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.

Catheter fracture: a rare complication of totally implantable venous devices.

The use of totally implantable venous devices (TIVDs) has revolutionised the care and quality of life of oncology patients. Although considered to be generally safe, catheter fracture is a rare but serious complication. The 'pinch-off' syndrome is caused by the compression of the catheter between the clavicle and first rib, and may lead to fracture and possible dislocation of the catheter. We report here the case history of two patients with metastatic breast cancer who developed the 'pinch-off' syndrome, first recognised by difficulty in line aspiration and pain during injection of the catheter. In one case, there was complete fracture with migration of the catheter tip to the right pulmonary artery. In both cases, the lines were removed without serious injury to the patient. All patients with TIVDs should be investigated for possible catheter fracture if they develop pain over the superior anterior chest wall and/or there is difficulty or pain during aspiration or injection.

Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer.

Patients undergoing primary chemotherapy for invasive breast cancer consented to a core biopsy of the invasive breast primary pre- and 24 h postchemotherapy. The resulting tissue was analysed for apoptosis, Ki67, ER and HER-2 using immunohistochemical techniques. These data were then used to evaluate the relationship between these biological markers and response to chemotherapy and overall survival. Response rate to chemotherapy in this group was 86%, 16 patients (25%) achieved a clinical complete response and 41 (63%) a partial response. Prechemotherapy there was a significant correlation between Ki67 and apoptotic index (AI), r=0.6, (P<0.001). A significant rise in AI (P<0.001), and fall in Ki67 (P=0.002) was seen 24 h following chemotherapy. No relationship was seen between pretreatment AI and clinical response, but higher Ki67 and growth index (Ki67/AI ratio, GI) did correlate with clinical response (both r=0.31, P<0.025). No correlation was seen between the change in AI or Ki67 at 24 h and clinical response or survival. Significant changes in apoptosis and proliferation can be demonstrated 24 h following chemotherapy, but these changes do not relate to clinical response or outcome in this study. Pretreatment proliferation and GI are however predictive of response to chemotherapy in breast cancer.

Bone marrow transplantation for myelodysplastic syndrome--who? when? and which?

Although allogeneic transplantation has resulted in long-term disease-free survival in some patients with myelodysplastic syndromes (MDS), the morbidity and mortality of this approach remains high. Additionally, many patients are not candidates for such an approach because of their age or comorbid factors. Autologous transplantation and the use of reduced intensity conditioning prior to allogeneic stem cell transplantation has provided less toxic alternatives as well as increased the numbers of patients eligible for some form of transplantation. While bone marrow transplantation clearly has a role in the treatment of MDS, the decision to proceed to transplantation is not always easy and the optimal approach has not been clearly defined. Improvement in patient selection and novel approaches to transplantation will hopefully allow for more effective, less toxic results.

Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention.

Interest in chemoprevention in oncology using suppressants of prostaglandin (PG) synthesis has been stimulated by epidemiological observations that the use of aspirin and other non-steroidal inflammatory drugs (NSAIDs) is associated with reduced incidence of some cancers, including cancer of the breast. The main target of NSAID activity is the cyclooxygenase (COX) enzyme. Two isoforms of COX have been identified: COX-1, the constitutive isoform; and COX-2. the inducible form of the enzyme. COX-2 can undergo rapid induction in response to many factors such as bacterial lipopolysaccharides, growth factors, cytokines and phorbol esters. COX-2 is overexpressed in some malignancies including carcinoma of the breast. It has been suggested that such enhanced expression may lead to increased angiogenesis such that the inhibition of COX-2 might have a general anticancer effect via decreased blood vessel formation. In addition, an association between COX-2, its main product PGE2 and aromatase activity in human breast cancer suggests that such inhibitors might have an additional, specific prophylactic mechanism for this tumour. New COX-2 inhibitors are already licensed for use in the treatment of arthritis and are well tolerated. Their potential role in chemoprevention of mammary carcinogenesis in rats has already been investigated. What remains to be seen is if these findings can be extrapolated to human studies.

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.

HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer.

