Review

Does the timing of breast cancer surgery in pre-menopausal women affect clinical outcome? : an update

Anushka Chaudhry¹ , Michael L Puntis¹ , Panos Gikas¹ and Kefah Mokbel^1,2

¹  Dept. of Breast Surgery, St George's Hospital, University of London, Tooting, UK

²  The Princess Grace Hospitals, 42-52 Nottingham Place, London W1M 3FD, UK

author email corresponding author email

International Seminars in Surgical Oncology 2006, 3:37doi:10.1186/1477-7800-3-37

The electronic version of this article is the complete one and can be found online at: http://www.issoonline.com/content/3/1/37

Received:	27 August 2006
Accepted:	1 November 2006
Published:	1 November 2006

© 2006 Chaudhry et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

There is some evidence that breast cancer surgery during the luteal phase in pre-menopausal women is associated with a better clinical outcome, however the evidence for this is still equivocal.

In this paper, after summarizing the normal physiology of the menstrual cycle, we examine how such an association may occur and provide a comprehensive review of the literature in the area.

Background

Breast cancer is a significant disease affecting over 41,000 women each year in the UK [1]. One in three of these patients are younger than 55 when the diagnosis of breast cancer is made, and almost all will undergo wide local excision or mastectomy.

Amongst the significant sub-group of pre-menopausal patients the tumour is likely to be subject to cyclical fluctuations in the hormonal milieu. Any impact on survival from the coordination of surgery with the phase of the menstrual cycle should therefore be explored and changes to clinical practice could be implemented as indicated.

There is some evidence that breast surgery during the luteal phase in pre-menopausal women is associated with better outcomes, however the evidence for this is not consistent (see table 1)

Although there are data suggesting that hormonal factors influence tumour characteristics and behaviour, however there is no definitive evidence that surgery should be scheduled to avoid the follicular phase. A number of studies have investigated the biochemical and clinical response of tumours resected during the various phases of the menstrual cycle [2-4]. In addition, the hormonal status of a patient may have an impact on intra-operative factors such as bleeding [5], and may be also significant for the timing of core biopsies [6].

In this paper, after summarizing the normal physiology of the menstrual cycle, we examine how such an association may occur and provide a comprehensive review of the literature in the area.

Normal physiology

The menstrual cycle is a rhythmic preparation for extrusion of an ovum and subsequent pregnancy if the ovum is fertilized. The events are under the influence of the hypothalamic gonadotrophins follicle stimulating hormone (FSH) and luteinising hormone (LH) that regulate the release of sex steroid hormones estrogen and progesterone from the ovarian interstitium. These in turn prime the ovarian follicles and induce ovulation. Assuming that Day 0 is the first day of menstrual flow of the last menstrual period, all hormones are low for the first 4–5 days. This is the early period of follicular development. Estrogens gradually rise for the next 3–4 days followed by a rapid peak by 12^th day which is the day before the LH and FSH peak. Ovulation then occurs 24–36 h after the LH peak by about the 14^th day. The second peak of estrogen occurs about a week after ovulation and is opposed by a progesterone peak. Furthermore, progesterone shows a small increase in concentration corresponding to the LH surge. Hence estrogen remains unopposed during the follicular phase, up to Day 12, while during the rest of the cycle progesterone opposes the action of estrogen.

The hypotheses

In 1989 Hrushesky et al. were the first to propose that premenopausal patients with breast cancer who underwent surgery during the luteal phase of the menstrual cycle had higher disease-free and overall survival rates than did patients operated on during other phases of the cycle [7]. It is indeed an intriguing aspect of the treatment of breast cancer that the timing of breast surgery, in relation to menstrual cycle phase and hence hormonal status, might influence the natural history and prognosis of the disease. The biological-endocrinological basis for this is two-fold:

Firstly, in the follicular phase, estrogens reduce immune activity, phagocytic activity and circulating levels of IL-2 therefore potentially increasing metastatic potential of breast cancer cells [8]. At the same time they stimulate the activity of insulin-like growth factor (IGF), which has been proven in several studies to have an important mitogenic effect on breast cells [9-11]. Furthermore, angiogenesis, a process vital for the progression of many tumours and hence for their ability to metastasise, is favoured by high circulating levels of estrogens since they promote expression of vascular endothelial growth factor (VEGF) [12,13].

