- Optimum management of locally advanced breast cancer is multidisciplinary.
- Neoadjuvant chemotherapy is the mainstay of management.
- Primary surgical treatment may be acceptable in selected patients.
Breast cancer is the second most common cancer in the world and increasing in incidence (1 in 8 women) worldwide and it is the second most common cause of cancer-related death in women aged 45–55 years1. Locally advanced disease is characterized clinically by features suggesting infiltration of the skin or chest wall by tumor or matted involved axillary lymph nodes1,2. Depending on referral patterns and clinical definitions, between 1 in 12 and 1 in 4 patients present with locally advanced disease3. They may arise because of its position in the breast (eg, if the lesion is peripheral), because of neglect, which is common in the developing world, or because the cancer is biologically aggressive (inflammatory cancers and the majority of those with peau d’orange) and definitely requires neoadjuvant chemotherapy2,3. The 5-year survival rate of locally advanced breast cancer varies between 1% and 30% due to differences in definition and the different forms of breast cancer, and the overall median survival is about 2 to 2.5 years4. The majority (80%) die of metastatic disease. As local and regional relapse is a major problem affecting 50% of patients, loco-regional control of breast cancer is associated with improve disease-specific survival2,4–6.
In contrast to early-stage disease for which level 1 evidence exists for the majority of treatment options, there are few recognized therapeutic standards of care in locally advanced breast cancer, particularly after first-line anti-human epidermal growth factor type 2 receptor (HER2) (trastuzumab) treatment7. Patients with hormone-sensitive disease have a much longer survival than those with insensitive disease4,8. Thus, a multidisciplinary approach in breast cancer would provide the optimum management geared at eradicating or slowing down the growth of these occult metastases and improve survival2,5. Further studies in the form of clinical trials may ascertain the role of surgery in locally advanced breast cancer in settings where a multidisciplinary approach is not available.
A 42-year-old African perimenopausal woman who absconded from treatment a year after diagnosis of right breast cancer presented with a painless right upper-quadrant breast mass. An incision biopsy of the lump had confirmed an invasive ductal carcinoma. She had no anorexia or weight loss, but she felt tired and unwell. On examination, she appeared clinically well with no pallor. She had a protruding and almost ulcerating large right upper-quadrant breast mass of about 7 cm in diameter. It was fixed to the adjacent breast tissue and to the overlying transverse biopsy scar. There was no nipple discharge or retraction. The mass was immobile with ill-defined margins and tender only on deep palpation. The breast had indurated and edematous surrounding skin with evidence of lymphatic infiltration (peau d’orange). There were no brawny, erythematous skin changes to suggest an inflammatory cancer. A large and fixed central axillary lymph node was palpable, but there was no palpable supraclavicular lymph node nor edema of the arm. There were no satellite regional skin metastases. Chest and abdominal examinations were unremarkable. A bilateral breast ultrasound scan revealed a multilocular cystic nodular mass of 51 by 39 mm in diameter in the upper outer quadrant of the right breast consistent with a breast carcinoma (Fig. 1). A chest x-ray and ultrasound scan of the liver excluded metastatic disease. A clinical staging of T3, N2, M0 breast carcinoma was made. A full blood count revealed a hemoglobin level of 11 g/dL and serum biochemistry including liver function tests were normal. She consented to a simple mastectomy and axillary clearance to level II (level of the axillary vein).
