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Breast papers


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Sentinel node localisation in patients with breast cancer. Fleet M M, Going J J, Stanton P D, Cooke T G. Br J Surg 1998; 85: 991-993.

Axillary nodal status is the most important prognostic factor in patients with breast cancer. Formal axillary clearance is the best staging procedure, however, it is associated with significant morbidity. About 60% of axillary dissections show no evidence of metastatic disease. As a result, axillary sampling (removal of 4 nodes) has been proposed as an alternative means of assessing nodal status. Staging errors can occur following axillary sampling and this procedure is associated with a higher local recurrence rate. Intra-operative lymph node mapping has been suggested so as to allow identification of the first draining node (the 'sentinel' node) and to reduce the morbidity associated with axillary surgery. The aim of this study was to assess the reliability of sentinel node biopsy in predicting axillary lymph node status. In total, 68 patients with breast cancer underwent breast surgery (38 mastectomy & 30 wide local excision). All underwent sentinel node biopsy. The node was identified by injection of 2.5% Patent Blue dye adjacent to the primary tumour and the axilla was explored 10 minutes post-injection. The sentinel node was excised and submitted for both frozen section and paraffin histological assessment. All patients then proceeded to an axillary clearance. A sentinel node was identified in 82% of patients. Histological examination of this node predicted nodal status in 95% of cases. Sentinel node biopsy had a sensitivity of 83% and specificity of 100%. It was concluded that sentinel node biopsy may allow a selective policy of formal axillary dissection in node-positive patients.

Non-operative treatment of breast abscesses. Tan S M, Low S C. Aust N Z J Surg 1998; 68: 423-424.

Breast abscesses have traditionally been treated by incision and drainage. This invariably requires hospital admission, surgery under general anaesthesia, dressing of a granulating wound and may result in unacceptable scar. Needle aspiration and oral antibiotics has been suggested as an alternative means of treatment. The aim of this study was to assess the outcome of conservative treatment of non-lactational breast abscesses. Twenty-one women with mainly periareolar abscesses were studied and 19 underwent needle aspiration under local anaesthesia. Patients were given oral antibiotics (either Augmentin & cloxacillin or cefuroxime and metronidazole) for ten days. Two patients elected for surgery. Two-thirds of patients were treated as out-patients. The mean number of aspirations required per patient was 2.4. Only three patients developed recurrent abscesses at the same site. It was concluded that most non-lactational abscesses can be treated conservatively by aspiration and do not require surgery.

Detection of residual disease following breast conserving surgery. Beck N E, Bradburn M J, Vincenti A C, Rainsbury R M. Br J Surg 1998; 85: 1273-1276.

An assessment of the completeness of tumour excision is an integral part of breast conserving surgery. Positive histological margins is known to be a risk factor for local recurrence, but, the accuracy of current histological margin analysis is unclear. This study compared the results of resection margin analysis, histological examination of tumour bed biopsies and examination of the excised tumour cavity in 144 patients with 'early' breast cancer undergoing breast conserving surgery. All patients underwent standard wide local excision followed by four tumour bed biopsies and finally complete excision of the tumour bed. The presence of invasive or in-situ disease was noted. Overall, positive margins or residual disease was found in 43% patients. Residual disease was found at the resection margin in 27%, in bed biopsies in 17% and in the cavity in 27%. Margin analysis proved to be a poor predictor of the completeness of excision. It was concluded that examination of the entire cavity was may increase the detection of residual disease.

Reoperation for locally recurrent breast cancer in patients previously treated with conservative surgery. Salvadori B, Marbudini E, Miceli R et al. Br J Surg 1999; 86: 84-87.

In the treatment of early breast cancer the outcome in terms of overall and disease-free survival are similar whether mastectomy and axillary clearance or wide local excision, breast radiotherapy and axillary surgery are performed. Traditionally local recurrence in the conserved breast has been managed by mastectomy. The aim of this study was to evaluate the outcome of re-excision or mastectomy in those patients who developed intra-breast recurrence following breast conserving surgery. Between 1970 and 1989, 2544 patients underwent quadrantectomy, axillary surgery and radiotherapy. Of these patients 209 developed breast recurrence, 12 of which was considered inoperable due to extensive breast involvement. Of the remaining 197, 134 (70%) underwent mastectomy and 57 (30%) had a further re-excision. Patients were followed up for a mean of 73 (1-192) months. This was not a randomised controlled trial and as a result the groups were not well matched. At five years the survival in the mastectomy group was 70% and in the re-excision group 85%. There was no difference in disease-free survival. There was an increased incidence of a second breast recurrence (19% vs. 4%) in the re-excision group. It was concluded that the type of surgery after local recurrence had no effect on survival and that further breast conservation may be appropriate in selected patients.

Accuracy of intraoperative frozen-section analysis of axillary nodes. Dixon J M, Mamman U & Thomas J et al. Br J Surg 1999; 86: 392-395.

Approximately 50% of all patients with symptomatic breast cancers and only 10% of patients with screen-detected tumours have axillary lymph node involvement. Axillary lymph node status is the most important prognostic factor and both pre-operative clinical and radiological assessment of lymph node status have been shown to be inaccurate. Axillary surgery both stages and treats the axilla, however, the only patients to benefit from axillary surgery are those with involved nodes. Intraoperative assessment of axillary lymph node status would allow selection of patients who would benefit from axillary lymph node dissection. Identification of the node-negative patient has been the stimulus for the introduction of sentinel node biopsy. However, intraoperative frozen-section analysis of the sentinel node has been shown to have a high false negative rate. The aim of this study was to assess the accuracy of intraoperative frozen-section analysis of axillary lymph nodes. Eighty-eight patients undergoing mastectomy or wide local excision had a four node axillary sample submitted for frozen section analysis. They were a highly selected group of patients considered at low risk of having positive nodes. Nodes were submitted for both frozen and paraffin section analysis. Frozen section produced an accurate assessment of nodal status in 81 of the 88 patients. It however missed axillary nodal metastases in 7 of the 26 patients with positive nodes on a paraffin sections (sensitivity = 73%, specificity = 100%). It was concluded that frozen-section analysis of axillary lymph nodes should not be recommended for routine assessment of axillary nodal assessment.

The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30 year results of a randomised. controlled trial. Veronesi U, Marubibi E, Mariani L, Valagussa, Zucali R. Eur J Cancer 1999; 35: 1320-1325.

Axillary nodal sampling or dissection has been included in almost all operative procedures for invasive breast cancer. Like the axillary nodes, the internal mammary nodes represent an important lymphatic drainage route of the breast. However, for many years surgery to the internal mammary nodes has been ignored. To evaluate the possible role of dissection of the internal mammary nodes in breast cancer surgery, a large international trial was started in 1963 comparing radical mastectomy with radical mastectomy and internal mammary lymph node dissection. Patients did not receive adjuvant radiotherapy or chemotherapy. The results was published in 1976 and showed no survival advantage from this extended surgery. This paper reports the long-term results of patients from the Milan Cancer Institute entered into this trial. Overall 737 patients with non-disseminated breast cancer were randomised to the two treatment arms. As previously published, there was no survival advantage associated with the more extensive treatment. However, 20% patients had positive internal mammary nodes. This was associated with significantly worse prognosis independent of the axillary nodal status. They concluded that the prognostic value of internal mammary nodal status was high and that biopsy of a selected node might be considered useful in the staging process.

Radiotherapy in breast-conserving treatment for ductal carcinoma in-situ: first results of EORTC randomised phase III trial 10853.  Julien J-P,  Bijker N,  Fentiman I S et alLancet 2000;  255:  528-233.

Ductal carcinoma in-situ (DCIS) has been increasingly recognised since the introduction of screening mammography.  It is invariably clinically occult, presenting as microcalcification and accounts for 15% of all breast cancers.  In recent years, breast-conserving surgery has been more widely used in the treatment of invasive breast cancer yet it remains a paradox that mastectomy has remained the treatment of choice for DCIS.  The extent surgery and in particular the use of breast radiotherapy in patients with DCIS remains to be defined.  This study was an international randomised trial of radiotherapy after breast-conserving surgery in patients with DCIS.  Between 1986 and 1996, patients with completely excised DCIS less than 5 cm in diameter were randomised to receive no additional treatment (n=503) or breast radiotherapy - 50 Gy over 5 weeks (n=507).  The primary end-point was invasive or non-invasive local recurrence and analysis was on an intention-to-treat basis.  The mean follow up was 4.3 yrs.  In the group who did not undergo radiotherapy 83 patients developed local recurrence (44 DCIS; 40 invasive).  In the radiotherapy group 53 (29 DCIS; 24 invasive) local recurrences occurred.  The 4-year local relapse free survival was 84% in the no additional treatment group and 91% in the radiotherapy group (log rank p=0.005;  hazard ratio = 0.62).  There was a similar reduction in the risk of invasive and non-invasive recurrences.  The results published in this study were similar to those from the NSABP B-17 study.  It was concluded that radiotherapy after local excision of DCIS reduces the risk of both non-invasive and invasive local recurrence in the ipsilateral breast.

