Pirkko Kellokumpu-Lehtinen

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.

DNA sequence copy number increase at 8q: A potential new prognostic marker in high-grade osteosarcoma

Histologic response to chemotherapy is currently the best prognostic parameter in high‐grade osteosarcoma but it can be evaluated only after several weeks of chemotherapy. Thus a prognostic parameter known at the time of diagnosis would be of great clinical benefit. In the present study, we present the results of 31 primary high‐grade osteosarcomas analyzed by comparative genomic hybridization (CGH). CGH allows for genome‐wide screening of a tumor by detecting alterations in DNA sequence copy number. The most frequent aberrations were copy number increases at 1q21 in 58% of the tumors and at 8q (8q21.3‐q22 in 52% and 8cen‐q13 in 45%), followed by copy number increases at 14q24‐qter (35%) and Xp11.2‐p21 (35%). The most common losses were detected at 6q16 (32%) and 6q21‐q22 (32%). Patients with a copy number increase at 8q21.3‐q22 and/or at 8cen‐q13 had a statistically significant poor distant disease‐free survival (p = 0.003) and showed a trend toward short overall survival (p = 0.04). Patients with a copy number increase at 1q21 showed a trend toward short overall survival (p = 0.04). Thus, specific genetic aberrations detected at the time of the diagnosis could be used in prognostic evaluation of high‐grade osteosarcoma. Int. J. Cancer (Pred. Oncol.) 84:114–121, 1999.

Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer.

PURPOSE Pertuzumab is a humanized monoclonal antibody inhibiting human epidermal growth factor receptor 2 (HER2) dimerization. The aim of this phase II trial was to assess the antitumor activity and safety profile of pertuzumab monotherapy in patients with HER2-negative metastatic breast cancer. The utility of biomarkers detected in paraffin-embedded tissue as predictors of response was also explored. PATIENTS AND METHODS This was an international, multicenter, open-label, randomized phase II study. Patients (n = 79) with centrally confirmed HER2-negative metastatic breast cancer were randomly assigned to receive pertuzumab once every 3 weeks with a loading dose of 840 mg followed thereafter by either 420 mg (arm A) or 1,050 mg (arm B). Patients were stratified by country and prior taxane therapy. RESULTS Of 79 patients who were randomly assigned, 78 were included in the intent-to-treat population. In arm A (n = 41), two patients had partial responses, and 18 patients (44%) experienced stable disease (SD) lasting > or = 12 weeks. In arm B (n = 37), SD was observed in 14 patients (38%). Overall, six of 78 patients responded or had SD > or = 6 months. Pertuzumab was generally well tolerated, and most adverse events were mild to moderate. Decline in left ventricular ejection fraction of > or = 10% and/or to less than 50% was observed in eight patients, with one case of congestive heart failure in arm A. Pharmacokinetic data supported a fixed dose of pertuzumab once every 3 weeks. CONCLUSION The limited efficacy observed in this study, generally SD of relatively short duration, suggested little benefit of further investigation of single-agent pertuzumab in unselected patients with HER2-negative 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.

Leukemia-inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways.

Leukemia‐inhibitory factor (LIF) is an inflammatory cytokine with pleiotropic activities. LIF was originally described as a differentiation factor of a murine leukemia cell line and was subsequently found to possess a broad spectrum of biological functions. Although LIF has been extensively studied in the hematopoietic system, little is known about its effects in solid tumors. We investigated the role of LIF in breast, kidney and prostate cancers. Using a clonogenic assay, we found that LIF significantly stimulated proliferation of 2 estrogen receptor‐positive breast cancer cell lines (MCF‐7 and T47‐D) in a dose‐dependent fashion at concentrations ranging from 10 to 200 ng/ml. This effect was observed both in the presence of FCS and under serum‐ and estrogen‐free culture conditions, suggesting that the effect of LIF is direct and does not depend on estrogen or any other cytokine. Neither line produced LIF protein, as assessed by ELISA. In contrast, the estrogen receptor‐negative breast cancer line MDA MB‐231 produced LIF but did not respond to either LIF or its neutralizing antibodies. Similarly, increasing concentrations of LIF did not affect the growth of primary kidney (A‐498), metastatic kidney (ACHN) and prostate (DU 145) cancer cell lines. These lines produce LIF, however, and antibodies to LIF significantly suppressed their proliferation, suggesting that they were maximally stimulated by the endogenously produced cytokine. Taken together, our data suggest that LIF acts as either a paracrine or an autocrine growth factor for breast, kidney and prostate cancers.

Hormone-resistant metastatic prostate cancer : comparisons between estramustine phosphate and low-dose epirubicin treatments

We compared the effect and toxicity of estramustine phosphate and weekly low-dose epirubicin in a prospective randomized trial in 41 patients with metastatic prostate cancer refractory to hormonal manipulation. No significant difference between treatment modalities was seen. Palliation was reached in over 60% of patients. The median survival was 15 months in both groups. Toxicity was mild. Further, we investigated the effect of epirubicin after the failure of preceding estramustine phosphate therapy in additional 20 patients. Pain relief was achieved in 50% of these patients. The median survival was 10 months. Toxicity was acceptable.