Estrogen receptor determination and long term survival of patients with carcinoma of the breast.

To investigate whether or not hormone receptor determination gives independent prognostic information for long term survival of patients with carcinoma of the breast, we studied 1,392 patients with early carcinoma of the breast. Patients were part of two prospective, multi-institutional trials, the first begun in 1974 and the second in 1980. Estrogen receptor assays were performed on all primary specimens taken of the carcinoma of the breast. Initial treatment for all patients was a modified radical mastectomy. Nine hundred and seventeen patients had negative axillary nodes and were observed without additional therapy. Four hundred and seventy-five had positive nodes and were randomized to receive combination chemoendocrine adjuvant therapy. One thousand and sixty-three (76.4 per cent) of the patients were found to have estrogen receptor positive (ER+) tumors (greater than or equal to 3 femtomoles per milligram cytosol of protein). The ten year over-all survival rate of 65.9 per cent was significantly better than that of 329 (23.6 per cent) patients with estrogen receptor negative (ER-) tumors (less than 3 femtomoles per milligram cytosol protein), who had a ten year over-all survival rate of 56.0 per cent (p = 0.0001). Higher estrogen receptor values were associated with Caucasian (p = 0.0001) and postmenopausal patients (p = 0.0001). In a proportional hazards regression model, patients with ER+ tumors had a significantly longer over-all survival period (p = 0.0001), but only a marginally improved disease-free survival time (p = 0.07) when compared with patients who had ER- tumors. These results indicate that ER determination does have prognostic value for long term over-all survival of patients with carcinoma of the breast. The greater importance of ER analysis to over-all compared with disease-free survival may be related to more easily managed recurrent disease among the ER+ group.

Local-regional breast cancer recurrence following mastectomy.

Local-regional recurrence patterns were investigated in 1392 patients with breast cancer. Primary treatment for all patients included a mastectomy. Nine hundred seventeen patients had negative nodes and did not receive systemic therapy. Four hundred seventy-five patients had node metastases and were randomized to receive different combinations of chemoendocrine therapy. Follow-up ranged between 5 and 16 years. Two hundred thirty (25.8%) node-negative patients have had recurrences, with the initial recurrence being local-regional in 9.2%. Two hundred forty-two (50.9%) node-positive patients have had recurrences, with the initial recurrence being local-regional in 17.1%. Larger tumors and more extensive node involvement were associated with more first local-regional recurrences. The relative percent of first local-regional recurrence among patients in whom cancer recurred was similar for node-negative and node-positive patients (35.4% and 33.5%, respectively). In 63.6% of patients in whom cancer recurred, first local-regional recurrence were distant. Larger tumors, more extensive node involvement, and a shorter disease-free interval after mastectomy were associated with more rapid appearance of distant recurrence among these patients.

Short-term tamoxifen plus chemotherapy: superior results in node-positive breast cancer.

Three hundred eleven patients with node-positive breast cancer were randomized to one of three adjuvant treatments: cyclophosphamide (Cytoxan), methotrexate, and 5-fluorouracil; all of the above with tamoxifen citrate; or all of the above with tamoxifen and bacillus Calmette-Guerin vaccination. Local therapy for all patients was a modified radical mastectomy. Estrogen receptors were measured on all primary tumors. Patients were stratified by the number of positive nodes (one to three nodes and more than three nodes) and estrogen-receptor value (less than 3 femtomole/mg and greater than or equal to 3 femtomole/mg). Follow-up is available, with a mean of 9.1 and maximum of 14.2 years. In this study the efficacy of short-term tamoxifen is apparent over that of chemoimmunotherapy alone and continues to be significant with prolonged follow-up. The addition of tamoxifen to chemoimmunotherapy significantly prolonged disease-free survival among patients with estrogen receptor-positive tumors who were postmenopausal, who had larger tumors (greater than 3 cm), or who had more extensive axillary node involvement (more than three nodes). Tamoxifen improved overall survival for patients with estrogen receptor-positive tumors larger than 3 cm. The addition of bacillus Calmette-Guerin Cytoxan, methotrexate, 5-fluorouracil, and tamoxifen did not significantly alter disease-free or overall survival.

Breast cancer survival and perioperative blood transfusion.

