Nils Wilking

ADJUVANT TAMOXIFEN IN EARLY BREAST CANCER: OCCURRENCE OF NEW PRIMARY CANCERS

The frequency of new primary cancers was studied in 1846 postmenopausal patients included in a randomised trial of tamoxifen as an adjunct to primary surgery for early breast cancer. The median follow-up was 4.5 years (range 0.5-10.5 years). The number of new cancers in the tamoxifen group (n = 57) did not differ significantly from that in the control group (n = 70). However, in tamoxifen patients second breast cancers occurred less often and endometrial cancer occurred more often than in the controls. The increase in endometrial cancers was probably related to the agonistic oestrogenic effects of tamoxifen and was most pronounced in those treated for over 2 years.

Correlation of Vascular Endothelial Growth Factor Content With Recurrences, Survival, and First Relapse Site in Primary Node-Positive Breast Carcinoma After Adjuvant Treatment

PURPOSE To determine the predictive value of vascular endothelial growth factor (VEGF) for relapse-free survival (RFS) and overall survival (OS) in primary node-positive breast cancer (NPBC) after adjuvant endocrine treatment or adjuvant chemotherapy. MATERIALS AND METHODS VEGF was quantitatively measured in tumor cytosols from 362 consecutive patients with primary NPBC using an enzyme immunoassay for human VEGF(165). Adjuvant treatment was given to all patients, either as endocrine therapy (n = 250) or chemotherapy (n = 112). The median follow-up time was 56 months. RESULTS Univariate analysis showed VEGF to be a significant predictor of RFS (P =.0289) and OS (P =.0004) in the total patient population and in patients who received adjuvant endocrine treatment (RFS, P =.0238; OS, P =.0121). In the group of patients who received adjuvant chemotherapy, no significant difference was seen in RFS, but a difference was seen in OS (P =.0235). Patients with bone recurrences tended to have lower VEGF expression (median, 2.17 pg/microg DNA) than patients with visceral metastasis (4.41 pg/microg), brain metastasis (8.29 pg/microg), or soft tissue recurrences (3.16 pg/microg). Multivariate analysis showed nodal status (P =.0004), estrogen receptor (ER) status (P <.0001), and tumor size (P =.0085) to be independent predictors of RFS. VEGF was found to be an independent predictor of OS (P =.0170; relative risk [RR] = 1.82), as were ER (P <.0001; RR = 5.19) and nodal status (P =.0002; RR = 2.58). For patients receiving adjuvant endocrine treatment, multivariate analysis showed VEGF content to be an independent predictor of OS (P =.0420; RR = 1.90) but not of RFS. CONCLUSION The results suggest that VEGF(165) content in tumor cytosols is a predictor of RFS and OS in primary NPBC. VEGF content might also predict outcome after adjuvant endocrine treatment, but further studies in a prospective setting with homologous treatments are required.

Topoisomerase II{alpha} Gene Amplification Predicts Favorable Treatment Response to Tailored and Dose-Escalated Anthracycline-Based Adjuvant Chemotherapy in HER-2/neu-Amplified Breast Cancer: Scandinavian Breast Group Trial 9401.

PURPOSE Amplification of the HER-2/neu and topoisomerase IIalpha (TOP2A) genes has been linked to the effects of anthracyclines. Their role in predicting the outcome of anthracycline-based adjuvant chemotherapy for breast cancer patients has remained controversial. PATIENTS AND METHODS The present substudy of the Scandinavian Breast Group trial 9401, in which an epirubicin-based regimen (nine courses of tailored and dose-escalated fluorouracil, epirubicin, and cyclophosphamide [FEC]) was compared with three or four courses of standard FEC followed by bone marrow-supported high-dose chemotherapy (cyclophosphamide, thiotepa, and carboplatin), included high-risk breast cancer patients (with eight or more positive axillary lymph nodes or at least five nodes with additional poor prognostic indicators). Amplification of HER-2/neu was determined retrospectively in paraffin-embedded tumor tissue sections by chromogenic in situ hybridization. TOP2A was tested only in HER-2/neu-amplified tumors. RESULTS HER-2/neu amplification alone, which was present in 32.7% of the tumors, was a strong prognostic factor for short relapse-free (P = .0034) and overall survival (P = .0008) but showed no direct association with treatment assignment. TOP2A coamplification, which was present in 37% of HER-2/neu-amplified tumors, was associated with better relapse-free survival in patients treated with tailored and dose-escalated FEC (hazard ratio [HR] = 0.45; P = .049). A statistical multivariate Coxs regression analysis confirmed the predictive significance of TOP2A coamplification (HR = 0.30; P = .020) in HER-2/neu-amplified tumors. There was no such association in patients with HER-2/neu-amplified tumors without TOP2A gene amplification. CONCLUSION Coamplification of HER-2/neu and TOP2A may define a subgroup of high-risk breast cancer patients who benefit from individually tailored and dose-escalated adjuvant anthracyclines.

