Date post: | 18-Dec-2015 |
Category: |
Documents |
Upload: | pierce-oliver |
View: | 217 times |
Download: | 0 times |
Breast Cancer
Cathy Percival, RN, FALU, FLMIVP, Medical DirectorAIG Life and Retirement
Cell Differentiation
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
Cell proliferation is a physiological process that occurs in almost all tissues
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 Genetically directed process of cell self-destruction
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 A class of diseases or disorders characterized by uncontrolled
proliferation of cells and the ability of these cells to invade other tissues
Invasive cancers arise through a series of molecular alterations at the cell level
Damage to DNA results in unregulated growth, causing mutations to genes that encode for proteins controlling cell division
Many mutation events may be required to transform a normal cell into a malignant cell
Causes of Mutations
These mutations can be caused by: Carcinogens
Physical or chemical agents
Exposure to radioactive materials Genetics Repeated exposure to cell injury
Inflammation Certain viruses Exposure to environmental factors
Tobacco smoke—35% of all cancer deaths Alcohol
Carcinogens 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
Classification systems based on potential of substance to cause cancer
International Agency for Research on Cancer (IARC/WHO) National Toxicology Program Environmental Protection Agency
Malignant TumorsCharacteristics
Evade apoptosis Ability to promote blood vessel
growth 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 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
124.6 cases/100,000 220,097 diagnosed/40,931 deaths in 2011 (CDC) Increased incidence due to:
Early detection—increased screening Change in reproductive patterns Dietary changes Decreased activity
Mortality has improved slightly due to: Early detection Improved treatment modalities
Male breast cancer Accounts for 1% of all breast cancers 2,078 diagnosed/443 deaths in 2011 (CDC)
SEER Data 2014 Estimates
232,670 women diagnosed (226,870 in 2012) 40,000 deaths (39,510 in 2012)
1 in 8 women will be diagnosed w/ breast cancer during their lifetime 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
LocalizedRegionalDistantUnstaged
0.00%
20.00%
40.00%
60.00%
80.00%
100.00%
120.00%
LocalizedRegionalDistantUnstaged
Percent of Cases
5-Year Survival
61%
32%
5%
2%
98.5%
84.6%
25.0%
49.8%
Breast Cancer Risk Factors Advanced Age Family History
FH of ovarian cancer in women <50 yrs
One first-degree relative, or 2 or more relatives w/ breast cancer
Personal history Prior hx of breast cancer
4-5x increased risk of new primary breast cancer
+BRCA1/BRCA2 mutation 55-65% lifetime risk Accounts for 5-10% of all
breast cancers Breast bx w/ atypical
hyperplasia Breast bx w/ LCIS or DCIS
Reproductive history Early age at menarche (<12
yrs) Late age at menopause Late age of first pregnancy
Prolonged estrogen exposure
Use of HRT Current or recent use of oral
contraceptives Lifestyle factors
Adult weight gain Sedentary lifestyle Alcohol consumption
Environmental factors Radiation to the breast Mantle radiation to treat
Hodgkin’s disease
Breast AnatomyBreasts Milk-producing glands situated
on front of chest wall Each breast contains 15-20
lobes arranged in a circular fashion
Each lobe is comprised of many lobules, at the end of which are glands where milk is produced in response to hormones
6-10 major ducts exit the nipple
Most breast cancers are adenocarcinomas—epithelial tumors that develop from cells lining the ducts or lobules
Breast Abnormalities Hyperplasia
Overproduction of normal appearing cells
Atypical hyperplasia
Cells begin to take on abnormal appearance
In-situ cancer
Invasive cancer
Types of Breast Cancer Ductal carcinoma in-situ (DCIS) Lobular carcinoma in-situ (LCIS)
Incidence has doubled over last 25 yrs Infiltrating (invasive) ductal carcinoma
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)
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:
Higher nuclear grade Comedonecrosis Younger age at onset Larger size Presence of palpable nodule Multiple in situ lesions
DCIS Histologic Grading Grade I—Low grade
Cells appear very similar to normal cells or atypical ductal hyperplasia cells
Grade II—Moderate grade Cells appear less like normal cells Cells grow at faster rate
Grade III—High grade More rapid growth Higher risk of invasive cancer Comedo necrosis
Patterns of Low-Moderate DCIS Papillary DCIS
Cancer cells are arranged in a finger-like pattern within the ducts
Micropapillary—term used when cells are very small
Cribiform DCIS Appearance of gaps between cancer cells
