R. Dansey

Breast cancer in men. Clinical features, hormone receptor status, and response to therapy

Stage, estrogen receptor status, treatment and survival of 29 men with breast cancer attending the Breast Clinic of the Johannesburg Hospital between 1976 and 1985 are reviewed. Most patients had locoregionally advanced disease at presentation. Estrogen receptors (ER) were detected in significant concentration in 15/23 (65%). Local control was achieved in the majority, 19/26 (73%), by either surgery or radiation therapy alone or by combined modality treatment. Fifteen of 23 patients tested (65%) were ER‐positive (>10 fmol/mg protein). For patients with metastatic disease hormone receptor status was predictive of response to hormonal manipulation. Tamoxifen was the most acceptable and frequently used form of hormone therapy with 7/12 patients responding. Combination chemotherapy gave a response rate comparable to that seen in women with breast cancer.

Lack of a significant independent effect of race on survival in breast cancer

In an analysis of 2033 patients with breast cancer from two population groups presenting to the Combined Breast Clinic of the Johannesburg and Hillbrow Hospitals, black patients were found to present with more advanced stage disease (P > 0.0001) and to have a poorer prognosis within each stage than whites (P > 0.005‐>0.001). Intrastage inhomogeniety was indicated by the finding that black patients had significantly more advanced T and N categories within stage grouping as compared to white patients (P = 0.013‐P > 0.001). A multivariate analysis controlling for age, T and N in nonmetastatic showed that when these factors were taken into consideration there was no significant independent effect of race on survival. The data indicate that the poorer prognosis which has been previously reported for black patients probably results from intrastage variability of disease bulk, supporting the use of the TNM rather that the stage grouping system for prognostication. Age differences also were evident when the two population groups were compared, with breast cancer in blacks appearing to present at an earlier age. further analysis showed that these age differences were related to the age structure of the two populations and that breast cancer probably does not occur at a younger age in black subjects. Ethnic origin, does not appear to play a significant independent role in the prognosis of breast cancer in women.

Adjuvant chemotherapy (CMF) for stage III breast cancer: A randomized trial ☆

A randomized trial of the effect of adjuvant CMF chemotherapy in patients with Stage III breast cancer receiving primary local radiation or local radiation plus surgery, failed to reveal a survival benefit from early systemic treatment. The subset of premenopausal patients receiving chemotherapy did, however, show a significant prolongation of disease-free survival from 23 to 55 months. Overall survival of this subgroup was not increased. The study included the use of two dose levels of CMF to assess whether higher chemotherapy doses would be more effective. No dose effect was observed. Initial local control with radiation therapy or radiation plus surgery was achieved in the majority (90.9%). Distal recurrence and death from metastatic disease were the major causes of treatment failure. Treatment benefit among premenopausal patients was mainly delayed onset of distal metastatic disease. Among premenopausal patients, salvage therapy for metastatic disease appeared more effective in those not previously exposed to systemic treatment.

P-glycoprotein immunostaining correlates with ER and with high Ki67 expression but fails to predict anthracycline resistance in patients with advanced breast cancer

SummaryIn an attempt to further define the clinical utility of p-glycoprotein immunostaining in breast cancer, we examined 101 specimens from patients with advanced breast cancer. There was a significant correlation between estrogen receptor status and p-glycoprotein expression but only for low levels of p-glycoprotein. Premenopausal status appeared to correlate with increased p-glycoprotein expression, but this probably reflects patient selection as premenopausal patients had higher prior exposure to anthracyclines and were more likely to have received chemotherapy as initial treatment. P-glycoprotein expression was highly significantly correlated with expression of the proliferation related antigen Ki67, suggesting that p-glycoprotein expression may well be cell cycle dependent, with overexpression occurring in rapidly cycling cells. These findings may explain reported findings of modulation of p-glycoprotein expression by agents such as anti-oestrogens. P-glycoprotein positive staining did not, however, predict chemotherapy treatment failure or survival duration.

Aromatisation of Androstenedione by Human Breast Cancer Tissue: Correlation with Hormone Receptor Activity and Possible Biologic Significance

The conversion of 1 beta [3H] androstenedione to estrone in the presence of NADPH by breast cancer homogenates was assessed in tumors from 35 subjects together with estrogen and progesterone receptor concentration. Breast cancers from post menopausal women had significantly higher aromatase activity than those from premenopausal women. Although in many instances the local production of estrogens was sufficient to the capable of exerting a biologic effect, there was, however, no correlation with tumor estrogen or progesterone receptor content. Further studies of the biological significance of tumor aromatisation will depend on direct observation of tumor aromatase and response to suitable doses of aromatase inhibitors.

High-dose 4'-epiadriamycin for treatment of breast cancer refractory to standard dose anthracycline chemotherapy: achievement of second responses.

High-dose 4-epiadriamycin chemotherapy (110-150 mg/m2) was administered to 18 patients (95 treatment cycles) with advanced breast cancer refractory to or showing progression after prior treatment with adriamycin containing combination chemotherapy regimens. Thirteen out of 18 patients showed an objective response to therapy including 1 with complete and 12 with partial response. Although haematologic suppression was profound (mean granulocyte nadir 0.3 +/- 0.1 x 10(6)/l) recovery was rapid and there was no evidence of cumulative haematologic toxicity. Cardiac toxicity was not encountered during therapy even after cumulative doses greater than 1,200 mg/m2 of anthracycline drugs. Although the response rate was high, response duration was short (median 5.8 months).

