Re: Mastectomy and Oophorectomy by Menstrual Cycle Phase in Women With Operable Breast Cancer
Journal of the National Cancer Institute
In their article recently published in the Journal, Love et al. (1) present provoking evidence that in a cohort of Vietnamese premenopausal breast cancer patients the timing of initiation of adjuvant hormone therapy (oophorectomy + tamoxifen) during the luteal phase of the menstrual cycle improves 5-year disease-free and overall survival. These data add fuel to the fire of the ongoing controversy on the role of the timing of breast cancer surgery during the menstrual cycle, and adding the new
... mension of the timing of adjuvant hormone therapy initiation. Although the data are intriguing from both a biological and a clinical perspective, we believe that a note of caution in their interpretation is in order and we fully agree with the comments made by Dr. Hortobagyi in the accompanying editorial (2). In our opinion, the piece of evidence regarding the interactions between hormone receptor (HR) status and the timing of hormonal intervention is especially problematic. In fact, the statement that "similar levels of benefit of oophorectomy during the luteal phase [were] seen in patients with ER-positive or ERnegative cancers" appears to be somewhat in contrast with the observation that in the entire series, recently published in the Journal of Clinical Oncology (3) , "only patients with hormone receptor-positive tumors benefited from the adjuvant treatment." Moreover, our group has recently shown that in premenopausal women with operable breast cancer who did not receive any adjuvant hormone treatment, the timing of surgery during the follicular or luteal phase, although not prognostic per se, does complement the prognostic relevance of HR status (4). Recently, we have analyzed these data further and found that the menstrual phase at the time of surgery was indeed prognostic in patients with HR-positive cancers, with patients operated upon in the follicular phase having statistically significantly better outcome (P ס .04 for both disease-free and overall survival), but not in patients with HRnegative cancers (P ס .4 and P ס .6 for disease-free and overall survival, respectively); on the other hand, although of borderline prognostic significance in the whole population (P ס .07 and P ס .02 for disease-free and overall survival, respectively), HR status was a powerful prognostic factor for patients in the follicular phase (P ס .005 and P ס .002 for disease-free and overall survival, respectively), but not for patients in the luteal phase (P ס .85 and P ס .58 for disease-free and overall survival, respectively), even after adjusting for other prognostic factors. On the basis of this evidence, we created a hybrid prognostic variable including both parameters (follicular phase [F] at the time of surgery and positive HRs, F+) and tested it in multivariate analysis ( Table 1 ). The results indicate that the hybrid F+ variable was an independent prognostic factor for disease-free survival and, quite surprisingly, the single most important prognostic factor for overall survival. In our opinion, these results call for a more detailed analysis of the data by Love et al. (1) before a final conclusion can be made on whether the advantage observed for hormone treatment initiation in the luteal phase really derives from the timing of the therapeutic intervention rather than from a simple prognostic interaction. Such analysis should be performed on both adjuvant hormone-treated and untreated patients, and its results would be even more interesting in light of the unsettled question regarding differences in breast cancer hor-mone dependency in Asian, rather than in Western, women. MICHELE MILELLA DIANA GIANNARELLI VIRGINIA FERRARESI MARCELLA MOTTOLESE CLAUDIO BOTTI CECILIA NISTICÒ REFERENCES (1) Love RR, Duc NB, Dinh NV, Shen TZ, Havigurst 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. (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. (3) Love RR, Duc NB, Allred DC, Binh NC, Dinh NV, Kha NN, et al. Oophorectomy and tamoxifen adjuvant therapy in premenopausal Vietnamese and Chinese women with operable breast cancer. J Clin Oncol 2002;20: 2559-66. (4) Milella M, Nisticò C, Ferraresi V, Vaccaro A, Fabi A, D'Ottavio AM, et al. Breast cancer and timing of surgery during menstrual cycle: a 5-year analysis of 248 premenopausal women. Breast Cancer Res Treat 1999;55: 259-66. (5) Papaldo P, Lopez M, Cortesi E, Foggi CM, Antimi M, Lepidini G, et al. Adjuvant epirubicin and cyclophosphamide (EC)±lonidamine (L)±G-CSF (G) in 506 stage I-II breast cancer patients (pts): %-year results of a multicentric randomized phase III trial [abstract]. Proc ASCO 1998;17:m6a.