Breast Cancer and Effective Treatment - An Overview

D.A. Dube

Cancer: A malignant tumor of epithelial origin tending to infiltrate and give rise to new growth or metastases. Also called carcinoma.

Fig 1: Carcinoma of breast

Different kinds of Cancer

The four most common cancers are:

Breast Cancer, Colon Cancer, Lung Cancer, Prostate Cancer
Cancers of Blood and Lymphatic Systems:
Hodgkin's disease, Leukemias, Lymphomas, Multiple Myeloma, Waldenström's Disease
Skin cancers:
Malignant Melanoma, Skin Cancer
Cancers of Digestive Systems:
Head and Neck Cancers, Esophageal Cancer, Stomach Cancer, Cancer of Pancreas, Liver Cancer, Colon and Rectal Cancer, Anal cancer
Cancers of Urinary system:
Kidney Cancer, Bladder Cancer, Testis Cancer, Prostate Cancer
Cancers in women:
Breast Cancer, Ovarian Cancer, Gynecological Cancers, Choriocarcinoma
Miscellaneous cancers:
Brain Tumors, Bone Tumors, Characinoid Tumor, Nasopharyngeal Cancer, Retroperitoneal sarcomas, Soft Tissue Tumors, Thyroid Cancer, Cancers of Unknown Primary Site

Stages of Breast Cancer:

Stage 0

This stage is used to describe non-invasive breast cancer. There is no evidence of cancer cells breaking out of the part of the breast in which it started, or of getting through to or invading neighboring normal tissue. LCIS and DCIS are examples of stage 0.

Fig 2: Cribriform DCIS of breast

Stage I

This stage describes invasive breast cancer (cancer cells are breaking through to or invading neighboring normal tissue) in which

• The tumor measures up to two centimeters, AND
• No lymph nodes are involved.

Stage II

This stage describes invasive breast cancer in which:

• The tumor measures at least two centimeters, but not more than five centimeters, OR
• Cancer has spread to the lymph nodesunder the arm on the same side as the breast cancer. Affected lymph nodes have not yet stuck to one another or to the surrounding tissues, a sign that the cancer has not yet advanced to stage III. (The tumor in the breast can be any size.)

Stage III

Stage III is divided into subcategories known as IIIA and IIIB.

Stage IIIA

Stage IIIA describes invasive breast cancer in which:

• the tumor measures larger than five centimeters, OR
• there is significant involvement of lymph nodes. The nodes clump together or stick to one another or surrounding tissue.

Stage IIIB

This stage describes invasive breast cancer in which a tumor of any size has spread to the breast skin, chest wall, or internal mammary lymph nodes (located beneath the breast right under the ribs, inside the middle of the chest).
Stage IIIB includes inflammatory breast cancer, a very uncommon but very serious, aggressive type of breast cancer. The most distinguishing feature of inflammatory breast cancer is redness involving part or all of the breast. The redness feels warm. You may see puffiness of the breast's skin that looks like the peel of a navel orange ("peau d'orange"), or even ridges, welts, or hives. And part or all of the breast may be enlarged and hard. A lump is present only half of the time. Inflamatory breast cancer is sometimes misdiagnosed as a simple infection.

Stage IIIC

A tumour of any size that has spread to the lymph node behind the breastbone and under the arm, or to the lymph nodes under or above the collarbone.

Stage IV

This stage includes invasive breast cancer in which

• a tumor has spread beyond the breast, underarm, and internal mammary lymph nodes, and
• a tumor may have spread to the supraclavicular lymph nodes (nodes located at the base of the neck, above the collarbone), lungs, liver, bone, or brain.

"Metastatic at presentation" means that the breast cancer has spread beyond the breast and nearby lymph nodes, even though this is the first diagnosis of breast cancer. The reason for this is that the primary breast cancer was not found when it was only inside the breast. Metastatic cancer is considered stage IV.

Fig 3: Genetic Screening for Breast Cancer

Causes1:

Some factors may slightly increase a woman’s risk of developing the disease and these are described below.

• Having had breast cancer.
• Having had certain types of benign breast disease (lobular carcinoma in situ or atypical lobular hyperplasia).
• Women who are taking hormone replacement therapy (HRT), or have recently taken it, have a slightly increased risk of breast cancer. Detailed information about HRT and breast cancer is in our health professionals section Younger women who take HRT because they have had an early menopause, or have had their ovaries removed, do not have an increased risk of breast cancer until after the age of 50.
• Taking the contraceptive pill very slightly increases a woman's chance of developing breast cancer.
• Women who do not have children are slightly more likely to develop breast cancer then women who have children.
• Women who start their periods early (early puberty) or have a late menopause have a slightly higher risk of breast cancer.
• Women who have never breastfed are slightly more likely to develop breast cancer than women who have breastfed for more than a year.
• Being overweight, once you have had your menopause, can increase the risk of breast cancer.
• Drinking a lot of alcohol over many

Inherited faulty genes: A very small number (from 1 in 20 to 1 in 10) of breast cancers are thought to be caused by inherited faulty genes. Two breast cancer genes have been identified: BRCA1 and BRCA2.