Management of the axilla in operable breast cancer treated by breast conservation: a randomised clinical trial.  Chetty U, Jack W, Prescott R J et al. Br J Surg 2000;  87:  163-169.

The relative roles of surgery and radiotherapy in the management of the axilla in patients undergoing breast surgery is unclear.  A full level III axillary clearance is advocated by many surgeons for all invasive breast cancers.  However, 50% of tumours up to 5 cm in diameter and 90% of tumours below 1 cm in diameter have no axillary metastases.  There is, however, no reliable preoperative or intraoperative method of determining axillary node status.  Histological examination of the axillary nodes obtained by a four-node sample has been shown to stage the axilla as accurately as a full clearance.  The aim of this study was to compare the efficacy and morbidity of nodal clearance and sampling with radiotherapy in patients with operable breast cancer. Patients with operable breast cancer were randomised to either a level III axillary clearance (n=232) or axillary node sampling (n=234).  Radiotherapy was given selectively but not to those undergoing axillary clearance.  In the latter part of the trial only those patients with positive nodes on axillary sampling were given radiotherapy.  Upper limb morbidity was assessed.  When the different surgical techniques were compared there was no difference in the rate of loco-regional recurrence or distant metastases.  Morbidity was lowest in those undergoing sampling without radiotherapy.  Radiotherapy to the axilla in those who had a node sample significantly reduced shoulder movement.  Axillary clearance was associated with significant lymphoedema of the upper limb.  It was concluded that a selective policy for the management of the axilla is associated with no increase in axillary recurrence compared with routine axillary clearance.  Patients who are node negative after axillary sampling can avoid the morbidity associated with radiotherapy or a full axillary clearance. 

Comparison between low and high pressure suction drainage following axillary clearance.  Wedderburn A, Gupta R, Bell N, Royle G. Eur J Surg Oncol 2000;  26:  142-144.

Suction drainage is routinely used to reduce the incidence of seroma formation following axillary surgery.  The length of time that these drains remain in-situ influences the duration of the postoperative stay.  The aim of this study was to compare the duration and volume of drainage and the incidence of seroma formation with the use of two types of closed drainage systems.  The systems compared were the high vacuum Redivac drain (300-600 mmHg) and the low vacuum Exudrain (75 mmHg).  Following axillary surgery all patients were randomly allocated, based on hospital number, to one of the two drainage systems.  The volume drained was measured daily.  The duration of hospital stay and the number of complications were also recorded.  Drains were removed when the daily volume fell below 30 ml or the drain had been in-situ for 8 postoperative days.  Drains remained in-situ for a mean of 5 days in both groups.  There was no difference in the mean total volume drained between the two groups.  There were no complications specific to drain use.  It was concluded that the two drainage systems are equally effective.  Low pressure drains may be advantageous as they obviate the need for bottle changes, are more comfortable and require less time and effort to manage. 

Breast cancer patients treated without axillary surgery - clinical implications and biologic analysis.  Greco M,  Agresti R,  Cascinelli N et al.  Ann Surg 2000;  232:  1-7.

The role of axillary dissection in patients with small breast cancers is controversial. It has been suggested that axillary nodal dissection in patients with T1 tumours is over treatment as over 75% of these patients do not have axillary lymph node metastases.  The decision to excise clinically negative nodes is usually solely based on the need for the important prognostic information obtained by such surgery.  As axillary surgery is responsible for most of the morbidity following breast cancer surgery efforts have been made to identify groups of patients in which axillary surgery can be avoided.  This has involved the determination of other useful prognostic factors that might guided the use of adjuvant therapy.  The aim of this study was to evaluate the effect of avoiding axillary surgery on local control and the risk of distant metastases in patients with small breast cancers.  It also evaluated a panel of pathological and biological parameters evaluated on the primary tumour that might be useful in predicting metastatic spread.  Between 1986 and 1994, in a prospective non-randomised pilot study, 401 patients underwent breast cancer surgery without axillary dissection.  During follow up, patients with clinical evidence of axillary recurrence underwent salvage surgery.  The biological characteristics of the primary tumour were investigated by immunohistochemistry and four pathological characteristics were evaluated (size, grade, laminin receptor and c-erb-2 receptor).  During a five-year follow up period there was a low rate (6.7%) of axillary nodal metastases, particularly in patients with T1a and T1b tumours.  Surgery was a safe and feasible salvage treatment without technical difficult in all cases of axillary recurrence.  The rate of axillary recurrence was higher in patients with T1c (15%) and T2 (34%) tumours.  Analysing the primary tumour both pathological and biological parameters were predictive of metastatic spread and could replace the information obtained from the nodal status.  It was concluded that axillary nodal dissection could be avoided in patients with T1a and T1b tumours without an adverse outcome.  In these patients adjuvant therapy could be based on prognostic information obtained from the primary tumour.  

Impact of mammographic interval on stage and survival after the diagnosis of contralateral breast cancer. Kaas R, Hart A A M, Besnard A P E, Peterse J L, Rutgers E J T. Br J Surg 2001; 88: 123-127.

In patients with treated breast cancer, the risk of developing a contralateral tumour is two to six times greater than that of developing a primary breast cancer in the general population. Metachronous contralateral breast cancers occurs at a rate of approximately 1% per year and screening of treated patients is therefore justified. Regular screening leads to an improvement in stage distribution for second cancers but the optimal screening interval is unknown. The aim of this study was to compare the outcome of metachronous contralateral breast cancers detected during follow-up using different mammographic intervals. A retrospective analysis was performed of patients treated for breast cancer between 1976 and 1990 who had their details recorded in the tumour registry of the Netherlands Cancer Institute. Patients who developed contralateral breast cancer were identified and stratified into two groups according to mammographic interval. Data was available for 275 patients who developed contralateral breast cancer. Annual mammography was performed in 51% who were a mean of 5 years younger at diagnosis. Patients who had annual or biennial mammography had comparable rate of impalpable lesions, 30% and 27% respectively. There was no difference in tumour stage and the five year disease-free survival was 75% in both groups. When the contralateral tumour was detected by mammography, disease-free survival was better irrespective of the stage of the ipsilateral breast cancer. It was concluded that there was no difference in stage distribution or disease-free survival after the diagnosis of contralateral breast cancer. Survival was improved in those patients in whom the contralateral breast cancer was first detected by mammography.

Morbidity following sentinel lymph node biopsy versus axillary lymph node dissection for patients with breast cancer. Schrenk P, Rieger R, Shamiyeh A, Wayand W. Cancer 2000; 88: 608-614.

Axillary lymph node dissection (ALND) in patients with breast cancer is performed to both stage the disease and to obtain locoregional control. As many patients receive adjuvant therapy irrespective of their nodal status, the value of routine lymph node dissection has been questioned. This is especially so as the morbidity associated with ALND is considerable. Complications following ALND include lymphoedema, sensory disturbances and restriction of shoulder movement. Because of these complications attempts have been made to develop new techniques that will accurately stage the axilla but without the associated morbidity. One such technique is sentinel node (SN) biopsy. The aim of this study was to prospectively compare postoperative morbidity in 35 patients undergoing a Level 1 or 2 ALND with 35 patients undergoing SN biopsy. Patient characteristics were comparable between the two groups. Postoperative follow up was 15.4 months in the SN group and 17.0 months in the ALND groups. ALND dissection was associated with a significant increase in arm circumference, subjective lymphoedema, pain, sensory disturbance and restricted shoulder movement. The type of surgery did not affect daily living. It was concluded that SN biopsy is associated with negligible morbidity compared with complete axillary dissection.

High incidence of micrometastases in breast cancer sentinel nodes.  Mann G B,  Buchanan M,  Collins J P,  Lichtenstein M.  Aust NZ J Surg 2000;  70:  786-790.

