Tumor Biology and Human Genetics
P53 mutation and differential response to neoadjuvant chemotherapy in women with locally advanced breast cancer: Results from the I-SPY trial (CALGB 150007/1500012 and ACRIN 6657)
Background: Independent of other factors, p53 status may influence sensitivity to anthracycline (A)- and taxane (T)-based chemotherapy. We investigated p53 as a predictive marker of differential neoadjuvant chemoresponse by examining change in MRI longest diameter (LD) during sequential A- then T-based chemotherapy in a prospective clinical trial. Methods: 171 patients (pts) with newly diagnosed locally advanced breast cancer received neoadjuvant A- then T-based chemotherapy. LD were obtained pretherapy, between regimens, and posttherapy but prior to surgery. P53 mutation analysis was performed on pretherapy tissue using gene chip technology, SSCP, and sequencing. Subtypes were by IHC: LumA (ER/PR+/HER2-), LumB (ER/PR+/HER2+), Basal (triple negative), HER2 (HER2+/ER/PR-). Results: 99 pts had p53 mutant (M) tumors and 72 were wildtype (WT). M and WT did not differ by age, menopausal status, or HER2. M were significantly more common among basal (71%) and HER2 (59%) than Lum A (24%). Anthracycline response did not differ between WT and M within subtypes. Within HER2, Basal, and LumB, WT had higher taxane- and overall responses than M; within LumB these were statistically significant (p=0.03 and 0.05 respectively). Conclusions: P53 mutation status may affect chemosensitivity even within hormone receptor/HER2 subsets. In this dataset response to anthracycline appeared independent of p53 status within subtypes, while WT tumors responded better to taxanes and overall in LumB, with a similar trend among basal and HER2. Mutational subset and correlative analyses with gene expression, molecular subtyping, and IHC data are ongoing and will be presented.
|MRI response % change in longest diameter (LD)||Luminal A P53 mutant||Luminal A P53 wildtype||Luminal B P53 mutant||Luminal B P53 wildtype||Basal P53 mutant||Basal P53 wildtype||HER2+/ER- P53 mutant||HER2+/ER- P53 wildtype|
|T1-T3 (anthracycline response)|
|No. of patients||14||48||5||14||20||10||12||8|
|T3-T4 (taxane response)|
|T1-T4 (overall response)|
|No. of patients||15||48||5||14||25||10||13||9|
No significant financial relationships to disclose.