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ADVANCED BREAST CANCER

Dr AF del Valle Commentators: Drs MC Mayet/FG Madela Moderator: Ms I Buccimazza TABLE OF CONTENT Introduction Definitions Epidemiology Incidence Management of locally advanced breast cancer Evaluating the response to primary systemic therapy Surgical considerations and technicalities Primary metastatic breast cancer Inflammatory breast carcinoma Other advanced breast malignancies o Sarcomas o Lymphomas o Malignant phylloides tumour Conclusion References INTRODUCTION 1, wjs invited commentary Breast cancer remains a common and frequently fatal disease and is the most commonly diagnosed cancer in women. Worldwide more than 1.2 million women are diagnosed annually with breast cancer. Annually more than 8000 new cases are diagnosed and more than 3000 women die from breast cancer in South Africa. Clinical breast cancer research has focused on effective methods to detect breast cancer at its earliest stages and on standardized treatments to cure the disease after diagnosis. In developed countries, most patients (> 80%) with breast cancer present with operable disease. Advanced breast cancer is a common occurrence in developing countries, accounting for a large proportion of cancer-related morbidity and mortality in all regions of the developing world. The patient profile differs from that reported in developed countries, suggesting a different spectrum of the disease. Poorer outcomes compared to developed countries, are largely attributed to the advanced stage at diagnosis and lack of comprehensive multimodal treatment opportunities. The rising incidence and mortality rates of breast cancer, as well as the high cost of treatment and limited resources available, demand that it continues to be a focus of attention for public health authorities and policy-makers worldwide. Sem No: 02 Date: 22/01/2011

DEFINITIONS 2

2 Advanced breast cancer includes locally advanced disease and metastatic disease. Locally advanced disease refers to a heterogeneous group of tumours from slow growing to rapidly proliferating and aggressive tumours that are characterised clinically by size, features suggesting infiltration of the skin or chest wall by tumour, and/or nodal status. These patients do not have distant metastatic disease. The spectrum is defined according to the American Joint Committee on Cancer (AJCC) clinical TNM (Tumour/ Node/ Metastasis) stages. LABC operable at presentation Stage IIIA: T3 with any N; N2 with any T1 T3 LABC inoperable at presentation Stage IIIB: T4a, skin; T4b, chestwall; T4c (a+b) Stage IIIC: N3 with any T T4d (Inflammatory Breast Cancer) Metastatic cancer refers to disease beyond the locoregional site, with spread (in order of occurrence) preferentially to bones, lung, soft tissues, liver and brain. These patients are classified: Stage IV: any T any N, M1. EPIDEMIOLOGY wjs invited commentary Some studies have suggested that the pathology of breast cancer in developing countries results in a more aggressive disease. Notwithstanding the late presentation due to a plethora of politico-socio-cultural reasons, and further compounding factors such as competing health care needs, inadequacies in healthcare standards, infrastructure and a prevailing culture of poor follow-up, some irrefutable data has been reported. Patients are approximately one decade younger and the disease is associated with more aggressive prognostic and predictive features. Despite the lack of sound scientific epidemiological data to explain this phenomenon, data on the pathology has revealed a higher proportion of node positive disease, grade 3 and hormone-receptor negative tumours. The data on Her-2-neu status in developing countries is scarce; however, available information hints at low rates of Her-2-neu positive tumours. INCIDENCE (5;6;7;8;9) With the increased use of screening mammography, especially in the developed world, the proportion of patients with locally advanced disease has decreased. In populations that receive regular screening mammography, the percentage of patients with locally advanced disease is less than 5%. Notwithstanding the above, the exact worldwide incidence of advanced breast cancer is unknown. According to the 12th edition of Cancer Management: a multidisciplinary approach

3 (2009), 20%-25% of patients present with LABC, and metastatic disease is found at presentation in 5%-10% of patients. Data from the National Cancer Institutes Surveillance, Epidemiology and End Results (SEER) programme, indicate that 7% of the patients have stage III disease at diagnosis. In South Africa approximately 60% of all cases present with locally advanced disease when cure is impossible. This may be due to lack of screening program for early detection, and awareness. Data from a number of South African hospitals shows that only 22% of black patients present with early cancer (stages I and II) compared with around 69% of those who are not black. Conversely, stages III and IV are most prevalent in black women (77.8%) compared with non-black women (30.7%). This clearly has a major effect on survival rates. Most patients in both Stage IIIA and IIIB groups die as a consequence of distant metastases, and in a significant fraction of patients the local recurrence rate after regional therapy is also high. According to the SEER data, the 3- and 5- year relative survival rates for women with Stage III disease are 70% and 55% respectively. Median survival of women with Stage III disease is 4.9 years. The average period of survival after diagnosis of Stage IV disease is between 18-24 months, but differs widely depending on endocrine status of the tumour (endocrine responsive > endocrine unresponsive) and site of metastasis (bone - 19 months compared to 3 months with brain metastases) MANAGEMENT OF LOCALLY ADVANCED BREAST CANCER 12-15 Guidelines for the treatment of LABC, with particular reference to low-resource countries, have been published. These state that neoadjuvant chemotherapy (NACT) should be standard treatment for LABC in all resource settings; and that multidisciplinary teams should be available for the management of breast cancer patients, irrespective of resource setting. Diagnosis and Pre- treatment evaluation If a breast cancer is suspected, a biopsy is necessary to confirm the diagnosis. This follows on a diagnostic bilateral mammogram and ultrasound of the breast. The highest diagnostic yield is when the core needle biopsy is performed under image-guidance. Important information needed to assist with the treatment plan is obtained from this non-operative pathology report. This includes prognostic markers such as grade, p53 status and the presence/ absence of lymphovascular invasion, as well as predictive markers which guide targeted therapy. The leading predictive markers that define treatment in breast cancer are the estrogen- and progesterone receptors (ER and PR receptors) and the human epidermal growth factor status (Her-2-neu). The advent of new genetic tests, derived with the aim of improving the accuracy of prediction, has also emphasized the role of proliferative genes, including Ki67. Although not included in the existing guidelines of the American Society of Clinical Oncology, new data suggests that Ki67 may be an important prognostic and predictive marker.