in the affected breast ducts
Solid DCIS Cancer cells completely fill the affected
breast ducts
Comedo Pattern DCIS
Comedonecrosis Areas of dead (necrotic) cancer cells that
build up inside the tumor Due to the rapid growth of malignant cells, some
cells don’t receive adequate nourishment and die off
DCIS—2 Subtypes
DCIS Characteristic Comedo NoncomedoNuclear Grade High LowEstrogen Receptor Negative PositiveHER2 Overexpression Present AbsentDistribution Continuous MultifocalNecrosis Present AbsentLocal Recurrence High LowPrognosis Worse Better
Lobular Carcinoma In Situ (LCIS)
Considered a biomarker of increased breast cancer risk
10-20% of women w/ LCIS will develop invasive breast cancer w/in 15 years
Increases lifetime risk of invasive cancer to 12x 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
2.8/100,000 women Peak incidence in women aged 40-
50
Invasive Breast Cancers Invasive Ductal Carcinoma
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 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
Medullary carcinoma Soft, fleshy mass that resembles
medulla in the brain Affects women in late 40’s-early
50’s More common in women w/ BRCA1
mutation High-grade in appearance and low-
grade in behavior Mucinous (colloid) carcinoma
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
Usually small and composed of tubular structures—low grade w/ good prognosis
Being diagnosed more frequently Papillary carcinoma
Moderate grade cancer w/ finger-like projections
DCIS often also present
Metaplastic breast cancer Replacement of one
differentiated cell type w/ another differentiated cell type
Histologic presence of two or more cellular types
High-grade, aggressive malignancy
Mammary Paget disease Malignant epithelial cells
derived from underlying ductal adenocarcinom
Invades into the skin of the nipple and areolar areas
Inflammatory breast cancer Advanced, aggressive cancer Presents w/ breast pain and
skin changes Often mistaken for other breast
conditions Invades skin and lymph system
Diagnosis Signs/symptoms
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
Imaging studies Mammogram Ultrasound MRI Nuclear imaging
Biopsy Needle biopsy
FNA, Core Excisional biopsy
Histologic Features Important in determining course of treatment
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 HER2 status
Prognostic Indicators Tumor size Axillary lymph node status Lymphatic/vascular invasion Patient age Histologic grade Histologic subtypes
Tubular Mucinous (colloid) Papillary
Response to neoadjuvant therapy ER/PR status HER2 gene amplification and/or
overexpression Markers of proliferation
Histologic Grade Represents aggressive potential of the tumor Scoring based on 3 factors:
Differentiation % of carcinoma composed of tubular structures 1: >75% 2: 10-75% 3: <10%
Nuclear features 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 Speed of tumor cell division 1: <7 mitoses/hpf 2: 8-14 mitoses/hpf 3: >15 mitoses/hpf
Histologic Grade Overall Grade
Grade 1: score of 3-5 Well-differentiated tumors
More favorable prognosis
Grade 2: score of 6-7 Moderately-differentiated tumors
Grade 3: score of 8-9 Poorly-differentiated tumors
More aggressive Worse prognosis
Breast Cancer Staging American Joint Committee on Cancer (AJCC)
staging system
Groups patients into 4 stages according to TNM system T (primary tumor size) N (lymph node status) M (distant metastasis)
Primary Tumor (T) Tx—Primary tumor cannot be assessed T0—No evidence of primary tumor Tis—In-situ Tis—Paget disease of the nipple w/ no tumor T1—Tumor <2cm T1mic—Microinvasion <0.1cm T1a—Tumor >0.1 but not >0.5cm T1b—Tumor >0.5 but not >1cm T1c—Tumor >1cm but not >2cm T2—Tumor >2cm but not >5cm T3—Tumor >5cm T4—Tumor of any size, w/ direct extension to (a) the chest wall or (b) skin only,
as described below T4a—Extension to chest wall, not including the pectorallis T4b—Edema or ulceration of the skin of the breast or satellite skin nodules
confined to the same breast T4c—Both T4a and T4b T4d—Inflammatory disease
Regional Lymph Nodes (N) Nx—Regional lymph nodes cannot be assessed N0—No regional lymph node metastasis N1—Metastasis in movable ipsilateral axillary lymph node(s) N2—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
N2a—Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures
N2b—Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph nodes
N3—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
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)
Distant Metastasis (M) Mx—Distant metastasis cannot
be assessed
M0—No distant metastasis
M1—Distant metastasis
Staging Stage of breast cancer at
