C. Andreetta

Expression of periostin in human breast cancer

Background: Periostin is a secreted adhesion protein, normally expressed in mesenchime-derived cells. Aberrant expression of the periostin gene in epithelial tumours seems to play a role in angiogenesis and metastases. Aims: To investigate periostin expression in a consecutive series of breast carcinomas and correlate it with established biological and prognostic factors. Methods: A consecutive series of 206 breast carcinomas was investigated by immunohistochemistry with a specific antiperiostin antibody. Immunohistochemical expression of oestrogen and progesterone receptors, Ki-67 (MIB-1), HER-2/neu, VEGF-A, VEGFR-1 and VEGFR-2 was analysed. Periostin expression was also investigated in MCF-7 and MDA-468 cell lines by immunohistochemistry, western blot and quantitative RT-PCR. Localisation of periostin was investigated in MCF-7 cells by the green fluorescent protein (GFP) approach. Results: Periostin was highly expressed in carcinoma cells, but not in normal breast tissues. The pattern of expression was mainly cytoplasmic. However, in 12% of cases a nuclear reactivity was observed. Nuclear periostin significantly correlated with tumour size, and with expression of oestrogen receptor, progesterone receptor, VEGF-A, VEGFR-1 and VEGFR-2. A nuclear localisation of periostin was also observed in MCF-7 and MDA-468 cell lines. In MCF-7 cells the nuclear localisation of periostin was also shown by transfection of a vector expressing a GFP-periostin chimeric protein. Conclusions: Results indicate that the aberrant gene expression of periostin in breast cancer cells is associated with an abnormal nuclear localisation of the protein. The nuclear localisation of periostin in breast cancer may induce significant biological effects.

Measures of Outcome in Metastatic Breast Cancer: Insights From a Real-World Scenario

No gold standard treatment exists for metastatic breast cancer (MBC). Clinical decision making is based on knowledge of prognostic and predictive factors that are extrapolated from clinical trials and, sometimes, are not reliably transferable to a real-world scenario. Moreover, misalignment between endpoints used in drug development and measures of outcome in clinical practice has been noted. The roles of overall survival (OS) and progression-free survival (PFS) as primary endpoints in the context of clinical trials are the subjects of lively debate. Information about these parameters in routine clinical practice is potentially useful to design new studies and/or to interpret the results of clinical research. This study analyzed the impact of patient and tumor characteristics on the major measures of outcome across different lines of treatment in a cohort of 472 patients treated for MBC. OS, PFS, and postprogression survival (PPS) were analyzed. The study showed how biological and clinical characteristics may have different prognostic value across different lines of therapy for MBC. After first-line treatment, the median PPS of luminal A, luminal B, and human epidermal growth factor receptor 2 (HER2)-positive groups was longer than 12 months. The choice of OS as a primary endpoint for clinical trials could not be appropriate with these subtypes. In contrast, OS could be an appropriate endpoint when PPS is expected to be low (e.g., triple-negative subtype after the first line; other subtypes after the third line). The potential implications of these findings are clinical and methodological.

Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer

BACKGROUND AND AIMnCapecitabine is an orally bioavailable prodrug that is converted to 5-fluorouracil through several enzymatic steps, the last of which is mediated by thymidine phosphorylase (TP). TP has been reported to be expressed at higher levels in cancer tissue compared with normal counterpart. The present study aimed at evaluating the potential relationship between TP expression and benefit from capecitabine in patients with metastatic breast cancer (BC).nnnMETHODSnImmunohistochemistry for TP and other biological markers was carried out on paraffin-embedded cancer tissues of 61 patients with BC treated with at least three cycles of capecitabine as single agent for metastatic disease. All patients had received capecitabine 1000 mg/m(2) b.i.d. days 1-14 every 21 days. The following variables were analyzed as potential determinants of benefit from capecitabine: TP expression, estrogen receptor (ER) and progesterone receptor status, human epidermal growth factor receptor-2 (HER-2) status, MIB-1 expression, performance status at the beginning of capecitabine treatment, stage at diagnosis, grade, presence of visceral metastases at the beginning of capecitabine treatment, and previous chemotherapy.nnnRESULTSnOverall, median time to progression (TTP) was 6.5 months (range 1.4-33). On multivariate analysis, ER status [hazard ratio (HR) for progression = 0.31; 95% confidence interval (CI) = 0.15-0.64; P = 0.002], presence of visceral metastases at the beginning of capecitabine treatment (HR = 2.30; 95% CI = 1.21-4.39; P = 0.01), and capecitabine as first- or second-line treatment (HR = 2.28; 95% CI = 1.21-4.32; P = 0.01) independently predicted TTP. TP was highly expressed in 34 of 61 cases (55.7%). In the subgroup of patients with TP-expressing tumor, TTP was significantly longer in patients who received anthracyclines and taxanes before capecitabine (median TTP 7.5 versus 3.3 months, P = 0.01, log-rank test). Similarly, patients with a TP-positive tumor showed a longer TTP if they received taxanes before capecitabine than patients with TP-positive tumor who did not receive this treatment (7.3 versus 3.4 months, P = 0.03).nnnCONCLUSIONSnThese data provide further evidence that TP expression in BC could represent a biomarker of sensitivity to capecitabine treatment. Prospective studies with translational approach are desirable to confirm the predictive and prognostic role of TP.

