John F. Stewart

Oestrogen receptors, sites of metastatic disease and survival in recurrent breast cancer

Two hundred and seventy eight patients with advanced breast cancer who had oestrogen receptor (ER) analyses performed on primary or recurrent tumours were studied. Oestrogen receptor (ER) positive (ER ≧ 5 fmole receptor/mg cytosol protein) tumours recurred significantly more commonly in bone and ER negative (ER < 5 fmole receptor/mg cytosol protein) tumours recurred significantly more often in liver and brain. Patients with ER positive tumours had a significantly better survival after relapse. ER analysis of either primary or recurrent tumour gives some indication of the natural history of breast cancer.

Adriamycin alone or combined with vincristine in the treatment of advanced breast cancer

One hundred and nineteen women with advanced breast cancer treated previously by endocrine therapy but no prior chemotherapy were given adriamycin 70 mg/m2 i.v. on day 1 of a 3-weekly cycle for 8 courses, followed by a regimen of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) until relapse. They were allocated randomly to receive either no treatment (group A) or vincristine 1.4 mg/m2 i.v. on days 1 and 8 during treatment with adriamycin (group AV). In 107 evaluable patients objective responses were seen in 30/53 patients (57%) in group A and in 28/54 patients (52%) in group AV. The projected dose of adriamycin received was 78% in group A and 75% in group AV; and 60% for vincristine in group AV. The subjective and haematological toxicity for adriamycin was similar in both groups, but 65% of patients treated with vincristine developed neurotoxicity. The median duration of objective regressions was the same for both groups (7 months), and the median time to failure was 5 months for group A and 6 months for group AV respectively. The median survival of the responders tended to be longer in group AV (17.5 months) than in group A (13 months), but this difference was not statistically significant (P = 0.112). It is concluded that there is no advantage therapeutically in combining vincristine and adriamycin in patients with advanced breast cancer.

Steroid Receptors and Prognosis in Operable (Stage I and II) Breast Cancer

Four hundred and forty-seven women with operable (TNM stage I or II) breast cancer in whom oestrogen receptors (ER), progesterone receptors (PgR) or both receptors had been assayed were studied. Receptor status was independent of axillary nodal status, but infiltrating duct carcinomas that were ER-, PgR- or ER-PgR- were more likely to be anaplastic (P less than 0.001). Four hundred patients with follow-up and uniform treatment were analysed for post-operative disease-free interval (DFI) and survival. No significant difference in DFI existed between patients with ER+ and ER- tumours or PgR+ and PgR- tumours, although there was a trend for longer DFI for ER+ and PgR+. DFI was longer in patients with better-differentiated (grade 1 and 2) tumours than with anaplastic (grade 3) tumours. In patients with ER+ tumours, those with grade 1 and 2 tumours had a longer DFI than those with grade 3 tumours (P less than 0.005). Survival was significantly longer in patients with ER+ tumours compared to those with ER- tumours (P less than 0.001), but there was no such association between tumour PgR and survival. Survival of patients with ER+PgR+ tumours was significantly longer than those with ER-PgR- tumours (P less than 0.025) and, in patients with no evidence of axillary nodal involvement, significantly longer than those with ER+PgR- tumours. Survival in patients with nodal involvement was influenced by histological grade, being longer in those with grade 1 or 2 tumours compared to those with grade 3 tumours. For ER+ tumours, survival was longer in patients with grade 1 or 2 than with grade 3 tumours. These results suggest that steroid receptors significantly affect survival but not DFI. This effect is most closely related to ER content, with relatively little additional information accruing from analysis of PgR. Histological grade influences both DFI and survival, and analysis of both grade and ER content may give a more accurate indication of prognosis in operable breast cancer.

Contribution of prednisolone to the primary endocrine treatment of advanced breast cancer

Two hundred and four patients with progressive locally advanced or metastatic breast cancer not controllable by local therapy alone, and who had had no prior systemic therapy for advanced disease, were treated by primary endocrine therapy according to menopausal status. Premenopausal patients received ovarian irradiation (O) whilst postmenopausal patients received tamoxifen 10 mg b.d. (T). Patients were randomised to receive either no additional treatment or prednisolone 5 mg b.d. (P). In 180 evaluable patients, T + P induced significantly more responses than T alone (26/73 vs 9/72, P less than 0.01) and the addition of P to O in premenopausal patients also induced more responses than O alone (7/16 vs 4/19), but this difference was not significant and accrual of premenopausal patients continues. There was a trend for patients receiving T + P to have a longer survival than those receiving T alone (median 25 vs 16 months). These trends occurred in patients with tumours positive for oestrogen receptors and when receptor status was unknown; patients with receptor-negative tumours had a negligible response to endocrine treatment. P mitigated the occurrence of hypercalcaemia and tumour flare sometimes seen with T alone.