4 Ki67 is a proliferation antigen detected by immunohistochemical staining. It is a reliable indicator of cell proliferation rate, being clearly expressed in the nuclei of actively proliferating cells. Ki67 staining index scores of 0% - 15% are classified as low; 16% - 25% as medium and 26% - 100% as high. Ki67 measurement at baseline is a highly prognostic factor in breast cancer. High Ki67 levels are associated with well-known markers of poor prognosis: younger age at diagnosis, larger tumour size, axillary node involvement, higher grade, lymphovascular invasion, endocrine-unresponsiveness, Her-2-neu overexpression and p53 mutation. In early breast cancer, Ki67 used in conjunction with other prognostic markers assists clinicians in deciding which patients will benefit most from intensive chemotherapy. Other current applications of Ki67 measurements include comparing values at baseline and 12 weeks to predict long-term outcomes on a particular endocrine treatment, response to a particular treatment and possible acquired resistance to a particular treatment. Yerushalmi R, Woods R, Ravdin PM et al. Ki67 in breast cancer: prognostic and predictive potential. The Lancet Oncology 2010, Volume 11, Issue 2: 174 183 Dowsett M, Ahern R, Salter J et al. Who would have thought a single Ki67 measurement would predict long-term outcome? Breast Cancer Research 2009, 11(Suppl 3):S15 http://breast-cancer-research.com/supplements/11/S3/s15 The recommended metastatic evaluation includes: History and physical examination Laboratory investigations: Full blood count, liver enzymes, calcium levels Chest X-ray Ultrasound abdomen In resource-enhanced areas, a CT scan of the chest, abdomen and pelvis is recommended, as it is more sensitive for metastatic disease. Bone scan Therapy Advanced breast cancer is recognised as a systemic disease and so a multimodal, multidisciplinary approach to the management is imperative. Sequential modality treatment using primary systemic therapy (PST), surgery and radiotherapy (RT) is regarded as preferred treatment. Endocrine therapy (ET) is added if receptors are positive and biological therapy where appropriate and affordable. Patients with locally advanced breast cancer should receive PST, usually in the form of neoadjuvant chemotherapy (NACT) as the initial component of their therapy to make inoperable tumours amenable to resection, and possibly enhance their chances of breast conserving surgery. For operable tumours initial mastectomy followed by adjuvant chemotherapy (CT) is also a reasonable option. In total, patients should receive between six and eight cycles of anthracycline and/ or taxane

5 based regimens, usually given in sequence. NACT should be followed by modified radical mastectomy for tumours that are operable. Patients who are treated with surgery should receive postoperative radiation therapy (RT) to minimize the risks of local recurrence. Patients with inoperable tumours after NACT can be crossed over to alternate NACT, (i.e. a taxane if the initial treatment was anthracycline based) or can proceed to RT, either as definitive local therapy, or as a form of primary therapy with a view to subsequent surgery once resectability is re-evaluated. An operative evaluation is done after a total dose of 4650Gy to the breast and regional lymphatics. If the tumour is still inoperable, an additional dose of 20-25Gy is applied either with external irradiation using shrinking fields or with 1921r implant to a total dose of 75-80 Gy. The boost dose is determined by the volume of residual disease. Supraclavicular fields should not receive > 60Gy if there is a brachial plexopathy risk. A further option in these patients is a salvage mastectomy followed by adjuvant RT. Women with endocrine responsive tumours should receive additional benefits from endocrine therapy (ET) for a total of 5 years to further reduce the risk of a recurrence. ALGORITHM FOR ADVANCED BREAST CANCER Neoadjuvant chemotherapy (6 cycles FEC +/- taxanes) (T3 lesions, titanium marker pre- Rx)

Mastectomy and ALND

Whole breast RT ET (if receptor positive) In patients over-expressing the HER-2-neu oncogene, targeted therapy in the form of Herceptin is given. This can be administered concurrently with NACT (but not if the regime includes an anthracyline, as this increases the cardiac toxicity); then continued in the adjuvant setting concurrently with RT and ET (when indicated) EVALUATING THE RESPONSE OF PRIMARY SYSTEMIC THERAPY Primary systemic therapy is defined as the first systemic treatment a patient receives after cancer is diagnosed and indicates that subsequent therapies are intended. NACT is commonly used; however the definition also incorporates targeted therapy and hormone manipulation.

6 Neoadjuvant chemotherapy (NACT) It was first used in the early 1970s for the treatment of inoperable locally advanced or inflammatory breast cancer. Based on a large body of clinical evidence and on the fact that primary breast cancer is today considered a systemic disease with a locoregional component, primary systemic therapy is now increasingly considered for women with operable disease for reducing mortality with lower toxicity, improving surgical options, and acquiring early information on response and biology of the disease. Induction of a pathologic complete response (pCR) should be one of the primary goals of neoadjuvant therapy because patients with no evidence of tumor cells in the breast or in the lymph nodes after treatment may have a longer disease-free survival (DFS) and overall survival (OS). Moreover, PST increases the rate of BCS and is associated with a lower rate of positive axillary lymph nodes at the time of surgery. Major individual trials and a meta-analysis, which was published in 2005, have assessed response and benefit of PST and have helped to identify factors that are predictive of response, recurrence, and effect on survival. Those trials included patients who had large primary tumours and patients who had T2 tumours. The Focus Group noted that all major studies and clinical trials that were available for analysis were conducted in countries with enhanced or maximal resources. No trials were available from countries with limited or basiclevel resources. In a study by Saghir et al, those results were reviewed and analyzed in order to emphasize the aspects related to large and locally advanced tumours along with issues related to low-resource countries. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 study tested 4 cycles of combined doxorubicin and cyclophosphamide (AC) followed by surgery versus surgery followed by AC. The results established that preoperative AC chemotherapy does not harm patients and is at least as effective as postoperative adjuvant therapy. The NSABP B-27 study tested the addition of docetaxel to AC, either preoperatively or postoperatively. The Aberdeen trial (TAX 301) tested preoperative docetaxel after the administration of combined cyclophosphamide, vincristine, doxorubicin, and prednisone as neoadjuvant therapy. Those trials produced concordant results regarding improved breast-conservation rates and higher pathologic complete response (pCR) rates with the addition of preoperative docetaxel. A benefit also was noted from using alternating noncross-resistant regimens in the smaller TAX 301 study. Better survival was reported in responders, but the overall effects on survival were conflicting. Those trials mostly were underpowered to determine the survival effect of modest improvements in the pCR rate. A very recent update of the NSABP B-18 trial continued to demonstrate no statistically significant differences in disease-free survival (DFS) or overall survival between the preoperative and postoperative groups. The addition of docetaxel to AC in the B-27 Protocol study increased significantly the proportion of patients who had a pCR (26% vs 13 %,). After 16 years of follow-up, the patients in that study who achieved a pCR continued to have superior DFS and overall survival outcomes compared patients who did not achieve a pCR. It also is noteworthy that there was a marginal survival benefit in the NSABP B-18 study in the preoperative arm for younger patients; this may turn out to be important in low-resource countries, where there are greater percentages of young women with breast cancer.

