Treatment of Breast Cancer

KAREN L. MAUGHAN; MARK A. LUTTERBIE; PETER S. HAM

KAREN L. MAUGHAN, MARK A. LUTTERBIE, MD, AND PETER S. HAM, MD

Am Fam Physician. 2010;81(11):1339-1346

A more recent article on breast cancer treatment is available.

See related editorial on page 1330.

Patient information: See related handout on breast cancer treatment, written by the authors of this article.

Author disclosure: Nothing to disclose.

Understanding breast cancer treatment options can help family physicians care for their patients during and after cancer treatment. This article reviews typical treatments based on stage, histology, and biomarkers. Lobular carcinoma in situ does not require treatment. Ductal carcinoma in situ can progress to invasive cancer and is treated with breast-conserving surgery and radiation therapy without further lymph node exploration or systemic therapy. Stages I and II breast cancers are usually treated with breast-conserving surgery and radiation therapy. Radiation therapy following breast-conserving surgery decreases mortality and recurrence. Sentinel lymph node biopsy is considered for most breast cancers with clinically negative axillary lymph nodes, and it does not have the adverse effects of arm swelling and pain that are associated with axillary lymph node dissection. Choice of adjuvant systemic therapy depends on lymph node involvement, hormone receptor status, ERBB2 (formerly HER2 or HER2/neu) overexpression, and patient age and menopausal status. In general, node-positive breast cancer is treated systemically with chemotherapy, endocrine therapy (for hormone receptor–positive cancer), and trastuzumab (for cancer overexpressing ERBB2). Anthracycline- and taxane-containing chemotherapeutic regimens are active against breast cancer. Stage III breast cancer typically requires induction chemotherapy to down-size the tumor to facilitate breast-conserving surgery. Inflammatory breast cancer, although considered stage III, is aggressive and requires induction chemotherapy followed by mastectomy, rather than breast-conserving surgery, as well as axillary lymph node dissection and chest wall radiation. Prognosis is poor in women with recurrent or metastatic (stage IV) breast cancer, and treatment options must balance benefits in length of life and reduced pain against harms from treatment.

Breast cancer is the second most common cause of cancer mortality in women in the United States.¹ One in eight women will be diagnosed in her lifetime.² Breast cancer treatments continue to evolve, and although family physicians do not generally make primary decisions about these therapies, understanding their rationale and underlying evidence can help with the care of their patients during and after cancer treatment. Table 1 lists the five-year survival prognosis for each stage of breast cancer.^3,4

Clinical recommendation	Evidence rating	References
Breast-conserving surgery should be followed by radiation therapy in women with early-stage invasive or locally advanced breast cancer.	A	⁸
Sentinel lymph node biopsy results in fewer arm complications compared with axillary lymph node dissection in the treatment of breast cancer.	A	^9–11, ²⁰
Axillary lymph node dissection should be performed in women who have breast cancer with clinically palpable lymph nodes.	C	³²
Aromatase inhibitors, with or without tamoxifen, should be offered to all postmenopausal women with hormone receptor–positive breast cancer.	A	¹², ³⁸, ⁴⁰, ^51–53
Chemotherapy should be offered to all women who have breast cancer with positive lymph nodes.	C	⁴⁷
Trastuzumab (Herceptin) should be offered to all women with breast cancer that is overexpressing ERBB2.	A	¹³, ¹⁴
Preoperative chemotherapy for locally advanced breast cancer increases the success of breast-conserving surgery.	A	¹⁶, ²¹

Cancer stage	Classification	Five-year survival rate (percent)
0	In situ	100*³
I, IIa, IIb	Early invasive	98.0 (local)*³
I, IIa, IIb	Early invasive	83.6 (regional)*³
IIIa, IIIb, IIIc IV	Locally advanced†	57⁴
IIIa, IIIb, IIIc IV	Metastatic†	23.4*³

Breast cancer prognosis and treatment options are generally based on tumor-node-metastasis staging.⁵ Lymphovascular spread, histologic grade, hormone receptor status, ERBB2 (formerly HER2 or HER2/neu) overexpression, comorbidities, and patient menopausal status and age are also important factors. Table 2 outlines typical treatment options by cancer stage and type.^6–22