Thymidine phosphorylase expression is associated with time to progression in patients receiving low-dose, docetaxel-modulated capecitabine for metastatic breast cancer

BACKGROUNDnPreclinical data have indicated a synergistic interaction between docetaxel and capecitabine by means of taxane-induced up-regulation of thymidine phosphorylase (TP). On the basis of such premises, we conducted a phase II trial to determine the activity and tolerability of weekly docetaxel plus capecitabine in patients with metastatic breast cancer (MBC). Furthermore, we explored the relationship between TP tumor expression and benefit from this regimen.nnnPATIENTS AND METHODSnPatients received docetaxel 36 mg/m(2) i.v. on days 1, 8, and 15 and capecitabine orally 625 mg/m(2) b.i.d. from days 8 to 21. Cycles were repeated every 4 weeks. In the correlative study, we evaluated the TP expression by immunohistochemistry and the TP messenger RNA expression by real-time RT-PCR in the primary tumor.nnnRESULTSnForty-seven women were enrolled. In the intention-to-treat analysis, objective responses were achieved in 24 patients (51%). Fourteen additional patients (30%) had stable disease. The median time to progression (TTP) was 6 months (range 1-44 months). Median survival was 17 months (range 1-48 months). Overall, the treatment was well tolerated. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). A significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009). Interestingly, a subgroup analysis confirmed this TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3).nnnCONCLUSIONSnThis study indicates that a regimen with low doses of capecitabine plus weekly docetaxel is active against MBC. The correlative analysis provides preliminary evidence that TP expression may be a predictive marker for therapeutic benefit.

Cognitive functions and elderly cancer patients receiving anticancer treatment : A prospective study

It has been reported that anticancer treatment may cause cognitive impairment. Elderly patients in particular could be at increased risk for treatment-related cognitive deterioration. A consecutive series of cancer out-patients >or=65 years old were prospectively assessed by means of a neuropsychological test Cambridge Cognitive Examination (CAMCOG) test at baseline, and after 3 and 6 months from study entry. Patients were categorized in three groups (group 1, no anticancer treatment; group 2, receiving chemotherapy; group 3, receiving endocrine therapy). Comprehensive geriatric assessment was performed at the three time points evaluation. Sixty-one patients were enrolled (32, 16 and 13, in groups 1, 2, and 3, respectively). At baseline, cognitive function was directly correlated to Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scores and was associated with higher educational level and absence of depression. Overall, cognitive function did not worsen across time in each group. However, more patients in the CT group showed worsening in memory skills, and more patients in the ET and CT group experienced reduction in the attention score.

Phase II, randomized trial of preoperative epirubicin-paclitaxel +/- gefitinib with biomarker evaluation in operable breast cancer.

