CHEMOTHERAPY OF

BREAST CANCER

BY: SACHIN PRAKASHPHARM D 3RD YEAR

KARAVALI COLLEGE OF PHARMACY,MANGALORE

13Q1624

INTRODUCTIONOBreast cancer is cancer that

develops from breast tissue.OBreast cancer ,the second

leading cause of cancer deaths in women,is the disease women fear most.

OBreast cancer can also occur in men, but it's far less common.

• In the last 30 years, doctors have made great strides in early diagnosis and treatment of the disease and in reducing breast cancer deaths.

• 80% of breast cancers occur in women older than age 50.

• In 1975, a diagnosis of breast cancer usually meant radical mastectomy – (removal of the entire breast along with underarm lymph nodes and muscles underneath the breast. )

• Today, radical mastectomy is rarely performed. Instead, there are more and better treatment options, and many women are candidates for breast-sparing operations.

ETIOLOGYO The two variables most strongly associated

with the occurrence of breast cancer are gender and age.

O Breast cancer is also caused by a genetic abnormality (a “mistake” in the genetic material). However, only 5-10% of cancers are due to an abnormality inherited from your mother or father. About 90% of breast cancers are due to genetic abnormalities that happen as a result of the aging process and the “wear and tear” of life in general.

TYPES OF BREAST CANCER

RISK FACTORSO Gender: female (1% males)O Race: more common in whites.O Age: increases as a woman gets older. O Relative : (mother or sister).O Menstrual history :early on set late

menopauseO Childbirth: first child After the age of 30 or

having no children at all.

Pregnancy and breastfeeding are protective against breast cancer

• Obesity

• Diet: Fat & Alcohol

• Lack of Physical Activity: Stress

• Radiation Exposure

• History of cancer: Breast, Uterus, Cervix, Ovary

• Hormones: Estrogens in Hormone replacement therapy & Birth control pills

• Genetics:Certain conditions that are inheritated

70% have no risk factors

CLINICAL MANIFESTATION

General ■ The patient may not have any symptoms, as breast cancer may be detected in asymptomatic patients though routine screening mammography.

Local Signs and Symptoms■ A painless, palpable lump is most common.■ Less common: Pain; Nipple discharge, Retraction or dimpling, Skin edema, Redness or warmth.■ Palpable local-regional lymph nodes may also be present. Signs and Symptoms of Systemic Metastases■ Depends on the site of metastases, but may include bone pain,difficulty breathing, abdominal pain or enlargement, jaundice,mental status changes.

PATHOPHYSIOLOGYO Breast cancer is a malignant tumor that starts in the cells of the

breast. Like other cancers, there are several factors that can raise the risk of getting breast cancer. Damage to the DNA and genetic mutations can lead to breast cancer have been experimentally linked to estrogen exposure. Some individuals inherit defects in the DNA and genes like the BRCA1, BRCA2 and P53 among others. Those with a family history of ovarian or breast cancer thus are at an increased risk of breast cancer.

O The immune system normally seeks out cancer cells and cells with damaged DNA and destroys them. Breast cancer may be a result of failure of such an effective immune defence and surveillance.

O These are several signalling systems of growth factors and other mediators that interact between stromal cells and epithelial cells. Disrupting these may lead to breast cancer as well.

DIAGNOSISO Laboratory Tests ■ Tumor markers such as cancer antigen (CA 27.29) or carcinoembryonic antigen (CEA) may be elevated. ■ Alkaline phosphatase or liver function tests may be elevated in metastatic disease.O Other Diagnostic Tests ■ Mammogram (with or without ultrasound, breast MRI or both). ■ Biopsy for pathology review and determination of tumor estrogen/progesterone receptor (ER/PR) status and HER2 status. ■ Systemic staging tests may include: chest x-ray, chest CT, bone scan, abdominal CT or ultrasound or MRI.

Mammogram of normal and cancer breast.

TREATMENTThe main types of treatment for breast cancer are:O Surgery.O Radiation therapy.O Chemotherapy.O Hormone therapy.O Targeted therapy.O Bone-directed therapy.