Cancer stage and type		Primary treatment	Node evaluation	Adjuvant therapy
Cancer stage and type		Primary treatment	Node evaluation	Hormone receptor negative	Hormone receptor positive	ERBB2 overexpression
Stage 0: in situ
	Lobular carcinoma in situ	No treatment or consider prophylaxis with tamoxifen⁶	—	—	—	—
	Ductal carcinoma in situ	Breast-conserving surgery (consider mastectomy if extensive or multifocal) and radiation therapy	—	—	—	—
Stages I and II: early-stage invasive		Breast-conserving surgery⁷ and radiation therapy⁸	SLN biopsy^9–11 or ALN dissection*	Chemotherapy†	Chemotherapy and endocrine therapy¹²	Chemotherapy and trastuzumab (Herceptin)^13,14
Stage III: locally advanced
	Noninflammatory	Induction chemo-therapy,¹⁵ followed by breast-conserving surgery‡^16–19 and radiation therapy	ALN dissection or SLN biopsy²⁰	Induction chemotherapy^15,21	Induction chemotherapy and post-operative endocrine therapy	Induction chemotherapy and postoperative trastuzumab
	Inflammatory	Induction chemotherapy, followed by mastectomy and radiation therapy	ALN dissection	Induction chemotherapy^15,21	Induction chemotherapy and post-operative endocrine therapy	Induction chemotherapy and postoperative trastuzumab
Stage IV: metastatic
	Initial or recurrent	Address patient’s treatment goals; radiation therapy or bisphosphonates for bone pain	—	Chemotherapy	Endocrine therapy with or without chemotherapy	Trastuzumab with or without chemotherapy
Recurrent
	Local after breast- conserving surgery	Mastectomy	ALN dissection§	Chemotherapy\|\|	Chemotherapy and endocrine therapy¶	Chemotherapy and trastuzumab
	Local after mastectomy	Wide excision	ALN dissection**
	Local inoperable	Induction chemotherapy	ALN dissection

Stage 0: In Situ

Lobular carcinoma in situ is an incidental microscopic finding of abnormal tissue growth in the lobules of the breast. It does not progress to, but increases the risk of, subsequent invasive breast cancer in either breast by approximately 7 percent over 10 years.²³ Local and systemic therapies are not indicated, but affected women should undergo rigorous breast cancer surveillance. The National Comprehensive Cancer Network recommends annual mammography and clinical breast examination every six months.²⁴ Patients should be offered information about chemoprevention with selective estrogen receptor modulators (SERMs), such as tamoxifen.⁶

Conversely, ductal carcinoma in situ (DCIS) can progress to invasive breast cancer. Breast-conserving surgery followed by radiation therapy is standard treatment for DCIS; however, mastectomy may be recommended for extensive or multifocal disease. Pathologic lymph node evaluation is not usually performed because nodal metastasis is rare. There is conflicting evidence regarding endocrine therapy with tamoxifen in women with DCIS.^25,26 Given the risks of tamoxifen and the low risk of recurrence of DCIS, routine use of tamoxifen in women with DCIS is not recommended.

Stages I and II: Early-Stage Invasive

SURGERY

Modified radical mastectomy has traditionally been the standard of care for early-stage invasive breast cancers. However, breast-conserving surgery has been favored more recently. This therapy involves removing the tumor without removing excess healthy breast tissue, with the outcome of a breast that is more aesthetically acceptable to the patient than the outcome from radical mastectomy. Radiation therapy following breast-conserving surgery decreases local recurrence and improves cancer-specific survival rates to rates equivalent to those with mastectomy.⁸ Breast-conserving surgery has the highest success rate in women with early-stage breast cancer, but it is not recommended for women at high risk of local recurrence.²⁷ Table 3 lists qualifications for consideration of breast-conserving surgery.⁷ Women with early-stage breast cancer may opt for mastectomy because of contraindications to radiation therapy or because of personal preference.

