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Breast Cancer

 

Breast Cancer

Epidemiology

Risk Factors

Diagnosis

History

Physical Examination

Breast Imaging

 Mammography

Ultrasound

MRI

Biopsy

Systemic Evaluation

Pathology

Normal breast anatomy

Lobular Carcinoma in situ (LCIS)

Ductal Carcinoma in situ (DCIS)

Invasive Breast Cancer

Receptors Status

Grading

Breast Cancer Staging

Molecular characterization

Oncotype DX

Mammaprint

Spread

Therapy

Lobular Carcinoma in situ (LCIS)

Ductal Carcinoma in situ (DCIS)

Invasive Cancer

Surgery

Radiation therapy

Drugs therapy

Chemotherapy

Hormonal therapy

Biologic therapies

References

 

Epidemiology

Breast cancer is the most prevalent malignancy and the second cause of cancer related death among women (1). According to the World Health Organization's (WHO) World Cancer Report, 2003, more than one million new cases of breast cancer are diagnosed worldwide each year (2, 3). In 2009, about 192,370 women are estimated to be diagnosed with breast cancer (1), and more than 40,000 patients are expected to die from this disease in the USA (1). In Arab countries, population-based screening is not a common practice; locally advanced disease accounts for higher percentage of the newly diagnosed breast cancers there (4, 5).

Risk Factors

The causes of breast cancer in the majority of patients remain undetected. Risk factors for this malignancy include: 

  1. Patient’s sex. Breast cancer is much more prevalent among females than among males. The estimated number of new cases of breast cancer in the USA during the year 2009 is about 192,370 women, versus 1910 men (1).

  2. Age. There is increase in the incidence of breast cancer with increasing age (6). Breast cancer is the leading cause of cancer related death among women between the ages of 20-59 years (1).

  3. Family history and genetic factors. Genetic factors play an important role in breast cancer. The risk for a woman to develop breast cancer is 1.5 to 3 times higher if she has a sister or a mother who suffer from breast cancer (6). Mutations in some genes were found to result in increased risk for breast cancer. Mutations in Breast Cancer Associated Gene 1 & 2 (BRCA1, BRCA2) results in increased incidence of breast and ovarian cancer. These mutations are associated with breast cancer in young women.

  4. Menstrual cycle. Breast cancer risk increase with the number of menstrual cycles that the woman experiences during her life. Late menarche, early menopause, and pregnancy are associated with less menstrual cycles and thus a lower risk for breast cancer.

  5. Breast feeding. Women who breastfeed their children seems to have less breast cancer. The odds ratios for breast cancer are lower with increasing duration of breastfeeding (7).

  6. Obesity. Obesity is a risk factor for breast cancer (6, 8, 9). Increased physical activity is associated with lower risk for breast cancer (9).

  7. Radiation. Previous radiation therapy to chest wall increases the risk for breast cancer.  

Diagnosis

History. Taking history from the patient is very important for the diagnosis of any breast pathology. The main questions for the patient are:

1.      Is there any lump in the breast, in the underarm area, or in the neck region?

2.      Did the patient note any new asymmetry in the breasts?

3.      Is there a retraction of the nipple?

4.      Is there any change in the texture of the breast skin? Any ulceration of the breast skin?

5.      Is there a history of cancer for the patient or his relatives?

Physical Examination. Inspection. Physical examination starts with inspection of both breasts. The physician pays special attention to any lumps or irregularities in the breast structure, and to the skin texture of the breast. Early stages of breast cancer are usually unnoticed by inspection. Centrally located breast tumors may result in retraction of the nipple. Breast cancer infiltrating the skin may results in change of the skin texture of the affected breast. Advanced breast cancer with ulceration of the skin can be easily seen by inspection. Palpation. Palpation of the breast and its lymph node draining areas (underarm, above and below the clavicle, and the area beside the sternum) is pivotal for the diagnosis and evaluation of breast cancer. Systematic approach for breast examination is employed by most oncologists, with special attention for areas indicated by the patient, suspected by inspection, or specified in previous imaging procedures that the patient already performed.   