Secondly, in the luteal phase the increase in circulating levels of endogenous progesterone may modulate the proliferation of normal and neoplastic breast tissue and increase intercellular cohesion thereby reducing metastatic potential [14,15]. Progesterone also acts to regulate the IGF1 (pro-mitotic effect)/TGFb (anti-mitotic effect) balance. Moreover progestogens act to reduce the number of estrogen receptors expressed on breast cells hence limiting estrogenic stimulation and as a result promoting breast cell apoptosis [16].

Excision of tumours in the presence of unopposed oestrogen has been reported to be associated with improved survival. This was initially suggested by the better outcomes of peri- and post-menopausal patients. Thin patients, with less peripheral aromatase, have lower oestrogen compared to obese patients [17]. An improved outcome in these groups has been demonstrated in meta-analysis in both pre and post menopausal patients [18] but this does not prove causation. Furthermore, many patients in these groups may have compounding factors causing the variation in survival.

It has been demonstrated that there is a reduced breast tumour growth during the pre or peri-ovulatory phases, but the tumour then increases in size during the post-ovulatory phase, before shrinking back towards the original dimension. In animal studies, mice with faster cycles have slower tumour growth rates. This correlation has even been demonstrated in animal models of non-hormone dependant tumours (sarcoma) [19].

Increased adrenergic immunosuppression

During the menstrual cycle, fluctuation in hormone levels produce a modulation of adrenergic mechanisms and through this NK cells responsible for metastasis control become suppressed secondary to increased adrenergic tone during the follicular phase [20]. Animal studies have also confirmed this correlation between NK metastasis suppression and adrenergic modulation during oestrous, which can be increased with an exogenous beta agonist [21].

Vascular endothelial growth factor

In the female reproductive system angiogenesis occurs as a normal process and is essential for normal tissue development. In the ovary new blood vessel formation facilitates oxygen and nutrient delivery and allows the transfer of hormones to targeted cells, ovarian follicles and the corpus luteum have been shown to produce several angiogenic factors, of which vascular endothelial growth factor (VEGF) is thought to be paramount. VEGF levels fluctutate within the breast with greater concentrations occurring during the luteal phase [22], interestingly there is no evidence for a corresponding fluctuation in serum levels [23]. This modulation of proangiogenic cytokines in the breast may contribute to the reduced potential for metastasis in tumours resected during the luteal phase [22-24].

Tumour epidermal growth factor

A prospective study of premenopaual women measured the concentrations of oestrogen, porlaction, progesterone, tumour epidermal growth factor and tumour epidermal growth factor receptor. While levels of tumour epidermal growth factor remained constant EGFR levels peaked during the follicular phase [25]. This cyclical up-regulation may contribute to the worse prognosis potentially associated with surgery during this phase. Other studies have demonstrated that the EGF receptor is localised in the epithelial cells during the luteal phase [26].

Other factors

Surgery for benign disease such as mammaplasty, associated with reduced intraoperative bleeding and avoidance of a post-operative drain if carried out during the periovulatory phase [5]. Increased tumour vascular invasion and Her-2 expression during the follicular phase ans regulation of matrix metallo-proteinases (MMP 2 & 9) and MMP tissue inhibitors (TIMP-1 & 2) are also potential factors [27-29].

Review of the literature

In the following paragraphs we will attempt to review the literature, so far published on this intriguing hypothesis, and therefore identify the clinical implications that such a hypothesis has in relation to the treatment of breast cancer. There has been no comprehensive systematic review of literature since 2001, despite recent published evidence in this area.

The relationship between the menstrual cycle and surgical outcome was first described by Hrushesky in 1989 [7]. Based on a retrospective study of 44 patients, it was postulated that surgery carried out on premenopausal patients during the luteal phase confers higher disease free survival (DFS) compared to patients who underwent surgery at other times.

