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    • Breast Cancer Treatment

    Treating breast cancer involves treatment of the primary tumor with surgery, radiation therapy, or both, as well as systemic treatment with chemotherapy, hormonal therapy, biologic therapy, or any combination thereof.

    The need for any or all of these treatments are based upon the results of tests done at the time of diagnosis.

    Diagnostic tests will reveal the following:

    • Histologic cancer subtype
    • Grade of the cancer
    • Features of the primary tumor (such as ER/PR positivity or over-expression of HER2)
    • Status of the axillary lymph nodes
    • Presence or absence of metastatic disease
    • Patient menopausal status
    • Patient age and co-morbid conditions (reflected in performance status)

    The treatment options that follow are for invasive breast cancer. Patients diagnosed with so-called carcinoma in situ have non-invasive cancer. These patients often undergo surgical resection without axillary lymph node removal. They are monitored closely with physical exams every 6 months for 5 years, then annually, as well as with annual mammograms. Some patients may benefit from tamoxifen therapy for 5 years after surgery for non-invasive breast cancer, to decrease the risk of disease recurrence.

    Common Treatment Options

    SURGERY

    Up until the late 1970s, the surgical procedure of choice for early stage breast cancer was a radical mastectomy. This procedure involves removal of the entire breast, as well as removal of the chest wall muscles. It is a very debilitating surgery but was performed under the assumption that breast cancer spread in a logical fashion: from the breast, to the chest wall, then to distant sites. A more extensive surgery could therefore lead to a better cure rate.

    It has been established for some time that breast cancer more often spreads early, when the primary tumor is still very small. More radical surgeries do not lead to better cure rates. Therefore, the surgical procedure of choice today is a modified radical mastectomy (MRM), which spares the chest wall muscles.

    An alternative to MRM is lumpectomy followed by radiation therapy to the breast. This is also called breast-conserving therapy. It MUST include radiation therapy. Patients are most often potential candidates if they have smaller (less than 4 cm) tumors. Absolute and relative contraindications are listed below. If none of these apply, long-term survival for between MRM and breast-conserving therapy are similar, and the choice is often based on patient preference.

    Absolute contraindications to breast-conserving therapy:

    • Prior radiation therapy to the breast or chest wall
    • Pregnancy (due to the need for radiation therapy)
    • Margins positive for cancer after lumpectomy
    • Relative contraindications to breast-conserving therapy:
    • Active connective tissue disease of the skin, such as scleroderma or lupus
    • Tumors greater than 5 cm
    • Patients less than 35 years old with known breast cancer gene mutations (these patients have an increased risk of cancer in the same breast if MRM is not done)

    All patients undergo sentinel lymph node biopsy at the time of surgery. If the sentinel node is negative for cancer, then no further examination of the axillary lymph nodes is done. If the sentinel node is positive, then removal of at least 10 axillary lymph nodes is performed to quantitate the number that are positive. Patients have a progressively increasing chance of disease recurrence if 1 to 3 nodes versus 4 to 9 nodes versus 10 or more nodes contain breast cancer.

    RADIATION THERAPY

    Radiation therapy is almost always employed following a lumpectomy, as it decreases local recurrences by 30%. This should take the form of whole breast irradiation, with CT-scan-based treatment planning to minimize radiation exposure to the heart and lungs. The timing of radiation therapy after surgery is also very important. Many chemotherapy drugs have a risk of radiation recall (sometimes called radiation flare). If radiation therapy is given before or during treatment with these drugs, the patient may experience redness, pain and swelling at the site of previous radiation therapy. For this reason, radiation therapy is given after completion of cycles of adjuvant chemotherapy. It may be given at the same time as adjuvant trastuzumab or hormonal therapy.

    Patients with positive axillary lymph nodes (stage II disease) may be candidates for post-mastectomy radiation therapy to the chest wall and regional lymph nodes. Overall survival is extended with this treatment approach. The largest benefit is seen in women with 4 or more positive lymph nodes, but radiation therapy should also be strongly considered in women with 1 to 3 positive nodes.

    In addition to use for early-stage breast cancer, radiation therapy is used extensively in the treatment of metastatic breast cancer. It may be used to treat:

    • A large primary tumor, especially a tumor that is causing pain and/or lymphedema
    • Painful bone metastases
    • Central Nervous System (CNS) metastases
    • Lung metastases, especially those causing respiratory problems

    CHEMOTHERAPY

    There are three ways to give chemotherapy for breast cancer. Each is described in detail below.

