Perjeta

PERJETA® is a first-line treatment for HER2-positive metastatic breast cancer.

• PERJETA is an FDA-approved treatment for HER2-positive metastatic breast cancer. It is a targeted therapy used as part of a first-line HER2-positive metastatic breast cancer treatment plan, in combination with Herceptin (trastuzumab) and docetaxel (chemotherapy).

PERJETA is referred to as a HER2 dimerization inhibitor (HDI).

PERJETA is referred to as a HER2 dimerization inhibitor (HDI).

• Learn more about HDIs.

HER family receptors are activated by ligand-induced dimerization, or receptor pairing.3 Dimerization is a critical step in HER family-mediated signaling, and HER receptors are able to homodimerize or heterodimerize with

What is HER2-positive breast cancer?

All cells have HER2 receptors, including healthy cells and cancer cells. In HER2-positive breast cancer, tumor cells have more HER2 receptors than normal. Too much HER2 makes these cancer cells grow and divide too rapidly.

NONCANCEROUS CELL

What is HER2-positive breast cancer?

All cells have HER2 receptors, including healthy cells and cancer cells. In HER2-positive breast cancer, tumor cells have more HER2 receptors than normal. Too much HER2 makes these cancer cells grow and divide too rapidly.

HER2-POSITIVE CANCER CELL

Cancer treatments called HER2-targeted therapies have been developed to target the HER2 receptor.

PERJETA is one of those HER2-targeted therapies.

PERJETA is a targeted therapy for treating HER2-positive metastatic breast cancer.

PERJETA was designed to search for and attack cancer cells with too much HER2HER2 tells cancer cells to grow by sending signalsHER2 works by sending signals that tell cells to grow and divide One way that HER2 can send signals is by pairing with other HER receptors. This process is called dimerization

PERJETA is a targeted therapy for treating HER2-positive metastatic breast cancer.

PERJETA works with Herceptin to target HER2 PERJETA and Herceptin both target HER2 but work in different waysPERJETA is thought to block one method of signaling so that certain receptors are unable to pair (dimerization) with HER2Together, PERJETA and Herceptin are thought to create a stronger blockade against HER2 signals, helping to slow down cancer cell growth

HER2 signaling could inhibit the growth of tumors.

PERJETA is proven to help control cancer growthAdding PERJETA to Herceptin and docetaxel (chemotherapy) increased the time people lived without their cancer growing or spreading by an average of 50%, compared with people who took Herceptin and docetaxel (chemotherapy) alone

PERJETA is a targeted therapy used as part of a first-line HER2-positive metastatic breast cancer treatment plan. This treatment plan includes Herceptin and docetaxel, a type of chemotherapy. PERJETA and Herceptin both target HER2 but are believed to work in complementary ways. The combination may increase death of cancer cells.

ERJETA helped people live longer

On average, people who were given PERJETA, Herceptin, and docetaxel (chemotherapy) lived significantly longer than people given only Herceptin and docetaxel (chemotherapy)

PERJETA is proven to shrink tumors

80% of people taking the PERJETA combination had their tumors shrink, compared to 69% of people taking Herceptin and docetaxel (chemotherapy) alonePeople who had their tumors shrink maintained this response, on average, for 62% longer on the PERJETA combination compared with people taking only Herceptin and docetaxel (chemotherapy) (20.2 months vs 12.5 months)

PERJETA is taken together with Herceptin, another HER2 therapy

THE BREAST

A. Embryologically: belong to integument

B. Functionally: part of reproductive system

1. Respond to sexual stimulation

2. Feed babies

I. Introduction/General Information

Breast, continued …

C. Modified apocrine sweat glands

- apex of cell becomes part of secretion and breaks off

D. Present in males and females

A. Position and Attachment1. Lateral aspect of pectoral region2. Located between ribs 3 and 6/73. Extend form sternum to axilla4. Surrounded by superficial fascia5. Rest on deep fascia

II. Anatomy

Breast Anatomy

6. Fixed to skin & underlying fascia by fibrous C.T. bands

a. Cooper’s (Suspensory) Ligaments

b. Ligaments may retract when breast tumors are present

Position & attachment, continued ….