Sentinel node (SN) biopsy has been advocated as a method of allowing selective axillary dissection for patients with invasive breast cancer. It offers the chance to gain prognostic information and to formulate treatment plans without the need for axillary dissection in node-negative patients.  The anticipated reduction in morbidity and the presumed equivalence of this technique is currently the subject of ongoing clinical trials.   After SN biopsy the pathologist is presented with between one and 4 nodes rather than the 15 to 20 nodes retrieved after a full axillary dissection.  This offers the potential for a more intensive analysis of the smaller number, which may in turn lead to a more accurate pathological assessment.  With the use of either immunohistochemistry (IHC) or polymerase chain reaction (PCR)  'micrometastatic disease' can be detected in either the bone marrow or lymph nodes of breast cancer patients, the presence of which may confer a worse prognosis on the patient.  The aim of this study was to audit the presence of lymph node micrometastases in 62 consecutive patients (1998-2000) undergoing SN biopsy.  All SN were initially examined and reported using haematoxylin and eosin (H&E) staining.  All histologically-negative SN nodes were submitted for examination with a polyclonal anticytokeratin antibody in order to detect micrometastases.  Overall, a SN was identified in 51 of the 62 patients.  There was one false negative case.  A total of 10 of the 51 nodes contained metastases identified on H&E staining.  A total of 10 of 41 H&E-negative nodes had micrometastases detected by IHC.  Micrometastases were more common in patients with large tumours.  It was concluded that SN biopsy can accurately assess the axilla in most patients with early breast cancer.  That a significant proportion of histologically negative nodes will contain micrometastases identifiable with IHC.  Although the clinical significance of these is uncertain, the available evidence suggests that they have a poorer prognosis than other patients with histologically-negative axillary lymph nodes.

Tubular carcinoma of the breast:  prognosis and response to adjuvant systemic therapy.  Kitchen P R B,  Smith H J,  Henderson M A et al.  Aust NZ J Surg 2001;  71:  27-31.

Tubular carcinoma of the breast usually presents as a small lesion with distinctive histological features.  It is uncommon, accounting for only about 1% of all breast cancers, but is being detected more commonly following the introduction of screening mammography.  It has an improved prognosis compared with non-tubular histological types and two studies have suggested that node-positivity is not an adverse prognostic factor.  Tubular carcinomas appear to have a good prognosis irrespective of tumour size or nodal status.  This raises the question as to whether all patients with tubular carcinomas should undergo axillary dissection and also whether those shown to be node-positive require systemic adjuvant therapy.  The aim of the present study was to examine the long-term prognosis of patients with tubular breast carcinoma and to elucidate the relative roles of axillary surgery and adjuvant therapy.  Eighty-six patients with tubular carcinoma were identified from a large worldwide database of 9520 breast cancer patients entered into randomised adjuvant therapy trials by the International Breast Cancer Study Group.  The patients were followed up for a median of 12 years. Overall, 42 (49%) were node-positive with 33 (79%) having between one and 3 involved nodes.  Ten (32%) tumours less than 1 cm diameter were node-positive. Patients with node-positive tubular carcinoma had a significantly better 10-year relapse-free survival and overall survival compared with non-tubular node-positive cases.  Overall survival was similar for node-positive and node-negative tubular carcinoma.  In total, 71 (83%) patients received some form of adjuvant therapy.  There was an 85% decrease in the risk of death for patients who had received more than one course of chemotherapy compared with those who had not (hazard ratio 0.15, CI 0.03-0.82. p=0.03).  It was concluded that compared to other histological types of breast cancer, tubular carcinomas had a better long-term prognosis.  Adjuvant chemotherapy may further improve prognosis but involvement of axillary nodes may not be an indicator of an adverse outcome in this group of patients.

Breast-conserving therapy for Paget's disease of the nipple.  Bijker N,  Rutgers E J T,  Duchateau et al.  Cancer 2001;  91:  472-477.

Paget's disease of the nipple is an uncommon manifestation of breast cancer, presenting in 1-3% of all cases.  Almost all cases are associated with the presence of underlying ductal carcinoma in situ (DCIS) or invasive cancer.  The prognosis for patients with Paget's disease is usually determined by the stage of the underlying cancer.  To achieve adequate local control mastectomy has traditionally been the standard treatment.  Little has been published regarding the role of breast conserving surgery (BCS) in the selected group with localised disease.  In 1987 the EORTC initiated a multicentre registration study to assess the feasibility of BCS with radiotherapy for patients with Paget's disease .  Overall, 61 patients without evidence of invasive cancer were registered.  Most patients (97%) presented without an associated palpable mass.  Histologically 93% had DCIS within 5 cm of the nipple.  In the remaining 7%, Paget's disease alone was found.  Treatment comprised of complete excision of the nipple-areola complex with histological evidence of tumour-free margins.  All patients received postoperative radiotherapy.  The primary endpoint was local recurrence.  At a median follow-up of 6.4 years, 4 of the 61 patients developed local recurrence (1 DCIS; 3 invasive).  One patient with invasive local recurrence died of metastatic disease.  The 5-year local recurrence rate was 5.2%.  It was concluded that BCS is a feasible alternative for patients with Paget's disease and a limited extent of underlying DCIS.  To achieve good local control BCS should be combined with radiotherapy.

Risk, severity and predictors of physical and psychological morbidity after axillary lymph node dissection for breast cancer.  Ververs J M M A,  Roumen R M H,  Vingerhoets A J J M et al.  Eur J Cancer 2001;  37:  991-999.

Axillary lymph node dissection (ALND) has been the standard axillary therapy for patients with invasive breast cancer.  It provides regional control of disease and is also important in adjuvant therapy decision-making.  However, it has become increasingly apparent that ALND may cause severe physical morbidity, such as oedema, pain, numbness, loss of strength and impaired range of movement.  Psychosocial and adaptational problems have also been reported.  The aim of this study was to investigate the nature and severity of arm-related complaints amongst breast cancer patients following ALND and to study the effects of this treatment-related morbidity on daily life and well-being.  400 patients who underwent ALND as part of breast cancer surgery completed a treatment-specific quality-of-life questionnaire.  The mean time since surgery was 4.7 years (range 0.3 to 28 years).  More than 20% reported pain, numbness of loss of strength and 9% reported severe oedema.  None of the complaints appeared to diminish over time.  Irradiation of the axilla and supraclavicular area was associated with a 3.6-fold higher risk of oedema (OR = 3.57; 95% CI 1.66-7.69) causing many patients to give up leisure activities or sport.  Women who underwent irradiation of the breast or chest wall more often reported to have a sensitive scar than women who did not receive radiotherapy.  Women less than 45 years had a six times higher risk of numbness to the arm (OR 6.49;  CI 2.58-16.38), compared with those older 65 years of age.  It was concluded that both the physical and psychological morbidity following ALND was considerable and the investigation of less invasive techniques for the staging of the axilla should be pursued.

Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation.  Bartelink H,  Horiot J-C, Poortmans P et al.  N Eng J Med 2001;  345:  1378-1387.

Several randomised controlled trials and meta-analyses have shown similar survival rates after breast-conserving surgery (BCS) and mastectomy in patients with early breast cancer. Following microscopically complete excision, irradiation of the whole breast with 50 Gy reduces the rate of local recurrence from approximately 35% to 10%. Little is know about the effect of irradiation of the breast at doses higher than 50 Gy. The aim of this study was to evaluate the effect of a supplementary dose of radiation to the tumour bed on the rates of local recurrence among patients who received radiotherapy after BCS for early breast cancer. After wide local excision and axillary dissection, patients with Stage I or II breast cancer received 50 Gy of irradiation to the whole breast in 2 Gy fractions over a 5 week period. Patients with a microscopically complete excision were randomly assigned to receive either no further local treatment (n=2657) or an additional localised dose of 16 Gy, usually given in eight fractions by means of an external electron beam (n=2661). During a median follow-up period of 5.1 years, local recurrence was observed in 182 patients in the standard treatment and 109 patients in the additional irradiation group. The five-year actuarial rates of local recurrence were 7.3% (95% CI; 6.8-7.6) and 4.3% (95% CI; 3.8-4.7) respectively (p<0.001), yielding a hazard ratio for local recurrence of 0.59 (99% CI; 0.43-0.81) associated with additional dose. Patients 40 years old or younger benefited most. No difference was found in the rates of metastases or overall survival. It was concluded that in patients with early breast cancer who undergo BCS and receive 50 Gy irradiation to the whole breast, an additional dose of 16 Gy of radiation to the tumour bed reduces the risk of local recurrence, especially in younger patients.

Five-node biopsy of the axilla: an alternative to axillary dissection of level I-II in operable breast cancer.  Ahlgren J,  Homberg L, Bergh J, Lijegren G.  Eur J Surg Oncol 2002;  28:  97-102.