    • Adjuvant therapy, following surgery
    • Neoadjuvant therapy, before surgery
    • Therapy for metastatic disease

    Adjuvant Chemotherapy Rationale for Stage I and II Breast Cancers:

    • 25 to 30% of stage I patients and up to 90% of stage II patients have undetectable micromestastases at the time of diagnosis, which greatly increases the risk of recurrence after surgery.
    • Positive axillary lymph nodes (stage II) are the most important prognostic factor for recurrence and long-term survival. These patients have a very high risk of recurrence if not given some sort of systemic therapy following surgery.
    • Stages I and II breast cancer are curable with available systemic therapies.

    Adjvuant chemotherapy is the treatment of choice for ALL stage II patients who are ER/PR negative and many who are ER/PR positive, especially those with tumors greater than 1 cm. Adjuvant chemotherapy is also recommended for stage I (lymph node negative) patients, unless the tumor is less than 0.5 cm. Adjuvant therapy may also be deferred in stage I patients who have many co-morbid disease states and are at increased risk for side effects from chemotherapy. Note that in most clinical trials of adjuvant chemotherapy, women over the age of 70 years were excluded. Treatment of these elderly women should be balanced with the risk of toxicity.

    Chemotherapy after surgery improves survival in BOTH pre- and post-menopausal women, although it is more effective in ER/PR negative patients. Multi-drug regimens are the standard, given for 4 to 6 cycles. Regimens that include an anthracycline agent (e.g., doxorubicin or epirubicin) add a small but significant survival advantage, especially in patients who over-express HER2 and in patients with positive axillary lymph nodes. Regimens that include paclitaxel or docetaxel may be preferred for patients who are ER/PR negative.

    There are many choices for adjuvant chemotherapy. The appropriate chemo regimen greatly depends upon that patient’s risk of side effects. For example, if a patient has underlying diabetes with peripheral neuropathy, then a non-paclitaxel containing regimen would be preferred, as paclitaxel also causes peripheral neuropathy. Likewise, patients with known coronary artery disease may opt not to receive doxorubicin due to the risk of heart failure.

    The following is a list of preferred adjuvant chemo regimens:

    • AC (doxorubicin + cyclophosphamide)
    • AC followed by weekly paclitaxel
    • Dose-dense AC followed by paclitaxel (drugs are given every 2 rather than every 3 weeks)
    • (Note: This strategy MUST be given with colony-stimulating factors such as G-CSF)
    • TAC (docetaxel, doxorubicin, cyclophosphamide)
    • TC (docetaxel + cyclophosphamide)
    • The following are alternative adjuvant regimens:
    • AC followed by docetaxel or paclitaxel every 3 weeks
    • CMF (cyclophosphamide, methotrexate, fluorouracil)
    • EC (epirubicin + cyclophosphamide)
    • FAC (fluorouracil, doxorubicin, cyclophosphamide)
    • FEC (fluorouracil, epirubicin, cyclophosphamide)

    Neoadjuvant Chemotherapy Rationale for Stage III Breast Cancers:

    • Shrink a large tumor prior to surgery, to make it more amenable to complete resection.
    • Identify drug sensitivity or resistance early.
    • Earlier treatment of micrometastases.

    The preferred and alternative regimens listed for adjuvant therapy also apply for neoadjuvant therapy. In some cases, response to neoadjuvant therapy is sufficient to permit breast-conserving therapy. If the patient over-expresses HER2, then trastuzumab as discussed below should be added to neoadjuvant chemotherapy. If the full course of planned chemotherapy is administered before surgery, then there is no role for additional chemotherapy after surgery.

    Chemotherapy Rationale for Metastatic Breast Cancer (Stage IV)

    Metastatic breast cancer is generally considered incurable. Therefore the goals of treatment are improvement in symptoms, and sometimes, improvement in survival. The choice of which agent(s) to offer to these patients depends greatly on the drugs they previously received in the adjuvant setting. If anthracyclines had not been given, for example, then the AC regimen may be offered. If taxanes had not been given, they are generally first-line for metastatic disease. Capecitabine is usually the preferred third-line drug, after disease progression with doxorubicin and the taxanes.

