Treatment Options for Early-Stage Breast Cancer: Information for Primary Care Providers

Introduction

This article is for clinicians, including internists, family practitioners, nurse practitioners, physician assistants, and gynecologists, whose patients have received a first-time breast cancer diagnosis. It is intended to assist you in counseling these patients as they make treatment decisions. The primary source for this article is Breast Cancer Treatment (PDQ), from the National Cancer Institute (NCI). Other literature sources are cited when appropriate.^[1] The information is formatted in bullets to make it easier to read and remember.

This article is intended to be a companion to a booklet designed for patients with early-stage breast cancer, entitled "Surgery Options for Women With Early-Stage Breast Cancer," by the NCI, which is available in English and Spanish and is free (up to 20 copies at a time) from the NCI (1-800-4-CANCER), and also available online from the National Research Center (NRC) for Women & Families (http://center4research.org/breast-cancer-booklet.html) or on the NCI Web site (http://cancer.gov/cancertopics/breast-cancer-surgery-choices).

The NRC for Women & Families promotes the health and safety of women, children, and families, by using objective, research-based information to encourage more effective treatments, programs, and policies. The Center achieves its mission by gathering and analyzing medical and scientific information and translating it into user-friendly materials that are made widely available to health professionals, consumers, the media, and policy makers.

Approach to the Patient With Early-Stage Breast Cancer

Breast cancer is the most common type of cancer in women. The increased use of screening mammography has resulted in earlier detection, and women diagnosed in these early stages have more treatment options than ever before, as well as a greater chance of survival. Patients' first conversations about their diagnosis are often with their primary care providers, gynecologists, or other nononcologists. This article is especially intended for them.

Important points include:

• Case definition: Early-stage breast cancer is categorized as clinical stage I or II or IIIA. Ductal carcinoma in situ (DCIS), which is stage 0, is also often included;
  
  
• Approximately 180,000 new cases of invasive breast cancer will be diagnosed in women in the United States this year;
  
  
• Approximately 90% of these cases will be categorized as early-stage breast cancer;
  
  
• Treatment options for early-stage breast cancer are different from those for more advanced disease; and
  
  
• The survival rate is much higher for early-stage breast cancer.^[1]

Staging of Breast Cancer

• Noninvasive breast cancer and precancerous conditions often are called "stage 0" breast cancer;
  
  
• The most prevalent types of stage 0 are DCIS and lobular carcinoma in situ (LCIS);
  
  
• The most prevalent is DCIS, a noninvasive cancer diagnosed in about 60,000 US women every year; and
  
  
• Less likely to be diagnosed is LCIS, which is not cancer and does not usually require any surgery.

Note: This article includes treatment for DCIS but not for LCIS.

Ductal Carcinoma in Situ (DCIS)

• Abnormal cells are confined to the milk ducts and have not spread beyond the ductal epithelium to the surrounding breast tissue, lymph nodes, or any other part of the body;
  
  
• DCIS is also referred to as an "intraductal carcinoma";
  
  
• DCIS is not invasive but has the potential to become invasive; and
  
  
• Treatment for DCIS is very similar to treatment for a stage I (early-stage invasive) cancer.^[1]

Invasive Breast Cancer (Stages I-IV)

The American Joint Committee on Cancer uses a staging classification system that categorizes the primary tumor, regional lymph nodes, and pathologic classification. For this article, we used the simpler, traditional classification system.

Stage I. The primary tumor is 2 cm or less in diameter with no lymphatic spread.

Stage II.

• IIA: No tumor is found in the breast or the tumor less than 2 cm in diameter, and cancer is found in 1-3 axillary lymph nodes; or no tumor is found in the breast or the tumor is 2 cm or less, and cancer is found in internal mammary lymph nodes on sentinel lymph node biopsy (SLNB); or no tumor is found in the breast or tumor is less than 2 cm, has spread to 1-3 axillary lymph nodes, and cancer is found in internal mammary lymph nodes on SLNB; or tumor is larger than 2 cm but less than 5 cm and hasn't spread to the lymph nodes.
  
  
• IIB: The tumor is between 2 cm and 5 cm with spread to 1-3 axillary lymph nodes, and/or cancer is found in internal mammary lymph nodes on SLNB; or the tumor is over 5 cm but does not grow into the chest wall or skin and has not spread to the lymph nodes.

