P.C. Willsher

A comparison outcome of male breast cancer with female breast cancer

BACKGROUND It is unclear whether breast cancer has a similar prognosis in males and females. METHODS A 20-year retrospective study of all male breast cancer patients in our region was undertaken. We compared this series with a group of females matched for the major prognostic factors and an unmatched series of female patients treated over the same period. RESULTS Forty-one patients with invasive cancer and 2 with ductal carcinoma in situ were identified. One invasive cancer was treated with radiotherapy, 40 had surgery. Local recurrence occurred in 23% and axillary recurrence in 40% of cases. Male and female patients (n = 123) matched for the major prognostic factors showed a similar outcome for disease-free interval (P = 0.90) and survival (P = 0.27). However, both the above groups had a significantly worse outcome than the unmatched series of female patients with breast cancer. CONCLUSIONS When prognostic factors are allowed for, male and female breast cancer patients have a similar outcome. This suggests that such features should be taken into account when determining management for males with breast cancer just as they are in females.

Prognostic significance of serum c-erbB-2 protein in breast cancer patients.

SummaryThe tissue expression of c-erbB-2 protein in breast cancer is a marker of poor prognosis in a number of studies. More recently it has also been suggested that c-erbB-2 expression may predict response to systemic therapy in patients with advanced breast cancer. The measurement of c-erbB-2 protein in the serum of breast cancer patients has now been reported, but the significance of this finding is not clear. In this study an ELISA assay was used to measure c-erbB-2 in the sera of 23 normal controls, 46 benign breast disease patients, and 119 breast cancer patients. Elevated serum c-erbB-2 protein levels were detected in 13% (3/23) of normal controls, 15% (7/46) of benign disease patients, 15% (7/46) of Stage I/II patients, 26% (9/35) of Stage III patients, and 21% (8/38) of Stage IV patients. The tissue expression of the c-erbB-2 protein showed no association with detection of the serum c-erbB-2 protein (p = 0.31). In the 67 Stage III and IV patients who had assessable disease the presence of the c-erbB-2 protein in the serum bore no relationship to response to hormonal therapy (p = 0.71). Serum detection of the c-erbB-2 protein in Stage I/II patients predicted for a worsening of both survival outcome (p = 0.002) and disease free interval (p = 0.002). A worse outcome was also seen for the Stage III patients (p = 0.04) and Stage IV patients, although the latter did not reach statistical significance (p = 0.27).This study found that the presence of c-erbB-2 in the serum of breast cancer patients was of prognostic significance for all stages of disease.

The clinical relevance of static disease (no change) category for 6 months on endocrine therapy in patients with breast cancer.

This study reports on the clinical relevance of the static disease (SD) category in 255 breast cancer patients on endocrine therapy. All patients had received first- and second-line endocrine therapy and were assessed for response by the International Union Against Cancer (UICC) criteria. We did not include patients who received first-line endocrine therapy but did not or have not yet proceeded to second-line hormone therapy, e.g. died from rapidly progressive disease, started chemotherapy for rapidly progressive disease, remained in long-term remission on first-line endocrine therapy. We analysed survival from initiation of first-line endocrine therapy by the remission criteria, i.e. complete response (CR), partial response (PR), static disease (SD) or progressive disease (PD), achieved on that therapy. Patients were divided into those with metastatic breast cancer (MBC) and non-metastatic disease. There was no significant difference in survival from starting first-line endocrine therapy between patients who obtained CR, PR or SD: all three groups of patients survived significantly longer than patients who showed PD within 6 months (all P < 0.0001 except CR versus PD [MBC] which was P < 0.002). Equally, for second-line endocrine therapy there was no difference in survival between patients who obtained CR, PR or SD: all three groups (CR, PR and SD) survived significantly longer than PD (all P < 0.0003 except for CR versus PD which was P < 0.003 for non-metastatic and P < 0.059 for MBC). Durable SD appears to be a clinically useful criteria of therapeutic remission.

Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer.