    Single agents or combinations may be given. Remember, the goal here is symptom management rather than cure. If the patient experiences side effects, a different drug(s) should be offered. Combinations of drugs lead to a higher response rate but not longer overall survival.

    Preferred single-agents for metastatic breast cancer:

    • Any anthracycline (doxorubicin, liposomal doxorubicin, epirubicin)
    • Any taxane (paclitaxel, docetaxel)
    • Capecitabine
    • Gemcitabine
    • Vinorelbine

    Preferred combinations for metastatic breast cancer:

    • AC (doxorubicin + cyclophosphamide)
    • EC (epirubicin + cyclophsophamide)
    • FAC (fluorouracil, doxorubicin, cyclophosphamide)
    • FEC (fluorouracil, epirubicin, cyclophosphamide)
    • AT (doxorubicin + docetaxel)
    • CMF (cyclophosphamide, methotrexate, fluorouracil)
    • GT (gemcitabine + paclitaxel)
    • Docetaxel + capecitabine

    Ixabepilone is a new chemotherapeutic agent with a novel mechanism of action. It is approved with or without capecitabine for metastatic breast cancer that is refractory to anthracyclines and taxanes. At this time, most clinicians would consider ixabepilone an alternative regimen for patients (not preferred), due to limited follow-up data.

    If a patient fails to respond to more than three sequential drugs or regimens OR at any time declines to a poor performance status, then supportive (palliative) care should be considered.

    TRASTUZUMAB

    HER2 is a growth factor receptor found on the surface of many cells. It is over-expressed on 20 to 25% of breast cancers and 15 to 30% of ovarian cancers. These cancers have a poorer prognosis, are more aggressive, and tend to recur after primary treatment. Fortunately, several anti-HER2 therapies are approved in the U.S. for the treatment of breast cancer. The most commonly used is trastuzumab, a monoclonal antibody directed against the HER2 receptor. It binds to the HER2 receptor and blocks its effects.

    Measuring for the presence of HER2 over-expression can be done in one of two ways:

    • Staining for the presence of the receptors on tumor cell surfaces. This is a subjective rating reported by the pathologist as 1+, 2+ or 3+. The higher the amount of receptor, the more likely the patient is to respond to trastuzumab. Most trastuzumab studies included patients who were scored as 3+ on staining for HER2 receptors.
    • Identifying the presence of multiple copies of the HER2 gene in the nucleus of breast cancer cells. This is reported as the number of gene copies and is a more accurate analysis of HER2 status than staining for receptors.

    Note that there is a high rate of false negatives and false positives when testing for over-expression of HER2. Analysis for presence of the HER2 gene is considered more accurate and should be done whenever possible. ANY analysis of HER2 over-expression must be done at a laboratory accredited to carry out HER2 testing.

    Adjuvant Trastuzumab for Stage I and II Breast Cancers

    Adjuvant trastuzumab is recommended for ALL stage II patients with over-expression of HER2. It has been shown in multiple clinical trials to improve survival in these patients. Note that this is trastuzumab in addition to chemotherapy, NOT instead of chemotherapy. Adjuvant trastuzumab is also recommended for patients with stage I breast cancer if the tumor is greater than 1 cm. Use in patients with tumors less than 1 cm should be balanced with potential side effects of trastuzumab, especially the risk of cardiac toxicity, as well as the cost.

    Adjuvant trastuzumab is given weekly or every 3 weeks for one year. It generally follows chemotherapy and may be given at the same time as adjuvant radiation therapy and/or hormonal therapy. Due to the risk of additive cardiac toxicity, trastuzumab should NOT be given at the same time as anthracyclines. It may be given at the same time as other chemotherapy.

    The following are preferred trastuzumab-containing adjuvant regimens:

    • AC (doxorubicin + cyclophosphamide) followed by weekly paclitaxel and concurrent trastuzumab
    • TCH (docetaxel, cyclophosphamide, trastuzumab)
    • (TCH may be preferred in patients with heart disease; It causes a lower incidence of cardiac toxicity)
    • The following are alternative trastuzumab-containing adjuvant regimens:
    • Docetaxel + trastuzumab followed by FEC (fluorouracil, epirubicin, cyclophosphamide)
    • AC followed by docetaxel and concurrent trastuzumab

    Trastuzumab for Metastatic Breast Cancer

    Trastuzumab was actually first approved for the treatment of metastatic breast cancer. It has a 30% response rate as first-line therapy and a 10 to 15% response rate after failing multiple chemotherapy regimens. In all cases of metastatic breast cancer, trastuzumab should be added to chemotherapy if the patient’s cancer over-expresses HER2 and continued, even if chemotherapy drugs are changed.

