L. Seymour

Tumor factors predicting for prognosis in metastatic breast cancer: The presence of P24 predicts for response to treatment and duration of survival

Fifty‐one patients with metastatic breast cancer were investigated to determine tumor parameters with prognostic significance. Investigations included determinations of P24 content by immunocytochemical means using a monoclonal antibody to P24 protein; immunocytochemical analysis of estrogen and progesterone receptors; ploidy analysis by flow cytometry, and histologic grading. There were significant correlations between the presence of P24 and estrogen receptor, between histologic grade and P24 expression, and between estrogen and progesterone receptors. of the tumor factors investigated only P24 protein was, however, of prognostic significance. Patients with P24‐positive tumors had a significantly higher rate of response to treatment as well as more prolonged duration of response and duration of survival from diagnosis of metastatic disease. None of the other variables investigated were significantly predictive of outcome. P24 protein may be a useful predictor of prognosis in metastatic breast cancer.

Interferon plus tamoxifen treatment for advanced breast cancer: in vivo biologic effects of two growth modulators.

The effects of interferon-alpha (IFN) plus tamoxifen (TMX) in the treatment of advanced breast cancer were assessed. Changes of in vivo biologic determinants including hormone receptors, P24 protein, Ki-67 and growth factor expression were evaluated. Seven patients with advanced, heavily pretreated, breast cancer with accessible disease, underwent biopsy prior to and after sequential treatment with IFN and IFN plus TMX. Clinically 4/7 patients responded to treatment with one complete and three partial remissions. Apart from the favourable response rate the sequential in vivo changes in expression of tumour variables were of considerable interest. IFN treatment consistently increased the expression of the estrogen receptor (ER) and of the estrogen regulated protein P24 while decreasing the expression of the proliferation associated antigen Ki-67. Addition of TMX on the other hand resulted in a reduction of ER expression to pre-IFN levels and a rise in progesterone receptor (PR) expression. When the effect of either IFN or IFN plus TMX on the expression of two growth factors was assessed they were found to be somewhat variable. While PDGF expression tended to be suppressed, there was no clinical correlation with response to therapy. TGF beta expression was found in all patients prior to treatment and while all non-responders showed reduction of TGF beta following treatment, the alterations were variable amongst responders (including two patients with increased expression, one with no change, and one with decreased expression). It is concluded that both IFN and TMX exert multiple effects on the expression of tumour biologic variables and that while the study confirmed some of the predictions from in vitro models, the in vivo effect are more complex than has been appreciated from the models. From the clinical point of view, it might be expected that treatment which enhances the expression of ER in tumours should have a positive effect on the response to TMX.

Detection of P24 protein in human breast cancer: influence of receptor status and oestrogen exposure.

The expression of oestrogen regulated protein, P24, was investigated in 69 breast cancers. At initial evaluation P24 protein was detected significantly more frequently and was present in significantly higher concentration in oestrogen receptor positive than in receptor negative tumours. There was, however, no correlation between P24 staining and progesterone receptor, tumour ploidy or proliferative index. Nineteen patients received a short course of treatment with diethylstilboestrol. Following treatment with oestrogen, P24 staining became positive in 7/13 tumours previously negative for P24, including six tumours which were oestrogen receptor negative. Oestrogen administration also caused an increase of the proliferation index in 12/19 tumours, including 5/7 that were oestrogen receptor positive and 7/12 that were oestrogen receptor negative. In some instances oestrogenic stimulation of proliferation occurred together with increased P24 expression; in other instances proliferation index increased without induction of P24 synthesis. The in vivo effects of oestrogen in clinical breast cancer thus appear to show dissociation between enhancement of protein synthesis and cellular proliferation.

Response to second‐line hormone treatment for advanced breast cancer. Predictive value of ploidy determination

Twenty‐two patients who previously responded to first‐line hormonal therapy were evaluated for factors which would predict for response to second hormonal manipulation. Investigations performed at progression after initial hormone response included immunocytochemical estimation of estrogen and progesterone receptors as well as flow cytometric analysis of tumor ploidy. Approximately 50% of patients were found still to be estrogen receptor positive at relapse from first‐line hormone treatment. Progesterone receptor had, however, usually become negative. Nine of the 22 patients responded to second‐line hormonal therapy. Second hormone responses occurred with equal frequency among hormone receptor‐positive and hormone receptor‐negative patients. Tumor ploidy, as determined by flow cytometric study did, however, predict for response. Eight of 12 patients with diploid tumors responded to second‐line hormone therapy whereas only one of ten with aneuploid tumors responded. Flow cytometric analysis appears to be a promising technique for prediction of second hormone response after relapse from first‐line hormone manipulation.

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.

High-dose etoposide in treatment of metastatic breast cancer.

High-dose etoposide (1,500-2,500 mg/m2) was used for the treatment of 23 previously treated patients with advanced breast cancer. Six of 23 (26%) showed objective regression with a median duration of response of 5 months. Responses were seen at all sites apart from bone. Response was related to dose level with 11/23 responses of measurable lesions occurring at doses greater than or equal to 2,000 mg/m2 as compared to 2/23 responses at a dose of 1,500 mg/m2. The treatment regimen was able to be given on an outpatient basis with only routine supportive measures. High-dose etoposide may come to play a role in high-dose combination chemotherapy regimens for advanced breast cancer.