SURGERYO Surgery aims to remove the breast

cancer with a margin (border) of normal tissue to reduce the risk of the cancer coming back in the breast (known as local recurrence) and to try to stop any spread in the body. The amount of tissue removed depends on the area of the breast affected and the size of the cancer in the breast.

TYPES OF SURGERY1) Breast-conserving surgeryO This type of surgery is sometimes called partial (or

segmental) mastectomy. It is also sometimes called lumpectomy or quadrantectomy. In this surgery, only the part of the breast containing the cancer is removed. The goal is to remove the cancer as well as some surrounding normal tissue.

O side effects: Include pain, temporary swelling, tenderness, and hard scar tissue that forms in the surgical site. As with all operations, bleeding and infection at the surgery site are also possible.

2) MastectomyMastectomy is surgery to remove the entire breast. All of the breast tissue is removed, sometimes along with other nearby tissues.

a) Simple mastectomy: Also called total mastectomy, the surgeon removes the entire breast, including the nipple, but does not remove underarm lymph nodes or muscle tissue from beneath the breast.

b) Skin-sparing mastectomy: In this procedure, most of the skin over the breast (other than the nipple and areola) is left intact. This approach is only used when immediate breast reconstruction is planned.

c) Modified radical mastectomy: This procedure is a simple mastectomy and removal of axillary (underarm) lymph nodes.

Radical mastectomy: In this extensive operation, the surgeon removes the entire breast, axillary lymph nodes, and the pectoral (chest wall) muscles under the breast. side effects: wound infection, hematoma (buildup of blood in the wound), and seroma (buildup of clear fluid in the wound).

3) Lymph node surgerya) Axillary lymph node dissection (ALND): In

this procedure, anywhere from about 10 to 40 lymph nodes are removed from the area under the arm (axilla) and checked for cancer spread.

b) Sentinel lymph node biopsy (SLNB): Removes the first lymph node(s) to which a tumor is likely to spread (these are called the sentinel nodes). Removing many lymph nodes increases the risk of lymphedema , to lower this risk, doctors may use a sentinel lymph node biopsy (SLNB).

side effects: As with any operation, pain, swelling, bleeding, and infection are possible.

4) Reconstructive surgery• After having a mastectomy (or some breast-

conserving surgeries), a woman might want to consider having the breast mound rebuilt; this is called breast reconstruction. These procedures are done to restore the breast's appearance after surgery.

Chronic pain after breast surgerySome women have problems with nerve (neuropathic) pain in the chest wall, armpit, and/or arm after surgery that doesn’t go away over time. This is called post-mastectomy pain syndrome (PMPS) because it was first described in women who had mastectomies, but it can also happen after breast-conserving therapy.

RADIATION THERAPY

O Radiation therapy (also called radiotherapy) uses high-energy rays to kill cancer cells. It affects cells only in the part of the body that is treated with the radiation. Breast cancer radiation therapy may be used to destroy any remaining mutated cells that remain in the breast or armpit area after surgery.

O Radiation is also used to treat cancer that has spread to other areas, for example to the bones or brain.

O Radiation therapy can be given externally (external beam radiation) or internally (brachytherapy).

External beam radiationO This is the most common type of

radiation therapy for women with breast cancer. The radiation is focused from a machine outside the body on the area affected by the cancer.

O The extent of radiation depends on whether mastectomy or breast-conserving surgery (BCS) was done and whether or not lymph nodes are involved.

O If mastectomy was done and no lymph nodes had cancer, radiation is targeted at the chest wall and the places where any drains exited the body.

• If BCS was done, most often the entire breast gets radiation, and an extra boost of radiation is given to the area in the breast where the cancer was removed to prevent it from coming back in that area. 

• If cancer was found in the lymph nodes under the arm, radiation may be given to this area as well. In some cases, the area treated may also include supraclavicular lymph nodes (nodes above the collarbone) and internal mammary lymph nodes (nodes beneath the breast bone in the center of the chest).

• Breast radiation is most commonly given 5 days a week (Monday through Friday) for about 5 to 6 weeks.