Cooper’s Suspensory Ligaments

Position & attachment, continued …

6. Left breast is usually slightly larger

7. Base is circular, either flattened or concave

8. Separated from pectoralis major muscle by fascia, retromammary space

Retromammary Space

Retromammary Space

Anatomy, continued …

B. Structure

1. Outer surface convex, skin covered

2. Nipple:a. At fourth intercostal spaceb. Small conical/cylindrical

prominence below center

Nipple location

4th intercostal space

Structure, continued …

c. Surrounded by areola: pigmented ring of skin

d. Thin skinned region lacking hair, sweat glands

e. Contains areolar glands


3. Areola: contains dark pigment that intensifies with pregnancy

a. Circular and radial smooth muscle fibers

b. Cause nipple erection

Areola


4. Each breast consists of ~ 20 lobes of secretory tissue

a. Each lobe has one lactiferous ductb. Lobes (and ducts) arranged radially c. Embedded in connective tissue &

adipose of superficial fasciad. Lobes composed of lobulese. Lobules comprise alveoli

Lobes and Lobules


5. Excretory (lactiferous) ducts converge toward areola

a. Form ampullae (collection sites of lactiferous sinuses)

b. Ducts become contracted at base of nipple

Excretory (lactiferous) ducts


6. Secretory epitheliuma. Changes with hormonal signals

b. Onset of menstruationc. Pregnancy (glands begin to enlarge at 2nd month)d. After birth, 1st secretion is colostrom (contain

antibodies)


7. “Tail of Spence” = axillary tail a. prolongation of upper, outer

quadrant in axillary direction

b. Passes under axillary fascia

c. May be mistaken for axillary lymph nodes

“Tail of Spence”Axillary Tail


8. Fatty Tissue: surrounds surface, fills spaces between lobesa. Determines form & size of breast

b. No fatty deposit under nipple & areola

Breast: Fatty Tissue

Structure, continued …C. Vessels & nerves

1. Arteries: derived from thoracic branches of three pairs of arteries

a. Axillary arteries

1) continuous with subclavian a. 2) gives rise to external

mammary ( = lateral thoracic) artery

Vessels & Nerves, continued …

b. Internal mammary (thoracic) arteries

1) first descending branch of subclavian artery 2) supply intercostal spaces & breast3) used for coronary bypass surgery

c. Intercostal arteries:

1) numerous branches from internal & external mammary arteries

2) supply intercostal spaces & breast

Subclavian a.

Axillary a.

External mammary (thoracic) a.

Internal mammary (thoracic) a.

Arterial Supply to the Breast

Vessels & Nerves, continued …

2. Veins: a. form a ring around the base of the nipple (“circulus

venosus”)

b. Large veins pass from circulus venosus to circumference of mammary gland, then to

c. External mammary v to axillary v or

d. Internal mammary v to subclavian v

Veins draining the Breast

Subclavian vein

External mammary vein

Breast Anatomy, con’t…

3. Innervation: derived from:

a. anterior & lateral cutaneous nerves of thorax

b. spinal segments T3 – T6


4. Lymphatics: clinically significant!a. Glandular lymphatics drain into anterior axillary (pectoral) nodes central axillary nodes apical nodes deep cervical nodes subclavicular (subclavian) nodes

b. Medial quadrants drain into parasternal nodes

Subclavian nodes

Axillary nodes

Lateral pectoral nodes

Parasternal nodes

Lymph Nodes of the Breast

Lymphatics, continued …

c. Superficial regions of skin, areola, nipples: -form large channels & drain into pectoral nodes

d. NOTE: axillary nodes also drain lymph from arm

Lymph Nodes and Lymph Drainage

Axillary Nodes

Routes of Metastasis• From medial lymphatics to parasternal nodes

– Then to mediastinal nodes

• Across the sternum in lymphatics toopposite side via cross-mammary pathways

– Then to contralateral breast

• From subdiaphragmatic lymphatics to nodes in abdomen– Then to liver, ovaries, peritoneum

Subdiaphragmatic Lymph Channels

Channels to Contralateral Breast

Axillary Lymph Channels

Major Routes of Metastasis


D. Anomalies1. Inverted nipple: congenital or due to cancer2. Ectopic nipple:

a. “polythelia” or “hyperthelia”b. additional nipples along milk line

3. Amastia 4. Micromastia

Anomalies, continued …

5. Macromastia

6. Gynecomastia a. breast development of male in areolar

region

b. noted in males who smoke marijuana at puberty

III. Diseases of the BreastA. Most are readily detectable

B. Etiology unknown, influencing factors

1. Sex

2. Heredity

3. Endocrine influence

a. Menstruation – tenderness from fluid engorgementb. Post-menopause

1) decrease of fibro-cystic disease2) increase in cancer

c. Pregnancy

Diseases of the breast, continued …

Diseases of the Breast, continued …

C. General symptoms & signs1. Nipple discharge

a. always significant if not pregnant.

b. May be due to benign pituitary tumor.

