An overview on current Strategies in Breast Cancer Therapy

 

G K Sudhakar1*, Vasudev Pai2, Arvind Pai1

1Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal University,  Manipal-576104, Karnataka, INDIA.

2Department of Pharmacognosy, Manipal College of Pharmaceutical Sciences, Manipal University,  Manipal-576104, Karnataka, INDIA.

 

 

ABSTRACT:

Breast cancer is the most common forms of female cancers. External factors like obesity, late pregnancies or no pregnancies, use of tobacco and alcohol have increased the risk of cancer in women. Targeted therapy is new type of cancer treatment that uses drugs precisely and attaches cancer cells with minimum damage to normal cells. It is multimodality cancer treatment regimens that include chemotherapy, surgery and radiation therapy. It has limited toxicity and target cancer cells which carry specific receptors (estrogen receptor). Third generation Aromatase Inhibitors (AIs) like Exemestane are emerging as potential therapeutic agents for breast cancer.

 

 

KEYWORDS: Radiation therapy, Monoclonal antibody, Selective estrogen receptor modulators (SERM), Estrogen receptor down regulator (ERD), Aromatase Inhibitors(AIs).

 

INTRODUCTION:

Cancer is a group of disease characterized by uncontrolled growth and spread of abnormal cells that cause cells in the body to change and grow out of control. Breast cancer is one of the most common form of female cancers. It is leading cause of death among women. (Accounting for 35% of all cancers and 20% of all cancer deaths)worldwide [1].The Indian Council of Medical Research (ICMR) registry records a figure of 100,000 every year as new case in Indian women, 40 % of them die either of late detection or shyness of subjects to get examined [2].

 

Risk factors for developing breast cancer

Many of known risk factors such as age, family history, age at first full-term pregnancy, early menarche, late menopause and breast cancer are listed in Table 1.

 

Table 1: Factors that Increase Relative risk for Breast cancer in women

Relative risk

Factor

1.1 – 2.0 Factors that affects hormones

Late age at first fall-term pregnancy (>30 years)

Early menarche (< 12 years)

Late menopause (> 55 years)

No full-term pregnancies

Never breastfed a child

Recent oral contraceptive use

Recent and long term use of Estrogen and Progestin Obesity (Postmenopausal) 

 

 

Treatment Options

Breast cancer treatment involves in getting rid of cancer as completely as possible and preventing its recurrence. This includes local and systemic therapy Table 2.

 

 

Table 2: Different treatment options for breast cancer.

Local therapy

Surgery

·     Lumpectomy

·     Mastectomy

Radiation therapy

·     External radiation

·     Internal radiation

 

Systemic therapy

Biological therapy

·     Herceptin (Trastuzumab)

·     Lapatinib

·     Bevacizumab

Chemotherapy

·     Cyclophosphamide

·     Methotrexate

·     Fluorouracil

·     Doxorubicin

·     Epirubicin

·     Paclitaxel

·     Docetaxol

Hormone therapy

·     Selective Estrogen receptor modulators (SERMS) Tamoxifen, Roloxifene

·     Estrogen Receptor Down Regulators (ERDs) Faslodex (Fulvestrant)

·     Progestins Megestrol

·     Aromatase Inhibitors (AIs)

·     Exemestane, Anastrozole, Letrozole

 

 

Local Therapy

It is used to treat the tumor without affecting the rest of the body. Surgery and radiation therapy are included in this category.

 

Surgery

The primary goal of surgery is to remove cancer from the breast and to assess the stage of disease.In lumpectomy only cancerous tissue plus a rim of normal tissue is removed. Sample mastectomy includes removal of the entire breast. Lumpectomyis always followed by about 5 to 7 week of radiation therapy.A women who chooses lumpectomy and radiation will have the same expected long term survival as if she had chosen mastectomy [3].

 

Radiation therapy

It is used to destroy cancer cells remaining in the breast, chest wall or under arm area after surgery or to reduce the size of tumor before surgery [4]. There are two type of radiation therapy namely 1) External radiation (Focused from a machine outside the body on the area affected over a period of 5 to 7 weeks) and 2)Internal radiation therapy (brachytherapy) where radioactive substance sealed in needles, seeds, wires or catheters that are placed directly into or near the cancer tissue.

 

Systemic therapy

Systemic therapy includes biological therapy, chemotherapy and hormone therapy. Systemic treatment given to patients well in advance before surgery is called neoadjuvant therapy. Neoadjuvant therapy helps to shrink the tumor enough to make surgical removal easy. This has been found to be as effective as therapy given after surgery in terms of survival, disease progression and recurrence [5]. Systemic treatment given to patients after surgery is called adjuent therapy. Adjuent therapy helps to kill any undetected tumor cells that may have migrated to other parts of the body. Tumor size, histology and presence of cancer in axillary nodes are considered in the decision whether to use adjuvant systemic therapy.

 

Biological therapy

About 15-30% of breast cancers excessively produce growth promoting protein HER2. These tumors tend to grow faster and are generally more likely to recur than tumors that do not over produce HER2. Herceptin (Trastuzumab) is a monoclonal antibody that directly targets HER2 protein of breast tumors. It offers a survival benefit for same women with metastatic breast cancer [6].Lapatinib has been found to be effective in delaying disease progression in women with HER2 positive advanced breast cancer who have become resistant to Trastuzumab [7].Bevacizumabis also a monoclonal antibody against circulating vascular endothelial growth factor, slows tumor growth in women whose cancer has metastasized by blocking growth of new vessels that increase blood supply to the tumor [8].

