Modulation of molecular marker expression by induction chemotherapy in locally advanced breast cancer: correlation with the response to therapy and the expression of MDR1 and LRP.
OBJECTIVE
To assess if molecular markers are able to predict the response to induction chemotherapy in locally advanced breast cancer, and if any variation in their expression is associated with the degree of axillary lymph node invasion.


METHODS
Between 1995 and 1999, 48 patients with locally advanced breast cancer were submitted to induction chemotherapy at Fundación Tejerina--Centro de Patología de la Mama, Madrid, Spain. The patients carried either tumors larger than 5 cm in diameter with clinically positive axillary nodes, T4a or T4b tumors regardless of size, or inflammatory carcinomas. All received between 3 and 6 cycles of CAF standard polychemotherapy (Cyclophosphamide, Doxorubicin and 5-Fluorouracil) with the exception of one patient, who received CMF therapy (Cyclophosphamide, Methotrexate and 5-Fluorouracil), and another one, who received Taxotere-Doxorubicin. After completion of their induction chemotherapy scheme, 1 patient showed a "complete clinical response" (CCR, with disappearance of all clinical and radiological signs of tumor presence), 36 (75.0%) patients showed a "partial response" (PR, > 50%), 10 (20.8%) showed "no response" (NR, < 50%), and finally one progressed under treatment. Core biopsies were performed in all cases prior to treatment for histological diagnosis which allowed for the determination of the following parameters by means of immunohistochemistry: hormone receptors (ER and PR), oncogenes and tumor suppressor genes (c-erb-B2 and p53) and the proliferation marker Ki67. Initial tumor size, histologic and nuclear grade and histologic variety were also included as variables of the study. After chemotherapy, 37 patients were submitted to a rescue mastectomy at our center. The same aforementioned parameters were determined once again on the operative specimen, together with MDR1 expression (using two different antibodies) and LRP expression. As outcome variables, objective response to treatment and the presence of invaded axillary nodes were considered.


RESULTS
Only the expression of the proliferation-associated Ki67 antigen, as well as nuclear grade were affected significantly (p < 0.05) by the previous chemotherapeutic treatment. All other studied parameters showed no significant change in expression. More disappointingly, even, none of the studied variables showed any significant power for predicting either an objective response to treatment, or the presence of invaded axillary nodes at surgery. Both outcome end-points were also unrelated to each other. Overexpression of the multidrug-resistance gene or the LRP gene, finally, showed no correlation whatsoever with the previous response to chemotherapy.


CONCLUSIONS
According to these results, the parameters employed by us are of no practical use for predicting the response to treatment or the presence of invaded nodes at rescue surgery in locally advanced breast cancer. Clinical and surgical assessment remain thus the mainstay of treatment for this group of patients.
Schneider
J
J
Fundación Tejerina-Centro de Patología de la Mama, Madrid, Spain.
Lucas
R
R
Sánchez
J
J
Ruibal
A
A
Tejerina
A
A
Martín
M
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001365:Axilla; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008207:Lymphatic Metastasis; D008727:Methotrexate / Q000008:administration & dosage; D009363:Neoplasm Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012074:Remission Induction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002945:Cisplatin; D003520:Cyclophosphamide; D004317:Doxorubicin; D005472:Fluorouracil; D019394:Ki-67 Antigen; D008727:Methotrexate; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016159:Tumor Suppressor Protein p53