BRCA1-like profile predicts benefit of tandem high dose epirubicin-cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial.

BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide.

MRI features of intraductal papilloma of the breast: sheep in wolf's clothing?

BACKGROUND: Intraductal papillomas often present as small, smooth masses, dilated ducts or microcalcifications at mammography and as smooth, hypoechoic masses at sonography. At magnetic resonance imaging (MRI), intraductal papillomas often present as small smooth masses, however, often with strong enhancement with type 2 or 3 time intensity curves. The result of the MR analysis is therefore not infrequently inconclusive in order to characterize the mass as benign or malignant. PURPOSE: To characterize the appearance of intraductal papillomas of the breast at MRI, and determine whether the application of diagnostic rules described in literature could contribute to correctly classifying the lesions as benign. MATERIAL AND METHODS: Twenty patients with histologically proven intraductal papillomas were included. Two radiologists independently reviewed the MR images of the breast. The BI-RADS(®) nomenclature was used to describe morphology and contrast-enhancement kinetics. Interobserver agreement in the interpretation of the MR images by the two investigators was performed. Kappa coefficient was calculated as index for the level of agreement. Subsequently, three sets of diagnostic rules, including the Göttinger score described by Fischer and the interpretation flowcharts according to Kinkel and to Tozaki were applied to characterize whether a biopsy should be recommended or not. RESULTS: All papillomas presented as masses on dynamic contrast-enhanced MRI. Only five papillomas showed a round, oval, or lobulated shape combined with smooth margins and continuous rise of the time intensity curve. Using the Göttingen score, biopsy would be recommended in 16 patients. Based on the interpretation flowcharts of Kinkel and of Tozaki, an additional 13 and 10 papillomas, respectively, were correctly classified as benign. Dilated ducts were visible in 10 patients. The interobserver agreement was good or excellent for all included variables. CONCLUSION: Including systematic analysis of breast MRI to the diagnostic protocol and interpreting the images according to predetermined diagnostic rules, most solitary intraductal papillomas of the breast may be correctly characterized as benign.

Y-box-binding protein YB-1 identifies high-risk patients with primary breast cancer benefiting from rapidly cycled tandem high-dose adjuvant chemotherapy.

PURPOSE: To investigate the potential of Y-box-binding protein YB-1, a multifunctional protein linked to tumor aggressiveness and multidrug resistance, to identify patients with breast cancer likely to benefit from dose-intensified chemotherapy regimens. PATIENTS AND METHODS: YB-1 was immunohistochemically determined in 211 primary tumors from the prospective, randomized West German Study Group WSG-AM-01 trial in high-risk (> or = 10 involved lymph-nodes) breast cancer (HRBC). Predictive impact of YB-1 was assessed by multivariate survival analysis, including time-varying factor-therapy interactions. RESULTS: At median follow-up of 61.7 months, patients receiving rapidly cycled tandem high-dose therapy (HD; two cycles [2x] epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) every 14 days, followed by 2x epirubicin 90 mg/m(2), cyclophosphamide 3,000 mg/m(2), and thiotepa 400 mg/m(2) every 21 days) had better disease-free survival (DFS; hazard ratio [HR] = 0.62; 95% CI, 0.44 to 0.89) and overall survival (OS; HR = 0.59; 95% CI, 0.4 to 0.89) than those receiving conventional dose-dense chemotherapy (DD; 4x epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), followed by 3x cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) every 14 days). High YB-1 was associated with aggressive tumor phenotype (negative steroid hormone receptor status, positive human epidermal growth factor receptor 2 and p53 status, high MIB-1, unfavorable tumor grade) and poor OS (median 78 v 97 months; P = .01). In patients with high YB-1, HD yielded a 63-month median DFS (P = .001) and a 46-month median OS advantage (P = .002) versus DD. In multivariate models, patients with high B-1 receiving HD (v DD) had one third the hazard rate after 20 months for DFS and one sixth after 40 months for OS. CONCLUSION: In a randomized prospective cancer therapy trial, for the first time, a strong predictive impact of YB-1 on survival has been demonstrated: enhanced benefit from HD (v DD) therapy occurs in HRBC with high YB-1. Future trials could therefore address optimal chemotherapeutic strategies,taking YB-1 into account.

