Clinical Pharmacology breast cancer by Dr.Waleed Elnahas Lecturer of surgical oncology Hosam Elghadban Assistant Lecturer of surgery

Incidence ** Age:- 40-50 yr NO age is immune after puberty ** Sex:- ♀:♂= 99:1 (the commonest tumor in female) ** Side:- Left > right Bilateral-----» Simultaneous 1% -----» Metachronous 5% ** Site:- Upper outer quadrant 60% -----» most of mammary tissue ** Geographic:- West > east Developed > developing

Etiology (predisposing factors) 1-Genetic: A-Young age < 30 yr b- Mostly Bilateral c- Multiple relatives with cancer breast (>3) -Hereditary breast cancer :5–10% BRCA-1: Long arm of chromosome 17q BRCA-2: Long arm of chromosome 13q Li-Fraumeni syndrome :P53, Short arm chromosome 17p

2- Endocrinal (Hormonal): - Not married, null Para, elderly primigravida (> 35 yr) and non-lactating female. - Early menarche or late menopause due to prolonged exposure to estrogen. 3- Exposure to radiation: - Nuclear war. - Medical purposes (diagnostic or therapeutic being greater for exposures in childhood and adolescence than after age of 40 years). 4-drugs : estrogen , contraceptive pills more than 10 years (uncertain)

pathology World Health Organization Classification of Carcinoma of the Breast Noninvasive carcinoma -Ductal carcinoma in situ -Lobular carcinoma in situ Invasive carcinoma -Invasive ductal carcinoma -- 80% -Invasive lobular carcinoma – 10% -Mucinous carcinoma -- 2% -Medullary carcinoma – 5% -Papillary carcinoma -- 1% -Tubular carcinoma – 1% -Adenoid cystic carcinoma -Secretory (juvenile) carcinoma -Apocrine carcinoma -Carcinoma with metaplasia (metaplastic carcinoma) -Inflammatory carcinoma -Other : sarcoma, lymphoma and melanoma Paget's disease of the nipple

Spread Direct spread:- 1. Intrinsic: to surrounding breast tissue 2. Extrinsic: ** To the skin causing ulceration & fungation . ** To deep structures: Pectoral fascia, pectoral muscles & chest wall Lymphatic spread:- Haematogenous spread:- Transcoelomic spread:-

Clinical picture ** Symptoms: A- Asymptomatic:- discovered accidentally during screening programs B- Symptomatic:- 1. Mass (commonest presentation) 2. Pain: (Very Rare 10%) 3. Nipple discharge: - Bloody discharge in duct carcinoma 4. Skin & nipple manifestations 5. Manifestations of metastasis:-

Signs: A) General examinations: 1 ** Signs: A) General examinations: 1. Chest: signs of pleural effusion or mediastinal L.N. 2. Abdominal examination: - Hepatomegaly - Ascites. 3. P/R or P/V: nodules in the Douglas’ pouch or Krukenberg’s tumor. 4. Bone: for tenderness, swelling & pathological fracture

B) Local examination: 1- inspection ** Breast: compared to healthy side ** Nipple & areola: may show ** the skin: 1) Skin dimpling, Tethering & Puckering 2) ulceration & fungation: 3) Peau d’orange (Pitted edema): 4) Cancerous satellite nodules (late sign): 5) Cancer en cuirasse ** The mass: ** the axilla ** The arm

2- palpation palpate breasts with both the flat of your hand and fingers. with flat fingers compress breast tissue follow systematically, in a circular pattern around the nipple or along the radial lines (simulate a clock) or vertical segments and feel the entire breast, including the tail near the axilla. Examine criteria of the mass : site, size, shape, consistency Examine axillary lymph nodes