In 1991 Badwe et al [27], suggested that unopposed oestrogen may be associated with increased mortality, with a 10 year survival rate of 54% in the patients whose surgery took place during days 2–13, compared to 84% in those undergoing surgery between days 0–2 and 13–32.

A large meta-analysis using a fixed effect model of 37 published studies (n = 10476) was conducted in 2000 [28] and demonstrated a 15% (+/- 4%) increase in survival when tumours were resected during the luteal phase (p = 0.003), however three further studies [29-31] have been carried out since then, adding significantly to the body of evidence in this field.

In 2002, a retrospective analysis of prospectively collected data and serum samples from 249 pre-menopausal patients undergoing resection of breast tumours showed that in both node positive and node negative tumours, the 10 year survival is improved by carrying out surgery during the luteal phase which was defined by both last menstrual period (LMP) and serum progesterone [29]. The 10-year survival for node positive cases undergoing follicular phase surgery was 33% compared with 78% in those having surgery at other times of the menstrual cycle.

Conversely, a prospective study of 360 pre-menopausal patients, published in 2001, using hormonal assays to time the menstrual phase demonstrated no prognostic influence of coordinating surgery with the luteal phase [30]. Furthermore, a more recent small study of 36 patients showed that the recurrence rate and relapse-free survival were not significantly different with the menstrual timing of surgery [31]. However, patients with early breast cancer undergoing surgery during the follicular phase and those with advanced breast cancer resected during the luteal phase appeared to show better prognosis than corresponding controls operated during the other phases.

Table 1 summarises the key studies in this field including several studies [32-44] already used in the 2000 meta-analysis [28].

Discussion

There is clearly a controversy surrounding the most appropriate timing of breast cancer surgery and there is inconsistent evidence supporting the notion that resection during the luteal phase improves outcome. Twenty-two out of the 40 studies published were in favour of luteal phase surgery compared with 9 studies in favour of follicular phase surgery [28]. The remainder of studies (n = 9) showing no significant difference between the two phases. However breast cancer amongst pre-menopausal women is such a critical topic that even modest advantages in outcome should be exploited.

Many of the initial studies in this field were undertaken retrospectively and often relied on inaccurate assessment of the hormonal status of the patient. Using the LMP to define the cycle phase is thought to be inaccurate since factors such as peri-operative stress and the impact of a recent diagnosis of breast cancer may result in disruption of the normal menstrual cycle or even an anovulatory cycle. However recent studies have been conducted prospectively and with sound methodology, relying on serum hormone analysis to define the menstrual phase in addition to the LMP and have added significantly to the available data regarding the appropriate timing of breast surgery.

There is still discordance between studies and well-conducted prospective studies have provided evidence, both for and against, rescheduling surgery to the luteal phase. Meta-analysis [28] has demonstrated that luteal phase surgery leads to improved survival and this policy has been already adopted in some centres especially in node positive, and hormone receptor positive tumours. However this meta-analysis should be interpreted with extreme caution since it has significant inherent limitations including the presence of significant heterogeneity between studies, publication bias, the lack of defining criteria for study inclusion and the lack of adjustments for confounders and covariates.

Rescheduling surgery to coincide with the luteal phase would appear to be a simple intervention that can be considered in order to improve outcome, however there are further considerations. If scheduling surgery is dependant on the hormonal status of the patient then the available window for surgery becomes more limited, which will place increased logistical demands on the unit and surgeons performing breast cancer surgery, it is even possible that surgery may have to be delayed while waiting for the appropriate phase.

While studies vary in their conclusions, it may be prudent to defer the large scale rescheduling of breast cancer surgery until a sound biological hypothesis is defined, and corroborated by ongoing randomised controlled trials that use biochemical testing to accurately define the cycle phase. Furthermore, trials examining the potential role of neo-adjuvant endocrine therapy to counteract unopposed oestrogen during the follicular phase are required.