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial

BACKGROUND Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. METHODS 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. FINDINGS At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. INTERPRETATION Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

Health related quality of life in different states of breast cancer

ObjectivesThe aim of this study was to describe the health related quality of life (HRQoL) in different breast cancer disease states using preference-based measures.Material and MethodsA total of 361 consecutive breast cancer patients attending the breast cancer outpatient clinic at Karolinska University hospital Solna for outpatient visits between April and May 2005 were included in the study. The EQ-5D self classifier and a direct Time Trade Off (TTO) question were used to estimate the HRQoL in different breast cancer disease states.ResultsPatients in their first year after a primary breast cancer had a mean EQ-5D index value of 0.696 (95% confidence interval (CI): 0.634–0.747)). Patients in their first year after a recurrence had a mean EQ-5D index value of 0.779 (CI: 0.700–0.849). Patients who had not had a primary breast cancer diagnosis or a recurrence during the previous year had a mean EQ-5D index value of 0.779 (CI: 0.745–0.811). Patients with metastatic disease reported the lowest HRQoL values, and had a mean EQ-5D index value of 0.685 (CI: 0.620–0.735). The main driver behind the reduction in HRQoL was pain and discomfort as well as anxiety and depression. TTO values were higher for all diseases states compared to the EQ-5D index values.ConclusionThis study shows that breast cancer is associated with a reduction in HRQoL. This effect is most pronounced for patients with metastatic disease.

Basoluminal Carcinoma: A New Biologically and Prognostically Distinct Entity Between Basal and Luminal Breast Cancer

Purpose: Breast carcinomas expressing basal epithelium cytokeratins constitute a tumor subgroup that is typically hormone receptor negative and shows a distinct gene expression profile. Based on variable basal cytokeratin immunostaining patterns, we hypothesized that the “basal phenotype” tumor group may comprise more than one biological entity. Experimental Design: Basal cytokeratins 5 and 14 (CK5/14) were stained by immunohistochemistry and the percentage of positive cells was defined by image analysis. The results thus obtained were compared with clinicopathologic characteristics and relapse-free survival. Results: Of the 506 breast tumors, 53 (10.5%) showed immunoreactivity for CK5/14. Basal cytokeratin expression showed up as two microscopically distinguishable subtypes, i.e., a uniformly positive type (“basal”) and a partially positive type (“basoluminal”) often displaying a checkerboard-type intratumoral heterogeneity. These subgroups could also be separated with a third basal cytokeratin (CK17, P < 0.0001). Both basal and basoluminal subtypes were hormone receptor negative and of high grade, but differed with respect to the Ki-67 labeling index (P = 0.0014), vimentin (P = 0.005), and c-kit (P = 0.02), which were more frequently expressed in basal than in basoluminal tumors. In contrast, the amplification of HER-2 was found almost exclusively in the basoluminal subgroup (P = 0.009). Compared with the basal tumors, basoluminal tumors associated with significantly shorter relapse-free survival (P = 0.01), which was not explained by their more frequent HER-2 amplification. Conclusions: We conclude that the intratumoral heterogeneity in basal cytokeratin expression can be used to define two distinct breast cancer subtypes, basal and basoluminal, with distinctive features related to proliferation activity, oncogene and biomarker status, and patient survival.