The effect of perioperative blood transfusion on disease-free and overall survival was studied in 812 patients with stages I and II breast cancer, followed up prospectively in a multicenter study. All patients initially underwent a modified radical mastectomy. Patients with axillary node-negative, stage I cancer were followed up without additional therapy. Patients with axillary node-positive, stage II cancer were randomized to receive adjuvant chemoendocrine therapy. Transfusion was done in 35.8% of the patients with stage I and in 37.3% of the patients with stage II cancer. For the patients with stage II cancer, perioperative blood transfusion did not affect disease-free or overall survival. For the patients with stage I cancer, perioperative blood transfusion resulted in a worse disease-free and overall survival (p = 0.05 and 0.02, respectively), which was particularly evident for those patients who received more than 1 unit. This study suggests that stage of disease, adjuvant therapy, number of transfusions, and duration of follow-up must be considered in further analyses.

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.

Primary hyperparathyroidism. A review of the long-term surgical and nonsurgical morbidities as a basis for a rational approach to treatment.

We studied long-term morbidity after parathyroid surgery for primary hyperparathyroidism in 100 patients and compared it with the long-term morbidity of medical follow-up from the literature. The surgical treatment of primary hyperparathyroidism was associated with negative results of neck explorations, persistent hypercalcemia, recurrent hypercalcemia, permanent hypoparathyroidism, or recurrent laryngeal nerve damage in 13 (19%) of 68 patients followed up for five years postoperatively. A review of medical follow-up as reported in the literature showed progression of disease in 8% to 22% of patients followed up for five to ten years. There was no convincing evidence that mild primary hyperparathyroidism resulted in progressive osteoporosis or renal failure. Furthermore, no significant improvement in hypertension, peptic ulcer disease, or renal function followed successful parathyroid surgery. Unless future studies demonstrate progressive osteoporosis or renal damage in untreated, mild primary hyperparathyroidism, medical follow-up is a reasonable alternative to surgery in the compliant patient over 50 years of age.

Recurrence patterns in a prospective study of patients with stage II breast cancer treated with endocrine-chemotherapy.

Local-regional versus distant recurrence patterns were investigated for 311 patients with stage II node-positive breast cancer who were part of an endocrine-chemotherapy adjuvant breast cancer trial. After mastectomy patients were randomized to receive either cytoxan, methotrexate, and 5-fluorouracil (CMF) (1 year) or CMF with tamoxifen (1 year) with or without bacillus Calmette-Guérin (BCG). With a median follow-up of 92.1 months, 55.3% of the patients had recurrences. The first site of recurrence was local-regional for 31.4% of patients and distant for 68.6%. This pattern of first recurrence was not associated with treatment groups, menopausal status, race, estrogen receptor value, number of positive lymph nodes, or tumour diameter. Although patients with a first local-regional recurrence had a better overall prognosis compared with those with a first distant recurrence, 52.2% of those patients with an initial local-regional recurrence developed a distant recurrence within 12 months. Among patients who had a recurrence, 48.3% had a local-regional recurrence at some time during their follow-up. Conclusions from this study are (1) patterns of recurrence were not affected by the addition of antiestrogen therapy to chemotherapy; (2) for the variables tested, including number of positive nodes and tumor diameter, no association with recurrence patterns was found; and (3) most patients (52.2%) with a first local-regional recurrence will develop a distant recurrence within 1 year.

Assessment of tamoxifen as adjuvant therapy in stage II breast cancer: a long-term follow-up.

Results of a prospective, randomized clinical trial of three treatment regimens--cyclophosphamide, methotrexate, and 5-fluorouracil (C); C plus the antiestrogen, tamoxifen citrate (CT); and CT plus bacillus Calmette-Guerin (CTBCG)--in 311 women with stage II breast cancer are reported. The data were analyzed by univariate (product limit and log rank) analysis and by multivariate analysis. Estrogen receptors were measured in all primary tumors. The mean follow-up period was 78.2 months. The regimens containing tamoxifen citrate significantly decreased the risk of recurrence in patients with positive estrogen receptors. The addition of tamoxifen does not, however, appear to provide an advantage in overall survival. No benefit in disease-free or overall survival was observed resulting from the addition of BCG to the treatment regimen. The design of the study did not permit an evaluation of the efficacy of the chemotherapy used inasmuch as all patients received it.