A very wide elliptical incision incorporating the nipple, areola, and biopsy scar ran transversely across the chest to enable total excision of the breast and the large tumor. Medially, the breast tissue was dissected off the pectoralis fascia of the anterior thoracic wall. Laterally, the dissection continued until the axillary tail was reached, which was then mobilized from the overlying skin and underlying musculature. The lower axillary nodes were removed en bloc, with ligation of remaining tissues at the apex of the dissection to avoid the retraction away of the contained vessels when divided (Fig. 2). This was facilitated by an upward retraction of the pectorals minor muscle and manipulation of the draped abducted ipsilateral arm. Care was taken to avoid the nerve supply to serratus anterior and latissimus dorsi, both closely applied to the lateral chest wall, which forms the medial border of the axilla. The axillary vein encountered before the artery or brachial plexus at the apex of the axilla marked the upper limit of the dissection. Hemostasis was secured with suture ligation and cautious use of diathermy. Two closed suction drains were inserted: one for the flaps and the other for the axilla. The patient lost about 200 mL of blood and was transfused 2 units of blood perioperatively. The mastectomy specimen was sent for histologic examination (Fig. 3). The drains were removed on the fifth postoperative day. She had no reduction in shoulder movement, and was discharged on the seventh postoperative day on the antiestrogen, tamoxifen 20 mg daily. A draining wound sinus in the lateral edge of the mastectomy scar took a further 2 weeks to heal. She was entirely happy with an external prosthesis worn over the mastectomy scar (Fig. 4). The pathologist received a mastectomy specimen of 18.0×17.0×13.5 cm. There was a huge lymphatic tissue of 8 cm diameter containing a tumor of 5 cm diameter at its tail. The histology confirmed invasive ductal carcinoma of 7.5 cm diameter with fibrotic and necrotic reaction close to the margins of the incision. There was no facility for assessing prognostic markers such as basic estrogen receptor, progesterone receptor, and HER2/neu status. She commenced adjuvant radiotherapy to the mastectomy bed a month later followed by 6 cycles of anthracycline chemotherapy. She had no local recurrence or distant metastases at 2 years’ follow-up.
Locally advanced breast cancer is, by definition, incurable because of putative micrometastases, but worthwhile symptom control and extension of survival are achievable2,4–6. It is also of note that large operable cancers fixed to the muscle are not necessarily locally advanced. All but 1 study published after 2010 support the surgical removal of the primary tumor in patients with stage IV disease10–14. This case demonstrated the management of clinically locally advanced disease of the breast with heavy nodal involvement (T3, N2, M0) (Table1)15,16. Mastectomy is generally not indicated in locally advanced disease, but some weeks or months after neoadjuvant treatment with a combination of cytotoxic drugs or initial hormonal treatment. Better pathologic assessment of the vicinity of the tumor, local tumor spread as related to local capillaries and lymphatics, and regional lymph node involvement along with knowledge of the estrogen receptor and HER2 tumor biomarkers would optimize treatment, but were not available due to the resource-poor setting. Neoadjuvant chemotherapy downstages the breast and axilla and enhances surgical loco-regional control, and has the initial benefit of immediately attacking the putative occult micrometastases (Table2)9,17,18. The patient’s choice was, however, for primary surgical treatment followed by adjuvant chemoradiotherapy. Nevertheless, some locally advanced cancers, principally those with direct skin involvement because of position or neglect, but with favorable biology as in this case, are suitable for primary surgical treatment2,6,7,18. Simple mastectomy with axillary clearance to level II has the same survival outcome as the modified radical mastectomy (Patey) in which the pectoralis major is widely retracted and the pectoralis minor removed to allow the axillary contents to be cleared2,9,18. Mobilization of apical glands and the axillary tail using the breast for traction provides en bloc lymphadenectomy (Figs. 2, 3). In both approaches, in addition to a lack of oncological compromise, the main advantage over Halstead’s radical mastectomy, which includes excision of the sternal head of the pectoralis major and pectoralis minor, is aesthesis and minimal morbidity19. The axillary fold is maintained and there is no hollowing below the clavicle. It also gives a stronger and more useful arm (Fig. 4).
