Rowa’ Al-Ramahi

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The strongest risk factors for breast cancer are female gender and increasing age.

Additional risk factors include endocrine factors (e.g., early menarche, nulliparity, late age at first birth, hormone replacement therapy), genetic factors (e.g., personal and family history, mutations of tumor suppresser genes [BRCA1 and BRCA2]), and environmental and lifestyle factors (e.g., radiation exposure).

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Breast cancer cells often spread undetected by contiguity, lymph channels, and through the blood early in the course of the disease, resulting in metastatic disease after local therapy.

The most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain.

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The initial sign in more than 90% of women with breast cancer is a painless lump that is typically solitary, unilateral, solid, hard, irregular, and nonmobile.

Less common initial signs are pain and nipple changes. More advanced cases present with prominent skin edema, redness, warmth, and induration.

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Symptoms of MBC depend on the site of metastases, but may include bone pain, difficulty breathing, abdominal pain or enlargement, jaundice, and mental status changes.

Many women first detect some breast abnormalities themselves, but it is increasingly common for breast cancer to be detected during routine screening mammography in asymptomatic women.

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Initial workup for a woman presenting with a localized lesion or suggestive symptoms should include a careful history, physical examination of the breast, three-dimensional mammography, and, possibly, other breast imaging techniques such as ultrasound & MRI.

Breast biopsy is indicated for a mammographic abnormality that suggests malignancy or for a palpable mass on physical examination.

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Stage is based on the size of the primary tumor extent & size (T1–4), presence and extent of lymph node involvement (N1–3), and presence or absence of distant metastases (M0–1). Simplistically stated, these stages may be represented as follows:

✓ Early Breast Cancer Stage 0: Carcinoma in situ or disease that

has not invaded the basement membrane. Stage I: Small primary tumor without

lymph node involvement. Stage II: Involvement of regional lymph

nodes.

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Locally Advanced Breast Cancer Stage III: Usually a large tumor with

extensive nodal involvement in which node or tumor is fixed to the chest wall; also includes inflammatory breast cancer, which is rapidly progressive.

✓ Advanced or Metastatic Breast Cancer Stage IV: Metastases in organs distant

from the primary tumor.

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The development of malignancy is a multistep process with preinvasive (or noninvasive) and invasive phases. The goal of treatment for noninvasive carcinomas is to prevent the development of invasive disease.

The pathologic evaluation of breast lesions establishes the histologic diagnosis and presence or absence of prognostic factors.

Most breast carcinomas are adenocarcinomas and are classified as ductal or lobular.

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Tumor size and the presence and number of involved axillary lymph nodes are primary factors in assessing the risk for breast cancer recurrence and subsequent metastatic disease.

Other disease characteristics that provide prognostic information include histologic subtype, nuclear or histologic grade, lymphatic and vascular invasion, and proliferation indices.

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The estrogen receptor & progesterone receptor are 2 hormone receptors used as indicators of prognosis and to predict response to hormone therapy.

HER2/neu (HER2) overexpression is associated with transmission of growth signals that control aspects of normal cell growth and division.

Overexpression of HER2 is associated with increased tumer aggresiveness,rates of recurrence & mortality.

Genetic profiling tools provide additional prognostic information to aid in treatment decisions for subgroups of patients with otherwise favorable prognostic features.

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The goal of therapy with early and locally advanced breast cancer is cure.

The goals of therapy with MBC are to improve symptoms, improve quality of life, and prolong survival.

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The treatment of breast cancer is rapidly evolving. Specific information regarding the most promising interventions can be found only in the primary literature.

Treatment can cause substantial toxicity, which differs depending on the individual agent, administration method, and combination regimen. Because a comprehensive review of toxicities is beyond the scope of this chapter, appropriate references should be consulted.

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Local-Regional Therapy Surgery alone can cure most patients with

in situ cancers and approximately one-half of those with stage II cancers.

Breast-conserving therapy (BCT) is appropriate primary therapy for most women with stage I and II disease; it is preferable to modified radical mastectomy because it produces equivalent survival rates with cosmetically superior results. BCT consists of lumpectomy (i.e., excision of the primary tumor and adjacent breast tissue) followed by radiation therapy (RT) to prevent local recurrence.

