Search

Background: Ideally, intraoperative sentinel lymph node (SLN) analysis in breast cancer should be automated, have high concordance with extensive histopathology, and be applicable in any hospital setting. A prospective multicentre evaluation of the one-step nucleic acid amplification (OSNA) automated molecular diagnostic system of SLN analysis was undertaken., Methods: Intraoperative examination of SLNs from 204 patients with breast cancer was performed by OSNA at four sites in the UK. Half of each SLN was assessed by OSNA (for cytokeratin 19 mRNA) and the remaining half was paraffin embedded for intensive histological examination at ten levels. Discordant cases were reanalysed by further molecular biological techniques and by additional histological examination of all remaining nodal material to ascertain whether the discordance was due to an uneven distribution of metastases, known as tissue allocation bias (TAB)., Results: After exclusion of samples affected by TAB, the overall concordance rate for OSNA versus histopathology was 96.0 per cent, with a sensitivity of 91.7 per cent and a specificity of 96·9 per cent. The median time to process a single SLN was 32 (range 22-97) min, and that for two nodes 42 (30-73) min., Conclusion: OSNA enables accurate automated intraoperative diagnosis and can be used successfully in different UK hospitals. When the SLN is shown to be positive, the patient can undergo immediate axillary clearance under the same anaesthetic rather than having a delayed second procedure., (Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

The purpose of this study was to determine whether primary breast cancer patients showed evidence of circulating tumour cells (CTCs) during follow-up as an alternative to monitoring disseminated bone marrow tumour cells (DTCs) by immunocytochemistry and reverse transcriptase (RT)-PCR for the detection of micrometastases. We planned to compare CTC and DTC frequency in low-risk and high-risk patients. We identified two cohorts of primary breast cancer patients who were at low (group II, T(1)N(0), n=18) or high (group III, >3 nodes positive (with one exception, a patient with two positive nodes) n=33) risk of relapse who were being followed up after primary treatment. We tested each cohort for CTCs using the CellSearch system on 1-7 occasions and for DTCs by immunocytochemistry and RT-PCR on 1-2 occasions over a period of 2 years. We also examined patients with confirmed metastatic disease (group IV, n=12) and 21 control healthy volunteers for CTCs (group I). All group I samples were negative for CTCs. In contrast, 7 out of 18 (39%) group II primary patients and 23 out of 33 (70%) group III patients were positive for CTCs (P=0.042). If we count only samples with >1 cell as positive: 2 out of 18 (11%) group II patients were positive compared with 10 out of 33 (30%) in group III (P=0.174). In the case of DTCs, 1 out of 13 (8%) group II patients were positive compared with 19 out of 27 (70%) in group III (P<0.001). Only 10 out of 33 (30%) patients in group III showed no evidence of CTCs in all tests over the period of testing, compared with 11 out of 18 (61%) in group II (P=0.033). A significant proportion of poor prognosis primary breast cancer patients (group III) have evidence of CTCs on follow-up. Many also have evidence of DTCs, which are more often found in patients who were lymph node positive. As repeat sampling of peripheral blood is more acceptable to patients, the measurement of CTCs warrants further investigation because it enables blood samples to be taken more frequently, thus possibly enabling clinicians to have prior warning of impending overt metastatic disease.

The objective of this study was to evaluate the clinical response of locally advanced breast cancer (LABC) to neoadjuvant (NA) chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and to study the role of docetaxel in patients who fail to respond to first-line chemotherapy. Patients were enrolled who had primary tumours without distant metastasis that were too extensive for conservative surgery. All underwent NA chemotherapy for breast cancer and thereafter surgery and/or radical radiotherapy. NA chemotherapy with FEC was administered to 88 patients between February 1998 and June 2005. A median of 6 cycles of FEC (range 1-8) was given, followed in 21 cases by a median of 4 cycles (range 2-6) of docetaxel. Where clinically established, with FEC the clinical complete response (cCR) was 22/81 (27%), clinical partial response (cPR) 41/81 (51%), clinical stable disease (cSD) 18/81 (22%). In patients where the response to FEC was regarded as insufficient, docetaxel was given. Response rates were cCR 3/21 (14%); cPR 10/21 (48%), cSD 8/21 (38%). There were 11 cases of pathological complete response (pCR), 9 in the FEC-only group and 2 in the docetaxel group. Following chemotherapy 49 (56%) patients underwent mastectomy, 32 (36%) breast conserving surgery and 5 (6%) radical radiotherapy, giving a breast conservation rate of 42%. Two patients died before receiving surgery or radical radiotherapy. The results show that neoadjuvant FEC is a reasonable NA therapy in breast cancer and that docetaxel is effective in FEC refractory cases. Only 8 of 81 (10%) assessable patients did not respond to any chemotherapy, giving an overall clinical response rate of 90%, which is comparable to studies in which taxanes were given irrespective of response to preceding therapy with antracycline including regimes.

