Breast cancer Amsalu Degu (B.Pharm, M.Pharm in Clinical Pharmacy, MSc in Pharmacology) USIU-Africa School of Pharmacy and Health Sciences 1 Objectives • At the end of this session, the students are expected to: List factors associated with an increased risk of breast cancer understand the histological classification of breast cancer Assess patients for signs and symptoms related to breast cancer in early and late stages of the disease understand the TNM staging of breast cancer Determine the treatment goals for early-stage, locally advanced, and metastatic breast cancer. Determine appropriate indications for endocrine therapy, chemotherapy, and biologic therapy for patients with breast cancer Identify monitoring parameters 2 Introduction • Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast • Starts when cells in the breast begin to grow out of control • Most breast cancers begin in the ducts that carry milk to the nipple (ductal cancers). • Some start in the glands that make breast milk (lobular cancers) 3 4 Epidemiology • 2nd leading cause of cancer death in women, exceeded only by lung cancer. • The disease occurs almost entirely in women, but men can get it, too • The left breast is involved more frequently than the right 5 Epidemiology 6 Risk factors • The exact etiology is unknown • Age – incidence increases with age – median age diagnosis is b/n 60-65 years • Gender – females have higher incidence than males • Genetics – BRCA1, BRCA2, p53 mutation • A family history of breast cancer 7 Risk factors • Endocrine factors (prolonged exposure to estrogens) – Early menarche< 12 years – Nulliparity – Late menopause ≥ 55years – Late age at first full term birth ≥ 30yrs – long term use of hormonal replacement therapy 8 Risk factors • Environmental & lifestyle factors – Diet- Increased fat & caloric intake – Obesity-Increased free circulating estrogen – Smoking – Alcohol – Reduced physical activity – Radiation in younger women <30yrs 9 10 Case study: Risk factors 11 Histological classification • Invasive carcinoma – Ductal • the most common (80%) type of breast invasive ductal carcinomas • Starts in a milk duct of the breast • Lobular –Starts in the milk-producing glands (lobules) • Non-invasive carcinoma: ductal or lobular 12 Types of Breast Cancer • Endocrine receptor-positive (ER and PR) – About 80% of all breast cancers are “ER-positive • HER2-positive – aggressive and fast-growing – Accounts for 20% of breast cancers • Triple positive – positive for ER, PR and HER2 • Triple negative – not positive for ER, PR & HER2 – more common in younger women – grow & spread faster than most other types of breast cancer 13 Types of breast cancer • About 50-70% of patients with primary or metastatic breast cancer have HR- positive tumors • HR positivity – Associated with a superior response to hormone therapy • HR positive tumors are more common in postmenopausal patients than in premenopausal patients • HR positive cancers tend to grow more slowly than HR-negative 14 Clinical Presentation • Common early symptoms – painless lump (90% of cases) that is typically solitary, unilateral, solid, hard and irregular. – Stabbing or aching pain (10% of cases) • Uncommon early symptoms – Nipple discharge (3% of women & 20% of men) – Eczema appearance of the nipple – Prominent skin edema, redness, warmth, and induration of the underlying tissue 15 Clinical Presentation • Metastatic symptoms – Bone pain – Difficulty breathing – Abdominal enlargement – Jaundice – Mental status changes – Tissues most commonly involved with metastases are lymph, skin, bone, liver, lungs, and brain 16 Clinical Staging • Stage I represents small primary tumor without lymph node involvement • stage II the majority of disease involves regional lymph nodes Stages I and II are often referred to as early breast cancer. It is in these early stages that the disease is curable. • Stage III also referred to as locally advanced disease usually represents a large tumor with extensive nodal involvement in which either node or tumor is fixed to the chest wall. 17 Clinical Staging • Stage IV – is characterized by the presence of metastases to organs distant from the primary tumor – is often referred to as advanced or metastatic disease 18 19 Screening: American Cancer Society recommendations • Women age 40-44 – should have the choice to start annual breast cancer screening with mammograms if they wish to do so • Women age 45-54 – should get mammograms every year • Women 55 and older – should switch to mammograms every 2 years, or can continue yearly screening • Average risk women – if she doesn’t have a personal history of breast cancer, a strong family history of breast cancer, or a genetic mutation known to increase risk of breast cancer 20 21 Screening • Individuals considered high risk – Have a known BRCA gene mutation – Untested for the BRCA gene mutation but have a first-degree relative with a BRCA mutation – Have a strong family history of breast cancer – For screening: Annual mammography & breast MRIs should be initiated starting at the age of 30 years – Screening with breast MRI is recommended in highrisk individuals. 