Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel

Background: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wildtype p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy. Experimental Design: Each patient was randomly assigned to treatment with epirubicin 90 mg/m2 (n= 109) or paclitaxel 200 mg/m2 (n = 114) every 3rd week as monotherapy for 4–6 cycles. Patients obtaining a suboptimal response on first-line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy. Principal Findings: While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/ CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007) but also MDM2 309TG/GG genotype status (p = 0.012) were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039) but not among individuals with TP53 mutated tumors (p.0.5). Conclusion: TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy

Comparing the Prognostic Value of PTEN and Akt Expression with the Mitotic Activity Index in Adjuvant Chemotherapy-Treated Node-Negative Breast Cancer patients aged <55 years

Background: The prognostic value of the PI3K/Akt/mTOR pathway and PTEN in invasive breast cancer (IBC) is controversial. Cell proliferation, especially the Mitotic Activity Index (MAI), is strongly prognostic in lymph node-negative (LNneg) invasive breast cancer. However, its prognostic value has not been compared with the value of Akt and PTEN expression. Material and Methods: Prognostic comparison of Her2Neu, p110alpha (PIK3CA), Akt, mTOR, PTEN, MAI and cell-cycle regulators in 125 LNneg patients aged <55 years with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)-based adjuvant systemic chemotherapy. Results: Twenty-one (17%) patients developed distant metastases = DMs (median follow-up: 134 months). p110alpha correlated (p = 0.01) with pAkt but only in PTEN-negatives; pAkt correlated (p = 0.02) with mTOR. PTEN-negativity correlated with high MAI, high grade and ER-negativity (p = 0.009). The MAI was the strongest prognosticator (Hazard Ratio = HR = 2.9, p = 0.01). Her2Neu/p110α/Akt/mTOR features have no additional prognostic value to the MAI. PTEN had additional value but only in MAI < 3 (39/125 = 31%; 8% DMs). 19/39 = 49% of the MAI < 3 patients have combined MAI < 3 / PTEN+ with 0% DMs, contrasting 15% DMs in MAI < 3 / PTEN− (p = 0.03). Conclusions: In T1−3N0M0 adjuvant CMF-treated breast cancer patients aged <55 years, MAI was the strongest survival predictor. The PI3K/Akt/mTOR pathway and cell-cycle regulator characteristics had no additional prognostic value, but PTEN has. Patients with combined MAI < 3 & PTEN-positivity had 100% survival. The small subgroup of MAI < 3 patients that died were PTEN-negative

Success predictors of adjuvant chemotherapy in node-negative breast cancer patients under 55 years

Abstract. Background: Adjuvant systemic chemotherapy (ASCT) in lymph node-negative breast (LN−) cancers improves survival. The majority of (LN−) patients receive ASCT when the St. Gallen criteria or its modifications are used, as accurate identifiers which patients benefit from ASCT are lacking. This may imply over-treatment in many patients. Aim: To evaluate which patients or primary tumor factors predict ASCT success. Material and method: Retrospective analysis by single and multivariate survival analysis of clinical and tumor characteristics in (LN−) breast cancers &lt;55 years, related to ASCT (n = 125) or-not (n = 516). Results: The two patient groups did not differ in age, tumor diameter, grade, type, number of mitoses and other factors. Fourteen-year survival for the ASCT and non-ASCT patients was 83% and 74% (Hazard Ratio = HR = 0.33; p &lt; 0.0001, 9% absolute = 12% relative difference). Subgroup analysis showed that the recurrence-free survival = RFS of ASCT treated vs. non-treated patients differed in patients with grade 1 cancers (p = 0.008), grade 2 cancers (p = 0.004), grades 3 (p = 0.02), tumors under and 2 cm (p = 0.001 and 0.0002), oestrogen receptor-positive or -negative tumors (p = 0.003, 0.04), MAI &lt; 10 and 10 (p = 0.005, 0.003) and fibrotic focus absent (p = 0.002). With multivariate analysis the most important predictor of ASCT effect was the MAI. In patients with slowly proliferating tumors (MAI &lt; 3) no advantage was found between patients treated-or-not with adjuvant chemotherapy (RFS = 92% and 91%, p = 0.13, p = 0.63 for overall survival), contrasting those with MAI 3 (p = 0.0001; HR = 0.32, 95% CI 0.18-0.58). Conclusion: MAI is the strongest predictor of adjuvant systemic chemotherapy success. In patients with MAI &lt; 3 (31% of all patients), ASCT does not improve survival

LOH at 1p31 (ARHI) and Proliferation in Lymph Node-Negative Breast Cancer

Background: The mitotic activity index (MAI) is a strong prognosticator in node-negative invasive breast cancer patients. Recently, a correlation between the MAI and specific chromosomal aberrations at chromosome 1p was described

Success Predictors of Adjuvant Chemotherapy in Node-Negative Breast Cancer Patients Under 55 years1

Background: Adjuvant systemic chemotherapy (ASCT) in lymph node-negative breast (LN−) cancers improves survival. The majority of (LN−) patients receive ASCT when the St. Gallen criteria or its modifications are used, as accurate identifiers which patients benefit from ASCT are lacking. This may imply over-treatment in many patients. Aim: To evaluate which patients or primary tumor factors predict ASCT success. Material and method: Retrospective analysis by single and multivariate survival analysis of clinical and tumor characteristics in (LN−) breast cancers <55 years, related to ASCT (n = 125) or-not (n = 516). Results: The two patient groups did not differ in age, tumor diameter, grade, type, number of mitoses and other factors. Fourteen-year survival for the ASCT and non-ASCT patients was 83% and 74% (Hazard Ratio = HR = 0.33; p < 0.0001, 9% absolute = 12% relative difference). Subgroup analysis showed that the recurrence-free survival = RFS of ASCT treated vs. non-treated patients differed in patients with grade 1 cancers (p = 0.008), grade 2 cancers (p = 0.004), grades 3 (p = 0.02), tumors under and ≧2 cm (p = 0.001 and 0.0002), oestrogen receptor-positive or -negative tumors (p = 0.003, 0.04), MAI < 10 and ≧10 (p = 0.005, 0.003) and fibrotic focus absent (p = 0.002). With multivariate analysis the most important predictor of ASCT effect was the MAI. In patients with slowly proliferating tumors (MAI < 3) no advantage was found between patients treated-or-not with adjuvant chemotherapy (RFS = 92% and 91%, p = 0.13, p = 0.63 for overall survival), contrasting those with MAI ≧ 3 (p = 0.0001; HR = 0.32, 95% CI 0.18–0.58). Conclusion: MAI is the strongest predictor of adjuvant systemic chemotherapy success. In patients with MAI < 3 (31% of all patients), ASCT does not improve survival