Oestrogen receptor-alpha (ERalpha) is an important prognostic marker in breast cancer and endocrine therapies are designed to inhibit or prevent ERalpha activity. In vitro studies have indicated that phosphorylation of ERalpha, in particular on serine 118 (S118), can result in activation in a ligand-independent manner, thereby potentially contributing to resistance to endocrine agents, such as tamoxifen and aromatase inhibitors. Here we report the immunohistochemistry (IHC) of S118 phosphorylation in 301 primary breast tumour biopsies. Surprisingly, this analysis shows that S118 phosphorylation is higher in more differentiated tumours, suggesting that phosphorylation at this site is associated with a good prognosis in patients not previously treated with endocrine agents. However, we also report that S118 phosphorylation was elevated in tumour biopsies taken from patients who had relapsed following tamoxifen treatment, when compared to pre-treatment biopsies. Taken together, these data are consistent with the view that S118 phosphorylation is a feature of normal ERalpha function and that increases in levels of phosphorylation at this site may play a key role in the emergence of endocrine resistance in breast cancer.

Local recurrence in breast cancer surgery is related to the completeness of excision. Histological analysis of excision margins is time consuming and impractical for use intra-operatively. Our group evaluated breast imprint and scrape cytology (ISC) for the assessment of excision margins in a feasibility study in 1993-4, with 10 year clinical follow-up. Twenty-six consecutive women undergoing 27 wide local excisions for breast cancer had excision margins prospectively assessed with intra-operative ISC blinded to histology. All ISC results were ready (range 22-30 min) before surgery was completed. ISC agreed with histology in 21/27 (=78%) and disagreed in 6/27 (=22%) of the cases. In two cases with local recurrence, histology was positive in one case, whereas ISC margins were positive in both. Intra-operative ISC is reliable and could help the surgeon to excise more tissue to prevent a second (re-excision) operation. ISC margins may predict clinical outcome, although a larger interventional follow-up study is required.

Recent advances in digital imaging have made Faxitron microradiography an attractive alternative to intra-operative conventional specimen radiography (CSR) for the excision of wire-localized breast lesions. Faxitron specimen analysis time, usefulness of digital image manipulation and re-excision rates were evaluated in comparison to CSR in 299 consecutive wire-localized excisions for mammographically suspicious non-palpable breast lesions (172 procedures with Faxitron, 127 with CSR) in a non-randomized study. The corresponding mean operation times were 34.7 vs. 42.7 min and the respective re-excision rates were 19.8% vs. 31.5% (no significant difference on chi analysis P < 0.1). Faxitron digital image manipulation led to cavity biopsies in 50% (60/121) of the cancer excisions. In 19 of these (16%), histological excision margins were converted from incomplete to complete. The shorter Faxitron mean operating time enables an additional wire-localized operation per theatre list. Digital imaging guides the surgeon for additional cavity biopsies, resulting in re-excision rates as good as CSR.