First-Line Chemotherapy of Advanced Breast Cancer with Mitoxantrone, Cyclophosphamide and Vincristine

Seventy-five patients with stage 4 breast cancer were treated with a first-line chemotherapy regimen consisting of cyclophosphamide 600 mg/m2, mitoxantrone 12 mg/m2, and vincristine 1.4 mg/m2 (CNV). Objective response was seen in 61/75 (81%) with 17/75 (23%) complete remission (CR). Median duration of response was 38 weeks overall and 51 weeks for patients achieving CR. CNV is an effective regimen for the treatment of advanced breast cancer.

Prolonged Survival in Follicular Non Hodgkins Lymphoma is Predicted by Achievement of Complete Remission with Initial Treatment: Results of a Long Term Study with Multivariate Analysis of Prognostic Factors

Prognostic factors among 200 patients with follicular non-Hodgkins Lymphoma (NHL) (categories B to D of the Working Formulation) requiring systemic therapy were investigated. In univariate analyses factors that had a favourable influence on survival included complete response to treatment, female sex and age < 60 years, while the presence of B-symptoms was a weakly adverse prognostic factor. In a multivariate analysis only the achievement of CR (chi square = 5.9, p = 0.015) and sex (chi 2 = 5.9, p = 0.015) were significant prognostic factors for survival. Not only was achievement of CR predictive of survival, CR duration > or = 2 years was associated with median overall survival in excess of 6 years. These results suggest that patients who are responsive to first line chemotherapy have a good prognosis and that experimental treatments such as high dose chemotherapy with hemopoetic rescue should be reserved for patients who either fail to achieve CR with initial therapy or who relapse within 2 years of initial treatment.

Idarubicin plus Cytarabine versus Doxorubicin plus Cytarabine in Induction Therapy for Acute Non- Lymphoid Leukaemia: A Randomized Trial.

A randomized trial comparing idarubicin plus cytarabine (IDA/Ara-C) with doxorubicin plus cytarabine (ADM/Ara-C) in induction therapy for ANL,L was carried out. The IDA/Ara-C regimen consisted of idarubicin 20 mg/m(2) p.o. given on days 1, 2 and 3 plus cytarabine 25 mg/m(2) as a loading dose followed by 100 mg/m(2) by continuous infusion daily × 7 days. The ADM/Ara-C regimen consisted of adriamycin 30 mg/m(2) on days 1, 2 and 3 and the same dose of cytarabine. Patients who responded to the first cycle with at least 502, reduction of marrow blasts received a second treatment cycle followed by a consolidation cycle of the same treatment for those in CR at the end of 2 cycles. 35/52 (6770 receiving ADM/Ara-C achieved CR, with 25 (48%) patients in CR after a single treatment cycle. 28/48 (58%) receiving ADM/Ara-C achieved CR of whom 11 (23%) went into remission after the first treatment cycle. IDA/Ara-C caused less nausea and vomiting, less stomatitis, a shorter duration of neutropenia and less need for platelet support than ADM/Ara-C. The median duration of CR is 62 weeks for IDA/Ara-C and 48 weeks for ADM/Ara.-C. These differences are not statistically significant. Clinical cardiotoxicity occurred in 4/48 patients treated with ADM/Ara-C. No clinical cardiac toxicity was observed in those receiving IDA/Ara-C. The mean post-treatment ejection fraction was, in addition, lower for ADM/Ara-C than for IDA/Ara-C. It is concluded that IDA/Ara-C is an effective and safe induction therapy for ANLL.

Treatment of Hodgkin’s Disease with MOPP Chemotherapy: Effect of Dose and Schedule Modification on Treatment Outcome

An analysis of the therapy details of 99 patients receiving primary MOPP chemotherapy for Hodgkins disease revealed that treatment modification was a frequent occurrence. The mean cumulative dose calculated as a percentage of the projected ideal dose was 76%. Dose modifications of individual components of the MOPP combination were, however, variable and in part reflected disease-related factors, e.g. patients with stage 4 disease received significantly less vincristine than those with less advanced disease. An initial univariate analysis of factors influencing remission showed that the remission rate was significantly lower among those patients who had (a) liver involvement and (b) drug doses less than 75% of the ideal cumulative dose. Among the individual drug dosages, modification of the vincristine dose appeared to be the most significant treatment-related factor associated with lower remission rates. In a multivariate analysis where both disease-related and treatment-related factors were taken into account drug dosage remained a significant prognostic factor. The most important factors adversely affecting initial remission were the presence of liver involvement and reduction of the drug intensity index (cumulative dose divided by cumulative time). Disease-free survival was adversely influenced mainly by the presence of B symptoms and to a lesser degree, but still significantly, by a lower cumulative vincristine dose. Total survival was, however, influenced adversely only by the presence of B symptoms. The quality of MOPP therapy appears to play a significant role in determining the outcome of Hodgkins disease.