The three dominant oxidative biotransformations of estradiol were examined in 10 normal women and 33 females with breast cancer by using a recently devised radiometric method. Estradiol tracers, labeled with 3H specifically in the 17a, C-2, or 16a position, were used to measure both the rate and extent of 17P-ol oxidation (the initial metabolic step) and the subsequent 2-and 16a-oxidative reactions. The mean ± SEM values for the extent of estradiol metabolism at these three specific sites were 76.9 ± 5.3%, 31.1 ± 4.0%, and 9.3 ± 0.8%, respectively, in normal subjects. Corresponding data in patients with breast cancer-i.e., 73.0 ± 4.2%, 32.7 ± 2.7%, and 14.9 ± 1.5%-revealed a significantly greater extent of 16a-hydroxylation in the latter population. Because the 16a-hydroxylated compounds (including estriol) are themselves potent estrogens, these changes may have important hyperestrogenic consequences that could have a bearing on the etiology of the disease.Endocrine factors have been implicated in the initiation or promotion, or both, of mammary tumorigenesis based on data collected from several sources. These include both experimental studies using animal models and epidemiological and clinical investigations in human subjects (1). Thus, certain features of the menstrual history and age at parity, which can lengthen the period ofexposure to estrogens secreted by the ovaries, appear to be associated with an increased risk for the disease (2, 3). On the other hand, oophorectomy prior to age 35 can lessen the risk of breast cancer (3). Because an augmentation in estrogen secretion could be implicated in the etiology of the human disease, numerous studies have been conducted to detect such an increase in women with, or at high risk to develop, breast cancer (4). Although some investigators have reported significant differences in urinary or plasma estrogen levels, or both, between these subjects and normal individuals (5-7), these findings have not been consistent and have been challenged by others (8, 9). An alternative and possibly more viable hypothesis that an alteration in estrogen metabolism is associated with breast cancer (4, 10) has also been the subject of extensive investigations.The metabolism of estradiol, which is primarily oxidative, consists ofan initial oxidation ofthe 17/3-hydroxy group to yield estrone. This steroid is subsequently metabolized mainly through either of two alternate hydroxylative pathways; namely, hydroxylation at the C-2 or the 16a position (11). These hydroxylations are of particular interest in that they constitute competing reactions whose products are themselves active compounds characterized by markedly different biological properties. The 16a-hydroxyestrogens-estriol and 16a-hydroxyestrone-demonstrate uterotropic activity comparable to that of the parent hormone, estradiol (12, 13). On the other hand, the principal 2-hydroxyestrogens-2-hydroxyestrone and 2-methoxyestrone exhibit virtually no peripheral estrogenic effects but appear to play a regulatory role in neur...

Treatment of mammary carcinoma by partial mastectomy rather than by total mastectomy and axillary dissection may diminish the chances of long-term cure by risking incomplete removal of all local carcinoma at the initial operation. This study was undertaken to determine by pathologic examination how often carcinoma might remain in the breast and axilla after partial mastectomy. The operation was simulated in 203 mastectomy specimens after operations for unilateral invasive carcinoma. In so far as could be determined on gross examination, the entire primary lesion was included in the quadrant which was excised in the simulated procedure. Among 100 women with primary lesions less than 2 cm in diameter, 26% had carcinoma in the breast which remained after simulated partial mastectomy. Six percent of them also had axillary node metastases. An additional 30% only had axillary node metastases. When the primary lesion was more than 2 cm in diameter, 38% of patients had carcinoma in the breast after simulated partial mastectomy, of whom 29% also had axillary metastases. After simulated partial mastectomy, carcinoma was found in 80% of breasts from patients with lesions in the subareolar area, in contrast with 25-3570 of patients with a primary carcinoma in one of the four quadrants. None of the 9 patients with medullary and colloid carcinomas that measured under 2 cm had axillary metastases or carcinoma in the breast outside of the primary quadrant. The findings suggested that a familial history of breast carcinoma or a large primary lesion may be associated more often with multifocal disease, but factors such as age at diagnosis, axillary status, and the mammogram report did not have significant predictive value for distinguishing between patients who did or did not have carcinoma in breast tissue after the primary had been removed by a simulated partial mastectomy. NTENSE CONTROVERSY HAS BEEN GENERATED I in the past several years by the proposal that total mastectomy is now an unnecessarily extensive and disfiguring operation for the treatment of primary operable invasive breast carcinoma.* Advocates of conservative surgery contend that radical mastectomy was essential in the past because many more patients presented with advanced disease.' They maintain that today the majority of patients are being treated at an Presented in part at the 27th Annual Meeting of the James Ewing Society. Maui. HI, April 8-13, 1974. The authors express their appreciation for the invaluable assistance of Miss Jane Taylor and Miss Donna Nager in the preparation of this study.Received for publication November 15, 1974. earlier stage and that it is possible to select patients who can be cured by partial rather than total mastectomy.2 Two serious difficulties must be faced in selecting patients for partial mastectomy. First, the operation should remove all carcinoma in the breast if it is to achieve maximum local control. To ensure this requires a reliable method of identifying patients with carcinoma limited to a single quadrant of the brea...