    Trastuzumab adds an average of one year of survival versus chemotherapy alone. The preferred chemotherapy drugs to combine with trastuzumab in metastatic breast cancer are docetaxel, paclitaxel (with or without carboplatin), vinorelbine, and capecitabine. As with adjuvant therapy, trastuzumab should NEVER be given at the same time as anthracyclines.

    HORMONAL THERAPY

    As with chemotherapy, hormonal therapy may be given adjuvantly, after surgery, for stage I and II breast cancer, as well as for the treatment of metastatic disease. The caveat is that patients MUST be ER/PR positive. This is determined by staining for the presence of the receptors on tumor cell surfaces, in a manner similar to testing for the HER2 receptor.

    ER/PR positivity indicates that their breast cancer uses estrogens and/or progesterones as growth factors. Hormonal therapies are aimed at either decreasing the supply of endogenous hormones or blocking their action in the tumor.

    Available agents include the following:

    • Tamoxifen: SERM (selective estrogen receptor modulator) – Binds to estrogen receptors on breast cancer cells, but does not exert an effect, thereby inhibiting the effects of endogenous estrogen ñ In some tissues (e.g., the bone, the uterus), tamoxifen acts like an estrogen.
    • Anastrozole, Letrozole, Exemestane: Aromatase inhibitors decrease the production of estrogen in the adrenal glands and fat (the primary source on post-menopausal women). These agents are NOT effective in premenopausal women, whose primary source of estrogen is the ovaries.
    • Fulvestrant: Pure estrogen antagonist – Unlike tamoxifen, blocks the effects of estrogen in all tissues.
    • Leuprolide, Goserelin: These agents cause ovarian ablation, which decreases estrogen and progesterone production from the pituitary gland. This treatment approach is used in premenopausal breast cancer patients who are ER/PR positive.

    Adjuvant Hormonal Therapy for Stage I and II Breast Cancers

    Premenopausal patients who are ER/PR positive and have stage I or II breast cancer should receive adjuvant tamoxifen for five years plus ovarian ablation therapy with leuprolide or goserelin, after completing adjuvant chemotherapy. Note that many premenopausal women will experience early menopause after adjuvant chemotherapy and may be candidates for an aromatase inhibitor. This MUST be documented prior to initiating hormonal therapies, so that the most appropriate drugs are chosen.

    There are many adjuvant hormonal options for the post-menopausal patient who is ER/PR positive and has stage I or II breast cancer. Hormonal therapy should begin after completion of chemotherapy (if given). None of these options have been compared head-to-head (all were compared to 5 years of tamoxifen alone), and it is not known if initial, sequential or extended use of aromatase inhibitors is better.

    Therefore, all of these are considered reasonable choices:

    • Aromatase inhibitor for five years
    • Tamoxifen for 2-3 years followed by 2-3 years of an aromatase inhibitor (5 years total)
    • Tamoxifen for 5 years followed by 5 years of an aromatase inhibitor (10 years total)
    • Tamoxifen for 5 years (ONLY recommended in patients who have a contraindication to or are intolerant to aromatase inhibitors)

    Note that anastrozole, letrozole, and exemestane are generally considered to be equivalent aromatase inhibitors in the adjuvant setting, with similar efficacy and side effect profiles.

    Hormonal Therapy for Metastatic Breast Cancer

    Most patients who have recurrent metastatic breast cancer will have received tamoxifen in the adjuvant setting, and many will have also received anastrozole or letrozole as described above. If it has been less than one year since stopping adjuvant hormonal therapy, patients are assumed to be resistant to those drugs and a different agent will need to be chosen for therapy. If is has been more than one year since hormonal therapy, then either tamoxifen or an aromatase inhibitor may be used.

    A clinical trial with a new agent is also always a good option. Exemestane is often the third-line therapy of choice (after tamoxifen and anastrozole/letrozole). There is also data that fulvestrant injected once monthly is equivalent to daily oral exemestane in these patients.

