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