Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial.

BACKGROUND: The incidence of local recurrence (LR) after conservative surgery for early breast cancer without adjuvant therapy is unacceptably high even with favourable tumours. The aim of this study was to examine the effect of adjuvant therapies in tumours with excellent prognostic features. METHODS: Patients with primary invasive breast cancer <2 cm diameter, grade 1 or good prognosis special type, and node negative, treated by wide local excision (WLE) with clear margins were randomised into a 2 × 2 clinical trial of factorial design with or without radiotherapy and with or without tamoxifen. Trial entry was allowed to either comparison or both. FINDINGS: The actuarial breast cancer specific survival in 1135 randomised patients at 10 years was 96%. Analysis by intention to treat showed that LR after WLE was reduced in patients randomised to radiotherapy (RT) (HR 0.37, CI 0.22-0.61 p<0.001) and to tamoxifen (HR 0.33, CI 0.15 - 0.70 p<0.004). Actuarial analysis of patients entered into the four-way randomisation showed that LR after WLE alone was 1.9% per annum (PA) versus 0.7% with RT alone and 0.8% with tamoxifen alone. No patient randomised to both adjuvant treatments developed LR. Analysis by treatment received showed LR at 2.2%PA for surgery alone versus 0.8% for either adjuvant radiotherapy or tamoxifen and 0.2% for both treatments. CONCLUSIONS: Even in these patients with tumours of excellent prognosis, LR after conservative surgery without adjuvant therapy was still very high. This was reduced to a similar extent by either radiotherapy or tamoxifen but to a greater extent by the receipt of both treatments.

A randomised trial of primary tamoxifen versus mastectomy plus adjuvant tamoxifen in fit elderly women with invasive breast carcinoma of high oestrogen receptor content: long-term results at 20 years of follow-up.

BACKGROUND: Long-term analysis of a randomised trial in Nottingham comparing tamoxifen versus surgery as initial treatment demonstrated that in oestrogen receptor (ER)-unselected cases, surgery achieved better local control, with no difference in overall survival. It was suggested that for patients with ER-rich tumours, local control and survival may be comparable. We now present long-term follow-up of a randomised trial designed to address this clinical scenario. PATIENTS AND METHODS: One hundred and fifty three fit elderly (≥70 years) women with clinically node-negative primary invasive breast carcinoma <5 cm of high ER content [histochemical (H) score ≥100] were randomised 2:1 to primary tamoxifen (Tam) (N = 100) or mastectomy with adjuvant tamoxifen (Mx + Tam) (N = 53). RESULTS: With median follow-up of 78 months, there was no statistically significant difference in 10-year rates of regional recurrence (9.0% versus 7.5%), metastasis (8.0% versus 13.2%), breast cancer-specific survival (89.0% versus 86.8%) or overall survival (64.0% versus 66.0%) between Tam and Mx + Tam; however, local control was inferior with Tam (local failure rates 43.0% versus 1.9%; P < 0.001). CONCLUSION: Irrespective of the degree of ER positivity, surgery achieved better local control. However, there was excellent and similar survival in both groups. Tam could be considered in those who are 'frail', refuse or prefer not to initially undergo surgery.

A randomised trial of mastectomy only versus tamoxifen for treating elderly patients with operable primary breast cancer-final results at 20-year follow-up.

A recent Cochrane review of trials involving elderly women with operable primary breast cancer showed no significant difference in overall survival between surgery (±adjuvant tamoxifen) and primary endocrine therapy using tamoxifen. We report the final results of a randomised pilot trial comparing primary tamoxifen and wedge mastectomy as initial treatment in this population. One hundred and thirty-one women >70 years with early operable primary breast cancer (<5 cm), unselected for oestrogen receptor (ER), entered the trial in 1982-1987. Sixty-eight patients were allocated to tamoxifen only and 67 to wedge mastectomy only, as primary treatment. At 20 years of follow-up, the median time to local failure was significantly shorter in the tamoxifen arm though approximately one-fifth of patients in this group did not develop local failure requiring mastectomy. There was no difference in regional recurrence, distant metastases or overall survival between the mastectomy and tamoxifen arms. In this small study, primary endocrine therapy achieved local control in 30% of those surviving at 5 years and 20% at 10 years, unselected for ER. The primary therapy used did not significantly affect regional recurrence, incidence of distant metastases or overall survival. Primary endocrine therapy should certainly be considered in those patients with ER positive tumours and who are unfit (based on life expectancy) for or refuse surgery.

ONCOPOOL - a European database for 16,944 cases of breast cancer.