In experimental models, human epidermal growth factor receptor-2 (HER-2) amplification leads to estrogen independence and tamoxifen resistance in estrogen receptor (ER)-positive human breast cancer cells. Some but not all reports suggest an association between HER-2 positivity and hormone independence in breast cancer patients. This study aimed to evaluate the antiproliferative effects of endocrine therapy in HER-2-positive/ER-positive primary human breast cancer. The effect on proliferation (Ki67) of hormone therapy was assessed at 2 weeks and/or 12 weeks in biopsies from 115 primary breast cancers with ER-positive tumors. The patients took part in one of 3 neoadjuvant trials of hormonal therapy with a SERM (tamoxifen or idoxifene) or an aromatase inhibitor (anastrozole or vorozole). HER-2 status was assessed by immunocytochemistry and fluorescence in situ hybridization (FISH). Fifteen patients were defined as HER-2 positive by both immunohistochemistry and FISH, with the remaining 100 patients HER-2 negative. Geometric mean Ki67 levels were substantially higher in HER-2-positive than HER-2-negative tumors (27.7% versus 11.5%, respectively; P = 0.003). In HER-2-negative patients, Ki67 was reduced by 62 and 71% at 2 and 12 weeks, respectively (P < 0.0001 for both), but HER-2-positive patients showed no significant fall. The proportional change in Ki67 was significantly different between HER-2-positive and -negative patients (P = 0.014 at 2 weeks; P = 0.047 at 12 weeks). Mean ER levels were lower in the HER-2-positive patients (P = 0.06) but the change in Ki67 was impeded even in those with high ER. Apoptotic index was reduced by 30% at 2 weeks in the HER-2-negative group. However, there were no statistically significant differences in apoptotic index between the groups. It is concluded that ER-positive/HER-2-positive primary breast carcinomas show an impeded antiproliferative response to endocrine therapy that nonetheless may vary between individual treatments. This together with high baseline proliferation is likely to translate to poor clinical response.

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.

Are randomized trials of hormone replacement therapy in symptomatic women with breast cancer feasible?

OBJECTIVE: To evaluate the feasibility of conducting a large randomized trial of HRT in symptomatic women with early-stage breast cancer. DESIGN: Open randomized study. SETTING: Outpatient clinics at The Royal Marsden and St. George's Hospitals, London. PATIENT(S): One hundred postmenopausal women with early-stage breast cancer, experiencing vasomotor symptoms and/or vaginal dryness. INTERVENTION(S): Randomization (1:1) to HRT or no HRT for 6 months. MAIN OUTCOME MEASURE(S): Acceptance, continuance rates, and the reasons eligible women declined study entry. RESULT(S): Acceptance (38.8%) and continuance rates (>80%) were encouraging. The efficacy of HRT did not appear to be antagonized with concomitant tamoxifen. Seventy-five percent of women continued HRT after the study ended. Three women developed metastatic disease. Two used HRT. CONCLUSION(S): Despite informed consent, a national UK randomized trial of HRT should be feasible and has now been planned. Successful implementation necessitates the provision of information about HRT and the estrogen deficiency side effects of breast cancer therapy to health professionals and women with breast cancer.

Understanding the experience of prophylactic bilateral mastectomy: a qualitative study of ten women.

Prophylactic bilateral mastectomy represents a new and controversial cancer prevention strategy for women at high-risk of familial breast cancer, the psychosocial implications of which are yet to be fully explored. A qualitative methodology was therefore adopted to provide a discovery-orientated study of the perspectives of ten women who had undergone prophylactic mastectomy and the views of eight of their partners. Each participant was interviewed with the aim of exploring the personal experiences of surgery, factors associated with psychological adjustment and the impact on the family. Data were transcribed and systematically analysed using Grounded Theory. Themes emerging from participants' accounts formed seven significant categories that represented women's key experiences: (i) deciding; (ii) telling; (iii) experiencing surgery and recovering; (iv) maintaining womanliness; (v) processing the loss; and (vi) moving on. The importance of the social context in women's experience and difficulties of isolation/eliciting support were also highlighted: (vii) isolation and being supported. A core category of 'Suffering and countering multiple loss' considered central to women's experience, integrated the seven significant categories and provided further conceptualisation of women's experience. Implications for clinical practice are highlighted.

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.

Local relapse in primary breast cancer patients with unexcised positive surgical margins after lumpectomy, radiotherapy and chemoendocrine therapy.

BACKGROUND: Inadequate surgical excision with residual involvement of resection margins by tumour after breast conservation results in increased local recurrence rates. To reduce this risk positive margins are, therefore, usually excised. Systemic treatment with tamoxifen or chemotherapy reduces local recurrence, along with radiotherapy. However, no studies to date have examined the correlation between chemoendocrine treatment, together with radiotherapy, and local relapse in patients with unexcised involved resection margins, having had breast conservation treatment. PATIENTS AND METHODS: The histopathology reports were reviewed of 184 patients who were treated from June 1991 to August 1995 within our randomised study of neoadjuvant versus adjuvant chemoendocrine therapy with mitozantrone and methotrexate (2M) +/- mitomycin-C (3M) and tamoxifen, used concurrently with radiation following conservation surgical treatment. Histological resection margin was considered positive if ductal carcinoma in situ (DCIS) or invasive carcinoma was present microscopically less than 1 mm from the excision margin. RESULTS: Although 38% of patients had unexcised microscopically involved margins, local relapse rate as first site of relapse was only 1.9% after a median follow up of 57 months. There was no difference in distant relapse (P = 0.2) and survival (P = 0.5) between the positive and negative margins groups. CONCLUSIONS: The presence of positive unexcised margins does not have a significant effect on outcome in patients who are treated with chemoendocrine therapy together with radiotherapy. Further clinical trials are required.

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.