Although axillary clearance does not improve survival as death is from distant metastases, it removes axillary disease and prevents regional recurrence, allows assessment of the nodal status for prognostic purposes, and selection for adjuvant treatment20,21. Axillary dissection is performed either in continuity (en bloc) with a mastectomy or through a counter incision as an adjunct to quandrantectomy. This will avoid the need for axillary radiation, but the latter will require adjuvant radiotherapy to the tumor bed and breast, only to yield a 7% local recurrence rate equivalent to those obtained by primary mastectomy9. In patients with clinically palpable nodes, a full axillary clearance is the treatment of choice2,6,9,20–22. However, axillary clearance to level II (medial border of pectoralis minor and just below the axillary vein) offers satisfactory disease control for the majority of cases and the best cost benefit. The higher the level of clearance, the higher will be the morbidity (ie, stiff shoulder, lymphedema, axillary vein thrombosis). Skip lesions are rare, and if level III nodes are affected, it is likely that the level IV nodes (supraclavicular nodes) are also involved, which is equivalent to metastases (M1)23. Thus, the anatomico-pathologic rationale for sentinel node biopsy in staging the axilla in early, impalpable, or screen-detected breast cancer so as to avoid unnecessary axillary dissection24. Treatment of the axilla is either by dissection or by radiotherapy, but not both. Axillary radiotherapy after surgery to the axilla is contraindicated because of the highest risk of lymphedema and disabling shoulder stiffness20–22. Thus, if axillary dissection is performed and there is heavy lymph node in the axilla, all palpable lymph nodes should be excised. Only rarely is tumor found encasing the axillary vein and this is usually fairly easy to dissect20–22,25. Recurrent axillary disease represents residual untreated disease and usually occurs with metastases at other sites requiring appropriate systemic therapy with or without local treatments25,26. For the small group of patients below 60 years of age with medially placed tumors, internal mammary node biopsy through the second intercostal space is required to identify those who require adjuvant chemotherapy9.
Radiotherapy is the mainstay of local therapy as it can produce high rates of local remission in both the breast and the axilla27. However, when radiotherapy is used alone, only 30% of patients remain free of loco-regional disease at death28. Likewise, breast-conserving surgery alone is associated with high rates (25% to 30%) of local recurrence (Tables3, 4). Postmastectomy radiotherapy would improve disease-free survival of patients with a high risk of local recurrence as in this case with a large tumor size (>5 cm), peau d’orange, heavy nodal involvement, and possible poor histologic grade and vascular involvement29. By combining appropriate systemic therapy and radiotherapy, response rates of over 80% have been reported and over two thirds of patients retain loco-regional control at death30,31.
Primary hormonal therapy can be given to patients with locally advanced breast cancer, which are estrogen receptor positive and appear to be relatively slow growing or indolent8,31. Recently, targeted molecular therapy with the monoclonal antibody (Trastzumab) that binds the HER2 arrests the G1 phase of the cancer cell cycle and decreases cell proliferation in early and advanced breast cancer32. It improves disease-free survival and overall survival in the adjuvant setting and improves progression-free survival and overall survival when added to chemotherapy in patients with metastatic breast cancer33. The choice of treatments is outlined in Table5.
Thus, the optimum management of locally advanced breast cancer requires a multidisciplinary approach. Although neoadjuvant treatment strategies are the mainstay of management, selected patients with slow-growing or indolent tumors with nodal involvement only, in low-resource areas may benefit from a safe, expeditious, and effective loco-regional control with simple mastectomy, and an en bloc level II axillary clearance2,6,13,34. Further studies in the form of a clinical trial should ascertain the role of surgery in locally advanced breast cancer, especially in resource-poor settings.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors acknowledge the nurses for the perioperative care of the patient and the medical student, Tembi efie Derrick, for providing the images.
Conflict of interest statement
The authors declare that they have no financial conflict of interest with regard to the content of this report.
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin 2009;59:225–49.
2. Tryfonidis K, Senkus E, Cardoso MJ, et al. Management of locally advanced breast cancer
—perspectives and future directions. Nat Rev Clin Oncol 2015;12:147–62.
3. Newman LA. Epidemiology of locally advanced breast cancer
. Semin Radiat Oncol 2009;19:195–203.
4. Giordano SH. Update on locally advanced breast cancer
. Oncologist 2003;8:521–30.
5. Kesson EM, Allardice GM, George WD, et al. Effects of multidisciplinary team working on breast cancer
survival: retrospective, comparative, interventional cohort study of 13,722 women. BMJ 2012;344:e2718.
6. El Saghir NS, Adebamowo CA, Anderson BO, et al. Breast cancer
management in low resource countries (LRCs): consensus statement from the Breast Health Global Initiative. Breast 2011;20(suppl 2):S3–11.
7. Rastogi P, Anderson SJ, Ber HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008;26:778–85.
8. Muss HB. Endocrine therapy for advanced breast cancer
: a review. Breast Cancer
Res Treat 1992;21:15–26.
9. Veronesi U. Treatment of primary breast cancer
. Ballieres Clin Oncol 1998;2:175–93.