Breast Imaging

Mammography. Mammography is used both for screening and diagnosis of suspicious lesions of the breasts.

Ultrasound. Ultrasound is used to further define any suspicious lesion discovered either by physical examination or mammography. Ultrasound is also utilized to guide core needle biopsy or fine needle aspiration (FNA).  

MRI. The role of MRI in diagnosis and management of primary breast cancer is not clear-cut. MRI may be important in young women with dense breast tissue (which usually is difficult to evaluate by mammography), other clinical scenarios in which MRI may be of benefit are cases in which there is an enlarged lymph node in the underarm with proved biopsy of breast cancer, but all other studies (physical examination, mammography and ultrasound) do not show where the primary tumor is. In such situations MRI may give the answer. MRI can also be used to follow young healthy women with proved genetic mutation in BRCA1 or BRCA2 genes, in order to detect any malignancy at an early stage.    

Biopsy. Tumor biopsy is critical for the diagnosis of breast cancer, and to discriminate it from other non-malignant lesions. For large palpable lesions, biopsy can be performed without the guidance of imaging. For impalpable lesions, the biopsy is usually performed under the guidance of an imaging modality (mammography/ ultrasound). Fine Needle Aspiration (FNA) or Tru-cut biopsy (thicker needle that cuts part of the lesion) is usually used to obtain tissue from the suspicious mass. Once material from the tumor is obtained, pathological evaluation under microscope can be performed. If an enlarged lymph node is detected in the axilla (underarm), additional biopsy should be obtained from it as well.

Systemic Evaluation. Systemic evaluation is a work up that is done to test if cancer has spread outside the breast or its regional lymph nodes. Systemic evaluation is performed to answer the question: Have this breast cancer send metastasis? Stage I breast cancer (node negative breast cancer and tumors less than 2 c"m) rarely send metastasis at time of diagnosis and systemic evaluation is not usually necessary. For node positive breast cancer and tumors larger than 2 c"m systemic evaluation should be considered. Systemic evaluation usually includes bone scan (to exclude bone metastasis), CT scan of the chest, and abdominal CT or ultrasound.  

Pathology

Normal breast anatomy. Breast tissue contains glands (mammary glands which are responsible to milk production after child delivery). These glands end in lactiferous ducts that drain into pores in the nipple. 

Lobular Carcinoma in situ (LCIS). LCIS is a premalignant lesion. Women with LCIS are at higher risk to develop breast cancer in the same breast in which the lesion was detected, as well as in the contralateral (the other) breast. (See treatment of LCIS below).

Ductal Carcinoma in situ (DCIS). DCIS is non-invasive cancer (do not send metastasis), but is a precursor for invasive carcinoma, and thus should be treated. Treatment of DCIS usually includes surgery± radiation therapy. (See treatment of DCIS below).

Invasive Breast Cancer. Invasive cancer is a malignant disease (tumor with ability to send metastasis). The two major pathological entities of invasive breast cancer are: Invasive Ductal Carcinoma (IDC) and Invasive Lobular Carcinoma (ILC). IDC have some variants with better prognosis: A. Tubular Carcinoma, this cancer is composed of well differentiated cells, B. Mucinous (colloid) carcinoma- tumor cells produce a mucos/jelly-like material, these tumors are usually well differentiated, highly express estrogen receptor (good thing) and usually do not express HER2 (less aggressive tumor); mucinous carcinoma is less likely to metastasize to lymph nodes compared to other breast cancers. C. Adenoid Cystic carcinoma of breast is rare and has a good prognosis, with low metastatic potential.   

Receptors Status. Each malignant breast tissue, obtained either through breast biopsy or operation (partial or total breast excision), should be evaluated for the expression of:

A.    Estrogen Receptor (ER).

B.     Progesterone Receptor (PR).

C.     Human Epidermal growth factor Receptor 2 (HER2).

The evaluation of the receptors status is determined by a method called immunohistochemistry. The results range from 0 to +3. For ER and PR the percent of tumor cells stained for the specific receptor is evaluated as well. For HER2, results of 0 or +1 are regarded as negative, results of +3 as positive, and +2 as inconclusive. If the result is +2 a more specific study should be performed, this study is called "FISH" (Fluorescence in Situ hybridization).  