7 Patients who are treated with neoadjuvant chemotherapy need to be monitored carefully for evidence of response. Response rates are assessed after 3 cycles of NACT. Patients with LABC who have tumours that respond to primary chemotherapy fare better than those who have nonresponding tumours. Definitions for response evaluation of primary systemic therapy Clinical definition (WHO) Complete response: no palpable mass detectable (cCR) Partial response: reduction in the product of two longest perpendicular diameters of > 50% Stable disease: reduction in the product of two longest perpendicular diameters of < 50% No clinical response: increase of < 25% in the tumour diameter product Progressive disease: increase of > 25% in the tumour diameter product Imaging definition No tumour visible by mammogram and/or ultrasound and/or MRI Pathological definition Only focal invasive tumour residuals in the removed breast tissue Only in situ tumour residuals in the removed breast tissue (pCR inv) No invasive or in situ tumour cells (pCR) No malignant tumour cells in breast and lymph nodes (pCR breast and nodes) In developing countries NACT with an anthracycline- containing regimen is administered to downsize lesions and allow them to be resectable via mastectomy. Clinical response rates of between 60% and 80% can be achieved, but less than 20% of patients achieve a complete pathologic response, which is considered an important prognostic factor and an important determinant of outcome. Despite similar patient profiles and challenges, there is variability, even within developing countries, to tumour response rates to NACT and patient outcomes. A recent paper by Arowolo et al. reported a clinical response rate of only 51%, with no patient achieving a complete pathological response. The 5-year survival rate of 11.9% in their study is also in stark contrast with that reported from other developing countries, where 5-year survival rates in excess of 50% have become the norm. This raises certain questions regarding possible chemo-resistant clones or even the use of generic chemotherapy agents with less active ingredients. Other factors associated with poor outcomes included margin status and the lack of comprehensive multi-modal therapy (radiotherapy and endocrine treatment)

Neoadjuvant Endocrine Therapy (NAET) (17) LABC has been treated with anti-oestrogen therapy or by the removal of sources of oestrogen production, either by ovarian suppression or ovarian ablation in premenopausal women or by the use of aromatase inhibitors (AIs) in postmenopausal women. A French study at the Bergonie Institute in Bordeaux demonstrated that neoadjuvant endocrine therapy is feasible and useful. That study included patients who were treated from 1984 to 1996 at a single institution. In total, 199 postmenopausal women were given first-line tamoxifen. Ninetyseven patients had operable disease (T2 tumors >30 mm, T3 tumours, N0/N1 lymph node status), and 102 patients had T4 tumours. The mean treatment duration was 5.3 months. A breast-conservation rate of 53% was noted for patients with T2 and T3 tumors, and the rate for patients with T4 tumors was 44%. Many phase 2 studies have demonstrated that tamoxifen produces clinical response rates that range between 37% and 81%.51 Data on tamoxifen also were extracted from randomized studies that used it in a control arm and compared it with AIs, as noted below. Letrozole was compared with tamoxifen in a randomized trial in 324 postmenopausal patients. The duration of preoperative therapy in that tamoxifen versus letrozole study (P024) was 4 months. None of the 324 patients were candidates for BCS, and 14% had inoperable disease. In that study, 170 patients were randomized to receive tamoxifen, and 154 patients were randomized to receive letrozole. The response rates were 41% with tamoxifen and 60% with letrozole. The BCS rate was 36% with tamoxifen and 48% with letrozole.

9 Therefore, in postmenopausal women, AIs produce better response rates than tamoxifen and are recommended in countries with enhanced and maximal resources. However, in low resource countries, tamoxifen still is useful, because it produced reasonable response rates between 36% and 41% in the studies noted above. In women with inoperable LABC who have negative or unknown receptor status for whom PST is indicated, chemotherapy should be the first choice. In elderly patients who have tumors that are slow-growing, well differentiated, and probably hormone receptor-positive, tamoxifen is justified, even if the receptor status is unknown. For premenopausal women, ovarian ablation by surgery or irradiation remains a viable option in low-resource countries; ovarian suppression with lutenizing hormone-releasing hormone (LHRH) analogues may be given to patients in countries with enhanced and maximal resources. The cost of LHRH analogues does not justify their use in countries with limited resources. The Focus Group noted that the great majority of data regarding PST were obtained with chemotherapy, and the role of primary endocrine therapy remains to be determined. Data indicate that primary endocrine therapy is feasible and is certainly an acceptable approach for elderly women with ER-positive breast cancer. However, ER-positive LABCs in most women are treated optimally with both chemotherapy (preoperatively) and endocrine therapy (postoperatively) in a sequential fashion; and, in that context, the role of primary endocrine therapy still is undefined. Similarly, it is not known whether any patient with LABC can be treated optimally with endocrine therapy alone.

10 SURGICAL CONTROL AND TECHNICALITIES Patients with locally advanced disease can have a five-year survival rate of around 30% to 50%. Achieving local control of the disease can improve their quality of life and length of their survival. Primarily inoperable breast cancer is converted to operable breast cancer by the use of primary systemic therapy. Definition of Operability Operability is defined as the ability to remove tumor without dissecting through macroscopically abnormal tissue and without the necessity to employ a free graft for skin cover. This goal is typically achieved by a standard mastectomy. However, patients may remain inoperable by the classic criteria after neo-adjuvant chemotherapy. In these cases, palliative local therapy, either non-surgical or surgical, to promote comfort and hygiene and control wound breakdown need to be considered. Bulky axillary nodal disease The definition of operability pertains only to the breast; yet surgical loco-regional control for breast cancer involves both the breast and axilla. The status of the axilla is the single most important prognosticator in breast cancer: it accurately stages the disease and therefore determines the need for specific adjuvant therapy. Although local control is not the primary aim of axillary surgery, it is intuitive to remove all gross disease. In LABC bulky nodal disease fixed to axillary structures poses a unique challenge. Good level of evidence guiding management is lacking; often institutional bias and personal preference dictates the course of action. Our policy is to anticipate the inoperable axilla and obtain a CT scan to determine the extent of nodal involvement and ascertain resectability. Encasement of the vessels and brachial plexus preclude surgical resection. Patients are either offered further systemic therapy, or axillary radiotherapy. The prognostic information lost by the non-surgical management will not impact on further treatment or survival. The literature does not provide guidelines when an irresectable nodal mass is found intraoperatively. Options include ligation and resection of the axillary veintogether with the nodal mass; debulking the nodal mass, further chemotherapy and re-evaluation for resectability, or axillary radiotherapy. We do not favour axillary vein resection as it increases the morbidity without prolonging survival. A reasonable course of action is to debulk the axilla and refer the patient for axillary radiotherapy. Mastectomy considerations 1,2 ,3, 4 Mastectomy is associated with significant skin flap complications ranging from 18% - 30% (average 26%). These increase the morbidity and health care cost, result in prolonged hospitalization and delay the initiation of adjuvant therapy (chemotherapy or radiotherapy). It is known that the perfusion to the subdermal plexus of the skin is controlled by the autonomic nervous system in response to variations in metabolic demands and environment. Temperature, tissue perfusion and neural stimuli can affect flap perfusion and contribute to complications. However, it remains important to ensure that the blood supply to the subdermal plexus is not compromised. In this respect it is important to understand risk factors