 

Chemotherapy

Chemotherapy is cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by arresting their further division. It depends on many factors like size of the tumor, number of lymph nodes involved the presence of estrogen or progesterone receptors and the amount of HER2 neu protein made by cancer cells. Studies haveshown that, in most cases, a combination of drugs will be more effective than a single drug for breast cancer treatment [9].The most common drugs used in combination in early breast cancer are Cyclophosphamide, Methotrexate, Fluorouracil, Doxorubicin, Epirubicin, Peclitaxel and Docetaxel.

 

Hormone therapy

Hormone therapy is used where drugs block the effect of Estrogen- a hormone that may encourage the growth of breast cancer cells. It is used for adjuent therapy and for advanced cancers in patients with hormone-receptor positive tumors. Generally they perform one or more of the following functions like a) Block hormone receptor itself b) Destroy the ovaries (which produce estrogen) and c) Suppresses estrogen production.

 

 

 

Selective estrogen receptor modulators (SERMs) compete for binding to Estrogen receptors and reduce the number of receptors available for binding to endogenous estrogen. This approach has proven effective as an anticancer strategy and has led to the development of efficacious antiestrogens such as Tamoxifen, Raloxifene and Toremifene[10]. The only estrogen receptor down regulatori.eFulvestrant is effective for the treatment of breast cancer which is not responding to Tamoxifen treatment [11].

 

Inhibition of Aromatase is one of the most effective approaches for reducing growth stimulatory effects of estrogens. Effective Aromatase Inhibitors (AIs) have been developed as therapeutic agents for controlling estrogen dependent breast cancer. Investigations on the development of AIs began in 1970s and have been expanded greatly in the past four decades[12].

 

AIs are mainly divided in to three generations, categorized based on chronology of clinical trials and as type – I and Type – II inhibitors based on their mechanism of action Table 3.The use of first and second generation AIs in the treatment of breast cancer has been limited. Third generation inhibitors (Anastrozole, Letrozole, Exemestane) are extremely potent and specific in blocking Aromatase at nanomolar concentrations. These inhibitors are capable of reducing endogenous estrogen in postmenopausal women to undetectable levels while having no palpable effects on other hormone classes.

 

AIs have fewer side effects than Tamoxifen because they do not cause endometrial cancer and very rarely cause blood clots. But they can cause Osteoporosis, bone fractures because they completely deplete estrogen in postmenopausal women. AIs like Exemestane is preferred over Tamoxifen as the first line of hormonal treatment for hormone receptor positive breast cancer in postmenopausal women [13].

 

Table 3: Classification of Aromatase Inhibitors

Generation

Type – I

Steroidal Aromatase Inhibitors (SAIs)

Type – II

Non-Steroidal Aromatase Inhibitors (NSAIs)

First

None

Aminoglutethimide

Second

Formestane

Fadrozole, Rogletimide

Third

Exemestane (Aromasin)

Anastrozole

Letrozole

Vorozole

CONCLUSION:

In high percentage of cases, breast cancer proves to be hormone dependent because tumor progression is dependent on high level of circulating estrogens. Third generation AIs are emerging as potential therapeutic agents for breast cancer.

 

REFERENCES:

1.       Bandi, P. et, al Breast Cancer Facts and figures 2009-2010; American cancer society: Atlanta, 2010

2.       ICMR. National cancer Registry Programme, In consolidated report of the population based cancer registries 2008; New Delhi. 2008

3.       Fisher, B et al; Twenty year follow up of randomized trial comparing total mastectomy, lumpectomy and lumpectomy plus irradiation for treatment of invasive breast cancer. N Engl. J. Med. 2002, 347, 1233-1241.

4.       Early breast cancer trialistsCollaborative group,Favorable and unfavorable effects on long term survival of radiotherapy for early breast cancer: An overview of randomized trials. Lancet 2008, 355, 1757-1770

5.       Mauri, D. et. Al Neoadjuvent versus adjuvant systemic treatment in breast cancer: a meta-analysis J. Natl Cancer Inst. 2005

6.       Vogal CL et al: Efficacy and safety of Trastuzumab as a single agent in first line treatment of HER2. Overexposing metastatic breast cancer J ClinOncol 20:719-726, 2002.

7.       Dennis J. Slamonet al: Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2.N Engl. J. Med.2009; 344: 783-792.

8.       Bedard PL et al: Beyond Trastuzumab: Overcoming resistance to targeted HER2 therapy in breast cancer. Curr Cancer Drug Targets 2009;9: 148-162.

9.       Hortobagyi GN: Treatment of breast cancer.N Engl. J. Med. 2006, 354, 974-984.

10.    Carmichael PL. Mechanisms of action of Antiestrogens: relevance to clinical benefits and risks.Cancer Invest. 1998;16(8):604-611.

11.    Howell A, Abram P. Clinical Development of Fulvestrant Cancer Treat. Rev 2005;31: Suppl 2: S3-S9.

12.    Murthy JN et al: Aromatase Inhibitors; A new paradigm in breast cancer treatment. Curr. Med. Chem. Anticancer Agents 2004;4:523-534.

13.    Coombes RC et al: A randomized trial of Exemestane after two to three years of Tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl. J. Med. 2004, 350, 1081-1092.

 

Received on 01.12.2013

Modified on 12.12.2013

Accepted on 14.12.2013

© A&V Publication all right reserved

Research J. Pharmacology and Pharmacodynamics. 5(6): November –December 2013, 353-355