Estrogen and progesterone receptors: Correlation of response rates, site and timing of receptor analysis

Summary156 patients with advanced breast cancer of known estrogen receptor (ER) and progesterone receptor (PgR) status treated by endocrine therapy were studied. Regarding values for ER and PgR ⩾ 5 fmole/mg cytosol protein as positive, patients were divided into 4 phenotypic subgroups: ER+PgR+ (43%), ER+PgR− (26%), ER−PgR+ (8%), and ER−PgR− (23%). In patients with tumor phenotype ER+PgR+, responses were seen in 20/30 (67%) assessable initial treatments when receptor assays were performed on tumor recurrence or on primary tumor immediately before endocrine therapy, and in only 11/32 (34%) assessable initial treatments when receptor analysis was performed on primary tumor and there was intervening local therapy before endocrine therapy was started for tumor recurrence (P<0.05).Responses to first endocrine therapy for each tumor phenotype were ER+PgR+ 50%, ER+PgR− 27%, ER−PgR+ 27%, and ER−PgR− 6%. Four of 16 (25%) patients with ER+PgR+ tumors responded to subsequent secondary endocrine therapy, but such responses were not observed in 20 patients with other tumor phenotypes.Duration of response was similar for each phenotype, but patients with ER−PgR− tumors had a significantly shorter survival from time of initial endocrine treatment than patients of any other phenotype.These results suggest that repeat steroid receptor assays on accessible tumor immediately before endocrine therapy may result in improved predictability.156 patients with advanced breast cancer of known estrogen receptor (ER) and progesterone receptor (PgR) status treated by endocrine therapy were studied. Regarding values for ER and PgR ⩾ 5 fmole/mg cytosol protein as positive, patients were divided into 4 phenotypic subgroups: ER+PgR+ (43%), ER+PgR− (26%), ER−PgR+ (8%), and ER−PgR− (23%). In patients with tumor phenotype ER+PgR+, responses were seen in 20/30 (67%) assessable initial treatments when receptor assays were performed on tumor recurrence or on primary tumor immediately before endocrine therapy, and in only 11/32 (34%) assessable initial treatments when receptor analysis was performed on primary tumor and there was intervening local therapy before endocrine therapy was started for tumor recurrence (P<0.05). Responses to first endocrine therapy for each tumor phenotype were ER+PgR+ 50%, ER+PgR− 27%, ER−PgR+ 27%, and ER−PgR− 6%. Four of 16 (25%) patients with ER+PgR+ tumors responded to subsequent secondary endocrine therapy, but such responses were not observed in 20 patients with other tumor phenotypes. Duration of response was similar for each phenotype, but patients with ER−PgR− tumors had a significantly shorter survival from time of initial endocrine treatment than patients of any other phenotype. These results suggest that repeat steroid receptor assays on accessible tumor immediately before endocrine therapy may result in improved predictability.

Quantitative comparison of estradiol and progesterone receptor contents of primary and metastatic human breast tumors in relation to response to endocrine treatment

Cytosol receptors for estradiol (RE) and progesterone (RP) in breast tumors from women attending one clinic have been analyzed. The analysis involved a single concentration of [3H] ligand and low speed centrifugation of homogenates. Analysis of tumors immediately before the start of first endocrine treatment indicated a poor response rate in patients with tumor RE <20 fmol/mg protein. A cut-off value of 20 fmol/mg protein gave the best discrimination between responders and nonresponders in both pre- and postmenopausal patients. An appreciable number of responses (17%) was seen with RP negative tumors (<5 fmol/mg protein) and analysis of this receptor alone is not recommended. Combined analysis of RE and RP indicated good response rates for RE+ RP+ (64%) and RE − RP+ (67%) tumors and a low response rate for RE− RP− (9%) tumors. Responses also occurred in patients with RE+ RP− tumors (30%). The influence of cut-off value and menopausal status on clinical usefulness of combined RE and RP analysis is discussed. Data are also presented on the clinical value of receptor analyses on primary tumors in predicting the endocrine sensitivity of subsequent metastatic disease. Receptor results for tumors obtained at different times from the same patient are presented and discussed. Receptor phenotype of some tumors does change with time and this is influenced by receptor amount, histological appearance, and intervening treatment.SummaryCytosol receptors for estradiol (RE) and progesterone (RP) in breast tumors from women attending one clinic have been analyzed. The analysis involved a single concentration of [3H] ligand and low speed centrifugation of homogenates. Analysis of tumors immediately before the start of first endocrine treatment indicated a poor response rate in patients with tumor RE <20 fmol/mg protein. A cut-off value of 20 fmol/mg protein gave the best discrimination between responders and nonresponders in both pre- and postmenopausal patients. An appreciable number of responses (17%) was seen with RP negative tumors (<5 fmol/mg protein) and analysis of this receptor alone is not recommended. Combined analysis of RE and RP indicated good response rates for RE+ RP+ (64%) and RE − RP+ (67%) tumors and a low response rate for RE− RP− (9%) tumors. Responses also occurred in patients with RE+ RP− tumors (30%). The influence of cut-off value and menopausal status on clinical usefulness of combined RE and RP analysis is discussed.Data are also presented on the clinical value of receptor analyses on primary tumors in predicting the endocrine sensitivity of subsequent metastatic disease.Receptor results for tumors obtained at different times from the same patient are presented and discussed. Receptor phenotype of some tumors does change with time and this is influenced by receptor amount, histological appearance, and intervening treatment.