Internal Radiation

O Sometimes called partial-breast radiation or brachytherapy, for use after lumpectomy. Internal radiation methods typically use small pieces of radioactive material, called seeds, which are placed in the area around where the cancer was. The seeds emit radiation into the surrounding tissue. The area that's very close to the site of the original cancer is the area that is at highest risk of recurrencence.

TYPES:1)Interstitial brachytherapy: In this approach, several small, hollow tubes called catheters are inserted into the breast around the area where the cancer was removed and are left in place for several days. Radioactive pellets are inserted into the catheters for short periods of time each day and then removed.

2)Intracavitary brachytherapy: This is the most common type of brachytherapy. A device is put into the space left from BCS and is left in place until treatment is complete. There are several different devices that can be used: MammoSite®, SAVI®, Axxent®, and Contura®.

Mammosite insertion

Mammosite tube

SIDE EFFECTSO Radiation therapy can have side effects,

and these vary from person to person.O The most common side-effects are:O Sunburn-type skin irritation of the

targeted area (which may range from mild to intense)

O Red, dry, tender, or itchy skinO Breast heavinessO fatigue

CHEMOTHERAPYO Chemotherapy is a treatment

using anti-cancer (also called cytotoxic) drugs which aims to destroy cancer cells. It is known as a systemic treatment.

O Many different types of chemotherapy drugs are used to treat breast cancer. They can be given in different ways and in different combinations, according to an individual’s situation.

Chemotherapy can be given in several ways. For breast cancer the drugs are most commonly given: • into a vein (intravenously) • by mouth (orally) as a tablet or capsule.

1) Intravenous chemotherapy :The most common way involves inserting a small needle and plastic tube called a cannula into a vein, either in the back of the hand or lower arm. The needle is removed and the plastic tube left in place. The diluted drugs are then slowly injected into the vein. If a large volume of fluid is used it can be given as an infusion (drip) through the cannula over a fixed period of time. • The cannula will usually be on the opposite arm to

where you had (or are having) surgery. This is to avoid the risk of lymphoedema.

2) Oral chemotherapy: This is chemotherapy taken by mouth and it may be given either as tablets or capsules.

3) Electrochemotherapy : It is a new treatment and is not widely available. It’s sometimes used to treat breast cancer that has spread to the skin. Chemotherapy is injected either directly into the area of skin affected or into the bloodstream. An electric pulse is then used to help the chemotherapy reach the cancer cells. Once inside the cancer cells, the chemotherapy destroys them.

SIDE EFFECTS: • risk of infection from not having enough white blood cells, anaemia (a drop in the number of red blood cells) and bruising and bleeding • sickness (nausea) and vomiting • hair loss or thinning • sore mouth (mucositis) • mouth ulcers • fatigue.

Chemotherapy Regimens• Doxorubicin 60 mg/m2 IV• Cyclophosphamide 600

mg/m2 IV• Fluorouracil 500 mg/m2 IV• Epirubicin 100 mg/m2 IV

bolus• Methotrexate 40 mg/m2 IV,• Paclitaxel 175 mg/m2 IV

Hormone therapyO Hormone therapy is another form of

systemic therapy. It is most often used as an adjuvant therapy to reduce the risk of the cancer coming back after surgery, but it can be used as neoadjuvant treatment, as well. It is also used to treat cancer that has come back after treatment or has spread.

O A woman's ovaries are the main source of the hormone estrogen until menopause. 

O Estrogen promotes the growth of cancers that are hormone receptor-positive.

Hormonal therapy medicines treat hormone-receptor-positive breast cancers in two ways:• By lowering the amount of the hormone

estrogen in the body.• By blocking the action of estrogen on breast

cancer cells.

• Hormonal therapy medicines are NOT effective against hormone-receptor-negative breast cancers.

Drugs that block estrogen1) Tamoxifen:  Tamoxifen blocks estrogen receptors in

breast cancer cells.it is called a selective estrogen receptor modulator or SERM.

• This drug is taken by mouth, most often as a pill.• The most common side effects of these drugs

include fatigue, hot flashes, vaginal dryness or discharge, and mood swings.