The progesterone receptor antagonist, Onapristone, is an effective endocrine agent in experimental breast cancer models. This study aimed to investigate this agent as first-line endocrine therapy in patients with breast cancer. However, owing to the recognition in this and other clinical studies that some patients on Onapristone developed liver function test abnormalities, the development of this drug and recruitment to the study stopped in 1995. 19 patients either with locally advanced breast cancer (n = 12) or who were elderly, unfit patients with primary breast cancer (n = 7) received Onapristone 100 mg/day. Seventeen of the 19 tumours expressed oestrogen receptors (ER) whilst 12 of the 18 tumours tested expressed progesterone receptors (PgR). Tumour remission was categorised by International Union Against Cancer criteria. One patient was withdrawn after 4.5 months while her disease was static. Of the remaining 18 patients, 10 (56%) showed a partial response and 2 (11%) durable static disease (> or = 6 months), giving an overall tumour remission rate of 67%. The median duration of remission was 70 weeks. Transient liver function test abnormalities developed in a number of patients, mainly during the first 6 weeks of treatment. In conclusion Onapristone can induce tumour responses in human breast cancer.

Investigation of primary tamoxifen therapy for elderly patients with operable breast cancer

Abstract Tamoxifen therapy in elderly patients (> 70 years) with operable breast cancer has been investigated by two trials in our unit. The first compared tamoxifen with surgery alone: 62% patients eventually failed tamoxifen, 47% required surgery. But 37% had control of the primary tumour with tamoxifen alone for over 5 years. To identify those with a long-term response to tamoxifen a second trial included cases with high oestrogen receptor (ER) content. Patients were randomized to tamoxifen 20 mg daily ( n = 94) or mastectomy and adjuvant tamoxifen ( n = 53). Only 3% of patients initially progressed on tamoxifen, compared to 26% in the first trial. In the second trial at a median followup of 3 years, 32% of patients receiving tamoxifen had developed local relapse, but only 16% needed surgery. Patients with static disease after 6 months on tamoxifen had a significantly shorter duration of control and were more likely to require mastectomy compared to partial or complete responders. To select patients with long-term control of the primary tumour with tamoxifen we propose a two stage selection where cases with low ER are excluded, and those with static response of the primary tumour at 6 months have the tumour removed.

Change in Expression of ER, bcl-2 and MIB1 on Primary Tamoxifen and Relation to Response in ER Positive Breast Cancer

Pre-treatment oestrogen receptor (ER) expression in breast cancer predicts for rate of response to endocrine therapy but not for the quality or duration of response (DofR). ER is known to be down-regulated by anti-oestrogens. This study has tested the hypothesis that the degree of down-regulation of ER and the ER-regulated marker bcl-2 are associated with the quality and duration of tamoxifen response. 80 patients with ER+ve breast cancer (H-score ≥10) receiving primary tamoxifen (n=51 Stage I–II elderl; n=29 Stage III) underwent sequential tumour biopsies for immunocytochemical assessment of ER, bcl-2 and the proliferation marker MIB1. Median follow-up is 45 months. By 6-months on therapy three patients had attained complete response (CR), 27 partial response (PR); 44 static disease (SD) and six progression (PD) by UICC criteria. Greater decrease in ER and bcl-2 H-score from pre-treatment to 6 weeks (p=0.035, p=0.037) and ER and bcl-2 H-score from pre-treatment to 6 months (p=0.058, p=0.036) were significantly associated with better quality of response (CR/PR vs SD/PD). Greater 6-week and 6-month reduction in bcl-2 H-score (p=0.041, p=0.036) and 6-week reduction in MIB1 (p=0.013) were significantly correlated with longer DofR. This study demonstrates that greater down-regulation of ER and the ER-regulated protein bcl-2 on primary tamoxifen are significantly associated with a better quality of response and bcl-2 and the proliferation marker MIB1 a longer duration of response in ER+ve breast cancer.

Predictors of response to second-line endocrine therapy for breast cancer

This study reports on factors predicting response tosecond-line endocrine therapy in 250 patients with breastcancer for which they were assessable for responseby the International Union Against Cancer (UICC) criteria.Clinical details relating to first-line endocrine therapy wereavailable for all patients. We have not includedin this study patients who received first-line endocrinetherapy but did not or have not yetproceeded to second-line hormone therapy – e.g. diedfrom rapidly progressive disease, started chemotherapy for rapidlyprogressive disease, or remained in long-term remission onfirst-line endocrine therapy.One hundred and fifty nine patients (72%) achievedremission (objective response and static disease [OR +SD]) on first-line endocrine therapy with a medianduration of 19 months. For second-line endocrine therapythe remission rate was 53% (132/225) with amedian duration of 15 months. Tumour grade andoestrogen receptor status of the primary tumour wereshown to be independent predictors of response tosecond-line endocrine therapy while response to first-line endocrinetherapy was a predictor of the duration ofresponse to second-line endocrine therapy. In the sub-groupof patients who showed OR or SD toboth first and second-line therapies, there was nocorrelation between the time to progression (TTP) onfirst and second-line therapies.