2. Local pain, tenderness 3. Duration of lesion4. Size, rate of growth

Symptoms & Signs, continued …

5. Retraction sign: “dimpling” involving skin, nipple or areola

6. Mobility of massa. Benign = movable

1) not attached 2) not invasive

b. Malignant = attached 1)May grow into bone

7. Consistency of mass

a. Cysts = fluctuant; compressible

b. Fibroadenoma = rubbery

c. Carcinoma = firm, hard (like gravel)

8. Axillary area lymph node enlargement

Symptoms & Signs, continued …

1. Infection = usually during or after lactation

a. Recurrent, subareolar abscessb. TB of the breast

2. Trauma = contusion 3. Hypertrophy = seen in either sex at

adolescence

a. Gynecomastia = in males

D. Benign breast conditions

b. Other causes

1) testicular or pituitary tumor2) cirrhosis 3) hypogonadism = not enough testosterone4) estrogen administration for prostate cancer

Hypertrophy, continued …

Breast Cancer

Breast cancer originates in breast tissue and arises from the ductal tissue of the breast and, less

commonly, the lobulartissue. There are several forms of breast cancer based, in part, on cellular and

genetic characteristics,

Types of Breast Cancer

HER2-Positive Overabundance of the HER2 protein classifies the breast cancer as HER2-positive and causes breast cancer

cells to multiply, spread more rapidly, and survive longer than other

breast cancers

63

Ductal Carcinoma in situ (DCIS)

Illustration © Mary K. Bryson

Ductal cancer cells

Normal ductal cellCarcinoma refers to

any cancer that begins in the skin or other tissues that cover internal organs

Hormone Receptor-Positive Breast cancer cells that express hormone receptors for estrogen (ER) and/or progesterone (PR) are dependent on the signaling

of those receptors

65

Invasive Ductal Carcinoma (IDC – 80% of breast cancer)

• The cancer has spread to the surrounding tissues


Ductal cancer cells breaking through the wall

Triple Negative Some women have a more difficult-to-treat form of breast cancer known as "triple-negative," which means they test negative for 3 main receptors

(HER2, ER, andPR) Each form of breast cancer has a different prognosis.

The American Society of Clinical Oncology recommends that all women diagnosed with breast cancer have tumor marker tests, which can help

identify which type of breast cancer a patient has and help determine the best treatment options.

67

Range of Ductal Carcinoma in situ

Illus

trat

ion

© M

ary

K.

Bry

son

68

Invasive Lobular Carcinoma (ILC)


Lobular cancer cells breaking

through the wall

69

Cancer Can also Invade Lymph or Blood Vessels


Cancer cells invade

lymph duct

Cancer cells invade blood vessel

Breast Cancer Demographic StatisticsBreast cancer is the second most commonly

diagnosed cancer and the second leading cause of cancer deaths among women in the United States. In 2010, more than 207,090 American women were diagnosed and nearly 40,000 died of

breast cancer.One in 4 women has HER2-positive breast cancer, a

more aggressive type associated with a poorer prognosis.

Breast Cancer EpidemiologyFamily history of breast cancer, or personal history of breast abnormalities, early age at first menstrual period, obesity, and physical inactivity can contribute to development of

breast cancerInheritance of mutations in specific genes, such as BRCA1 and BRCA2 contributes to

the relative risk of developing breast cancer

72

Mammography

• Use a low-dose x-ray system to examine breasts

• Digital mammography replaces x-ray film by solid-state detectors that convert x-rays into electrical signals. These signals are used to produce images that can be displayed on a computer screen (similar to digital cameras)

• Mammography can show changes in the breast up to two years before a physician can feel them

73

Computer-Aided Diagnosis

• Mammography allows for efficient diagnosis of breast cancers at an earlier stage

• Radiologists misdiagnose 10-30% of the malignant cases

• Of the cases sent for surgical biopsy, only 10-20% are actually malignant

National Cancer Institute

CAD systemscan assist

radiologists toReduce theseproblems

74

What Mammograms Show

Two of the most important mammographic indicators of breat cancers

– Masses

– Microcalcifications: Tiny flecks of calcium – like grains of salt – in the soft tissue of the breast that can sometimes indicate an early cancer.