2) Toremifene (Fareston®):  Toremifene is a drug similar to tamoxifen. It is also a SERM and has similar side effects.

3) Fulvestrant (Faslodex®):  Fulvestrant is a drug that first blocks the estrogen receptor and then also eliminates it temporarily. It is not a SERM – it acts like an anti-estrogen throughout the body.

Treatments to lower estrogen levels1) Aromatase inhibitors (AIs):  letrozole (Femara),

anastrozole (Arimidex), and exemestane (Aromasin). They work by blocking an enzyme (aromatase) in fat tissue that is responsible for making small amounts of estrogen in post-menopausal women. They cannot stop the ovaries from making estrogen, aIso are taken daily as pills.

2) Ovarian ablation: Removing or shutting down the ovaries (ovarian oblation), the main source of estrogens, effectively makes the woman post-menopausal.

• Permanent ovarian ablation can be done by surgically removing the ovaries. This operation is called anoophorectomy,also done with drugs called luteinizing hormone-releasing hormone (LHRH) analogs, such as goserelin (Zoladex®) or leuprolide (Lupron®).

Less commonly used types of hormone therapy•  Megestrol acetate (Megace®) is a progesterone-

like drug used that can be used as a hormone treatment of advanced breast cancer.

• Androgens (male hormones) may rarely be considered after other hormone treatments for advanced breast cancer have been tried. They are sometimes effective, but they can cause masculine characteristics to develop such as an increase in body hair and a deeper voice.

Targeted therapyO Targeted cancer therapies are drugs or

other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines“.

O These therapies include hormone therapies, signal transduction inhibitors, gene expressionmodulator, apoptosis inducer, angiogenesis inhibitor, immunotherapies, and toxin delivery molecules.

SIDE EFFECTSThe most common side effects seen with targeted therapies are diarrhea and liver problems, such as hepatitis and elevated liver enzymes.  Other side effects seen with targeted therapies include:• Skin problems (acneiform rash, dry skin, nail changes,

hair depigmentation)• Problems with blood clotting and wound healing• High blood pressure• Gastrointestinal perforation (a rare side effect of

some targeted therapies)

• SOME MONOCLONAL ANTIBODIES• Trastuzumab (Herceptin)- man-made versions of a

very specific immune system protein. They are given into a vein (IV).

• Pertuzumab (Perjeta®)- IV• Ado-trastuzumab emtansine (Kadcyla™)-attached

to a chemotherapy drug. It is also given IV.• Lapatinib (Tykerb)- Not an antibody. It is given as a

pill.

Bone-directed therapyO When cancer spreads to bones, it can cause pain

and lead to bones breaking (fractures) and other problems. Drugs like Bisphosphonates and Denosumab can lower the risk of these problems.

BisphosphonatesO Bisphosphonates are drugs that can be used to

help strengthen bones and reduce the risk of fractures and pain in bones that have been weakened by metastatic breast cancer. Examples include pamidronate (Aredia®) and zoledronic acid (Zometa®). They are given intravenously (IV).

O Bisphosphonates may also help against bone thinning (osteoporosis) that can result from treatment with aromatase inhibitors or from early menopause as a side effect of chemotherapy.

SIDE EFFECTS• Flu-like symptoms and bone pain•  Kidney problems, so people with poor kidney

function may not be able to be treated with these drugs.

•  Osteonecrosis (damage) in the jaw bones or ONJ

Denosumab• Denosumab (Xgeva®, Prolia®) is another drug

that can help reduce the risk of problems from breast cancer metastasis to the bone. It works differently from bisphosphonates.

• it seemed to help prevent problems like fractures (breaks) better than zoledronic acid. It also can help bones even after bisphosphonates stop working.

•  drug is injected under the skin every 4 weeks.

SIDE EFFECTSO  low blood levels of calcium and phosphateO  ONJO does not seem to affect the kidneys, so it is

safe to take if patient have kidney problems.

Denosumab can also be used to strengthen bones in breast cancer patients with weak bones who are being treated with aromatase inhibitors. When it is used for this purpose, it is given less often (usually every 6 months).

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