Stage III.

• IIIA: No tumor is found in the breast, but cancer is found in 4-9 axillary lymph nodes or it has enlarged the internal mammary lymph nodes; or the tumor is 5 cm or smaller and has spread to 4-9 axillary lymph nodes, or it has enlarged the internal mammary lymph nodes; or the tumor is larger than 5 cm but does not grow into the chest wall or skin. It has spread to 1-9 axillary lymph nodes or to internal mammary nodes.
  
  
• IIIB: Tumor has grown into the chest wall or skin and has not spread to the lymph nodes; or it has spread to 1-3 axillary lymph nodes, and/or cancer is found in internal mammary lymph nodes on SLNB; or it has spread to 4-9 axillary lymph nodes, or it has enlarged the internal mammary lymph nodes. Inflammatory breast cancer is classified as stage IIIB unless it has spread to distant lymph nodes or organs.
  
  
• IIIC: The tumor is any size or can't be found, and tumor has spread to 10 or more axillary lymph nodes; or tumor has spread to the lymph nodes under or above the clavicle; or tumor involves axillary lymph nodes and has enlarged the internal mammary lymph nodes; or tumor involves 4 or more axillary lymph nodes, and cancer is found in internal mammary lymph nodes on SLNB.

Stage IV. Stage IV involves metastatic spread of breast cancer to distant areas of the body. Inflammatory breast cancer is classified as stage IV if it has spread to distant lymph nodes or organs.^[1,2]

Breast Cancer Survival Rate by Stage

• Predictions of survival are based on staging of breast cancer;
  
  
• Accuracy of cancer staging is critical and can determine treatment options;
  
  
• Choices between breast-conserving surgery (BCS) or mastectomy, and decisions in regard to chemotherapy and hormone therapy, are guided by cancer stage; and
  
  
• Patients should be encouraged to seek second opinions from surgeons, oncologists, and pathologists (Table).

Table. Breast Cancer Survival Rate by Stage^[2]

Stage	5-Year Relative Survival Rate
0	100%
I	100%
IIA	92%
IIB	81%
IIIA	67%
IIIB	54%
IV	20%

Survival rates are not yet available for stage IIIC breast cancer because this stage was defined only a few years ago.

Treatment of Early-Stage Breast Cancer

Overview of Local/Regional Treatment Options for Early-Stage Breast Cancer (Stages I, II, and IIIA)

• Two options for surgery
  
  
  • BCS, eg, lumpectomy, followed by radiation
    
    
  • Modified radical mastectomy or simple mastectomy (with or without breast reconstruction)
    
    
• NCI treatment protocols and long-term research indicate that survival is equivalent for either surgical option
  
  
• BCS can be less physically and emotionally traumatic (Figures 1-4).

Figure 1. Treatment algorithm for patients with early-stage breast cancer: ductal carcinoma in situ (DCIS) patients.

Figure 2. Treatment algorithm for patients with early-stage breast cancer: premenopausal breast cancer patients stages I, II, and III.

(Click to enlarge)

Figure 3. Treatment algorithm for patients with early-stage breast cancer: postmenopausal breast cancer patients stages I, II, and III; hormone receptor-positive.

Figure 4. Treatment algorithm for patients with early-stage breast cancer: postmenopausal breast cancer patients stages I, II, and III; hormone receptor-negative.

Treatment Options for DCIS

• The treatment options for DCIS listed by the NCI are:
  
  
  • BCS plus radiation with or without tamoxifen
    
    
  • Total mastectomy with or without tamoxifen
    
    
  • BCS without radiation
    
    
• BCS is recommended for most patients with DCIS or early-stage invasive cancers
  
  
• The National Surgical Adjuvant Breast and Bowel Project B-17 (NSABP B-17) study, funded by NCI, compared lumpectomy with lumpectomy plus radiation in 818 women with DCIS, and found that radiation significantly reduced the occurrence of ipsilateral cancers
  
  

• At the 12-year follow-up, radiation reduced the occurrence of invasive cancer from 17% to 8% and recurrent DCIS from 15% to 8%
  
  
• Comedo necrosis was the only significant predictor for recurrence
  
  
• A similar study by the European Organization for Research and Treatment of Cancer (EORTC) with a slightly shorter follow-up found similar benefits for radiation for invasive breast cancer (13% lowered to 8%) or recurrence of DCIS (14% reduced to 7%).
  