ONCOPOOL is a retrospectively compiled database of primary operable invasive breast cancers treated in the 1990s in 10 European breast cancer Units. Sixteen thousand and nine hundred and forty four cases were entered, with tumours less than 5 cm diameter in women aged 70 or less (mean age 55). DATA: Data were date of birth, mode of diagnosis, pathology (size, lymph node status, grade, type, lympho-vascular invasion and hormone receptor) and therapies and outcome measures: first local, regional or distant recurrences, contralateral primary, date and cause of death. TUMOUR CHARACTERISTICS: Mean diameter 1.8 cm, 66% lymph node negative, 24% 1-3 lymph nodes involved and 10% had 4 or more involved. Grade 1, 29%; Grade 2, 41%; and Grade 3, 30%. Polynomial relationships were established between grade, stage and size. Seventy-five percent were oestrogen receptor (ER) positive. ER closely related to grade. OUTCOMES: Overall Survival was 89% at 5 years from diagnosis, 80% 10 years and 73% 15 years; Breast Cancer-Specific survivals were 91%, 84% and 79%. Survival strongly related to the Nottingham Prognostic Index (NPI). Cases detected at screening had 84% 10-year survival, those presenting symptomatically 76%. ER positive cases treated with adjuvant hormone therapy had a reduction in risk of death of 13% over those not receiving adjuvant therapy (p=0.000). ER negative cases treated with chemotherapy showed a risk reduction of 23% over those not receiving chemotherapy (p=0.000).

The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast.

UNLABELLED: The new gene expression molecular taxonomy of breast cancer places medullary carcinoma in the basal group. The basal group is considered to have a poor prognosis, but medullary carcinoma is considered to have a better prognosis than other grade 3 carcinomas. The prognostic significance of tumour associated inflammation, an important feature of medullary carcinomas, remains controversial. The aim of this study was to assess the prognostic importance of medullary histological type and inflammation in breast cancer. One thousand five hundred and ninety-seven patients who received no systemic adjuvant treatment and who had a median follow up of 9.5 years were studied. RESULTS: Prominent inflammation was associated with high histological grade and with better survival [relative risk (RR) 0.57, 95% confidence intervals (CI) 0.44-0.74] on multivariate analysis. Typical and atypical medullary carcinomas (n=132) did not have significantly different survival and were grouped together. Medullary carcinoma did not have significantly different prognosis than grade 3 ductal carcinoma with prominent inflammation, but both had a better prognosis than grade 3 ductal carcinoma without prominent inflammation (P<0.0001 and P=0.03). These differences were independent of other prognostic factors. These results question the current separation of typical and atypical medullary carcinoma. Prominent inflammation is associated with a better prognosis, and may explain the better prognosis in medullary carcinoma compared with grade 3 ductal carcinoma without prominent inflammation. The good prognosis of medullary carcinoma emphasises the heterogeneity of basal-like breast carcinomas. Further studies are needed to investigate the difference in survival between medullary carcinoma and other forms of basal carcinomas and the role of inflammation in any such differences in behaviour.

Incidence of intramammary nodes in completion mastectomy specimens after axillary node sampling: implications for breast conserving surgery.

BACKGROUND: Axillary node sampling (ANS) is widely used in conjunction with breast conserving surgery in the treatment of primary breast cancers in the UK. Some evidence suggests that axillary staging techniques can miss intramammary nodes contained within the axillary tail of the breast. This study aims to assess the incidence of such nodes in completion mastectomy specimens in women who have had previous breast conserving surgery and ANS. METHODS: One hundred and fifty-seven completion mastectomy specimens were obtained from women who had previous breast conserving surgery and ANS, at the Nottingham Breast Institute over a 3-year period. The pathology samples underwent detailed histological examination to identify lymph nodes, and determine their disease status. RESULTS: Seventy-six (48%) of completion mastectomy specimens contained intramammary lymph nodes. Fifteen patients were upstaged (lymph node stage) because of the histological findings at completion mastectomy. One patient from the study population received additional systemic treatment, as a result of the upstaging. CONCLUSION: The incidence of intramammary nodes in this series correlates with previous data. This study shows that in breast cancer patients who undergo ANS, intramammary nodes, if present and more so positive, are unlikely to change systemic treatment decisions, but may increase the number of patients needing radiotherapy and or further axillary dissection.

Reading the prognosis of the individual with breast cancer.