Currently, the therapy for breast cancer is determined by immunohistochemical staining of the primary tumour for oestrogen receptor alpha (ERalpha). However, a proportion of ERalpha-positive patients fail to respond to tamoxifen and a proportion of ERalpha-negative patients show response. Here, we describe a novel procedure for the purification of malignant breast epithelial cells in an attempt to identify these patients at an early stage. Using this procedure, we are able to purify malignant cells to >90% purity as determined by immunohistochemical staining, cytology and fluorescent in situ hybridisation (FISH). While the malignant cells can be maintained in culture they do not proliferate in contrast to purified breast epithelial cells from reduction mammoplasties. Moreover, ERalpha and progesterone receptor (PR) expression is maintained in malignant cells, whereas normal epithelial cells rapidly lose ERalpha and PR. Functional studies were performed on the separated malignant cells in terms of their response to oestradiol and tamoxifen. Four out of the seven ERalpha-positive tumours showed a significant reduction in cell numbers after tamoxifen treatment compared to oestradiol, ERalpha negative tumours failed to show a response. We conclude that (a) it is possible to purify and maintain breast cancer cells for a sufficient period to permit functional studies and (b) ERalpha is retained in culture facilitating the use of these cells in studies of the mechanism of endocrine response and resistance in vitro.

Purpose: We previously developed a quantitative system for the detection of cytokeratin 19 (CK-19) transcripts using reverse transcriptase polymerase chain reaction (PCR) to detect breast carcinoma cells in blood and bone marrow. The aim of this study was to determine the value of this system in monitoring patients with metastatic disease and to compare it with an established immunocytochemical method., Patients and Methods: Patients with progressive, locally advanced, and metastatic breast cancer (all stage IV) who were due to start systemic treatment were recruited. Blood samples were analyzed for CK-19 transcripts using quantitative PCR (QPCR) and immunocytochemistry (ICC) throughout their course of treatment., Results: One hundred forty-five blood samples were obtained from 22 patients over 13 months. Seventy-two (49.6%) of these samples were positive by QPCR, and 56 (42%) of 133 were positive by ICC. Of the 133 specimens analyzed by both techniques, 95 (71.4%) had the same results for each, and of the 71 samples that were positive, 40 (56%) were positive by both methods. The relationship between the number of cells detected and the QPCR values was statistically significant (P <.0001). Of the 25 courses of assessable treatment, 17 (68%) of 25 treatment outcomes (either response or disease progression) were reflected by QPCR measurements, and 12 (57%) of 21 were reflected by ICC. During the course of the study, five patients showed a response, and of these, ICC was in agreement in four cases (80%) and QPCR in three cases (60%). Eighteen courses of treatment resulted in progression of the disease; however, only 15 of these were assessable by ICC. ICC was in agreement in eight (53%) of 15 of these cases, and QPCR in 15 (83%) of 18 cases., Conclusion: Circulating carcinoma cells are frequently found in patients with metastatic breast cancer. In the majority of patients, cancer cell numbers as evaluated by QPCR or ICC reflected the outcome of systemic treatment.

One hundred and sixteen patients with locally advanced or metastatic breast cancer were randomized to receive CMF (cyclophosphamide 600 mg m(-2) day 1 and 8 i.v., 5-fluorouracil 600 mg m(-2) day 1 and 8 i.v., methotrexate 40 mg m(-2) day 1 and 8 i.v., monthly for 6 cycles) or MM (methotrexate 30 mg m(-2), mitoxantrone 6.5 mg m(-2), both i.v. day 1 3-weekly for 8 cycles) as first line treatment with chemotherapy. Objective responses occurred in 17 patients out of 58 (29%) who received CMF and nine out of 58 (15%) who received MM; 95% confidence interval for difference in response rates (-1%-29%), P = 0.07. No statistically significant differences were seen in overall survival or time to progression between the two regimes although a tendency towards a shorter progression time on the MM regime must be acknowledged. There was, however, significantly reduced haematological toxicity (P < 0.001) and alopecia (P < 0.001) and fewer dose reductions and delays in patients randomized to MM. No statistically significant differences were seen between the two regimes in terms of quality of life (QOL). However, some association between QOL and toxicity was apparent overall with pooled QOL estimates tending to indicate a worsening in psychological state with increasing maximum toxicity over treatment. Despite the fact that results surrounding response rates and time to progression did not reach statistical significance, their possible compatibility with an improved outcome on CMF treatment must be borne in mind. However, MM is a well-tolerated regimen with fewer side-effects than CMF, which with careful patient management and follow-up, therefore, may merit consideration as a first-line treatment to palliate patients with metastatic breast cancer who are infirm or elderly.

