Breast Cancer Cathy Percival RN FALU FLMI VP

Breast Cancer Cathy Percival, RN, FALU, FLMI VP, Medical Director AIG Life and Retirement

Cell Differentiation n n Process by which a less specialized cell becomes a more specific, functional cell Involves the activation or inactivation of certain genes in response to the cell’s interactions w/ neighboring cells

Cell Proliferation & Apoptosis n Cell proliferation is a physiological process that occurs in almost all tissues n n n Genes control the process of cell division Normal growth requires a balance between the activity of genes that promote proliferation and those that suppress it Apoptosis n Genetically directed process of cell self-destruction n n Programmed cell death Activated either by the presence of a stimulus or removal of a suppressing agent Eliminates DNA-damaged or superfluous cells Normally the balance between proliferation and cell death is tightly regulated to ensure the integrity of organs and tissues

Carcinogenesis

Cancer n A class of diseases or disorders characterized by uncontrolled proliferation of cells and the ability of these cells to invade other tissues n Invasive cancers arise through a series of molecular alterations at the cell level n Damage to DNA results in unregulated growth, causing mutations to genes that encode for proteins controlling cell division n Many mutation events may be required to transform a normal cell into a malignant cell

Causes of Mutations n These mutations can be caused by: n Carcinogens n n Exposure to radioactive materials Genetics Repeated exposure to cell injury n n n Physical or chemical agents Inflammation Certain viruses Exposure to environmental factors n n Tobacco smoke— 35% of all cancer deaths Alcohol

Carcinogens n n n Substances and exposures that can lead to cancer Directly alter DNA of gene or cause increased rate of cell division that could result in changes to DNA Varying levels of cancer-causing potential n Classification systems based on potential of substance to cause cancer n n n International Agency for Research on Cancer (IARC/WHO) National Toxicology Program Environmental Protection Agency

Malignant Tumors Characteristics n n Evade apoptosis Ability to promote blood vessel growth n n n n Unlimited growth potential Self-sufficiency of growth factors Insensitivity to anti-growth factors Increased cell division rate Altered ability to differentiate Ability to invade neighboring tissues Ability for metastasis to distant sites Microscopic findings n n n Large number of dividing cells Variation in nuclear size and shape Variation in cell size and shape Loss of specialized cell features Loss of normal tissue organization Poorly defined tumor boundary

Breast Cancer Facts Leading cause of cancer in women n 124. 6 cases/100, 000 220, 097 diagnosed/40, 931 deaths in 2011 (CDC) Increased incidence due to: n n n n Early detection—increased screening Change in reproductive patterns Dietary changes Decreased activity Mortality has improved slightly due to: n n n Early detection Improved treatment modalities Male breast cancer n n n Accounts for 1% of all breast cancers 2, 078 diagnosed/443 deaths in 2011 (CDC) SEER Data n 2014 Estimates n n n 1 in 8 women will be diagnosed w/ breast cancer during their lifetime n n n 232, 670 women diagnosed (226, 870 in 2012) 40, 000 deaths (39, 510 in 2012) 12. 38% of women On January 1, 2011, there were almost 2. 9 million women in the US living w/ breast cancer (2. 7 million in 2009)

Leading Causes of Cancer Deaths Among Females in 2009 (American Cancer Society)

Percent of Cases & 5 -Year Relative Survival by Stage 2% Percent of Cases 5% 32% 61% 98. 5% 84. 6% 49. 8% 25. 0% 5 -Year Survival

Breast Cancer Risk Factors n n Advanced Age Family History n n n FH of ovarian cancer in women <50 yrs One first-degree relative, or 2 or more relatives w/ breast cancer n n n n n 4 -5 x increased risk of new primary breast cancer n +BRCA 1/BRCA 2 mutation n Prior hx of breast cancer 55 -65% lifetime risk Accounts for 5 -10% of all breast cancers Breast bx w/ atypical hyperplasia Breast bx w/ LCIS or DCIS Use of HRT Current or recent use of oral contraceptives Lifestyle factors n n Early age at menarche (<12 yrs) Late age at menopause Late age of first pregnancy Prolonged estrogen exposure n Personal history n Reproductive history Adult weight gain Sedentary lifestyle Alcohol consumption Environmental factors n n Radiation to the breast Mantle radiation to treat Hodgkin’s disease

Breast Anatomy Breasts n Milk-producing glands situated on front of chest wall n Each breast contains 15 -20 lobes arranged in a circular fashion n Each lobe is comprised of many lobules, at the end of which are glands where milk is produced in response to hormones n 6 -10 major ducts exit the nipple n Most breast cancers are adenocarcinomas—epithelial tumors that develop from cells lining the ducts or lobules

