Austin J Cancer Clin Res. 2016; 3(1): 1066.
Ayesha T1*, Muhammad AT2 and Azhar K3
1Department of Pharmaceutical Services, Ghurki Trust Teaching Hospital, Pakistan
2Department of Pharmaceutical Services, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pakistan
3Department of Pharmaceutical Services, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pakistan
*Corresponding author: JTariq Ayesha, Department of Pharmaceutical Services, Ghurki Trust Teaching Hospital, House #27, Muslim Street, Itahad Colony Samanabad, Lahore, Pakistan
Received: March 13, 2016; Accepted: July 11, 2016; Published: July 13, 2016
Breast cancer is one of the malignant tumors that commences in the breast tissues. In this malignant tumor, cells of the breast tissue have potential of abnormal proliferation which is suspected by clinically findings such as thickening of breast, formation of breast lump, Nipple discharge and skin changes. Breast cancer is considered as heterogeneous disorder whose aetiology is multifactorial. Generally, triple assessment tool is used in clinical evaluation of breast abnormalities. This triple assessment tool comprises of: Clinical examination of presenting complaints such as breast mass, nipple discharge, breast pain, skin retraction and arm swelling; Imaging tests(mammography and ultrasound) and tissue sampling (biopsy, fine needle aspiration cytology and needle core biopsy). In Pakistan, breast cancer is the most common cancer and it ranks first among other malignancies. In 2014, only in the Lahore district, total malignancies reported were 5,521 in which 1,425 cases were of breast cancer with distribution of 1,393 and 32 among females and males respectively. In this study, we review the types, basic prognostic tools for the assessment of breast cancer and its prevalence trend from the last 10 years in Pakistan.
Keywords: Breast cancer; Prevalence; Risk factors
The primary malignant neoplasm that starts in the cells of breast tissue is usually termed as breast cancer . Cancer of breast usually starts in the ducts and lobule . Cancer cells of breast can secede from its primary site and may proliferate. The proliferation of malignant cells is so fast to invade and metastasize in to different remote areas of body . The prognosis and correct treatment of breast cancer is highly dependent on good perception about normal anatomy of breast . The female breast is generally made up of milk producing glands (lobules), milk carrying ducts (from lobules to nipple) and stroma (comprises of fatty tissues and connective tissues enclosing lobules, tiny milk ducts, blood vessels and lymphatic vessels as well . Mostly breast cancer starts in the cells lining of milk carrying ducts, called as ductal Ca breast . Some breast cancers begin in the lobules (lobular Ca breast) while diminutive number commencing in other tissues of breast (Figure 1) .
Figure 1: Anatomy of breast.
The interrelation of lobules and ducts form a closed system like twigs on a tree trunk. The cancer that is enclosed or restricted inside this closed system is termed as in-situ/non invasive breast cancer while the invasive breast cancer is that in which cancer proliferate from closed system of ducts-lobules and metastasizes in to surrounding tissues [8,9]. The lymphatic system of breast plays a vital role in the metastasis of cancerous cells . The lymphatic system is usually comprises of lymph nodes (cells of immune system), lymphatic vessels (carrying clear fluid of lymph) and lymph (contain tissue fluid, waste products and immune system cells) . In the breast, the majority of lymphatic vessels link to the lymph nodes underneath the arm (axillary nodes) while some of the lymphatic vessels attach to the lymph node contained by chest (internal mammary nodes) and either above the collarbone (supraclavicular nodes) or below the collarbone(infraclavicular nodes) .
The breast cancer is of different types depending upon the way the cancerous cells appear under the microscope (carcinoma and sarcomas) and the proteins on cancer cells (hormone receptor positive/triple negative) . Some important types of breast cancer are as follows:
Ductal carcinoma in situ (DCIS): Other name of this carcinoma is intraductal carcinoma. DCIS is usually belongs to non invasive type of cancer because it is limited to only ductal system and does not harm the neighboring tissues [14,15]. In this cancer, cells lining the milk ducts are altered to cancer cells that can’t grow outside the breast (Figure 2). DCIS is also contemplated as pre-cancer because in some cases it can progress to turn into invasive cancers . Among non-invasive, DCIS is the most frequently diagnosed cancer with 1 in every 5 breast cancer patients .
Figure 2: Abnormal duct cells in DCIS.
Invasive ductal carcinoma (IDC): Among invasive carcinomas, IDC is the most frequent type of breast cancer. The alternative term used for IDC is infiltrating ductal carcinoma . This carcinoma also begins in the milk ducts but have capability to spread in the adjacent tissues via lymphatic system in to other body parts. According to American cancer society, it is roughly estimated that out of every 10 invasive Ca breast 8 patients are suffering from invasive ductal carcinoma [19,20].