AIM: To obtain better survival estimates for the individual than is provided by placement in an NPI group. METHOD: Consecutive primary operable breast cancers treated at Nottingham City Hospital 1990-1999. Ten year % actuarial survivals plotted for 10 ranges of NPI from 2.0 to 6.9. There is an excellent inverse correlation between median NPI value for each range and survival at 10 years. To enable estimation of survival for all individual values of NPI, a curve fitting technique applied to these results (by G.B.) gave the formula to estimate survival from the individual's NPI score: 10 year % survival for the individual=-3.0079 x NPI(2)+12.30 x NPI+83.84. This gave an r(2) of 0.98. RESULTS AND CONCLUSION: Greater accuracy in individual survival prediction is obtained by dividing women into 10 groups by NPI scores than in the originally described six groups; rank order of survival in relation to NPI score is preserved. A curve fitting technique has been applied to these data to give a formula for the prediction of 10 year survival for every 0.1 value of NPI.

Survival of invasive breast cancer according to the Nottingham Prognostic Index in cases diagnosed in 1990-1999.

UNLABELLED: The Nottingham Prognostic Index (NPI) is a well established and widely used method of predicting survival of operable primary breast cancer. AIMS: Primary: To present the updated survival figures for each NPI Group. Secondary: From the observations to suggest reasons for the reported fall in mortality from breast cancer. METHODS: The NPI is compiled from grade, size and lymph node status of the primary tumour. Consecutive cases diagnosed and treated at Nottingham City Hospital in 1980-1986 (n=892) and 1990-1999 (n=2,238) are compared. Changes in protocols towards earlier diagnosis and better case management were made in the late 1980s between the two data sets. RESULTS: Case survival (Breast Cancer Specific) at 10 years has improved overall from 55% to 77%. Within all Prognostic groups there are high relative and absolute risk reductions. The distribution of cases to Prognostic groups shows only a small increase in the numbers in better groups. CONCLUSION: The updated survival figures overall and for each Prognostic group for the NPI are presented.

Guidelines on the standards for the training of specialised health professionals dealing with breast cancer.

According to EUSOMA position paper 'The requirements of a specialist breast unit', each breast unit should have a core team made up of health professionals who have undergone specialist training in breast cancer. In this paper, on behalf of EUSOMA, authors have identified the standards of training in breast cancer, to harmonise and foster breast care training in Europe. The aim of this paper is to contribute to the increase in the level of care in a breast unit, as the input of qualified health professionals increases the quality of breast cancer patient care.

EUSOMA accreditation of breast units.

EUSOMA (European Society of Mastology) is the organisation representing Breast Cancer Specialists in all disciplines, covering all aspects of breast cancer from risk and prevention, through diagnosis and treatment of the primary tumour, follow-up, treatment of recurrent and advanced disease, pathology, reconstruction, psychology and audit. EUSOMA Guidelines have been published on several aspects of breast cancer and are on service provision as well as giving clinical guidance and providing the basis for audit.

Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma.

This study aimed to test the hypothesis that lymphovascular invasion adds prognostic information to histological grade and tumour size in node-negative invasive carcinoma of the breast. Lymphovascular invasion was assessed in haematoxylin and eosin tumour sections from 2760 patients with node-negative invasive breast carcinoma treated with definitive surgery. Patients were divided into two groups: 990 in the no adjuvant therapy series (diagnosed in 1974-1988) with median follow-up of 13 years; and 1765 in the selective adjuvant therapy series (1988-2000) with median follow-up of 6.8 years. Lymphovascular invasion was identified in 19% of tumours and was associated with larger tumour size, higher histological grade and younger age. Overall, survival was associated on multivariate analysis with lymphovascular invasion, histological grade and tumour size in both patient series, and with histological type in the no adjuvant therapy series. In conclusion, lymphovascular invasion is an independent prognostic factor in node-negative breast cancer and should be considered in decisions about adjuvant treatment in this group of women.

Expression and co-expression of the members of the epidermal growth factor receptor (EGFR) family in invasive breast carcinoma.

