March 11

Breast Cancer

2013
Submitted by :Inderpreet Singh Student ID:S203759

Critical assessment of improved treatment for new medicinal products than traditional treatments

BREAST CANCER
Courage doesnt always roar. Sometimes courage is the little voice at the end of the day that says Ill try again tomorrow, Mary Anne Radmacher.

ABSTRACT:Breast cancer is most common type of cancer in women and is responsible for 2nd largest no. of deaths among cancer patients. This article reviews the breast cancer incidence, pathophysiology, classification, current treatments and diagnostics and their side-effects and comparing them to new developments in breast cancer treatments. There are lots of novel drug targets being discovered and novel treatments are being explored by which it can be treated successfully. With the emergence of new sophisticated radiation techniques, genetic screening tools and 3D diagnostic imaging techniques there is increase in rate of early detection of breast cancer. With the advents of targeted treatment like estrogen receptor pathway down regulators and HER2 antagonists the success rate of cancer management increases many folds and with less risk to patients. These new drugs are even effective against most resistant cancers. These new drugs and techniques used are quite expensive right now but still the patient outcome profiles are lucrative enough to continue exploring further. Also, there is a quest to find the cheaper alternatives and thus it accelerates the need for continuous research to benefit the patient health as a result these new medicinal products provide improved treatments to patients.

INTRODUCTION:Cancer or malignant neoplasm is diverse group of diseases which involve unregulated cell growth. In cancer the cells divide and grow uncontrollably, giving rise to malignant tumors. It may spread to nearby or distant body parts through lymphatic system or Blood stream by a process called Metastasis. Cancer can eventually develop in any organ in the body accounting for more than 200 diverse kinds of cancer.(1) Breast cancer changes you, and the change can be beautiful, Jane Cook, breast cancer survivor. Breast cancer is that group of cancer that originate from breast tissue. It most commonly originates from the inner lining of the milk ducts or the lobules that supply the ducts with milk. (2)

BREAST CANCER INCIDENCE:It accounts for 23% of overall cancer incidences in women. GLOBALLY:1) It is most common type of cancer diagnosed and leading cause of cancer related deaths in women worldwide.(3) 2) In every 19 seconds a case of breast cancer is diagnosed and every 74 seconds, somewhere in world there is a death due to it.(3) 3) In 2010 alone more than 425,000 women worldwide died from it.(4) 4) The incidence rates have risen to 30% in western countries due to changes in reproductive patterns in last 25 years but the mortality rates have been stable or decreasing due to early screening by mammography and better treatments.(3)

Source:-SEER Cancer Statistics Review 1975-2009 (Vintage 2009 Populations), Figure 4.1 (5)(16)

Source:-SEER Cancer Statistics Review 1975-2009 (Vintage 2009 Populations), Figure 4.5 (5)(16)

USA:- 1) It is second most prevailing reason for deaths after lung cancer in cancer deaths in USA. (8) 2) The BRCA1/BRCA2 genetic mutation only account for 5-10 % of total breast cancer cases in USA. (8) 3) There are approximately 3 million survivors (breast cancer) alive in the U.S.A today, the largest group of cancer survivors in the country.(9) 3) 5 years relative survival rate for women with breast cancer is :- 99% for local stage disease (cancer that has not undergo metastasis); 84 % for regional stage disease; 23 % for distant stage disease (10)

Source:-SEER Cancer Statistics Review 1975-2009 (Vintage 2009 Populations), Figure 4.11 (5)(16)

PATHOPHYSIOLOGY:Breast cancer like all other cancers occurs due to defects in DNA either hereditary or damage to DNA by environment interaction. When cells lose control over their dividing and attaching to other cells it develops cancer. Apoptosis (programmed cell death) is process of cell suicide when it no longer in need. There are some protective protein clusters like PI3K/AKT and RAS/MEK/ERK pathways which protect cells from apoptosis. Some mutations in the genes along this pathway makes them permanently on. This leads to cancer in combination of other mutations. PTEN protein is responsible for regulation of these pathways. So, when gene for PTEN mutates it develops cancer by letting PI3K/AKT pathway stuck in on position.(6)

