Author Lisa Wiechmann MD
Breast cancer is the leading cause of death in women 40-55 years of age. It represents the second leading cause of cancer death among american women (all ages) following lung cancer. Approximately 1 in 8 (12.5%) american women will be diagnosed with breast cancer during thier lifetime, and the risk of dying from the disease is approximately 3.4%. Breast cancer accounts for approximately 30% of cancers in women. It’s incidence increases rapidly after 40 years of age and after menopause the rate of increase is slower. Furthermore incidence of breast cancer has been steadily increasing over the past 70 years as demonstrated by data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER). Part of this increase has been attributed to an increased detection rate related to the use of mammography. Survival rates have also increased steadily for women with local and regional disease and this is probably due to both earlier detection of cancer and improvement in therapies.
Medullary carcinoma of the breast represents less than 5% to 7% or ivasive breast cancers. Some studies have associated it with a more favorable prognosis, but the difficulty in reproducing its diagnosis histologically, has led to significan controversy. Overall at 10 years there appears to be no difference in recurrence rates between patients with medullary carcinomas and other subtypes of invasive breast cancer.Clinically, medullary carcinoma presents at a slightly younger age (late 50s, early 60s) as a palpable mass, usually in the upper outer quadrant. Rarely, it has been documented in men; it is associated with BRCA-1 mutations in many cases.The mammographic features of medullary carcinoma include the presence of a well defined mass and the absence of calcifications. On ultrasound, these carcinomas are usually well defined , lobulated , hypoechoic masses.
Multiple factors appear to be involved in the pathogenesis of breast cancer: these include genetic factors, environmental factors and endocrine factors. Gender is the most important risk factor for the development of breast cancer, which occurs 100 times more frequently in women than in men. This is due to endocrine factors as mentioned above: factors that increase the number of menstrual cycles (exposure to estrogen) such as nulliparity, late pregnancy (after 30 years of age), early menarche and late menopause( > 30 years menstrual time), are associated with an increased risk of breast cancer. Protective factors include moderate levels of exercise, and a longer lactation period. exposure to exogenous estrogens (oral contraceptive pills and hormone replacement therapy if prolonged in their duration- > 10 years) has though data is controversial. Age is an important risk factor for the development of breast cancer ( which translates in years of exposure to estrogen) ( risk of white American woman at 30 years 1:5,900, at 80 years 1:290)
Infiltrating lobular carcinoma is present in 5%-10% of breast cancers. It has a typical microscopic appearance characterized by small cells in a single-file (indian file) that typically grow around ducts and lobules. Lobular carcinomas are frequently multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges and serosal surfaces. Clinically they may present as poorly defined areas of thickening of the breast. Radiologically microcalcifications may be present or absent.
Prior history of breast cancer is a significant risk factor for the development of breast cancer[0.5-1 per year of follow-up] . proliferative breast diseases have now been found to increase the risk of breast cancer slightly 1.5-2 times the risk (papillomas, florid hyperplasia without atypia, sclerosing adenosis), moderately – 4 to 5 times the risk (Atypical ductal and lobular hyperplasia) and severely- 8 to 10 times the risk (lobular carcinoma in situ).
Environmental factors include exposure to ionizing radiation (mantle radiaton therapy for Hodgkin’s lymphoma -75-fold increase in risk, survivors of the atomic bomb) if exposure was before age 30) and potentially obesity (controversial) and alcohol ( no conclusive evidence). In mice a virus called mouse mammary tumor virus (MMTV), transmitted through the mother’s milk, causes breast cancer in suckling mice. No such virus has been identified in humans to this date.
Any family history of breast cancer increases a woman’s risk of breast cancer, especially if found in first degree relatives. Such risk is dependent on the characteristics of the cancer in relatives ( age at presentation, unilateral or bilateral, number of relatives with cancer).