The interaction of estrogen receptor status and race in predicting prognosis for stage I breast cancer patients.

As part of a multi-institutional breast cancer data base, 501 stage I, node negative patients have been followed prospectively with a median of 89 months. Patients were treated by a modified radical mastectomy without postoperative therapy. Estrogen receptor (ER) content of the primary tumor was determined in all cases. For the entire patient group at 10 years, the disease-free survival (DFS) rate is 72% and the overall survival (OS) rate is 85%. Both ER value and race (black versus white) were found to be significant prognostic variables for DFS (p = 0.008 and 0.02, respectively) and for OS (p = 0.0001 and 0.01, respectively). ER positive patients had a better DFS and OS rate compared with ER negative patients (74% versus 66% and 90% versus 68%, respectively). Black patients had significantly worse DFS and OS rates compared with white patients (64% versus 74% and 75% versus 86%, respectively). Statistical interaction between the ER and race variables was apparent when comparing the similar DFS for ER positive white (75%), ER negative white (72%), and ER positive black (73%) patients in contrast to a DFS of less than 42% at 10 years for the ER negative black patients. An analysis of the data for the ER negative black patients suggested that the postmenopausal ER negative black patients are at particularly high risk of recurrence and death from breast cancer.

Adjuvant endocrine therapy, cytotoxic chemotherapy and immunotherapy in stage II breast cancer: 6-year result.

Six-year results of a prospective, randomized clinical trial of three treatment regimens [(1) cytoxan, methotrexate and 5-fluorouracil (CMF); (2) CMF plus the antiestrogen drug, tamoxifen (CMFT); (3) CMFT plus Bacillus Calmette-Guerin (BCG) vaccinations] in 312 women with stage II breast cancer are reported. Addition of tamoxifen to CMF therapy significantly decreased the number of recurrences at 6 years in ER + patients with greater than or equal to 4 positive axillary lymph nodes, and in those with tumor diameter in excess of 3 cm. The beneficial effect of tamoxifen appeared to be independent of the menopausal status. Addition of tamoxifen to CMF had no effect on disease-free survival in ER + patients with 1-3 positive axillary lymph nodes or in patients with ER--tumors. Addition of BCG vaccinations had no discernible effect on disease-free survival. ER measurements in the primary tumor provide important prognostic information regardless of treatment, with ER + patients having increased overall survival after 6 years. Further follow-up is needed to determine whether tamoxifen is delaying recurrence or preventing it in a subset of these patients.

Benign and malignant breast disease: magnetic resonance and radiofrequency pulse sequences.

Thirty patients with suspected abnormality of the breasts on mammography were evaluated with magnetic resonance imaging (MRI) in a blind fashion. Spin-echo (SE) 250/30 msec scans were used to screen the examined breast. At the location of the suspected abnormality, inversion recovery (IR) 1000/30/300, SE 1000/30, and SE 1000/120 scans were performed. On the basis of these magnetic resonance images and experience with 70 previously studied patients, abnormalities of the breasts were grouped into five patterns. Ten malignant lesions exceeded 1 cm in diameter and were all correctly diagnosed by mammography and MRI. Of the remaining 20 benign conditions, four were suspicious for malignancy on MRI compared to eight with mammography. The shape of the lesion and the change in its signal intensity with different MR radiofrequency pulse sequences allows differentiation between a benign and a malignant process. On the basis of this preliminary experience, it seems MRI may have an adjunctive role to screening mammography. SE 1000/120 scans show higher signal intensity from carcinoma than from normal duct tissue, fibrocystic disease, and fibroadenoma. In this respect, it may allow some tissue specification in the breast.

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.

Antiestrogen-cytotoxic chemotherapy and bacillus Calmette-Guerin vaccination in stage II breast cancer: seventy-two-month follow-up.