Grading

Grading of breast cancer relies on the pathological appearance of the tumors cells. There are three grades:

Grade 1: Low grade = well differentiated cells (good prognosis).

Grade 2: Intermediate grade.

Grade 3: High grade= poorly differentiated cells (highly malignant).

Breast Cancer Staging

Breast cancer is classified according to the TNM staging system suggested by the American Joint Committee on Cancer (AJCC) (10). The staging system takes into account the primary tumor characteristics (T1-T4, see table below), lymph nodes involvement (N0-N3, see table below), and the presence (M1) or absence (M0) of distant metastasis. Regarding the lymph nodes involvement, presence of tumor cells within a lymph node with a diameter of more than 2 mm is defined as metastasis; between 0.2- 2 mm micro-metastasis; and less than 0.2 mm as isolated tumor cells. The clinical meaning of micro-metastasis and isolated tumor cells are not totally clear. Pathologic staging of lymph nodes relies upon the number of involved nodes: N0 = no lymph node involvement; N1= 1-3 lymph nodes with metastasis; N2= 4-9 lymph nodes with metastasis; N3 ≥ 10 lymph nodes with metastasis. 

TNM definitions in Breast Cancer Staging

 Breast cancer staging

 

Breast Cancer Staging

Breast Cancer Staging 

 

Molecular characterization

Oncotype DX. This test examines breast tissue embedded in paraffin (after biopsy or operation, the resected breast tissue is embedded in paraffin to facilitate histological examination, and to preserve the tissue for long period of time). Oncotype DX tests the RNA levels of 21 genes. 16 of these 21 genes are related to cancer, while the other five are reference genes tested to calibrate the results. The test was primarily designed to predict the likelihood of breast cancer recurrence for women with node-negative, estrogen-receptor-positive (stage I) invasive breast cancer treated after operation with Tamoxifen only (11, 12). Oncotype DX assay gives a number for each test called "Recurrence Score". The likelihood of distant recurrence at 10 years increases continuously with an increase in the Oncotype DX assay Recurrence Score® result (11, 12), Oncotype DX assay was able to stratify these patients into three main groups: Low risk for recurrence, Intermediate risk, and High risk. Women with low recurrence score are usually treated with hormonal therapy only (no chemotherapy is given after breast operation); women with high recurrence score are usually treated with both chemotherapy and hormonal therapy; intermediate group treatment is usually individualized. Another study showed that Oncotype DX Recurrence Score in women with stage I, node negative, estrogen receptor positive breast cancer tumors, can predict which women will benefit from chemotherapy. Women with high recurrence score (score ≥31) had a large benefit from chemotherapy. Patients with low recurrence score (< 18) derived minimal, if any, benefit from chemotherapy treatment, recurrence score of 18-31 is a gray zone (13). Recent results show that Oncotype DX test can predict response to chemotherapy in women with breast cancer and 0-3 positive axillary lymph nodes (14). 

Mammaprint. Mammaprint test the expression of RNA of a set of 70 genes related to breast cancer by microarrays method (15, 16). The test utilizes fresh frozen breast cancer tissue. The test (approved by the FDA) is useful in predicting time to distant metastasis in women who are under age 61 who have tumor size equal to or less than five centimeters and no evidence that the cancer has spread to lymph nodes (lymph node negative) (15-17).

Recently a study that compared different prediction tests based on molecular characteristics found that there is high concordance between Mammaprint and Oncotype DX (18).

Spread

Breast cancer usually sends metastasis first to regional lymph nodes. Lymph nodes of the axilla (underarm) are usually the first to be affected; other regional lymph nodes affected by breast metastasis are the supraclavicular lymph nodes, infraclavicular lymph nodes, and internal mammary lymph nodes. Distant lymph nodes may be involved but it's rare to find distant lymph node metastasis without regional lymph node involvement. Breast cancer may send metastasis to every organ, but the most involved tissues are the bones, lungs, liver and brain.  