The epidermal growth factor receptor (EGFR) family plays an important role in breast carcinogenesis. Much interest has been focused recently on its members because of their potential role as prognostic indicators in breast cancer and their involvement in cancer therapy. We have evaluated more than 1500 cases of invasive breast carcinoma immunohistochemically using tissue microarray technology to examine the expression of EGFR family receptor proteins. We have found that 20.1 and 31.8% of cases were positive for EGFR and c-erbB-2, respectively, and 45 and 45.1% of tumours overexpressed for c-erbB-3 and c-erbB-4, respectively. The expression of either EGFR or c-erbB-2 was associated with other bad prognostic features and with poor outcome. Neither c-erbB-3 nor c-erbB-4 had any association with survival. c-erbB-2 had an independent prognostic effect on overall and disease-free survival (DFS) in all cases, as well as in the subset of breast carcinoma patients with nodal metastases. Several hetero- and homodimeric combinations have been reported between the EGFR members. Those dimers can evoke diverse signal transduction pathways with variable cellular responses. We stratified cases according to their co-expression of receptors into distinct groups with different receptor-positive combinations. Patients whose tumours co-expressed c-erbB-2 and c-erbB-3, as well as those whose tumours co-expressed EGFR, c-erbB-2 and c-erbB-4 showed an unfavourable outcome compared with other groups, while combined c-erbB-3 and c-erbB-4 expression was associated with a better outcome. In cases showing expression of one family member only (homodimers), we found a significant association between c-erbB-4 homodimer-expressing tumours and better DFS. In contrast, patients with c-erbB-2 homodimer-expressing tumours had a significant poorer DFS compared with other cases. These data imply that the combined profile expression patterns of the four receptor family members together provide more accurate information on the tumour behaviour than studying the expression of each receptor individually.

Woman feels breast lump--surgeon cannot: the role of ultrasound in arbitration.

The role of ultrasound scanning (USS) in patients complaining of a breast lump where the clinical examination (CE) is normal is not clearly defined. To determine this in greater detail, all patients complaining of a breast lump underwent CE. Where no lump could be found, but was still reported by the patient, an USS was performed. All lesions underwent biopsy and/or aspiration, as well as mammography in suspicious cases or those over 40 years of age. This cohort represented 5% of all referrals in the study period. Four hundred and twenty women were prospectively studied in this way. Median follow up is 3.4 years (range 2.5-4.2 years). Twenty two had solid lumps (of which 3 were cancers) and 48 had cysts. Nineteen patients re-presented with symptoms in the same breast (median time = 12 months (range 4.5-20 months), all of which were imaged on USS: 15 cysts and 4 further cancers (3 in the same quadrant as the original lump, one contralateral) were identified. Women with symptomatic breast lumps and a normal CE can be considered a reliable indication that cancer is very unlikely to be present (negative predictive value = 0.98). Ultrasound may be a suitable complimentary investigation, which will relieve symptoms in those with cysts and can detect small clinically--and sometimes mammographically--occult breast cancers.

Expression of luminal and basal cytokeratins in human breast carcinoma.

We have examined basal and luminal cell cytokeratin expression in 1944 cases of invasive breast carcinoma, using tissue microarray (TMA) technology, to determine the frequency of expression of each cytokeratin subtype, their relationships and prognostic relevance, if any. Expression was determined by immunocytochemistry staining using antibodies to the luminal cytokeratins (CKs) 7/8, 18 and 19 and the basal markers CK 5/6 and CK 14. Additionally, assessment of alpha-smooth muscle actin (SMA) and oestrogen receptor status (ER) was performed. The vast majority of the cases showed positivity for CK 7/8, 18 and 19 indicating a differentiated glandular phenotype, a finding associated with good prognosis, ER positivity and older patient age. In contrast, basal marker expression was significantly related to poor prognosis, ER negativity and younger patient age. Multivariate analysis showed that CK 5/6 was an independent indicator for relapse free interval. We were able to subgroup the cases into four distinct phenotype categories (pure luminal, mixed luminal/basal, pure basal and null), which had significant differences in relation to the biological features and the clinical course of the disease. Tumours classified as expressing a basal phenotype (the combined luminal plus basal and the pure basal) were in a poor prognostic subgroup, typically ER negative in most cases. These findings provide further evidence that breast cancer has distinct differentiation subclasses that have both biological and clinical relevance.

Phenotypic similarities in bilateral breast cancer.

Bilateral breast cancers that develop at similar times in an individual are likely to have been subjected to similar hormonal, environmental and genetic influences during tumourogenesis compared with metachronous tumours. As such, it is possible that tumour phenotype in synchronous bilateral breast cancer may display similar biological characteristics. The aim of this study was to identify phenotypic similarities between synchronous and metachronous bilateral breast cancers which may suggest a common origin. Thirty-three cases of synchronous and 46 cases of metachronous bilateral breast cancer that displayed similar tumour type were analysed for concordance in relation to various histological and immunohistochemical parameters. A higher level of concordance was demonstrated for synchronous cases with the highest level seen for oestrogen receptor. It is likely that this is related to similar tumourogenic pathways occurring at equivalent exposure times to various environmental and hormonal influences, although, in a proportion of cases, inherited genetic factors may play a role.

Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer.