11 for flap necrosis and to abide by simple surgical principles. Wound morbidity following mastectomy is related to the creation of large thin flaps, and the use of cautery. Very thin flaps should be avoided as they tend to develop necrosis. A flap thickness of 5 mm is recommended. Flap thickness refers to the measurement of the skin flap at it most distal aspect. There currently is no standardized method for measuring mastectomy skin flap thickness intra-operatively, and this remains a surgical judgment call. The use of calipers may be helpful. Flap length usually refers to the superior flap length as this is typically the longest flap in a mastectomy. A longer flap length is associated with flap necrosis, consistent with the concept that the blood supply of longer flaps is more tenuous, likely due to the greater area of vascular disruption required when a mastectomy is performed. Excessively long flaps should be avoided, as should wound closure under tension. Careful pre-operative planning will identify patients at risk for large defects and facilitate the planning of autologous tissue cover. Evidence suggests that the use of cautery is associated with an increase in the incidence of flap necrosis. Increased thrombosis of subdermal vessels caused by cautery results in relative ischemia of skin flaps. Wound healing is a complicated process. Factors contributing to, or complicating the wound healing process include body habitus, age, co-morbidities, prolonged operative time, collagen disorders, infection, past radiation exposure, immune status, and steroid use. There is presently no standard for evaluating skin flaps intra-operatively and no method to quantitatively evaluate mastectomy skin perfusion. Techniques currently utilized to evaluate mastectomy flap viability intra-operatively range from crude, subjective methods such as detection of skin discoloration, evaluation of bleeding edges and assessment of capillary refill, to more sophisticated methods: the intravenous sodium fluorescein test (Wood's lamp method); near infrared spectroscopy and Transcutaneous electrical nerve stimulation (TENS). A recent article in the SAJS reported on the use of transdermal nitroglycerin application in preventing and healing flap ischemia after modified radical mastectomy However, rather than relying on alternative methods, the focus should be on preventive measures to minimize skin flap complications. These should reinforce basic surgical principles: avoiding skin closure under tension; ensuring adequate perfusion to the flaps by respecting the recommended thickness and length; and minimizing the use of cautery, which invariably leads to a degree of burn. Pectoralis fascia: preserve or remove? Mastectomy remains the dominating surgical option in LABC. The radical mastectomy introduced by Halsted, which included removal of the pectoral major muscle, was abandoned in 1950s 1960s when more limited surgery was introduced as imaging modalities and adjuvant treatment options improved. The modified radical mastectomy of Patey spared the pectoral muscle, but removed the pectoralis fascia. The pectoral fascia has been regarded both as a marker for the pathologist to evaluate the deep margin and as a tumour barrier. Many surgical guidelines recommend the removal of the fascia to ensure radicality. It is well documented that chest-wall recurrence is associated with an increased risk of distant

12 metastases and death from breast cancer. In the setting of early breast cancer requiring a mastectomy, a recent Swedish study revealed an increased risk for a chest-wall recurrence among patients with preserved fascia. They concluded that fascia-sparing mastectomy can endanger patients without any benefit provided beyond the facilitation of primary implant-based breast reconstruction, as the fascia assists with retaining muscular coverage around the implant. Excess axillary folds (Dog ears) The best way to treat axillary folds after breast surgery is prevention. Proper preoperative planning and incision marking helps the surgeon better determine the best incision to prevent this problem. Often the ellipse needs to be extended further laterally so that the closure does not result in noticeable dog ears. At the time of operation one must extend the resection of fat and subcutaneous tissue latterly beyond the incisions so that the skin closes without a fold. During surgical intervention, if one finds that there are dog ears present as the wound is being sutured, it is wise to try to correct this during the procedure. This can be accomplished by extending the length of the elliptical incision and by removing more fat and subcutaneous tissue by direct resection or suction lipoplasty. Although axillary folds may not seem like a significant medical problem, they can be a great concern to the patient. A surgeon who pays attention to the details to prevent and/or correct this problem will have a much happier patient after this procedure. PRIMARY METASTATIC BREAST CANCER (MBC) MBC is a heterogeneous disease that has a variety of clinical scenarios, ranging from solitary metastatic lesions to diffused and multiple organ involvement. Overall survival (OS) of patients with MBC is slowly but steadily improving and the risk of death is decreasing by 12% each year. A distinctive subset of patients who are most likely to gain substantial benefit from an intensified multidisciplinary therapeutic approach is represented by oligometastatic disease, which is characterized by solitary or few detectable metastatic lesions that are usually limited to a single organ. This population of potentially curable disease is estimated to be 1-10% of newly diagnosed MBC. Should MBC be treated by surgery? Historically, such an approach was not considered worthwhile because in most patients disease subsequently recurred because of undetected additional microscopic metastic foci. The promising results of recent series of MBC patients undergoing curative surgery or radiotherapy for both primary tumors and distant metastasis and the long term survival achieved with modern systems therapies raised justified interest and renewed the discussion in this complex topic. Role of Systemic Treatment Many reports from prospective clinical trials examine the effects of endocrine, cytotoxic, targeted, or combination treatments in MBC. Despite initial response, most patients develop progresive disease within 12-24 month, the median survival of endocrine non responsive or resistant MBL is 18-24 month and less than 50% of patients live 5 years.

13 However some patients who achieve a complete response (CR) remain free of overt disease for prolonged periods. Some times even beyond 20 years. This long term survivors are usually young and have good performance status and limited metastatic disease. Although this fraction represent a minority of patients, this finding challenges the common believe that MBC is universally fatal and raises the question of curability of this disease. Adjuvant systemic therapy after local treatment. The role of adjuvant systemic therapy after local treatment of solitary metastasis(surgical resection or radiation therapy) has been investigated in many non randomised trials ,the addition of systemic therapy is based on the assumption that micrometastasis exist in the majority of this patients and might be eradicated in at least some of them. Available data suggest that at 5 years after local treatment for recurrent or metastatic lesions followed by adjuvant systemic therapy, 36%-52% of patients remain alive and without evidence of relapse. Regional chemotherapy. The ability to deliver high concentrations of cytotoxic drugs to isolated tumor sites makes regional chemotherapy a possible alternative in patients with single metastatic foci, especially if not amenable to other local treatments. Surgery for lung and liver metastasis. Identified prognostic factors for lung resection include disease free interval and number of metastases (disease free interval >36 month and solitary metastasis being the most favorable). Pulmonary resections in MBC patients , apart from the potential therapeutic value, is also an important diagnostic tool, especially in patients with a suspected first recurrence, as it allows for differentiating the diagnosis from a primary lung cancer and benign lesions. Surgery to remove liver metastasise is an accepted modality of treatment in patients with colorectal cancer. The role in breast cancer is much less recognized. In various series of hepatic resections for breast cancer metastases, the reported median survival ranged from 14.5-63 months and the 5 year survival from14%-61% in general comparing well with nonsurgically treated patients. Interestingly, in contrast to lung metastases, where most of resected patients develop recurrence outside the lung ,in case of hepatic resections most recurrence occurred in the liver ,repeated resections may give favorable results in some patients. Radiofrequency ablation is a relative new treatment modality that uses thermal energy to induce coagulation necrosis in tumor cells.Effective local control can be achieved in solitary lesions less than 3 cm in diameter. This therapy provides promising survival rates in patients with no viceral extrahepatic disease or with single bone metastases. Bone metastases. Currently a number of strategies are employed to manage bone metastases. These include surgery, radiation therapy, chemotherapy, and antiresorptive drugs (biphosphonates). Radiotherapy and orthopaedic surgery are used to palliate pain and repair pathological fractures.