Therapy

Lobular Carcinoma in situ (LCIS). LCIS is a premalignant state, women with LCIS are at higher (and equal) risk to develop breast cancer in both breasts (19) and thus local treatment (partial resection of the breast or resection of one breast) are not advised. Women with LCIS should be followed closely to allow the detection of any breast malignancy at an early stage. Preventive treatments include bilateral mastectomy (resection of both breasts) with or without breast reconstruction, or hormonal therapy with tamoxifen (20, 21).

Ductal Carcinoma in situ (DCIS). Surgery is an important arm in the treatment of DCIS. For women suffering from DCIS, with disease limited to a part of the breast (according to preoperative assessment e.g. mammography), partial breast resection (lumpectomy) or total breast resection (mastectomy) should be performed. If DCIS lesions are scattered in different areas of the breast, lumpectomy may turn to be impossible, and total breast removal should be performed (mastectomy). If the resection margins after lumpectomy contain DCIS, re-lumpectomy or mastectomy should be performed. After lumpectomy, radiation therapy should be delivered to the breast remnant tissue, and this measure decreases the possibility of recurrence by 50% (22, 23). Axillary lymph node dissection is not necessary in women with pure DCIS. For patients with a DCIS that stains positive for estrogen receptor or progesterone receptor, treatment with tamoxifen for 5 years is recommended as a preventive treatment after operation.

Invasive Cancer. Treatment of invasive breast cancer relies on three different arms:

1) Surgery. Surgery is used for localized breast cancer (non metastatic disease localized to the breast ± underarm (axillary) lymph nodes). Resection of breast cancer is the most important part in the treatment of localized disease. For small tumors, partial breast resection (lumpectomy) can be satisfactory when complemented by radiation therapy (24, 25). For large breast tumors, or tumors involving the breast skin or nipple, resection of the whole breast may be inevitable. In selected cases, women with large breast tumor (without skin involvement) who desire breast preservation may benefit from neo-adjuvant chemotherapy, administered before the operation to shrink the tumor size, allowing partial breast resection with good cosmetic results (26, 27).   

Determination of metastatic disease to regional lymph nodes is preferably performed using sentinel lymph node biopsy: in this method a dye or a radioactive material is injected to the tumor bed (tissue surrounding the tumor) and after 10-50 minutes the surgeon tracks the lymph nodes to which the dye or the radioactive material drained, and excise them. The sentinel lymph node/s are then examined under the microscope, if tumor metastasis is found in the sentinel lymph nodes, then a full dissection of the axillary lymph nodes is performed. This methods spare the patient an unnecessary lymph node dissection when the sentinel lymph node is negative (less side effects like arm swelling) (28, 29)

2) Radiation therapy. There are several clinical settings in which radiation therapy is used:

  1. Lumpectomy: radiation therapy should be given after lumpectomy (partial breast resection) as preventive measure. Radiotherapy should be given after the completion of postoperative chemotherapy. For patients without regional lymph nodes metastasis, only the breast is treated with radiation. In the cases of lymph node involvement, both the breast and the regional lymph nodes should be treated with radiotherapy (24, 25).

  2. Mastectomy: radiation therapy is given after mastectomy if lymph nodes are involved or if the tumor diameter is larger than 5 cm. For lymph node positive patients, both the chest wall and the regional lymph nodes are irradiated (30).   

3) Drugs therapy. Drug therapies in breast cancer are divided into 3 main categories: Chemotherapy, hormonal therapy and biologic therapies.

  1. Chemotherapy. Chemotherapy is used in breast cancer in three main settings:

  1. Neoadjuvant treatment: Chemotherapy given before breast cancer operation due to large tumors, to allow better resection and/or breast conservation (partial resection instead of mastectomy). Neoadjuvant chemotherapy does not give survival advantage upon adjuvant chemotherapy (26, 27).