Another main cause includes mutation in BRCA1 and BRCA2 genes, which are involved in DNA repair mechanisms. These mutations could be inherited or acquired. The mutated genes dont facilitate correction of errors in DNA and allow further mutations leading to development of malignant cancer. Some cases of it are experimentally related to estrogen exposure. Faulty immune system which did not remove malignant cells and abnormal growth factor signaling between epithelial and stromal cells can also facilitate malignant neoplasms. Overexpression of leptin in adipose tissue has also been seen related to cancer development.(7) CLASSIFICATION SCHEMES:Breast cancer has many different classification systems based on pathology, grade, stage of cancer, protein & gene status, histological appearance. Classification based on histological appearance are as follow:1) 2) 3) 4) 5) 6) 7) 8) Ductal carcinoma in situ (DCIS) Invasive ductal carcinoma (IDC) Medullary carcinoma Lobular carcinoma in situ (LCIS) Invasive lobular carcinoma (ILC) Tubular carcinoma Metastatic breast cancer Triple negative breast cancer

Invasive ductal carcinoma SOURCE:- Ananya Mandal, Breast Cancer Classification

Ductal carcinoma in situ

http://www.news-medical.net/health/Breast-Cancer-Classification.aspx(13)

CLINICAL SYMPTOMS:Typically there are less to no symptoms of breast cancer in initial stages. But, on later stages it develops some symptoms. Early screening by mammogram help in detecting it in initial stages. More than 80 % of breast cancer are first discovered by feeling a lump by women themselves. Other symptoms are:-Presence of a lump or thickening different from other breast tissue in breast or armpit region.(11) -one breast is larger than other, change in shape and size of nipple(inverted nipple).(11) -leaking out of clear or bloody fluids from nipple indicates breast cancer.(11) -Ulcers on skin of breast, redness, swelling and puckered nipple. -Acute weight lose. -Pain in breast bone and swelling in arm next to cancerous breast.

Source: http://en.wikipedia.org/wiki/Breast _cancer (12)

Early signs of cancer

CURRENT TREATMENTS:There are myriad of therapies available for cancer treatment but the efficacy depends upon the type and stage of the breast cancer. After positive screening/diagnosing the doctor will advise you available treatments and help to choose one. SURGERY:In it there is removal of cancerous breast and some nearby tissue to get rid of breast cancer. It is usually followed by chemotherapy/radiotherapy. It is of 2 types:1) LUMPECTOMY:- It is Breast conserving surgery, in it just tumor or the little surrounding breast tissue is removed. It may also be partial mastectomy or quadrantectomy. The chosen method depends upon type of cancer and size of tumor. 2) MASTECTOMY:- It is whole removal of breast. It is generally followed by reconstructed surgery to recreate the removed breast. Lymph nodes are also removed from armpit. The extent of clearing of lymph nodes depends whether cancer has spread to lymph nodes or not.

RADIOTHERAPY:It involves use of controlled radiation regimen to kill cancerous cells and it generally given after surgery or chemotherapy to kill remaining cancerous cells. It is begun after a month of surgery or chemotherapy and sessions are 3-5 days a week for 3-6 weeks, lasting for few minutes a each. It may be focused on either affected breast only or whole chest wall depending on type and stage of cancer.

CHEMOTHERAPY:In it the anti-cancer drugs are given to patient to kill cancer cells. The drugs are administered in combination of 3 usually via intravenous route or as tablets once in 2-3 weeks for 4-8 months time-span. It is of 2 types:1) Adjuvant chemotherapy:- It is administered after surgery to remove and destroy the cancer cell which are not removed. 2) Neo-adjuvant chemotherapy:- It is administration of drugs before surgery to shrink the size of tumor.

HORMONE THERAPY:Some breast cancer are hormone receptor positive cancers, means they contain receptors for estrogen and progesterone and respond to these hormones. These kind cancers grow and stimulated by normal female hormones in the body. So, by lowering the hormones in body these cancers growth can be stopped. It is usually given after surgery or chemotherapy sessions for very long times only to the HR positive cancers. It readily lowers the recurrence rate. Tomoxifen (stops binding of estrogen to estrogen receptor positive cancer cells), Aromatase inhibitors like Ansatrozole, Exemastane and Letrozole (stops formation of estrogen), Goserelin (Luteinising hormone-releasing hormone agonist) are few most common hormone therapy drugs given.(15)