22 Diagnosis • Triple assessment of any symptomatic breast mass by – Palpation – Radiology (mammography, ultrasound and MRI scan) – Fine-needle aspiration cytology – Virtually all breast cancer is diagnosed by biopsy of a nodule detected either on a mammogram or by palpation 23 Prevention M.P. should include information on both tamoxifen and raloxifene in her talk. 24 Prevention • Surgery (prophylactic mastectomy) – Women who are considered high risk for breast cancer may decide to undergo prophylactic mastectomy with reconstruction • Chemoprevention – Two agents approved for prevention are tamoxifen (20mg/day*5yrs)& raloxifene (60 mg daily*5yrs) 25 Management • Treatment is stratified according to the extent of the disease – Surgery – chemotherapy – Radiotherapy – hormonal therapy – biological agents 26 Treatment: early breast cancer (stage I & II) • Goal of therapy – Curative • Surgery alone can cure most – modified radical mastectomy (total mastectomy with ipsilateral axillary lymph node dissection) – Breast-conservation therapy (lumpectomy & 4-6weeks radiation therapy) • All patients with stage II breast cancer should be considered for systemic adjuvant therapy 27 Radical mastectomy 28 Lumpectomy 29 Treatment: locally advanced breast cancer (stage III) • locally advanced breast cancer – Refers to breast carcinomas with significant primary tumor & nodal disease • consists of a combination of surgery, radiation & chemotherapy administered in an aggressive approach 30 Treatment: locally advanced breast cancer (stage III) • Goal of therapy – to cure the disease • initial approach to therapy should be chemotherapy with the goal of achieving resectability • Neoadjuvant chemotherapy – most tumors respond with >50% decrease in tumor size – Chemotherapy regimens are similar to those used in the adjuvant setting – most of the available data support the use of anthracycline containing regimens 31 Treatment: locally advanced breast cancer (stage III) • Neoadjuvant endocrine therapy – may be an option for patients HR-positive tumors who are unable to receive chemotherapy (e.g.,multiple comorbid conditions) • Adjuvant radiation therapy – should be administered to all locally advanced breast cancer patients to minimize local recurrences regardless of the type of surgery 32 Treatment: metastatic breast cancer (stage IV) • Goal of treatment – to improve symptoms, maintain quality of life & extend survival • important to choose therapy with good activity while minimizing toxicities • Can be treated with Hormonal therapy (preferred if HR +ve)- first line and second line Systemic cytotoxic agents for hormone refractory disease 33 Palliation of metastatic breast cancer • Palliative Surgery – Commonly offered to patients with brain metastases, spinal cord compression, fractures, or symptomatic pleural or pericardial effusions not controlled by other means Palliative radiation – Offered to patients with bone metastases, brain metastases, spinal cord compression 34 Adjuvant chemotherapy regimens in nodepositive breast cancer • Chemotherapy is usually initiated within 3 weeks of surgical removal of the primary tumor • The basic principle of adjuvant therapy – The regimen with the highest response rate in advanced disease should be the optimal regimen for use in the adjuvant setting 35 36 37 38 Adjuvant Endocrine therapy • Goals of therapy – to decrease circulating levels of estrogen and/or – to prevent the effects of estrogen at the breast cancer cell (targeted therapy) through blocking the hormone receptors • combinations have not demonstrated any efficacy benefits but have increased toxicity 39 Adjuvant Endocrine therapy • • • • Antiestrogens: Tamoxifen oophorectomy ovarian irradiation luteinizing hormone–releasing hormone (LHRH) agonists: Goserelin, Leuprolide • aromatase inhibitors: Anastrozole, Letrozole Exemestane 40 Adjuvant Endocrine therapy • Tamoxifen – was the “gold standard” adjuvant hormonal therapy – antiestrogenic in breast cancer cells – have estrogenic properties in other tissues and organs – can be used in both premenopausal & postmenopausal women with metastatic breast cancer who have tumors that are hormone-receptor-positive 41 Adjuvant Endocrine therapy • Aromatase inhibitors – Effectively reduce the level of circulating estrogens, as well as estrogens in the target organ. – a standard of care for postmenopausal women with HR positive early stage & metastatic breast cancer – Treatment duration: for five years • because there is no data to support the benefit of extended treatment beyond this duration 42 Adjuvant Endocrine therapy • Early studies – found no benefit to taking tamoxifen for more than the standard 5 years • Recent studies – found that taking tamoxifen for 10 years lowered recurrence rates, reduced breast cancer risk in the opposite breast, and improved survival • postmenopausal women have been able to take an aromatase inhibitor instead of tamoxifen, but they can take either medicine. • aromatase inhibitor do not work in premenopausal women 43 • According to American Society of Clinical Oncology (ASCO) guideline – women postmenopausal after 5 years should be offered continued tamoxifen for up to 10 years, or switch to up to 5 years of an AI – If postmenopausal at start of hormonal therapy, women should be offered – tamoxifen for 10 years, or – AI for 5 years, or – tamoxifen for 5 years, then switch to AI for up to 5 years, or – tamoxifen for 2 to 3 years, then switch to AI for up to 5 years 44 Endocrine Therapies Used for Metastatic Breast Cancer 45 Chemotherapy regimens: metastatic breast cancer 46 47 Adjuvant Biologic Therapy: Trastuzumab • a monoclonal antibody directed against the HER-2/neu receptor • The overexpression of HER-2/neu is associated with increased transmission of growth signals that control aspects of cell growth & division • Indicated for treatment of adjuvant & metastatic breast cancer in patients who have tumors that overexpress HER-2/neu 48 Adjuvant Biologic Therapy: Trastuzumab • should not be given concurrently with the anthracyclines because of an increased risk of cardiotoxicity • Baseline and every 3 months cardiac function tests are required during treatment • Side Effects – Infusion reactions (fever, chills, rigors), nausea, vomiting – pain at tumor site , headaches, dizziness, dyspnea – hypotension, heart failure 49 50 Bisphosphonates adjunct therapy • Recommended in breast cancer metastasized to bone to reduce bone pain and fractures • Pamidronate (90 mg) & zoledronate (4 mg) can be given IV once each month • given in combination with calcium & vitamin D 51 Management of male breast cancer • Investigation is identical to that of the female patient • The majority of male breast cancers are hormone-positive – candidates for adjuvant endocrine therapy. • For most men with breast cancer, tamoxifen is the preferred agent 52 Prognostic factors for breast CA • Patient age – Patients diagnosed at age younger than 35 years have a worse prognosis. • Tumor size – In general, patients with a larger tumor have a worse prognosis 53 Prognostic factors for breast CA • Lymph node involvement – Patients with node-positive disease have a worse prognosis. • Hormone-receptor status – Patients with ER & PR negative tumors have a worse prognosis. • HER-2/neu protein expression – Patients with HER-2/neu over expression have a worse prognosis 54 Monitoring parameters • Early & locally advanced breast cancer – Physical examination to detect breast cancer recurrence – Annual mammography – Symptom-directed work-up • Metastatic breast cancer – patients are monitored monthly for signs of disease progression or metastasis to common sites, such as the bones, brain, or liver – Pain – Mental status or other neurological findings – Laboratory tests • Liver function tests • Complete blood count • Calcium, electrolytes • tumor markers: CA 15-3, CA 27-29, CEA 55 Case study: breast cancer • C.D. has two first-degree relatives with early-age breast cancer. • This would indicate an inherited genetic mutation. • Genetic testing for the presence of BRCA1 and BRCA2 mutations should be 56 discussed with C.D. Case study: breast cancer • What are the typical signs and symptoms of breast cancer and does C.D. have any? – C.D. had a painless lump identified on mammogram 57 Case study: breast cancer • C.D. will need to undergo a biopsy and full staging with a CT scan of the chest, abdomen, and pelvis and a bone scan 58 Case study: breast cancer • Invasive ductal carcinoma is the most common type • have stage II disease based on the size of her disease and the involvement of ipsilateral lymph nodes. 59 Case study: breast cancer Size of the tumor, lymph node involvement, Pathologic testing of the breast tumor (ER and PR and HER2 status) 60 Case study: Breast cancer • C.D. could either undergo breast-conserving surgery plus radiation therapy or a modified radical mastectomy • But with C.D.’s family history she may also choose to undergo bilateral mastectomies to prevent the development of contralateral breast cancer. 61 Case study: Breast cancer • Based on this information, C.D. would be a candidate for surgery & chemotherapy (based on the tumor size and lymph node–positive disease), followed by hormonal therapy due to her ER/PR-positive disease. 62 Case study: breast cancer 63 Case study: breast cancer C.D. should be counseled on the common toxicities associated with her chemotherapy, such as myelosuppression, nausea/vomiting, alopecia, neuropathy, cardiomyopathy, and hypersensitivity reactions 64 Case study: breast cancer • C.D. is premenopausal, so she would start with tamoxifen therapy 65