  2. Adjuvant chemotherapy: Adjuvant chemotherapy is given after curative breast operation (lumpectomy or mastectomy ± axillary lymph node dissection) in order to eliminate microscopic tumor focuses and to decrease the probability of breast cancer recurrence. Adjuvant chemotherapy is usually given to women with primary breast tumors larger than 1 cm and/or women with node positive breast cancer (axillary lymph nodes with tumor metastasis). For women without lymph node involvement, tumors larger than 1 cm but less than 5 cm, positive estrogen receptors and negative HER2 receptors, further evaluation of the need of chemotherapy can be performed using molecular characterization of the tumor with tests such Oncotype DX or Mammaprint. These tests evaluate the risk of breast cancer recurrence, and the possible impact of chemotherapy treatment on the specific patient. A discussion between the clinician and the patient is usually necessary before ordering these tests and after receiving the results, in order to make a rational treatment plan. Anthracyclines are drugs that inhibit an enzyme in the cells called topoisomerase 2; these drugs play a pivotal role in the treatment of breast cancer. Doxorubicin (Adriamycin) and Epirubicin are the main anthracyclines used in the treatment of breast cancer in the adjuvant setting, and are given usually in combination with other chemotherapeutic drugs (e.g. Cyclophosphamide (Cytoxan). Anthracycline-based polychemotherapy reduces the annual breast cancer death rate by about 38% for women younger than 50 years of age when diagnosed and by about 20% for those of age 50—69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics (31). Such regimens are significantly more effective than the non Anthracycline containing regimen named CMF chemotherapy (31).

    Some of the famous combination chemotherapy protocol:

    a.       AC: Adriamycin (doxorubicin) + Cyclophosphamide given once every 3 weeks x 4 cycles (32, 33).

    b.      AC→T: [Adriamycin (doxorubicin) + Cyclophosphamide] every 21 days for 4 cycles → Taxol (paclitaxel) every 21 days x 4 cycles (34).

    c.       AC→T (dose dense): [Adriamycin (doxorubicin) + Cyclophosphamide] every 14 days for 4 cycles → Taxol (paclitaxel) every 14 days x 4 cycles (every treatment is followed by GCSF support, e.g. Filgrestim) (35)

    d.      AC→T: [Adriamycin (doxorubicin) + Cyclophosphamide] every 21 days for 4 cycles → Taxol (paclitaxel) every 7 days x 12 cycles (36).

    e.       TAC: [Docetaxel (Taxotere) + Adriamycin (doxorubicin) + Cyclophosphamide] every 21 days x 6 cycles (37).

    f.       TC: [Docetaxel (Taxotere) + Cyclophosphamide] every 21 days x 4 cycles (38).

    g.      CMF: Cyclophosphamide + 5FU+ Methotrexate (different schedules for administration and cycles timing) (39).

    For HER 2 positive patients see protocols including the biological therapies- below.

  3. Chemotherapy for advanced metastatic disease: chemotherapy in this case is given to decrease tumor size, palliate symptoms resulting from the tumor masses, and to increase overall survival of patients. As the goal of these treatments is palliative, highly aggressive chemotherapeutic protocols are not widely used. Some of the treatment options used: 

a.       AC: Adriamycin (doxorubicin) + Cyclophosphamide given once every 3 weeks x 4 cycles (32, 33).

b.      Single agent Doxorubicin (Adriamycin).

c.       Single agent pegylated liposomal doxorubicin (Doxil/ Caelyx) (40).

d.      Single agent Paclitaxel (Taxol) (41).

e.       Single agent Docetaxel (Taxotere) (42).

f.       Single agent Capecitabine (Xeloda).

g.      Single agent Gemcitabine (Gemzar).

h.      Single agent Vinorelbine (Navelbine).

 

  1. Hormonal therapy. Pathology reports of breast cancer biopsies and the pathology reports after breast surgery (lumpectomy or mastectomy) should include a description of the estrogen receptor (ER) and progesterone receptor (PR) status of the tumor. For patients with positive ER and/or PR expression, hormonal therapy is usually utilized as part of the treatment plan. The main three hormonal treatment modalities are:

A.    Tamoxifen. Tamoxifen is used to treat both pre-menopausal and post-menopausal women suffering from breast cancer, both in the adjuvant and metastatic setting.

B.     Aromatase Inhibitors. Aromatase inhibitors are not active in premenopausal women. In postmenopausal women aromatase inhibitors are effective in ER positive patients.