Breast Abnormalities n Hyperplasia n n Overproduction of normal appearing cells Atypical hyperplasia n Cells begin to take on abnormal appearance n In-situ cancer n Invasive cancer

Types of Breast Cancer n n Ductal carcinoma in-situ (DCIS) Lobular carcinoma in-situ (LCIS) n n Infiltrating (invasive) ductal carcinoma n n n n n Incidence has doubled over last 25 yrs Most common— 75% of all breast cancers Infiltrating lobular carcinoma (<15%) Medullary carcinoma (5%) Mucinous (colloid) carcinoma (<5%) Tubular carcinoma (1 -2%) Papillary carcinoma (1 -2%) Metaplastic breast cancer (<1%) Mammary Paget disease (1 -4%) Inflammatory breast cancer

Ductal Carcinoma In Situ (DCIS) n n n n 64, 000 cases diagnosed each year Cells show malignant changes but have not invaded through the basement membrane Accounts for >85% of in situ lesions Classic finding of clustered microcalcifications on mammogram Precurser lesion ½ of DCIS lesions that do occur do so as invasive cancers Risk factors for recurrence: n n n Higher nuclear grade Comedonecrosis Younger age at onset Larger size Presence of palpable nodule Multiple in situ lesions

DCIS Histologic Grading n Grade I—Low grade n n Grade II—Moderate grade n n n Cells appear very similar to normal cells or atypical ductal hyperplasia cells Cells appear less like normal cells Cells grow at faster rate Grade III—High grade n n n More rapid growth Higher risk of invasive cancer Comedo necrosis

Patterns of Low-Moderate DCIS n Papillary DCIS n n n Cribiform DCIS n n Cancer cells are arranged in a finger-like pattern within the ducts Micropapillary—term used when cells are very small Appearance of gaps between cancer cells in the affected breast ducts Solid DCIS n Cancer cells completely fill the affected breast ducts

Comedo Pattern DCIS n Comedonecrosis n Areas of dead (necrotic) cancer cells that build up inside the tumor n Due to the rapid growth of malignant cells, some cells don’t receive adequate nourishment and die off

DCIS— 2 Subtypes DCIS Characteristic Nuclear Grade Estrogen Receptor HER 2 Overexpression Distribution Necrosis Local Recurrence Prognosis Comedo High Negative Present Continuous Present High Worse Noncomedo Low Positive Absent Multifocal Absent Low Better

Lobular Carcinoma In Situ (LCIS) n Considered a biomarker of increased breast cancer risk n n n 10 -20% of women w/ LCIS will develop invasive breast cancer w/in 15 years Increases lifetime risk of invasive cancer to 12 x that of normal women May diffusely involve both breasts Does not show up on mammogram, but is incidentally found during breast biopsy done for another reason Incidence has doubled over the last 25 yrs n n 2. 8/100, 000 women Peak incidence in women aged 40 -50

Invasive Breast Cancers n Invasive Ductal Carcinoma n n n Also called infiltrating ductal carcinoma Malignant cells invade, or spread, from milk ducts to surrounding breast tissue Most common adenocarcinoma of the breast Metastasizes via lymphatic system Risk increases w/ age Invasive Lobular Carcinoma n n Begins in lobules of breast and invades into surrounding breast tissue Accounts for <15% of invasive breast cancers Tends to be multicentric Increased risk of bilateral disease

Less Common Breast Cancers n Medullary carcinoma n n n Mucinous (colloid) carcinoma n n Tumor is made up of abnormal cells that “float” in pools of mucin Affects post-menopausal women ages 60’s-early 70’s Less aggressive—good prognosis Tubular carcinoma n n n Soft, fleshy mass that resembles medulla in the brain Affects women in late 40’s-early 50’s More common in women w/ BRCA 1 mutation High-grade in appearance and low-grade in behavior Usually small and composed of tubular structures—low grade w/ good prognosis Being diagnosed more frequently Papillary carcinoma n n Moderate grade cancer w/ finger-like projections DCIS often also present n Metaplastic breast cancer n n Mammary Paget disease n n n Replacement of one differentiated cell type w/ another differentiated cell type Histologic presence of two or more cellular types High-grade, aggressive malignancy Malignant epithelial cells derived from underlying ductal adenocarcinom Invades into the skin of the nipple and areolar areas Inflammatory breast cancer n n Advanced, aggressive cancer Presents w/ breast pain and skin changes Often mistaken for other breast conditions Invades skin and lymph system