Endocrine response and resistance in breast cancer: A role for the transcription factor Fos

We have previously demonstrated that elevated Fos expression may be important in de novo endocrine resistance in breast cancer. However, changes in Fos expression during endocrine response and subsequently on acquisition of resistance are unknown. This study immunocytochemically monitors Fos protein within sequential biopsies from primary human breast cancer patients obtained pre‐treatment (T1), during tamoxifen therapy (T2, T3) and on disease progression (T5), examining in parallel proliferation [i.e., MIB1 (Ki67) immunostaining, mitotic activity], cellularity and endocrine response. Significantly diminished Fos, proliferation and cellularity were observed after 6 weeks of therapy in patients exhibiting a better quality and/or duration of response, while modest Fos increases and a maintained proliferation and cellularity were seen in poorer responders. Decreases in Fos, proliferation and cellularity at 6 months similarly hallmarked better responders. We confirmed a significant association between de novo resistance and elevated Fos and proliferation. Additionally, however, these parameters increased at the time of disease relapse over pre‐treatment and “on therapy” values. Our data indicate that tamoxifen response involves a reduction in both tumor cell proliferation and cell survival, potentially entailing diminished Fos protein expression in better‐responding patients. Our data are also supportive of elevated Fos expression being involved in the departure from endocrine control inherent in both primary and acquired resistance. Int. J. Cancer (Pred. Oncol.) 84:54–61, 1999.

Locally advanced primary breast cancer: medium-term results of a randomised trial of multimodal therapy versus initial hormone therapy

We report the medium-term (median follow-up=52 months) results of a prospective randomised trial of multimodal therapy (neoadjuvant chemotherapy, Patey mastectomy, postoperative radiotherapy and adjuvant hormone therapy) (n=56) versus initial hormone therapy (n=52) for locally advanced primary breast cancer. Compared with multimodal therapy, initial hormone therapy was associated with reduced number of therapies for disease control (mean=3.6 versus 4.9) and mastectomy rate (31%). Multimodal therapy conferred better initial locoregional control and a longer disease-free interval. Nevertheless, there was no statistically significant differences in the rates of survival, metastasis and uncontrolled locoregional disease, as well as in the time to metastasis between the two therapy groups. Regardless of the therapy groups, oestrogen receptor positivity conferred a lower metastasis rate, better survival and locoregional control. Thus, initial hormone therapy may be a reasonable option for managing locally advanced primary breast cancer, especially for oestrogen receptor-positive tumours.

Audit of a conservative management policy of the axilla in elderly patients with operable breast cancer

Between April 1982 and February 1994, 344 women aged > 70 years with cancers < 5 cm in diameter were treated at the City Hospital Breast Unit. The majority were enrolled in two successive randomized trials. One hundred and sixty patients had primary therapy with tamoxifen alone and were subsequently treated with mastectomy if the primary cancer progressed. Fifty-three women with a high oestrogen receptor (ER) status in the tumour received mastectomy and post-operative tamoxifen. One hundred and thirty-one patients underwent primary surgery (104, mastectomy; 27, wide local excision) and did not receive adjuvant tamoxifen. Only the 184 (131 + 53) patients who underwent primary definitive surgery have been included in this study. Patients undergoing primary surgery without palpable lymph nodes (n = 159) did not undergo axillary exploration. Twenty-five women who were noted pre-operatively to have clinically palpable lymph nodes underwent excision of obviously enlarged lymph nodes in the axilla in addition to primary surgery; small nodes that measured less than around 1 cm were left in place. None received axillary clearance or axillary irradiation. The median follow-up is 54 months. Twenty-three of 159 (14%) patients without palpable nodes, and four of 25 (16%) with palpable nodes, have subsequently developed axillary recurrence. Grade 3 tumours were associated with a higher rate of regional recurrence. Regional relapse was treated successfully with different therapeutic modalities (surgery, radiotherapy or endocrine manipulation) and none have died from uncontrolled regional disease.