Baha'uddin M. Arafah

Estrogen and progesterone receptors in the prediction of response of breast cancer to endocrine therapy

This review presents our experience with the use of estrogen receptors (ER) and progesterone receptors (PgR) in the prediction of response to endocrine therapy in stage IV breast cancer. Presence of ER (>3 fmol/mg cytosol protein) significantly predicted response to the antiestrogen tamoxifen and to hypophysectomy. ER‐negative patients did not respond to either modality of therapy in our series. The absolute amount of ER did not significantly improve our ability to predict response to hormone treatment. In our experience, limited to a small number of patients, the presence of PgR in addition to ER did not increase the probability of response to endocrine therapy. Our findings underscore the usefulness of ER measurement in the prediction of response to either antiestrogen therapy or hypophysectomy in metastatic breast cancer.

Androgen‐induced remissions after antiestrogen and hypophysectomy in stage IV breast cancer

Fluoxymesterone (Halotestin), 10 mg p.o. BID, was given to 33 women with Stage IV breast cancer who had previously been treated with the antiestrogen tamoxifen (Nolvadex) and of whom 17 had also undergone hypophysectomy. Objective remissions were obtained in 13 patients (39%) with an average duration of 11+ months. Response rate to fluoxymesterone was similar in patients who had previously responsed to tamoxifen and in those who had failed. Duration of response was longer in the former group (12+ vs. 8 months), but this difference was not statistically significant. Of 17 patients who had been previously treated with tamoxifen and hypophysectomy, seven obtained further remission from fluoxymesterone for an average duration of ten months. Two patients with remissions from fluoxymesterone had previously failed to respond both to antiestrogen therapy and to the removal of the pituitary gland. Androgens appear to be an effective sequential endocrine treatment of Stage IV breast cancer after tamoxifen and hypophysectomy. The mechanism by which androgens induce tumor regression in some patients is probably not an antiestrogenic effect or an indirect effect mediated through the pituitary gland, but perhaps a direct action at the tumor level.

Hormone Receptors: An Update and Application

The introduction of measurements of hormone receptors in breast cancer tumor specimens provides a major advance in selection of patients likely to have hormone-dependent cancers. Endocrine adjuvant treatment for estrogen-positive breast cancers in both pre- and postmenopausal women has been shown to be effective in delaying recurrence. Whenever possible, estrogen and progesterone receptors should be measured in tumor tissue from all patients with breast cancer.

Endocrine versus endocrine plus five-drug chemotherapy in postmenopausal women with stage II estrogen receptor-positive breast cancer

Postmenopausal women who underwent modified radical mastectomy for Stage II, estrogen receptor (ER)‐positive breast cancer were randomized to receive endocrine treatment (tamoxifen [T], 40 mg daily for 3 years) alone versus endocrine treatment plus five‐drug chemotherapy (Cytoxan [cyclophosphamide, C], methotrexate [M], 5‐fluorouracil [F], vincristine [V], and prednisone [P], CMFVP, for 1 year). Chemotherapy consisted of oral P (1 month), oral C (12 months), and intravenous MFV weekly for the first 3 months, biweekly for 3 months, and triweekly for 6 months. Patients were entered into the study from October 1979, to October 1985, and the median follow‐up is 55 months. Results show that with 94 postmenopausal women, disease‐free survival (DFS) is significantly greater (P = 0.04, log‐rank test; P = 0.03, multivariate analysis) in patients receiving CMFVPT as compared to those receiving T alone. These results suggest that intensive chemotherapy combined with T is more effective in delaying recurrence than T alone in postmenopausal patients.

RECOVERY OF PITUITARY FUNCTION FOLLOWING SURGICAL REMOVAL OF LARGE NONFUNCTIONING PITUITARY ADENOMAS

Pituitary function was evaluated in eleven patients with large nonfunctioning pituitary adenomas before and 3 months after surgical adenomectomy. The longest anteroposterior dimension from the anterior wall to the dorsum of the sella on a lateral skull x‐ray ranged between 22 and 45 mm. All adenomas were confirmed histologically and had negative immunostaining for GH, PRL, ACTH and HCG.

Gradual recovery of lactotroph responsiveness to dynamic stimulation following surgical removal of prolactinomas: Long-term follow-up studies☆☆☆

Prolactin-secreting pituitary adenomas were selectively removed through a transsphenoidal approach from 120 women. Basal serum PRL levels (measured one to six months after surgery) were normal in 96 patients and decreased appreciably but not to normal in the remaining 24 patients. Dynamics of PRL secretion were studied at three to four months in 81 patients who had normal basal PRL level. Two different patterns of response to provocative stimuli were noted in these patients. In one group (group I, n = 65), patients had greater than 100% rise in serum PRL following TRH or perphenazine (Pz) administration. However, when analyzed as a group, the mean +/- SEM incremental responses (delta PRL) to TRH and Pz in these patients (29.9 +/- 1.9, 20.4 +/- 1.5 ng/mL) were significantly less (P less than 0.005 and P less than 0.001) than those of normal women (38.8 +/- 5, 33 +/- 5 ng/mL, respectively). Nineteen of these patients were restudied 12 to 72 months after surgery. The responses to provocative stimulation at that time were improved and similar to normal women. In contrast, in the second group (n = 16) of patients (group II), the responses to stimulation with the same agents were blunted or absent and remained so during subsequent studies. Recurrence of the hyperprolactinemia was noted in 11 of the 16 patients in group II and in only two of 65 patients in group I. The daily serum PRL levels in the immediate postoperative period were higher in patients from group II than those from group I. We conclude that transsphenoidal surgery is an optimal form of therapy for patients with PRL-secreting adenomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Tamoxifen-induced remission in breast cancer by escalating the dose to 40 mg daily after progression on 20 mg daily: A case report and review of the literature

An 80‐year‐old woman with metastatic breast cancer to the lungs and bones was treated with tamoxifen, 10 mg twice daily, with arrest of disease of six months duration. At the time of progression, increasing the dosage to 20 mg twice daily resulted in an objective remission now lasting 8+ months. This finding indicates that in this patient, the taxoxifen dosage of 40 mg/daily had a significantly higher anti‐tumor effect than 20 mg/daily. Pertinent literature on the correlation of response with tamoxifen dosage is reviewed.

Sequential endocrine therapy and chemotherapy in metastatic breast cancer: Effects on survival

SummaryFollow-up data of 113 patients with stage IV breast cancer treated with the antiestrogen tamoxifen show that the duration of remission is in average in excess of 21 months with a median of 16 months. Survival from start of antiestrogen therapy was significantly longer in patients who responded to tamoxifen, in those with dominant site of disease in the soft tissue, and in those with less extensive metastatic involvement. Overall survival from onset of metastasis was also much longer in patients who had responded to tamoxifen than in those who had failed (median of 52 and a half months vs 23 months). Hypophysectomy and androgen therapy used sequentially after antiestrogen each induced further remissions in almost half of the patients with a median duration of 16 months and 10 months respectively. Five drug chemotherapy used in most patients after maximum benefit had been obtained with endocrine therapy induced remissions in two-thirds of the patients with a median duration of 8 months. Adriamycin used sequentially as a single agent induced significant further palliation in almost half of the patients with a median duration of 4 and a half months. We conclude that sequential endocrine therapy and chemotherapy is highly effective in the treatment of stage IV breast cancer and offers prolonged survival to patients with hormone responsive tumors.