Lobular carcinoma in situ (LCIS): Among non invasive breast carcinomas, LCIS is especially infrequent type of carcinoma which primarily considered as an indicator that cancer may develop in the breast. Some recent studies has been renamed the LCIS into lobular neoplasia because it is observed as peculiar growth in the number of cells milk glands (Figure 3) [21,22].
Figure 3: Abnormal cells in LCIS.
Invasive lobular carcinoma (ILC): Invasive lobular carcinoma is also known as infiltrating lobular carcinoma. It ranks 2nd after IDC. ILC begin in the lobules of breast (as a delicate thickening) and has greater ability to metastasize in to other body organs [23,24]. Rather than IDC, it might be difficult to observe ILC by means of mammogram. Its prevalence among other invasive breast cancer is 1 out of ten breast cancer patients diagnosed as ILC .
Inflammatory breast cancer (IBC): This cancer is an unusual and extremely destructive type of invasive breast cancer that is found to account for 1-3% of all breast cancers . It is responsible to block the lymphatic vessels of breast so the breast looks distended, enlarged, red and inflamed . Rather than a restricted dense mass/ lump, IBC is typically developed in layers. Additionally, it could confer the breast skin a wide, potholed appearance .
Paget disease of nipple: This breast cancer also starts in the ducts because it is continually linked with either DCIS or IDC but expand to the areola of the nipple and the nipple skin become irritating and scaly with area of bleeding and discharge . It is very uncommon type of cancer because out of all breast cancers it is account for only 1% [30,31].
Other types of breast cancers are Phyllodes tumor (cancer of connective tissues of breast) , Angiosarcoma (cancer of blood and lymph vessels of breast) , Adenoid cystic (or adenocystic) carcinoma , Low-grade adenosquamous carcinoma (this is a type of metaplastic carcinoma) , Medullary carcinoma, Mucinous (or colloid) carcinoma, Papillary carcinoma, Tubular carcinoma, Metaplastic carcinoma (most types, including spindle cell and squamous), Micropapillary carcinoma and Mixed carcinoma (has features of both invasive ductal and lobular) [5,36].
Intrinsic subtypes of breast cancer: Classification of breast cancer on the basis of presence or absence of receptor [37,38].
A. ER positive
- Luminal A: ER and PgR positive, HER2 negative, Ki-67 ‘low’.
- Luminal B (HER-2 NEGATIVE): ER positive, HER2 negative, and at least one of Ki-67 ‘high’, PgR ‘negative or low’.
- Luminal B( HER-2 POSITIVE): ER positive, HER2 overexpressed or amplified, Any Ki-67, Any PgR.
- Erb-B2 over expression (HER2 positive ‘non-luminal’ ):
- HER2 over-expressed or amplified, ER and PgR absent.
- Basal-like(Triple negative ‘ductal’): ER and PgR absent, HER2 negative.
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B. ER negative
Something that increases the possibility to acquire a cancer is called risk factor. Risk factors that have influence on breast cancer are:
Females have greater chance (100 times) to develop breast cancer as compared to man because females have more estrogen and progesterone hormones which encourage the cancer cells growth in breast . The probability of having breast cancer is higher with older age . In addition, having family history of breast cancer , personal history of breast cancer, chest region including breast expose to radiation, dense breast tissues , certain benign breast lesions (nonproliferative lesions, proliferative lesions without atypia and proliferative lesions with atypia) , female who had their 1st menstrual period before the age 12 yrs, use of oral contraceptives , obesity after the period of menopause , lack of physical exercise, exposure to diethylstilbestrol , use of Depotmedroxyprogesterone acetate (DMPA) , use of combinational hormonal therapy after menopause, alcohol drinking, inadequate diet (less intake of fibrous food, fruits and vegetables) and exposure to environmental chemicals (Pesticides such as DDE, polychlorinated biphenyls) are major contributing risk factors for breast cancer [48,49].
It has been reported in some recent studies that approximately 5-10% cases of breast cancer are the results of genetic mutation (that inherited from their parents) [50,51]. The mutation in the genes of BRCA1, BRCA2, ATM, TP53, CHEK2, PTEN, CDHI, STK11 and PALB2 are the recognized contributors toward breast cancer .
Generally in the primitive stage, breast carcinomas don’t exhibit any signs but as the tumor cells proliferate and metastasize, it can cause some changes in the breast tissues . The most common symptoms relating to breast cancer are: development of lump/mass , distension and inflammation of breast , skin of nipple and areola becomes itchy and crusty , painful feeling in the breast , nipple retraction , discharge of fluid other than milk from the nipple and breast skin show crumpling and indentation [58,59].