75

Detection of Malignant Masses

Malignant masses have a more spiculated appearance

malignant

benign

76

Mammogram – Difficult Case

• Heterogeneously dense breast

• Cancer can be difficult to detect with this type of breast tissue

• The fibroglandular tissue (white areas) may hide the tumor

• The breasts of younger women contain more glands and ligaments resulting in dense breast tissue

77

Mammogram – Easier Case

• With age, breast tissue becomes fattier and has fewer glands

• Cancer is relatively easy to detect in this type of breast tissue

78

Different Views

Top-to-Bottom

Side-to-Side

MRI - Cancer can have a uniqueappearance – many small irregularwhite areas that turned out to becancer (used for diagnosis)

Benign Conditions, continued

4. Tumors & cystsa. Fibroadenoma =

most common benign

breast tumor

Tumors and Cysts, con’t…

b. Breast Cyst1. Benign2. May be aspirated if large

c. Fibrocystic breast changes

1) 20%+ of remenopausal women

2) discomfort, cysts3) treatment rarely

required 4) More likely to not

detect a developing cancer

Benign conditions, continued …

d. Intraductal papilloma

- may produce “chocolate” or bloody discharge from nipple

e. Lipoma: common

- fatty tumors

Tumors & cysts, continued ….

1. Most common malignant tumor among women

2. 1/8 of women will develop breast cancera. 1/6 in Orange Countyb. 1/5 in San Francisco

3. Generally no discomfort

Carcinoma of the breast

Progression to Breast Cancer

4. Physical signs:a. Slowly growing, painless massb. May demonstrate retracted nipplec. May be bleeding from nippled. May be distorted areola, or breast

contoure. Skin dimpling in more advanced stages

with retraction of Cooper’s ligaments

Carcinoma of breast, continued …

f. Attachment of mass

g. Edema of skin

1)with “orange skin” appearance (peau d’orange)

2) due to blocked lymphatics

h. Enlarged axillary or deep cervical lymph nodes

Physical signs, continued …

Breast Cancer, con’t…

5. Common sites for metastasisa. Lungs & pleurab. Skeleton system (skull, vertebral column,

pelvis)c. Liver

6. Atypical carcinomasa. Inflammatory carcinoma (hormonal,

chemotherapy) b. Paget’s disease of the breast

pagget's disease

89

Scalar Field

• A scalar field is a n-dimensional space with a scalar value attached to each point in the space (e.g., a gray-scale image)

90

Scalar Field and Gradient

• A scalar field is a n-dimensional space with a scalar value attached to each point in the space (e.g., a gray-scale image)

• The derivative of a scalar field results in a vector field called the gradient– i.e., the gradient is a vector field

• which points in the direction of the greatest rate of increase of the scalar field, and

• whose magnitude is the greatest rate of change

Black representingHigher values

91

Gradient

The derivative of a scalar field results in a vector field called the gradient

– i.e., the gradient is a vector field

• which points in the direction of the greatest rate of increase of the scalar field, and

• whose magnitude is the greatest rate of change

Black representingHigher values

92

Cartesian Gradient

For an image function I(P) where P is a pixel, the Cartesian gradient at P is:

y

PIx

PI

Pg )(

)(

)(

xPI

yPI

P )(

)(

arctan)(

Orientation:

yPI

xPIPm )()()(

22

Magnitude:

)(P

)(Pg

P

( )I P

y

( )I P

x

( )

tan( )

I PyI Px

93

Radial Gradient

• The radial gradient vector has the same magnitude as the Cartesian gradient vector, but

• the orientation is given as:

)(P

)(Pg

P

)()()( PPPr

)(Pr

)(P

Radial gradient

94

Feature: Spiculation [Huo et al.]

• Extract the mass using a region-growing technique

• The maximum gradient and its angle relative to the radial direction are computed

• Calculate the full-width at half-maximum (FWHM) from the cumulative gradient orientation histogram

95

Feature: Spiculation [Chan et al.]

• Determine the outline of the segmented mass

• Obtain the rubber-band-straightening-transformed image– The spicules become

approximately aligned in a similar direction

• The rectangular region can then be subjected to texture analysis

96

Breast Calcifications

• Calcifications show up as white spots on a mammogram

• Round well-defined, larger calcifications (left column) are more likely benign

• Tight cluster of tiny, irregularly shaped calcifications (right column) may indicate cancer

97

Calcification Features

• The morphology of individual calcification, e.g., shape, area, and brightness

• The heterogeneity of individual features characterized by the mean, the standard deviation, and the maximum value for each feature.

• Cluster features such as total area, compactness

98

Database Approach toComputer-Aided Diagnosis

• The database consists of a large number of images with verified pathology results

• Diagnosis is done by submitting the suspected mass region as a query to retrieve similar cases from the database

Content-based image retrieval techniques can provide radiologists “visual aids” to increase confidence in their diagnosis

99

A Mammography CAD System[Giger et al.]