14 Biphosphonates are a class of drugs that target bone resorption by inhibiting osteoclastic activity which drives the formation of osteolytic bone metastases, leading to bone pain and fracture. Brain metastases Indications for surgical removal includes: solitary lesions >3 cm. lesion in non eloquent regions of the brain. one symptomatic lesion with multiple non symptomatic lesion(symptomatic lesion shoul be resected and the remaining lesions should be treated with radiotherapy. INFLAMMATORY BREAST CANCER (IBC) IBC is a rare, distinct clinicopathological entity, rather than a subtype of LABC, accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, aggressive behaviour (local and distant metastases) from onset of disease, and a poor prognosis (lower overall survival compared with other breast cancers). Risk Factors Despite the many epidemiological characteristics of IBC which have been studied, there are few established risk factors for IBC. Strongest associations include African American ethnicity, high body mass index and younger age at disease onset. Clinical presentation The age of onset is typically younger than other breast cancers. Primary IBC presents with onset breast enlargement and changes in the skin overlying the breast (erythema, warmth, edema and significant tenderness), but often without a discrete underlying mass, in a previously normal breast. Blockage of lymphatic channels results in wheals of the skin in the breast mound, and general induration of the breast. Approximately 55% 85% of patients present with clinically palpable metastases to the axillary or supraclavicular nodes. Neglected LABC can develop secondary inflammatory characteristics that mimic primary IBC, but should be distinguished from the latter as these secondary inflammatory breast cancers may follow a more indolent course, and can be treated as other locally advanced breast tumours. Differential Diagnosis Because of its rarity, IBC is commonly misdiagnosed as bacterial mastitis and abscess. However, it is important to note that IBC is not a true inflammatory process, not being associated with fever, localized pain or leukocytosis. Uncommon presentations of other poorly differentiated invasive cancers associated with extensive lymphovascular invasion in the breast and overlying skin (high-grade non-Hodgkin lymphoma, acute leukemia, melanoma, angiosarcoma and metastatic poorly differentiated carcinoma from other organ sites) are generally excluded by morphological and immunohistochemical findings; postradiation dermatitis and congestive heart failure causing unilateral breast edema.

15 Pathology The pathology is invasion of the dermal lymphatics by tumour emboli, resulting in blockage of the breast lymphatics leading to breast edema. The increased collagen deposition and edema of the reticular dermis results in skin thickness measuring up to 8mm. The cells composing the emboli are of high nuclear grade with a ductal phenotype. This form of invasive tumour may or may not form a distinct mass. It infiltrates the stroma diffusely and is distributed as several foci of invasive carcinoma, of varying size, with adjacent uninvolved parenchyma. The dermal lymphatic spaces are studded with tumour emboli. These dermal tumour emboli are readily demonstrated by skin punch biopsies 2mm 8mm in diameter from the most prominent area of skin discoloration. The biology has important differences from other breast cancers. Factors which correlate highly with an IBC phenotype include over-expression of RhoC GTPase and the lost inflammatory breast cancer (LIBC) protein; and highly angiogenic characteristics. The tumours tend to be high grade, aneuploid, hormone-receptor negative, with a high S-phase fraction and p53 mutations. Notwithstanding differences in biologic characteristics prognostic factors are similar to those for LABC. Negative prognostic factors predicting poorer survival include axillary node involvement, negative ER status, extensive breast edema and p53 mutations. Treatment Dismal outcomes with single modality local therapies (surgery or radiotherapy) were reported in the 1970s prior to the advent of active chemotherapy regimens. With combined modality therapy overall survival rates of 40% at 5 years and 33% at 10 years are reached: a significant improvement over historical controls, where median survival times were < 15 months; 5 year survival rates were < 5% and local relapses as high as 50%. The optimal treatment for IBC is sequential, multi-modal therapy. The initial component should be primary chemotherapy (CT) with an anthracyline-based regimen, or an anthracycline-taxane combination. Several studies have reported response rates up to 70% with primary CT. Patients with a pathological complete response have 5 and 10 year overall survival rates of 89% and 45% respectively compared to 64% and 31% for those with residual disease. Disease-free survival at 15 years is 44% compared with a 7% rate in nonresponders. Definitive local control is then achieved with surgery, which improves the local control rate and survival for patients with a good response to primary CT. The optimal surgical procedure for these patients is mastectomy with axillary node dissection. It is important that surgery completely resects residual gross disease with negative margins; positive margins are associated with a poorer prognosis. After local surgical therapy, patients should receive further CT in the adjuvant setting, as the risk of relapse remains high. Patients who do not respond to primary CT should be considered for primary radiotherapy, thereafter re-assessed for operability. Most patients receive radiotherapy following mastectomy after primary CT. The most important region targeted for radiotherapy is the chestwall: enough coverage of potential tumour emboli within dermal lymphatics must be assured. To achieve broad chestwall coverage and minimize intrathoracic organ damage, a combination of electron and photon tangent fields are used.

16 The lymph nodes within the axillary, infraclavicular, supraclavicular and internal mammary regions are also targeted. Those with endocrine-responsive tumours should receive adjuvant endocrine therapy for 5 years to minimize the risk of recurrence. Outcomes and future directions Despite progress made in the treatment of this disease, only one-third of women are cured. Further advances in the understanding and treatment of IBC are needed. Novel local therapies currently under investigation include the use of accelerated hyperfractionated radiotherapy and pre-operative radiotherapy. Both therapies are associated with higher complication rates and at present are not considered standard care. Novel systemic therapies encompass the molecular targets identified in IBC. Targeted therapy against Her-2 and EGFR is promising; molecular targets in vasculolymphatic pathways (angiogenesis, lymphangiogenesis and vasculogenesis) have shown greater potential in IBC than in non-IBC. The discovery of distinctive biologic features has paved the way for the development of new therapies. IBC has been shown to over-express RhoC which is important in signal transduction and regulation of the cytoskeleton. Farnesyl transferase inhibitors (tipifamib) have been shown to reverse the invasive phenotype of RhoC GTPase-over-expressing cell lines in the pre-clinical setting. The results of a recent clinical trial are eagerly awaited. OTHER ADVANCED BREAST MALIGNANCIES Breast sarcomas First described in 1928 by Chelius, these account for <1% of all breast malignancies with an annual incidence of approximately 17.5 new cases for 1 million women in the United States. The rarity of these lesions has resulted in breast sarcoma typically addressed as a heterogeneous group of tumours including malignant phylloides tumor. Mammary sarcomas should be limited to tumours arising from interlobular mesenchymal elements comprising the supporting stroma. These include: liposarcoma leiomyosarcoma osteogenic sarcoma chondrosarcoma malignant fibrous hystiocytoma fibrosarcoma rhabdomyosarcoma primary angiosarcoma post radiotherapy angiosarcoma

