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Breast cancer: risk factor, sign&symptoms, daignosis, stages,pathophysiology, treatment

Breast cancer| risk factor|sign & symptoms|diagnosis|stages of breast cancer|pathophysiology|treatment of breast cancer|prevention

Breast cancer

Breast cancer is a malignancy originating from breast tissue. Disease confined to a localized breast lesion is referred to as early, primary, localized, or curable. Disease detected clinically or radiologically in sites distant from the breast is referred to as advanced or metastatic breast cancer (MBC), which is usually incurable.

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.
breast cancer
Breast cancer

Risk factor

Two variables most strongly associated with occurrence of breast cancer are gender and advancing age. Additional risk factors include endocrine factors (eg, early menarche, nulliparity, late age at first birth, and hormone replacement therapy), genetic factors (eg, personal and family history, mutations of tumor suppresser genes [BRCA1 and BRCA2]), and environmental and lifestyle factors (eg, radiation exposure).

sign & symptoms

A painless lump is the initial sign of breast cancer in most women. The typical malignant mass is solitary, unilateral, solid, hard, irregular, and nonmobile. Nipple changes are less commonly seen. More advanced cases present with prominent skin edema, redness, warmth, and induration.
symptoms of breast cancer


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.

Diagnosis

Initial workup should include a careful history, physical examination of the breast, three-dimensional mammography, and, possibly, other breast imaging techniques, such as ultrasound and magnetic resonance imaging (MRI).

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

stages of breast cancer

Stage (anatomical extent of disease) is based on primary tumor extent and size (T1–4), presence and extent of lymph node involvement (N1–3), and presence or absence of distant metastases (M0–1). The staging system determines prognosis and assists with treatment decisions. 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 invasive tumor without lymph node involvement
• Stage II: Involvement of regional lymph nodes
✓ Locally Advanced Breast Cancer
• Stage III: Usually a large tumor with extensive nodal involvement in which the 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.

Pathophysiologic evaluation

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

• Pathologic evaluation of breast lesions establishes the histologic diagnosis and confirms the presence or absence of prognostic factors.

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

Treatment

EARLY BREAST CANCER

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 often primary therapy for stage I and II disease; it is preferable to modified radical mastectomy because it produces equivalent survival rates with cosmetically superior results. BCT includes removal of part of the breast, surgical evaluation of axillary lymph nodes, and radiation therapy (RT) to prevent local recurrence.

• 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 BCT.

• Axillary lymph nodes should be sampled for staging and prognostic information. Lymphatic mapping with sentinel lymph node biopsy is a less invasive alternative to axillary dissection; however, the procedure is controversial in certain patient populations.

Systemic Adjuvant Therapy

• 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.

• Administration of chemotherapy, endocrine therapy, or both results in improved disease-free survival (DFS) and/or overall survival (OS) for all treated patients.

• The National Comprehensive Cancer Network (NCCN) practice guidelines are updated at least annually and should be consulted for treatment recommendations.

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

ADJUVANT CHEMOTHERAPY

• Early administration of effective combination chemotherapy at a time of low tumor burden should increase the likelihood of cure and minimize emergence of drugresistant tumor cell clones. Combination regimens have historically been more effective than single-agent chemotherapy.

• Anthracycline-containing regimens (eg, doxorubicin and epirubicin) reduce the rate of recurrence and death as compared with regimens that contain cyclophosphamide, methotrexate, and fluorouracil.

• The addition of taxanes, docetaxel and paclitaxel, to adjuvant regimens comprised of the drugs listed above resulted in reduced risk of distant recurrence, any recurrence, and overall mortality compared with a nontaxane regimen in node-positive breast cancer patients. The use of taxane-containing regimens in node-negative patients remains controversial.

• Initiate chemotherapy within 12 weeks of surgical removal of the primary tumor. Optimal duration of adjuvant treatment is unknown but appears to be 12 to 24 weeks, depending on the regimen used.

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

• Dose-dense adjuvant regimens for node-positive breast cancer resulted in prolonged DFS and OS. No benefit in DFS or OS was shown for sequential versus concurrent chemotherapy but sequential therapy appears to be less toxic.

