Breast Cancer Treatment & Management

Surgery is considered primary treatment for breast cancer, as many patients with early-stage disease are cured with surgery alone. The goals of breast cancer surgery include complete resection of the primary tumor with negative margins to reduce the risk of local recurrences, and pathologic staging of the tumor and axillary lymph nodes for providing necessary prognostic information. Several different types of operations are available for the treatment of breast cancer.

Adjuvant treatment for breast cancer involves radiation therapy and a variety of chemotherapeutic and biologic agents.

Surgical treatment of invasive breast cancer may consist of lumpectomy or total mastectomy.In breast cancer patients who have clinically negative nodes, surgery typically includes sentinel lymph node dissection for staging the axilla. Go to Surgical Treatment of Breast Cancer for more information on these topics. In addition to surgery, the use of radiation therapy, chemotherapy, or both may be indicated.

Breast-conserving radiation therapy

The purpose of radiation therapy following breast-conserving surgery is to eradicate local subclinical residual disease while reducing local recurrence rates by approximately 75%. Based on results from several randomized controlled studies, radiation to the intact breast is considered standard of care, even in the lowest-risk disease with the most favorable prognostic features.

There are 2 general approaches used to deliver radiation therapy: conventional external beam radiotherapy (EBRT) and partial-breast irradiation (PBI). Whole-breast radiotherapy (WBRT) consists of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is often followed by a boost dose specifically directed to the area in the breast where the tumor was removed.

Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin desquamation. Late toxicity (lasting 6 mo or longer following treatment) may include persistent breast edema, pain, fibrosis, and skin hyperpigmentation. Rare side effects include rib fractures, pulmonary fibrosis, cardiac disease (left breast treatment), and secondary malignancies such as radiation-induced sarcoma (0.5%).

Partial-breast irradiation is employed in early stage breast cancer following breast-conserving surgery as a way of delivering larger fraction sizes while maintaining a low risk of late effects. Several techniques that can deliver this therapy include interstitial brachytherapy (multiple catheters placed through the breast) and intracavitary brachytherapy (a balloon catheter inserted into the lumpectomy site [ie, MammoSite]).

Treatment is typically for 5 days, twice daily. These techniques have shown low local recurrence rates comparable to EBRT in several nonrandomized studies.

The American Society of Breast Surgeons (ASBrS) recommends the following selection criteria when considering patients for treatment with accelerated partial breast irradiation:

• Age 45 years and older
• Invasive ductal carcinoma or DCIS
• Total tumor size (invasive and DCIS) 3 cm or smaller
• Negative microscopic surgical margins of excision
• Axillary lymph node/sentinel lymph node negative

Potential complications of partial-breast irradiation are catheter placement, followed by removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, or disease recurrence.

Postmastectomy radiation therapy

Clinical practice guidelines developed by ASCO along with several prospective, randomized clinical trials recommend postmastectomy radiation therapy be performed using the following criteria:

• Positive postmastectomy margins
• Primary tumors larger than 5 cm
• Involvement of 4 or more lymph nodes

Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 4500-5000 cGy to the axillary and supraclavicular regions. For patients who undergo axillary lymph node dissection and are found to have no lymph node involvement, axillary radiation therapy is not recommended.

Meta-analyses have shown postmastectomy radiation therapy combined with regional nodal radiation therapy significantly decreases the rate of local relapse and breast cancer mortality. Currently, the benefit of radiation therapy for women with 1-3 positive axillary lymph nodes is uncertain, and studies are ongoing.

Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the reduction in mortality rate. Adjuvant treatment of breast cancer is designed to treat micrometastatic disease, or breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis. Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality. Go to Adjuvant Therapy for Breast Cancer for more information on this topic.

Ductal carcinoma in situ

Currently, the standard treatment of DCIS is surgical resection with or without radiation. Adjuvant radiation and hormonal therapies are often reserved for younger women, patients undergoing lumpectomy, or comedo subtype.

Approximately 30% of women with DCIS in the US are treated with mastectomy with or without reconstruction, 30% with conservative surgery alone, and 40% with conservative surgery followed by whole-breast radiation therapy. Axillary or sentinel lymph node dissection is not routinely recommended for patients with DCIS. Studies have identified metastatic disease to the axillary nodes in 10% of patients.