The Importance of Early Diagnosis

Individual randomized controlled trials (RCTs)2,3 and meta-analyses4,5 have demonstrated the advantage of an invitation to screening, and detailed analysis of tumor characteristics and long-term survival have demonstrated the prognostic advantage of incrementally smaller tumors at the time of diagnosis6. Although the technology of mammography offers the unique advantage of detecting occult breast cancer, the data on tumor size and survival also indicate there is an advantage to detecting palpable tumors at the earliest opportunity7,8. The reduction in mortality in the RCTs of mammographic screening was predicted by reductions in the rates of lymph node-positive disease, and the magnitude of the reduction in the rate of advanced disease

Treating breast cancer with surgery

• Lumpectomy (wide local excision)
• Segmental excision (quadrantectomy)
• Mastectomy

Lumpectomy (wide local excision):

This is the removal of the breast lump, together with some surrounding tissue. A lumpectomy is usually followed by radiotherapy treatment to the remaining breast tissue. This is known as breast conserving therapy. It removes the least amount of breast tissue, but leaves a small scar and sometimes a small dent in the breast. For most women, the appearance of the breast after lumpectomy is good.

Segmental excision (quadrantectomy):

This is similar to a lumpectomy, but involves removing more of the breast tissue. It is less commonly used than lumpectomy. The effect of this type of surgery is more noticeable than lumpectomy, particularly in women who have small breasts. The treated breast is usually smaller than the other breast and has a dent in the area where the surgery is done. In women with large breasts it is usually less noticeable.

Mastectomy ⁹: Removal of the whole breast (mastectomy) may be necessary if

The breast lump is large in proportion to the rest of the breast tissue, there are several areas of cancer cells in different parts of the breast, the lump is just behind the nipple, there is a small invasive breast cancer, but a widespread area of DCIS (ductal carcinoma in situ).

Fig 4: Histopathologic image from ductal cell carcinoma in situ (DCIS) of breast Hematoxylin- eosin stai

A simple mastectomy removes only the breast tissue. A simple mastectomy and node sampling removes the breast tissue and the lower levels of lymph glands, within the armpit. A modified radical mastectomy removes all the breast tissue and all of the lymph nodes in the armpit. It may also be referred to as a total mastectomy and axillary clearance.

Fig 5: Mastectomy specimen containing a very large cancer of the breast

Fig 6: Typical microscopic (gross) appearance of cut surface of Mastectomy specimen

Treating breast cancer with radiotherapy ^10:

Radiotherapy treats cancer by using high-energy rays to destroy the cancer cells, while doing as little harm as possible to normal cells.

Treating breast cancer with chemotherapy

Chemotherapy is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells.
Zoladex11 is a chemotherapy drug used to treat breast cancer and prostate cancer. It is also used in non cancerous endometrial conditions. Its generic name is goserelin acetate.
Zoladex works by starving breast cancer cells of estrogen. Estrogen plays a key role in the development of breast cancer cells. Zoladex is given by an injection under the skin. It is usually given monthly or every three months.
Femara is a chemotherapy drug used to treat breast cancer in postmenopausal estrogen receptor positive breast cancer patients. Its generic name is letrozole.
Femara is classified as a aromatase inhibitor. Femara doesn't allow the enzyme aromatase to convert androgens into estrogen. Without estrogen, the tumor cannot grow and can shrink. Femara has relatively no common side effects. Side effects that may be experienced include hot flashes, bone and joint pain, nausea, fatigue, and back pain.
Taxol is a chemotherapy drug used commonly to treat breast cancer. Its generic name is Paclitaxel. It is also used to treat ovarian, lung, prostate, bladder, melanoma, esophageal cancer and other solid tumor cancers. Taxol is given through an IV.
Side Effects: Side effects of Taxol include diarrhea, mouth sores, mild nausea and vomiting, hair loss, pain in the joints, low blood counts and numbness and tingling in hands and feet. Taxol is normally given for about three hours every three weeks. Males or females cannot use it at the time of conception. Women are advised not to use the birth control pill, either. Taxol is a mitotic inhibitor, meaning it stops cells growth.