Localized tumor*

Negative surgical margins

No diffuse (inflammatory) or multicentric cancer

No malignant-appearing mammographic abnormality after surgery

No previous radiation therapy to the breast or chest wall (precludes further radiation therapy)

EVALUATION OF REGIONAL LYMPH NODES

The status of axillary lymph nodes (ALNs) determines the need for radiation therapy and adjuvant systemic therapy. ALN dissection at the time of surgery was standard care until the 1990s, but often resulted in pain, numbness, swelling, and decreased mobility in the affected arm. In patients with clinically negative nodes, a negative intraoperative sentinel lymph node (SLN) biopsy precludes the need for ALN dissection.

SLN biopsy reduces arm symptoms compared with ALN dissection.^9–11 SLN biopsy has a sensitivity of 95 to 100 percent, a false-negative rate of 5.5 percent,²⁸ and a negative predictive value of 98 percent.^29,30 A prospective analysis provides evidence that patients with early-stage breast cancer who have a negative SLN have improved disease-free and overall survival compared with patients who have a negative ALN dissection.³¹ This is most likely because of more accurate axillary staging in patients from the SLN group. ALN dissection is indicated for all women with palpable lymph nodes or a positive SLN.³²

Radiation Therapy

Typically, whole-breast radiation is performed following breast-conserving surgery to treat subclinical disease. A review of 10 randomized controlled trials (RCTs) comparing breast-conserving surgery with and without radiation showed that radiation in addition to surgery significantly reduced the five-year local recurrence rate, regardless of the use of adjuvant systemic therapy (7 versus 26 percent; number needed to treat [NNT] = 5), and appeared to decrease the 15-year breast cancer mortality risk (30.5 versus 35.9 percent; NNT = 18).⁸ According to a systematic review of three RCTs, the sequencing of chemotherapy and radiation therapy does not appear to have a major effect on survival or recurrence as long as radiation is commenced within seven months of surgery.³³ Radiation therapy is expensive and time-consuming, and shorter therapies can be appealing. Five-year results appear favorable in studies evaluating brachytherapy and compressed schedules of radiation; however, long-term data are lacking.^34,35

ADJUVANT SYSTEMIC THERAPIES

Most women with early-stage breast cancer receive adjuvant systemic therapies. Chemotherapy, endocrine therapy, and tissue-targeted therapies enhance definitive local therapy (surgery, radiation therapy, or both), substantially decreasing cancer recurrence and disease-specific death. Node-positive disease benefits most from systemic therapy. Table 4 outlines the medications typically used with these therapies.^24,36–46

Therapy type	Medication	Typical course of treatment
Chemotherapy²⁴	Anthracyclines
	Doxorubicin (Adriamycin)	IV every 14 to 21 days for four to six cycles; used in combination with a taxane (docetaxel [Taxotere] or paclitaxel [Taxol]), cyclophosphamide, and/or fluorouracil
	Epirubicin (Ellence)	IV day 1 or days 1 and 8, every 21 to 28 days for three to eight cycles; used in combination with cyclophosphamide or fluorouracil
	Taxanes
	Docetaxel	IV every 21 days for three to four cycles; used in combination with doxorubicin, epirubicin, cyclophosphamide, and/or fluorouracil
	Paclitaxel	IV every seven to 21 days for four to 12 cycles; used in combination with doxorubicin and cyclophosphamide
Endocrine	Aromatase inhibitors
	Anastrozole (Arimidex)	Oral tablet daily for five years; used alone or in sequence with tamoxifen^36,37
	Exemestane (Aromasin)	Oral tablet daily for at least two to five years; used alone or in sequence with tamoxifen^38,39
	Letrozole (Femara)	Oral tablet daily for two to five years; used alone or in sequence with tamoxifen^40,41
	Gonadotropin-releasing hormone agonist
	Goserelin (Zoladex)	Subcutaneously every one to three months for two years^42,43
	Selective estrogen receptor modulators
	Tamoxifen	Oral tablet daily for two to five years; used alone or in sequence with an aromatase inhibitor³⁶
Tissue-targeted	Monoclonal antibody
Tissue-targeted	Trastuzumab (Herceptin)	IV with first dose of chemotherapy regimen and then every one or three weeks to complete one year^44–46

