Albert Segaloff

Current status of estrogen and progesterone receptors in breast cancer

Breast cancer is often hormone responsive, since growth or regression of tumors can often be modulated by appropriate endocrine manipulations. Estrogen and progesterone appear to be major hormones involved in regulation of breast tumor growth. It has been recently argued that a more accurate marker of hormonal responsiveness might result if an end product of an intact estrogen response system were measured instead of the initial hormone binding step. Progesterone receptor (PgR) has been investigated in this regard since it can be readily measured in human breast tumors and there is clear evidence in experimental breast tumor model systems that PgR is under acute estrogen control. PgR is rarely found in ER‐ metastatic breast tumors but is present in approximately 59% of ER+ metastatic tumors, especially in those tumors with high levels of ER. Preliminary clinical correlation of ER, PgR and response to endocrine therapy is encouraging. The response rate is significntly higher if the tumor contains both ER and PgR than if the tumor contains ER alone.

In vivo metabolism of Δ1, 17α-methyltestosterone in man

Summary Δ 1 ,6β-hydroxy-17α-methyltestosterone was isolated from the urine of a patient after administration of Δ 1 ,17α-methyltestosterone. Another metabolite, in which ring A appears not to have been metabolized, was isolated but not as yet finally identified.

COMBINED ANDROGEN AND ANTIMETABOLITE THERAPY OF ADVANCED FEMALE BREAST CANCER A Report of the Cooperative Breast Cancer Group

A clinical trial of androgen and antimetabolite therapy of advanced female breast cancer was conducted in 110 patients by the Cooperative Breast Cancer Group. An objective regression rate of 20% was achieved in women receiving oral testolactone, 6% in patients given intravenous fluorouracil alone, and 14% when the androgen and antimetabolite were administered together. This randomized trial according to the CBCG protocol did not produce the high regression rate noted previously in a nonrandomized, nonprotocol evaluation of these drugs.

Hormonal therapy in cancer of the breast. XXIV. Effect of corticosterone or medroxyprogesterone acetate on clinical course and hormonal excretion.

A total of 44 patients with advancing cancer of breast were treated in a double‐blind study comparing corticosterone, NSC 9705, in a dose of 400 mg per day plus 3 Gm of potassium chloride, with medroxyprogesterone acetate, NSC 26386 (Provera), in a dose of 100 mg per day of the micronized preparation plus 3 Gm of potassium chloride. One of the 21 patients who received corticosterone sustained an objective regression of her advanced disease but none of the patients receiving medroxyprogesterone acetate were objectively improved. There were no apparent effects from medroxyprogesterone acetate on hormonal excretion patterns. Corticosterone produced increases in the excretion of formaldehydogenic corticoids and blue tetrazolium corticoids but not in Porter‐Silber chromogens. Corticosterone also induced significant increases in pregnanediol excretions.

Purification of Human Pituitary Follicle Stimulating (FSH) and Luteinizing (LH) Hormones.

Summary FSH and LH from human pituitaries have been isolated with high specific activities. Both FSH and LH had uterine weight increasing activity in immature rats and mice. The FSH had approximately the same activity as porcine and ovine FSH, however, LH was 10 times as active as pure ovine LH.

Identification of breast cancer patients with high risk of early recurrence after radical mastectomy: III. Steroid hormones measured in urine

The relationship of the levels of selected urinary steroid metabolites to breast cancer recurrence after radical mastectomy was studied. An analysis of variance of the steroid measurements suggested that the measurements standardized to per gram of creatinine were the appropriate measure to use in exploring these relationships. No significant associations were found for premenopausal patients; however, for postmenopausal patients, low levels of total 17‐ketosteroids were associated with a reduced two‐year recurrence‐free rate whereas low and high levels of OHA and high levels of total estrogens were associated with a relatively high two‐year recurrence‐free rate. Because of the large number of significance tests performed and the lack of consistent patterns, it is questionable whether the observed associations are of any importance. Including these steroid quantities in a multivariate regression model along with previously determined clinical prognostic factors indicated that the steroid determinations were the least important variables and did not make a significant contribution to the fit of the model.

