|MMP-2 immunoreactive protein in breast carcinoma and neoplastic cervical lesions.: MMP-2 is a new prognostic factor in breast carcinoma|
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Breast carcinoma is the most frequent malignancy among women in Finland as well as in other Western countries (Finnish Cancer Registry 1997, Parkin et al. 1997). It is a pathologically and clinically heterogenous disease with variable prognosis. Breast carcinomas are potentially highly malignant tumors due to their capacity to invade locally and metastasize. The prognosis of breast carcinoma has improved from the 1970s due to better access to mammography and the development of adjuvant therapy (Cady et al. 1996, Finnish Cancer Registry 1997, Edwards et al. 1998).
The incidence and prevalence of breast carcinoma have increased during the last decades in Finland and in other Western countries (Kelsey & Horn-Ross 1993, Garfinkel et al. 1994, Finnish Cancer Registry 1997, Parkin et al. 1997). In Finland over three thousand new breast carcinoma cases appear annually. In women < 40 years 146 and in women > 70 years 883 new breast carcinoma cases appeared in 1995 (Finnish Cancer Registry 1997). The incidence rate per 100 000 person-years has increased from 30 in the 1960s to 67.7 in 1994 (Finnish Cancer Registry 1997). In Western countries the high-risk population age-specific incidence increases rapidly between the ages 45-50, and again after 50 years of age at a slower pace (Stevens et al. 1982). The recurrence rate within 10 years is about 20-30% even in node-negative carcinomas due to residual disease or biologically aggressive disease (Macmillan et al. 1996).
Causes of breast carcinoma are multifactorial. Several risk factors for breast carcinoma have been found, including early menarche (RR (relative risk) 1-2), late full-term pregnancy (RR 2-4), age < 50 years (RR 4), upper social class (RR 2-4), postmenopausal obesity (RR 2-4) (Hayes 1996a, Trentham-Diez et al. 1997) as well as others, such as positive family history (relative risk at least 4 times that of population without the factor) (Egan et al. 1998), increased genetic risk (BRCA 1, 2) (Miki et al. 1994, Wooster et al. 1995), earlier benign breast disease, previous ionizing radiation (Hancock et al. 1993) or alcohol consumption (Friedenreich et al. 1993, Longnecker et al. 1995, Enger et al. 1999)). Early menopause, natural or surgical, is associated with decreased breast carcinoma risk and the protective risk is strongest in women with surgical menopause before age <40 years (Titus-Ernstoff et al. 1998). Also women with heavy physical activity have a lower risk of breast carcinoma (Coogan et al . 1997). Approximately 50% of women who develop breast carcinoma have no identifiable risk factors (Madigan 1995).
When the diagnosis of breast carcinoma has been confirmed, the primary tumor must be staged to determine prognosis and optimal treatment. Disease stage, tumor size and axillary node involvement were determined according to the UICC (International Union Against Cancer), TNM classification (Hermanek et al. 1992), and the histology of the tumors was reviewed and classified according to the World Health Organization (WHO) classification of breast tumors (Scarff et al. 1986). The breast carcinoma staging system is found in Table 2.
The most common type of carcinoma is infiltrative ductal carcinoma (70%) graded into well differentiated (grade 1), moderately differentiated (grade 2) and poorly differentiated (grade 3) carcinoma. The grading is based on three microscopic features: tubular differentiation, the degree of nuclear pleomorphism and the number of mitotic figures. There is a significant correlation between grade and prognosis (Schnitt 1993, Berg & Hutter 1995, Heywang-Köbrunner et al. 1997). Lobular carcinoma is the second most common histology group in breast carcinoma, followed by smaller groups such as medullar, mucinous, comedocarcinoma, Paget´s disease, papillary, tubular and inflammatory carcinoma (Berg & Hutter 1995).