Arm-related complications such as oedema, pain, numbness, weakness and impaired shoulder mobility are side-effects of axillary dissection.  The extent of axillary surgery is a well-established risk factor for this arm morbidity. However, information on histopathological axillary nodal status is still the most important prognostic factor for patients with primary breast cancer.  Axillary lymph node dissection is a reliable means of assessing nodal status but the therapeutic benefit of axillary surgery remains controversial.  The aim of this study was to assess whether a five lymph node biopsy provides as accurate information on the histological nodal status as a level I-II axillary dissection in patients with operable breast cancer, especially in women with a low risk of nodal metastases.  Between 1989 and 1997, 415 patients with operable breast cancer undergoing axillary surgery underwent a five-node axillary biopsy followed by a further dissection of level I-II of the axilla.  Overall, the sensitivity of the the five-node biopsy was 97% with a negative predictive value of 99% and a negative likelihood rati0 of 0.027.  Among patients detected by screening (n=204) and those clinically detected (n=197) the sensitivity of the five-node biopsy was 96% and 98% respectively, with negative predictive values of 99% and 98% respectively.  It was concluded that five-node biopsy of the axilla has good accuracy for correctly staging the axilla in both clinically and screen-detected patients.

Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status.  Haffty B G, Harrold E, Khan A J et al.  Lancet 2002;  359: 1471-1477.

The management of young women with newly diagnosed breast cancer is a challenge with complicated medical, psychological and social implications.  Early-onset breast cancer is associated with biologically more aggressive tumours and even after adjustment for tumour stage, local, regional and distant relapse rates are higher than in older women. Women with early-onset breast cancer are more likely to have a genetic predisposition.  The management of early-stage disease in women with mutations of the BRCA1 or BRCA2 gene is controversial. The aim of this study was to assess the long-term risk of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast conserving surgery followed by radiotherapy. Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy.  Of these women 127 were recruited into the study and underwent complete sequencing of the BRCA1 and BRCA2 gene.  Demographic, clinical, pathological and outcome data was recorded.  The primary endpoints were rates of ipsilateral and contralateral breast cancer in relation to the germline BRCA1/2 status.  Overall, 105 women were classified as having sporadic disease and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] and BRCA2 [7]).  At 12 years of follow up, the genetic group had significantly higher rates of ipsilateral (49% vs. 21%. p=0.007) and contralateral events (42% vs. 9%. p=0.001) than the sporadic group.  The majority of events were classified as second primary tumours.  No patient in the genetic group had undergone oophorectomy or was taking prophylactic tamoxifen.  It was concluded that patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours.  With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable.  Alternatively, bilateral mastectomy may be considered to minimise the risk of a second breast cancer.

Prophylactic oophorectomy in carriers of BRCA1 and BRCA2 mutations.  Rebbeck T R,  Lynch H T, Neuhausen S L et al.  N Eng J Med 2002;  346:  161-1622.

Women with germline BRCA1 or BRCA2 mutations have an increased risk of breast and ovarian cancer as compared with the general population.  Bilateral oophorectomy has been suggested as a means of reducing the risk, but the data on the resulting risk reduction is limited. Prophylactic oophorectomy is known to reduce the risk of breast cancer by 50% in carriers of the BRCA1 mutation.  The aim of this study was to determine the extent of risk reduction for both breast and ovarian cancer by prophylactic oophorectomy in women know to be either BRCA1 or BRCA2 carriers. Overall, 551 women with germline mutations of either BRCA1 or BRCA2 were identified form registries and studied for the occurrence of either breast or ovarian cancer.  The incidence of ovarian cancer in 259 women who had undergone bilateral oophorectomy was compared with 259 matched controls. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer in 99 women who had undergone prophylactic oophorectomy was compared with 142 matched controls.  The length of follow-up was 8 years in both groups.  Six (2%) women who underwent prophylactic oophorectomy had a diagnosis of Stage 1 ovarian cancer at the time of the procedure.  Two (0.8%) women received a diagnosis of papillary serous peritoneal carcinoma 4 and 9 years after bilateral oophorectomy. Amongst the controls, 58 (20%) received a diagnosis of ovarian cancer.  With the exclusion of the 6 women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial carcinoma (HR 0.04;  95% CI 0.01-0.16).  Of the 99 women who underwent prophylactic oophorectomy and were studied to determine the risk of breast cancer. breast cancer developed in 21 (21%) as compared with 60 (42%) in the control group (HR 0.47; 95% CI 0.29-0.77).  It was concluded that prophylactic oophorectomy reduces the risk of coelomic epithelial carcinoma and breast cancer in women with BRCA1 and BRCA2 mutations.

Oral contraceptives and the risk of breast cancer.  Marchbanks P A, McDonald J A, Wilson H G et al.  N Eng J Med 2002;  346:  2025-2032.

Available data suggest that women who currently use oral contraceptives or who have used them in the past 10 years have a slightly increased risk of breast cancer, where as those who used oral contraceptives longer ago do not have an increased risk.  As a result is is is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is also increased.  The aim of this study was to conduct a population-based, case control study to determine the risk of breast cancer among former and current users of oral contraceptives.  A total of 4575 women with breast cancer and 4682 controls (aged 35-64 years) were interviewed to assess oral contraceptive use.  Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk of breast cancer.  The relative risk was 1.0 (95% CI 0.8-1.3) for women who were currently using oral contraceptives and 0.9 (95% CI 0.8-1.0) for those who had previously used them.  The relative risk did not increase consistently with longer periods of use or higher oestrogen doses.  The results were similar amongst white and black women.  Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral contraceptive use at a young age.  It was concluded that among women from 35 to 64 years of age, current or former oral contraceptive use was not associated with a significantly increased risk of breast cancer.

Breast cancer and breastfeeding:  collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries.  Collaborative group on hormonal factors in breast cancer.  Lancet 2002;  360:  187-195.

Although childbearing is known to protect against breast cancer, what contribution breastfeeding has on this protective effect, is any, has been difficult to determine.  Breast feeding is closely related to many other aspects of childbearing and no single study has been large enough to characterise the relative contributions.  Individual data from 47 epidemiological studies in 30 countries that included information on breast feeding patterns and other aspects of child bearing were included and analysed centrally for 50,013 women with invasive breast cancer and 96, 973 controls.  Estimates of the relative risk for breast cancer associated with breast feeding in parous women were obtained after stratification by age, parity and age when their first child was born, as well as by study and menopausal status.  The study showed that women with breast cancer had on average fewer births than did controls (2.2.vs 2.6).  Fewer parous women with cancer than parous controls had ever breastfed (71% vs. 79%) and their average duration of breast feeding was shorter (9.8 months vs. 15.6 months).  The relative risk of breast cancer decreased by 4.3% (95% CI 2.9-5.8: p<0.0001) for every 12 months of breastfeeding in addition to a decrease of 7.0% (95% CI 5.0-9.0; p<0.0001) for each birth.  The size of the decline in the relative risk of breast cancer associated with breast feeding did not differ significantly for women in developed or under developed countries and did not vary significantly by age, menopausal status, ethnic origin, the number of births a woman had, her age when her first child was born, or any other personal characteristics examined.  It was estimated that the cumulative incidence of breast cancer in developed countries would be reduced more than half if women had the average number of births and lifetime duration of breast feeding that had been prevalent in under developed countries until recently.  Breast feeding could account for almost two-thirds of this estimated reduction in breast cancer incidence.  It was concluded that the longer women breast feed the more they are protected against breast cancer.  The lack of or short lifetime duration of breastfeeding typical of woman in developed countries makes a major contribution to the high incidence of breast cancer in these countries.

First results from the International Breast Cancer Intervention Study (IBIS-1): a randomised prevention trial.  IBIS Investigators.  Lancet 2002;  360:  817-824.