Nanoparticle Albumin-Bound Paclitaxel injection

NANOPARTICLE ALBUMIN-BOUND PACLITAXEL (Abraxane™) is chemotherapy agent used to treat breast cancer. It is made from the needles and bark of yew trees. It interferes with the growth of rapidly dividing cells, like cancer cells, and causes the cells to die. This medicine is for infusion into a vein. Other chemotherapy agents may increase the side effects seen with paclitaxel, bosentan, and certain types of medicines used to treat heart problems or high blood pressure, such as beta-blockers, calcium-channel blockers, or digoxin
Side Effects:
Rare or uncommon: vomiting, chest pain, difficulty breathing, wheezing
Common: low blood counts - nanoparticle al bumin-bound paclitaxel may decrease the number of white blood cells, red blood cells, and platelets. Signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine, mouth or throat sores or ulcers
pain, redness, swelling, or irritation at the injection site, slow or irregular heartbeat
tingling, pain, or numbness in the hands or feet, irritation at the injection site

Altretamine

Trade Name: Hexalen
Drug Type: Anti-cancer drug, referred as cytotoxic, or antineoplastic
Classification: Alkylating agent
It is given in capsule form, after meals
Common Side Effects: Nausea, vomiting, loss of appetite, low blood counts
Less Common Side Effects: tingling sensation in fingers/toes, stomach cramping, dizziness, weakness, depression, mood swings
Side Effects That Require Medical Attention: unusual bleeding, black or tarry stools, extreme confusion or fatigue

Doxorubicin

Trade Name: Adriamycin, Rubex
Drug Type: Anti-cancer drug, referred as cytotoxic, or antineoplastic
Classification: anthracycline antibiotic
Uses: bladder, breast, head and neck, liver, lung, ovary, pancreas, prostate, stomach, uterine cancer, leukemia (some types), lymphomas, mesothelioma, multiple myeloma, neuroblastoma, sarcomas, testis (germ cell), thyroid,
It is given IV (intravenously)
Common Side Effects: Pain along the site where the medication was given, vomiting, nausea, hair loss, mouth sores
Less Common Side Effects: changes in color of urine, watering eyes, darkening of nail beds, fertility problems

Fluorouracil, 5-FU injection

FLUOROURACIL, 5-FU (Adrucil®) is a chemotherapy agent used for treating many types of cancer including colon and rectal cancer, breast cancer, stomach cancer, and cancer of the head and neck. Fluorouracil interferes with the growth of cancer cells. Generic fluorouracil injections are available. Fluorouracil is for injection or infusion into a vein.
Side effects: Low blood counts - fluorouracil may decrease the number of white blood cells, red blood cells and platelets. You may be at increased risk for infections and bleeding. Pain, swelling, redness or irritation at the injection site, signs of infection - fever or chills, cough, sore throat, pain or difficulty passing urine, chest pain, confusion, diarrhea especially more frequent and/or severe watery diarrhea, difficulty breathing, drowsiness, mouth sores, nausea, vomiting, stomach pain.

Treating breast cancer with hormonal therapies^12,13

There are many different types of hormonal therapy and they work in slightly different ways. They are often given after surgery and radiotherapy for breast cancer, to reduce the chance of the cancer coming back. Hormonal therapy is usually given after chemotherapy. Hormonal therapies are only effective in women whose cancer cells have receptors for oestrogen and/or progesterone on their surface. This is known as being oestrogen- receptor positive (ER+) or progesterone-receptor positive (PR+).

Tamoxifen ¹⁴

Tamoxifen is known as an anti-oestrogen drug. It works by preventing oestrogen in the body from attaching to breast cancer cells and encouraging them to grow. It is used for women who have not yet had their menopause and may also be used for women who have had their menopause. For premenopausal women and women with very early-stage breast cancers, tamoxifen is the standard treatment.
It is available as tamoxifen and Nolvadex® and is taken as a daily tablet. The side effects may include: hot flushes and sweats, a tendency to put on weight (although this may be due to other effects such as going into the menopause), dryness of the vagina or an increased discharge from the vagina.

Aromatase inhibitors

Aromatase inhibitors work by blocking the production of oestrogen in body tissues, so they reduce the overall levels of oestrogen in the body. Aromatase inhibitors are used only in postmenopausal women. The most commonly used are anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®). Aromatase inhibitors, like all other medicines, may cause side effects. Many women can take aromatase inhibitors without any problems, but some may experience mild to moderate side effects. Unlike tamoxifen they do not increase the risk of blood clots and strokes. As aromatase inhibitors have only been used for a few years, the long-term side effects of taking them are not yet known. Some women find that they cause: hot flushes, feelings of sickness, joint pains, vaginal dryness.Taking aromatase inhibitors long-term may lead to the bones becoming more fragile, take calcium and vitamin D to maintain bone strength. In case of osteoporosis (thinning of the bones), aromatase inhibitors may not be a suitable treatment.

