Rolf Kaaresen

Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival

We present a general method for rigorously identifying correlations between variations in large-scale molecular profiles and outcomes and apply it to chromosomal comparative genomic hybridization data from a set of 52 breast tumors. We identify two loci where copy number abnormalities are correlated with poor survival outcome (gain at 8q24 and loss at 9q13). We also identify a relationship between abnormalities at two loci and the mutational status of p53. Gain at 8q24 and loss at 5q15-5q21 are linked with mutant p53. The 9q and 5q losses suggest the possibility of gene products involved in breast cancer progression. The analytical techniques are general and also are applicable to the analysis of array-based expression data.

Upper Limb Physical Function and Adverse Effects After Breast Cancer Surgery: A Prospective 2.5-Year Follow-Up Study and Preoperative Measures

OBJECTIVE To examine upper limb physical function and adverse effects after axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) in patients with breast cancer to identify impairments that can inform rehabilitation strategies. DESIGN Prospective longitudinal cohort. Upper limb measurements were studied preoperatively and 2.5 years after breast cancer treatment. SETTING Hospital setting. PARTICIPANTS Two groups of patients with early-stage primary breast cancer (N=391): the ALND surgery group (mean age, 55±10y) and the SLNB group (mean age, 57±10y). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Arm lymphedema (≥10% increased arm volume relative to control arm volume), grip strength (in kilograms), shoulder mobility, pain intensity during isometric shoulder abduction (on a 100-mm visual analog scale), and body mass index (kg/m(2)). Parametric/nonparametric tests were used for hypothesized changes and differences, and regression analysis was used for confounding factors. RESULTS We observed more adverse effects in women treated with ALND than with SLNB after 2.5 years (P<.05): arm lymphedema (17% vs 3%), grip strength reduction (12% vs 2%), and shoulder abduction-provoked pain (increase of 6% vs decrease of 50%). The adverse effects were similar for affected and control upper limbs for all outcomes except arm lymphedema, which occurred only on the affected side. CONCLUSIONS Adverse effects in both affected and control/unaffected upper limb were observed after 2.5-year follow-up in both ALND and SLNB groups, but a higher prevalence was observed in the ALND group. Thus, women going through ALND surgery may benefit from further postoperative physical therapy, including resistance and strength exercise, focusing on pain management.

Vascularization in primary breast carcinomas: Its prognostic significance and relationship with tumor cell dissemination

Purpose: The interaction between tumor cells, stroma, and endothelial cells is important for the dissemination of tumor cells. The aim of the present study is to examine vascularity in primary breast carcinomas and its prognostic significance and relationship with tumor cell dissemination. Experimental Design: A total of 498 invasive breast carcinomas were analyzed. Representative tumor sections were stained for CD34 and CD105, and vascularity was quantified by the Chalkley method. The relationship between Chalkley counts, vascular invasion, disseminated tumor cells (DTC) in the bone marrow, other clinicopathologic variables, and clinical outcome was evaluated. Results: High vascular grades determined by Chalkley counts were significantly associated with shorter distant disease–free survival and breast cancer–specific survival in all patients (P < 0.001, log-rank) and in node-negative patients not receiving adjuvant systemic therapy (P < 0.05). In multivariate analysis, both CD34 and CD105 Chalkley counts showed prognostic significance for distant disease–free survival (P = 0.014 and P = 0.026), whereas CD34 also showed prognostic significance for breast cancer–specific survival (P = 0.007). Vascular invasion and DTCs in the bone marrow showed independent prognostic significance. DTC did not discriminate survival for CD34 low Chalkley counts, whereas a very poor prognosis was observed for DTC-positive patients with high CD34 counts. In node-negative patients not receiving systemic chemotherapy, high CD34 and high CD105 counts in combination identified patients with unfavorable outcome, as opposed to all other CD34/CD105 combinations. Conclusions: Improved identification of risk groups could be obtained by adding CD34 and CD105 vascular analysis to DTC, vascular invasion, and other primary tumor factors. This may facilitate the selection of candidates for adjuvant systemic therapy.

Expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2 in invasive breast carcinoma: prognostic significance and relationship with markers for aggressiveness.

Dhakal H P, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, Wiedswang G, Bassarova A, Holm R, Giercksky K‐E & Nesland J M 
(2012) Histopathology 61, 350–364

Hospital-related differences in breast cancer management

A retrospective review is presented of 1353 consecutivepatients with histopathologically confirmed invasive breast carcinoma treatedradically with curative intent during the decade 1980–89.None had received adjuvant systemic therapy with hormonesor prolonged chemotherapy. The distribution of lymph-node negative(N−) and lymph-node positive (N+) patients was 75%and 25%, respectively.The treatment and outcome were analysed as regardsconventional prognostic parameters, in particular considering the axillarylymph-node status and the responsible hospital category (GeneralMunicipal Hospitals (MH)) versus Comprehensive Cancer Center (CC)).The most striking difference was detected as regardsthe number of examined lymph nodes. The mediannumber of nodes described at the MH was7, as compared to 14 at the CC(p < 0.001). In patients with pT1 tumoursthe highest rate of lymph-node positivity was observedwhen 10 or more axillary nodes were removed.Adjuvant radiotherapy reduced the loco-regional recurrence rate inthe N− patients, whereas only the regional recurrenceswere reduced among the N+ patients. The five-and 10-year tumor-related survival rates were 86% and76%, respectively, with no difference between the MHand the CC.As life-prolonging adjuvant hormone therapy and chemotherapy isnow available for patients with axillary lymph nodemetastases, it is important that patients with breastcancer are operated adequately with the aim toremove at least 10 axillary lymph nodes. Athorough examination of the axillary content should beperformed by the pathologist, and the number ofresected lymph nodes and metastases should be reported.The establishment of nation-wide standard criteria for themanagement of breast cancer is recommended.

Prognosis of radically operated breast carcinoma patients. A retrospective study of 167 consecutive patients with emphasis on histopathological grading, reproducibility and mean nuclear area

A retrospective study of 167 consecutive radically treated breast cancer patients with histopathologically confirmed ductal carcinoma is presented. The aim was to establish the prognostic significance and reproducibility of histopathological grading done independently by two pathologists. Furthermore, the value of measurements of mean nuclear area (MNA) in the primary tumour was assessed. The two pathologists reviewed the same histological sections using a three‐point scoring system based on tubular stuctures, number of mitoses and nuclear pleomorphism. Grading was identical for 70% of the tumours (Kappa value 0.51). With increasing MNA, the fraction of poorly differentiated tumours increased. In the univariate analysis, tumour‐related survival was significantly related to histopathological grading when G3 tumours were compared to G1/G2 tumours (p<0.05). In the multivariate analysis, tumour size (pT category), lymph‐node status and grading were the only significant factors influencing patient outcome (p<0.05). MNA had no significant prognostic value. A combination of tumour size and histopathological grading identifies a group of node‐negative patients (pT2 G2/G3) who may have a less favourable prognosis and for whom adjuvant treatment may be beneficial.

Abstract P3-07-06: Survival benefit increases after breast conserving therapy compared to mastectomy when axillary node status is positive in early stage breast cancer: A registry based follow-up study of Norwegian women with screening and interval detected breast cancer pr

