Breast cancer (BC) is the most common form of malignancy and the second leading cause of cancer mortality in women.1 It is estimated that 1 in 8 women will develop BC in their lifetime.1,2 Approximately 210,000 women were diagnosed with BC in 2010.1
The incidence of BC is on a downward trend in recent years.2 Some theorize that this can be partially attributed to the decline in postmenopausal hormone replacement therapy use since the Women's Health Initiative data were released in July 2002.3
The two general classifications of BC are invasive and noninvasive. Ductal carcinoma in situ (DCIS) is a stage 0 noninvasive BC with an excellent prognosis. Invasive ductal carcinoma and invasive lobular carcinoma (ILC) are the two most common types of invasive BC (IBC). Cancers containing both invasive ductal and lobular features are called invasive mammary carcinoma. Types of IBC associated with better outcomes include tubular, cribriform, secretory, adenoid cystic, and mucinous (colloid).4 IBC with micropapillary, inflammatory, medullary, squamous, or metaplastic features are associated with a more aggressive clinical course and poorer prognosis.4
High histologic grade and angiolymphatic invasion predict worse prognosis.5 The World Health Organization endorses criteria established by Bloom and Richardson as the most widely accepted histologic grading system.4 The Bloom Richardson scale is divided into three tumor grades: the lowest, well differentiated grade I; intermediate, moderately differentiated grade II; and the highest, poorly differentiated grade III. Histologic grade is predictive of disease-free survival (DFS) and 5-year treatment failure.4
Axillary lymph node involvement is predictive of prognosis and is one of the best indicators for overall survival (OS). Women with four or more positive nodes are associated with up to a 71% treatment failure rate at 10 years.4,5 Involvement of any regional nodes at diagnosis including supraclavicular, internal mammary, or subpectoral (Rotter's) nodes is predictive of worse prognosis and higher treatment failure rates.5 BC stage is determined by tumor size, extent of nodal involvement, and presence or absence of metastatic disease. The nationally accepted BC staging guidelines are available through the American Joint Committee on Cancer and were last updated in 2010.
Hormone receptor status is an important indicator of cancer behavior; tumors positive for estrogen receptors (ER) and progesterone receptors (PR) have a better prognosis than those with negative receptors.6 The Her-2/neu receptor is a type of epidermal growth factor tyrosine kinase receptor that participates in the control of epithelial cell growth and differentiation.6 Overexpression of Her-2/neu occurs in 20% to 30% of all BCs and can be identified by immunohistochemical (IHC) staining and/or fluorescence in situ hybridization.6 Her-2/neu positive tumors are more likely to be poorly differentiated and lymph node positive, and independently predict for a poorer prognosis.
Triple-negative IBCs (ER/PR/Her-2/neu negative) show aggressive clinical behavior, but can have a favorable prognosis if a pathologic complete response is achieved through the use of neoadjuvant (preoperative) chemotherapy regimens.7 Carriers of the genetic predisposition for BC termed BRCA1 are more likely to develop a triple negative IBC.7 A new class of antineoplastic agents aimed at inhibiting the polyadenosine diphosphate-ribose polymerase (PARP) enzymes, which are involved in the repair of damaged DNA, are among some of the most promising research advances for triple negative and BRCA1 positive IBC.7
Local treatment control
Local treatment decisions are based on surgical and radiation recommendations. In the past, surgery was usually the first step in BC treatment. More recently, neoadjuvant therapy is more widely accepted and utilized. In cases of known lymph node involvement, Her-2/neu positive features, triple negative cancers, inflammatory, or locally advanced disease presentation, neoadjuvant chemotherapy is offered to improve operability for locally advanced disease and the chance of breast conservation for larger tumors. Pathologic complete response, defined as the complete resolution of all invasive cancer, is an excellent prognostic indicator for disease-free survival and OS.