17 Typically breast sarcomas present as painless, mobile and well circumscribed breast masses. A history of rapid growth in a pre existing mass is common. Skin and nipple involvement are infrequent as is axillary node involvement unless in disseminated disease. The mean age at presentation is from 44-55 years. Mammographically these lesions appear as well circumscribed dense masses. Rarely osseous trabeculae within an osteogenic sarcoma may be noted. Histologically, sarcomas of the breast are similar to their more common counterpart occurring in other parts of the body. Breast sarcomas should be treated in a similar fashion as those occurring elsewhere in the body. Surgery is the mainstay of treatment. Wide local excision with negative margins is rarely possible. Mastectomy may be necessary in order to assure complete excision of larger tumors. ALND is only performed in the event of demonstrable metastatic axillary disease. Neoadjuvant chemo-radiation can be considered for larger tumors; the role of adjuvant radiotherapy has yet to be defined. Breast lymphomas Non-Hodgkins lymphomas of the breast are uncommon, occurring either as primary extranodal disease (PBL) or as a secondary manifestation of a systemic disease. Primary breast lymphomas (PBL) have a reported incidence of 0.04-0.5% of all breast malignancies and account for <1% of all patients with Non-Hodgkins lymphomas and approximately for 1.7% of all extranodal Non-Hodgkins lymphomas. The criteria for the diagnosis of primary breast lymphoma were suggested by Wiseman and Liao in 1972 and include: -adequate pathological evaluation -close association between lymphomatous infiltrate and mammary tissue -exclusion of either systemic lymphoma or extra mammary lymphoma, except simultaneous ipsilateral axillary node involvement. Patients with breast involvement as a result of progression or relapse of a previously diagnosed non-hodgkins lymphoma are considered as secondary breast lymphomas. Available information regarding PBL are difficult to analyze and compare because of relatively small numbers of patients in most series and the substantial differences in criteria of classification that has been used, such as lymphomas subtypes, histopathological terminology, treatment modalities and staging systems. Overall, the characteristic of this disease such as natural history, prognostic factors and impact of treatments have not been yet well established. Breast lymphoma and carcinoma usually have a similar clinical and radiological presentation. Patients generally present with a painless, enlarging breast mass. Both lymphomas and carcinomas are diseases of the middle aged and eldery, although a small subset (Burkitt lymphomas) present at a young age,

18 At present there are no clinical or radiological findings which allow differentiation between lymphoma and carcinoma of the breast. The cornerstone of diagnosis remains tissue biopsy and histopathological examination with appropriate immuno-phenotyping. The therapeutic management is controversial and is not fully established. The frequency of surgery has been declining since 1990 and is only indicated in lesions unresponsive to chemotherapy and radiotherapy, and for relapsing disease. Combined radiation and chemotherapy seems to be the most effective treatment, even in early stages of PBL. Most authors suggest that radio-chemotherapy should be the initial and in most instances the only treatment. This has been proposed as the gold standard of treatment for PBL. Malignant phylloides tumour In general, phylloides tumors of the breast are rare and comprise both stromal and epithelial elements. There are 3 forms: - benign - borderline - malignant subtypes There is no uniform agreement on the criteria for assigning the various subtypes or for predicting biological behaviour. A firm diagnosis of phylloides prior to an excisional biopsy or lumpectomy is uncommon. The mean age of presentation is 40 years, with patients presenting with a rapidly enlarging, painless breast mass. Phylloides tumours appear on ultrasound and mammography as fibroadenomas. Fine needle aspiration cytology and core needle biopsy are inadequate to reliably distinguish phylloides tumours from fibroadenomas (both are fibro-epithelial lesions), and between the benign and malignant variety of phylloides tumours. Excision biopsy is mandatory for a conclusive diagnosis. Treatment of phylloides tumors is possible with breast conserving surgery (BCS), provided local excision with tumor free margins of > 1cm or greater can be achieved. Total mastectomy is necessary for large lesions, if negative margins cannot be obtained with BCS and in malignant phylloides tumours. Since malignant phylloides tumors rarely metastazise to the axillary lymphnodes , ALND is not necessary unless nodes are pathologic on clinical examination. While epithelial components of most phylloides tumors contain ER (58%) and PR (75%) receptors, ET has no proven role in the treatment of malignant phylloides tumours. Similarly there is no evidence that adjuvant chemotherapy provides benefit in reducing the risk of recurrences or death. Local recurrence is the most common form of recurrence. Distant recurrences occur in the lung, either as solid nodules or thin walled cavities.

19 CONCLUSION Advanced breast cancer continues to be a frequent presentation in developing countries. Guidelines for the management of this disease in resource-constrained countries are available. However, the focus should be to reduce the incidence of advanced disease, thus decreasing the morbidity and cost associated with advanced disease. This can only be achieved by concerted efforts to detect disease early by introducing simple, sustainable screening programmes and awareness campaigns.

REFERENCES 1. (Guidelines for management of breast cancer: World Health Organization, Regional office for the Eastern Mediterranean, EMRO Technical Publications Series 31). 2. Advance Breast carcinoma Seminar 12 2008p 4. 3. Loubser Frieda et al. Epidemiology, risk factors and genetics of breast cancer, October 2008; Vol.26 No.10 CME:200-230. 4. Daniel A. Vorobiof, Freddy Sitas, and Gabriel Vorobiof Breast Cancer Incidence in South Africa. J Clin Oncol; 19:125s-127s. 2001 5. The freelibrary.com,breast screening in developing countriesOCTOBER,1ST 2008. 6. SH Giordano Update on LABC. The Oncologist dec2003: vol 8 (6):521-530, 7. GABRIEL N. HORTOBAGYI Management of Stage Ill Primary Breast Cancer With Primary Chemotherapy, Surgery, and Radiation Therapy. Cancer 62:2507-2516, 1988.) 8. Sharon H Giordano Update on locally advanced breast cancer-, The Oncologist 2003: 8: 521-530/ LABC1. 9. Advanced Breast carcinoma. Seminar 12 /2008 p6. 10. Advances in neoadjuvant (primary) systemic therapy with cytotoxic agents 11. Michael Untch and Gunter von Minckwitz, Breast Cancer Research 2009, 11:203)11) (Locally Advanced Breast Cancer Treatment Guideline Implementation With Particular Attention to Low- and Middle-Income Countries, Nagi S. El Saghir et al. Cancer 2008;113(8 suppl):231524/ Treatment guidelines pdf) 12. Guidelines for management of breast cancer: World Health Organization, Regional office for the Eastern Mediterranean, EMRO Technical Publications Series 31 13. Predicting response to neoadjuvant chemotherapy in breast cancer:molecular imaging,sistemic biomarkers and cancer metabolism (review).oncology reports 20:699703,2008)(Review: Recent advances in systemic therapy 14. Advances in neoadjuvant (primary) systemic therapy withcytotoxic agents 15. Michael Untch and Gunter von Minckwitz, Breast Cancer Research 2009, 11:203 16. Nagi S. El Saghir et al. Locally Advanced Breast Cancer Treatment Guideline Implementation With Particular Attention to Low- and Middle-Income Countries Cancer 2008;113(8 suppl):231524/ Treatment guidelines pdf 17. Ines Buccimazza. Invited Commentary: The Impact of Neoadjuvant Chemotherapy on Patients with Locally Advanced Breast Cancer in a Nigerian Semiurban Teaching Hospital: A Single-Center Descriptive Study, , World J Surg (2010) 34:17791781) 18. Nagi S. El Saghir et al. Locally Advanced Breast Cancer Treatment Guideline Implementation With Particular Attention to Low- and Middle-Income Countries, Cancer 2008;113(8 suppl):231524/ Treatment guidelines pdf