This paper examines the correlation between axillary lymph node status and primary tumour characteristics in breast cancer and whether this can be used to select patients for axillary lymphadenectomy. The results are based on a retrospective analysis of 909 patients who underwent axillary dissection in our unit. Axillary lymph nodes containing metastases were found in 406 patients (44.7%), all with invasive carcinomas, but in none of the 37 carcinomas-in-situ. Nodal status was negative in all T1a tumours, but lymph node metastases were present in 16.3% and 35.7% of T1b and T1c tumours respectively. When histological grade was taken into account, positivity for grade I T1b and T1c tumours fell to 13.6% and 26.7% respectively. Lymph node metastases were found in 85% of patients with lymphovascular invasion in their tumours as compared to only 15.4% of those without and in 45.5% of oestrogen and progesterone receptor-positive tumours. When one or both hormone receptors were absent this figure was much higher. It appears that for T1a breast cancers axillary dissection is not necessary, whereas for T1b, T1c and grade I T2 tumours other histopathological parameters should be taken into consideration in deciding who should undergo axillary lymphadenectomy.

Purpose: Previous reports have indicated that reverse transcriptase polymerase chain reaction (RT-PCR) for cytokeratin 19 (CK-19) may be useful in the management of patients with breast cancer. However, the specificity of this technique is low, principally because of a high rate of false-positive results. To improve the specificity of this assay, we developed a quantitative RT-PCR methodology that enables an estimate to be made of the number of CK-19 transcripts in blood and bone marrow samples., Patients and Methods: We examined 45 peripheral-blood samples and 30 bone marrow samples from patients with a variety of nonneoplastic conditions using nested RT-PCR for CK-19. We also examined bone marrow and peripheral-blood samples from 23 patients with primary breast cancer and peripheral-blood samples from 37 patients with metastatic breast cancer. The number of CK-19 transcripts was estimated in positive specimens by competitive PCR and normalized to the number of ABL transcripts as an internal control for the quality and quantity of cDNA. RT-PCR results were compared with the numbers of CK-19-positive cells detected by immunocytochemistry., Results: Analysis of samples from patients without cancer enabled us to define an upper limit for the background ratio of CK-19 to ABL transcripts (1:1,000 for blood samples and 1:1,600 for bone marrow samples). Using these figures as cut-off points, elevated CK-19: ABL ratios were detected in peripheral-blood samples of 20 of 37 (54%) patients with metastatic breast cancer and in bone marrow samples of 14 of 23 (61%) patients with primary breast cancer. Only three of 23 (13%) primary breast cancer peripheral-blood samples and none of the control samples were positive by these criteria. Only two of 23 patients (9%) with primary breast cancer showed immunocytochemically detectable cells in the blood; 10 of 23 (43%) showed immunocytochemically detectable cells in the bone marrow. Of 36 patients with metastatic breast cancer, eight (22%) showed positive events., Conclusion: Quantitative RT-PCR for CK-19 detects a percentage of patients with breast cancer and may enable the progression or regression of the disease to be monitored.

A 67 year old woman presented with a right breast lump which proved to be a grade 2 invasive ductal carcinoma with axillary lymph node metastasis. She had a five year history of CD5 positive chronic lymphocytic leukaemia, which never required treatment. Immunoperoxidase stains for CD5, using the monoclonal antibody NCL-CD-54C7, showed that there was extensive infiltration of axillary lymph nodes with CD5 positive B lymphocytes. Strong staining for CD5 was also seen in the carcinoma cells within the breast and lymph node metastases. It has recently been suggested that there is a tumour suppresser locus in chronic lymphocytic leukaemia at 13q12.3 near or at the BRCA2 locus. Deletion of regions on chromosome 13q containing the BRCA2 and RB1 genes has also been reported in sporadic breast cancers. These observations suggest that there may be a link between these two diseases acting through chromosome 13, but amplification of several microsatellite repeat markers failed to show any loss of heterozygosity or repeat instability at either these or several other loci on chromosome 13. Examination of additional such cases is needed to perform a more comprehensive study of the significance of positive CD5 staining of breast carcinoma.