  

• The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 study randomized more than 1800 women undergoing BCS and radiation for DCIS to adjuvant tamoxifen vs placebo for 5 years
  
  
• NSABP B-24 found that tamoxifen significantly reduced recurrence in the ipsilateral breast and contralateral breast cancer in DCIS patients who undergo BCS
  
  

• At 5 years, only 2% of the BCS women in the tamoxifen group had developed ipsilateral invasive breast cancer, compared with 4% without tamoxifen
  
  
• At 5 years, tamoxifen reduced the incidence of contralateral breast neoplasms (invasive and noninvasive) from 2.3% per year to 1.8% per year^[3]
  
  

• Research is under way to determine which DCIS patients are at the lowest risk for recurrence so that radiation is not necessary
  
  
• A larger randomized clinical trial comparing BCS and tamoxifen with or without radiation is also under way.

Many Women Eligible for Breast-Conserving Treatment Don't Receive It

• At least 3 out of 4 women diagnosed with breast cancer are candidates for breast-conserving treatment (BCT), which consists of BCS and radiation;
  
  
• Only 49% of women with stage I or DCIS and 29% of women with stage II undergo BCT^[4];
  
  
• BCT is much more expensive than mastectomy in the short term because of the cost of radiation^[5];
  
  
• Low-income women, less-educated women, and uninsured women are less likely to undergo BCT^[6,7]; and
  
  
• Younger women are more likely to undergo BCT, and women over 80 years are also more likely to undergo BCT.^[7,8]

Factors Unrelated to Diagnosis That Influence Women's Decisions When Choosing Between BCT and Mastectomy

• Women who are more fearful of a recurrence tend to choose mastectomy;
  
  
• Women who are more fearful of dying of breast cancer tend to choose mastectomy;
  
  
• Women who greatly fear radiation tend to choose mastectomy;
  
  
• Decision-making process between the clinician and the patient influences decision; many mastectomy patients say that their physicians recommended mastectomy;
  
  
• High cost of radiation may deter lumpectomy; and
  
  
• Distance from a radiation facility and lack of convenient access deter lumpectomy.^[9]

Absolute Contraindications to BCT for Women With Early-Stage Breast Cancer

• Two or more primary tumors in separate quadrants of the breast (multicentric disease), or persistence of positive margins after a reasonable surgical attempt usually indicates that a mastectomy is the preferred treatment;
  
  
• Women with a history of prior therapeutic irradiation are not ideal candidates because radiation is often an adjunct to BCS, and women should not undergo breast radiation again; and
  
  
• Women who are pregnant are not ideal candidates for BCS because radiation is often an adjunct and radiation is contraindicated in pregnancy. In some cases, pregnant women can undergo BCS and delay radiation until after the baby is born.^[10]

Relative Contraindications to BCT for Women With Early-Stage Breast Cancer

• Women with a history of collagen vascular diseases, such as lupus or scleroderma, tend to tolerate irradiation poorly and may do better with mastectomy
  
  
• The presence of multiple tumors in the same quadrant (multifocal disease) may be a contraindication
  
  
• Cosmetic considerations are part of the decision-making process
  
  
  • Removal of a large tumor from a small breast may not provide a suitable aesthetic outcome to some patients
    
    
  • Breast implants for previous augmentation may interfere with lumpectomy or radiation.^[11,12]

Assessing Lymph Node Status

• Traditionally, ipsilateral axillary lymph node dissection is performed to determine stage and until recently had been the standard technique for women receiving either mastectomy or BCT;
  
  
• Six percent to 30% of women develop lymphedema as a result of this procedure^[13];
  
  
• SLNB is a newer, less-invasive approach to staging breast cancer that is being performed by a growing number of surgeons; and
  
  
• SLNB is associated with less morbidity than a complete axillary lymph node dissection.