Nuclear karyopherin alpha2 expression predicts poor survival in patients with advanced breast cancer irrespective of treatment intensity.

Intensive lymph node involvement indicates poor prognosis in breast cancer patients. The significance of other molecular prognostic factors in this subgroup is unclear. Karyopherin alpha2 (KPNA2) has been reported as an important factor of tumorgenesis and progression of breast cancer. The aim of present study was to evaluate the impact of KPNA2 expression on prognosis of patients with high risk breast cancer (HRBC) and response intensive chemotherapy within the randomized WSG-AM-01 trial. KPNA2 nuclear expression (>10% vs. <10% of nuclei) was measured by immunohistochemistry on tissue arrays of 191 patients randomized to tandem high dose vs. conventional dose-dense chemotherapy in HRBC with >9 positive lymph nodes and correlated with clinical outcome (median follow-up of 63.3 months) by Kaplan-Meier and multivariate Cox hazard model analysis, including, molecular subtypes determined by k-clustering (k = 5). KPNA2 overexpression (n = 74, 39%) significantly correlated with shorter event-free and overall survival (OS) in both therapy arms by univariate analysis. Multivariate analysis showed that the overexpression of KPNA2 was an independent prognostic factor of decreased OS HR = 1.86 [95% CI: 1.07-3.23, p = 0.03]. This predictive value was independent of basal-like/Her-2/neu subtypes, significantly associated with KPNA2 and was addressed particularly to G2 tumors. Our data suggest the use of KPNA2 nuclear expression as novel prognostic marker in node-positive patients, especially in determination of G2 tumors in 2 subgroups of different prognosis. KPNA2 expression may be also considered as a marker for global chemoresistance, which can not be overcome by conventional dose-modification of chemotherapy in advanced breast cancer.

Nephron-sparing surgery of a low grade renal cell carcinoma in a renal allograft 12 years after transplantation.

Renal cell carcinoma (RCC) occurring in renal allografts after cadaveric kidney transplantation has rarely been observed. RCC accounts for 2.3% of all malignancies in the general population, but up to 4.8% of malignancies in renal transplant recipients. Most have been reported in the patient's own diseased kidneys, whereas RCC in the renal allograft occur in only 10%. Here, we describe an organ-preserving surgical technique of a malignant renal tumor in a kidney allograft using a harmonic scalpel (Ultracision) for tumor enucleation. Furthermore we demonstrate by DNA microsatellite analysis the tumor's genetic origin as donor related. Collectively, we suggest that patients with a well defined low grade RCC in the kidney allograft and altogether low malignancy and good allograft function should only undergo an organ-preserving procedure and short-term postoperative screening.

Challenging the concept of microinvasive carcinoma of the vulva: report of a case with regional lymph node recurrence and review of the literature.

BACKGROUND: It is widely accepted that vulvar carcinoma with a depth of invasion of less than one millimeter is sufficiently treated by vulvectomy or wide local excision without inguinal lymphadenectomy. CASE PRESENTATION: However, a patient with inguinal lymph node recurrence 21 months after radical vulvectomy for stage IA squamous cell carcinoma was observed. CONCLUSION: According to a review of the literature, there are five additional cases of metastasizing vulvar cancer with a depth of invasion of less than one millimeter. Therefore, the definition of microinvasive carcinoma of the vulva based on depth of invasion alone may not be as reliable as previously thought and does not rule out inguinal lymph node involvement or recurrence. Consequently, the necessity of inguinal node dissection for microinvasive carcinoma needs to be discussed on an individual basis taking into account the age of the patient as well as the potential morbidity of extended surgery.