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Anthracycline based chemotherapy decreases amplification status of Her-2/neu and topoisomerase II alpha genes in locally advanced breast cancer.

9521 Background: Coamplification of Her-2/neu (H) and topoisomerase II alpha (T), was associated with favorable local response to anthracycline-based therapy in locally advanced breast cancer (LABC). We sought to determine weather administration of anthracyclines would affect status of H and T genes located on close but distinct amplicons of chromosome 17 (CH17).


METHODS
122 previously untreated patients who had LABC and who had received neoadjuvant, anthracycline-based therapy were studied. Ratio of copy number of H or T versus CH17 was determined by fluorescence in situ hybridization before and after chemotherapy.


RESULTS
There were 54.9/62.3% of patients without H or T amplification (H/CH17<1.5; T/CH17<1.2), 6.6/4.9% of women with borderline H or T amplification (H/CH17=1.5-2; T/CH17=1.2-2), and 38.5/23.8 % of patients who showed clear amplification of H or T (H/CH17>2; T/CH17>2). All of the tumors with T amplification also had H amplification, but not vice versa. Women with H but not T amplification had shorter EFS (P=0.0752 versus P=0.803). However, neither H nor T amplification was significantly associated with response to anthracycline based chemotherapy (P =0.405/0.306). Interestingly, tumors with H or T amplification significantly decreased amplification status after neoadjuvant chemotherapy (H/CH17 -1.089±1.192, P<0.001 and T/CH17 -0.234±0.422, P=0.013). Moreover, decline in H/CH17 but not T/CH17 values, with cut-offs at -0.5/-0.2, was significantly associated with shorter EFS (P<0.001 versus P=0.835).


CONCLUSIONS
Amplification of both Her-2/neu and topoisomerase II alpha was significantly reduced in response to anthracycline based chemotherapy. Furthermore, tumors with therapy-induced decrease in Her-2/neu amplification relapsed early. Our data provide plausible mechanism for diminished trastuzumab efficacy in anthracycline pretreated patients and provide molecular rationale for administration of trastuzumab as the first-line treatment in patients with Her-2/neu amplified LABC. No significant financial relationships to disclose.