That oestrogen is the primary promotional factor for breast cancer has been well established for some time but attempts to control the incidence of breast cancer by decreasing the oestrogenic stimulus are more recent.  The marked reduction in the rate of contralateral tumours when tamoxifen is used in the adjuvant therapy of early breast cancer and the drugs apparently low toxicity profile, have led to the proposal that tamoxifen prophylaxis might be suitable for the reduction of breast cancer incidence in high-risk women.  Three previous clinical trials on the use of tamoxifen to prevent breast cancer have reported mixed results.  The overall conclusions have been support for a reduction in the risk of breast cancer but whether the benefits outweigh the risks is unclear.  This study was double-blind placebo-controlled randomised trial of tamoxifen (20 mg/day) for 5 years in 7152 women aged 35-70 years who were at increased risk of breast cancer.  The primary outcome measure was the frequency of breast cancer (including DCIS).  Analyses were on an intention-to-treat basis after exclusion of 13 women found to have breast cancer at baseline mammography.  After a median follow up of 50 months (IRQ 32-67), 69 breast cancers had been diagnosed in the 3578 women in the tamoxifen group and 101 in 3566 in the placebo group (Risk reduction = 32% (95% CI 8-50) p=0.013).  Age, degree of risk and the use of HRT did not affect the risk reduction.  Endometrial cancer was non-significantly increased and thromboembolic events were significantly increased with tamoxifen (43 vs.17, OR=2.5 (95%CI 1.5-4.4) p=0.001), particularly after surgery.  There was a significant excess of deaths from all causes in the tamoxifen group (25 vs11. p=0.028).  It was concluded that prophylactic tamoxifen reduces the risk of breast cancer by about one third.  Prophylactic use is contraindicated in women at high risk of thromboembolic events.  The overall risk to benefit ratio for the use of tamoxifen in the prevention of breast cancer remains unclear and the continued follow-up of current trials is essential.

The frequency of breast cancer screening:  results from the UKCCCR randomised trial.  The breast screening frequency trial group.  Eur J Cancer 2002;  38:  1458-1464.

In 1988, population screening for breast cancer was introduced nationally in the UK for women aged 50 to 64 years.  The interval between screens was chosen to be 3 years.  However, there have been no clinical trials comparing screening intervals and the optimum frequency for screening is unknown.  The aim of this trial was to investigate whether more frequent screening is advantageous.  Between 1989 and 1996, 99,389 women aged 50 -62 years who had been invited to a prevalent screen were randomly allocated after the scheduled prevalent screen date to the study arm (invited to three further annual screens) or to the control arm (invited to the standard single screen three years later).  Overall, 37,530 women in the study arm and and 38,492 women in the control arm attended the prevalent screen.  The primary endpoint was predicted breast cancer deaths.  The prediction was based on both the Nottingham Prognostic Index (NPI) and a similar method derived from survival data from a series of tumours in the Swedish Two-County trial (2CS).  Both indices were based on the size, lymph node status and histological grade of the invasive tumours diagnosed in the two arms of the trial.  The pathology of the cases diagnosed was subject to review by two pathologists using standard criteria.  The tumours diagnosed in the study arm were significantly smaller than those diagnosed in the control arm (p=0.05).  The relative risk of death from beast cancer for the annual compared with three-yearly screened group was 0.95 (95% CI: 0.83-1.07. p=0.4) using the NPI and 0.89 (95% CI:  0.77-1.03. p=0.09) using the 2CS.  It was concluded that shortening the screening interval in this age group is predicted to have a relatively small effect on beast cancer mortality.  Improvements to the screening programme should be targeted more productively on areas other then the screening interval, such as improving screening quality.

The Canadian National Breast Screening Study-1:  Breast cancer mortality after 11 to 16 years of follow-up.  Miller A B,  To T,  Baines C J,  Wall C.  Ann Intern Med 2002;  137:  305-312.

Whilst the value of breast cancer screening in women over the age of 50 years remain controversial, the efficacy of mammographic screening at a younger age remains unproven.  The Canadian National Breast Screening Study-1, was an individually randomised trial in women 40 to 49 years of age at study entry, designed to asses the efficacy of annual mammography, breast physical examination and instruction on breast self-examination in reducing breast cancer mortality.  Analysis at 7-years and 10-years of follow-up had shown no reduction in breast cancer mortality.  Between 1980 and 1985, 50,430 women were recruited between 40 and 49 years of age, who were no pregnant, had no previous diagnosis of breast cancer and who had not had mammography in previous 12 months.  Prior to randomisation all women underwent breast examination and were instructed on breast self examination.   Women were then randomised to two groups.  One group (n=25,214) underwent annual mammography and annual follow-up for five years.  The other group (n=25,216) received standard community care with annual follow-up for five years.  The primary outcome measure was breast cancer mortality.  By 16-years of follow-up there had been 105 breast cancer deaths in the mammography group and 108 breast cancer deaths in the standard care group (RR=1.06, 95% CI 0.80-1.40).  A total of 592 cases of invasive cancer and 71 cases of in-situ disease were diagnosed in the mammography group compared with 552 and 29 cases respectively in the standard care group.  It was concluded that after between 11 to 16 years of follow-up, annual mammographic screening with breast examination and self-examination had not reduced breast cancer mortality compared with usual community care. 

Twenty-year follow-up of a randomised study comparing breast-conserving surgery with radical mastectomy for early breast cancer.  Veronesi U,  Cascinelli N,  Mariani L et al.  N Eng J Med 2002;  347:  1227-1232.

For most of the 20th century, radical mastectomy was the treatment of choice for breast cancer irrespective of tumour size or type.  The possibility of attempting a surgical procedure that would conserve the breast was not widely considered until the 1970s.  In 1973, a trial was started in Milan to compare the efficacy of radical mastectomy with that of breast-conserving surgery (BCS).  The 20-year follow-up data from this study is presented in this paper.  From 1973 to 1980, 701 women with breast cancers measuring no more than 2 cm in diameter and without palpable axillary lymphadenopathy were randomly assigned to undergo radical mastectomy (n=349) or BCS (quadrantectomy) followed by radiotherapy to the ipsilateral breast (n=352).  After 1976, patients in both groups who had positive axillary nodes also received cyclophosphamide, methotrexate and fluorouracil chemotherapy.  Overall, 30 women in the group that underwent BCS had a recurrence of tumour in the same breast, whereas 8 women in the radical mastectomy group had local recurrence (p<0.001).  The crude cumulative incidence of these events was 8.8% and 2.3% respectively after 20 years of follow-up.  In contrast, there was no significant difference between the two groups in the rates of contralateral breast carcinoma, distant metastases or second primary cancers.  After a median follow-up of 20 years, the rate of death from all causes was 41.7% in the groups that underwent BCS and 41.2% in the radical mastectomy group (p=1.0).  The respective death rates from breast cancer was 26.1% and 24.3% (p=0.8).  It was concluded that the long-term survival rate among women who undergo BCS is the same as that among women who underwent radical mastectomy.  BCS is therefore the treatment of choice for women with relatively small breast cancers.

Role of magnetic resonance imaging in the diagnosis and single-stage surgical resection of invasive lobular carcinoma of the breast.  Munot K,  Dall B,  Achuthan R,  Parkin G,  Lane S,  Horgan K.  Br J Surg 2002;  89:  1296-1301.

Invasive lobular carcinoma (ILC) is histologically represented by diffusely infiltrative tumour cells in linear arrays and represent around 10% of all breast cancers.  A surrounding desmoplastic reaction is less evident than in invasive ductal carcinoma.  As a result, they often fail to produce a discrete mass and are difficult to define on palpation.  Similarly, they are often radiolucent and often cause minimal or no mammographic abnormality.  They present a diagnostic challenge even with thorough triple assessment.  Contrast-enhanced MRI has a high sensitivity for the diagnosis of breast cancer.  There is also evdience of improved preoperative determination of breast cancer extent compared with conventional imaging.  The aim of this study was to determine whether MRI had any advantage for the characterisation of ILC.  Twenty patient with histologically proven ILC underwent preoperative imaging with MRI.  MRI was performed to aid the detection of malignancy in 6 patients with a clinically suspicious presentation but normal or indeterminate imaging on mammography and ultrasound.  In 14 patients MRI was performed to determine tumour extent.  MRI accurately identified malignancy in 5 of the 6 patients with normal or indeterminate conventional imaging.  In 7 of the 14 patients in whom MRI was performed to determine tumour extent, it provided significant additional information.  These included 4 patients in whom conventional imaging grossly underestimated tumour size, 2 patients in whom MRI identified an unsuspected contralateral tumour and one patient in whom MRI identified invasion of the pectoral muscles.  The correlation between tumour size on histological examination was better with MRI (r=0.967) than with mammography (r=0.663) or ultrasound (r=0.673).  It was concluded that MRI can provide considerable additional information in the detection and characterisation of ILC.

Sentinel lymph node biopsy alone without axillary lymph node dissection - follow up of sentinel lymph node negative breast cancer patients.  Reitsamer R,  Peintinger F,  Prokop E et al.  EJSO 2003;  29:  221-223.  