It is unusual to obtain responses after two different sequential regimens in patients with metastatic breast cancer. In this retrospective analysis, data were examined on 22 patients who had already received two or three different regimens for metastatic breast cancer before being treated with 100 mg/m2 docetaxel (or 75 mg/m2 if clinically warranted). 13 patients received three or more courses and 21 patients were assessable for response. 5 of 21 assessable patients (24%) responded for 3-11 months and a further 6 (29%) stabilised. Toxicity (WHO grade 3 and/or 4), principally neutropenia, stomatitis and fluid retention, occurred in 10 patients. We conclude that docetaxel is an active agent in heavily pretreated patients with metastatic breast cancer, but care should be taken to minimise side-effects in this group of patients.

The aim of this study was to determine whether reverse transcriptase polymerase chain reaction (RT-PCR) for keratin 19 (K19) provides additional information when combined with immunohistochemistry when used to detect micrometastases in blood and bone marrow in patients with primary breast cancer. We studied 78 patients with breast cancer who had no evidence of distant metastases. We collected blood and bone marrow, separated the mononuclear fraction and carried out RT-PCR and immunohistochemistry for K19. RT-PCR was done by two 40-cycle rounds using nested primers. In initial experiments, RT-PCR was shown to be capable of detecting one tumour cell in one million normal bone marrow cells, which was at least 10 times more sensitive than immunohistochemistry, while retaining specificity. Five per cent of the peripheral blood and 22% of the bone marrow samples contained K19 positive cells by immunohistochemistry staining. Using RT-PCR, these proportions increased to 25% and 35%, respectively. This represents a significantly greater detection frequency (P < 0.001 and P = 0.03, respectively). RT-PCR for K19 is a more sensitive method for detecting micrometastases in patients with primary breast cancer when compared with immunohistochemistry.

We have used polymerase chain reaction (PCR) to measure keratin 19 mRNA in order to detect breast cancer cells invading axillary lymph nodes. In a consecutive series of 125 patients with primary breast cancer, 75 patients had no evidence of lymph node involvement by conventional histology. A total of 530 lymph nodes from these patients were examined and 106 (20%) gave a keratin 19 product detectable by Southern hybridisation. This correlated with primary tumour size (P<0.001). These 106 nodes came from 23 patients. Thus, using this technique, 23/75 (30.6%) patients were found to have evidence of lymph node involvement who would otherwise have been designated lymph node negative.

Fine-needle aspiration cytology (FNAC) of the breast was performed in 491 patients over a 3-year period. Some 365 examinations (74.3 percent) were performed by palpation and the remaining 126 (25.7 percent) by stereotaxis. Ninety-six patients were excluded because of inadequate follow-up. Using a standard method of reporting the results 247 smears were classified as C1 and C2, but based on clinical and radiological criteria excision biopsy was recommended and performed in 122 patients with these lesions. Twenty-two per cent of C2 lesions were found to be malignant after histological examination. Forty-two patients with C3 or C4 cytology were advised to have excision biopsy and 41 had surgery. In all but one case the lesion was found to be malignant histologically. Definitive surgery was performed on 106 patients with C5 cytology and the diagnosis of malignancy was confirmed histologically in 105 of them. FNAC is a useful diagnostic tool in breast screening but in view of the number of false-negative results, cytology alone is unreliable and, therefore, full triple assessment is recommended.

Although recent epidemiologic studies suggest that silicone augmentation of the breast is not associated with an increased risk of mammary carcinoma, cases of breast carcinoma arising in augmented breasts are being increasingly encountered as a large number of patients who had augmentation are getting older. A case of a 51-year-old woman with a 20-year history of breast augmentation who developed an invasive cribriform carcinoma associated with extensive microcalcification is presented. The patient had submammary silicone implants 20 years ago that were replaced, because of local complications, in subpectoral positions 10 years later. Dispersive X-ray microanalysis failed to demonstrate silicone in sections of the tumor and adjacent breast tissue. Appropriately fixed tumor tissue was available for electron microscopic examination. The tumor cells were rich in mitochondria, and their luminal surfaces were endowed with abundant microvilli, but the cell surfaces that came closest to the calcified microspheriols were devoid of microvilli and had cellular buddings between the microspheriols. It is suggested that the tumor cells might have been actively involved in the process of microcalcification.