Diagnosis n Signs/symptoms n n n Imaging studies n n n Most breast cancers are asymptomatic Palpable lump or nodule found on self-exam or by MD Skin or nipple changes Bloody nipple discharge Lymph node enlargement Mammogram Ultrasound MRI Nuclear imaging Biopsy n Needle biopsy n n FNA, Core Excisional biopsy

Histologic Features n Important in determining course of treatment n n n n n Size Status of surgical margin Presence or absence of estrogen receptor (ER) and progesterone receptor (PR) Nuclear and histologic grade Proliferation Vascular invasion Tumor necrosis Quantity of intraductal component HER 2 status

Prognostic Indicators n n n Tumor size Axillary lymph node status Lymphatic/vascular invasion Patient age Histologic grade Histologic subtypes n n n n Tubular Mucinous (colloid) Papillary Response to neoadjuvant therapy ER/PR status HER 2 gene amplification and/or overexpression Markers of proliferation

Histologic Grade n n Represents aggressive potential of the tumor Scoring based on 3 factors: n Differentiation n n Nuclear features n n n % of carcinoma composed of tubular structures 1: >75% 2: 10 -75% 3: <10% Pleomorphism—presence of multiple variations in appearance of malignant cells 1: Small, uniform cells 2: Moderate increase in size and variation 3: Marked variation Mitotic count n n Speed of tumor cell division 1: <7 mitoses/hpf 2: 8 -14 mitoses/hpf 3: >15 mitoses/hpf

Histologic Grade n Overall Grade n Grade 1: score of 3 -5 n Well-differentiated tumors n n Grade 2: score of 6 -7 n n More favorable prognosis Moderately-differentiated tumors Grade 3: score of 8 -9 n Poorly-differentiated tumors n n More aggressive Worse prognosis

Breast Cancer Staging n n American Joint Committee on Cancer (AJCC) staging system Groups patients into 4 stages according to TNM system n T (primary tumor size) n N (lymph node status) n M (distant metastasis)

Primary Tumor (T) n n n n Tx—Primary tumor cannot be assessed T 0—No evidence of primary tumor Tis—In-situ Tis—Paget disease of the nipple w/ no tumor T 1—Tumor <2 cm T 1 mic—Microinvasion <0. 1 cm T 1 a—Tumor >0. 1 but not >0. 5 cm T 1 b—Tumor >0. 5 but not >1 cm T 1 c—Tumor >1 cm but not >2 cm T 2—Tumor >2 cm but not >5 cm T 3—Tumor >5 cm T 4—Tumor of any size, w/ direct extension to (a) the chest wall or (b) skin only, as described below T 4 a—Extension to chest wall, not including the pectorallis T 4 b—Edema or ulceration of the skin of the breast or satellite skin nodules confined to the same breast T 4 c—Both T 4 a and T 4 b T 4 d—Inflammatory disease

Regional Lymph Nodes (N) n n n n n Nx—Regional lymph nodes cannot be assessed N 0—No regional lymph node metastasis N 1—Metastasis in movable ipsilateral axillary lymph node(s) N 2—Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis N 2 a—Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures N 2 b—Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph nodes N 3—Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or w/o axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of axillary lymph node N 3 a—Metastasis in ipsilateral infraclavicular lymph node(s) N 3 b—Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) N 3 c—Metastasis in ipsilateral supraclavicular lymph node(s)

Distant Metastasis (M) n Mx—Distant metastasis cannot be assessed n M 0—No distant metastasis n M 1—Distant metastasis

Staging n Stage of breast cancer at time of diagnosis is the most important prognostic indicator

Breast Cancer Staging 5 -year survival n n n Stage Stage 0: 1: 2: 3: 4: 99 -100% 95 -100% 86% 57% 20% Takes into account: n n Tumor size Degree of penetration Invasion to lymph nodes and adjacent organs Presence of metastasis

Biomarkers n Prognostic n n Predictive n n Independent measures of prognosis such that the presence or absence of the biomarker is associated w/risk or recurrence and mortality Predict whether or not a patient will respond to a given therapy Important breast cancer biomarkers n n n Estrogen receptors (ER) Progesterone receptors (PR) Human epidermal growth factor receptor (HER 2)

