Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer.

BACKGROUND: Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial. PATIENTS AND METHODS: Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells). RESULTS: A total of 55 primary tumor samples from the TAMRAD trial­25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group­were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6-34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient. CONCLUSIONS: A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.

Contrast enhanced magnetic resonance imaging underestimates residual disease following neoadjuvant docetaxel based chemotherapy for breast cancer.

AIMS: We prospectively compared the ability of magnetic resonance imaging (MRI) to measure residual breast cancer in patients treated with different neoadjuvant chemotherapy regimen. METHODS: Forty patients with locally advanced breast carcinoma underwent neoadjuvant chemotherapy. Twelve patients received 5-fluoro-uracyl-epirubicin-cyclophosphamide (FEC-group, six cycles), 28 (DXL-group) received docetaxel-based chemotherapy (six cycles DXL-epirubicin: 13 patients, eight cycles DXL alone: 15 patients). All patients had baseline and preoperative MRI. The spread of pathologic residual disease (PRd) was compared to preoperative MRI measures according to chemotherapy regimen. RESULTS: MRI over/underestimation of the spread of residual tumour was never superior to 15mm in FEC group, whereas it appeared in 11/28 (39%, 30-48%-95% CI) patients in DXL group (p=0.017). Tumour shrinkage led to single nodular residual lesions in FEC group, whereas vast numerous microscopic nests were observed in docetaxel group in pathology. CONCLUSION: Among tumours treated with a taxane-containing regimen, residual disease was frequently underestimated by MRI because of PRd features.