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 wild-type 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/m(2) (n = 109) or paclitaxel 200 mg/m(2) (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.

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. METHODS: Analysis of MAI, immunohistochemical staining patterns for proliferation-associated phosphohistone H3 (PPH3), phosphorylated ERK1/2, p21, cyclin E, Ki67 and cyclin D1 proteins; and prognosis in 158 adjuvant chemotherapy-treated T1-2N0M0 invasive breast cancer patients, analysis of LOH at 1p31 (including ARHI) using the dinucleotide repeats D1S207, D1S430 and D1S464 in 76 patients. Single and multivariate survival analysis was used to evaluate the importance of the various markers tested. RESULTS: LOH at 1p31 did not correlate with MAI nor provide prognostic information. Phosphohistone H3 was the best prognosticator for patients in all age groups with 20 year distant metastasis free survival of distant metastases 93% vs. 72% respectively (p=0.004, HR=4.5). In multivariate analysis, phosphohistone H3<13 vs. > or =13 exceeded the prognostic value of the mitotic activity index. CONCLUSIONS: LOH at 1p31 is common in breast cancer, and correlates with loss of proliferation-associated proteins, but not with MAI, PPH3 or prognosis. PPH3 is the best prognosticator in this study group of adjuvant chemotherapy-treated lymph node-negative breast cancer patients.

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/p110alpha/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 T(1-3)N(0)M(0) 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.

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 >or=2 cm (p=0.001 and 0.0002), oestrogen receptor-positive or -negative tumors (p=0.003,0.04), MAI < 10 and >or=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 >or=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.

[Thyroid surgery in Rogaland]. / Thyreoideakirurgi i Rogaland.

BACKGROUND: Thyroid surgery is performed at both hospitals in Rogaland county. In this retrospective study we compare clinical features, including preoperative diagnostics, type of surgery, and recorded postoperative complications. MATERIALS AND METHODS: Between 1994 and 1998, 380 patients (89% women) underwent thyroid surgery. Data were retrieved from hospital records and surgical notes. Non-parametric methods were employed for statistical analysis. RESULTS: The annual operative incidence per 100,000 inhabitants was 20.5; there was no significant difference between the two hospitals. Median age was 45 years (range 14-85). Two thirds of the procedures were done at Rogaland Central Hospital (SiR). At Haugesund Hospital (HS) 31% of the 120 patients were operated in the department of ear-nose-throat diseases. Ultrasound of the thyroid gland was requested more often at HS, whereas thyroid scintigraphy was more frequently done at SiR. Fine needle aspiration cytology was performed on 80% of the patients, including non-representative samples in 13% at HS and 8% at SiR, respectively. Hemithyroidectomy was the most frequently performed operation. The operative mortality was zero. Postoperative complications were few: permanent hypoparathyroidism was encountered in two (0.5%) patients and unilateral permanent vocal cord paralysis in five (1.1%) patients. INTERPRETATION: Our results are in accordance with national and international standards. Observed differences in preoperative diagnostics are most likely explained by different traditions among general practitioners and different access to imaging modalities. Implementation of updated guidelines for referral and work up of this group of patients are warranted.

[Radiotherapy after breast-conserving surgery in the treatment of breast cancer: early results from a non-university hospital in Norway]. / Strålebehandling etter brystbevarende kirurgi.

BACKGROUND: In 1998 the first radiotherapy unit located outside a university hospital in Norway was established at Rogaland Central Hospital. MATERIAL AND METHODS: Results from 222 consecutive patients treated between June 1999 and March 2002 are presented. Median time to follow up was 25 months (range 8-41). All patients underwent a lumpectomy combined with a complete axillary dissection or a sentinel node biopsy. The entire breast was irradiated using 6MV photon energy to a total dose of 50 Gy. RESULTS: As of October 2002, there has not been registered any local breast failures. Three patients developed distant metastases and subsequently died from their disease. Contralateral breast cancer has occurred in one patient. The relative number of patients treated with breast conservation therapy, as compared to the total number of patients operated, has not changed after a unit of radiotherapy was established locally. INTERPRETATION: Our findings show that radiotherapy after breast-conserving surgery can be performed safely in a non-university hospital such as Rogaland Central Hospital.