SIDE-EFFECTS OF CURRENTLY AVAILABLE TREATMENTS:Patients being treated with Radiotherapy or chemotherapy experience lots of side effects. SIDE EFFECTS FROM RADIOTHERAPY:Patients being treated with radiotherapy may suffer from lymphedema and swelling in breasts inducing pain. It is generally due to blockage of lymph nodes as an deteriorating effect of therapy itself. It also includes irritation, soreness, burns, fatigue and darkening of skin area which is exposed to radiation.(14) SIDE-EFFECTS IN CHEMOTHERAPY:Chemotherapy in actually applied to kill cancer cell also have harmful effects on normal cells which lead to these side effects as nausea, vomiting, hair loss, mouth ulcers, bone marrow depression/Anemia, loss of appetite and increased chances of opportunistic infections.(14) SIDE EFFECTS OF SURGERY:Physical deformation and loss of self-confidence if large portions or whole breast has been removed. If surgery is not successful there are chances of recurrence. SIDE EFFECTS OF HORMONE THERAPY:Common ones are hot flushes and sweats, change to your periods, less libido, mood changes, fatigue, painful joints, vaginal dryness and less interest in sex.(14)

NEW ADVANCEMENTS IN DIAGNOSIS :A) LAB TESTS:1) Gene expression study:The risk of cancer coming back after surgery has been linked to some genetic patterns in recent years findings. Some lab tests have been developed based on these findings, such as Oncotype DX, MammaPrint and PAM50 tests. 2) Circulating tumor cells:It has been found that in many women with breast cancer, the cancer cells break away from tumor and enter the bloodstream. These circulating cells can then be detected via sensitive lab test.

B) NEW IMAGING TECHNIQUES:1) Scintimammography (molecular breast imaging):In this a radioactive tracer called technetium sestamibi is used. It is injected in a vein and it then bind to cancer cells and is detected by special sensing camera. Its role in breast cancer findings is still being studied and hopes to be as accurate as high cost MRI scans are. Main advantage is in case of younger women, where breasts are more dense and usual mammograms are difficult to comprehend.(15) 2) Tomosynthesis (3d mammography):It is advancement to the regular mammogram. For this the breast is slightly pressed and machine fires many low doses X-ray beams and take images of different slices of breast. Then it combines all images into 3-D. It provides the doctors more clarity over problem areas. It has been approved by VDA back in 2011. But its role is still unclear in regular screening and diagnosis.(15)

NEW ADVANCES IN BREAST CANCER TREATMENTS AND PREVENTION:1) ONCOPLASTIC SURGERY:Breast conservative surgeries can be practiced only in early-stage breast cancers. But in other cases mastectomy may have been practiced leading to

breasts with different sizes and shapes. In recent years for such cases this problem has been resolved by combing cancer surgeries and plastic surgeries procedures in one at time of cancer removal. This is very new realm in breast cancer surgery so very few doctors are comfortable with it by now. 2) RADIATION THERAPY:Hypo-fractionated radiation or accelerated partial breast irradiation may be as effective while are of shorter duration treatment. These are applied in cases of post-surgery radiation therapy. 3) NEW CHEMOTHERAPY DRUGS:PARP inhibitors are new class of drugs that target cancers caused by BRCA mutations. Clinical trials conducted around it shows promising results in treating of ovarian , prostate and breast cancers. More studies are being conducted to find their effectiveness in non-BRCA mutation cancers too.(15) 4) TARGETED THERAPIES:a. HER2 drugs:- New drug for patients who have higher expression of HER2 protein in cancer cells. It is ado-trastuzumab emtansine (TDM-1) is combination of monoclonal antibody in Herceptin attached to chemotherapeutic drug DM-1. So, it takes the drug directly to the cancer cells. It is found to be more effective than the standard trastuzuman and taxane (paclitaxel).(15) b. Anti-angiogenesis drugs:- It has been found that more aggressive breast cancer types have new blood vessels formed around the tumor to nourish it. So, by using anti-angiogenesis drugs it may result in decrease in tumor size or aggressiveness. But more studies need to conducting in this field to have any meaningful data for this approach. (15) c. Other targeted drugs:- Afinitor is drug given to help hormone therapy. It is prescribed along Aromasin for Hormone receptor positive breast cancer in post-menopausal women. Everolimus has also been find to be better in shrinking breast tumors before surgery in combination with letrozole.(15)

5) CHEMOPREVENTION:Fenretinide has found to be lowering the risk of breast cancer as much as tamoxifen.