Use of SLNB in Assessing Lymph Node Status

• SLNB is sometimes used for axillary staging in invasive breast cancer;
  
  
• A radioactive and/or blue dye is injected into the area around the tumor that travels along the lymphatic channels that drain the tumor;
  
  
• Tumor-corresponding axillary lymph node(s) are identified, removed, and immediately analyzed by a pathologist;
  
  
• If "sentinel" lymph nodes are negative, further dissection is not needed;
  
  
• If cancer is detected in these sentinel lymph nodes, surgeons then proceed with a complete axillary node dissection for further analysis;
  
  
• Studies have shown a 98% to 100% concordance between SLNB and complete axillary lymph node dissection;
  
  
• Using SLNB and performing axillary node dissection if the sentinel node is positive is a common practice;
  
  
• Compared with axillary lymph node dissection, less research is available on the long-term effectiveness of SLNB; and
  
  
• With SNLB, morbidity of the axillary staging procedure is lower because it is less invasive.^[1]

Adjuvant Therapies

• The choice to recommend adjuvant therapy depends on several predictive factors;
  
  
• These include age of the patient, tumor size, lymph node status, grade of tumor hormone receptor status, and HER2 status; and
  
  
• All of these factors must be carefully weighed when making treatment decisions.

External Beam Radiation Therapy

• Radiation therapy is recommended following BCS for stage I, II, or IIIa breast cancer;
  
  
• Following radiation therapy, 15-year survival rates increase and 20-year cancer recurrence rates decrease;
  
  
• Standard external beam irradiation usually requires 5-8 weeks of treatment administered up to 5 days per week; and
  
  
• Some regions of the country do not have many radiation centers, and the long commutes for patients may make it impossible for them to choose lumpectomy with radiation.^[1]

Radiation side effects.

• Common side effects of radiation therapy include fatigue, skin irritation, and a heavy or firm feeling in the affected breast;
  
  
• These symptoms tend to improve over weeks or months;
  
  
• Lymphedema can also result from irradiation of the axillary structures, although this is more likely to occur as a result of lymph node dissection;
  
  
• The development of lymphedema has an impact on long-term morbidity;
  
  
• The potential risk for radiation-induced cardiac mortality has been virtually eliminated by advances in radiation therapy technique; and
  
  
• Rarely, brachial plexus injury or second malignancies are caused by radiation therapy.^[1]

Radiation advances.

• Clinical trials are under way for accelerated partial breast irradiation (APBI)
  
  
• Advantages of this technique include a quicker completion time (usually days vs weeks), less exposure to radiation, and better patient tolerability
  
  
• Several ABPI techniques are being evaluated
  
  
  • These include brachytherapy (which delivers radiation close to the site) via catheters or intracavitary balloons, or
    
    
  • Intraoperative radiation therapy (which is administered once during BCS)
    
    
• With the exception of intraoperative radiation, each of these methods is invasive and more expensive than standard external beam irradiation
  
  
• Patient selection criteria are still being developed
  
  
• Many insurance companies are not yet covering APBI, so there can be added expenses to patients
  
  
• These partial breast irradiation therapies are considered experimental.^[14]

Hormone Therapy

Tamoxifen hormone therapy and aromatase inhibitors.

• Hormone therapy is effective for women with estrogen receptor-positive breast cancer and DCIS;
  
  
• Tamoxifen is the most common, most studied type of hormonal therapy;
  
  
• Long-term research on aromatase inhibitors is not yet completed;
  
  
• Short-term research on postmenopausal women has indicated that aromatase inhibitors alone, or after 2-5 years of tamoxifen, results in a significant but modest increase in disease-free survival compared with tamoxifen alone;
  
  
• There is no difference between tamoxifen and aromatase inhibitors for overall survival for postmenopausal women;
  
  
• Because aromatase inhibitors do not block the production of estrogen from the ovaries, they are not usually used in premenopausal women; and
  
  
• Studies are under way, but there are no available data on aromatase inhibitors for premenopausal women or for treatment of DCIS.^[1]

Tamoxifen.