Breast cancer micrometastases in axillary lymph nodes have been detected by serial sectioning and immunohistochemistry, and shown to have prognostic significance. We have used polymerase chain reaction (PCR) to see whether we could further improve the detection rate of micrometastases. Fifty-seven axillary lymph nodes from patients with breast cancer were examined histologically to assess the proportion of tumor involvement. Immunohistochemical staining with the use of an anti-keratin 19 antibody confirmed the histological findings. Reverse transcription PCR was then performed on extracted RNA by using K19 primers, and all 18 histologically involved nodes yielded the expected 460-base pair product. Of 39 histologically negative nodes, 4 (10%) gave K19 bands detectable with ethidium staining and a further 10 (28%) gave K19 bands after Southern hybridization. To further increase the detection sensitivity a two stage amplification was performed by using nested primers, and K19 product was found in lymph nodes from patients without cancer, as well as in all the nodes from cancer patients. This was shown to be genuine low level expression from endogenous mRNA template, and not derived from amplification of a K19 pseudogene. Reducing the number of PCR cycles in the two amplification steps did not allow sufficient discrimination between normal nodes and those involved nodes in which K19 expression was only detectable after Southern hybridization. The optimal "cut-off" point to distinguish involved nodes from normal nodes remained at the level of 40 cycles of PCR and Southern hybridization. PCR, using K19 as a tumor marker, has been demonstrated in this study to improve the detection of micrometastases in axillary lymph nodes in patients with breast cancer: sensitivity is limited by the specificity of the tumor marker.

This study was aimed at comparing screen-detected and symptomatic breast carcinomas with regard to the prevalence of positive immunostaining for c-erb-B-2 oncoprotein. Paraffin sections of 81 breast carcinomas detected through the National Screening Programme were examined for the over-expression of c-erbB-2 oncoprotein using the avidin-biotin immunoperoxidase technique and 2 different specific antibodies: 21N and 4D5. Twenty-one other carcinomas detected in symptomatic patients were similarly examined for comparison. The screen-detected lesions were of 2 types: palpable and impalpable which required needle localization prior to surgical removal. Of the 81 screen-detected tumours, only 8 were c-erbB-2 positive, compared with 5 out of 21 non-screen-detected tumours. When only invasive carcinomas were considered, 5 out of 63 screen-detected cases were positive, compared with 5 out of 15 symptomatic cases. Four out of the 5 screen-detected positive invasive carcinomas were clinically palpable. Our results show an obvious trend towards a lower prevalence of c-erbB-2 oncoprotein over-expression in screen-detected carcinomas. As this over-expression is thought to be associated with increased tumour aggressiveness, the findings suggest a low prevalence of aggressive tumours in screen-detected lesions, particularly impalpable invasive carcinomas, identified so far.

The presence of oestrogen and progesterone receptors was studied in paraffin sections of 81 screen-detected breast carcinomas using the monoclonal antibodies ER-ICA and PgR-ICA (Abbott) and the immunoperoxidase technique. The immunohistological results were compared with the results of the standard dextran-coated charcoal biochemical assay in 28 tumours which were big enough to provide tumour tissue for this assay. Sixty-three cases (78%) were oestrogen receptor positive and 62 (77%) were progesterone receptor positive. There was no statistical difference between receptor positivity in palpable or impalpable, in situ or invasive tumours. In the 28 cases where the biochemical assay was carried out, the two methods gave similar results in 23 (82%) and 21 (75%) tumours for oestrogen and progesterone receptors respectively. The majority of the remaining tumours, with one exception, were positive with immunohistology and negative with biochemistry. A good correlation was also present between the mean numerical biochemical values and the semiquantitative histological scores for both receptors. It is concluded that assessment of receptor status of small screen-detected carcinomas is feasible using routinely processed paraffin sections. There is reasonably good correlation with the results obtained by the standard dextran-coated charcoal biochemical assay, but more genuine receptor positive cases are detected by immunohistology.