TX :Primary tumor cannot be assessed T0 :No evidence of primary tumor American Joint Committee on Cancer TNM Staging System for Breast Cancer Primary Tumor (T) TX :Primary tumor cannot be assessed T0 :No evidence of primary tumor Tis: Carcinoma in situ Note: Paget's disease associated with a tumor is classified according to the size of the tumor. T1: Tumor 2 cm or less in greatest dimension T1mic :Microinvasion 0.1 cm or less in greatest dimension T1a :Tumor more than 0.1 cm but not more than 0.5 cm in greatest dimension T1b :Tumor more than 0.5 cm but not more than 1 cm in greatest dimension T1c :Tumor more than 1 cm but not more than 2 cm in greatest dimension T2 :Tumor more than 2 cm but not more than 5 cm in greatest dimension T3 :Tumor more than 5 cm in greatest dimension T4a :Extension to chest wall not including pectoralis muscle T4b: Edema (including peau d'orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast T4c :Both T4a and T4b T4d :Inflammatory carcinoma

NX: Regional lymph nodes cannot be assessed (e.g., previously removed) Regional Lymph Nodes (N)  NX: Regional lymph nodes cannot be assessed (e.g., previously removed) N0 :No regional lymph node metastasis N1: Metastasis to movable ipsilateral axillary lymph node(s) N2 : N2a :Metastases in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures N2b :Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastasis N3 N3a :Metastasis in ipsilateral infraclavicular lymph node(s) N3b :Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) N3c :Metastasis in ipsilateral supraclavicular lymph node(s)

M ( METASTASIS) MX : metastasis can no be assessed M0 : no metastasis M1 : metastasis

American Cancer Society Screening Recommendations Annual mammograms, starting at age 40 Clinical breast exams every year starting at age 40 every 3 years for women age 20-39 Self-breast exams monthly, starting at age 20

Breast Self-Exam – Step 1 Begin by looking at your breasts in the mirror with your shoulders straight and your arms on your hips. Here's what you should look for: Breasts that are their usual size, shape, and color. --Breasts that are evenly shaped without visible distortion or swelling. If you see any of the following changes, bring them to your doctor's attention: --Dimpling, puckering, or bulging of the skin. --A nipple that has changed position or become inverted (pushed inward instead of sticking out). --Redness, soreness, rash, or swelling.

Breast Self-Exam – Step 2 Raise your arms and look for the same changes.

Breast Self-Exam – Step 3 Feel your breasts while lying down, using your right hand to feel your left breast and then your left hand to feel your right breast. Use a firm, smooth touch with the first few fingers of your hand, keeping the fingers flat and together. Cover the entire breast from top to bottom, side to side—from your collarbone to the top of your abdomen, and from your armpit to your cleavage

Breast Self-Exam – Step 4 Finally, feel your breasts while you are standing or sitting. Many women find that the easiest way to feel their breasts is when their skin is wet and slippery, so they like to do this step in the shower. Cover your entire breast, using the same hand movements described in Step 3.

Investigations: Mammography (con’t) 􀁺 Standard mammography: depends on density of the tissue and its ability to stop xray beam from exposing film placed on the other side of the breast. Digital mammography works on the same principle, but there is also some ability to manipulate the image by computer. Main advantage is storage of the films.

Ultrasound Since solid tissue and collections of fluid look the same on mammography, ultrasound is very useful in telling whether a mass is solid or fluid, and, if solid, if characteristics are suspicious. Cyst

MRI MRI relies on completely different type of wave energy: a strong magnet that affects the charge in the nuclei. As magnetic force is applied and then released, different types of tissue send back different types of radio waves. MRI can be extremely useful in very dense breasts, hereditary cases

Fine Needle Aspiration Fine needle aspiration of a palpable mass 􀁺 Fine needle aspiration takes individual cells out of mass. Can be done for palpable or non-palpable masses. Does not show architecture, especially wall of duct, so best used to confirm strong suspicions. C0 No epithelial cells C1 Inadequate C2 Benign C3 Atypia C4 Suspicious C5 Malignant

Core Biopsy done on palpable and non palpable 􀁺 Core biopsy can also be done on palpable and non palpable abnormalities, and on microcalcifications. B1 Normal tissue / unsatisfactory B2 Benign B3 Lesion uncertain malignant potential B4 Suspicion of malignancy B5a In situ malignancy B5b Invasive malignancy

