CORRESPONDENCE

Re: Mastectomy and Oophorectomy by Menstrual Cycle Phase in Women With Operable Breast Cancer

Gianluigi Ferretti, Serena Di Cosimo, Paolo Carlini, Paola Papaldo, Alessandra Fabi, Francesco Cognetti

G. Ferretti, S. Di Cosimo, P. Carlini, P. Papaldo, A. Fabi, F. Cognetti, Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy.

Correspondence to: Gianluigi Ferretti, M.D., Divisione Oncologia Medica A, Polo Oncologico Regina Elena, Via Elio Chianesi 53, 00128 Rome, Italy (e-mail: gia.fer{at}flashnet.it).

According to Love et al. (1), premenopausal women with breast cancer had better disease-free and overall survival when they received mastectomy and oophorectomy with adjuvant tamoxifen therapy during the luteal phase rather than during the follicular phase of the menstrual cycle, regardless of hormone receptor status. Commenting on these data in his editorial, Dr. Hortobagyi (2) underlines that "despite reports to the contrary, there is no scientifically valid evidence that any endocrine intervention is effective for patients with estrogen receptor-negative tumors" and "there is no compelling biologic rationale to think that ovarian ablation will work in patients with estrogen receptor-negative tumors."

Estrogen affects cell signaling by binding to the estrogen receptor (ER) and promoting the transcription of ER-responsive genes. However, estrogen may also have ER-independent activity. Estrogen activates Akt and downstream anti-apoptotic signaling molecules through the phosphatidylinositol 3-kinase pathway (3). Estrogen has also been found to activate the mitogen-activated protein kinases, extracellular signal-regulated kinase Erk-1 and Erk-2, driving growth factor-dependent cellular responses through the G protein-coupled receptor homolog GPR30 (4). By contrast, tamoxifen can induce apoptosis and growth arrest by ER-mediated or ER-independent mechanisms (5). Although these preclinical data are not yet documented to be of clinical significance in breast cancer, the ability of tamoxifen to work independently of the ER has been shown in melanoma and glioma clinical trials (5).

We agree with Dr. Hortobagyi that the data from Love et al. "raise again the spectrum of the utility of an endocrine intervention in patients with estrogen receptor-negative tumors" (2). In fact, patients with ER-negative cancers in the oophorectomy and tamoxifen arm who had a mastectomy during the luteal phase of the menstrual cycle had better overall survival (P = .02) than did those who had surgery during the follicular phase (1). Some interesting evidence could explain these results. Although estrogen represents a major stimulant of mammary cell proliferation, the effect of progesterone remains controversial. Breast cell mitotic activity reaches its peak during the progesterone-dominant luteal phase. However, it has been suggested that progesterone decreases the invasiveness and metastatic potential of breast cancer cells, and that raised progesterone levels at the time of surgery confer a better prognosis to breast cancer patients. Moreover, although rats are protected from breast cancer by levels of estrogen and progesterone resembling those detected during pregnancy (6), neither hormone alone is sufficient to induce the same protective effect. It is noteworthy that the increased survival of breast cancer patients with subsequent full-term pregnancy could be consistent with an antitumor effect of pregnancy itself (7). This evidence could be associated with the sustained release of balanced levels of both estrogen and progesterone, partially observed also during the luteal phase.

Tumor expression of genes (such as p53 and matrix metalloproteinase-9) affecting the proliferation, metastatic potential, and postoperative production of angiogenic factors in the surgical wound could vary during the menstrual cycle and thus could potentially explain the improved survival of some patients who were operated on during the luteal phase of the menstrual cycle. Whether and how these factors could be responsible for the favorable outcome related to endocrine interventions in the luteal phase, as reported by Love et al. (1), is still unknown.

REFERENCES

1 Love RR, Duc NB, Dinh NV, Shen TZ, Havighurst TC, Allred DC, et al. Mastectomy and oophorectomy by menstrual cycle phase in women with operable breast cancer. J Natl Cancer Inst 2002;94:662–9.[Abstract/Free Full Text]

2 Hortobagyi GN. The influence of menstrual cycle phase on surgical treatment of primary breast cancer: have we made any progress over the past 13 years? J Natl Cancer Inst 2002;94:641–3.[Free Full Text]

3 Tsai EM, Wang SC, Lee JN, Hung MC. Akt activation by estrogen in estrogen receptor-negative breast cancer cells. Cancer Res 2001;61:8390–2.[Abstract/Free Full Text]

4 Filardo EJ, Quinn JA, Bland KI, Frackelton AR, Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol 2000;14:1649–60.[Abstract/Free Full Text]

5 Gelmann EP. Tamoxifen induction of apoptosis in estrogen receptor-negative cancers: new tricks for an old dog? J Natl Cancer Inst 1996;88:224–6.[Free Full Text]

6 Guzman RC, Yang J, Rajkumar L, Thordarson G, Chen X, Nandi S. Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy. Proc Natl Acad Sci U S A 1999;96:2520–5.[Abstract/Free Full Text]

7 Gelber S, Coates AS, Goldhirsch A, Castiglione-Gertsch M, Marini G, Lindtner J, et al. Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer. J Clin Oncol 2001;19:1671–5.[Abstract/Free Full Text]



             
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