In DCIS, whole-breast radiotherapy is delivered over 5-6 weeks after surgery, reducing the local recurrence rate by approximately 60%. Roughly 50% of local recurrences are invasive breast cancer. Meta-analyses of randomized controlled trials comparing radiation therapy versus observation after surgery for DCIS have demonstrated slightly higher rates of contralateral breast cancer after radiation therapy (3.85% vs 2.5%). Studies comparing accelerated partial breast radiation given over 5 days to standard whole-breast radiotherapy are currently under way.

Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patients treated with breast-conserving surgery and radiation for DCIS. Currently, a clinical trial evaluating the role of the aromatase inhibitor anastrozole as adjuvant therapy in DCIS has met its accrual and results are anticipated.

Lobular carcinoma in situ

The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial prospectively studied the efficacy of tamoxifen in the prevention of breast cancer and included patients with LCIS.^[8] The researchers found a 55% risk reduction in women treated with tamoxifen.

Overall, treatment options include observation and close follow-up care with or without tamoxifen, and bilateral mastectomy with or without reconstruction. No evidence exists of therapeutic benefit from local excision, axillary dissection, radiotherapy, or chemotherapy. The presence of LCIS in the breast of a woman with ductal or lobular cancer does not require further immediate surgery on the opposite breast. Mirror biopsy of the contralateral breast, once advocated in the treatment of LCIS, is mainly of historic interest.

Originally, the reason for grouping LABC and IBC was the recognition that both diseases had little or no chance of cure from local therapy alone, and they were considered inoperable for that reason. The definition of locally advanced disease has broadened to include patients who are technically operable but who have large primary tumors (>5 cm).

It is important to recognize, however, that the reasons for using neoadjuvant therapy are different in women who have large primary tumors, in which the goal is to increase the possibility of breast-conserving surgery, than in those who have disease that meets the original criteria of LABC or IBC, for whom the administration of systemic treatment is essential to make definitive local treatment possible with the intent of cure.

Because the prognosis for women with T3N0 (stage IIB) and T3N1 (stage IIIA) breast cancer is better overall than it is for those with classically defined LABC (IIIB, IIIC) or IBC (IIIB, T4d), it is important to know the relative proportions of patients in each category when results of a clinical trial are reported. Not only may one expect better disease-free and overall survival for stage IIB and IIIA patients, but also the likelihood of achieving a pathologic complete response (pCR) from neoadjuvant treatment, a well-recognized surrogate for long-term outcome, is inversely related to tumor size.

It is also important to recognize that staging criteria in the sixth edition of the AJCC Cancer Staging Handbook differs from its predecessors in ways that are relevant to the patient groups discussed here: women with T3 tumors were previously considered to have stage III disease and are so reported in the older literature; women with resectable tumors who are found to have 4 or more involved axillary lymph nodes after initial surgery, formerly called stage II, are currently grouped as IIIA.

The revised staging system is better for defining prognostic subgroups, but the practical relevance of grouping together all patients who typically receive "up front" chemotherapy remains, as their treatment outcomes are usually reported as a function of the particular neoadjuvant program employed.

Inflammatory breast cancer

IBC is a clinical diagnosis that implies presentation with the cardinal signs of inflammation (calor, rubor, and tumor) involving the breast, although the calor (warmth) may be subtle and the tumor (mass) may not be appreciated as something discrete. Indeed, even when a localized mass is apparent in IBC, the true extent of the disease (as shown by performing skin biopsies from the surrounding, normal-appearing skin) is usually greater than apparent on physical examination. It was originally described as having an erysipeloid border, but only a minority of cases have this component of a raised edge.

In Western countries, the frequency of IBC is low, between 1% and 2% of all breast cancers, but it is much higher in some parts of the world, such as northern Africa, for reasons that are not known. IBC tends to occur at a younger age than LABC. Pathologically, it was originally associated with the classic finding of involvement of subdermal lymphatics, although this finding is not in itself diagnostic of IBC (it may occur with LABC as a secondary phenomenon).

This disease is more likely to stain negatively by IHC for ER and PR, somewhat more likely to be positive for HER2 overexpression, and both angiogenesis and lymphangiogenesis appear to be increased by microvessel density or RNA-based gene expression arrays. Within IBC, however, may be found the same molecular subtypes of breast cancer as originally described for non-inflammatory breast cancer.