Surgery remains the first treatment for tumors with a size that favors a good cosmetic outcome, and without lymph node involvement. Mastectomy offers no survival advantage over lumpectomy followed by radiation therapy. However, breast conservation is not recommended if there is extensive tumor involvement, inflammatory presentation, or multifocal disease. Patients need to know that mastectomy will not impact OS and in some cases, radiation therapy will still be necessary for adequate local control. The National Comprehensive Cancer Network (NCCN) considers margins clear if there is greater than or equal to 1 mm of normal tissue between the tumor and the surgical margin, though many institutions favor obtaining margins greater than or equal to 2 mm.8 Sentinel lymph node dissection (SLND) with axillary node dissection for those with positive sentinel lymph nodes (SLNs) has long been the surgical standard of care. Recently, SLND without axillary dissection for patients with one or two positive sentinel nodes has been shown to be adequate evaluation of the axillary nodes if tumors are less than 5 cm; there is no obvious clinical node involvement, preoperative systemic treatment was not given, and adequate systemic therapy and radiation to the entire breast and/or chest wall is planned.9 Axillary lymph node dissection remains the standard for bulky axillary disease, tumors greater than 5 cm, after preoperative treatment, and if partial breast radiation or no radiation is planned.
Radiation therapy is typically given after surgical and chemotherapy regimens have been completed, but prior to initiating hormonal therapy. Standard whole breast radiation therapy consists of treatment 5 days per week for 5 weeks followed by a 1-week boost to the lumpectomy site. Accelerated partial breast irradiation (APBI) can be administered by several different methods and occurs after surgery (but before chemotherapy) once surgical margins are confirmed to be clear. The APBI treatments can last 5 to 14 days depending on the delivery modality. Patients must meet strict criteria to be considered a candidate for APBI. Long-term outcomes are still unknown, although early data are promising.
There are occasional exceptions to the standard of care for radiation therapy after breast conservation. For women 70 years of age and older with ER positive tumors, negative lymph nodes, and clear surgical margins, radiation therapy may not be recommended. 31 All patients with breast conserving surgery should have a radiation oncology consultation for the most appropriate radiation therapy recommendations.
Chemotherapy for IBC reduces the chance of systemic recurrence and may be given as neoadjuvant or adjuvant (postoperative) treatment. Staging workup with computerized tomography scan of the chest, abdomen and pelvis, and a bone scan should be done before initiating chemotherapy when there is locally advanced disease, lymph node involvement, or clinical symptoms suggesting metastatic disease (see Preferred adjuvant or neoadjuvant chemotherapy regimens).8
IBC does not always require chemotherapy. NCCN's acceptance of a 21 gene RT-PCR (reverse transcriptase-polymerase chain reaction) assay in the management of early stage I or II, ER positive, Her-2 negative, and node negative BC greater than 0.5 cm has been a breakthrough in breast oncology care.8 Oncotype DX is a 21-gene recurrence score (RS) assay that is performed on the excised breast tumor to help determine the risk of recurrence and the benefit of chemotherapy, assuming that 5 years of hormonal treatment is planned.10,11 This approach moves the prognostic assessment from a clinical one based on stage and a few tumor characteristics to a more biologic assessment of malignant potential based on assessment of characteristics unique to the tumor. Oncotype DX RS of greater than or equal to 31 carries a strong recommendation for systemic chemotherapy as these women appear to receive the greatest improvement in DFS with chemotherapy.8,10,11 An Oncotype DX RS of less than 18 predicts that chemotherapy is unlikely to improve DFS.8,10,11 Women with Oncotype DX RS between 19 and 30 should carefully discuss with their medical oncologist the potential benefit from systemic chemotherapy versus risks.8,10,11 Ongoing prospective clinical trials may better define the role of chemotherapy for patients with mid-range Oncotype DX RS. Current predictions from Oncotype DX testing are based on retrospective (although robust and multiple) analyses and therefore have inherent limitations.
BCs are considered to be ER and PR positive if 10% or more of the cells stain positive by IHC assay. The more strongly positive, the greater the benefit from endocrine therapy. ER positive tumors respond to hormonal therapy in about 50% to 60% of cases.6 If the tumor is also PR positive then the response rate (RR) rises from 70% to 80%.6 ER and PR negative tumors have less than 10% RR to hormonal therapy.6 There are two classes of hormonal agents for BC: selective ER modulators (SERMs) and aromatase inhibitors (AIs). The latter are appropriate only for women who are postmenopausal.