Recently attention has been focusing on genetic alterations that determine predisposition to breast cancer. Numerous autosomal dominant conditions have been found to be associated with increased risk of breast cancer: these include Li-Fraumeni Syndrome, Muir-Torre Syndrome, Cowden Disease, Peutz-Jeghers Syndrome and possibly Ataxia – telangiectasia carriers. Approximately 5-10% of breast cancer results from inheritance of germline mutations of genes (BRCA-1 and BRCA-2); such genes are inherited in autosomal dominant pattern with varying penetrance. BRCA-1 and BRCA-2 are tumor suppressor genes and loss of both alleles is required for initiation of breast cancer. They appear to be involved in DNA-repair pathways and control of the cell cycle. BRCA-1 is located on chromosome 17q and contains 22 coding exons (1863 amino acid protein). BRCA-1 mutations ( of which more than 500 are known) determine predisposition in up to 45% of hereditary breast cancers and in 80% or more of hereditary ovarian cancers. Women carrying the mutation have up to a 90% lifetime risk of breast cancer and a 40% lifetime risk of ovarian cancer. Carcinomas associated with the presence of BRCA-1 are typically invasive ductal carcinomas, are poorly differentiated and are hormone – receptor negative. They are also more frequently bilateral, have an earlier onset and are associated with the presence of other malignancies including ovarian cancer, and possibly colon cancer and prostate cancer.
The Jewish Ashkenazi population displays a 10 fold higher frequency of 2 founder mutations (185delAG and 5382insC) therefore screening of such mutations in then above population is indicated.
BRCA-2 is located on chromosome 13q and contains 26 coding exons (3418 amino acids). The biologic function of the gene transcript has yet to be delineated, but is thought to pertain to DNA repair mechanisms. More than 250 mutations of the BRCA-2 gene have been described and the lifetime risk of carriers has been estimated at 85% or more( ovarian lifetime risk 20%). Male carriers of the BRCA-2 mutations carry a 6% lifetime risk of breast cancer (100 fold increase from controls). Carcinomas associated with the presence of BRCA- 2 are usually well differentiated invasive ductal carcinomas and more frequently express hormone receptors. BRCA-2 associated breast cancers are frequently bilateral and may be associated with other malignancies including ovarian, prostate, colon, pancreas, gallbladder, bile duct, and stomach cancers as well as melanoma. A founder mutation (999del5) is observed in the Icelandic and Finnish populations.
The interaction of many different risk factors in the initiation of breast cancer has lead to the creation and use of risk-assessment models. This helps predict the risk of management and determine the best course of action. The most frequently used model was designed by Gail in 1970 and incorporates age at menarche, number of breast biopsies, age at first live birth and the number of first degree relatives with breast cancer. It is used to predict the risk of developing breast cancer per decade of life. One of the disadvantages of this model is that it doesn’t take into account age at which a family member was diagnosed and whether the disease occurred in both breasts — early onset and bilateral disease suggesting a BRCA mutation carrier
Numerous software programs incorporating the Gail model are available. One example is given below. Further links may be found at http://bcra.nci.nih.gov/brc
The Claus model, when compared with the Gail model, incorporates more information on family history. Both risk assessment models do not take into consideration risk factors such as diet, obesity, use of oral contraceptives, lactation or radiation exposure.
reference www3.utsouthwestern.edu/ cancergene/Gail1.pn
Identification of BRCA mutation carriers
Four steps are required for the accurate identification of BRCA carriers
- Comprehensive multigenerational history
- Assessment of appropriateness of genetic testing in patient
- Genetic counseling
- Interpretation of results
Adequate identification of risk ( BRCA mutations + other risk factors) will lead to sound medical decision making by both patient and physician. Use of hormone replacement therapy, timing of mammographic screening , chemoprevention and use of prophylactic mastectomies( which reduce the risk of breast cancer by 90%) and oophorectomies are all part of this decision making process.