Mitozantrone (Novantrone) has recently been incorporated into a new combination chemotherapy regimen with mitomycin-C and methotrexate (MMM) against advanced breast cancer. We have compared MMM (mitozantrone 8 mg m-2 i.v. q 3 weekly, methotrexate 35 mg m-2 i.v. q 3 weekly, mitomycin-C 8 mg m-2 i.v. q 6 weekly) with CMF (cyclophosphamide 100 mg orally, days 1-14, methotrexate 35 mg m-2 i.v., days 1 and 8, 5-FU 1,000 mg i.v., days 1 and 8, q 4 weekly), each regimen with folinic acid rescue, in a randomised trial, 29/57 evaluable patients treatment with MMM achieved an objective response (51%) compared with 33/55 treated with CMF (60%). Overall median survival was 16 months for MMM and 12 months for CMF. Subjective toxicity was low for both regimens and the only significant difference was in incidence of diarrhoea (50% for CMF vs 21% for MMM). Haematological toxicity was similar, leading to treatment delays and/or dose reductions in 35% patients with CMF vs 43% with MMM. Thrombocytopenia was significantly increased in MMM (34% vs 14%). No clinical cardiotoxicity was seen, but a significant reduction in left ventricular ejection fraction occurred in four patients on CMF vs 2 on MMM. MMM is an active, well tolerated new chemotherapy regimen for advanced/metastatic breast carcinoma with an efficacy and toxicity spectrum very similar to CMF.

The accurate non-surgical diagnosis of breast lumps allows assessment of breast cancer patients for conservation or neoadjuvant primary treatment before surgical intervention. We have analysed the accuracy of clinical assessment, fine needle aspiration cytology (FNAC), and mammography in over 868 women seen in a symptomatic breast clinic. Clinical examination by an experienced breast physician, together with FNAC, detected over 99% of the cancers with a 12% false positive rate. A cytological diagnosis of definite carcinoma was obtained in 69% of women with breast cancer with no false positive result from the women with benign conditions producing a 100% positive predictive value. These results indicate that it would be acceptable to give pre-surgical systemic endocrine or chemotherapy to women with positive cytology which is therefore a prerequisite for a neoadjuvant therapy programme.

The color Doppler signals in 60 patients with breast masses were assessed subjectively, and a regional grading method was developed for quantitation of displayed blood vessel density. Among 21 patients with breast carcinoma, moderate or high flow was demonstrated in all but one, with an average of 0.5 vessels per square centimeter and color pixels occupying 12.2% of the image area. Among 33 patients with benign disorders, no flow was demonstrated in 25 and slight to moderate flow was seen in five, with an average of 0.01 vessels per square centimeter, occupying 0.8% of the image area. Cancers as small as 10 mm in diameter were positive for flow. High-velocity flow was seen only in malignancies; it was observed in four cases and may have been due to arteriovenous shunting. Flow was less readily detected in recurrent tumors; two of seven tumors were weakly positive. Color Doppler shows promise as an adjunct to ultrasound imaging in the differential diagnosis of breast lesions.

Between 1972 and 1982, 60 patients with histologically proven duct carcinoma in situ (DCIS) without evidence of invasive disease were treated by surgery alone. Treatment was not randomised and was total mastectomy (19), subcutaneous mastectomy (6) or local excision (35). Follow-up was by clinical examination and mammography with a median follow-up of 9 years (range 4-16 years). Twenty-six patients (43%) have recurred locally. The estimated proportion recurrence free at 7 years is 59% (95% CI 46-72%). Local recurrence on the chest wall occurred in one patient having total mastectomy and in the chest wall or nipple in three patients having subcutaneous mastectomy. Twenty-two patients recurred locally in the breast after conservative surgery. The 7-year recurrence-free rates were 94%, 44% and 45% respectively in the three groups. Of those patients who recurred locally 14/26 (54%) did so with invasive disease. Of the 34 who did not develop local recurrence, two developed metastases. The only factor which correlated with local recurrence and invasive local recurrence on multivariate analysis was conservative surgery (hazard ratio 4.71 (1.59-14.0), P = 0.001, and 4.05 (1.00-18.7), P = 0.03, respectively). DCIS can be an aggressive local disease and local excision may be inadequate treatment.

Palpable breast nodules in 143 patients attending our primary diagnosis breast clinics were assessed by clinical examination, needle cytology, mammography, ultrasonography and magnetic resonance imaging (MRI). The diagnostic accuracy of all test combinations was compared with the final diagnosis of malignant or benign disease. Two-test combinations increased the sensitivity of diagnosis over that of the individual tests to between 93% and 100% except for MRI/mammography and MRI/cytology. The combinations of three or more tests increased the sensitivity further, but at the expense of an increased false-positive rate. MRI does not appear to have an important role in the primary diagnosis of breast cancer. Mammography is necessary because of the possibility of occult or multifocal disease. Clinical examination was associated with a high false-positive rate. The combination of cytology and ultrasound was best at correctly diagnosing malignancy, but in this series only 42% of patients underwent ultrasound examination. The role of breast ultrasound together with needle aspiration cytology for the diagnosis of malignancy in palpable breast nodules deserves further evaluation.