• Tamoxifen improves survival rates from 65% to 74% over 15 years and reduces recurrence from 45% to 33% over 15 years in premenopausal and postmenopausal women with estrogen receptor-positive tumors^[15];
  
  
• The combination of tamoxifen and chemotherapy has shown benefit in premenopausal and postmenopausal women with hormone receptor-positive breast cancer;
  
  
• In postmenopausal women, 3-year disease-free survival was increased to 84% from 67% by a combination of chemotherapy (doxorubicin and cyclophosphamide) plus tamoxifen^[1];
  
  
• Optimal length of tamoxifen therapy, regardless of node status, appears to be 5 years^[16]; 1-2 years is less effective;
  
  
• Tamoxifen therapy should not be continued for more than 5 years^[16]; and
  
  
• In women with DCIS who undergo BCT, tamoxifen reduces breast cancer events and the incidence of contralateral breast neoplasms.^[1]

Aromatase inhibitors.

• Aromatase inhibitors are approved as a first-line treatment of postmenopausal women with estrogen receptor-positive breast cancer of all stages;
  
  
• The 3 current aromatase inhibitor treatment options are 5 years of aromatase inhibitor therapy, 2-3 years of tamoxifen followed by 2-3 years of aromatase inhibitor therapy, or 5 years of tamoxifen followed by 5 years of aromatase inhibitor therapy for postmenopausal women;
  
  
• When tamoxifen alone was compared with an aromatase inhibitor (exemestane, letrozole, or anastrozole), and with tamoxifen followed by each aromatase inhibitor, disease-free survival was higher for the aromatase inhibitor or for 2-3 years of tamoxifen followed by an aromatase inhibitor.^[1]

Side effects of tamoxifen and aromatase inhibitors.

• Tamoxifen has several serious risks: increased incidence of endometrial cancer and venous thromboembolism, especially for women over 50 years of age^[1,17];
  
  
• Tamoxifen therapy can be associated with side effects that are similar to those experienced in menopause, including hot flashes and irregular periods^[17];
  
  
• Aromatase inhibitors increase the risk for osteoporosis compared with tamoxifen or placebo;
  
  
• Exemestane also increases the risk for visual disturbances, arthralgia, and diarrhea;
  
  
• Letrozole increases the risk for cardiac events;
  
  
• Experiencing these unpleasant side effects can adversely affect a patient's quality of life;
  
  
• Close monitoring of women for symptoms, such as abnormal uterine bleeding, is warranted; and
  
  
• Women taking tamoxifen should receive annual pelvic exams.^[1]

Ovarian Ablation

• In premenopausal women, typically tamoxifen is used either combined with or instead of suppression therapy (surgically or with luteinizing hormone-releasing hormone agonists); and
  
  
• Ovarian ablation with surgery or radiation therapy reduces the risk for recurrence of breast cancer.

Biologic Therapy

• About 20% of breast cancers make an excessive amount of the protein HER2, which is found on their cell surface;
  
  
• These tumors tend to grow faster and recur more often than other tumors;
  
  
• Trastuzumab (Herceptin, Genentech) is a biologic therapy that has become the standard of care for patients with HER2-positive breast cancer; and
  
  
• Two NCI-sponsored clinical trials showed that patients who received trastuzumab in combination with chemotherapy had a 52% decrease in the risk for breast cancer recurrence compared with patients who received chemotherapy alone.^[1]

Chemotherapy

• The decision to use chemotherapy should be informed by the guidance of a medical oncologist;
  
  
• The choice of agents and specific regimen used is based on the size and lymph node status of the tumor, and the performance status and other comorbid conditions of the patient;
  
  
• Combination chemotherapy has been shown to reduce mortality from breast cancer in all women who receive it regardless of nodal status or whether they receive tamoxifen;
  
  
• For women 50-69 years of age, combination chemotherapy showed a small but statistically significant improvement in 10-year survival rates from 67% to 69% when nodes were negative and from 46% to 49% for those with node-positive disease^[18];
  
  
• More research is needed to determine whether combination chemotherapy also slightly increases survival rates for women who are younger than 50 years;
  
  
• Duration of treatment was at least 6 months with no additional benefit shown for treatments longer than 6 months; and
  
  
• The combination of tamoxifen with chemotherapy has shown benefit in women with estrogen receptor-positive breast cancer (see section on tamoxifen).^[1]

Chemotherapy side effects.

• Side effects from chemotherapy are specific to the particular agents chosen;
  
  
• Common side effects include fatigue; gastrointestinal upset, such as nausea and vomiting; alopecia (hair loss); and cytopenias (decrease in blood cell counts); and
  
  
• These unpleasant side effects can affect a patient's quality of life, but many can be controlled or alleviated.