Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer?

PURPOSE: This retrospective analysis aimed to identify whether breast cancer patients receiving radiotherapy alone following a complete clinical remission (cCR) to neoadjuvant chemotherapy had a worse outcome than those treated with surgery. PATIENTS AND METHODS: One hundred thirty-six patients who had achieved a cCR to neoadjuvant chemotherapy for early breast cancer were identified from a prospectively maintained database of 453 patients. Of these, 67 patients had undergone surgery as their primary locoregional therapy, and 69 patients had radiotherapy alone. Outcome was assessed in relation to local recurrence-free survival, disease-free survival, and overall survival. RESULTS: Median follow-up was 63 months in the surgery group and 87 months in the no surgery group. Prognostic characteristics were well balanced between the two groups. For surgery and no surgery, respectively, there were no significant differences in disease-free survival or overall survival (5-year, 74% v 76%; 10-year, 60% v 70%, P =.9) between the two groups. There was a nonsignificant trend toward increased locoregional-only recurrence for the no surgery group (21% v 10% at 5 years; P =.09), but no long-term failures of local control. Patients in the no surgery group who also achieved an ultrasound complete remission had a 5-year local recurrence rate of only 8%. CONCLUSION: In patients achieving a cCR to neoadjuvant chemotherapy, radiotherapy alone achieve survival rates as good as with surgery, but with higher local recurrence rates. Ultrasound may identify a low recurrence rate subgroup for assessing no surgery in a prospective trial.

A retrospective study comparing the individual modalities of triple assessment in the pre-operative diagnosis of invasive lobular breast carcinoma.

AIMS: Early invasive lobular breast carcinoma (ILC) is associated with few symptoms and signs. The individual sensitivity of clinical examination, mammography, ultrasonography, cytology and core biopsy have each been reported to be of limited value. The aim of this study was to evaluate the accuracy of triple assessment in the pre-operative detection of patients identified to have ILC from their surgical pathology. METHODS: Pure ILC was defined as tumours containing at least 90% lobular features. The triple assessment of 273 patients diagnosed primarily at our institution were reviewed. RESULTS: 87.5% of women were symptomatic and 12.5% were screen detected. The mean patient age was 59 (range 30-81) years and the median tumour size was 26 (range 5-110) mm. The main mammographic abnormalities were a spiculated lesion (33.3%), an ill-defined mass (33.3%) or architectural distortion (23.5%). The sensitivities for detecting ILC of each modality were: clinical examination (76.6%), mammography (79.8%), ultrasound examination (93.9%), fine-needle aspiration cytology (FNAC) (60.5%) and core biopsy (90.8%). Combining the three modalities of clinical examination, imaging and cyto/pathology increased the pre-operative detection rate of ILC. CONCLUSION: Triple assessment is useful in the diagnosis of ILC. As the features of ILC may be subtle, a high index of suspicion is required to facilitate early diagnosis.

Multimodality therapy in inflammatory breast cancer: is there a place for surgery?

BACKGROUND: In many centres surgery is used as part of a combined modality approach to the treatment of inflammatory breast cancer (IBC). Nevertheless, its value is controversial given the high risk of metastatic relapse and poor overall prognosis. We have reviewed patients with true IBC prospectively treated at the Royal Marsden Hospital in chemotherapy trials to assess further the role of surgery as part of combined modality treatment. PATIENTS AND METHODS: Fifty-four patients who had responsive or stable disease to primary chemotherapy went on to have either radiotherapy alone (n = 35) or surgery plus radiotherapy (n = 19); the decision on surgery was based partly on clinician preference and partly on clinical response. RESULTS: The 35 patients undergoing radiotherapy alone had a median progression-free survival (PFS) of 16 months and median overall survival (OS) of 35 months. Twenty-four patients (69%) have relapsed with a total of twelve (34%) relapsing locally. In comparison, the 19 patients receiving both surgery and radiotherapy had a PFS of 20 months, and a median OS of 35 months. Fifteen patients (79%) have relapsed, eight (42%) of these locally. None of these differences were statistically significant. CONCLUSIONS: These results do not suggest a clinical advantage for surgery in addition to chemotherapy and radiotherapy for patients with IBC. They support the need for a prospective randomised trial to address this question.