Chemotherapy. Chemotherapy is the standard of care for women with node-positive cancer or with a tumor larger than 1 cm. Hormone receptor–negative disease derives more benefit from chemotherapy than hormone receptor–positive disease.⁴⁷ Factors such as age and comorbidities also influence the decision to use chemotherapy. Most studies suggest a small benefit for treatment with anthracyclines or taxanes over other chemotherapies,¹² particularly in women with tumors overexpressing ERBB2.⁴⁸ A systematic review of 12 studies demonstrated disease-free and overall survival advantages when using a taxane-containing regimen for premenopausal and post-menopausal women with early-stage breast cancer.⁴⁹ A meta-analysis of 13 RCTs determined that adding a taxane to an anthracycline-based regimen improved disease-free survival (five-year risk reduction = 5 percent) and overall survival (five-year risk reduction = 3 percent).⁵⁰

Endocrine Therapy. Endocrine therapies, such as SERMs, aromatase inhibitors, and gonadotropin-releasing hormone agonists, prevent estrogen production or block estrogen, thereby preventing stimulation of an estrogen-sensitive tumor. In premenopausal women, ovarian ablation or oophorectomy may be considered. Endocrine therapy is not effective against cancers that are lacking hormone receptors. Five years of treatment with tamoxifen reduces the breast cancer death rate (absolute risk reduction = 9.2 percent over 15 years; NNT = 11).¹²

Aromatase inhibitors should be considered in all post-menopausal women with hormone receptor–positive breast cancer. They block the conversion of androgens to estrogen in postmenopausal women. Trials consistently show that aromatase inhibitors reduce the risk of relapse of early-stage breast cancer both in direct comparison with and after completion of tamoxifen.^36,38,51,52 A large RCT showed that treatment with letrozole (Femara) following five years of treatment with tamoxifen decreased the incidence of contralateral breast cancer and improved disease-specific survival in patients who were node positive.⁵³ None of these studies showed improvement in overall survival compared with tamoxifen.^{36,38,51–53} Many women tolerate aromatase inhibitors better than tamoxifen.⁴⁰ Aromatase inhibitors are not indicated for premenopausal women.

Tissue-Targeted Therapy. Approximately 20 to 30 percent of early-stage breast cancers overexpress ERBB2.^44,45 These cancers generally have a worse prognosis. A humanized anti-ERBB2 monoclonal antibody, trastuzumab (Herceptin), improves disease-specific and overall survival when added to anthracyclines and paclitaxel (Taxol) chemotherapy in women with node-positive and high-risk, node-negative breast cancers overexpressing ERBB2.^13,14 The combination of trastuzumab and anthracyclines must be used with caution, however, because cardiac toxicity will develop in 2 to 3 percent of patients over two years of treatment.

Stage III: Locally Advanced

Locally advanced breast cancer (LABC) includes tumors larger than 5 cm, extensive regional lymph node involvement, direct involvement of underlying chest wall or skin, tumors considered inoperable but without distant metastases, and inflammatory breast cancer. Induction chemotherapy followed by local therapy (surgery, radiation therapy, or both) is becoming the standard of care. Five-year survival can be achieved in 55 percent of patients presenting with noninflammatory LABC.⁵⁴ The most important prognostic factors are response to induction chemotherapy and lymph node status.

INDUCTION SYSTEMIC THERAPIES

Induction Chemotherapy. Patients with LABC who achieve an excellent response to induction chemotherapy have outcomes similar to those in patients with early-stage disease.¹⁵ Preoperative chemotherapy downsizes the local tumor, facilitating breast-conserving surgery. With induction chemotherapy, 75 percent of patients have a reduction in tumor size greater than 50 percent.²¹ Preoperative chemotherapy increases breast conservation rates, but also increases the rate of local recurrence. However, local recurrence is not increased as long as surgery remains part of the treatment, even after complete tumor regression.²¹ Mastectomy may be the best option in the case of poor response to induction chemotherapy, or based on patient preference.