Table 2. Clinical staging system for breast carcinoma
|TX||Primary tumor not assessable|
|T0||No evidence of primary tumor|
|Tis||Carcinoma in situ|
|T1||Tumor 2 cm or less 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 into chest wall or skin edema or skin ulceration or satellite skin nodules confined to the same breast or inflammatory carcinoma|
|N (Regional lymph nodes)|
|NX||regional lymph nodes not assessable|
|N0||No regional lymph node involvement|
|N1||Metastasis to movable ipsilateral axillary lymph nodes|
|N2||Metastasis to ipsilateral axillary lymph nodes fixed to one another or to other structures|
|N3||Metastasis to ipsilateral internal mammary lymph nodes|
|MX||Distant metastasis cannot be assessed|
|M0||No distant metastasis|
|M1||Distant metastasis present|
Many prognostic factors have been identified in breast carcinoma. The most commonly used indicators for prognosis include the clinical stage of the disease, tumor size (Chevallier et al. 1990, Joensuu & Toikkanen 1991, Galea et al. 1992), lymph node metastases (Du-Toit et al. 1990, Pisansky et al. 1993, Ravdin et al. 1994, Barth et al. 1997), tumor grade (Bloom & Richardson 1957), estrogen or progesterone receptor status of the primary tumor (Chevallier et al. 1990, Castagnetta et al. 1992, Strierer et al. 1993). In patients with small primary tumors (less than 1 cm) metastatic axillary nodes are present in <10 %-20% of the patients (Carter et al. 1989, Chadha et al. 1995). In many studies low ER and PR rates are predictive of early recurrence and short overall survival (Fisher et al. 1981, Clark et al. 1993, Pichon et al. 1996). The expression of estrogen and progesterone receptor suggests a high likelihood of response to hormone therapy. They were the only prognostic and predictive tumor markers rekommended for routine clinical use in breast carcinoma (ASCO (American Society of Clinical Oncology) Tumor Marker Panel 1996). Grade 3 ductal tumors are associated with poor prognosis and grade 1 tumors with better outcome (Toikkanen & Joensuu 1990). The metastatic potential of tubular, mucinous, medullary or papillary carcinoma is lower than in ductal carcinoma (Toikkanen & Joensuu 1990, Silverstein et al. 1996).
Different biomarkers include aneuploidy, overexpression of the HER-2, cyclin D1, p53 oncogenes, absence of bcl-2 expression, growth factors, Ki-67, S-Phase fraction, Cathepsin, and angiogenesis (Gullick et al. 1991, Kallioniemi et al. 1991, Isola et al. 1992, Weidner et al. 1992, Poller et al. 1993, Railo et al. 1993, Guidi et al. 1994, Marks et al. 1994, Fox et al. 1994, MacGrogan et al. 1995, Weinstat- Saslow et al. 1995, Hayes et al. 1996b, Clark 1998, Dowsett 1998, Sjögren et al. 1998) are associated to prognosis. The list of potential prognostic and predictive factors for breast carcinoma is long but the validated prognostic and predictive factors very short (Clark 1999).
The overall 5-year survival rate in Finland in unselected breast carcinoma patient material is 80%. In node-positive breast carcinoma the 5-year overall survival rate is 69% (Finnish Cancer Registry 1997).
Most of the breast carcinoma cases are operated by means of modified mastectomy or with breast-preserving techniques with an axillary evacuation. Postoperative radiotherapy covering the axillary, supraclavicular and internal mammary lymph nodes and the chest wall around the mastectomy scar is commonly used if the carcinoma is large, the axillary lymph nodes are positive or if the operation is breast-preserving (Cuzick et al. 1994, Arriagada et al. 1995, Harris & Morrow 1996).
Adjuvant chemo- or hormonal therapy is usually given to breast carcinoma patients who have node-positive primary breast carcinoma or large carcinoma (T3-4), or whose tumors have poor histological differentiation or are hormone- receptor negative (Gelber et al. 1993, Goldhirsch et al. 1995, Finnish Breast Cancer Group 1999). Adjuvant chemotherapy is usually given to premenopausal patients and adjuvant antiestrogen therapy to postmenopausal patients (Gelber et al. 1993, Howell et al. 1996, Fossati et al. 1998). In premenopausal patients with receptor-positive tumors after adjuvant chemotherapy tamoxifen was recommended for follow-up treatment (Goldhirsch et al. 1996). Preoperative chemotherapy is used for subgroups of patients with large tumors (greater than 5 cm) based on the idea of reducing tumor size before surgery, developed earlier in hormonal studies (Fisher et al. 1997). New approaches to drug therapy of breast cancer include strategies to increase dose intensity, e.g. dose escalations, dose density, scheduling and the use of cytokines. Also other new modalities such as inhibitors of cancer cell proliferation, exploitation of growth factor receptors, monoclonal antibodies have been used (Norton 1997).