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RT is administered to the entire breast over 4 to 6 weeks to eradicate residual disease after BCT. Reddening and erythema of the breast tissue with subsequent shrinkage of total breast mass are minor complications associated with RT.

Simple or total mastectomy involves removal of the entire breast without dissection of underlying muscle or axillary nodes. This procedure is used for carcinoma in situ where the incidence of axillary node involvement is only 1% or with local recurrence following breast conservation therapy.

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Axillary lymph nodes should be sampled for staging and prognostic information. Lymphatic mapping with sentinel lymph node biopsy is a new, less invasive alternative to axillary dissection; however, the procedure is controversial because of the lack of long-term data.

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Systemic adjuvant therapy is the administration of systemic therapy following definitive local therapy (surgery, radiation, or both) when there is no evidence of metastatic disease but a high likelihood of disease recurrence. The goal of such therapy is cure.

Chemotherapy, hormonal therapy, or both result in improved disease-free survival and/or overall survival (OS) for all treated patients.

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The National Comprehensive Cancer Network practice guidelines reflect the trend toward the use of chemotherapy in all women regardless of menopausal status, and the addition of hormonal therapy in all women with receptor-positive disease regardless of age or menopausal status.

Genetic tests are being prospectively validated as decision-support tools for adjuvant chemotherapy in ER +, node-negative patients to identify characteristics of the primary tumor that may predict for the likelihood of distant recurrence and death.

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Early administration of effective combination chemotherapy at a time of low tumor burden should increase the likelihood of cure and minimize emergence of drug-resistant tumor cell clones.

Combination regimens have historically been more effective than single agent chemotherapy

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Anthracycline-containing regimens (e.g., doxorubicin and epirubicin) significantly reduce the rate of recurrence and improve OS 5 and 10 years after treatment as compared with regimens that contain cyclophosphamide, methotrexate, and fluorouracil.

Both node-negative and nodepositive patients benefit from anthracycline-containing regimens.

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The addition of taxanes, docetaxel and paclitaxel, a newer class of agents, to adjuvant regimens resulted in consistently and significantly improved disease-free survival and OS in node-positive breast cancer patients. The use of taxane containing regimens in node negative patients remains controversial.

Chemotherapy should be initiated within 12 weeks of surgical removal of the primary tumor. The optimal duration of adjuvant treatment is unknown but appears to be on the order of 12 to 24 weeks depending on the regimen used.

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Dose intensity refers to the amount of drug administered per unit of time, which can be achieved by increasing dose, decreasing time, or both. Dose density is one way of achieving dose intensity by decreasing time between treatment cycles.

Dose-dense regimens may be considered as options for adjuvant therapy for node-positive breast cancer.

Increasing doses in standard regimens appears to not be beneficial and may be harmful.

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Decreasing doses in standard regimens should be avoided unless necessitate by severe toxicity.

Short-term toxicities of adjuvant chemotherapy are generally well tolerated, especially with the availability of serotonin-antagonist and substance P/neurokinin 1-antagonist antiemetics and colony-stimulating factors.

Survival benefit for adjuvant chemotherapy in stage I and II breast cancer is modest. The absolute reduction in mortality at 10 years is 5% in node negative and 10% in node-positive disease.

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Adjuvant Biologic Therapy Trastuzumab in combination with adjuvant

chemotherapy is indicated in patients with early stage, HER2-positive breast cancer. The risk of recurrence was reduced up to 50% in clinical trials.

Unanswered questions with the use of adjuvant trastuzumab include optimal concurrent chemotherapy, optimal dose, schedule and duration of therapy, and use of other concurrent therapeutic modalities.

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Tamoxifen, toremifene, oophorectomy, ovarian irradiation, luteinizing hormone–releasing hormone (LHRH) agonists, and aromatase inhibitors are hormonal therapies used in the treatment of primary or early-stage breast cancer.

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Adjuvant Endocrine Therapy Tamoxifen was the gold standard for

adjuvant hormonal therapy for 3 decades & is generally considered the adjuvant hormonal therapy of choice for premenopausal women. It has both estrogenic and antiestrogenic properties, depending on the tissue and gene in question.

Tamoxifen 20 mg daily, beginning soon after completing chemotherapy and continuing for 5 years, reduces the risk of recurrence and mortality.