Does thyroid substance improve response of breast cancer to surgical castration

Under the aegis of the Cooperative Breast Cancer Group, 13 principal investigators studied a total of 218 female patients with metastatic carcinoma of the breast. All patients either were menstruating actively or were less than 1 year past the menopause; all had histologic proof of breast cancer and progression of tumor documented either by physical examination or by roentgenograms. Both incidence of remission and survival time were compared between patients treated either by surgical castration or by surgical castration plus thyroid substance. The incidence of remission was 27.5% for the control group and 25.7% for the group treated with thyroid substance; the survival time for the two groups was identical, with 50% surviving 30 months or longer. We conclude that the effects of surgical castration were not enhanced by the addition of thyroid substance.

An evaluation of the effect of vincristine added to cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone in advanced breast cancer

SummaryA multi-institutional randomized clinical trial was carried out to evaluate the effect of vincristine (V) added to cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) for the treatment of metastatic breast cancer. There were 427 patients entered into the study and randomly assigned to one of the two treatments, i.e. the five drug therapy CMFPV or the four drug therapy CMFP. The differences in patient survival and tumor response between the two treatment groups were not statistically significant. The data were also analyzed using multivariate procedures to determine those factors ascertained at entry into the study which were predictors of survival or predictors of response to therapy. The one factor that predicted both response and survival was performance status. An additional important predictor of survival was sites of metastatic involvement. Other significant predictors of response were menopausal age, BUN, and hematocrit.

Hormonal therapy of breast cancer

The oldest hormonal therapy for advanced breast cancer is the castration of women who are still menstruating. There are many clinicians who believe that evidence is overwhelming that those who fail to respond to castration have tumors that are nonresponsive to hormonal change. Therefore they employ cytotoxic chemoterhapy instead of administrative hormonal agents for those women who fail to respond to castration. It is more important however to recognize for those who do respond well to castration and who have a tumor progressing again that the longer and more dramatic the remission to castration the greater is the change of responding to another hormonal change. All hormonal therapies should be tried particularly in a responsive case. The side effects of hormonal therapy appear to be more difficult for a patient than the side effects of cytotoxic therapy.

SCREENING HORMONAL AGENTS FOR ANTICANCER ACTIVITY IN MAN

There are, of course, many human tumors not yet adequately tested for their responsiveness to hormonal agents. The screening process in man therefore must be adapted to yield information as to whether a tumor is truly responsive. I t is useless simply to treat patients in an unorganized fashion and hope for results so dramatic that they cannot fail to be recognized. With the untested type of tumor, this stage of screening both tumors and hormonal agents becomes one of pioneering exploration. It is necessary to try a series of tumors of the type in question to see if they will respond favorably, usually selecting the best known and most potent available hormonal agent, or ablative procedures designed to produce profound changes in the hormonal internal milieu. This type of exploration is limited only by the scope of the investigator’s imagination and the availability of patients with specific tumors and hormonal materials, although end points of activity sufficiently sensitive to show favorable effects, should they occur, must be determined. However, once one is able to ascertain that a given tumor is responsive to changes in its hormonal environment, it is possible to set up an adequate screening method in man in the search for the most effective agents against the specific tumor. Such is the case for advanced breast cancer. It may seem unnecessary to some but, since we are discussing screening methods, it is imperative to realize that, for maximum benefit, patients must be assigned to therapy groups by some method that cannot be manipulated, such as the drawing of consecutively numbered envelopes containing the patient assignments, based on an adequate random method. Wherever possible, the therapy should be dispensed by number, in form physically the same as the reference standard, that is, double blind. However, in the interest of good patient care, a means of breaking the code for a given patient must be at hand in case the patient’s medical status should require it. It is my own considered opinion that, when there is a known effective agent for treating a given type of malignancy, it does not add to the screening efficiency to include a control group chosen on a random basis. In addition to offering no statistical or actual advantage, this constitutes a real and unnecessary cruelty to the patient, who might well have responded favorably to the known agent. It is also unnecessarily cruel (and probably impossible) to prevent patients from receiving subsequent therapy of possible benefit in order to obtain longevity figures for a given therapeutic modality. In devising an adequate screening system and applying it so that the greatest knowledge can be gained from treating the smallest number of patients, it is of utmost importance that the investigator be thoroughly versed in the natural history of the tumor in question. If not, he will only add to the mass of medical literature on dramatic response to therapy which is, in reality, only a measure