Anatomical Sites and Subsites (Fig. 1)
- Nipple (C50.0)
2. Central portion (C50.1)
3. Upper-inner quadrant (C50.2)
4. Lower-inner quadrant (C50.3)
5. Upper-outer quadrant (C50.4)
6. Lower-outer quadrant (C50.5)
7. Axillary tail (C50.6)
Regional Lymph Nodes
The regional lymph nodes are:
- Axillary (ipsilateral):interpectoral (Rotter) nodes along the axillary vein and its tributaries, which may be divided into the following levels:
- i) Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle
ii) Level Ii (mid-axilla): lymph nodes between the medial and lateral borders of the pectoralis minor muscle and the interpectoral (Rotter) lymph nodes
iii) Level III (apical axilla): lymph nodes medial to the medial margin of the pectoralis minor muscle including those designated as subclavicular, infraclavicular or apical
Note: Intrammamary lymph nodes are coded as axillary lymph nodes.
- Internal mammary (ipsilateral):lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia.
Any other lymph node metastasis is coded as distant metastasis (M1), including supraclavicular, cervical, or contralateral internal mammary lymph nodes nvasive ductal carcinoma
TN Clinical Classification
T – Primary Tumor
TX Primary tumor cannot be assessed
TO No evidence of primary tumor
Tis Carcinoma in situ: intraductal carcinoma, or lobular carcinoma in situ, or Paget disease of
the nipple with no tumor
Note: Paget disease associated with a tumor is classified according to the size of the
T1 Tumor 2 cm or less in greatest dimension
Tla 0.5 cm or less in greatest dimension
TIb More than 0.5 cm but not more than 1 cm in greatest dimension
TIc More than I cm but not more than 2 cm in greatest dimension
T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension
T3 Tumor more than 5 cm in greatest dimension
T4 Tumor of any size with direct extension to chest wall or skin
T4a Extension to chest wall T4b Edema (including peau d’orange), or ulceration of the skin of the breast, or satellite skin
nodules confined to the same breast
T4c Both 4a and 4b above
T4d Inflammatory carcinoma
Notes: Inflammatory carcinoma of the breast is characterized by diffuse, brawny induration of the skin with an erysipeloid edge, usually with no underlying palpable mass. If the skin biopsy is negative and there is no localized measurable primary cancer, the T category is pTX when pathologically staging a clinical inflammatory carcinoma (T4d).
Dimpling of the skin, nipple retraction or other skin changes, except those in T4b and 4d, may occur in T1, T2 or T3 without affecting the classification.
Note: Chest wall includes ribs, intercostal muscles and serratus anterior muscle but not pectoral muscle.
N – Regional Lymph Nodes
NX Regional lymph nodes cannot be assessed (e.g. previously removed)
N0 No regional lymph node metastasis
N1 Metastasis to movable ipsilateral axillary node(s)
N2 Metastasis to ipsilateral axillary node(s) fixed to one another or to other structures
N3 Metastasis to ipsilateral internal mammary lymph node(s)
The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York, Inc.The tumor staging system for breast cancer published by the American Joint Committee on Cancer (AJCC) was modified extensively in 2002. When compared to the classification published in 1997, the major differences are as listed: 1) reclassification of nodal status based on number of positive lymphnodes ( axilla) , differentiation between micrometastases and macrometastases, identifiers to indicate the use of specific techniques ( immunohistochemistry,molecular biology), surgical technique ( sentinel lymphnode biopsy ), and a reclassification of metastasis to internal mammary nodes, and supraclavicular nodes (now designated N3 rather than M1 disease) .These changes have been shown to dramatically affect stage-specific survival.
pTN Pathological Classification
pT – Primary Tumor
The pathological classification requires the examination of the primary carcinoma with no gross tumor at the margins of resection. A case can be classified pT if there is only microscopic tumor in a margin. The pT categories correspond to the T categories. When classifying pT the tumor size is a measurement of the invasivecomponent. If there is a large in situ component (e.g. 4 cm) and a small invasive component (e.g. 0.5 cm), the tumor is coded pTl a.