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Tamoxifen is usually well tolerated. Symptoms of estrogen withdrawal (hot flashes and vaginal bleeding) may occur but decrease in frequency and intensity over time. Tamoxifen reduces the risk of hip radius & spine fractures. It increases the risks of stroke, pulmonary embolism, deep vein thrombosis, and endometrial cancer, particularly in women age 50 years or older.

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Premenopausal women benefit from ovarian ablation with luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin) in the adjuvant setting, either with or without concurrent tamoxifen. Trials are ongoing to further define the role of LHRH agonists.

Guidelines recommend incorporation of aromatase inhibitors into adjuvant hormonal therapy for postmenopausal, hormone-sensitive breast cancer.

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The following options are currently recommended: (1) an aromatase inhibitor for 5 years; (2) tamoxifen for 2 to 3 years, followed by an aromatase inhibitor for a total of 5 years of endocrine therapy; or (3) tamoxifen for 5 years, followed by an aromatase inhibitor for another 5 years.

Experts believe that the three available aromatase inhibitors—anastrozole, letrozole, and exemestane—have similar antitumor efficacy and toxicity profiles. Adverse effects with aromatase inhibitors include bone loss/osteoporosis, hot flashes, myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhea.

The optimal drug, dose, sequence, and duration of administration of aromatase inhibitors in the adjuvant setting are not known.

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LOCALLY ADVANCED BREAST CANCER (STAGE III) Neoadjuvant or primary chemotherapy is the

initial treatment of choice. Benefits include rendering inoperable tumors

resectable and increasing the rate of BCT. Primary chemotherapy with either an

anthracycline- or taxane-containing regimen is recommended. The use of trastuzumab with chemotherapy is appropriate for patients with HER2-positive tumors.

Surgery followed by chemotherapy and adjuvant RT should be administered to minimize local recurrence.

Cure is the primary goal of therapy for most patients with Stage III disease.

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METASTATIC BREAST CANCER (STAGE IV) Endocrine Therapy Endocrine therapy is the treatment of choice for

patients who have hormone receptor-positive metastases in soft tissue, bone, pleura, or, if asymptomatic, viscera. Compared with chemotherapy, endocrine therapy has an equal probability of response and a better safety profile.

Patients are sequentially treated with endocrine therapy until their tumors cease to respond, at which time chemotherapy can be given.

Historically, the choice of an endocrine therapy was based primarily on toxicity and patient preference but study results have led to changes in MBC treatment.

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Aromatase inhibitors reduce circulating and target organ estrogens by blocking peripheral conversion from an androgenic precursor, the primary source of estrogens in postmenopausal women.

The third-generation aromatase inhibitors anastrozole, letrozole, and exemestane are more selective and potent than the prototype, aminoglutethimide.

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Anastrozole, letrozole, and exemestane are approved as second-line therapy of advanced breast cancer in postmenopausal women; anastrozole and letrozole are also approved for first-line therapy in these patients. When compared with tamoxifen, patients receiving anastrozole and letrozole had similar response rates and longer median time to progression as well as lower incidence of thromboembolic events and vaginal bleeding.

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Tamoxifen is the antiestrogen of choice in premenopausal women whose tumors are hormone-receptor positive, unless metastases occur within 1 year of adjuvant tamoxifen. Maximal beneficial effects do not occur for at least 2 months. In addition to the side effects described for adjuvant therapy, tumor flare or hypercalcemia occurs in approximately 5% of patients with MBC.

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Toremifene has similar efficacy and tolerability as tamoxifen and is an alternative to tamoxifen in postmenopausal patients. Fulvestrant is a second-line intramuscular agent with similar efficacy and safety when compared to anastrozole in patients who progressed on tamoxifen.

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Ovarian ablation (oophorectomy) is considered by some to be the endocrine therapy of choice in premenopausal women and produces similar overall response rates as tamoxifen. Medical castration with an LHRH analog, goserelin, leuprolide, or triptorelin, is a reversible alternative to surgery. If used as first-line therapy for MBC, combination therapy with tamoxifen is recommended.

Progestins are generally reserved for third-line therapy. They cause weight gain, fluid retention, and thromboembolic events.

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Chemotherapy

Chemotherapy is used as initial therapy for women with hormone receptor– negative tumors and after failure of endocrine therapy.