Recurrence and survival data at 10 years were examined for 147 women with single axillary lymph node metastases found in a modified radical or standard radical mastectomy. The cases were identified through a review of all patients with primary operable breast cancer treated at Memorial Hospital from 1964 to 1970. The patients were stratified into groups according to size of the primary tumor and of the metastatic deposit (micro less than or equal to 2 mm; macro greater than 2 mm) as well as level of the positive node. In the entire series, there was a significantly poorer prognosis among those patients with single macrometastases (30/77 patients; 39% recurrence rate) when compared with those having micrometastases (17/70 patients: 24% recurrence rate). A major prognostic difference emerged after stratification by tumor size. Within the first six years of the follow-up period, T1 patients with negative nodes and those with single micrometastases had similar survival curves, significantly better than those with macrometastases. However, at 12 years, the survival rats of those patients with either a micro- or macrometastases was nearly identical, and significantly worse than for those patients with negative lymph nodes. On the other hand, among women with primary tumors 2.1-5.0 cm (T2), patients with negative lymph nodes or single micrometastases had survival curves that did not differ significantly throughout the course of the follow-up period. Both had an outcome significantly better than observed for patients with macrometastases. These findings have important implications for our understanding of the clinical behaviour of breast cancer and for the stratification of patients entered into randomized treatment trials.

No abstract

A ten-year study of Stage III breast carcinoma has been reviewed in detail. The single most dominant variable was axillary nodal involvement. Four hundred and thirty patients had nodal metastases, 58 patients did not. Four hundred and thirty patients with axillary nodal involvement had fiveand ten-year recurrence rates of 68 and 77%, while the survival rates were 41 and 21%, respectively. Life span was influenced by extent of nodal disease, being best for those with micrometastases only, and worse for those with four or more positive nodes. Skin edema, infiltration, or ulceration in the positive node group were grave signs. Muscle invasion or node matting, however, did not appear to influence length of life. Postoperative prophylactic therapy did not appear to affect survival rates. Radiation therapy alone did not influence either local recurrence or survival rates. Not enough time has elapsed to evaluate the results of postoperative chemotherapy. Patients who underwent oophorectomy and radiation therapy appeared to do better, but the number of patients was small. Of the 58 patients without nodal invasion, 82% were alive at five years and 75% were alive at 10 years. Grave signs did not influence the survival rate in this group. While the majority of patients with Stage III carcinoma had unfavorable variables, there were some patients who demonstrated a low recurrence rate and a long survival time. Aggressive treatment should be designed to save those patients who can be helped and to improve those patients whose life expectancy is limited. There is no place for timid initial treatment whether by operation or by irradiation. It must be given with intent to cure even though palliation is most often attained.