Induction Endocrine Therapy. Induction endocrine therapy (tamoxifen with or without aromatase inhibitors) is less effective than chemotherapy and may be most appropriate for older patients not willing to accept chemotherapy-related toxicity. Patients with hormone receptor–positive LABC are generally best served by combined induction chemotherapy and endocrine therapy following surgery.

Induction Tissue-Targeted Therapy. There are few solid data about the use of tissue-targeted therapy (trastuzumab) as induction therapy. Because of the benefit of adding trastuzumab to adjuvant chemotherapy in early-stage breast cancer, 12 months of postoperative trastuzumab is recommended for patients who have LABC with ERBB2 overexpression.

LOCAL THERAPY

Tumor response to induction chemotherapy determines local therapy, such as surgery (mastectomy or breast-conserving surgery), radiation therapy, or both. Data from uncontrolled prospective studies indicate that 50 to 90 percent of women with LABC can be successfully treated with breast-conserving surgery after induction chemotherapy, although no RCTs have been completed on this topic.^17,18 In patients whose cancer does not respond to induction chemotherapy, surgery is appropriate only if a complete resection can be attained. Extensive lymph node involvement (i.e., more than three axillary, internal mammary, or clavicular nodes), residual pathologic tumors larger than 2 cm, multifocal residual disease, and lymphovascular invasion increase the rate of local recurrence following breast-conserving surgery after induction chemotherapy and, therefore, warrant mastectomy.¹⁹

Most patients presenting with LABC have clinically positive lymph nodes and require ALN dissection. In patients with LABC and clinically negative nodes, SLN biopsy following induction chemotherapy has been shown to have a similar detection rate as in early-stage breast cancer without induction chemotherapy.²⁰ Even in patients who have clinically complete remission with induction chemotherapy, radiation therapy following surgery decreases the local recurrence rate.⁵⁵

INFLAMMATORY BREAST CANCER

Inflammatory breast cancer is relatively rare and is characterized by diffuse erythema and edema (peau d’orange), no palpable mass, early age at diagnosis, poor nuclear grade, negative hormone–receptor status, and poor survival outcome. Management is similar to that of noninflammatory LABC; however, because of the aggressiveness of inflammatory breast cancer, SLN biopsy and breast-conserving surgery are not recommended. After induction chemotherapy, patients are usually treated with mastectomy followed by chest wall radiation.

Stage IV: Metastatic

Some women, including those who relapse after treatment of early-stage breast cancer or LABC, will present with metastatic disease. Five-year survival is attained in only 23.3 percent of these patients³; therefore, it is important to understand the patient’s treatment goals.

Radiation therapy or bisphosphonates, along with endocrine therapy or chemotherapy, can palliate pain from bony complications. Systemic treatment depends on hormone receptor status, rate of disease progression, and patient willingness to tolerate adverse effects of treatment. Endocrine therapy is generally better tolerated than chemotherapy. In women with rapidly progressive disease, it may be better to treat with chemotherapy, which is more likely to induce a timely response. Trastuzumab with or without chemotherapy is a reasonable choice for the initial treatment of meta-static disease overexpressing ERBB2. Trastuzumab can be used in combination with endocrine therapy for susceptible tumors.

Recurrent Breast Cancer

Following initial treatment, breast cancer can recur locally, regionally (nodes), or at distant metastatic sites. Approximately 11 and 20 percent of patients treated with adjuvant therapies develop locoregional recurrence within five and 10 years, respectively.⁵⁶ Locoregional recurrence is an indicator of an aggressive tumor, and early recurrence carries a poor prognosis.⁵⁷ Recurrence without clinical metastases has a five-year survival of approximately 40 percent.²² Mastectomy is indicated for in-breast tumor recurrence after breast-conserving surgery, followed by repeat axillary staging. SLN biopsy is thought to be acceptable if lymph nodes were not removed initially and if there is no clinical evidence of lymph node involvement, although RCTs are lacking.^58,59

Wide local excision of the recurrent tumor is recommended for an isolated chest wall recurrence. If unresectable, induction chemotherapy may facilitate successful local treatment. If there is evidence of axillary involvement without distant metastases, axillary evaluation is recommended. Radiation therapy is recommended only in the setting of inoperable or incompletely resected recurrent disease. The benefit of adjuvant systemic chemotherapy for patients with recurrence is uncertain,⁶⁰ and a large randomized trial is underway.⁶¹ Until results are available, chemotherapy is recommended for recurrent cancer; endocrine therapy is recommend for hormone receptor–positive cancer; and trastuzumab is recommended for tumors overexpressing ERBB2.