Recommended guidelines have limited breast cancer gene ( BRCA1 ) mutation testing to individuals with a personal or family history of early onset breast and/or ovarian cancer, and those with multiple affected close relatives. Such large breast cancer families are rare in the general population, limiting the clinical application of the BRCA1 discovery. Previous reports have suggested an association between medullary breast cancer and BRCA1 mutation carriers. To test the feasibility of using these rare histological subtypes as an alternative to epidemiological factors, 42 cases of medullary cancer unselected for family history were screened for BRCA1 point mutations and large exon rearrangements. The large majority (83%) of these patients did not have significant family of breast or ovarian cancer. Two deleterious mutations resulting in a premature stop codon, and one exon 13 duplication were found. All mutations were detected in patients with typical medullary cancer, who had family history of multiple breast and ovarian cancers. Our findings suggest that medullary breast cancers are not an indication for BRCA1 mutation screening in the absence of significant family risk factors.

Local anaesthetic and steroid combined injection therapy in the management of non-cyclical mastalgia.

AIMS: We aimed to assess the effectiveness of a local anaesthetic and steroid combination injection therapy in the management of non-cyclical mastalgia. METHODS: Patients with non-cyclical mastalgia were assessed for rib tenderness (lateral chest wall tenderness-LCWT). The tenderest spot was injected with a combined preparation of 1 ml 2% lignocaine and 1 ml 40 mg depomedrone. Those who declined injection therapy were advised on topical or oral NSAIDs or reassurance. All patients were reassessed 6 weeks later. A successful outcome was taken as either a complete response (CR) or partial response (PR), i.e. pain although present is tolerated. RESULTS: One hundred and thirty eight women were diagnosed with LCWT. One hundred and four women were injected. Thirty-four women declined and were managed appropriately. At assessment 83 injected cases were successful (83%; CR n = 61, PR n = 22) compared to 13 non-injected cases (44.8%; CR n = 5, PR n = 8, P < 0.0001). No side effects were recorded. Sixteen cases recurred and were successfully re-injected. CONCLUSIONS: A steroid and local anaesthetic injection is an effective and safe treatment for LCWT.

Management of physiological gynaecomastia with tamoxifen.

AIMS: We aimed to confirm suggestions that tamoxifen therapy alone may resolve physiological gynaecomastia. METHODS: A prospective audit of the outcome of tamoxifen routinely given to men with physiological gynaecomastia was carried out at Nottingham. Men referred with gynaecomastia had clinical signs recorded, e.g., type (diffuse 'fatty' or retro-areolar 'lump'), size and possible aetiology. They were offered oral tamoxifen 20mg once daily for 6-12 weeks. On follow-up patients were assessed for complete resolution (CR), partial resolution where patient is satisfied with outcome (PR) or no resolution (NR). Success was either CR or PR. RESULTS: Thirty-six men accepted tamoxifen for physiological gynaecomastia. Median age was 31 (range 18-64). Tenderness was present in 25 (71%) cases. Sixteen men (45%) had 'fatty' gynaecomastia and 20 had 'lump' gynaecomastia. Tamoxifen resolved the mass in 30 patients (83.3%; CR=22, PR=8) and tenderness in 21 cases (84%; CR=0, PR=0). Lump gynaecomastia was more responsive to tamoxifen than the fatty type (100% vs. 62.5%; P=0.0041). CONCLUSIONS: Oral tamoxifen is an effective treatment for physiological gynaecomastia, especially for the lump type.

Incidence of clinically significant lymphoedema as a complication following surgery for primary operable breast cancer.

There has recently been considerable interest for the need for specialist lymphoedema nurses to be appointed in the NHS. However, we had noticed in our cancer follow-up clinics that the incidence of lymphoedema appeared to be very low. Treatment for primary breast cancer (>5 cm) has been surgery and low axillary sampling (ANS). Radiotherapy (RT) or axillary clearance is subsequently performed in patients found to be node positive. The patients are followed-up in the primary breast cancer (PBC) clinic weekly. Follow-up is initially at 3-month intervals up to 2 years and then 1 yearly indefinitely. We conducted a two phased study in patients being followed up in our post cancer clinic in order to identify the incidence of LE in these patients. Phase 1 involved symptomatic patients identified at routine follow up in a 15-week period and the number of patients reporting arm swelling was recorded. The aim of this was to provide an estimate to power a phase 2 study (prospective questionnaire based). Phase 2 was conducted over a 13-week period. All patients attending the clinic were administered modified FACT B4, EQ-50 and Speilberger questionnaires. A total of 1242 patients were examined and lymphoedema found in 5 (0.04%). Of these 5, 3 had undergone axillary clearance, 1 ANS plus radiotherapy and only 1 had ANS alone. A policy of ANS, with prophylactic treatment for lymph node positivity either by surgery or RT alone, gives a very low rate of lymphoedema.