Axillary lymph node dissection (ALND) has long been the surgical standard treatment of the axilla for breast cancer patients.  The rationale for this has been precise staging, useful prognostic information and the possibility of an improvement in survival.  ALND is however occasionally associated with significant morbidity.  Sentinel lymph node biopsy (SLNB) is a minimally invasive technique for axillary staging that is associated with a reduction in morbidity.  It has the potential to identify those patients who will not benefit from ALND and could therefore be spared unnecessary surgery.  The aim of this study was to evaluate the rate of axillary recurrence in SLN negative breast cancer patients after SLNB alone without further ALND.  Between May 1999 and February 2001, all patients who had primary invasive breast cancer and were SLN negative were eligible for inclusion in the study.  SLNB was performed by using the combined method with radioactive tracer and blue dye.  SLNs were examined by frozen section, standard H & E staining and immunohistochemistry.  SLN negative patients did not receive further ALND.  Patients were followed-up every three months and underwent annual mammography.  Overall, 116 patients with early breast cancer were included in the study.  All patients had negative SLNs on frozen section, H & E staining and immunohistochemistry.  The mean number of SLNs removed was 2.03.  Mean tumour diameter was 17 mm.  No local or axillary recurrence occurred at mean duration of follow-up of 22 months.  It was concluded that the absence of axillary recurrence after SLNB without ALND in SLN negative breast cancer patients supports the hypothesis that SLNB is accurate and safe while providing less surgical morbidity. Short-term results are very promising.  SLNB without ALND in SLN negative patients is an excellent procedure for axillary staging in a cohort of breast cancer patients with small tumours. 

Testicular tumours presenting as gynaecomastia.  Daniels I R,  Layer G T.  EJSO 2003;  29:  437-439.  

Gynaecomastia is the commonest benign breast condition seen in men and is defined as a generalised enlargement of the male breast.  It is common and may be seen in up to 40 - 65% of all adult males.  It may be unilateral or bilateral and is characteristically described as a tender, symmetrical, discoid enlargement of the breast.  The majority of cases reflect an elevated circulating ratio of oestrogens to androgens due to age, drugs or idiopathic factors.  Only rarely is the cause a testicular tumour.  The aim of this study was to assess those men with gynaecomastia who were shown to have a testicular tumour.  A retrospective review of 175 men who presented with breast enlargement or a 'lump' over a seven year period was performed. All patients were investigated by a protocol including biochemical assessment.  The median age was 44 years (range 18-89).  Overall, 127 had gynaecomastia, 8 had breast cancer and four had testicular tumours.  Of the men with testicular tumours, 2 had bilateral gynaecomastia; a testicular mass was palpable in two and the diagnosis confirmed on scrotal ultrasound in four.  It was concluded that the possibility of a testicular tumour be considered in any man presenting with gynaecomastia.  Clinical testicular examination is essential and the determination of serum tumour markers useful in the overall assessment of those presenting with 'true gynaecomastia'.

Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia and New Zealand:  randomised controlled trial.  UKCCR DCIS Working Party.  Lancet  2003;  362:  95-102. 

Before the NHS breast screening programme was introduced in 1998, only a small proportion of newly diagnosed breast cancers were ductal carcinoma in-situ (DCIS).  Initially, localised DCIS was treated by mastectomy and, although effective, this approach is now regarded as over-treatment for many screen-detected lesions.  Whilst there has been increasing recognition that breast conservation for invasive cancer is a safe alternative to mastectomy, there was initially little evidence to recommend breast conservation in women with DCIS.  The aim of this study was to assess the effectiveness of adjuvant radiotherapy and tamoxifen following breast conservation for screen-detected DCIS.  Using a 2 x 2 factorial design, between 1990 and 1998, 1694 patients were recruited from national breast screening programmes and were randomised to both adjuvant treatments in combination or singly or to no treatment, or to one treatment modality (e.g. radiotherapy) with an elective decision to give or withhold the treatment (e.g. tamoxifen).  Patients had complete surgical excision of the lesion confirmed by specimen radiography and histology.   Patients had been followed up for at least one year.  Median follow-up was 52 (range 2-118) months.  The primary endpoint was the incidence of ipsilateral invasive disease.  Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of overall DCIS  was decreased (HR = 0.68;  95% CI = 0.49 - 0.96, p = 0.03).  Radiotherapy reduced the incidence of ipsilateral invasive disease (HR = 0.45, 95% CI = 0.24 - 0.85, p = 0.01) and ipsilateral ductal carcinoma in situ (HR = 0.36,  95% CI = 0.19-0.66,  p = 0.0004) but there was no effect on the occurrence of contralateral disease.  There was no evidence of interaction between radiotherapy and tamoxifen.  It was concluded that radiotherapy can be recommended for patients with DCIS treated by complete local excision.  There is little evidence for the use of tamoxifen in these women.

High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer.   Rodenhuis S,  Bontenbal M,  Beex L V A M et al.  N Engl J Med 2003;  349:  7-16.

A number of small, uncontrolled studies have suggested that adjuvant high-dose chemotherapy with haematopoietic progenitor-cell infusion could be of benefit for high-risk breast cancer patients.  The aim of this study was to assess the efficacy of this treatment, in a randomised controlled trial,  in patients with 4 to 9 or 10 or more tumour-positive axillary lymph nodes.  Patients younger than 56 years of age who had undergone surgery for breast cancer and who no distant metastases were eligible if they had at least four tumour-positive axillary lymph nodes.  Patients in the conventional-dose group received flurouracil, epirubicin and cyclophosphamide (FEC) every three weeks for five courses, followed by radiotherapy and tamoxifen.  The high-dose treatment was identical, except that high-dose chemotherapy with autologous peripheral-blood progenitor-cell transplantation replaced the fifth course of FEC.  Of the 885 patients recruited into the study, 442 were assigned to the high-dose treatment and 443 to the conventional-dose group.  After a median follow-up of 57 months, the actuarial 5-year relapse-free rates was 59% in the convention-dose group and 65% in the high-dose group (HR = 0.83,  95% CI = 0.66 - 1.03.  p = 0.09).  In the group with 10 or more positive nodes, the relapse-free survival rates were 51% in the conventional-dose group and 61% in the high-dose group (HR = 0.71,  95% CI = 0.50-1.00,  p = 0.05).  It was concluded that high-dose alkylating therapy improves relapse-free survival amongst patients with stage II or III breast cancer with 10 or more positive axillary lymph nodes.

Breast cancer and hormone replacement therapy in the Million Women Study.  Million Women Study Collaborators.  Lancet 2003;  362:  419-427. 

Results from randomised controlled trials and from observational studies have shown that current and recent use of hormone-replacement therapy (HRT) increases the risk or breast cancer.  However, the effect of HRT on mortality from breast cancer is unclear.  Use of HRT preparation containing oestrogen-progestogen combinations may be associated with a greater risk of breast cancer than preparations containing oestrogen alone.  The Million Women Study, a cohort study of quarter of British women aged 50-64 years, was set up to investigate the relationship between various patterns of HRT use and breast cancer incidence and mortality.  Between 1996 and 2001 over a million women were recruited and provided information about HRT use and other personal details.  They were followed up for breast cancer incidence and death.  Half of the women had used HRT.  9364 incident invasive breast cancers and 637 breast cancer deaths were registered after an average of 2.6 and 4.1 years of follow-up respectively.  Current users of HRT at recruitment were more likely than never users to develop breast cancer (RR 1.66,  95% CI =1.58-1.75. p < 0.0001) and die from it (RR 1.22,  95% CI =  1.00-1.48.  p = 0.05).  Past users of HRT were however not at an increased risk of incident or fatal disease.  Incidence was significantly increased for current users of preparations containing oestrogen only (RR 1.30, 95% CI = 1.21-1.40.  p < 0.0001), oestrogen-progestogen (RR 2.00, 95% CI = 1.88-2.12. p < 0.0001) and tibolone (RR 1.45.  95% CI = 1.25-1.68.  p < 0.0001) but the magnitude of the associated risk was substantially greater for oestrogen-progestogen than for other types of HRT.  In current users of each type of HRT, the risk of breast cancer increased with increasing total duration of use.  Ten years use of HRT is estimated to result in five additional breast cancers per 1000 users of oestrogen only preparations and 19 additional cancers per 1000 users of oestrogen-progestogen preparations.  Use of HRT by women aged 50-64 years in the UK over the past decade has resulted in an estimated 20,000 extra breast cancers, 15,000 associated with oestrogen-progestogen preparations.  It was concluded that use of HRT is associated with an increased risk of incident and fatal breast cancer.  The risk is substantially greater for oestrogen-progestogen combinations than for other types.