New and Upcoming Treatment Options

With the development of gene sequencing, targeted therapies, and molecular diagnostics, breast cancer treatment has the potential to become directed toward each patient’s specific tumor characteristics. Estrogen and progesterone receptors are already used to predict a tumor’s response to hormone therapy (an example of a prediction of adjuvant therapy benefit is available at http://www.bmj.com/cgi/content-nw/full/337/jul11_2/a540/FIG3), and ERBB2 expression predicts response to treatment with trastuzumab.

Urokinase plasminogen activator and plasminogen activator inhibitor-1 are new prognostic markers. Newly diagnosed breast cancer with low concentrations of these markers has such a low risk of recurrence—especially in patients with hormone receptor–positive tumors receiving adjuvant endocrine therapy—that chemotherapy may provide only minimal benefits.⁶²

The Oncotype DX assay measures expression of 21 genes and predicts which patients with node-negative disease are less likely to benefit from chemotherapy.⁶³ Biomarkers are also being developed to predict severe drug-related toxicity.⁶³

Centers for Disease Control and Prevention. Breast cancer statistics. http://www.cdc.gov/cancer/breast/statistics. Accessed March 26, 2010.

American Cancer Society. Cancer facts and figures 2009. Atlanta, Ga.: American Cancer Society; 2009.http://www.cancer.org/downloads/STT/500809web.pdf. Accessed March 26, 2010.

Horner MJ, Ries LAG, Krapcho M, et al., eds. SEER cancer statistics review, 1975-2006. Bethesda, Md.: National Cancer Institute; 2009.http://seer.cancer.gov/csr/1975_2006. Accessed March 26, 2010.

American Cancer Society. Overview: breast cancer. Survival rates for breast cancer. http://www.cancer.org/docroot/CRI/content/CRI_2_2_3X_Survival_rates_for_breast_cancer_5.asp. Accessed April 8, 2010.

Breast. In: Greene FL, Page DL, Fleming ID, et al., eds. AJCC Cancer Staging Manual. 6th ed. New York, NYSpringer-Verlag;2002:223–240.

U.S. Preventive Services Task Force. Chemoprevention of breast cancer: recommendations and rationale. Rockville, Md.: Agency for Healthcare Research and Quality; July 2002. http://www.ahrq.gov/clinic/3rduspstf/breastchemo/breastchemorr.htm. Accessed February 8, 2010.

Morrow M, Strom EA, Bassett LW American College of Radiology; American College of Surgeons; Society of Surgical Oncology; College of American Pathology. Standard for breast conservation therapy in the management of invasive breast carcinoma.. CA Cancer J Clin. 2002;52(5):277-300.

Clarke M, Collins R, Darby S Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials.. Lancet. 2005;366(9503):2087-2106.

Mansel RE, Fallowfield L, Kissin M. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial [published correction appears in. J Natl Cancer Inst. 2006;98(12):876-609.

Helms G, Kühn T, Moser L, Remmel E, Kreienberg R. Shoulder-arm morbidity in patients with sentinel node biopsy and complete axillary dissection—data from a prospective randomised trial.. Eur J Surg Oncol. 2009;35(7):696-701.

Del Bianco P, Zavagno G, Burelli P. Morbidity comparison of sentinel lymph node biopsy versus conventional axillary lymph node dissection for breast cancer patients: results of the sentinella-GIVOM Italian randomised clinical trial.. Eur J Surg Oncol. 2008;34(5):508-513.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.. Lancet. 2005;365(9472):1687-1717.

Smith I, Procter M, Gelber RD HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.. Lancet. 2007;369(9555):29-36.