    The following are the therapeutic principles of hormonal therapy for metastatic ER/PR positive breast cancer:

    • A trial of at least 6 to 8 weeks is needed to assess for response.
    • Combinations of agents are NOT more effective than single agents.
    • If the patient progresses on one therapy, it is reasonable to try switching to another.
    • When initiating therapy, patients should be monitored closely for disease flare (a temporary worsening of symptoms lasting several weeks).
    • The goal of therapy is symptom management, NOT cure.

    Other Treatment Options

    BISPHOSPHONATES

    Pamidronate or zoledronic acid should be given once a month by vein in any patient with evidence of bone metastases. These drugs inhibit the breakdown of bone associated with breast cancer. These agents have historically been the treatment of choice for hypercalcemia due to bone metastases. They now have also been shown to decrease progression of the cancer in bone, decrease pain and decrease the need for radiation therapy to bone mestatases.

    These are all palliative outcomes:

    • Bisphosphonates do not affect long-term survival.
    • Patients with early stage breast cancer receiving adjuvant anastrozole or letrozole should also receive monthly injections of bosphosphonates to prevent the bone loss and fractures associated with these drugs. Tamoxifen does not cause a fracture risk because it is estrogenic in bone tissue. Pamidronate or zoledornic acid has been found to be safe for up to two years in adjuvant clinical trials.
    • Bisphosphonates are generally well tolerated. Side effects include fever/chills, pain at the injection site, bone pain, and transient kidney toxicity. Rarely, osteonecrosis of the jaw has been reported. To minimize this risk, patients should undergo a dental exam prior to initiating bisphosphonate therapy and should take supplemental calcium and vitamin D during therapy.

    BONE MARROW TRANSPLANT

    Bone marrow transplant (BMT) is also called hematopoietic stem cell transplant. The most common procedure is autologous BMT, in which the patientís own blood stem cells are harvested, then re-infused following very-high-dose chemotherapy. The rationale in breast cancer is that this is a very chemo-sensitive cancer and that drug resistance is common. High doses of chemotherapy, therefore, may be able to overcome resistance and cure more patients.

    In the 1980s and 1990s, numerous clinical trials were conducted that demonstrated a potential increase in survival with BMT for metastatic breast cancer. These were generally small trials and conducted at single centers. Larger, randomized trials versus conventional chemotherapy have failed to show a survival benefit. Therefore, this therapy is not offered outside of a clinical trial.

    LAPATINIB

    Lapatinib is a newer anti-HER2 therapy. It is an oral HER2 tyrosine kinase inhibitor and attacks over-expression of HER2 from a different place than trastuzumab. Instead of binding to and blocking the receptors on the surface of the cells, it blocks the transmission of the HER2 signal from the cell surface to the nucleus. It does this by inhibiting the so-called second messenger for HER2, a tyrosine kinase.

    Lapatinib has demonstrated activity in patients with metastatic breast cancer who have failed trastuzumab. Trials were in combination with capecitabine. Lapatinib did not lead to extended overall survival, but patients did have an extended time prior to disease progression, with manageable side effects (diarrhea, rash, hand-foot syndrome). This drug costs many hundreds of dollars per month; therefore, patients and clinicians will need to decide if the modest benefit is worth the cost of therapy. Lapatinib is also being studied in combination with chemotherapy and trastuzumab, as first-line in metastatic breast cancer.

    ANTIANGIOGENESIS AGENTS

    One of the most promising novel treatments for breast cancer is antiangiogenesis therapy. Drugs are given that inhibit blood vessel formation by the tumor, leading to cancer cell death and decreased spread of the tumor to distant organs. The most studied antiangiogenesis agent in breast cancer is bevacizumab. This is a monoclonal antibody targeting vascular endothelial growth factor (VEGF).

    Response rates are as high as 20% in patients who have failed multiple chemotherapy regimens. Bevacizumab is usually given in combination with chemotherapy, such as paclitaxel or capecitabine. Toxicity may be significant, with a risk of hypertension, blood clots, hemorrhage and GI perforation. Other antiangiogenesis agents being studied in breast cancer include oral agents such as sorafenib, sunitinib and thalidomide. These agents may be given as monotherapy or in combination with chemotherapy as well.

    There are many other agents being studied in clinical trials for treatment of breast cancer. These may be reviewed at www.clinicaltrials.gov.