Locally advanced breast cancer

LABC is more common in the US than is IBC, and, by the definition used here, may account for 10-15% of patients (this drops to about 5% if one uses the stricter definition of inoperable). Epidemiologically, LABC is associated with lower socioeconomic class and, probably for that reason, with black race in the US.

LABC encompasses both relatively indolent neglected tumors and those that have grown rapidly as a result of their inherent biology. It is as heterogeneous as invasive breast cancer in general, and, in most case series, LABC has a better long-term outcome than IBC, even when only inoperable cases are considered.

Evaluation of lymph nodes and response

Patients with LABC or IBC with clinically positive nodes should undergo a core biopsy before initiating chemotherapy. Those with clinically negative nodes may undergo sentinel node biopsy before they start treatment, or sentinel node determination may be delayed until after treatment is completed.

Theoretically, it should be preferable to perform sentinel node sampling up front, because chemotherapy might eradicate preexistent disease in the sentinel node and result in a false negative, and/or altered lymphatic drainage in large tumors might affect accuracy of the procedure. However, data from the NSABP B-27 neoadjuvant trial suggest that the false-negative rate for sentinel node biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative rate for patients undergoing initial resection.^[9]

In general, the best single test to evaluate the status of measurable tumor is ultrasonography, preferably done by the same operator to avoid interobserver variability. The mass often appears larger on physical examination than it does on sonogram, which can more effectively discriminate hypoechoic masses from surrounding stroma and/or hematoma. In IBC, MRI may be an important adjunct to response assessment. The role of PET scanning in the routine assessment of response remains to be determined.

No current imaging technique appears to be highly accurate for the prediction of complete pathologic response. Thus, the purpose of regular size assessment is to exclude continuation of therapy in a patient with a growing tumor (seen in < 5% with the initial treatment) and to suggest when maximal response of grossly evident disease has been achieved, as this may be the optimal time to proceed to resection.

Marked advancements are being made in the treatment of early stage breast cancer, but many women still develop recurrence and metastasis. In addition, 5-10% of breast cancer patients have metastatic disease at presentation. Although treatments for metastatic breast cancer continue to improve, there remains no cure once distant metastases develop.

Furthermore, although occasional patients with metastatic breast cancer benefit from surgical resection for an isolated recurrence and many require radiation therapy for palliation at a specific site (or definitive treatment of brain metastasis), in general, recurrent or metastatic breast cancer must be approached systemically such that the therapeutic effect reaches all sites of disease. There are 2 main interventions: hormone therapy and chemotherapy. Go to Adjuvant Therapy for Breast Cancer for more information on these topics.

As modern systemic chemotherapy has become more effective, some patients with intact primary tumors and metastasis can have long-term stable distant disease or even no evidence of residual metastatic disease following treatment. Recently, interest has increased in the role of surgical intervention for the intact primary tumor for these metastatic breast cancer patients. Several single-institution cohort and retrospective studies have examined this question, concluding that surgical resection of the intact primary tumor may provide a survival advantage.

It is still unknown whether a selection bias affects the findings of a survival advantage in favor of surgery, and no prospective, randomized control trial has ever been performed to address this question. However, the dogma to never operate in the setting of metastatic disease has certainly been dispelled in favor of critical evaluation of whether surgically achieved local control can lead to improved survival as a part of multimodal treatment.

Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene (Evista), are approved for reduction of breast cancer risk in high-risk women. Two NSABP trials (NSABP P1 and P2) showed that tamoxifen reduced the risk of DCIS and invasive breast cancer by 30-50%. In the NSABP P2 prevention trial, raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer but was 30% less effective than tamoxifen in reducing the risk of DCIS.

ACOG has updated its practice guidelines regarding pharmacologic intervention (eg, tamoxifen, raloxifene, aromatase inhibition) for breast cancer risk reduction.^[10] Some of the highlights of the expert panel's literature review are as follows:

Tamoxifen use for 5 years reduces risk of breast cancer for at least 10 years in premenopausal women, particularly ER-positive invasive tumors. Women 50 years or younger have few adverse effects with tamoxifen, and vascular/vasomotor adverse effects do not persist post treatment.