Tamoxifen, a SERM, is the only endocrine treatment for DCIS and for premenopausal women with ER positive IBC.12,13 Tamoxifen 20 mg daily for 5 years provides a 50% reduction in ipsilateral recurrence and contralateral BC and a 30% risk reduction for systemic recurrence of IBC.12 Women must use a barrier form of contraception if they are premenopausal and able to conceive as tamoxifen is teratogenic. Women with IBC who go into menopause while on tamoxifen can be switched to an AI either half-way through their tamoxifen course or once they have completed 5 years. Node positive postmenopausal women who received 5 years of the AI letrozole (Femara) after 5 years of tamoxifen showed an OS absolute benefit of 7.5%; those with node negative disease had a 4.8% benefit.12 Postmenopausal women with hormone receptor positive IBC receive more benefit from an AI than tamoxifen in the adjuvant setting. Letrozole, exemestane (Aromasin), and anastrozole (Arimidex) are the three available AIs tested against tamoxifen. Each showed about a 3% DFS advantage (but no OS advantage) over tamoxifen.12 AIs can also be used as neoadjuvant therapy in hormone receptor positive IBC in postmenopausal women. This can be particularly useful in women with hormone receptor positive IBC who are not good candidates for more aggressive chemotherapy due to comorbid conditions or age-related factors.
Metastatic BC (MBC)
Stage IV, or MBC is considered an incurable cancer. MBC becomes a chronic health condition in which many women can maintain an acceptable quality of life while undergoing treatment with intermittent adjustments when progression is documented. Fortunately, BC research has led to many treatment options that are available to women with MBC to help prolong their lives (see Chemotherapy regimens for MBC).8 Many of these can be used as monotherapy or in combination with other drugs to optimize response if appropriate. Patients with hormone receptor positive BC but without extensive visceral metastases should be treated with hormonal therapies until refractory to this approach, at which time chemotherapy should be initiated.
Recent discoveries and U.S. FDA actions that have impacted MBC treatment include new fulvestrant dosage guidelines, approval of eribulin mesylate for metastatic disease, withdrawal of approval of bevacizumab and approval of denosumab (Xgeva) for bone metastases.
Fulvestrant (Faslodex) is an ER antagonist given as an intramuscular injection that is used in ER positive MBC in postmenopausal women. There is improved progression-free survival when fulvestrant 500 mg is used versus the previous 250 mg dose regimen with no increase in toxicity.14 The study dosing regimen for fulvestrant 500 mg was given at days 0, 14, and 28 followed by every 28-day dosing thereafter.14 However, a dose adjustment is recommended for patients with moderate hepatic impairment.
The FDA approved eribulin mesylate (Halaven) in November 2010 for women with heavily pretreated MBC as it showed a statistically significant improvement in OS of a median of 2.5 months when compared to a treatment of the physician's choice.15 The most common adverse reactions associated with eribulin mesylate occurring 25% or more were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, constipation, and nausea.15,16 Eribulin is administered via I.V. infusion over 2 to 4 minutes on day 1 and 8 of a 21-day cycle.15,16
Bevacizumab (Avastin) is a monoclonal antibody targeting vascular endothelial growth factor receptor. Its approval in combination with taxane chemotherapy for first-line treatment of MBC was withdrawn by the FDA in December 2010 when additional studies showed no significant OS benefit and increased grade 3 to 5 toxicities.17,18 Appeal of this decision is expected and NCCN has not yet removed bevacizumab from its MBC management recommendations.
In December 2010, Denosumab (Xgeva) gained FDA approval as it was found to be superior to zoledronic acid (Zometa) in reducing skeletal-related events related to bone metastases.19 Denosumab is given subcutaneously and unlike zoledronic acid does not require renal monitoring.19 The adverse reaction profiles were otherwise fairly comparable, although there is slightly more risk of hypocalcemia with denosumab.19
Follow-up and survivorship
Once women have completed their individualized course of active treatment for their BC, close follow-up with an emphasis on wellness and survivorship is necessary. The first year after diagnosis, women should have a mammogram on the affected breast 6 months after the last breast conservation surgery, then again 6 months later. The timing of imaging on the affected breast should be coordinated with the contralateral annual mammogram at either 6-month follow-up. Because BC survivors are at increased risk of developing a second BC, digital breast imaging which has better sensitivity for detecting a new mass or calcifications is preferred over film-screen mammograms. Breast magnetic resonance imaging should be performed annually on those who are genetically predisposed for BC (BRCA1 or BRCA2 carriers). Clinical breast exams should occur every 3 to 6 months and monthly self-breast exams are encouraged. Women are at a consistent risk of relapse over the first 10 years after treatment.5
Women should be encouraged to participate in a regular exercise regimen and to lose weight if overweight per body mass index. In the Nurses' Health Study cohort, women with BC who were moderately active, described as at least 3 hours a week of exercise, had a 50% reduced risk of recurrence and BC death over inactive women.4 Women who exercise regularly, 5 or more days a week, show an improved overall prognosis if they are diagnosed with BC.4
Smoking cessation and consuming fewer than three alcoholic drinks per week are strongly encouraged. Women with a history of BC increase their risk of recurrence and BC death by 1.3- to 1.5-fold when regularly consuming 3 to 4 alcoholic drinks per week.20 This association is most evident in postmenopausal and overweight women with a history of BC.20
Patients should report new or palpable breast concerns, unusual neurologic symptoms, persistent pain, or unexplained respiratory symptoms. There are no recommended serum tumor markers that should be followed routinely for BC survivors.