In addition to the cyclical variation in cell cohesiveness, growth receptors and angiogenesis in tumours, there are a number of hypotheses that may account for the potential difference in survival. This underscores the need for further studies aiming to define which specific mechanisms may be responsible and such research will enhance our understanding of mammary carcinogenesis.

References

1. Cancer Statistics: Registrations, series MB1 33.

   Office for National Statistics

   Ref Type: Generic

2. Fentiman IS, Gregory WM: The hormonal milieu and prognosis in operable breast cancer.

   Cancer Surv 1993, 18:149-163. PubMed Abstract

3. Badwe RA, Wang DY, Gregory WM, Fentiman IS, Chaudary MA, Smith P, Richards MA, Rubens RD: Serum progesterone at the time of surgery and survival in women with premenopausal operable breast cancer.

   Eur J Cancer 1994, 30A(4):445-448. PubMed Abstract | Publisher Full Text

4. Pujol P, Daures JP, Brouillet JP, Chang S, Rouanet P, Bringer J, Grenier J, Maudelonde T: A prospective prognostic study of the hormonal milieu at the time of surgery in premenopausal breast carcinoma.

   Cancer 2001, 91(10):1854-1861. PubMed Abstract | Publisher Full Text

5. Sariguney Y, Demirtas Y, Findikcioglu F, Ayhan S, Latifoglu O, Cenetoglu S, Celebi C: Proper timing of breast reduction during the menstrual cycle.

   Ann Plast Surg 2004, 53(6):528-531. PubMed Abstract | Publisher Full Text

6. Macleod J, Fraser R, Horeczko N: Menses and breast cancer: does timing of mammographically directed core biopsy affect outcome?

   J Surg Oncol 2000, 74(3):232-236. PubMed Abstract | Publisher Full Text

7. Hrushesky WJ, Bluming AZ, Gruber SA, Sothern RB: Menstrual influence on surgical cure of breast cancer.

   Lancet 1989, 2(8669):949-952. PubMed Abstract | Publisher Full Text

8. Hrushesky WJ, Gruber SA, Sothern RB, Hoffman RA, Lakatua D, Carlson A, Cerra F, Simmons RL: Natural killer cell activity: age, estrous- and circadian-stage dependence and inverse correlation with metastatic potential.

   J Natl Cancer Inst 1988, 80(15):1232-1237. PubMed Abstract

9. Clarke RB, Howell A, Anderson E: Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone.

   Br J Cancer 1997, 75(2):251-257. PubMed Abstract

10. Dabrosin C: Increase of free insulin-like growth factor-1 in normal human breast in vivo late in the menstrual cycle.

    Breast Cancer Res Treat 2003, 80(2):193-198. PubMed Abstract | Publisher Full Text

11. Lavigne JA, Wimbrow HH, Clevidence BA, Albert PS, Reichman ME, Campbell WS, Giffen LA, Dorgan JF, Hartman TJ, Barrett JC, Hursing SD, Taylor PR: Effects of alcohol and menstrual cycle on insulin-like growth factor-I and insulin-like growth factor binding protein-3.

    Cancer Epidemiol Biomarkers Prev 2004, 13(12):2264-2267. PubMed Abstract

12. Wood PA, Bove K, You S, Chambers A, Hrushesky WJ: Cancer growth and spread are saltatory and phase-locked to the reproductive cycle through mediators of angiogenesis.

    Mol Cancer Ther 2005, 4(7):1065-1075. PubMed Abstract | Publisher Full Text

13. Coradini D, Veneroni S, Pellizzaro C, Daidone MG: Fluctuation of intratumor biological variables as a function of menstrual timing of surgery for breast cancer in premenopausal patients.

    Ann Oncol 2003, 14(6):962-964. PubMed Abstract | Publisher Full Text

14. Navarrete MA, Maier CM, Falzoni R, Quadros LG, Lima GR, Baracat EC, Nazario AC: Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle.

    Breast Cancer Res 2005, 7(3):R306-R313. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text

15. Soderqvist G, Isaksson E, von SB, Carlstrom K, Tani E, Skoog L: Proliferation of breast epithelial cells in healthy women during the menstrual cycle.