Role of axillary surgery in early breast cancer: review of the current evidence.

BACKGROUND: Controversy continues to surround the best practice for management of the axilla in patients with early breast cancer (EBC), particularly the clinically negative axilla. The balance between therapeutic and staging roles of axillary surgery (with the consequent morbidity of the procedures utilized) has altered. This is due to the increasing frequency of women presenting with early stage disease, the more widespread utilization of adjuvant chemoendocrine therapy and, more recently, the advent of alternative staging procedures, principally sentinel node biopsy (SNB). The aim of the present review is to critically analyse the current literature concerning the preferred management of the axilla in early breast cancer and make evidence-based recommendations on current management. METHODS: A review was undertaken of the English language medical literature, using MEDLINE database software and cross-referencing major articles on the subject, focusing on the last 10 years. The following combinations of key words have been searched: breast neoplasms, axilla, axillary dissection, survival, prognosis, and sentinel node biopsy. RESULTS: Despite the trend to more frequent earlier stage diagnosis, levels I and II axillary dissection remain the treatment of choice in the majority of women with EBC and a clinically negative axilla. CONCLUSIONS: Sentinel node biopsy has no proven superiority over axillary dissection because no randomized controlled trials have been completed to date. Despite this, SNB will become increasingly utilized due to encouraging results from major centres responsible for its development, and patient demand. Therefore if patients are not being enrolled in clinical trials strict quality controls need to be established at a local level before SNB is allowed to replace standard treatment of the axilla. Unless this is strictly adhered to there is a significant risk of an increase in the frequency of axillary relapse and possible increased understaging and resultant inadequate treatment of patients.

Which patients with early breast cancer need axillary clearance?

The role of axillary surgery in the management of early breast cancer is currently the topic of intense debate in the literature. There are strong indications that women are presenting with earlier tumours and hence the majority have negative axillary nodes making axillary dissection less beneficial both in terms of disease control and less likely to result in an alteration of management. Alternative less morbid axillary staging and non-axillary staging methods are being investigated, but sentinel node biopsy shows the most promise for reliable assessment of the axilla. This review aims to assess the current literature regarding the role of axillary surgery in breast cancer management. The reasoning why axillary dissection is still the gold standard in breast cancer management is explained and related to the other methods of axillary assessment and therapy. Suggested guidelines for current optimal management are made.

Is mastectomy overtreatment for Paget's disease of the nipple?

The standard local management for Paget's disease of the nipple is currently mastectomy although this may well represent overtreatment. The place of breast conserving surgery is somewhat uncertain. We have reviewed the casenotes of 146 patients with Paget's disease of the nipple, and compared the mortality and recurrence rates between 74 women who had undergone mastectomy and 31 women who had breast conserving surgery. There was no significant difference in either local or overall treatment failure rates between these two treatment groups. We conclude that breast conserving treatment maybe an appropriate alternative to mastectomy for the management of Paget's disease, where clear margins of excision can be achieved. However, a randomized prospective study is needed to confirm this.

Comparison of biochemical aromatase activity with aromatase immunohistochemistry in human breast carcinomas.