Oestrogen Receptors, Clinical Features and Prognosis in Stage III Breast Cancer

One hundred and twenty-four patients with stage III breast cancer who had oestrogen receptor analyses (ER) performed on primary tumour were studied. For operable disease (T3a, N0.1, M0), patients with ER-negative (ER less than 5 fmol/mg cytosol protein) tumours had a shorter duration of symptoms, but no other differences were observed at presentation. In patients with inoperable (T3b,4, N0.1, M0 or any T, N2.3, M0) tumours there were no differences in the clinical characteristics that rendered the primary tumour inoperable between those with ER+ or ER- tumours. The median disease-free interval (DFI) in patients with operable tumours and uninvolved axillary nodes was significantly longer in those with ER+ tumours (P less than 0.05). Median survival was significantly longer in patients with ER+ tumours than in those with ER- tumours (50 vs 27.5 months, P less than 0.05), and when survival was analysed according to various methods of initial treatment, it was significantly prolonged in patients with operable (T3a, N0.1, M0) ER+ tumours compared to those with operable ER- tumours. In patients with inoperable tumours no effect of ER status on prognosis was demonstrated. These results suggest that oestrogen receptor content may be a prognostic variable in patients with operable stage III breast cancer, but further studies of patients with similar methods of initial treatment are needed to confirm this. Patients with operable stage III tumours should be considered separately from those with locally advanced inoperable tumours in view of the significant differences in their survival prospects.

Adriamycin and mitomycin C as initial chemotherapy for advanced breast cancer

Adriamycin and mitomycin C in combination have been tested in the treatment of advanced breast cancer. In an initial pilot study 11 heavily pretreated patients received mitomycin C alone and 2 (18%) achieved partial responses. Subsequently, 27 patients who had not received prior chemotherapy for advanced breast cancer were treated with adriamycin 40 mg/m2 + mitomycin C 10 mg/m2 i.v. every 3 weeks. Six (22%) achieved complete and 10 (37%) achieved partial responses, giving an objective regression frequency of 59%. The median duration of response was 37 weeks (range 8-55+ weeks).

Post-operative serum sialyltransferase levels and prognosis in breast cancer

SummarySerum sialyltransferase (SST) activity was measured 10 days after mastectomy in 153 patients with operable breast cancer. Enzyme activity declined with time in storage (1–42 months). After correction for loss of activity in storage, patients with SST activity below the median value had a longer disease-free interval (DFI) than those with SST activity above the median, and this difference remained when patients were stratified by axillary nodal status, tumor size, and tumor grade. Survival was longer in patients with low SST activity. Postoperative elevation of SST indicates a poor prognosis in patients with operable breast cancer.

Results of endocrine therapy do not predict response to chemotherapy in advanced breast cancer

One hundred and four patients with advanced breast cancer treated with adriamycin +/- vincristine had had prior endocrine therapy. Of 28 responders to prior endocrine therapy a response to subsequent chemotherapy occurred in 15 (54%); the response frequency in the 76 non-responders to endocrine therapy was 51% (39 patients). The median time to treatment failure was not significantly different between responders to prior endocrine treatment and non-responders (7 months vs 5 months; P = 0.136). Although the median survival from starting chemotherapy tended to be longer in the endocrine responders (18 months) than in the non-responders (12 months), there was no significant difference between the two groups (chi = 2.749; P = 0.097). In a subgroup of 31 non-responders to endocrine therapy who had had stable disease (greater than or equal to 6 months) the median time to treatment failure was 6 months and median survival 13 months. This lack of differences existed for each subgroup of endocrine therapy. Response to prior endocrine treatment was not shown to be a determinant of response to subsequent chemotherapy.