COMMENTARY

Oophorectomy for Breast Cancer: History Revisited

Richard R. Love, John Philips

Affiliation of authors: Department of Medicine, Section of Medical Oncology, University of Wisconsin School of Medicine, Madison.

Correspondence to: Richard R. Love, M.D., M.S., 256 WARF, 610 Walnut St., Madison, WI 53726 (e-mail: rrlove{at}facstaff.wisc.edu).

Oophorectomy for the treatment of breast cancer is like taking aspirin for health: it keeps reappearing as an effective therapy with new twists. However, a closer look at the early history of oophorectomy suggests that perhaps the new twists are not new at all. In fact, a brief chronology of the early history of this intervention reveals facts and personages discrepant with common understandings.

It is important to note that oophorectomy was not first used as a treatment for breast cancer at all. A German surgeon, Alfred Hegar, apparently the first physician to perform the procedure on July 27, 1872, was treating benign disease. Although in his later work he recognized the physiologic effects on organs other than the breast from surgical menopause, he did not publish on the subject until 1878 (1). An American physician, Robert Battey, first performed a bilateral oophorectomy, which he called ovariotomy, three weeks later than Hegar on August 17, 1872. Because Battey published a report that same year, and thereby established historical priority, the surgical procedure became known as Battey's operation (2). Battey was prompted to carry out this radical surgery because of the death of a young patient whose course of ill health, similar to that of his operative case patient, had been characterized by the absence of regular menses. He reasoned that with removal of the ovaries, the source of the patient's multisystem malady would also be removed.

Recognition of the relationship of ovarian function to breast cancer was first noted when Thomas William Nunn reported the case history of a perimenopausal woman with breast cancer, whose disease regressed 6 months after her menstruation ceased (3). Although his case observation appears to be novel, it passed unnoted at the time. The oophorectomy-for-cancer pioneer was Albert Schinzinger, who first proposed surgical oophorectomy as a treatment for breast cancer at a congress of German surgeons April 24–27, 1889, but published his ideas only in abstract form (4,5). Although he appears to have suggested this therapy for both advanced disease and as prophylaxis against local recurrence, he himself never performed the surgery, and he was apparently never able to convince his colleagues to perform the procedure. Schinzinger observed that the prognosis for breast cancer appeared better in older women than in younger women and he reasoned that oophorectomy would make younger women prematurely old, thereby causing atrophy of the breast and of any cancer (4,5).

An important ancillary development for breast cancer therapy occurred in 1891 when George Redmayne Murray reported successfully treating a patient who had myxedema with sheep thyroid extract (6). In subsequent years, this thyroid therapy was used for the treatment of various diseases because of its properties as a powerful lymphatic stimulant. In this historical setting, independent of both the observation of Nunn and the suggestion of Schinzinger, although there is no record that his ideas were discussed in public or reported, George Thomas Beatson had for several years considered performing oophorectomy as a treatment for breast cancer in women because this practice of castration was used in cattle to continue lactation (7). Then, on June 15, 1895, Beatson performed a bilateral oophorectomy on a woman with extensive soft tissue recurrent breast cancer and then continued the treatment with thyroid extract that had begun a month earlier (7). Beatson reported on this and two other case patients in two issues of the Lancet published on July 11 and July 18, 1896 (7,8). During surgery on the first patient, Beatson noted that the left ovary was somewhat cystic (possibly a corpus luteum). The first and a subsequent report indicated that this patient experienced a complete remission and survived 4 years after the surgery (7,9). In a lengthy discourse on his rationale for this oophorectomy treatment, Beatson indicated that he thought oophorectomy would cause fatty degeneration of the malignant cells (7).

Thus, despite the historical credit he has been accorded for establishing oophorectomy as a treatment for breast cancer, Beatson's treatment was a compound endocrine therapy, with thyroid extract and oophorectomy. On November 27, 1896, A. Pearce Gould reported on the case history of a woman going through menopause who experienced a spontaneous remission of her metastatic breast cancer (10). The report of this patient and the observation of a similar patient who was under the care of a colleague, influenced an English surgeon, Stanley Boyd, to follow Beatson's lead and try surgical oophorectomy as a treatment for breast cancer, which he did for a patient with metastatic disease on December 22, 1886 (11). He reported this procedure for three case patients in April 1897, performed the first oophorectomy as adjuvant therapy on May 19, 1897, and published a paper on his first five case patients on October 2, 1897 (11,12). Boyd was unconvinced of the benefit of thyroid extract and emphasized that he omitted this therapy when treating his patients (13). He appeared to recognize mechanisms subsequently demonstrated to be operative with this therapy: "my working hypothesis is that internal secretion of the ovaries in some cases favors the growth of the cancer" (11). He described the ovaries in his first case patient as "well developed." Years later, in discussing a summary of the efficacy of oophorectomy treatment for breast cancer presented by Hugh Lett, Boyd commented that his first patient had survived 12 years after her oophorectomy (14). In the next few years, Boyd championed oophorectomy as an effective, although not curative, treatment and provided summary data in 1900, indicating that one third of breast cancer patients clearly benefited from this approach (15). In 1898, Frederick Page and William Bishop reported a case history of a patient with breast cancer in which thyroid extract was beneficial, although in toxic doses, and the benefit of oophorectomy alone which Boyd had evaluated, was more widely acknowledged (16).