Normal 25-hydroxy vitamin D levels above 30 ng/dL should be maintained through the use of over-the-counter supplements or monitored prescription replacement.21,22 Calcium should be obtained through food sources as calcium supplements have recently been linked with a higher incidence of cardiovascular events.23 Bone density should be monitored every 2 to 3 years for women on AIs. Low-dose daily aspirin, if not contraindicated by the patient's health history, can be considered as it seems to be helpful in preventing metastatic disease in survivors.24
Reducing risk factors for primary BC
Women with a history of lobular carcinoma in situ (LCIS), atypical ductal hyperplasia, atypical lobular hyperplasia, or atypical papillomas are at a three to five times greater risk of BC in their lifetime.4,25 Known BRCA1 or BRCA2 genetic mutations place women at 60% to 80% risk of BC.4 The Gail Risk Assessment model found at http://www.cancer.gov/bcrisktool/ can be used to estimate a woman's risk of developing BC in her lifetime if she is 35 years of age or older and without a history of LCIS or BC.
Extended hormonal exposure associated with earlier menstruation, later menopause, or use of combined hormone replacement therapy beyond the average age of menopause places women at increased risk for BC. The Nurse's Health Initiative study did not show a statistically significant increased risk of IBC associated with estrogen replacement therapy until after 15 years of use.26 This increased risk of IBC was associated primarily with ER and PR positive BC.26
BC relative risk increases by 7.1% for each 12 oz of beer, 4 oz of wine, or 1.5 oz liquor consumed per day.27
Consuming seven or more alcoholic drinks per week places postmenopausal women at increased risk of hormone receptor positive IBC, particularly ILC.28 New evidence reveals that women who currently smoke increase their risk of BC by 16%, while those who stopped smoking 20 or more years ago still have a 9% increased risk of BC compared to women who never smoked.29 Smoking intensity, number of years' exposure, and initiation of smoking in the teen years further increased the risk of BC.29 Second-hand smoke exposure for 10 or more years in childhood,10 or more years in adult workplace, and 20 or more years at home as an adult places women at a 32% excess risk of BC (about a 4% increase in relative risk) compared to those who had never been exposed.29
Physical activity lowers the incidence of BC and improves prognosis compared to inactive women.4 Moderate exercise 5 or more days a week for 30 minutes a day can reduce the risk of BC by 30% to 40%.30
BC treatment continues to move toward more individualized care. Innumerable clinical trials are ongoing to further advance treatment options and better understand this complex disease process. Patients should be encouraged to participate in clinical trials that are available at their institution. This continued research has allowed many mothers, daughters, wives, and sisters to call themselves survivors.
Preferred adjuvant or neoadjuvant chemotherapy regimens
The original table has been removed. Please visit The NCCN's Guideline for PatientsTM/Breast Cancer at http://www.nccn.com/files/cancer-guidelines/breast/index.html#/72/zoomed.
Chemotherapy regimens for MBC
* Doxorubicin (Adriamycin)
* Pegylated liposomal doxorubicin (Doxil)
* Paclitaxel (Taxol)
* Docetaxel (Taxotere)
* Albumin bound paclitaxel (Abraxane)
* Capecitabine (Xeloda)
* Gemcitabine (Gemzar)
Other microtubule inhibitors
* Vinorelbine (Navelbine)
* Eribulin (Halaven)
* Cyclophosphamide (Cytoxan)
* Cisplatin (Platinol-AQ)
* Ixabepilone (Ixempra)
Hormonal therapy in ER+ MBC
* Letrozole (Femara)
* Exemestane (Aromasin)
* Anastrozole (Arimidex)
* Tamoxifen (Nolvadex)
* Fulvestrant (Faslodex)
* Chemical ovarian suppression with Lupron or oophorectomy in premenopausal women
Her-2 positive MBC
* Paclitaxel + carboplatin + traztuzumab (Herceptin)
* Docetaxel + traztuzumab
* Vinorelbine + traztuzumab
* Capecitabine + traztuzumab
* Lapatinib + capecitabine
Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Breast Cancer V.2.2011. © National Comprehensive Cancer Network, Inc 2011. All rights reserved. Accessed November 9, 2011. To view the most recent and complete version of the guideline, go online to HYPERLINK “http://www.nccn.org/”www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
3. Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen and progestin in healthy menopausal women. JAMA. 2002;288(3):321–333.