The role of intratumoural aromatase in human breast cancer growth remains controversial. At the same time as the use of aromatase inhibitors in the clinical setting continues to increase, so does the need for a tool to predict the likely response to this treatment. Intratumoural aromatase is a candidate predictive marker. The presently accepted 'gold standard' methods of assessment of aromatase activity are biochemical assays. However, these are time-consuming and require relatively large amounts of fresh or frozen tissue which are frequently not available. The development of a reliable immunohistochemical technique for the assessment of intratumoural aromatase which could be applied rapidly to more readily available paraffin-embedded material is therefore highly desirable. Unfortunately aromatase immunohistochemistry is also an area of controversy; some authors describe localisation to the stromal compartment but others to the malignant epithelial cells themselves. The aim of this study was therefore to compare immunohistochemical scores using two different antibodies with biochemical aromatase activity. Taking a group of 29 human breast carcinomas we demonstrated a strong correlation between immunoreactivity with a monoclonal antibody (p = 0.01) but not with a polyclonal (p = 0.16). The monoclonal produced reactivity in both epithelial and stromal cells but the polyclonal in only stromal cells. The implications of these results are discussed together with the need for further studies.

Assessment of a scoring system for breast imaging.

BACKGROUND: Triple assessment is the standard method of assessing symptomatic breast lumps. There is an accepted format for reporting cytology but not for the reporting of mammograms or breast ultrasonographic images. This study describes a scoring system for reporting breast imaging methods. METHODS: Patients with symptomatic breast lumps seen during 1 year were included. All patients underwent triple assessment. Imaging studies were reported using a grading system from 1 to 5. The results of triple assessment were compared with the final histology. RESULTS: Some 127 women had both mammography and ultrasonographic imaging; the final grade was identical in 60 per cent. The positive predictive value of imaging reported as grade 5 or 4 combined with cytology of C5 or C4 was 100 per cent. All lesions with C3 cytology and benign imaging were benign on histological examination whereas if a C3 grade was combined with imaging grade 5 or 4, all the lesions were malignant. CONCLUSION: Combining the imaging grade with the results of aspiration cytology and clinical examination often predicts the final histology in patients with breast disease.

Hormone replacement therapy in women with previous breast cancer.

As breast cancer is known to be a tumour sensitive to the effects of endogenous oestrogens, clinicians are reluctant to prescribe hormone replacement therapy (HRT) to women with a history of previous breast cancer for fear of stimulating disease recurrence, and it is currently contraindicated in this group of women. However, an increasing proportion of breast cancer patients are requesting the use of HRT to relieve the symptoms of oestrogen deficiency, which are also a common side-effect of adjuvant therapy for breast cancer. Observational data on the use of HRT in breast cancer survivors has not demonstrated an increase in disease recurrence, but uncertainty will continue in the absence of data from prospective, randomized trials. This review aims to demonstrate why it is ethical and scientifically important to undertake such studies.

T-cell lymphoma in Hashimoto's thyroiditis.

An elderly Caucasian woman with a 2-year-history of hypothyroidism, treated with thyroxine, presented with a rapidly growing mass in the thyroid. The morphological and immunological features of this thyroid tumour were those of a peripheral T-cell lymphoma with an immunophenotype commonly associated with HTLV-1 positive-adult T-cell leukaemia/lymphoma, although serology for HTLV1 antibody was negative. Monoclonal gene rearrangements were demonstrated with T-cell receptor beta- and gamma-specific primers. There are several interesting features in this case (i): although primary B-cell lymphomas (MALT-associated lymphomas) of thyroid are a well-recognized sequel to thyroiditis, primary T-cell lymphomas are rare, even in areas of the world where adult T-cell lymphomas predominate; (ii) the tumour showed the typical immunophenotype of an HTLV-1 positive T-cell lymphoma but the patient is English, has not visited endemic areas, and is serologically negative for HTLV-1; (iii) the residual thyroid gland showed a florid lymphocytic thyroiditis with Hürthle cell change, typical of Hashimoto's thyroiditis; (iv) unlike other reports of thyroid T-cell lymphoma, which have presented with stage III-IV disease, this tumour presented in the favourable clinical stage of IE.

Radioimmunotherapy of breast cancer xenografts with monoclonal antibody ICR12 against c-erbB2 p185: comparison of iodogen and N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate radioiodination methods.