Romond EH, Perez EA, Bryant J. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.. N Engl J Med. 2005;353(16):1673-1684.

Buchholz TA, Hill BS, Tucker SL. Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy.. Cancer J. 2001;7(5):413-420.

Mieog JS, van der Hage JA, van de Velde CJ. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev. 2007;(2):CD005002.

Beriwal S, Schwartz GF, Komarnicky L, Garcia-Young JA. Breast-conserving therapy after neoadjuvant chemotherapy: long-term results.. Breast J. 2006;12(2):159-164.

Aguiar Bujanda D, Bohn Sarmiento U, Cabrera Suárez MA, Pavcovich Ruiz M, Limeres González MA, Aguiar Morales J. Epirubicin, cyclophosphamide and weekly paclitaxel as neoadjuvant chemotherapy for stage II and III breast cancer.. J Cancer Res Clin Oncol. 2006;132(5):332-338.

Chen AM, Meric-Bernstam F, Hunt KK. Breast conservation after neoadjuvant chemotherapy.. Cancer. 2005;103(4):689-695.

Classe JM, Bordes V, Campion L. Sentinel lymph node biopsy after neoadjuvant chemotherapy for advanced breast cancer: results of Ganglion Sentinelle et Chimiotherapie Neoadjuvante, a French prospective multicentric study.. J Clin Oncol. 2009;27(5):726-732.

Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis.. J Natl Cancer Inst. 2005;97(3):188-194.

Dunst J. Prognosis and treatment of locally recurrent breast cancer.. Breast Cancer Res. 2001;3(suppl 1):A23.

Chuba PJ, Hamre MR, Yap J. Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data.. J Clin Oncol. 2005;23(24):5534-5541.

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer. Version 1. 2010. October 2009.http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (subscription required). Accessed February 8, 2010.

Fisher B, Dignam J, Wolmark N. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial.. Lancet. 1999;353(9169):1993-2000.

Houghton J, George WD, Cuzick J UK Coordinating Committee on Cancer Research; Ductal Carcinoma in situ Working Party; DCIS trialists in the UK, Australia, and New Zealand. 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.. Lancet. 2003;362(9378):95-102.

Kurtz JM, Jacquemier J, Amalric R. Risk factors for breast recurrence in premenopausal and postmenopausal patients with ductal cancers treated by conservation therapy.. Cancer. 1990;65(8):1867-1878.

Ann Surg Oncol. 2009;16(2):266-275:Ann Surg Oncol.

van der Ploeg IM, Nieweg OE, van Rijk MC, Valdes Olmos RA, Kroon BB. Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: a systematic review and meta-analysis of the literature.. Eur J Surg Oncol. 2008;34(12):1277-1284.

Salem A. Sentinel lymph node biopsy in breast cancer: a comprehensive literature review.. J Surg Educ. 2009;66(5):267-275.

Langer I, Guller U, Hsu-Schmitz SF. Sentinal lymph node biopsy is associated with improved survival compared to level I & II axillary lymph node dissection in node negative breast cancer patients.. Eur J Surg Oncol. 2009;35(8):805-813.

Lyman GH, Giuliano AE, Somerfield MR. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer.. J Clin Oncol. 2005;23(30):7703-7720.

Hickey BE, Francis D, Lehman MH. Sequencing of chemotherapy and radiation therapy for early breast cancer. Cochrane Database Syst Rev. 2006;(4):CD005212.

Vicini FA, Baglan KL, Kestin LL. Accelerated treatment of breast cancer.. J Clin Oncol. 2001;19(7):1993-2001.

Whelan T, MacKenzie R, Julian J. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer.. J Natl Cancer Inst. 2002;94(15):1143-1150.

Baum M, Buzdar A, Cuzick J. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of post-menopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.. Cancer. 2003;98(9):1802-1810.

Arimidex (anastrozole) tablets [prescribing information]. Wilmington, Del.: AstraZeneca Pharmaceuticals LP; 2009. http://www1.astrazeneca-us.com/pi/arimidex.pdf. Accessed April 2, 2010.