Randomised clinical trial comparing level II and level III axillary node dissection in addition to mastectomy for breast cancer.  Tominaga T,  Takashima S,  Danno M et al.  Br J Surg 2004;  91:  38-43.  

As a result of randomised clinical trials, surgery for breast cancer has undergone several changes from radical mastectomy through modified radical mastectomy to breast conserving surgery.  All breast cancer surgery should be combined with an axillary staging procedure and this can often be a level II or level III axillary clearance.  In this study a randomised clinical trial was performed to determine which procedure was the most effective.   Between 1991 and 1993, 1209 women were recruited and randomised to either a level II or level III axillary node clearance.  In the women undergoing a level III axillary node clearance the pectoralis minor muscle was resected.   The main outcome measures were duration of operation, postoperative blood loss, morbidity and survival.  the 10-year cumulative survival rate was 87% after level II and 86% after level III axillary dissection (HR=1.02, p=0.931. log rank test).  The 10-year disease-free survival rate was 74% and 78% respectively (HR= 0.94. p=0.666).  Overall survival and disease-free rates in the two groups were similar after both procedures.  The duration of surgery was significantly shorter and blood loss significantly less after level II dissection.  In a survey of patient's symptoms on follow-up there was no significant difference between the two procedures.  It was concluded that addition of pectoralis minor resection and level III axillary lymph node dissection to mastectomy for stage 2 breast cancer did not improve overall or disease-free survival rates.

Late follow-up of a randomized trial of surgery plus tamoxifen versus tamoxifen alone in women aged over 70 years with operable breast cancer.  Fennessy M,  Bates T,  MacRae K et al.  Br J Surg 2004;  91:  699-704. 

Women aged over 70 years with breast cancer have often received less aggressive treatment than younger women because of their presumed shorter life expectancy, inability to tolerate active therapy and concerns about co-morbidity.  The aim of this study was to test the hypothesis that tamoxifen without surgery would provide adequate control of beast cancer for the remainder of life in elderly women, thereby sparing them surgery.  Women aged over 70 years with operable, invasive breast cancer were randomised to receive either tamoxifen alone or surgery plus tamoxifen.  The primary endpoint was time to treatment failure indicating initial primary treatment failure.  Overall mortality and death from breast cancer were also compared between the tow groups.  Between 1984 and 1991, 455 patients were included in the trial.  The analysis was based on a median follow-up of 12.7 years.  The time to treatment failure was significantly shorter in the tamoxifen alone group (HR 4.41.  95% CI 3.31 - 5.88).  Overall, 93 (40%) of 230 patients randomised to tamoxifen alone underwent surgery for the management of their disease.  Both overall mortality and mortality from breast cancer were significantly increased in the tamoxifen alone group.  It was concluded that omission of primary surgery in unselected elderly women with operable breast cancer who were fit for the procedure resulted in an increased rate of progression, therapeutic intervention and mortality.

Breast conserving surgery with resection of the nipple-areola complex for subareolar breast cancer.  Tausch C,  Hintringer T, Kugler F et al. Br J Surg 2005.  92:  1368-1371.

Surgeons have previously had reservations regarding breast-conserving therapy for centrally located breast cancer.  The reasons were frequent infiltration of the central ducts, increased risk of multicentricity and the uncertain status of resection margins.  In addition, the cosmetic results were expected to be poor.  Although there is little evidence that breast-conserving methods are safe for subareolar tumours, no restrictions exist in contemporary guidelines.  This prospective study was aimed to show whether breast-conserving surgery including excision of the nipple areola complex (NAC) is a reasonable alternative to mastectomy in terms of local recurrence and cosmetic result. This study was conducted between 1996 and 2002 and included 44 women with 45 breast cancers with suspected nipple involvement.  The breast was conserved and the NAC removed in all women.  Secondary mastectomy was performed in three women because the tumour was found to reach the resection margins.  The mean tumour size was 18 (range 4-50) mm.  Six women received preoperative chemotherapy.  Histologically, there seven pre-invasive and 35 invasive cancers.  No local failure had a occurred at a median follow up of 51 months.  Six women developed distant metastases, of whom five dies.  The cosmetic outcome was good or excellent in all women.  It was concluded that breast-conserving surgery is a safe and cosmetically acceptable alterative to mastectomy for subareolar breast cancer.

Value of fluorodeoxyglucose positron emission tomography in women with breast cancer.  Landheer M LE A,  Steffens M G,  Linkenbijl J H G et al.  Br J Surg 2005;  92:  1363-1367.

The presence of distant metastases is the most important prognostic factor in women with breast cancer and changes the intention of therapy from curative to palliative.  Accurate staging of both primary and recurrent breast cancers has a major impact on the choice of treatment.  Staging of breast cancer is routinely performed by ultrasonography of the liver, chest radiography and bone scintigraphy.  Fluorodeoxyglucose positron emission tomography (FDG-PET), an imaging modality utilising the increased uptake of glucose by tumour cells, is a valuable tool in the staging of a wide variety of malignancies.  The aim of this study was to evaluate FDG-PET in the staging of women with high-risk primary breast cancer or recurrent disease.  FDG-PET was performed in 42 women with a primary breast cancer and unfavourable characteristics or who had suspected relapse.  FDG-PET and conventional staging methods were compared.  The case of abnormality on FDG-PET, confirmation was always attempted.  Increased uptake was found in five of 17 women with primary breast cancer.  In the 25 patients with suspected relapse, FDG-PET showed increased uptake in 43 areas, 22 correctly confirming the area of suspected relapse and 21 indicating other sites of metastases.  Compared with conventional imaging, FDG-PET revealed additional lesions in two women with primary breast cancer and three with relapse.  Patient management was changed for five women. It was concluded that FDG-PET is a sensitive diagnostic method for the detection of distant metastases.  Its exact role in women with breast cancer remains to be defined.

Randomised clinical trial comparing blue dye with combined blue dye and isotope for sentinel lymph node biopsy in breast cancer.  Hung W K,  Chan C M,  Ying M et al.  Br J Surg 2005;  92:  1494- 1497.

Sentinel lymph node biopsy (SLNB) is a minimally invasive and accurate method of axillary staging in breast cancer.  Large-scale randomised trials evaluating SLNB are underway but the optimal mapping technique remains controversial.  Use of blue dye alone is effective but combing it with isotope marking can improve the success rate.  Use of isotope adds extra cost and there are radiation hazards.  The aim of this study was to compare the two techniques in a randomised trial.  Women with early breast cancer (less than 3cm diameter) and no palpable axillary nodes were recruited.  Women older than 70 years with multicentric tumours or previous surgery to the breast or axilla were excluded.  Patients were randomised to either blue dye alone or combined mapping for SLNB.  All women has a level 1 or level 2 axillary dissection after the SLNB.  A total of 123 patients were recruited of whom 5 were excluded from the analysis.  Blue dye alone was used in 57 women and 61 had combined mapping.  Baseline demographic details were similar in the two cohorts.  The success rate of SLNB was higher with combined mapping than with blue dye alone (100% vs. 86%. p=0.002).  The accuracy and false-negative rate were similar (accuracy 100% for combined mapping vs. 98% for blue dye; false-negative 0% vs. 5%).  It was concluded that combined mapping was superior to blue dye alone in identification of the SLN but accuracy and false-negative rates were similar.

Randomised multicentre trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer:  The ALMANAC Trial.  Mansel R E,  Fallowfield L,  Kissin M et al.  JNCI 2006;  98:  599-609.  

Sentinel lymph node biopsy (SLNB) in women with operable breast cancer is routinely used in some countries for staging the axilla despite limited data from randomized controlled trials on morbidity and mortality outcomes.  The aim of this study was to compare quality-of-life outcomes between patients with clinically node-negative breast cancer who received SLNB and patients who received standard axillary treatment.  The primary outcome measures were arm and shoulder morbidity and quality of life.  Between 1999 and 2003, 1031 patients were randomly assigned to undergo SLNB (n=515) or standard axillary treatment (n=516).  Patients with sentinel lymph node metastases proceeded to delayed axillary clearance or received axillary radiotherapy, depending on protocols at the treating institutions.  Intention-to-treat analysis of data at 1, 3, 6 and 12 months were presented.  The relative risk of lymphoedema and sensory loss for SLNB compared with standard axillary treatment at 12 months were 0.37 (95% CI = 0.23-0.60) and 0.37 (95% CI = 0.27-0.50) respectively.  Drain usage, length of hospital stay and time to resumption of normal daily activities after surgery were statistically lower in the SLNB group (p<0.001) and axillary operative time was reduced (p=0.55).  Overall, patient recorded quality-of-life and arm functioning scores were statistically significantly better in the SLNB group.  These benefits were seen with no increase in anxiety levels.  It was concluded that SLNB is associated with reduced arm morbidity and better quality-of-life than standard axillary dissection and should be the treatment of choice for patients who have early stage breast cancer with clinically negative nodes.