Both males and females are affected by this group of neoplasm but in males it is rarely reported and does not happen usually . Among women, breast cancer is most commonly diagnosed cancer both in developed and less developed countries. According to the global health estimates of WHO 2013, it is reported that worldwide breast cancer was the death reason of over 508,000 women in 2011 . Incidence rates for the breast cancer vary significantly from less developed to developed countries (such as 19.3/100,000 in eastern Africa and 89.7/100,000 in Western Europe).
From some recent studies, it has been reported worldwide that in year 2011, incidence rates for the breast cancer among men and women were 1.3/100,000, and 124.3/100,000 respectively [61,62]. In contrast to incidence rate, 0.3/100,000 and 21.5/100,000 were mortality rates that were recorded in that year for men and women respectively . WHO said in one of report that “Breast cancer rates are getting worse and it is not sparing even younger age group.” In less developed countries like Pakistan, women tend to die at greater rates than in developed countries because in general breast cancer is detected when it is in advanced stages .
In Pakistan, breast cancer is the most commonly diagnosed cancer. According to Punjab cancer registry 2014, total malignancies reported in the year 2014 is 5521, out of which 1425 cases were contributed by breast cancer with prevalence rate of 25.8% that is quite higher from the previous year’s [65,66]. According to Cancer registry report of Shoakat Khanum memorial cancer hospital and research center, total number of the cases of breast cancer reported from the last 10 years (2004-2014) are 13992, out which 13882 and 110 cases were contributed by females and males breast cancers respectively . Graphical representation (Graph 1 and 2) given at the end, show the prevalence trend of breast cancer in Pakistan from the last 10 years.
graph 1: Prevalence trend of breast cancer in both genders.
graph 2: Overall survival, autologous stem cell transplant (ASCT) versus no ASCT (p=0.12).
Generally, triple assessment tool is used in clinical evaluation of breast abnormalities. This triple assessment tool comprises of: Clinical examination of presenting complaints such as breast mass, nipple discharge, breast pain, skin retraction and arm swelling; Imaging tests (mammography and ultrasound); And tissue sampling (biopsy, fine needle aspiration cytology and needle core biopsy).
In order to diagnose the breast cancer, following diagnostic tests are used such as Clinical examination of breast (breast self examination and physical examination), imaging tests to differentiate benign and malignant carcinomas and biopsies . Other laboratory investigations are also used such as complete blood count with differentials (CBCD), renal and liver profile, chest X-ray with CT, abdominal ultrasound with CT of abdomen, bone scan, ECG and multiple gated acquisition (MUGA) scan if age >60, positron emission tomography (Figure 4) . Receptors test is also employed to evaluate the breast cancer type . In this test removed part of tumor (during biopsy/surgery) is assessed for the presence or absence of receptors (estrogen, progesterone, and HER-2). The presence of estrogen receptors on breast cancer is termed as estrogen positive cancers on the other hand cancers will be PR +ve if the receptor test is positive for progesterone and the tumors with over expression of HER-2 is characterized as HER-2 positive [71,72].
Figure 4: Flow chart for the breast cancer diagnosis.
Tests usually employed to analyze the biopsy/surgery samples are immunohistochemistry test (IHC), Fluorescent in situ hybridization (FISH) and Chromogenic in situ hybridization (CISH) . In addition to above tests, test of ploidy and cell proliferation rate are utilized to assess the abnormal DNA in the cells and rate of cell division by estimating the ki-67 labeling index that help in better prognosis . Gene expression profiling is used to find the pattern of different genes .
Different therapies are used to treat the breast cancer and treatment is highly depending upon the better prognosis and staging of cancer . Different options for breast cancer are surgery, radiation therapy, chemo therapy, hormonal therapy, targeted therapy and bone directed therapy . These treatment modalities are categorized in to two main groups such as:
Surgery and radiation therapies are the example of local therapy because their purpose is to treat the localized tumor without affecting the rest of the body parts . While chemotherapy, hormone therapy and targeted therapy belong to systemic therapy because they are directly introduced in to blood stream to attain access toward cancerous cells.
Administration of additional treatment to exterminate and restrain the clinically unnoticeable cancerous cells after primary surgery is termed as adjuvant therapy . The primary objective of this therapy is to prevent the recurrence of cancer . This prudent approach has been recognized to improve the survival in both node -ve and node +ve breast cancer in combination with systemic and hormonal therapy (optional). Through adjuvant therapy, survival of patients could be enhanced up to 10 years by 7%–11% in premenopausal women with early stage breast cancer and by 2-3% in women having age above 50 years .
Neoadjuvant therapy is defined as administration of treatment (chemotherapy or hormonal therapy) prior to surgery to reduce the tumor size . The possibility of cancer recurrence become also reduces by using this approach. In the treatment of locally advanced breast cancer, this pre-operative induction chemotherapy is considered as reasonable approach because of having higher response rate .
Surgery has been considered as most primitive and frequently used treatment option for breast cancer . Types of surgeries to remove breast tumors are mentioned in Table 1.