Coombes RC, Hall E, Gibson LJ Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer [published corrections appear in N Engl J Med. 2004;351(23):2461, and N Engl J Med. 2006;355(16):1746].. N Engl J Med. 2004;350(11):1081-1092.

Aromasin (exemestane) tablets [prescribing information]. New York, NY: Pfizer Inc.; 2008. http://www.pfizer.com/files/products/uspi_aromasin.pdf. Accessed April 2, 2010.

Thürlimann B, Keshaviah A, Coates AS Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer [published correction appears in N Engl J Med. 2006;354(20):2200].. N Engl J Med. 2005;353(26):2747-2757.

Femara (letrozole) tablets [prescribing information]. East Hanover, N.J.: Novartis Pharmaceuticals Corporation; 2010. http://www.femara.com/full-prescribing-information.jsp. Accessed April 2, 2010.

Hackshaw A, Baum M, Fornander T. Long-term effectiveness of adjuvant goserelin in premenopausal women with early breast cancer.. J Natl Cancer Inst. 2009;101(5):341-349.

Drugs.com. Zoladex. http://www.drugs.com/zoladex.html. Accessed April 2, 2010.

Slamon DJ, Godolphin W, Jones LA. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.. Science. 1989;244(4905):707-712.

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.. Science. 1987;235(4785):177-182.

Herceptin (trastuzumab) tablets [prescribing information]. South San Francisco, Calif.: Genentech, Inc.; 2009. http://www.gene.com/gene/products/information/pdf/herceptin-prescribing.pdf. Accessed April 2, 2010.

Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ. 10th St. Gallen conference. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007 [published correction appears in Ann Oncol. 2007;18(11):1917].. Ann Oncol. 2007;18(7):1133-1144.

Pritchard KI, Shepherd LE, O’Malley FP National Cancer Institute of Canada Clinical Trials Group. N Engl J Med. 2006;354(20):2103-2111.

Ferguson T, Wilcken N, Vagg R, Ghersi D, Nowak AK. Taxanes for adjuvant treatment of early breast cancer. Cochrane Database Syst Rev. 2007;(4):CD004421.

De Laurentiis M, Cancello G, D’Agostino D. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials.. J Clin Oncol. 2008;26(1):44-53.

Coates AS, Keshaviah A, Thürlimann B. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.. J Clin Oncol. 2007;25(5):486-492.

Goss PE, Ingle JN, Martino S. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.. N Engl J Med. 2003;349(19):1793-1802.

Goss PE, Ingle JN, Martino S. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17.. J Natl Cancer Inst. 2005;97(17):1262-1271.

Giordano SH. Update on locally advanced breast cancer.. Oncologist. 2003;8(6):521-530.

Ring A, Webb A, Ashley S. Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer?. J Clin Oncol. 2003;21(24):4540-4545.

Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy.. J Natl Cancer Inst. 2008;100(16):1179-1183.

van Tienhoven G, Voogd AC, Peterse JL. Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group.. Eur J Cancer. 1999;35(1):32-38.

Axelsson CK, Jonsson PE. Sentinel lymph node biopsy in operations for recurrent breast cancer.. Eur J Surg Oncol. 2008;34(6):626-630.

Karam A, Stempel M, Cody HS, Port ER. Reoperative sentinel lymph node biopsy after previous mastectomy.. J Am Coll Surg. 2008;207(4):543-548.

Rauschecker H, Clarke M, Gatzemeier W, Recht A. Systemic therapy for treating locoregional recurrence in women with breast cancer. Cochrane Database Syst Rev. 2001;(4):CD002195.

Wapnir IL, Aebi S, Gelber S. Progress on BIG 1-02/IBCSG 27-02/NSABP B-37, a prospective randomized trial evaluating chemotherapy after local therapy for isolated locoregional recurrences of breast cancer.. Ann Surg Oncol. 2008;15(11):3227-3231.

Jänicke F, Prechtl A, Thomssen C German N0 Study Group. Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1.. J Natl Cancer Inst. 2001;93(12):913-920.

Duffy MJ, Crown J. A personalized approach to cancer treatment: how biomarkers can help.. Clin Chem. 2008;54(11):1770-1779.