Zoladex® (Goserelin)

Zoladex is a type of drug known as a pituitary down-regulator, or LHRH analogue. It reduces the production of oestrogen-stimulating hormones by the brain. This lowers the level of oestrogen in the body in premenopausal women, but is reversible once the treatment is stopped. As Zoladex brings on a temporary menopause, many of its side effects are similar to those of the menopause. They include hot flushes and sweating, a low sex drive, headaches and mood changes. It is given as a monthly injection just under the skin of the abdomen.

Ovarian ablation

Ovarian ablation means stopping the ovaries from producing oestrogen by:

• removing the ovaries with surgery
• or giving a dose of radiotherapy to the ovaries.

Unfortunately, ovarian ablation brings on an early menopause, which can be upsetting, especially for a woman who was hoping to have children or complete her family. It also causes menopausal side effects such as hot flushes, dry skin, vaginal dryness and mood changes. However, these symptoms can be effectively treated.

Table 1: Hormonal Agents for the Treatment of Breast Cancer

Table 2: Recommendations for Adjuvant Chemotherapy of Breast Cancer

Treatment according to the stages of cancer:

Localized Cancer (Stages I and II):

The treatment of localized breast cancer involves control of the primary tumor, lymph node dissection and, in selected cases, systemic therapy. The same degree of local control is achieved with total mastectomy or partial mastectomy in combination with postoperative irradiation.15
Dissection may be limited to axillary levels I and II when the lymph nodes at these levels are free of tumor16. This approach decreases the risk of lymphedema and brachial neuropathy. Lymph node mapping may eliminate the need for axillary dissection in the majority of breast cancers.17

Locally Advanced Cancer (Stage III)

In most cases, stage IIIA disease results from the neglect of a smaller tumor. The breast cancer is then managed with surgery and adjuvant chemotherapy. Surgical treatment, including mastectomy with postoperative irradiation of the chest wall, may be required to prevent chest wall recurrence. Since stage IIIB breast cancer is very aggressive, local treatment alone is of limited benefit. Current treatment of stage IIIB breast cancer includes preoperative chemotherapy (and hormonal therapy, if the tumor is rich in hormone receptors), followed by surgery and radiation therapy. Chemotherapy should include an anthracycline.

Metastatic Cancer (Stage IV)

Metastatic breast cancer requires systemic treatment. Estrogen antagonists are front-line agents if the patient has not been exposed to them previously and if life-threatening metastases (hepatic or lymphangitic lung metastases) are not present. If the tumor progresses during treatment with estrogen antagonists, alternative hormonal therapies may be used to treat hormone-receptor­ positive tumors (HR+), and chemotherapy may be used to treat hormone-receptor­ poor tumors (HR-). In the presence of life-threatening metastases, chemotherapy is generally indicated, because this treatment works more rapidly than hormonal therapy.

Fig 7: Suggested approach to the treatment of metastatic breast cancer in older women.

Summary:

Cancer survivors are at increased risk for recurrence of their original malignancy; development of second primary malignancies; and medical, developmental, and psychological problems resulting from cancer therapy, genetic predisposition to cancer, and other risk factors. Surveillance following curative cancer treatment generally includes interval history and physical examinations every six months for five years. Thereafter, histories and examinations are recommended annually for breast cancer; every three months for two years, then every six months for three to five years for colorectal cancer; and every six months for five years, then annually for prostate cancer. Recommended laboratory tests and ancillary procedures include annual mammography of preserved breast tissue in breast cancer survivors, carcinoembryonic antigen level monitoring in conjunction with annual colonoscopy in colorectal cancer patients, and prostate-specific antigen measurements every six months for five years and then annually in prostate cancer survivors. In addition, family physicians should be attentive to concerns about altered body image or sexuality issues following curative surgical procedures. Continued emphasis on preventive health practices is encouraged. Physicians should remain alert to nonspecific symptoms or physical findings (e.g., mass, adenopathy) that can indicate cancer recurrence. In childhood cancer survivors, periodic evaluation that includes a plan for surveillance and prevention, incorporating risks based on previous cancer therapy, genetic predispositions, and personal behaviors, is recommended.

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About Authors:

Mr.D.A.Dube
Research Student, Padm. Dr. D.Y. Patil College of Pharmacy Akurdi- 44.

Prof. S.V.Deshpande
Head, Department of Pharmaceutical Chemistry, Padm. Dr. D.Y. Patil College of Pharmacy Akurdi- 44.

Mr. V.S.Soundale
Research Student, Padm. Dr. D.Y. Patil College of Pharmacy Akurdi- 44.

Prof. P.R. Mahaparale
Head, Department of Pharmaceutics, Padm. Dr. D.Y. Patil College of Pharmacy Akurdi- 44.