C-erbB2 p185 is a proto-oncogene product expressed in 25-30% of human invasive breast cancers that is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. It is minimally expressed in normal adult tissues (M. F. Press et al., Oncogene, 5: 953-962, 1990). For this reason, it is an attractive target for radioimmunotherapy and other antibody-directed therapies. ICR12 is a rat IgG2a monoclonal antibody directed against a protein epitope of the external domain of the c-erbB2 p185. We performed experiments to optimize the direct iodination of ICR12 with 131I using the IodoGen method, and we found impairment of immunoreactive fraction with increasing specific activity. N-Succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate (MATE) is a tin ester that can be radioiodinated easily and then coupled to the epsilon-amino group of lysine residues. This method has been shown to have improved uptake in tumors compared with antibody labeled by direct iodination (P. K. Garg et al., Nucl. Med. Biol., 20: 379-387, 1993). ICR12 could be labeled up to 16 mCi/mg by this technique without loss of immunoreactive fraction. Whole-body retention of MATE-labeled ICR12 was less than IodoGen (P < 0.0001). Radioimmunotherapy experiments in athymic mice bearing established MDA MB 361 human breast cancer xenografts showed growth inhibition for > 24 days at a dose of 600 microCi/mouse (P < 0.0001) when labeled by the IodoGen technique, and 12 days using the MATE method (P < 0.0001).

Clinical radioimmunolocalization with a rat monoclonal antibody directed against c-erbB-2.

Lymph node status is still the single most important prognostic factor in breast cancer and surgery remains the only reliable means of providing this information. This study evaluates using a highly specific radiolabeled monoclonal antibody to provide equivalent information. The optimum labeling conditions for radiolabeling a monoclonal antibody against the gene product of the protooncogene c-erbB-2 with Tc99m were established. This immunoconjugate was next evaluated in a mouse model system and averaged 20% localization of the total injected dose per gram of tumor at 24 h. Ten patients have had this immunoconjugate, with planar and tomographic reconstructed images being obtained at 24 h. The resulting images were compared to histopathological examination of the surgical specimens. Three patients acted as normal controls, two patients were selected on the basis of inappropriate sampling of adjacent ductal carcinoma in situ, three patients demonstrated only moderate antigen expression, and two patients demonstrated excellent tumor localization in both breast primary and regional node metastases. The high specificity of this antibody, ease of labeling, and excellent localization performance with a good antigen target encourage the development of this system as a method of localization and a potential means of antibody-guided therapy.

Modulation of Bcl-2 and Ki-67 expression in oestrogen receptor-positive human breast cancer by tamoxifen.

The expression of the bcl-2 proto-oncogene, which is associated with prolonged cell survival and prevention of programmed cell death, was investigated in human primary breast carcinomas prior to and following endocrine therapy with the anti-oestrogen, tamoxifen. Using the BCL-2-100 antibody, a 26-kD protein was detected by western immunoblot in the cytosols of oestrogen receptor (ER)+ve human breast cancers. In a cross-sectional study, the immunohistochemical expression of Bcl-2 was observed in 32% of invasive breast cancers, but in 65% of tumours treated with tamoxifen (P = 0.009). There was a significant association of Bcl-2 with ER status, with 64% of untreated and 88% of tamoxifen-treated Bcl-2-positive tumours being ER+ve. A significantly lower Ki-67 score was found in tamoxifen-treated tumours which were Bcl-2-positive compared with Bcl-2-negative (9.3 versus 24.6%, P = 0.01). In a separate series of sequential Trucut biopsies from 18 patients, the frequency of Bcl-2 expression was increased in ER+ve tumours from 3/12 to 8/11 following tamoxifen (P = 0.04). This was also associated with a significant reduction in mean Ki-67 score from 32 to 12% (P = 0.0004). The observations from this study clearly indicate that Bcl-2 in human breast cancer is associated with ER status, and that expression is enhanced in ER+ve tumours following tamoxifen, in association with reduced cell proliferation.