Probability of malignancy

Similar images ofknown diagnosis

Indicates the unknownlesion relative to alllesions in the database


PERJETA® (Pertuzumab)is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2). Pertuzumab is produced by recombinant DNA technology in a mammalian cell (Chinese Hamster Ovary) culture containing the antibiotic, gentamicin. Gentamicin is not detectable in the final product. Pertuzumab has an approximate molecular weight of 148 kDa. PERJETA is a sterile, clear to slightly opalescent, colorless to pale brown liquid for intravenous infusion. Each single use vial contains 420 mg of pertuzumab at a concentration of 30 mg/mL in 20 mM L-histidine acetate (pH 6.0), 120 mM sucrose and 0.02% polysorbate 20.

DESCRIPTION


Mechanism of Action Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC).


While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models


PERJETA® Pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. Based on a population PK analysis that included 481 patients, the median clearance (CL) of pertuzumab was 0.24 L/day and the median half-life was 18 days. With an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of pertuzumab was reached after the first maintenance dose.

Pharmacokinetics


1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in

combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast

cancer who have not received prior anti-HER2 therapy or chemotherapy for

metastatic disease.

INDICATIONS AND USAGE


1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with

trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced,

inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a

complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free

survival or overall surviva

INDICATIONS AND USAGE


DOSAGE AND ADMINISTRATION

The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes. When administered with PERJETA, the recommended initial dose of trastuzumab is 8 mg/kg administered as a 90-minute intravenous infusion, followed every 3 weeks by a dose of 6 mg/kg administered as an intravenous infusion over 30 to 90 minutes.



Metastatic Breast Cancer (MBC) When administered with PERJETA, the recommended initial dose of docetaxel is 75 mg/m2 administered as an intravenous infusion. The dose may be escalated to 100 mg/m2 administered every 3 weeks if the initial dose is well tolerated.



Neoadjuvant Treatment of Breast Cancer PERJETA should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer [see Clinical Studies (14.2)]: Four preoperative cycles of PERJETA in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) as given in Study 2 Three preoperative cycles of FEC alone followed by 3 preoperative cycles of PERJETA in combination with docetaxel and trastuzumab as given in Study 3 Six preoperative cycles of PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended) as given in Study 3

Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. There is insufficient evidence to recommend continued use of PERJETA for greater than 6 cycles for early breast cancer. There is insufficient evidence to recommend concomitant administration of an anthracycline with PERJETA, and there are no safety data to support sequential use of doxorubicin with PERJETA.



Dose Modification For delayed or missed doses, if the time between two sequential infusions is less than 6 weeks, the 420 mg dose of PERJETA should be administered. Do not wait until the next planned dose. If the time between two sequential infusions is 6 weeks or more, the initial dose of 840 mg PERJETA should be re-administered as a 60-minute intravenous infusion followed every 3 weeks thereafter by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes. PERJETA should be discontinued if trastuzumab treatment is discontinued. Dose reductions are not recommended for PERJETA.


Preparation for Administration

Administer as an intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix PERJETA with other drugs.

Preparation Prepare the solution for infusion, using aseptic technique, as follows: 1. Parenteral drug products should be inspected visually for particulates and

discoloration prior to administration.2. Withdraw the appropriate volume of PERJETA solution from the vial(s).3. Dilute into a 250 mL 0.9% sodium chloride PVC or non-PVC polyolefin

infusion bag.4. Mix diluted solution by gentle inversion. Do not shake. 5. Administer immediately once prepared. 6. If the diluted infusion solution is not used immediately, it can be stored at

2oC to 8oC for up to 24 hours. 7. Dilute with 0.9% Sodium Chloride injection only. Do not use dextrose (5%)

solution.


DOSAGE FORMS AND STRENGTHS

PERJETA (pertuzumab) 420 mg/14 mL (30 mg/mL) in a single-use vial

CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio 2.0 in the clinical studies. Only limited data were available for patients,whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC.

HER2 Testing

HER2 Testing

Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.

Metastatic Breast Cancer 1. The most common adverse reactions (> 30%) with PERJETA in

combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy.

Neoadjuvant Treatment of Breast Cancer 2. The most common adverse reactions (> 30%) with PERJETA in

combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia.

3. The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia.

4. The most common adverse reactions (>30%) with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia.

ADVERSE REACTIONS

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