C.     LHRH agonists/ovarian ablation. Luteinizing-hormone releasing hormone (LHRH) is a hormone produced by the hypothalamus, and is responsible for the release of the hormones FSH and LH from the pituitary. This release happens when there is a pulsatile secretion of LHRH. LHRH agonists that have long half life results in suppression of the release of LH and FSH, and hence ovarian suppression.  

  1. Adjuvant Hormonal Therapy.

 i.            Tamoxifen. For ER-positive disease, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% irrespective of the use of chemotherapy and of age (31). 5 years is significantly more effective than just 1—2 years of tamoxifen (31).

 ii.            Aromatase Inhibitors.

a.       Aromatase inhibitors after 2-3 years of tamoxifen:

a) Exemestane: Intergroup Exemestane Study showed that a switch to exemestane after 2-3 years of tamoxifen improves disease free survival (reduce recurrence of disease), and modestly improve patients overall survival (43).

b)  Anastrozole: Patients treated with tamoxifen for 2 years as adjuvant therapy are less likely to experience a recurrence of breast cancer and have improved overall survival if they switch to anastrozole compared with continuing tamoxifen for five years (44).

c) Letrozole: sequential treatment with letrozole after 2 years of tamoxifen, as compared with letrozole monotherapy, did not improve disease-free survival. There was no difference in overall survival between women treated with 5 years tamoxifen or 5 years letrozole (45).

b.      Aromatase inhibitors after 5 years of tamoxifen: Treatment with Letrozole after 5 year tamoxifen improves disease free survival (decrease the recurrence rate of the disease) but do not improve the patients' survival, except if lymph nodes were involved at presentation. The ideal period of letrozole treatment is not known, but should not exceed 2-5 years (46).

  1. Hormonal Therapy for Metastatic Disease.

Hormonal therapies for metastatic disease includes: Aromatase inhibitors for postmenopausal women (preferred), Tamoxifen, LHRH ± tamoxifen/ aromatase inhibitor (for premenopausal women), and Fulvestrant.

  1. Biologic therapies.  

a)      Trastusumab (Herceptin). Human epidermal growth factor receptor 2 (HER 2) is found on the cell surface of 20 to 30% of invasive breast carcinomas (47). Patients with tumors over-expressing HER2 may benefit from drugs that are targeted to this receptor. Trastusumab is a humanized antibody that targets the HER2 receptor. Tumor cells over-expressing HER2 are attacked by Trastuzumab, ultimately leading to less tumor proliferation. In the adjuvant setting, Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer (48, 49). The most used treatment regimen is AC→T+H: [Adriamycin (doxorubicin) + Cyclophosphamide] every 21 days for 4 cycles → Taxol (paclitaxel) every 21 days x 4 cycles + Trastuzumab (Herceptin) every 21 days for 1 year. Trastuzumab in combination with other chemotherapies was also reported in the adjuvant setting (50).  Women with metastatic breast cancer over-expressing HER2 also benefit when Herceptin is added to chemotherapy (51), hormonal therapy (52) or when given as a single agent (53). Recently, a report showed a benefit for continuing Herceptin, in women previously treated with Herceptin and progressed, together with chemotherapy. The effect on overall survival was not statistically significant, but overall response rates were more pronounced when Heceptin was continued beyond progression (54).

b)      Lapatinib. Lapatinib (Tykerb) is a medication given as an oral pill; it is a small molecule that is absorbed through the gastrointestinal track, and arrives to all body organs including the brain (as opposed to Herceptin which do not penetrate the blood-brain brier). Lapatinib inhibit the HER2 receptor through inhibiting its intracellular (tyrosine kinase) part. Lapatinib when added to capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab (55). Recent report by Kaufman et al. showed that Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer (56).

c)      Bevacizumab (Avastin).  Bevacizumab is a monoclonal antibody against VEGF. Initial therapy of metastatic breast cancer with bevacizumab plus paclitaxel as compared with paclitaxel alone, increases the objective response rate but do not prolong overall survival or improve quality of life (57). Adding Avastin to capecitabine in treatment of women with metastatic breast cancer didn't resulted in prolongation of life of these patients, nor resulted in slowing of the disease progression (58).

 

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