4. Barsky S, Gradishar W, Recht A, Urist M.The Breast: Comprehensive Management of Benign and Malignant Disease. Vols 1 and 2. 4th ed. Philadelphia, PA: Saunders Elsevier; 2009.
5. Rondeau V, Mathoulin-Pélissier S, Tanneau L, Sasco AJ, Macgrogan G, Debled M. Separate and combined analysis of successive dependent outcomes after breast conservation surgery: recurrence, metastases, second cancer and death. BMC Cancer
. 2010;10:697. http://www.ncbi.nlm.nih.gov/pubmed
6. Friedenreich CM, Woolcott CG, McTiernan A, et al.Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year long exercise intervention among postmenopausal women. J Clin Oncol. 2010;28(9):1458–1466.
7. Foulkes WD, Smith IE, Reis-Filho JS.Triple negative breast cancer. N Engl J Med. 2010;363(20):1938–1948.
9. Giuliano AE, Hunt KK, Ballman KV, et al.Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305(6):569–575.
10. Lo SS, Mumby PB, Norton J, et al.Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671–1676.
11. Mamounas EP, Tang G, Fisher B, et al.Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol. 2010;28(10):1677–1683.
12. Silva OE, Zurrida S.Breast Cancer: A Practical Guide. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2005.
13. Vogel VG, Costantino JP, Wickerham L, et al.Carcinoma in situ outcomes in national surgical adjuvant breast and bowel project breast cancer chemoprevention trials. J Natl Cancer Inst Monogr. 2010;2010(41):181–186.
14. Di Leo A, Jerusalem G, Petruzelka L, et al.Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594–4600.
15. Cortes J, O'Shaughnessy J, Loesch D, et al.Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomized study. Lancet. 2011 12;377(9769):914–923.
16. Mayden K. D.Eribulin mesylate: unique advancement in metastatic breast cancer. J Adv Pract Oncol. 2011;2:125–128.
19. Stopeck AT, Lipton A, Body JJ, et al.Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28(35):5132–5139.
20. Kwan ML, Kushi LH, Weltzien E, et al.Alcohol consumption and breast cancer recurrence and survival among women with early stage breast cancer: the life after cancer epidemiology study. J Clin Oncol. 2010;28(29):4410–4416.
21. Toner CD, Davis CD, Milner JA.The vitamin D and cancer conundrum: aiming at a moving target. J Am Diet Assoc. 2010;110:1492–1500.
22. Jacobs ET, Thomson CA, Flatt SW, et al.Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study. Am J Clin Nutr. 2011;93(1):108–117.
23. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR.Calcium supplements with or without vitamin D risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.
24. Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE.Aspirin intake and survival after breast cancer. J Clin Oncol. 2010;28(9):1467–1472.
25. Chun J, Pocock B, Joseph K, El-Tamer M, Klein L, Schnabel F.Breast cancer risk factors in younger and older women. Ann Surg Oncol. 2009;16(1):96–99.
26. Chen WY, Manson JE, Hankinson SE, et al.Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med. 2006;166(9):1027–1032.
27. Collaborative Group on Hormonal Factors in Breast Cancer. Alcohol, tobacco, and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 2002;87(11):1234–1245.
28. Li CI, Chlebowski RT, Freiberg M, et al.Alcohol consumption and risk of postmenopausal breast cancer by subtype: the Women's Health Initiative Observational Study. J Natl Cancer Inst. 2010;102(18):1422–1431.
29. Luo J, Margolis KL, Wactowski-Wende J, et al.Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study. BMJ. 2011;342:d1016.
30. Friedenreich CM, Orenstein MR.Physical activity and cancer prevention: etiologic evidence and biologic mechanisms. J Nutr. 2002;132(suppl 11):3456S–3464S.
© 2011 Lippincott Williams & Wilkins, Inc.