10. Dominici L, Najita J, Hughes M, et al. Surgery
of the primary tumor does not improve survival in stage IV breast cancer
. Breast Cancer
Res Treat 2011;129:459e65.
11. Rashaan ZM, Bastiaannet E, Portielje JE, et al. Surgery
in metastatic breast cancer
: patients with a favorable profile seem to have the most benefit from surgery
. Eur J Surg Oncol 2012;38:52e6.
12. Ly BH, Vlastos G, Rapiti E, et al. Local-regional radiotherapy and surgery
is associated with a significant survival advantage in metastatic breast cancer
patients. Tumori 2010;96:947e54.
13. Neuman HB, Morrogh M, Gonen M, et al. Stage IV breast cancer
in the era of targeted therapy: does surgery
of the primary tumor matter? Cancer 2010;116:1226e33.
14. Ruiterkamp J, Ernst MF. The role of surgery
in metastatic breast cancer
. EurJ Cancer 2011;47(suppl 3):S6e22.
15. International Union Against Cancer. TNM Classification of Malignant Tumours, 7th ed. London: Wiley-Blackwell; 2009.
16. Whitman GJ, Strom EA. Workup and staging of locally advanced breast cancer
. Semin Radiat Oncol 2009;19:211–21.
17. Scholl SM, Fourquet A, Aselain B, et al. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery
: preliminary results of a randomized trial. Ann Oncol 1991;30A:645.
18. Ogundiran TO, Ayandipo OO, Ademola AF, et al. Mastectomy for management of breast cancer
in Ibadan, Nigeria. BMC Surg 2013;13:59.
19. Maddox WA, Carpenter JT, Laws HL Jr, et al. A randomized prospective trial of radical (Halsted) mastectomy versus modified radical mastectomy in 311 breast cancer
patients. Ann Surg 1983;198:207–12.
20. Taylor I. How should the axilla be treated in breast cancer
? Eur J Surg Oncol 1995;21:2–7.
21. Fentiman IS, Mansel RE. The axilla: not a no-go zone. Lancet 1991;337:221–3.
22. Zarebczan Dull B, Neuman HB. Management of the axilla. Surg Clin North Am 2013;93:429–44.
23. Berg JW. The significance of axillary node levels in the study of breast carcinoma. Cancer 1955;8:776–8.
24. Nogushi M. Sentinel lymph node biopsy and breast cancer
? Br J Surg 2002;89:21–34.
25. Punglia RS, Morrow M, Winer EP, et al. Local therapy and survival in breast cancer
. N Engl J Med 2007;356:2399–405.
26. Kurt JM. Factors influencing the risk of local recurrence in the breast. Eur J cancer 1992;28:660–6.
27. Harris JR, Sawicka J, Gleman R, et al. Management of locally advanced
carcinoma of the breast by primary radiation therapy. Int J Radiat Oncol Biol Phys 1983;9:345.
28. Fischer B, Rockette H, Ribidoux A, et al. Effect of preoperative therapy for breast cancer
(BC) on loco-regional disease: first report of NSAP B-18. Proc ASCO 1994;13:64.
29. He ZY, Wu SG, Zhou J, et al. Postmastectomy radiotherapy improves disease-free survival of high risk of locoregional recurrence breast cancer
patients with t1-2 and 1 to 3 positive nodes. PLoS One 2015;10:e0119105.
30. Hortobagyi GN, Singletary SE, McNeese MDHarris JR, Lipmpman ME, Morrow M, Hellman S. Treatment of locally advanced
and inflammatory breast cancer
. Diseases of the Breast. Philadelphia: Lippincott-Raven; 1996:585–99.
31. Dixon MJ, Leonard RCF. Farndon JRHormones and chemotherapy. Breast and Endocrine surgery
, a Companion to Specialist Surgical Practice 1999. London: WB Saunders comp ltd.
32. Hortobagyi GN. Trastuzumab in the treatment of breast cancer
. N Eng J Med 2005;353:1734–36.
33. Paik S, Kim C, Wolmark N. HER2 status and benefit from adjuvant trastuzumab in breast cancer
. N Engl J Med 2008;358:14409–11.
34. Cardoso F, Costa B, Norton C, et al. International consensus guidelines for advanced breast cancer
(ABC 1). Breast 2012;21:242–52.