pN – Regional Lymph Nodes
The pathological classification requires the resection and examination of at least the low axillary lymph nodes (level 1) (see above). Such a resection will ordinarily include six or more lymph nodes.
pNX Regional lymph nodes cannot be assessed (not removed for study or previously removed)
pNO No regional lymph node metastasis
pNI Metastasis to movable ipsilateral axillary node(s)
pN1 a Only micrometastasis (none larger than 0.2 cm) (Fig. 9)
pN I 1b Metastasis to lymph node(s), any larger than 0.2 cm (Fig. 10)
pN1bi Metastasis to one to three lymph nodes, any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1bii Metastasis to four or more lymph nodes,any more than 0.2 cm and all less than 2.0 cm in greatest dimension
pN1biii Extension of tumor beyond the capsule of a lymph node metastasis less than 2.0 cm in greatest dimension
pN1biv Metastasis to a lymph node 2.0 cm or more in greatest dimension
pN2 Metastasis to ipsilateral axillary lymph nodes that are fixed to one another or to other structures
pN3 Metastasis to ipsilateral internal mammary lymph node(s)
Staging of breast cancer
|Staging Breast Cancer|
|Stage||Tumor Size||Lymph Node Involvement||Metastasis (Spread)|
|Less than 2 cm
Between 2-5 cm
More than 5 cm
No or in same side of breast
Yes, on same side of breast
|Stage||Tumor (T)||Node (N)||Metastasis (M)|
|Stage IIIB||T4||any N||M0|
|Stage IV||any T||any N||M1|
Source: American Joint Commission on Cancer and International Union Against Cancer
Breast Cancer Survival Rate by Stage
Health care professionals are able to be predict a patient’s survival rate based on the determined stage of breast cancer. The following chart is an approximate survival rate for each stage of breast cancer. Percentages will vary depending on individual medical situation.
Source: American Cancer Society
A five-year survival rate refers to the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer. After seven years, the survival rate decreases for each stage. The average Stage I breast cancer survival rate is 92%. The Stage II survival rate is 71%, Stage III survival rate is 39%, and the Stage IV survival rate is 11%.
It is important to remember that these survival rates are based on averages. Some women with advanced breast cancer live significantly longer than seven years. Researchers are constantly developing new treatment alternatives to prolong breast cancer survival.
Invasive lobular carcinoma is present in 5%-10% of breast cancers. It has a typical microscopic appearance characterized by small cells in a single-file (indian file) that typically grow around ducts and lobules. Lobular carcinomas are frequently multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusal sites such as the meninges and serosal surfaces. Clinically they may present as poorly defined areas of thickening of the breast. Radiologically microcalcifications may be present or absent.
Breast cancer accounts for 33% of all female breast cancers and represents the most frequent cause of death in women age 40-45 years. In the 1970s the estimated probability of developing breast cancer for a white American woman was 1:13, in the 1980s it was 1:11 and in 2002 12.5% of women develop breast carcinoma.
The incidence of breast cancer varies significantly among differennt countries, and is highest in Northern European countries and in the United States, intermediate in Southern America and Southern and Eastern Europe, and lowest in Asia (Japan, Singapore and urban China have seen a rise in rates with the advent of Western-style economy). Breast cancer incidence and mortality vary sigificatly within the United States. The incidence of breast cancer appears to be highest in white women from Hawaii (128:100,000) followed by those from San Fransisco and the Northeast.The lowes incidence is found in Utah(98:100,000) and New Mexico
The variation of incidence for African-American woment is relatively small ( 94-106:100,000)
Unlike most other illnesses a positive correlation has been noted between the lifetime risk of breast cancer and higher socioeconomic status.
Population and age distribution
There is significant variation among different populations in the incidence of breast cancer: as shown below, in the United States the African-American population has a slightly higher risk until the age of forty, after which there is crossover and the highest risk is in the white population.