time of diagnosis is the most important prognostic indicator
Breast Cancer Staging5-year survival
Stage 0: 99-100% Stage 1: 95-100% Stage 2: 86% Stage 3: 57% Stage 4: 20%
Takes into account: Tumor size Degree of penetration Invasion to lymph nodes
and adjacent organs Presence of metastasis
Biomarkers Prognostic
Independent measures of prognosis such that the presence or absence of the biomarker is associated w/risk or recurrence and mortality
Predictive Predict whether or not a patient will respond to a
given therapy
Important breast cancer biomarkers Estrogen receptors (ER) Progesterone receptors (PR) Human epidermal growth factor receptor (HER2)
Estrogen and Progesterone Receptors (ER and PR)
Proteins that allow cells to respond metabolically to estrogen and progesterone
Estrogen receptors are over-expressed in about 70% of breast cancers 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
Results in tumor formation
ER/PR status reflects tumor responsiveness to endocrine treatment
Weak prognostic but strong predictive biomarkers
Receptor status has less effect on the probability of recurrence and more effect on when, during the disease course, recurrence occurs
Receptor negative individuals have higher early recurrence rates Receptor positive individuals have higher later recurrence rates
HER2 Oncogene Promotes cellular proliferation Overexpression of HER2 is associated w/ increased disease
recurrence and a poor prognosis Present in 18-20% of invasive breast cancers
HER2 status has been shown to be predictive for response to certain chemotherapeutic agents and HER2-targeted therapies
Breast Cancer Treatment DCIS
Goal of treatment is to prevent local recurrence Lumpectomy w/ local radiation or mastectomy
LCIS Local tumor doesn’t progress Goal is to prevent development of other invasive
cancers Prophylactic mastectomy Chemoprevention using
hormonal therapy Use of aromatase inhibitor
drugs
Breast Cancer Treatment Invasive Breast Cancer
Goals of treatment: Complete elimination of all malignant cells w/ negative
margins 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 Lumpectomy or Mastectomy Lymph node evaluation
Axillary lymph node dissection (ALND) Sentinal node biopsy
Key lymph node draining the area of the lesion
Positive sentinal node biopsy usually results in full lymph node dissection
Adjuvant Treatment Localized radiation
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
Treatment of recurrent or metastatic breast cancer Treatment of micrometastatic disease
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 2 approaches
External-beam radiotherapy (EBRT) 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
Partial-breast irradiation (PBI) Delivers larger fraction sizes while maintaining a low risk of late
side effects Interstitial brachytherapy
Multiple catheters placed through the breast Intracavitary brachytherapy
Balloon catheter inserted into lumpectomy site Complications
Catheter placement followed by removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, disease recurrence, cosmetic issues
Side effects Fatigue, breast pain, swelling and skin desquamation Late toxicity (lasting >6 months after tx)
Breast edema, pain, fibrosis, skin hyperpigmentation Rare side effects: rib fractures, pulmonary fibrosis, cardiac disease, secondary
malignancies
Adjuvant Therapy Selective estrogen receptor modulators (SERMs)
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:
Tamoxifen (Nolvadex) Raloxifene (Evista) Toremifene (Fareston)
Aromatase inhibitor drugs 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 Cuts off supply of hormone to the tumor
First line therapy for metastatic disease These drugs include:
Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin)
Adjuvant Therapy HER2 targeted therapies:
Herceptin (Trastuzumab) Tykerb (Lapatinib) Perjeta (Pertuzumab) Kadcyla (Ado-trastuzumab emtansine)
May be used alone or in combination w/ other chemotherapeutic agents
Used to treat HER2+ breast cancers, advanced/metastatic breast cancer, and recurrent disease
Adverse effects Cardiotoxicity Inflammation of the liver Diarrhea Rash Thrombocytopenia Neutropenia
Mortality Risk Can extend out to many years after original diagnosis Older studies show reduced relative survival for up to
40 years after diagnosis due to: The breast cancer itself Secondary malignancies Cardiovascular disease as a complication of
adjuvant treatment Recurrence patterns
Most occur within the first several years after diagnosis
However risk of recurrence can extend for many years
Mortality from the disease has been observed 20 years or more after diagnoses
Secondary malignancies This risk remains constant over time