A prospective, randomized clinical trial of adjuvant treatment of 312 stage II breast cancer patients with use of chemotherapy, antiestrogen therapy, and immunotherapy is reported after 72 months of follow-up. The stratification of patients was based on nodal involvement and estrogen receptor (ER) assay of the primary tumors. Findings at 72 months indicate that antiestrogen therapy (tamoxifen, Nolvadex) added to chemotherapy with cyclophosphamide (Cytoxan), methotrexate, and fluorouracil (5-Fluorouracil) (CMF) resulted in significant delayed recurrence in ER-positive postmenopausal patients, ER-positive patients with four or more positive nodes, and ER-positive patients with tumors greater than 3 cm in diameter. The addition of nonspecific immunotherapy with bacillus Calmette-Guerin had no effect on disease-free survival. ER and progesterone receptor measurements in patients with primary breast cancer provide valuable prognostic information on subsequent recurrence and overall survival and should be documented in future clinical trials.

Progesterone receptors as a prognostic factor in Stage II breast cancer.

The presence of estrogen receptors in breast cancers is now accepted as a predictor of extended disease-free survival, but the relative value of progesterone receptors for this purpose has not been established. We have examined both receptors along with other risk factors in 189 patients receiving adjuvant therapy for Stage II breast cancer. The presence of either estrogen receptors or progesterone receptors was positively correlated with disease-free survival when analyzed separately, whether or not the adjuvant regimen included an endocrine component. However, when estrogen receptors and progesterone receptors were analyzed together in multivariate models, the presence of progesterone receptors was more significant than that of estrogen receptors for predicting time to recurrence, regardless of what other variables were included in the model. These data suggest that determination of the progesterone-receptor concentration is of equal or greater value than determination of the estrogen-receptor concentration for predicting the disease-free survival of patients with breast cancer. Future trials should include measurement of progesterone receptors.

Initial experience with nuclear magnetic resonance (NMR) imaging of the human breast.

Two patients with breast abnormalities, one malignant and one benign, were studied with nuclear magnetic resonance (NMR) imaging utilizing a cryogenic superconducting magnet. Three-dimensional NMR images were obtained in one case and single slice planar images were obtained in the other. The NMR images correlated well with the corresponding mammograms. Although both conditions exhibited a different signal intensity for the area of abnormality compared to adjacent ductal and fatty tissue, the configuration of the abnormal areas allowed distinction between benign and malignant process.

Adjuvant endocrine therapy, cytotoxic chemotherapy, and immunotherapy in stage-II breast cancer: five-year results.

Five-year results of a prospective, randomized clinical trial of three treatment regimes--(a) cytoxan, methotrexate, and 5-fluorouracil (CMF); (b) CMF plus the antiestrogen drug, tamoxifen (CMFT); and (c) CMFT plus bacillus Calmette-Guerin (BCG) vaccinations--in 312 women with stage-II breast cancer are reported. Estrogen receptors (ER) were measured in all of the primary tumors. Addition of tamoxifen to CMF therapy significantly decreased the number of recurrences at five years in ER positive patients with four or more positive axillary lymph nodes. Addition of tamoxifen to CMF had no effect on disease-free survival in ER-positive patients with 1-3 positive axillary lymph nodes or in patients with ER-negative tumors. Addition of BCG vaccinations had no discernible effect on disease-free survival. ER measurements in the primary tumor provide important prognostic information regardless of treatment, with ER-positive patients having lower recurrence rates and mortality after five years. ER measurements also have predictive value for response to endocrine therapy. Further follow-up is needed to determine whether tamoxifen is delaying recurrence or preventing it in a subset of these patients.

Estrogen receptor status as a prognostic indicator for stage I breast cancer patients.

The prognostic value of estrogen receptor determination was studied for 510 stage I (axillary node negative) breast cancer patients treated by mastectomy alone. Results at 60 months after mastectomy indicate that stage I patients whose tumors lack estrogen receptors fall into a significantly poorer prognostic group for both recurrence and survival than those whose tumors contain estrogen receptors. Within the postmenopausal group, estrogen receptor negative (ER -) patients are recurring more rapidly than estrogen receptor positive (ER +) patients. Within the premenopausal group, ER + patients have a recurrence rate identical to ER - patients, which is apparent only after prolonged follow-up. In contrast to postmenopausal ER + patients, premenopausal ER + patients appear to have no prognostic advantage over the ER - patients, and thus constitute a high risk group for which adjuvant endocrine therapy might prove beneficial.