Intraoperative assessment of sentinel lymph nodes using imprint cytology.  Clarke D,  Leung E,  Chachlani N et el.  World J Surg 2010;  34:  55-61.

Sentinel lymph node (SLN) biopsy has replaced axillary sampling as the axillary staging procedure of choice in patients with breast cancer. Accurate intraoperative evaluation of the SLN would allow axillary lymph node clearance to be performed during the initial operation when the SLN is positive for metastatic disease. The aim of the present study was to assess the accuracy of intraoperative imprint cytology (IC) of the SLN in two different institutions in the United Kingdom. All breast cancer patients who underwent a SLN biopsy using a standard protocol in two hospital breast units were included. The SLN was sent fresh to the pathology laboratory, where it was immediately processed and examined by a cytopathologist using IC. The intraoperative IC results were compared with the final histopathological results. No therapeutic decisions were made based on the results of IC in this study. A total of 166 patients were included, with 47 positive and 119 negative cases on final histology. Of the 47 patients who were positive on final histology, there were 29 positive and 18 negative cases on IC (sensitivity = 61.7%). All 119 patients who were negative on final histology were negative on IC (specificity, 100%). The negative and positive predictive value of the final histology was 86.9% and 100%, respectively. The accuracy of IC was 89.2%. It was concluded that the results from these two breast units are comparable with findings reported in the published literature, confirming that IC can be used to assess SLN biopsy intraoperatively. No unnecessary axillary node clearance would have been carried out based on the results of IC.

Long-term results of hypofractionated radiation therapy for breast cancer.  Whelan T J,  Pignol J-P, Levine M-N et al.  N Engl J Med 2010;  362:  513-520.  

The optimal fractionation schedule for whole-breast irradiation after breast-conserving surgery is unknown. This study was conducted to determine whether a hypofractionated 3-week schedule of whole-breast irradiation is as effective as a 5-week schedule. Women with invasive breast cancer who had undergone breast-conserving surgery and in whom resection margins were clear and axillary lymph nodes were negative were randomly assigned to receive whole-breast irradiation either at a standard dose of 50.0 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation as compared with 6.2% among the 622 women assigned to the hypofractionated regimen (absolute difference, 0.5 percentage points; 95% confidence interval [CI], 2.5 to 3.5). At 10 years, 71.3% of women in the control group as compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome (absolute difference, 1.5 percentage points; 95% CI, 6.9 to 9.8). It was concluded that 10 years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes.

Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: The American College of Surgeons Oncology Group Z0011 randomized trial.  Armando G,  McCall L,  Beitsch B et al.  Ann Surg 2010; 252:  426-433.  

Sentinel lymph node dissection (SLND) has eliminated the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumour-free. However, completion ALND for patients with tumour-involved SNs remains the standard to achieve locoregional control. Few studies have examined the outcome of patients who do not undergo ALND for positive SNs. This study reports the local and regional recurrence information from the American College of Surgeons Oncology Group Z0011 trial.  American College of Surgeons Oncology Group Z0011 was a prospective trial examining survival of patients with SN metastases detected by standard H and E, who were randomized to undergo ALND after SLND versus SLND alone without specific axillary treatment. Locoregional recurrence was evaluated. There were 446 patients randomized to SLND alone and 445 to SLND + ALND. Patients in the two groups were similar with respect to age, Bloom-Richardson score, oestrogen receptor status, use of adjuvant systemic therapy, tumour type, T stage, and tumour size. Patients randomized to SLND + ALND had a median of 17 axillary nodes removed compared with a median of only 2 SN removed with SLND alone (P < 0.001). ALND also removed more positive lymph nodes (P < 0.001). At a median follow-up time of 6.3 years, there were no statistically significant differences in local recurrence (P = 0.11) or regional recurrence (P = 0.45) between the 2 groups.  It was concluded that despite the potential for residual axillary disease after SLND, SLND without ALND can offer excellent regional control and may be reasonable management for selected patients with early-stage breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials.  Early Breast Cancer Trialists' Collaborative Group.  Lancet 2011; 378:  1707-1716.   

After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. This paper describes the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. A meta-analysis was undertaken of individual patient data for 10 801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 350% to 193% (absolute reduction 157%, 95% CI 137177, 2p<000001) and reduced the 15-year risk of breast cancer death from 252% to 214% (absolute reduction 38%, 1660, 2p=000005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 310% to 156% (absolute recurrence reduction 154%, 132176, 2p<000001) and from 205% to 172% (absolute mortality reduction 33%, 0858, 2p=0005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (1019%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 78% (95% CI 31125), 11% (20 to 42), and 01% (75 to 77) respectively (trend in absolute mortality reduction 2p=003). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 637% to 425% (absolute reduction 212%, 95% CI 145279, 2p<000001) and the 15-year risk of breast cancer death from 513% to 428% (absolute reduction 85%, 18152, 2p=001). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease. After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.  Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group.  Lancet  2013;  381:  805-816. 

For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. The aim of this study was to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years. Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. This paper reports the effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues.  Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=001), and reduced overall mortality (639 deaths vs 722 deaths, p=001). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 090 [95% CI 079102] during years 59 and 075 [062090] in later years; breast cancer mortality RR 097 [079118] during years 59 and 071 [058088] in later years). The cumulative risk of recurrence during years 514 was 214% for women allocated to continue versus 251% for controls; breast cancer mortality during years 514 was 122% for women allocated to continue versus 150% for controls (absolute mortality reduction 28%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12 894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 099 [089110]; p=084). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 187 (95% CI 113307, p=001 [including 02% mortality in both treatment groups]), stroke 106 (083136), ischaemic heart disease 076 (060095, p=002), and endometrial cancer 174 (130234, p=00002). The cumulative risk of endometrial cancer during years 514 was 31% (mortality 04%) for women allocated to continue versus 16% (mortality 02%) for controls (absolute mortality increase 02%). It was concluded that for women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.

Intraoperative ultrasound guidance for palpable breast cancer excision (COBALT trial): a multicentre, randomised controlled trial.  Krekel N M A,  Haloua M H,  Cardozo A M F et al.  Lancet Oncology  2013;  14:  48-54. 

Breast-conserving surgery for palpable breast cancer is associated with tumour-involved margins in up to 41% of cases and sometimes with excessively large excision volumes. Ultrasound-guided surgery has the potential to resolve both of these problems, thereby improving surgical accuracy for palpable breast cancer. The aim of this study was to compare ultrasound-guided surgery with the standard for palpable breast cancer - palpation-guided surgery - with respect to margin status and extent of healthy breast tissue resection. In this randomised controlled trial, patients with palpable T1T2 invasive breast cancer were recruited from six medical centres in the Netherlands between October, 2010, and March, 2012. Eligible participants were randomly assigned to either ultrasound-guided surgery or palpation-guided surgery in a 1:1 ratio via a computer-generated random sequence and were stratified by study centre. Patients and investigators were aware of treatment assignments. Primary outcomes were surgical margin involvement, need for additional treatment, and excess healthy tissue resection (defined with a calculated resection ratio derived from excision volume and tumour diameter). Data were analysed by intention to treat. Overall,  134 patients were eligible for random allocation. Two (3%) of 65 patients allocated ultrasound-guided surgery had tumour-involved margins compared with 12 (17%) of 69 who were assigned palpation-guided surgery (difference 14%, 95% CI 425; p=00093). Seven (11%) patients who received ultrasound-guided surgery and 19 (28%) of those who received palpation-guided surgery required additional treatment (17%, 330; p=0015). Ultrasound-guided surgery also resulted in smaller excision volumes (38 [SD 26] vs 57 [41] cm3; difference 19 cm3, 95% CI 731; p=0002) and a reduced calculated resection ratio (10 [SD 05] vs 17 [12]; difference 07, 95% CI 0410; p=00001) compared with palpation-guided surgery. It was concluded that compared with palpation-guided surgery, ultrasound-guided surgery can significantly lower the proportion of tumour-involved resection margins, thus reducing the need for re-excision, mastectomy, and radiotherapy boost. By achieving optimum resection volumes, ultrasound-guided surgery reduces unnecessary resection of healthy breast tissue and could contribute to improved cosmetic results and quality of life.

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