Possible side effects of surgeries
Breast conserving surgery
Other common names for this surgery are partial mastectomy and Lumpectomy. This surgery is performed to amputate a part of breast that is confined to cancer.
Pain, transient inflammation, soreness, bleeding, tough scar tissue and infection at the site of surgery are the possible side effects associated with theses surgeries.
Mastectomy is of following types
ii) skin sparing mastectomy
iii)modified radical mastectomy iv) radical mastectomy
In addition to pain and apparent change in the breast shape, the potential side effects of mastectomy include wound infection, hematoma and seroma.
Lymph node surgery
Lymph node surgery is the removal of lymph nodes (under arm) if breast cancer has spread and invade to lymph nodes. This surgery are of two types:
i) Axillary lymph node dissection
ii) Sentinel lymph node biopsy
Burning pain, arm swelling, bleeding, infection Lymphedema, frozen shoulder, lack of sensation of the skin on the upper and inner arm and lymphatic cording
Table 1: Types of surgeries to remove breast tumor.
One of the established methods for treating the early stage invasive breast cancer is Breast conservative therapy (BCT).one of the recent study carried out at Shoakat Khanum memorial hospital and research center reported that BCT has satisfactory long-term results in Pakistani women .
In radiotherapy, high energy rays are used to exterminate the cancerous cells. Radiotherapy is frequently used subsequent to breast surgery . The main purpose of this therapy is to lessen the possibility of cancer re-emergence in the breast tissues and neighboring lymph nodes. This therapy can be given by two ways: external beam radiation and internal radiotherapy (Figure 5) .
Figure 5: Types of radiotherapy.
A. External Beam Radiation Therapy
Intensity Modulated Radiation Therapy (IMRT), Conformal Radiation Therapy and Image-Guided Radiation Therapy (IGRT) are the External Beam Radiation Therapies used in Shoakat Khanum memorial cancer hospital and research center, Pakistan by Radiation Oncologists in order to treat various types of cancers according to subspecialties such as head and neck, brain, prostate, lung breast, and gynecological cancers. IMRT delivers doses of radiation with different intensity levels within 2mm square segments, which optimizes the radiation dose to the irregularly shaped tumors while minimizing the dose to surrounding structures, further reducing side effects. The IGRT permits the radiation oncologist to target the tumor by adjusting the radiation beam so that radiation with higher dose can be delivered safely .
B. Brachytherapy (Internal Radiotherapy)
In brachytherapy, radioactive seeds are carefully placed inside cancerous tissue and positioned to attack the cancer most effectively. A brachytherapy is an outpatient procedure that is effective in treating esophagus, lung, gynecologic, and breast cancers, among some others. SKMCH&RC is the only 3D HIGH DOSE RATE brachytherapy provider in Pakistan .
There are several side effects of radiotherapy such as Inflammation and heaviness in the breast; fatigue; skin changes in the treated area (redness, wound and peeling); brachial plexopathy; numbness, pain and weakness in the arm, shoulder and hand; cracking of the ribs; lymphedema and angiosarcoma are associated with external beam radiation . In addition Breast pain, redness of breast skin, bruising, infection, weakness and fracture of the ribs are related with brachytherapy .
Chemotherapy (anticancer treatment) is intended to kill the cancerous cells/abnormal growth in the body that could be administered either orally or by intravenously. This treatment is frequently delivered in cycles and continued for several months depending upon the recovery . Chemotherapeutic agents (Figure 6) are usually recommended for following three situations: after surgery (as adjuvant therapy), before surgery (as neoadjuvant therapy) and for advanced stage breast cancer (as palliative therapy). Chemotherapy is commonly used in combination of one or more drug .
Figure 6: Chemotherapeutic agents to treat the breast cancer.
Globally, carcinoma of breast is one of the most common malignancies among females. In Pakistan, breast cancer is most frequently diagnosed at young age with highest incidence rate of 50/100,000 as compared to west where it is more common after the age of 60. Approximately one in every nine Pakistani women is likely to suffer from breast cancer. This review summarized the types of breast cancer, potential causative agents, diagnostic tools, different treatments for this chronic disease and its prevalence trend in Pakistan from the last 10 years. Annual Punjab cancer registry report 2014 described that only in the Lahore district; total malignancies reported from Jan 2014-Dec 2014 were 5,521 in which 1,425 cases were of breast cancer with distribution of 1,393 and 32 among females and males respectively. Rigorous research is required in this field to aware the females because breast cancer management at advanced stages is a big challenge for developing countries.
Citation: Ayesha T, Muhammad AT and Azhar K. Prognosis, Prevalence Trend and Different Treatment Options of Breast Cancer in Pakistan. Austin J Cancer Clin Res. 2016; 3(1): 1066.