Patients of Jewish- Ashkenzi-ancestry have a higher risk of developing breast cancer as discussed in the genetics section.
reference http://cdmrp.army.mil/graphics/ bc_incidence.gif
Clinical presentation has changed significantly with the advent of mammography. In the past 55%-75% of breast cancers were diagnosed by self-examination, but currently mammographic screening programs have determined an increase in the identification of cancers that are non palpable and clinically occult.
Evaluation of the patient with potential breast cancer involves a multistep process that includes history, physical exam, ( routine breast self-examination remains an important diagnostic screening modality) and radiologic studies. Further investigations ( genetic analysis and biopsies) are guided by the findings within the three steps described above.
It is important the physical examination by complete: it should start with visual inspection ( peau d’orange, nipple inversion, erythema, asymmetry, masses, nipple changes), followed by examination in the sitting position including palpation of the breasts, axillary and supraclavicular lymphnode stations and the tail of the breast which is oftentimes overlooked). Palpation of the breast parenchyma is done with the patient in the supine position with the ipsilateral arm placed over the head. Additional evaluation in warranted for any palpable lesion in patients over 30 years of age seeing as physical exam cannot adequately differentiate between malignant and benign lesions( 20-40% error rate even among expert examiners)
Evaluation of a palpable lesion
Evaluation of a palpable lesion should be undertaken based on the individual characteristics of each patient
1) Mammography is usually the first step in this evaluation and serves two purposes. This is less accurate in youn patients with dense breast tissue and rarely used in patients under the age of 30( Ultrasound is used in such patients).
- a) Assessment of the risk of malignancy of the mass (Calcifications, spiculation, nipple changes, axillary adenopathy)
- b) Bilateral screening of non-palpable lesions
2) Fine needle aspiration (FNA) or core needle biopsy is usually the next step of the evaluation. Some advocate needle aspiration prior to mammographic evaluation, but a needle-puncture hematoma may confuse radiologic evaluation, and therefore mammography should precede biopsy.FNA is done with a 22 gauge needle and allows for differentiation between cystic and solid masses and provides a specimen for cytology.Oftentimes aspiration is curative for cystic lesions. Bloody cyst aspirate may be indicative of malignancy and should therefore always be sent for cytology (1% incidence of malignancy within breast cysts). Recurrent or complex (loculated ) cysts also have a greater incidence of malignancy. FNA provides material for cytologic evaluation of solid lesions. Once aspirated , the material is immediately fixed in 95% ethanol and sent to pathology. FNA , unlike core – needle biopsy- does not allow differentiation between in situ and invasive carcinoma.
3) For lesions with contradictory results , open biopsy remains the definitive test.
Evaluation of Non-palpable lesions
Mammography represents the main diagnostic modality for non-palpable lesions
Mammographic signs of cancer can be divided in two main classes: density changes and microcalcifications
Most of the recommendations for treatment of invasive breast cancer derive from the results of controlled, randomized, prospective trials performed by the National Surgical adjuvant breast and bowel project (NSABP)
Breast cancer is diagnosed at an early stage in 75% of cases ( T1, T2, N0, N1). When this is the case, two surgical options are available:
Breast conservation ( Lumpectomy + radiation)
Mastectomy ( with or without reconstruction)
Lymphnode status is assessed in the same session when indicated ( Sentinel lymphnode biopsy or axillary lymphnode dissection).
Breast conservation has been shown to be equal to mastectomy for patients with Stage I and II ( no difference in disease free survival- NSABP B-04), though patients must be willing to accept a 10% to 12% risk of local recurrence and conservation commits the patient to radiotherapy.When the decision is made between conservation and mastectomy, other factors need to be considered including breast size , tumor size, tumor multicentricity, patient age and tumor histology.
At this point there is no evidence that T3 lesions can be safely treated with breast conservation.
Localization. Preoperative needle localization of a breast cancer is used for non-palpable lesions. This is done by using either mammography or ultrasound to insert a fine wire that the surgeon follows to locate and remove the targeted area.