The choice of treatment depends on the individual. Agents used previously as adjuvant therapy can be repeated unless the cancer recurred within 1 year.

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Chemotherapy

Single agents are associated with lower response rates than combination therapy, but time to progression and OS are similar. Single agents are better tolerated, an important consideration in the palliative metastatic setting. Treatment with sequential single agents is recommended over combination regimens unless the patient has rapidly progressive disease, life-threatening visceral disease, or the need for rapid symptom control.

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Combination regimens produce objective responses in approximately 60% of patients previously unexposed to chemotherapy, but complete responses occur in less than 10% of patients. The median duration of response is 5 to 12 months; the median survival is 14 to 33 months. A specific chemotherapy regimen is continued until there is unequivocal evidence of progressive disease or intolerable side effects.

Anthracyclines and taxanes produce response rates of 50% to 60% when used as first-line therapy for MBC. Single agent capecitabine, vinorelbine, or gemcitabine have response rates of 20% to 25% when used after an anthracycline and a taxane (see Table 61-1).

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Anthracyclines and taxanes produce response rates of 50% to 60% when used as first-line therapy for MBC. Single agent capecitabine, vinorelbine, or gemcitabine have response rates of 20% to 25% when used after an anthracycline and a taxane.

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Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine in MBC patients who have progressive disease despite treatment with the above agents.

Response rates and time to progression were increased with combination therapy as compared with capecitabine alone.

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Biologic Therapy Trastuzumab, a monoclonal antibody

that binds to HER2, produces response rates of 15% to 20% when used as a single agent and increases response rates, time to progression, and OS when combined with chemotherapy.

It has been studied in doublet (taxane-trastuzumab; vinorelbinetrastuzumab) and triplet (trastuzumab-taxane-platinum) combinations but the optimum regimen is unknown.

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Trastuzumab is well tolerated, but the risk of cardiotoxicity is 5% with single-agent trastuzumab and unacceptably high in combination with an anthracycline.

Lapatinib, an oral tyrosine kinase inhibitor that targets both HER2 and the epidermal growth factor receptor, improved response rates and time to progression in combination with capecitabine, as compared to capecitabine alone, in patients previously treated with an anthracycline, taxane, and trastuzumab. The most common adverse events were rash and diarrhea.

The role of bevacizumab, a monoclonal antibody targeted against vascular endothelial growth factor, in MBC is currently not clearly defined.

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Radiation Therapy Radiation is commonly used to treat

painful bone metastases or other localized sites of disease including brain and spinal cord lesions. Pain relief is seen in approximately 90% of patients who receive RT.

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Three classes of agents being studied for pharmacologic risk reduction of breast cancer include retinoids, selective estrogen receptor modulators (SERMs), and aromatase inhibitors.

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The most clinical information is available for the SERMs, tamoxifen and raloxifene, which reduce the rates of invasive breast cancer in women at high risk for developing the disease. Rates of endometrial cancer and deep vein thromboses are higher in patients receiving tamoxifen but overall quality of life is similar between the two agents.

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EARLY BREAST CANCER The goal of adjuvant therapy in early-

stage disease is cure. Because there is no clinical evidence of disease when adjuvant therapy is administered, assessment of this goal cannot be fully evaluated for years after initial diagnosis and treatment.

Adjuvant chemotherapy can cause substantial toxicity. Because maintaining dose intensity is important in cure of disease, supportive care should be optimized with measures such as antiemetics and growth factors.

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LOCALLY ADVANCED BREAST CANCER The goal of neoadjuvant chemotherapy in

locally advanced breast cancer is cure. Complete pathologic response, determined at the time of surgery, is the desired end point.

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METASTATIC BREAST CANCER

Optimizing quality of life is the therapeutic endpoint in the treatment of patients with MBC. Many valid and reliable tools are available for objective assessment of quality of life.

The least toxic therapies are used initially, with increasingly aggressive therapies applied in a sequential manner that does not significantly compromise quality of life.

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Tumor response is measured by clinical chemistry (e.g., liver enzyme elevation in patients with hepatic metastases) or imaging techniques (e.g., bone scans or chest x-rays).

Assessment of the clinical status and symptom control of the patient is often adequate to evaluate response to therapy.

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