| Breast carcinoma is the leading cause of mortality in women, with over 300000 deaths annually, which is mainly due to the local or distant metastasis of the cancer cells. Haematogenous and lymphatic spread of carcinoma cells occurs at a relatively early stage of tumor growth. Metastatic spread is traditionally assessed by histopathological examination of axillary lymph nodes (ALNs). However, the predictive value of ALN status has its limitations; approximately 40 per cent of women with tumor-positive ALNs survive 10 years and, conversely, 25-30 per cent of patients with negative ALNs develop systemic recurrence.Prognostic factors are used to stratify the risk of developing distant disease to inform the decision about systemic therapy. In breast cancer, information on prognostic factors is gained from the primary tumor and regional lymph nodes. Tumor size, tumor grade, nodal status, vascular invasion and steroid receptor status are established prognostic elements while they can't be detected again after removal of primary tumor. It is essential to find an objective parameter to evaluate the clinical effect of systemic treatment and monitor disease progression.Recently, many studies about distant metastasis in the breast cancer patients have been done. Although no clinical metastatic evidence was found at the time of surgery, about 30 per cent of patients have had bone marrow micrometastasis. The major methods to detect micrometastasis are immunohistochemical staining of the nucleated cells from bone marrow with epithelial markers and reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of epithelial mRNA markers, such as cytokeratin 19. The purpose is to assess the prognostic value of marrow micrometastasis in breast cancer and therefore to conduct clinical treatment. Thus far, the conclusion is controversial and there are few studies about the correlation between bone marrow micrometastasis with RT-PCR and other prognostic factors.Haematogenous and lymphatic dissemination are two main pathways for breast cancer cells. So the detection of micrometastasis in breast cancer patients should include simultaneous detection in the bone marrow, axillary lymph node and peripheral blood. On one hand, we can characterize the cancer biologically; on the other hand, we can get an evaluation of the local or distant metastasis status in the patients with breast cancer, and thereby give a better information on clinical treatment.The detection of CK19mRNA was carried out with RT-PCR in 69 operable patients with breast cancer, the correlation between bone marrow micrometastasis and conventional prognostic factors was also analyzed. The results showed that the positive rate of bone marrow micrometastasis was 34.8%. There was no correlation between bone marrow micrometastasis and patient's age, tumor size, menstrual status or estrogen receptor. But bone marrow micrometastasis was correlated with lymph node involvement, VEGF level, the overexpression of Her-2 gene and other proliferating status of tumor cells. It indicated that a proportion of bone marrow micrometastasis mayoccur at the time of diagnosis and it could be used as an important prognostic factor. This study also detected the micrometastasis in peripheral blood, axillary lymph node and bone marrow simultaneously. The efficacy of adjuvant chemotherapy on bone marrow micrometastasis was studied, too. The results demonstrated that the positivity of the circulating tumor cells in peripheral blood was less than that in bone marrow. Bone marrow micrometastasis had a concord with lymph node micrometastasis. Lymph node micrometastasis by RT-PCR could be present in node-negative cases. Some bone marrow micrometastasis positive patients could become negative by adjuvant chemotherapy. It's concluded that the detection of micrometastasis by RT-PCR is a sensitive and specific method. Compared with bone marrow micrometastasis, the detection of circulating tumor cells in peripheral blood is less sensitive or specific. The detection of bone marrow micrometastasis is an index to evaluate the sensitivity of adjuvant chemotherapy so that it can help us to treat the breast cancer patients correctly and make an accurate prognosis.SECTION 1 THE CORRELATION BETWEEN BONE MARROW MICROMETASTASIS AND CONVENTIONAL PROGNOSTIC FACTORS IN PATIENTS WITH BREAST CANCERPurpose To study the correlation between bone marrow micrometastasis and other conventional prognostic factors in patients with breast cancer.Methods Bone marrow samples were obtained from 69 breast cancer patients at the time of surgery. The expression of CK19mRNA in bone marrow was detected with RT-PCR. The content of DNA, the distribution of cell cycle and the value of PCNA were investigated by flow cytometry. VEGF was tested with ELISA and the expression of Her-2 and ER was detected by immunohistochemistry. The correlation between bone marrow micrometastasis and other prognostic factors was studied.Results The positivity of bone marrow micrometastasis tested by RT-PCR in breast cancer patients was 34.8%. There was no correlation between bone marrow micrometastasis and tumor size, patient's age, menstrual status or ER (P>0.05). There was no correlation between bone marrow micrometastasis and CEA or CA15-3, either (P > 0.05). However, bone marrow micrometastasis was correlated with lymph node involvement, VEGF level, the over-expression of Her-2 gene and other proliferating status including DNA index, S phase fraction and PCNA (P < 0. 05). In node-negative patients, the positivity of bone marrow micrometastasis was 17.6%.Conclusions Bone marrow micrometastasis has no correlation with the common clinical features while does have correlation with those biological factors indicating cell proliferation or invasion. Some of patients with tumor-negative ALNs have the positive bone marrow micrometastasis.SECTION 2 THE SIGNIFICANCE OF CK19mRNA DETECTED IN PERIPHERAL BLOOD, LYMPH NODE AND BONE MARROW IN PATIENTS WITH BREAST CANCER AND THE EFFECT OF ADJUVANT CHEMOTHERAPY ON BONE MARROWMICROMETASTASISPurpose To study the micrometastasis in peripheral blood, lymph node and bone marrow in patients with breast cancer and the effect of adjuvant chemotherapy on bone marrow micrometastasis.Methods RT-PCR technique was used to detect the micrometastasis simultaneously in peripheral blood, lymph node and bone marrow in 69 operable patients with breast cancer and the effect of adjuvant chemotherapy on bone marrow micrometastasis was also investigated.Results The positivity of bone marrow micrometastasis tested by RT-PCR in breast cancer patient was 34.8%. The circulating tumor cells were found in 11 patients (15.9%). And lymph node micrometastasis was positive in 40 cases (58.0%) Out of the 35 node-positive cases, 32 cases were lymph node micrometastasis positive. Out of the 34 node-negative cases, eight cases were lymph node micrometastasis positive. 24 cases of bone marrow micrometastasis positive patients became negative after receiving six cycles of CAF adjuvant chemotherapy.Conclusions Detection of CK19mRNA by RT-PCR is a sensitive and specific method assessing micrometastasis in patients with breast cancer. Compared with the detection of bone marrow micrometastasis , the technique to detect the micrometastasis in peripheral blood is less sensitive or specific. The detection of bone marrow micrometastasis is a sensitive index to assess theeffect of adjuvant chemotherapy.
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