    Am J Obstet Gynecol 1997, 176(1 Pt 1):123-128. PubMed Abstract | Publisher Full Text

16. Ramakrishnan R, Khan SA, Badve S: Morphological changes in breast tissue with menstrual cycle.

    Mod Pathol 2002, 15(12):1348-1356. PubMed Abstract | Publisher Full Text

17. Ryan KJ: Biochemistry of aromatase: significance to female reproductive physiology.

    Cancer Res 1982, 42(8 Suppl):3342s-3344s. PubMed Abstract

18. Ursin G, Longnecker MP, Haile RW, Greenland S: A meta-analysis of body mass index and risk of premenopausal breast cancer.

    Epidemiology 1995, 6(2):137-141. PubMed Abstract

19. Wood PA, Hrushesky WJ: Sex cycle modulates cancer growth.

    Breast Cancer Res Treat 2005, 91(1):95-102. PubMed Abstract | Publisher Full Text

20. Shakhar K, Shakhar G, Rosenne E, Ben-Eliyahu S: Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity.

    Br J Cancer 2000, 83(12):1630-1636. PubMed Abstract | Publisher Full Text

21. Ben-Eliyahu S, Shakhar G, Shakhar K, Melamed R: Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis: possible clinical implications.

    Br J Cancer 2000, 83(12):1747-1754. PubMed Abstract | Publisher Full Text

22. Dabrosin C: Variability of vascular endothelial growth factor in normal human breast tissue in vivo during the menstrual cycle.

    J Clin Endocrinol Metab 2003, 88(6):2695-2698. PubMed Abstract | Publisher Full Text

23. McIlhenny C, George WD, Doughty JC: A comparison of serum and plasma levels of vascular endothelial growth factor during the menstrual cycle in healthy female volunteers.

    Br J Cancer 2002, 86(11):1786-1789. PubMed Abstract | Publisher Full Text

24. Heer K, Kumar H, Speirs V, Greenman J, Drew PJ, Fox JN, Carleton PJ, Monson JR, Kevin MJ: Vascular endothelial growth factor in premenopausal women–indicator of the best time for breast cancer surgery?

    Br J Cancer 1998, 78(9):1203-1207. PubMed Abstract

25. Oliver DJ, Ingram DM: Timing of surgery during the menstrual cycle for breast cancer: possible role of growth factors.

    Eur J Cancer 1995, 31A(3):325-328. PubMed Abstract | Publisher Full Text

26. Gompel A, Martin A, Simon P, Schoevaert D, Plu-Bureau , Hugol D, Audouin J, Leygue E, Truc JB, Poitout P: Epidermal growth factor receptor and c-erbB-2 expression in normal breast tissue during the menstrual cycle.

    Breast Cancer Res Treat 1996, 38(2):227-235. PubMed Abstract | Publisher Full Text

27. Badwe RA, Gregory WM, Chaudary MA, Richards MA, Bentley AE, Rubens RD, Fentiman IS: Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer.

    Lancet 1991, 337(8752):1261-1264. PubMed Abstract | Publisher Full Text

28. Badwe RA, Mittra I, Havaldar R: Timing of surgery during the menstrual cycle and prognosis of breast cancer.

    J Biosci 2000, 25(1):113-120. PubMed Abstract

29. Fentiman IS: 12. Timing of surgery for breast cancer.

    Int J Clin Pract 2002, 56(3):188-190. PubMed Abstract

30. Pujol P, Daures JP, Brouillet JP, Chang S, Rouanet P, Bringer J, Grenier J, Maudelonde T: A prospective prognostic study of the hormonal milieu at the time of surgery in premenopausal breast carcinoma.

    Cancer 2001, 91(10):1854-1861. PubMed Abstract | Publisher Full Text

31. Takeda Y, Yanagie H, Yoshizaki I, Eriguchi M: Does the timing of surgery for breast cancer in relation to the menstrual cycle or geomagnetic activity affect prognoses of premenopausal patients?