Tamoxifen and raloxifene are equally effective in reducing risk of ER-positive breast cancer in postmenopausal women. Raloxifene is associated with lower rates of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen. Evidence does not exist on whether either agent decreases mortality from breast cancer.

Recommendations include the following:

• For women with increased risk for breast cancer, offer tamoxifen (20 mg/d for 5 y) to reduce the risk of invasive ER-positive breast cancer
• In postmenopausal women, raloxifene (60 mg/d for 5 y) may also be considered
• Aromatase inhibitors (eg, anastrozole, exemestane, letrozole), fenretinide, or other SERMs are not recommended for use outside of a clinical trial

Follow-up guidelines

There is no consensus among oncologists as to the appropriate and optimal follow-up for long-term breast cancer survivors. The majority of relapses, both local and distant, occur within the first 3 years, especially in higher risk and ER-negative patients. The 2007 ASCO guidelines do not support the use of tumor biomarkers, including CEA, CA15.3, and CA27.29, for monitoring patients for recurrence after primary breast cancer therapy.

Table 6, below, lists the NCCN’s recommendations for breast cancer patients in the adjuvant setting.

Table 6. Follow-up Recommendations for Breast Cancer Survivors per NCCN Guidelines (Open Table in a new window)

Postsurgical imaging

Women who have had surgery for breast cancer may still require breast cancer screening with mammography. If a woman had a total mastectomy, then the other breast requires yearly follow-up, because she is still at higher risk of developing cancer in the remaining breast. If she had subcutaneous mastectomy, partial mastectomy, or lumpectomy, then that breast itself requires follow-up mammography.

The first mammogram is best performed 6 months postoperatively to provide a baseline for the new postoperative and radiation changes. Thereafter, mammography may be performed every 6-12 months for screening and follow-up. Go to Postsurgical Breast Imaging for more information on this topic.

Monitoring of metastatic disease

Recommendations for monitoring disease response in the metastatic setting vary. In general, monthly evaluations consisting of a history and physical examination to evaluate progression of disease and toxicities are reasonable.

Tumor markers, such as CEA, CA15.3, and CA27.29, can be used in conjunction with diagnostic imaging, history, and physical examination for monitoring while on active therapy. CA15.3 and CA27.29 levels correlate with the course of disease in 60-70% of patients, whereas CEA levels correlate in 40% of patients.

However, data are insufficient to recommend the use of CEA, CA15.3, or CA27.29 alone for monitoring response to treatment. Caution should be used when interpreting rising CEA, CA15.3, or CA27.29 levels during the first 4-6 weeks of a new therapy, as spurious early rises may occur.

Standardized guidelines for imaging are not yet established and should be tailored to each patient. In general, CT scanning (chest, abdomen, and pelvis), MRI, bone scanning, or PET/CT scanning are performed when symptoms change or tumor markers rise.

Circulating tumor cells are cells present in the blood that possess antigenic or genetic characteristics similar to a primary tumor type. The FDA has recently approved the CellSearch System (Veridex, Raritan, NJ) for the detection of circulating tumor cells in patients with metastatic breast cancer. This system captures circulating tumor cells using an immunomagnetic process with an epithelial cell adhesion molecule coated with magnetic beads and cytokeratin antibodies.

A circulating tumor cell is identified when it is cytokeratin- and DAPI-positive but CD45-negative. Studies done by Cristofanilli using the CellSearch System have shown a prognostic utility and predictive use for circulating tumor cells in metastatic breast cancer patients.^[11] Circulating tumor cell–positive patients (>5 CTCs/7.5 mL blood) were shown to have a worse progression-free survival (17%) and overall survival than the circulating tumor cell–negative patients (36%).

The presence of more than 5 circulating tumor cells before hormonal or chemotherapy treatment and following the first cycle of treatment also predict a worse outcome. However, studies to date have used small sample sizes, and no data have shown that use of circulating tumor cell testing affects overall survival or improves on quality of life.

Per ASCO guidelines, the use of circulating tumor cell testing in breast cancer is not recommended for the diagnosis of breast cancer, nor should test results influence treatment decisions. The Southwest Oncology Group (SWOG) is conducting a large, prospective trial to address the clinical use of circulating tumor cells in breast cancer.