BACKGROUND: Recent register studies on early stage breast cancer have shown better survival when women underwent breast-conserving treatment (BCT) compared to mastectomy (MTX). It is unclear if this is due to selection effects or to a systemic benefit of BCT compared to MTX. If there is a systemic benefit this could theoretically be more prominent in some subgroups of breast cancer. The aim of this study is to evaluate if there are any subgroups with early stage breast cancer that benefits more of BCT compared to MTX. METHOD: A cohort of 6.629 women aged 50-69 with primary operable breast cancer detected in the screening programme (on screening or between screening, interval cancer) were selected from January 1998 until December 2009 and followed up until end of 2010. Life tables for overall survival (OS) and breast cancer specific survival (BCSS) were calculated in surgery groups and stages. Corresponding Kaplan-Meier plots were stratified in T1N1M0 and Ductal Carcinoma. OS and BCSS were compared using Cox proportional hazard for estimating hazard ratio between BCT and MTX in crude and adjusted analysis. RESULTS: 5-years BCSS in T1N0M0 was 99% for both surgical cohorts (BCT and MTX). 5-years BCSS in T1N1M0 was 98% for women undergoing BCT and 91% for women undergoing MTX. Respectively, 10-years BCSS in T1N1M0 was 96% for women undergoing BCT and 83% for women undergoing MTX. In adjusted analysis, HR for breast cancer death for women with stage T1N1M0 undergoing MTX compared to BCT was 3.12 (95% CI: 1.71-5.72). Respectively, 3.67 (95% CI: 1.20-11.22) stratified on grade III and 4.89 (67 (95% CI: 1.25-19.01) stratified on hormone receptor negative disease. CONCLUSION: The benefit of BCT compared to MTX seems to increase with increasing severity of the breast cancer disease, positive nodal status (N1), grade III and hormone receptor negative disease. These finding indicate a systemic benefit of BCT compared to MTX. Citation Format: Olaf Johan Hartmann-Johnsen, Ellen Schlichting, Rolf Kaaresen, Jan Franz Nygaard. Survival benefit increases after breast conserving therapy compared to mastectomy when axillary node status is positive in early stage breast cancer: A registry based follow-up study of Norwegian women with screening and interval detected breast cancer pr [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-06.

Clinical Relevance of Early Disseminated Breast Cancer Cells Depends on Their Cytokeratin Expression Pattern.

Background: The factors determining the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients are largely unknown. Here we compared the specificity and clinical performance of two anti-cytokeratin(CK) antibodies frequently used for DTC detection, namely A45-B/B3 (A45) and AE1/AE3 (AE). Additionally we explored the CK gene expression patterns in primary breast tumors.Methods: Specificities of antibodies A45 and AE for selected CKs were assessed by 2-DE western blot analysis. Using these antibodies bone marrow aspirates from 391 breast cancer patients (M0, pT1-3, pN0-3) were screened for the presence of DTC. To obtain prognostic information, patients were followed up over a median of 83 months for time to relapse and 99 months for time to death. Two breast cancer patient datasets (Oslo (n=123), and van de Vijver et al. (NEJM 2002; n=295)) were analysed for CK primary tumor gene expression patterns and grouped by hormone receptor (HR) status of the primary tumors. T-tests and hierarchial clustering analyses were applied.Results: AE detected CK5, CK7, CK8, and CK19, whereas A45 recognized CK7 and CK18. In total, 24 of 391 patients (6.1%) were DTC-positive for A45, and 41 (10.5%) for AE. Although concordance between the two antibodies was 84.4%, overlap among positive cases was only 3.2%. DTC-positivity with AE and A45 was more frequent in patients of higher nodal status (p=0.019 and p=0.036, respectively). Nearly all patients with A45-positive DTC had hormone receptor-positive tumors (23/24), while detection of AE-positive DTC was more frequent among hormone receptor negative patients (p=0.006). Clear differences in primary tumor CK expression patterns between HR+ and HR- tumors were detected in both datasets. Compared to HR- tumors, CKs up-regulated in HR+ tumors were CK8 and 18, in addition CK19 in two datasets, whereas e.g. CK5, CK6, CK7, CK14, CK15, CK16, and CK17 were significantly down-regulated.Survival analyses of all patients revealed shorter distant disease-free survival (p=0.039) for patients with A45-positive DTC, whereas the prognostic relevance of AE-positive DTC was restricted to node positive patients.Conclusion: The clinical utility of immunocytochemical DTC detection depends on the anti-CK antibody used, which may reflect the complex CK composition of DTC. Tumor CK expression patterns and their correlation to antibody-sprecific DTC detection will further be explored by A45- and AE- staining of corresponding patient samples. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3021.