20 19. Breast radiation therapy guideline implementation in low and middle income countries 2008 cancer society(www.interscience.wiley.com)2008 20. Surgical options for massive breast enlargement in the metastatic setting.lisa A newman,MD MPH 10/08/2009 21. A.M fernandez,jose aguilar. Inmediate reconstruction after mastectomy for breast cancer:which risk factors affect it's course and final outcome?,j.jamcollsurg.2008,09 22. goiy s,rouzier r,missana mc et al.inmediate reconstruction after neoadjuvant chemotherapy:effects on adjuvant treatment starting and survival.ann surg oncol 2005;12:161-166. 23. carlson GW,styblo TM,lyles RH et al.local recurrence after skin sparing mastectomy:tumor biology or surgical conservatism?ann surg oncol 2003;10:108-112. 24. Olson JA Jr, McCall LM, Beitsch P, et al; American College of Surgeons Oncology Group Trials Z0010 and Z0011. Impact of immediate versus delayed axillary node dissection on surgical outcomes in breast cancer patients with positive sentinel nodes: results from American College of Surgeons Oncology Group Trials Z0010 and Z0011. J Clin Oncol. 2008;26:3530-3535. Abstract 25. Anscher MS, Jones P et al. Local Failure and Margin Status in Early-Stage Breast Carcinoma treated with conservation surgery and radiation therapy. Annals of Surgery 1993; 218 (1): 22-28 26. Bland KI. Surgical margins in Breast cancer: how wide? How accurate? How big? Does it make a difference? Current Surgery 2001; 58 (3): 248-253 27. s.eva singletary et al.feasibility of breast conservation surgery after induction chemotherapy for loccally advanced breast carcinoma.CANCER.june,1,1992,vol69,no 11. 28. Valagosa p et al.patterns of relapse and survival following radical mastectomy:analisis of 716 consecutive patients.CANCER 1978;48:1170-80. 29. donegan wl et al.a biostatistical study for locally recurrent breast carcinoma.surg gynaeobst 1966;122:529-40. 30. zimmerman kw et al.frequency,anatomical distribution and management of local recurrences after definitive therapy for breast cancer.CANCER.1966,19:67-74. 31. Varonesi et al.breast conservation is the treatment of choice in small breast cancer.long term results of a randomized trial.eur.j cancer 1990;26(6)668-701. 32. dalberg k et al.a randomised study of axillary drainage and pectoral fascia preservation after mastectomy for breast cancer.EJSO(2004)30,602-609

33. Detection of Locoregional and Distant Recurrences in Breast Cancer Patients by

Using FDG PET.William B. Eubank, MD, et al 34. Recurrent breast cancer:Mayoclinic.com/treatments and drugs. 35. Breast cancer recurrence.gaeainitiative.eu ferlay j et al,IARC GLOBOCAN 2000.cancer incidence,mortality and prevalence worldwide. 36. Pagani o et al.international guidelines for management of metastatic breast cancer.comentary JNCI VOL102,issue 7,april 7 2010. 37. rose an april;peter m siegel.emerging therapeutic targets in breast cancer bone metastases:current therapeutic intervention for breast cancer bone metastases.medscape 31 dec 2009 38. Victor tse.brain metastases:treatment and medication.medscape nov 2009. 39. David r brenin,THE UNKNOWN PRIMARY TUMOR PRESENTING WITH AXILLARY LIMPHADENOPATHY.google books 2004 40. David j winchester;david p winchester.'BREAST CANCER' google books 2006,414-416

21 41. Neri .A et al 'PRIMARY NON HODKING LYMPHOMA:SURGICAL APROACH.CASES JOURNA 2008,1:311NCCN practice guidelines in oncology 2010 vol 1 p 36-37 42. Kutun S, Ay AA, Ulucanlar H et al. Is transdermal nitroglycerin application effective in preventing and healing flap ischemia after modified radical mastectomy? SAJS 2010; 48 (4): 119 121 43. Rao R, Saint-Cyr M, Ma AMT, Bowling M et al. Prediction of post-operative necrosis after mastectomy: A pilot study utilizing optical diffusion imaging spectroscopy. World Journal of Surgical Oncology 2009; 7(91) 44. Wu Hongying, Zhang Chun Shan, Thakur B. Origin and countermeasure for common skin flap complications after radical operation for breast cancer. Kathmandu University Medical Journal 2006; Vol.4, No.1, Issue 13: 14 -17 Comment by Dr MC Mayet Morbidity of Axillary lymph node dissection Introduction Axillary lymph node dissection (ALND) has for several decades played a central role in the surgical management of breast cancer, having been the only form of axillary staging until recently. The procedure is, however, associated with potentially significant morbidity. Although post-ALND complications are often minor, in some cases they can persist for a long time following surgery, thereby affecting the quality of life of breast cancer survivors. Seroma formation and altered sensation of the upper limb are the two most common complications following ALND. Lymphedema is the most common potentially severe longterm complication following ALND. Major post-ALND complications (such as injury or thrombosis of the axillary vein and injury to the motor nerves of the axilla) are extremely rare. Meticulous surgical technique and careful selection of patients for postoperative radiation therapy are mandatory to prevent significant morbidity following ALND. The introduction of the technique of sentinel lymph node biopsy in clinical practice has resulted in a significant reduction in the incidence of post-ALND complications. Table 1: Classification of ALND morbidity Early Bleeding Seroma Surgical site infection Obliterative thrombophlebitis Lymphoedema Altered sensation Frozen shoulder

Late

Lymphoedema Lymphedema is a notoriously debilitating progressive condition with no known cure. The unfortunate patient faces a lifelong struggle of medical, and sometimes surgical, treatment fraught with potentially lethal complications. The underlying problem is lymphatic dysfunction, resulting in an abnormal accumulation of