Single high-dose etoposide and melphalan with non-cryopreserved autologous marrow rescue as primary therapy for relapsed, refractory and poor-prognosis Hodgkin's disease.

A simplified schedule of high-dose chemotherapy (HDC) consisting of melphalan (140 mg m-2) plus VP16 (2.5 g m-2) given over 12-18 h together with autologous non-cryopreserved autologous bone marrow transplant (ABMT) was used for treatment of relapsed (37 patients) and refractory (seven patients) patients and as first-line treatment (four patients) for poor-prognosis Hodgkins disease. Two patients had a second HDC-ABMT after relapse following prior HDC-ABMT, giving a total of 50 procedures among 48 patients. The haematological recovery rate was 98% with a complete response rate of the Hodgkins disease of > 90%. Factors significantly influencing response rate were performance status and the presence of liver involvement. Thirty-nine patients are alive, with 37 in continuous complete remission. The median duration of survival and median duration of remission have not been reached at a median follow-up time of 45 months. Adverse prognostic factors for survival were disease status at the time of HDC-ABMT (refractory versus relapse, with primarily refractory patients showing significantly poor survival) and the presence of liver involvement. High-dose chemotherapy with short-duration chemotherapy and non-cryopreserved bone marrow is an effective and safe treatment modality for patients with relapsed and poor-prognosis Hodgkins disease.

Nope for Relapsed Aggressive Diffuse Non-Hodgkin's Lymphoma

Forty three patients with relapsed, diffuse aggressive lymphoma (Working Formulation Categories G to J) were treated with a combination chemotherapy regimen consisting of mitoxantrone 10 mg/m2 iv day 1, vincristine 1.4 mg/m2 iv day 1 and 14, prednisolone 50 mg/m2 p.o. days 1-5 and etoposide 100 mg/m2 p.o. days 1-5 of each cycle (NOPE). Fourteen patients (34%) achieved complete remission and another 6/43 (15%) achieved a partial response. Factors which significantly affected response were the presence of early stage, absence of systemic symptoms, non-bulky disease and serum LDH value < 350 IU. Four patients are alive and in complete remission from 25+ to 45+ months after completion of therapy. Duration of response and survival was significantly influenced by the duration of the initial response to first chemotherapy. NOPE is an active and safe treatment regimen with a substantial complete remission rate in patients with relapsed non-Hodgkins lymphoma.

Sequential α-interferon and tamoxifen: in-vitro reversal of MDR-1 mediated multidrug resistance in the MCF-7 cell line

Abstract Chemotherapy drug resistance in breast cancer is mediated in part by the MDR-1 gene product, P-glycoprotein (PGP). Tamoxifen (TMX) is able to modulate the MDR-1 phenotype in vitro. Interferons modulate other biologic effects of TMX and may enhance the effect of TMX on PGP function. We have investigated the effects of combinations of α-interferon (IFN) and TMX on the MDR-1 phenotype and function in MCF-7 cells. IFN and TMX were both growth inhibitory to MCF-7 cells. Preincubation with IFN potentiated the antiproliferative effect of TMX even at low concentrations. Immunocytochemically detected staining for the external domain of PGP was increased by both TMX and IFN and the effect of the two agents appeared to be synergistic. Despite the increased expression of the external domain of PGP, in functional studies, as assessed by inhibition of 3 H vinblastine (VBL) efflux, TMX partially reversed the MDR-1 phenotype in both parental MCF-7 and a multidrug resistant subline MCF-7 mdr . Prolonged exposure to IFN during culture, followed by TMX + IFN resulted in a further and significant decrease of VBL efflux in this cell line as compared to after TMX alone. TMX and IFN both have antiproliferative as well as anti-PGP functional effects in this model. Further studies with these two agents in combination, in the setting of clinical drug resistance, appear to be warranted.

Influence of tumour oestrogen concentration on prognosis in breast cancer: studies in pre- and post-menopausal patients of different ethnic groups

Summary Epidemiologic and clinical evidence suggest that oestrogens play a role in sustaining and promoting breast cancer. The relationship of tumour oestrogen levels and other features of breast cancer is, however, poorly understood. The present study included 108 patients with primary breast cancer who had tumour oestrone (E1) and oestradiol (E2) as well as oestrogen and progesterone receptors and aromatization capacity measured. The patient population included both pre- and post-menopausal women and comprised both black and Caucasian subjects. Tumour oestrogen concentrations were significantly lower in premenopausal as compared to post-menopausal patients while E2 measurements were higher in premenopausal as compared to post-menopausal patients. There was no significant correlation between either tumour oestrogen level and hormone receptor status. Tumour oestrogen and progesterone receptor concentrations as well as tumour E1 concentrations were lower in black post-menopausal patients as compared to those found in white post-menopausal patients. In a multivariate analysis both disease free and overall survival were significantly lower in patients with higher tumour E1 levels. Other factors of prognostic significance were race, tumour size (T) and nodal status (N). These findings suggest that tumour hormone content may influence the behaviour of breast cancer independantly of hormone receptor status.