Prognostic significance of axillary nodal status in primary breast cancer in relation to the number of resected nodes

The prognostic significance of the number of metastatic axillary lymph nodes in relation to the number of identified nodes among 1,622 patients with operable breast cancer was assessed. We present a Coxs analysis of the prognostic significance of nodal status in relation to loco-regional recurrence, axillary recurrence, distant metastasis and death due to breast cancer respectively. As expected, the relative risks were generally higher for patients with nodal involvement, particularly those with 4 or more positive nodes or with few examined nodes. However, among those with more than 4 positive nodes the risk of distant metastases and death due to breast cancer was about the same irrespective of the number of nodes examined.

Radiation therapy in the management of brain metastases from breast cancer.

A retrospective analysis of 99 patients treated at Radiumhemmet, Karolinska Hospital 1979–1990 with palliative radiotherapy for brain metastases from breast cancer was performed. A relief of symptoms was obtained in 45% of patients. Median time from diagnosis of breast cancer until CNS metastases was 33 months. Median survival time with CNS metastases after diagnosis was 5 months. Prognostic indicators for survival were studied. Patients operated for a singular brain metastasis and irradiated postoperatively had a mean survival of 21 months while patients with multiple brain metastases and meningeal spread displayed a short median survival. Extracranial disease status influenced prognosis significantly. Radiation dose (CRE) did not correlate with survival.

Inhibition of tumor cell growth by monoterpenes in vitro: evidence of a Ras-independent mechanism of action.

(+)-Limonene (d-limonene) and related monoterpenes show chemopreventive activity against rodent mammary carcinoma and inhibit the growth of cancer cells in vitro. One suggested mechanism for the anti-tumorigenic effect of (+)-limonene is inhibition of the post-translational isoprenylation of growth controlling Ras oncoproteins. We have here examined the growth inhibitory effects of (+)-limonene and other related monoterpenes on PANC-1 pancreas carcinoma cells (carrying a K-ras mutation) and on 12V-H-ras-transformed rat fibroblasts. (+)-and (−)-perillyl alcohol, 7-methyl-perillyl alcohol, (+)-limonene oxide and (+)-perillic acid methyl ester were all found to efficiently inhibit cell growth at 1 mM, whereas (+)-limonene caused an approximately 50% growth reduction at 5 mM. Whereas BZA-5B, an inhibitor of Ras farnesyl transferase, was found to induce morphological reversion of 12V-H-ras-transformed cells, (+)-perillyl alcohol and (+)-limonene did not induce reversion. Furthermore, monoterpenes did not decrease MAP kinase enzyme activity or collagenase promoter activity in PANC-1 cells, two functions known to be down-stream from Ras. We conclude that although effective in inhibiting the growth of tumor cells harboring activated ras oncogenes, limonene and (+)-perillyl alcohol are unlikely to act by inhibiting Ras function.

Proliferating fraction during neoadjuvant chemotherapy of primary breast cancer in relation to objective local response and relapse-free survival.

In women with inoperable primary breast cancer or large T2 tumors, preoperative chemotherapy may induce tumor shrinkage, facilitate surgery and possibly improve survival. However, at present there are no reliable tumor cell parameters to predict which patients will benefit from preoperative chemotherapy. The aims of this study were to analyze the utility of tumor cell proliferation as assessed by Ki-67 staining in fine-needle aspirates from primary breast carcinomas to predict initial response to neoadjuvant chemotherapy as well as recurrence-free survival. The study comprised 51 women with primary breast cancer who received 3-4 courses of CEF (cyclophosphamide, epirubicin, 5-fluorouracil) as neoadjuvant chemotherapy. Tumor cells were procured through fine-needle aspiration biopsy prior to treatment. A second biopsy was performed before the second course of therapy in 33 women. Twenty-nine women (56%) experienced an objective local response after neoadjuvant treatment. During a median follow-up period of 39 months, 21 women (41%) developed disease recurrence. A decrease of more than 25% in proliferating fraction after the first course of chemotherapy correlated significantly with a decreased risk of disease recurrence (p = 0.033) but showed no significant correlation with local objective response. A multivariate analysis revealed that the decrease in proliferating fraction significantly (p < 0.05) added prognostic information to that of involved lymph nodes. These results suggest that changes in proliferating fraction as assessed by Ki-67 staining in fine-needle aspirates during preoperative chemotherapy may be of value in selecting postoperative adjuvant systemic treatment.