra A. Badwe, MD, MS Breast Unit

Tata Memorial Centre Parel, Mumbai

India 400012

e-mail: [email protected]

timing of surgery with regard to the menstrual cycle in women with primary breast cancer

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