    Biomed Pharmacother 2003, 57(Suppl 1):96s-103s. PubMed Abstract | Publisher Full Text

32. Nomura Y, Kataoka A, Tsutsui S, Murakami S, Takenaka Y: Lack of correlation between timing of surgery in relation to the menstrual cycle and prognosis of premenopausal patients with early breast cancer.

    Eur J Cancer 1999, 35(9):1326-1330. PubMed Abstract | Publisher Full Text

33. Mangia A, De LM, Barletta A, Marzullo F, Attolico M, Stea B, Petroni S, Labriola A, Cellamare G, Digiebi G, Altieri R, Schittuli F, Paradiso A: Timing of breast cancer surgery within the menstrual cycle: tumor proliferative activity, receptor status and short-term clinical outcome.

    J Exp Clin Cancer Res 1998, 17(3):317-323. PubMed Abstract

34. Paradiso A, Serio G, Fanelli M, Mangia A, Cellamare G, Schittulli F: Predictability of monthly and yearly rhythms of breast cancer features.

    Breast Cancer Res Treat 2001, 67(1):41-49. PubMed Abstract | Publisher Full Text

35. Goldhirsch A, Gelber RD, Castiglione M, O'Neill A, Thurlimann B, Rudenstam CM, Lindtner J, Collins J, Forbes J, Crivellani D, Coates A, Cavalli F, Simoncini E, Fey MF, Pagani O, Price K, Senn HJ: Menstrual cycle and timing of breast surgery in premenopausal node-positive breast cancer: results of the International Breast Cancer Study Group (IBCSG) Trial VI.

    Ann Oncol 1997, 8(8):751-756. PubMed Abstract | Publisher Full Text

36. Vanek VW, Kadivar TF, Bourguet CC: Correlation of menstrual cycle at time of breast cancer surgery to disease-free and overall survival.

    South Med J 1997, 90(8):780-788. PubMed Abstract | Publisher Full Text

37. Mondini G, Decian F, Sorice G, Friedman D, Spirito C, Costantini M, Sormani MP, Civalleri D: Timing of surgery related to menstrual cycle and prognosis of premenopausal women with breast cancer.

    Anticancer Res 1997, 17(1B):787-790. PubMed Abstract

38. Jager W, Sauerbrei W: Effect of timing of surgery during the menstrual cycle of premenopausal breast cancer patients.

    Breast Cancer Res Treat 1995, 34(3):279-287. PubMed Abstract | Publisher Full Text

39. Holli K, Isola J, Hakama M: Prognostic effect of timing of operation in relation to menstrual phase of breast cancer patient–fact or fallacy.

    Br J Cancer 1995, 71(1):124-127. PubMed Abstract

40. Kroman N, Hojgaard A, Andersen KW, Graversen HP, Afzelius P, Lokdam A, Juul C, Hoffmann J, Bentzon N, Mouridsen HT: Timing of surgery in relation to menstrual cycle does not predict the prognosis in primary breast cancer. Danish Breast Cancer Cooperative Group.

    Eur J Surg Oncol 1994, 20(4):430-435. PubMed Abstract

41. Corder AP, Cross M, Julious SA, Mullee MA, Taylor I: The timing of breast cancer surgery within the menstrual cycle.

    Postgrad Med J 1994, 70(822):281-284. PubMed Abstract

42. Saad Z, Vincent M, Bramwell V, Stitt L, Duff J, Girotti M, Jory T, Heathcote G, Turnbull I, Garcia B: Timing of surgery influences survival in receptor-negative as well as receptor-positive breast cancer.

    Eur J Cancer 1994, 30A(9):1348-1352. PubMed Abstract | Publisher Full Text

43. Gnant MF, Seifert M, Jakesz R, Adler A, Mittlboeck M, Sevelda P: Breast cancer and timing of surgery during menstrual cycle. A 5-year analysis of 385 pre-menopausal women.

    Int J Cancer 1992, 52(4):707-712. PubMed Abstract

44. Senie RT, Rosen PP, Rhodes P, Lesser ML: Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival.

    Ann Intern Med 1991, 115(5):337-342. PubMed Abstract

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