Can expression of apoptosis genes, bcl-2 and bax, predict survival and responsiveness to chemotherapy in node-negative breast cancer patients?
BACKGROUND
Although the status of the axillary lymph nodes is widely accepted to be associated with prognosis in breast cancer patients, there is a need for biomarkers to be analyzed as indicators of responsiveness to treatment. The objective of this study was to test the hypothesis that the expression of apoptosis genes, bcl-2 and bax, predicts survival and responsiveness to chemotherapy in node-negative breast cancer patients.


METHODS
One hundred thirty premenopausal women with primary breast carcinoma were studied for the expression of bcl-2 and bax genes. The relationship between the expression of bcl-2 and bax proteins and a series of markers of known prognostic value [such as tumor size, nuclear grade, receptors of the steroid hormones estrogen (ER) and progesterone (PgR)]. The association of these proteins with survival and responsiveness to chemotherapy was also examined.


RESULTS
Sixty (46%) and sixty-four (49%) breast cancer cases were found positive for bcl-2 and bax, respectively, as indicated by immunohistochemistry. A statistically significant association was found between expression of bcl-2 and tumor size (P = 0.001), low grade (grade I) (P = 0.002), positivity of ER (P = 0.001), positivity of PR (P = 0.03), and superior disease-free survival (DFS) (P = 0.04), and superior overall survival (OS) (P = 0.03). In contrast, no similar associations were observed for the bax gene. Overall, there was a trend toward an association between adjuvant chemotherapy and DFS (P = 0.08) and OS (P = 0.07). This trend became statistically significant when the patients were analyzed by individual gene expression. In bax-positive patients, chemotherapy improves 6-year DFS (P = 0.01) and OS (P = 0.03) while similar effects were not observed in the other subgroups of patients.


CONCLUSIONS
Our results indicated that bcl-2 expression is associated with a number of favorable prognostic factors and better clinical outcome, while bax expression seems to have positive predictive value for responsiveness to chemotherapy in lymph node-negative breast cancer patients.
Kymionis
G D
GD
Laboratory of Surgical Research, Hippokratio Hospital, Athens, Greece. kymionis@med.uoc.gr
Dimitrakakis
C E
CE
Konstadoulakis
M M
MM
Arzimanoglou
I
I
Leandros
E
E
Chalkiadakis
G
G
Keramopoulos
A
A
Michalas
S
S
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D007150:Immunohistochemistry; D015993:Life Tables; D008198:Lymph Nodes / Q000737:chemistry / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage*; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D051028:bcl-2-Associated X Protein; D002945:Cisplatin; D005472:Fluorouracil; D008727:Methotrexate