CRITIQUE:1) There is an increase in incidence rate from last few decades, but mortality rate have been stabilized or decreased somewhat. It has been only possible due to advancement in diagnostic techniques and improved treatments availability over time. Now a days there are lots of treatment options available to patients rather than just mastectomy in previous times, leading to increased patient quality life and longer life spans. 2) With the development of new drug targeted therapies and new class of chemotherapeutic agents the management of breast cancers have improved. Due to more selectivity to cancerous cells they did not impart any deteriorating effect on neighbor cells as in case of radiation therapy and unselective chemotherapeutic agents practiced earlier. 3) There has been increased chances of earlier detections of cancer in starting stages due to advancements in imaging techniques like Scintimammography and tomosynthesis as compared to normal 2D X-ray mammograms. This leads to increased response to chemotherapeutic drugs as cancer is not that aggressive in early stages and chances of recurrence become very low. 4) With new genetic diagnostics, doctors now compare defects in DNA/genes with standard and very accurately find the likelihood of cancer coming back after surgery by taking account of mutated genes. These tests initially were very costly but now with new improvements few cheaper alternatives have been developed. This all helps in deciding the best therapy for a type of cancer, patient is affected with.

CONCLUSION:With the progression of time, we are getting more and more developments in cancer research, whether its about early and more accurate diagnosis, classification of cancer based on new bio-markers and matching correct therapy to the type of cancer, harnessing the patients own immune system to fight the tumor cells and decreasing the side-effects of current medication. All this has been harnessed due to translation of new medicinal products into clinic. There are continuously new findings surfacing out in breast cancer research and still lots of processes involved in it are not known. There is a need to continuously push the research work further to get more advanced, better and selective treatments with less severe side-effects profile causing more benefit to patient health.

REFERENCES:1. Cancer Research UK (2013),How many types of cancers are there, available at: http://www.cancerresearchuk.org/cancer-help/about-cancer/cancerquestions/how-many-different-types-of-cancer-are-there 2. Sariego J (2010). "Breast cancer in the young patient". The American surgeon 76 (12): 13971401.PMID 21265355 3. American Cancer Society, Global Cancer Facts & Figures 2nd edition 4. Institute for Health Metrics and Evaluation, University of Washington, The Challenge Ahead: Progress and Setbacks in Breast and Cervical Cancer, September 2011. Also see: Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. www.thelancet.com September 15, 2011 5. SEER Cancer Statistics Review 1975-2009 (Vintage 2009 Populations), Figure 4.1; 4.5; 4.11,Available at: http://seer.cancer.gov/csr/1975_2009_pops09/index.html 6. 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium". Sunday Morning Year-End Review. 14 Dec 2009 7. Jard T, Perrier S, Vasson MP, Caldefie-Chzet F (January 2011). "Molecular mechanisms of leptin and adiponectin in breast cancer". Eur. J. Cancer 47 (1): 33 43.doi:10.1016/j.ejca.2010.09.005.PMID 20889333 8. Breast Cancer Facts and Figures 2011-2012 ACS 9. Siegel, Rebecca, et al. Cancer treatment and survivorship statistics, 2012, CA: A Cancer Journal for Clinicians, June, 14, 2012. http://onlinelibrary.wiley.com/doi/10.3322/caac.21149/full 10. American Cancer Society, Global Cancer Facts & Figures 2nd edition 11. April Cashin-Garbutt (2013), Breast Cancer Classification, Available at: http://www.news-medical.net/health/Breast-Cancer-Symptoms.aspx (accessed 10th March 2013) 12. Wikipedia (2012),Breast Cacner:clinical symptoms,Available at: http://en.wikipedia.org/wiki/Breast_cancer 13. Ananya Mandal (2013),Breast Cancer Classification, Available at: http://www.newsmedical.net/health/Breast-Cancer-Classification.aspx 14. Cancer Research UK (2013),Breast Cancer hormone therapy side effects, avaialable at: http://www.cancerresearchuk.org/cancer-help/type/breastcancer/treatment/hormone/breast-cancer-hormone-therapy-side-effects 15. American Cancer Society (2013), What`s new in breast cancer research and treatment, Available at: http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-newresearch (accessed 10th March 2013)

16. Howlader N, Noone AM, Krapcho M, et. al. (eds). SEER Cancer Statistics Review, 19752009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, 2012. Retrieved September 7, 2012.