The high rate of mortality associated with surgical oophorectomy discouraged many surgeons from performing this operation during the early years of the 20th century. The introduction of radiation castration further brought the procedure into disfavor. However, in the 1950s, Charles Huggins and Thomas Dao brought oophorectomy, this time combined with adrenalectomy, back to the mainstream of breast cancer therapies (17). In 1992, the Early Breast Cancer Trialists' Collaborative Group published a meta-analysis of updated data from clinical trials of adjuvant oophorectomy by radiation and by surgery conducted in the 1960s and 1970s, which suggested that, contrary to general opinion at the time, there were long-term benefits from these treatments, with increases in disease-free and overall survival (18). In the ensuing decade, several adjuvant trials were carried out and have been reported, which show direct evidence of the benefits from medical (with gonadotropin-releasing hormone agonists) or surgical oophorectomy, equivalent to those provided by cytotoxic chemotherapies, particularly in patients whose tumors express hormonal receptors (1921). Oophorectomy combined with tamoxifen appears to be equivalent to, or perhaps even superior to, standard chemotherapy regimens and is now recognized as an optional, first-line adjuvant treatment for patients with axillary node-negative and node-positive disease (2225). A recent article suggested that the benefits of surgical oophorectomy and adjuvant tamoxifen are statistically significantly greater when oophorectomy is performed during the luteal phase of the menstrual cycle (26). It was proposed that indirect, nonovarian hormonal effects of oophorectomy and adjuvant tamoxifen may partially explain this timing observation (26).

Thus, the adjuvant studies of the last decade have again brought to the fore surgical oophorectomy; a procedure that Schinzinger first proposed over a century ago, Beatson first performed in a patient who was possibly in the luteal phase of her menstrual cycle, and that Boyd first applied as an adjuvant treatment and then championed as an effective endocrine therapy by itself.

NOTES

Supported by Public Health Service grant CA64339 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and a grant from the Research Fund, Department of Medicine, University of Wisconsin School of Medicine.

REFERENCES

1 Hegar A. Die Castration der Frauen. Leipzig (Germany): Breitkopf und Hartel; 1878. p. 978.

2 Battey R. Normal ovariotomy—case. Atlanta Medical and Surgical Journal 1872;10:321–9.

3 Nunn TW. On cancer of the breast. London (U.K.): J. & A. Churchill; 1882. p. 71.

4 Schinzinger A. Ueber carcinoma mammae [abstract]. 18th Congress of the German Society for Surgery. Beilage zum Centralblatt fur Chirurgie 1889;16:55–6.

5 Schinzinger A. Ueber carcinoma mammae [abstract]. Verhandlungen der Deutschen Gesellschaft fur Chirurgie. 18th Kongress, Berlin, Apr 24–27, 1889. Berlin (Germany): Hirschwald; 1889. p. 28.

6 Murray GR. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. BMJ 1891;2:796–7.

7 Beatson CT. On treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1896;2:104–7.

8 Beatson CT. On treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment with illustrative cases. Lancet 1896;2:162–5.

9 Thomson A. Analysis of cases in which oophorectomy was performed for inoperable carcinoma of the breast. BMJ 1902;2:1538–41.

10 Spontaneous disappearance of secondary cancerous growths. Report on the meeting of the Clinical Society of London, November 27, 1896. BMJ 1896; 2:1642.

11 Boyd S. On oophorectomy in the treatment of cancer. BMJ 1897;2:890–6.

12 Treatment of inoperable carcinoma. Report of the British Gynaecological Society, April 8, 1897. BMJ 1897;1:1097–8.

13 Boyd S. Remarks on oophorectomy in the treatment of cancer of the breast. BMJ 1899;1:257–62.

14 Lett H. An analysis of 99 cases of inoperable carcinoma of the breast treated by oophorectomy. Report of the Royal Medical and Chirurgical Society. Lancet 1905;1:227–8.

15 Boyd S. On oophorectomy in cancer of the breast. BMJ 1900;2:1161–7.

16 Page F, Bishop WH. Recurrent carcinoma of the breast entirely disappearing under persistent use of thyroid extract continued for 18 months. Lancet 1898;1:1460–1.

17 Huggins C, Dao TL. Adrenalectomy and oophorectomy in treatment of advanced carcinoma of the breast. JAMA 1953;151:1388–94.

18 Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339:1–15, 71–85.[Medline]

19 Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy's Hospital, London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Lancet 1993;341:1293–8.[Medline]

20 Ejlertsen B, Dombernowsky P, Mouridsen HT, Kamby C, Kjaer M, Rose C, et al. Comparable effect of ovarian ablation (OA) and CMF chemotherapy in premenopausal hormone receptor positive breast cancer patients (PRP) [abstract]. Proc ASCO 1999;18:66a.

21 Jakesz R, Hausmaninger H, Samonigg H, Kubista E, Depisch D, Fridrik M, et al. Comparison of adjuvant therapy with tamoxifen and goserelin vs. CMF in premenopausal stage I and II hormone-responsive breast cancer patients: four-year results of Austrian Breast Cancer Study Group (ABCSG) trial 5 [abstract]. Proc ASCO 1999;18:67a.

22 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.[Abstract/Free Full Text]

23 Roché HH, Kerbrat P, Bonneterre J, Fargeot P, Fumoleau P, Monnier A, et al. Complete hormonal blockade versus chemotherapy in premenopausal early-stage breast cancer patients with positive hormone-receptor and 1–3 node-positive tumor: results of the FASG 06 Trial [abstract]. Proc ASCO 2000;19:72a.

24 Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Minutoli N, Aldrighetti D, et al. CMF vs. tamoxifen (TAM) plus goserelin (GOS) as adjuvant treatment for ER positive (ER+) pre-perimenopausal breast cancer (CA) patients (PTS). Preliminary results of the GROCTA 02 study [abstract]. Proc ASCO 1998;17:99a.

25 Goldhirsch A, Glick JH, Gelber RD, Coates AS, Senn HJ. Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 2001;19:3817–27.[Free Full Text]

26 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]

Manuscript received May 16, 2002; revised July 12, 2002; accepted July 22, 2002.


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