22 interstitial fluid containing high molecular weight proteins. This condition underscores the tremendous importance of a normally functioning lymphatic system, which returns proteins, lipids, and accompanying water from the interstitium to the venous circulation near the subclavian veininternal jugular vein junction, bilaterally. Unfortunately, lymphoedema is one of the more common and debilitating complications of axillary node dissection. Risk factors: *any procedure that disrupts lymphatics pathways or changes the fluid dynamics in the limb. partial mastectomy or lumpectomy. sentinel lymph node biopsy or axillary disection. compression. infection. trauma to the limb. *patient related risk factors: overweight. hypertension. heart disease. age. The incidence of lymphedema, using current techniques for axillary dissection, has decreased significantly. Removal of level III axillary nodes can increase the incidence from 3-10% when compared with limited level I and II dissection. Axillary lymph node dissection was previously considered to be the standard of care for all patients diagnosed with invasive breast cancer. However, axillary lymph node dissection carries a high rate of surgical morbidity (lymphedema rates of about 25%, shoulder dysfunction, wound infection, seroma, nerve damage, numbness, chronic pain, and, rarely, brachial plexus injury). Lymphedema occurs because a portion of the lymphatics that drain from the breast to the axilla, and those that drain from the arm are shared within the axilla. Early detection of lymphedema is paramount as lymphedema is potentially reversible when treated in its earliest stage. Compression garments and physical therapy with lymphatic massage are still the backbone for the treatment of lymphedema. Patients who have an axillary lymph node dissection should be cautioned about the risk of lymphedema and should take precautions to avoid breaks in the skin or infections in the affected extremity. Lymphedema may develop at any time after lymph node dissection but most commonly occurs within the first 2 years of the surgery. Although patients are commonly advised to avoid taking blood pressures or inserting IVs in the affected arm after axillary lymph node dissection, no level I or level II evidence supports that recommendation. Patients with chronic lymphedema for 10 years have a 10% risk of developing lymphangiosarcoma, the most dreaded complication of this disease. Patients with this tumor commonly present with a reddish purple discoloration or nodule that tends to form satellite lesions. It may be confused with Kaposi sarcoma or traumatic ecchymosis. This tumor is highly aggressive, requires radical amputation of the involved extremity, and has a very poor prognosis. The 5-year survival rate is less than 10%, and the average survival following diagnosis is 19 months. This malignant degeneration is most commonly observed in patients

23 with postmastectomy lymphedema (Stewart-Treves syndrome), where incidence is estimated to be 0.5%. Other complications of lymphedema include recurrent bouts of cellulitis and/or lymphangitis, deep venous thrombosis, severe functional impairment, cosmetic embarrassment. Neurologic injuries Neurologic injuries vary widely from mild traction neuralgias to major brachial plexus injuries. Traction injuries are usually the result of poor positioning and lack of padding to protect peripheral nerves. The brachial plexus may be spared by keeping dissection inferior to the axillary vein. The most common neurologic complaint postoperatively is numbness of the axillary skin and upper medial arm. This is secondary to transection of the intercostobrachial nerve as it crosses the axilla. Injury to the long thoracic nerve results in a winged scapula, while injury to the thoracodorsal nerve compromises internal rotation and abduction of the arm beyond 90 degrees. Vascular injuries These include injury or thrombosis of the axillary vein, which are extremely rare. Measures to prevent morbidity associated with axillary node dissection Intraoperative The keys to successful surgery of the breast include a thorough knowledge of anatomy, accurate assessment of the extent of disease. Axillary lymph node dissection for breast cancer is a complete en bloc removal of the level I and II lymph nodes. level I nodes are lateral to the pectoralis minor, level II are beneath the pectoralis minor, and level III are medial to the pectoralis minor. The level III nodes are not removed surgically unless there is suspicious or palpable adenopathy present. Skip metastasis to the axillary apex of level III without lower axillary involvement is very rare. Axillary lymph node dissection removes all nodal tissue defined by the borders of the axillary vein superiorly, the latissimus dorsi muscle laterally, the medial border of the pectoralis minor muscle medially, and the subscapularis muscle posteriorly. Care is taken to preserve the long thoracic and thoracodorsal nerves along their course through the axilla. Injury to the long thoracic nerve results in a winged scapula, while injury to the thoracodorsal nerve compromises internal rotation and abduction of the arm beyond 90 degrees. The median and lateral pectoral nerves may also be injured during axillary lymph node dissection. The antecostobrachial nerves run directly through the resection specimen and are typically sacrificed, resulting in a predictable pattern of cutaneous numbness in the inner arm region for most patients after this procedure. With growth in acceptance of breast conservation surgery, the door has been opened for even less invasive techniques such as sentinel node biopsy. Post operative Early patient mobility and range of motion exercises should be encouraged postoperatively, although the timing and degree should be tailored to the extent of the procedure performed (ie, lumpectomy vs skin-sparing mastectomy with immediate reconstruction). In a randomized, single-blinded clinical trial, Torres et al investigated whether early physiotherapy can reduce the percentage of patients who develop clinically significant

24 secondary lymphedema following breast cancer surgery. The study included 116 women (patients who did or did not receive early physiotherapy) who had undergone breast cancer surgery involving dissection of the ancillary lymph nodes. In the early physiotherapy group, treatment included manual lymph drainage, scar tissue massage, and progressive active and action-assisted shoulder exercises. At 1-year follow-up, the authors found that 25% of patients (14 patients) in the control group had developed secondary lymphedema, compared with 7% of patients (4 patients) in the early physiotherapy group. Torres et al concluded that in women who have undergone the above-described breast cancer surgery, early physiotherapy may help to prevent postoperative secondary lymphedema for at least 1 year. References
1. eMedicine Specialties Breast Cancer; Author: Mary Jo Wright, MD, Associate

Professor of Surgery, Chief of Breast Surgery Service, Tulane University School of Medicine; Medical Director, Breast Cancer Center, Medical Center of Louisiana, New Orleans Coauthor(s): Krzysztof Moroz, MD, Professor of Pathology, Director of Cytopathology, Tulane University Health Sciences Center; R Edward Newsome, MD, Program Director and Chief of Plastic Surgery, Henderson Chair in Surgery, Assistant Dean for Graduate Medical Education, Tulane University School of Medicine Updated: Sep 10, 2009 2. eMedicine Specialities > Oncology>Carcinoma of the Breast Breast Cancer: Treatment; Author: Rachel Swart, MD, PhD, Assistant Professor of Medicine, Department of Hematology and Oncology, Arizona Cancer Center, University of Arizona Coauthor(s): Leona Downey, MD, Assistant Professor of Internal Medicine, Section of Oncology and Hematology, University of Arizona, Arizona Cancer Center; Julie Lang, MD, Assistant Professor of Surgery and the BIO5 Institute, Director of Breast Surgical Oncology, University of Arizona; Patricia A Thompson, PhD, Assistant Professor, Department of Pathology, University of Arizona, Tucson; Robert B Livingston, MD, Professor of Clinical Medicine and Director, Clinical Research Shared Services, Arizona Cancer Center; Alison T Stopeck, MD, Associate Professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center; Director of Clinical Breast Cancer Program, Arizona Cancer Center; Medical Director of Coagulation Laboratory, University Medical Center; Director of Arizona Hemophilia and Thrombosis Center Updated: Dec 17, 2010 3. Medscape CME Oncology, Prof Pat W Whitworth Lymphoedema in breast cancer survivors: Update on early detection and treatment 23/06/2010. Olson JA Jr, McCall LM, Beitsch P, et al; American College of Surgeons Oncology group trials Z0010 and Z0011. Impact of immediate versus delayed axillary node dissection on surgical outcomes in breast cancer patients with positive sentinel nodes: results from American College of Surgeons Oncology group trials Z0011. J Clin Oncol. 2008;26:3530-3535 4. Expert review of Anticancer Therapy, Volume 6, Number 11, November 2006 , pp. 16291638(10)