CORRESPONDENCE

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

William J.M. Hrushesky

W. J. Hrushesky, School of Medicine, University of South Carolina, and Norman J. Arnold School of Public Health.

Correspondence to: William J. M. Hrushesky, M.D., W. J. B. Dorn, VAMC (Mail Code 151), 6439 Garners Ferry Road, Columbia, SC 29209–1639 (e-mail: William.Hrushesky{at}med.va.gov).

The recent paper by Love et al. (1) describing the effect of the menstrual cycle timing of breast cancer resection upon outcome represents the first prospective investigation of this question. The findings are consistent with those of our earlier retrospective studies (24). The outcome for patients undergoing mastectomy or lumpectomy and receiving concurrent oophorectomy is profoundly dependent on the menstrual cycle timing of surgery. The optimal time, during the luteal phase, is as predicted by our original murine and clinical studies (2,5,6).

The menstrual cycle phase-based outcome difference, though gratifying, was unexpected because the median follow-up of these patients should not have been adequate to demonstrate it. Almost all retrospective studies demonstrating similar outcome differences require an actual median follow-up in excess of 5 years. Interestingly, the earlier retrospective data showed that patients with more advanced breast cancer had the largest and earliest differences in outcome depending on surgery timing. The patient population studied by Love et al. (1) had, on average, more advanced breast cancer than did patients comprising a recent study (4), with average tumor sizes in the study by Love et al. (1) of more than 3 cm and involvement of an average of more than four axillary nodes. The prominence of menstrual cycle-dependent outcome in these patients may be the result, in part, of the extent of surgical wounding. Larger tumors with axillary node involvement require larger operations. The women in the study by Love et al. (1) who underwent both breast and ovarian resections also had more extensive surgical wounding by virtue of their concurrent abdominal surgery. The extent of the surgical wound is an important determinant of how soon the effect of its timing within the cycle becomes visible.

The effect of resection timing is not yet visible in those women undergoing mastectomy or lumpectomy but not subjected to oophorectomy because inadequate follow-up is available. This effect will show up in the data when each of these women has been followed for at least 5 years (median follow-up 7–10 years).

I agree with Dr. Hortobagyi’s penultimate conclusion in the accompanying editorial (7) that adequate prospective study of whether operative timing within the menstrual cycle is essential. Unfortunately, all of the ongoing prospective studies are seriously flawed. Any trial with a bona fide chance to determine whether the timing of surgery affects breast cancer cure must minimally require the following: 1) meticulously locate when in the hormonal cycle the operation is performed, 2) shield any resection timing assignment from bias by some form of randomization, and 3) make absolutely certain that any and all surgical interventions are carried out at the same time within each woman’s cycle. If any of these three essential requirements is absent, the results of the trial in question are uninterpretable. All ongoing studies violate at least one and sometimes all three of these essential requirements, as does Love’s study.

Finally, I cannot agree with the ultimate conclusion that Dr. Hortobagyi reaches, namely that ". . . there is no reason to time either breast surgery or ovarian ablation according to the phase of the menstrual cycle." It is really hard to understand what argument could be made for not employing a strategy with no risk and no cost that has the potential to save 10 000–12 000 American and 200 000–240 000 young women’s lives, worldwide, annually. This recommendation is, to me, unfathomable.

REFERENCES

1 Love RR, Duc NB, Dinh NV, Shen T, Havighurst TZ, 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 Hrushesky WJ, Bluming A, Gruber S, Sothern R. Menstrual influence on surgical cure of breast cancer. Lancet 1989;8669;949–52.

3 Hrushesky WJ. Breast cancer, timing of surgery, and the menstrual cycle: call for prospective trial. J Women’s Health 1996;5:555–66.

4 Hagen A, Hrushesky WJ. Menstrual timing of breast cancer surgery. Am J Surgery 1998;175:245–61.[Medline]

5 Ratajczak HV, Sothern RB, Hrushesky WJ. Estrous influence on surgical cure of a mouse breast cancer. J Exp Med 1988;168:73–83.[Abstract]

6 Sothern RB, Levi F, Haus E, Halberg F, Hrushesky WJ. Control of a murine plasmacytoma with doxorubicin-cisplatin: dependence on circadian stage of treatment. J Natl Cancer Inst 1989; 81:135–45.[Abstract]

7 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]


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