Estrogen and Progesterone Receptors (ER and PR) n Proteins that allow cells to respond metabolically to estrogen and progesterone n Estrogen receptors are over-expressed in about 70% of breast cancers n n n Binding of estrogen to the ER stimulates proliferation of mammary cells, causing increased cell division and DNA replication, leading to mutations Estrogen metabolism produces genotoxic waste Both of these processes cause disruption of cell cycle, apoptosis and DNA repair n Results in tumor formation n ER/PR status reflects tumor responsiveness to endocrine treatment n Weak prognostic but strong predictive biomarkers n Receptor status has less effect on the probability of recurrence and more effect on when, during the disease course, recurrence occurs n n Receptor negative individuals have higher early recurrence rates Receptor positive individuals have higher later recurrence rates

HER 2 Oncogene n n Promotes cellular proliferation Overexpression of HER 2 is associated w/ increased disease recurrence and a poor prognosis n n Present in 18 -20% of invasive breast cancers HER 2 status has been shown to be predictive for response to certain chemotherapeutic agents and HER 2 -targeted therapies

Breast Cancer Treatment n DCIS n n n Goal of treatment is to prevent local recurrence Lumpectomy w/ local radiation or mastectomy LCIS n n Local tumor doesn’t progress Goal is to prevent development of other invasive cancers n n n Prophylactic mastectomy Chemoprevention using hormonal therapy Use of aromatase inhibitor drugs

Breast Cancer Treatment n Invasive Breast Cancer n Goals of treatment: n Complete elimination of all malignant cells w/ negative margins n n n Positive margins are associated w/ at least a 2 -fold increase in same side breast tumor recurrence Prevention of lymph node invasion and metastasis Surgical Treatment n n Lumpectomy or Mastectomy Lymph node evaluation n n Axillary lymph node dissection (ALND) Sentinal node biopsy n Key lymph node draining the area of the lesion n Positive sentinal node biopsy usually results in full lymph node dissection

Adjuvant Treatment n Localized radiation n n Eradication of local subclinical residual disease Reduction of local recurrence rates Treatment of advanced/metastatic disease Considered standard of care, even in lowest-risk disease w/ the most favorable prognostic features Systemic chemotherapy n n Treatment of recurrent or metastatic breast cancer Treatment of micrometastatic disease n n n Malignant cells that have escaped the breast and regional lymph nodes but which have not yet had an identifiable metastasis Used to reduce risk of future recurrence Estimated to be responsible for 35 -72% of the reduction in mortality

Radiation Therapy n 2 approaches n External-beam radiotherapy (EBRT) n n Partial-breast irradiation (PBI) n n n Whole-breast radiotherapy (WBRT) consists of EBRT delivered to the breast over 5 -6 weeks followed by a boost dose specifically direct to the area of the breast where the tumor was removed Delivers larger fraction sizes while maintaining a low risk of late side effects Interstitial brachytherapy n Multiple catheters placed through the breast Intracavitary brachytherapy n Balloon catheter inserted into lumpectomy site Complications n Catheter placement followed by removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, disease recurrence, cosmetic issues Side effects n n Fatigue, breast pain, swelling and skin desquamation Late toxicity (lasting >6 months after tx) n n Breast edema, pain, fibrosis, skin hyperpigmentation Rare side effects: rib fractures, pulmonary fibrosis, cardiac disease, secondary malignancies

Adjuvant Therapy n Selective estrogen receptor modulators (SERMs) n n n Block the effects of estrogen in the breast tissue Reduce the development of tumors in the opposite breast by at least 1/3 3 drugs used: n n Tamoxifen (Nolvadex) Raloxifene (Evista) Toremifene (Fareston) Aromatase inhibitor drugs n n n Used in postmenopausal women May be superior to SERMs in preventing disease in the opposite breast Block the enzyme aromatase that converts androgens to estrogens in adipose tissue, adrenal glands and some breast tumors n n n Cuts off supply of hormone to the tumor First line therapy for metastatic disease These drugs include: n n n Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin)

Adjuvant Therapy n HER 2 targeted therapies: n n n May be used alone or in combination w/ other chemotherapeutic agents n n Herceptin (Trastuzumab) Tykerb (Lapatinib) Perjeta (Pertuzumab) Kadcyla (Ado-trastuzumab emtansine) Used to treat HER 2+ breast cancers, advanced/metastatic breast cancer, and recurrent disease Adverse effects n n n Cardiotoxicity Inflammation of the liver Diarrhea Rash Thrombocytopenia Neutropenia

Mortality Risk n n Can extend out to many years after original diagnosis Older studies show reduced relative survival for up to 40 years after diagnosis due to: n n The breast cancer itself Secondary malignancies Cardiovascular disease as a complication of adjuvant treatment Recurrence patterns n n Most occur within the first several years after diagnosis However risk of recurrence can extend for many years n n Mortality from the disease has been observed 20 years or more after diagnoses Secondary malignancies n This risk remains constant over time