• Concomitant or sequential administration of a taxane with an anthracycline-based regimen is standard of care in node-positive breast cancer.

• Dose increases in standard regimens appears to not be beneficial and may be harmful.

• Avoid dose reductions in standard regimens unless necessitated 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 myeloid growth factor

ADJUVANT BIOLOGIC THERAPY

• 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.

• 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.

ADJUVANT ENDOCRINE THERAPY

• Tamoxifen, toremifene, oophorectomy, ovarian irradiation, luteinizing hormone–releasing hormone (LHRH) agonists, and aromatase inhibitors (AI) are hormonal therapies used in the treatment of primary or early-stage breast cancer. Tamoxifen was the gold standard adjuvant hormonal therapy for three decades and 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. It is usually well-tolerated however, 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 and spine fractures. It increases the risks of stroke, pulmonary embolism, deep vein thrombosis, and endometrial cancer, particularly in women age 50 years or older.

• Premenopausal women benefit from ovarian ablation with LHRH agonists (eg, 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 AIs into adjuvant hormonal therapy for postmenopausal, hormone-sensitive breast cancer. Experts believe that anastrozole, letrozole, and exemestane have similar antitumor efficacy and toxicity profiles. Adverse effects with AIs include bone loss  or osteoporosis, hot flashes, myalgia/arthralgia, vaginal dryness/atrophy, mild headaches, and diarrhoea.

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 an anthracycline- and 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.

METASTATIC BREAST CANCER (STAGE IV)

• The choice of therapy for MBC is based on the site of disease involvement and the presence or absence of certain characteristics, as described below.

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.

• No one endocrine therapy has clearly superior survival benefit. Choice of agent is based primarily on mechanism of action, toxicity and patient preference.

• AIs are generally first line therapy in postmenopausal women. AIs reduce circulating and target organ estrogens by blocking peripheral conversion from an androgenic precursor, the primary source of estrogens in postmenopausal women. The thirdgeneration aromatase inhibitors anastrozole, letrozole, and exemestane are more selective and potent than the prototype, aminoglutethimide. When compared with tamoxifen, patients receiving AIs had similar response rates as well as lower incidence of thromboembolic events and vaginal bleeding.

• Tamoxifen, a selective estrogen receptor modulator (SERM) is the preferred initial agent when metastases are present in premenopausal women except when metastases occur within 1 year of adjuvant tamoxifen. In addition to the side effects described for adjuvant therapy, tumor flare or hypercalcemia occurs in approximately 5% of patients with MBC.

Chemotherapy

• Chemotherapy is used as initial therapy for women with hormone receptor–negative tumors; with rapidly progressive or symptomatic lung, liver, or bone marrow involvement; and after failure of endocrine therapy.

• The choice of treatment depends on patient characteristics, expected toxicities, and previous exposure to 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.

• 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-agents capecitabine, vinorelbine, and gemcitabine have response rates of 20% to 25% when used after an anthracycline and a taxane.

• Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine. Eribulin is a second antimicrotubule agent approved as monotherapy in patients who have received at least two prior chemotherapy regimens for MBC.

Biologic or Targeted Therapy

• Three anti-HER2 agents are available: trastuzumab, lapatinib, and pertuzumab. The majority of data supporting the role of these agents in MBC focuses on trastuzumab. Trastuzumab 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 and vinorelbine– trastuzumab) and triplet (trastuzumab–taxane–platinum) combinations, but the optimum regimen is unknown.

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

• Lapatinib is an oral tyrosine kinase inhibitor that targets both HER2 and the epidermal growth factor receptor. It demonstrated improved response rates and time to progression in combination with capecitabine, as compared with capecitabine alone.

Radiation Therapy

• 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.

PREVENTION OF BREAST CANCER

• SERMs and AIs are being studied for pharmacologic risk reduction of breast cancer.

• 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 developingthe disease. Rates of endometrial cancer and deep vein thromboses are higher in patients receiving tamoxifen, but the overall quality of life is similar between the two agents.

• Exemestane taken for 5-years significantly reduced the rates of invasive breast cancers with tolerable adverse events. Clinical trials with other AIs are underway. 


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