Evaluation of lymph nodes Assesment of the lyphnode status may be done in different ways. Fine needle aspiration may be performed before surgery if lymph nodes appear abnormal by ultrasound exam. Sentinel lymphnode biopsy is based on the principle that the sentinel lymph node (SLN) is the first one to receive lymphatic drainage from a primary breast cancer and therefore the node most likely to contain metastatic disease. It can be done using radiolabled colloid, vital blue dye, or both. Intraoperatively it is identified by the use of a handheld gamma probe or by visualization of blue dye or both. Limitations to the identfication of the SLN include: 1) palpable axillary adenopathy, 2) medial hemisphere location ( wiht negative preoperative lymphoscintigraphy),3) Large primary tumors(>5 cm ) drainage to multiple nodes, 4) previous axillary surgery, 6) larger biopsy cavity – distortion of lymphatic drainage- 7) Tumors treated with neoadjuvant chemotherapy in patients with nodal disease on presentation. Accuracy rates for SLN biopsy are quoted to be 97%-100% whereas false negative rates are 0%-29% in the literature.
For patients not undergoing breast conservation, breast reconstruction should be considered part of the cancer therapy.Such reconstruction can be immediate or delayed, though immediate carries a significant psychological benefit.Breast reconstruction is feasible in most cases. Numerous techniques are described
CThe histologic status of the axilla, age of the patient, size of the primary tumor and extrogen/proesterone receptor status determine whether or not the patient will receive chemotherapy as an adjuvant or neoadjuvant therapy. Further factors that are considered include tumor pathologic characteristics ( ploidy, S-phase fraction, c-erbB-2 oncogine amplification, cathepsin D status) and the general health of the patient.
Multidrug chemotherapeutic regimens appear to significantly reduce the risk of recurrence and death in both lymphnode positive and lymphnode negative patients. The most frequently used regimen includes cyclophosphamide, methotrexate and 5-fluorouracil (4-8 weeks). The indications to the use fo tamoxifen are currently being broadened ( originally indicated for post-menopausal women with estrogen receptor-positive breast cancer) The use of tamoxifen for 5 years ( independent of age / menopausal status) is associated with a 47% reduction in the risk of breast cancer recurrence and a 26% reduction in the risk of death. Tamoxifen therapy has the added benefit of decreasing morbidity and mortality relate to cardiovascular disease, of increasing bone density and lowering cholesterol . Complications related to the use of such medication include an increase in the risk of thromboembolic disease and endometrial cancer.
Taxanes ( paclitaxel and docetaxel) represent a class of drugs that works by stabilizing the polymerization of microtubules, therefore arresting the cell cycle in the G2/M phase. They result in lack of resistance with other classes of drugs and have been used in crossover protocols for patients with anthracycline resistant tumors.
Trastuzumab (Herceptin) is a monoclonal antibody against the HER-2 / neu gene which codes for a Tyrosine Kinase that is overexpressed in 25% of breast cancers. Trials are currently looking at its efficacy in multidrug combination regimens.
Radiation theraby can be delivered in the form of External beam radiation, Internal beam radiation, and intra-operative radiation. Radiation therapy is typically initiated 2-3 weeks after surgery or at the completion of postoperative chemotherapy. Daily outpatient radiation treatment lasts 5 o 6 weeks.
Numerous factors influence the prognosis of patients with breast cancer. The graphic representation below lists the factors associated with a poor prognosis
Breast Cancer Survival Rate by Stage
Patient’s survival rates are usually determined based on the stage of breast cancer.
|Staging Breast Cancer|
|Stage||Tumor Size||Lymph Node Involvement||Metastasis (Spread)|
|Less than 2 cm
Between 2-5 cm
More than 5 cm
No or in same side of breast
Yes, on same side of breast
Source: American Cancer Society
A five-year survival rates represent the average number of patients who are still alive five years after diagnosis with a specific stage of breast cancer.These survival rates are based on averages and are subject to significant variability between individuals