This paper reports a retrospective study of 69 breast biopsies carried out for surgically occult but radiologically apparent lesions. Specimen radiography was required to confirm excision. The group included 17 carcinomas. Review of the pre-operative mammogram reports provided by a 'pool' of general radiologists demonstrated a high sensitivity (88%), but poor specificity (32%), with an overall accuracy of 46%. 'Blind' review of the mammograms by one experienced mammographic radiologist showed high sensitivity (100%), good specificity (73%) and overall accuracy of almost 80%. This result shows the need for the most experienced radiologist available to be involved in deciding which of these difficult lesions require biopsy. This will reduce unnecessary breast surgery and highlights the role of clinical and radiological review instead of biopsy, the need for continuing self audit by radiologists and the need for regular communication between clinicians, radiologists and pathologists.

Seventy-four post-menopausal women with metastatic breast cancer were treated with a combination hormonal regimen consisting of tamoxifen, aminoglutethimide danazol and medroxyprogesterone acetate (POND). 72% of the patients had received no previous treatment. The overall response rate (complete and partial remission) was 43.5% with a median response duration of 19 months and a median survival of 27 months. The most common sites of response were in regional nodes and local chest wall disease. The major side-effects were those expected from the individual agents: nausea, lethargy, rash and oedema.

Epidemiological and experimental evidence indicates that oestrogens are involved in the carcinogenic promotion of human breast cancer. We have undertaken a pilot trial of tamoxifen, an anti-oestrogen, compared to placebo given to 200 women at a high risk of developing breast cancer. The results of this trial show that acute toxicity is low and that accrual and compliance are satisfactory. Furthermore, biochemical monitoring of lipids and clotting factors indicate that tamoxifen may reduce the risk of cardiovascular deaths. At this stage no untoward long-term risks have been identified, and it is therefore proposed that a large multicentre trial should be started.

Fifty-seven patients with large but potentially operable primary breast cancer were treated with primary medical therapy rather than initial mastectomy, using chemotherapy (15) or endocrine therapy (42) with the tumour remaining in situ. Of patients treated with chemotherapy, one (7%) achieved a complete remission, and eight (53%) a partial response (overall response rate 60%). Only one patient had progressive disease while on chemotherapy. Of patients who received endocrine therapy, one (2%) achieved a complete response, and 19 (45%) a partial response (overall response rate 47%). Two patients progressed on endocrine therapy. Only 10 patients have so far had a subsequent mastectomy (18%), and 17 (30%) have had radiotherapy and/or conservative surgery. The rest are still on medical therapy. With a median follow-up of 19 months (range 6-42 months) only two patients have had a local recurrence after being disease-free and none have developed uncontrollable local recurrence. Eight (14%) have developed distant metastases and four (7%) have died of metastatic disease. Primary medical therapy may offer an effective alternative to mastectomy for patients with operable breast carcinomas too large for conservative surgery and merits further study.

The hypothesis that oestrogen is an important promoter of human breast cancer raises the possibility that endocrine intervention could prevent the disease. Various methods of reducing oestrogenic activity have been proposed including dietary control, progestin therapy, and ovarian ablation. Tamoxifen is a synthetic anti-oestrogen of low toxicity with proven anti-proliferative activity in endocrine sensitive breast cancer which makes it an attractive alternative for a trial of endocrine prevention. We have undertaken a double-blind placebo-controlled pilot study to assess the feasibility of mounting a large multicentre study of tamoxifen in the prevention of breast cancer in high risk women. Two hundred women were randomised to tamoxifen or placebo during an 18 month accrual period. Acute toxicity was mild and serial studies of blood lipids, clotting factors, and bone mineral density suggested that no long-term deleterious effects are likely to be seen. It is estimated that 10,000 women would be required with a 10-15 year follow up in order to detect a 25% prevention effect.