Investigations for metastasis 1- abdominal ultrasound 2- chest x ray or CT 3- bone survey or bone scan

Established prognostic factors Nodal status Tumor size Lymph node Grade ER/PR Status Age Lymphatic invasion Histological tumor type Perinodular infiltration

Lumpectomy with breast irradiation Mastectomy TREATMENT OPTIONS FOR PRIMARY OPERABLE BREAST CANCER Objective Options Local control Lumpectomy Lumpectomy with breast irradiation Mastectomy Regional control Axillary lymph node dissection Regional irradiation Control of occult Chemotherapy micrometastatic disease Hormone therapy Improved function and cosmesis Breast-conserving therapy Reconstruction (immediate or delayed)

Localized breast cancer Surgery is mainstay Halsted, 1882, radical mastectomy John Hopkins Metastatic breast cancer Systemic treatment

Radical mastectomy A. Entire breast and a chest wall muscle is removed. LNs in the level 1 (B) and level 2 (C ), and even sometimes more distant lymph node groups (D, E and F) were also removed.

Modified radical mastectomy (MRM) A. Entire breast is removed Classically some lymph nodes in the level 1 (B) and level 2 (C ) were removed, called an axillary lymph node dissection. MRM = simple mastectomy + ALND

Breast conserving surgery Also called lumpectomy with safety margin with axillary clearance or sentinel lymph node biopsy RT should be followed

Adjuvant systemic treatment Hypothesis: Eradicate micrometastasis From effective treatment for overt (macro) metastasis Chemotherapy Hormone therapy

Adjuvant chemotherapy CMF, first generation, 1970s Cyclophosphamide Methotrexate 5-FU Benefit in Distant recurrence Survival

Adjuvant chemotherapy CAF or CEF, 2nd generation, 1980s Cyclophophamide Adramycin(or Epirubicin) 5-FU More toxic than CMF CAF better than CMF in high-risk group Axilla LN+ LN-, but tumor large or other risk factor

Adjuvant chemotherapy Incorporate Taxane TAC, 3rd generation, mid-1990s Taxotere Adriamycin Cyclophosphamide More toxic than CAF Better than CAF in high-risk group Need more time to observe

Adjuvant Herceptin Effective in Her2+ pts (HER-2 (Human Epidermal growth factor Receptor 2) also known as proto-oncogene Neu Over expression of this gene is correlated with higher aggressiveness in breast cancer. HER2 is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation). Effective in Her2+ pts ICH3+ FISH+ Herceptin + adjuvant chemotherapy Optimal role to be defined Concurrent or sequential? Maintenance ? Duration

Adjuvant hormone therapy In premenopausal woman Oophorectomy could control metastatic disease Tamoxifen Selective estrogen receptor antagonist Effective in pre- and post-menopausal Effective in adjuvant setting

Adjuvant hormone therapy Aromatase inhibitor Effective in post-menopausal state Aromatase, in fat tissue, Convert androgen to estrogen Main estrogen source in post-menopausal Exemestane : Aromasin Letrozole: Femara Anastrozole: Arimidex More effective than Tamoxifen

Adjuvant ovarian suppression Effective in pre-menopausal state Type Surgical ablation RT ablation GnRH analogue: Goserelin, Leupride Exact role to be defined Combination with chemotherapy? Combination with AI or TAM?

Radiation therapy Radiation kills the cancer cells left after surgery. Radiation therapy doesn't make you radio active. Radiation is painless when it’s delivered, but it will become more painful over time. Treatments will be given up to 5-7 weeks, 5 days a week. Treatments only take ½ hour so you can keep your routine. Your hair won’t fall out unless you are also taking chemotherapy. Your skin in the area may become red and easily irritated. You may feel tired even after its over. Radiation after surgery reduces the chances of the cancer reoccurring.

Treatment of metastatic dz Usual sites: bone, lung, liver, brain Incurable Goal: live with dz for longest time Systemic treatment is mainstay Chemotherapy Hormone therapy Palliative local therapy Radiotherapy Palliative surgery

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