PurposeTo evaluate the inxa0vivo effect of adding gefitinib to preoperative chemotherapy on the EGFR-dependent p42/44 MAPK in operable breast cancer (BC) patients. Secondary aims: to evaluate EGFR, (p)-EGFR, Ki67, apoptotic index (TUNEL test) and VEGFR2 expression from baseline to surgery, percentage of pathologic complete response (pCR), and toxicity.Patients and Methods90 patients with stage II-IIIA BC have been randomized to receive epirubicin 90xa0mg/sqm and paclitaxel 175xa0mg/sqm on day 1 plus: gefitinib 250xa0mg daily from day 5 to 16 (Arm A, intermittent), gefitinib 250xa0mg daily from day 1 to 21 (Arm B, continuous), or placebo (Arm C). Treatment plan: 4 courses every 3xa0weeks, followed by surgery.ResultsAfter preoperative therapy, 86/90 patients underwent surgery; 46 patients (51%) received breast conservative surgery. A pCR was observed in 4 patients. No significant differences in the expression of p42/44 MAPK, EGFR, (p)-EGFR, VEGFR2, proliferation index and apoptosis were observed comparing the combined Arms Axa0+xa0B vs C, and comparing Arm A vs B. Hematologic toxicities were not significantly different comparing Arms Axa0+xa0B vs Arm C, and comparing Arm A vs B. Significantly higher skin and mucosal toxicities were observed when comparing the two gefitinib Arms (Axa0+xa0B) vs Arm C (32% vs 9.6%, Pxa0=xa00.018; 57% vs 29%, Pxa0=xa00.009 respectively), while no significant differences were observed comparing Arm A vs B.ConclusionAdding gefitinib to chemotherapy did not result in different effects on the EGFR-dependent pathway, proliferation, apoptosis and VEGFR2 expression as compared to placebo, while enhancing skin and mucosal toxicity. The two schedules of gefitinib (intermittent vs continuous) did not result in different biologic effects.

Markers of the uPA system and common prognostic factors in breast cancer.

The urokinase plasminogen activator (uPA) system includes uPA and plasminogen activator inhibitor types 1 (PAI-1) and 2 that mainly act by regulating extracellular matrix degradation, and it is involved in tumor progression. The -675 4G/5G polymorphism of the PAI-1 gene regulates PAI-1 activity in serum. We aimed at studying the -675 4G/5G polymorphism of the PAI-1 gene and uPA, PAI-1, and cyclooxygenase-2 (COX-2) immunohistochemical expression in a series of breast cancer cases. Homozygosity for the 4G allele of the PAI-1 gene was associated with node-positive breast cancer ( P = .02). We showed a direct correlation between uPA and estrogen receptor expression ( P = .03); negative uPA expression was associated with negative hormonal expression, high tumor grade, and high proliferation index ( P < .05). A direct correlation was seen between uPA and PAI-1, uPA and COX-2, and PAI-1 and COX-2 expression ( P < .05). Interaction between uPA and COX-2 systems in breast cancer deserves further study.

Bone Scan for Baseline Staging in Invasive Breast Cancer at the Time of Primary Presentation

99mTechnetium-labeled methylene diphosphonate bone scan (BS) is the most commonly used imaging test to screen for skeletal metastases in patients with breast cancer. Since its introduction into clinical practice, a large number of studies have been conducted to explore the role of BS in the baseline staging work-up at the time of breast cancer diagnosis. Even though the policy of offering preoperative or perioperative BS is still widely diffuse, a lot of evidence in the literature suggests that routine BS examinations are not cost-effective and should be recommended in selected cases only. Based on current guidelines, the use of BS as a staging procedure is considered appropriate in patients with a high pre-test probability (prevalence) of bone metastases. This category is represented by patients with newly diagnosed high-risk breast cancer (i.e. pN2 or T4/pT4) or with symptoms or laboratory signs suspicious for bone involvement.

Highlights from the 42nd annual meeting of the American Society of Clinical Oncology: Atlanta, GA, USA, 2 – 6 June 2006

The results of ~ 3700 preclinical and clinical studies were presented at the 42nd annual meeting of the American Society of Clinical Oncology (ASCO) held 2 – 6 June 2006, in Atlanta, Georgia. The annual ASCO meeting is the largest forum in which oncology professionals from around the world report the latest advances in cancer research, encompassing a wide spectrum of subjects on molecular biology, prevention, diagnosis and therapy of tumours. The present report summarises some of the more important results of the studies presented at the meeting. In particular, the authors focused on findings from randomised Phase III trials that, in their opinion, are most likely to have an immediate effect on clinical practice. The top advances were grouped into four major themes (breast cancer, colorectal cancer, non-small cell lung cancer and selected presentations from the plenary session). In addition, selected Phase I and II studies on promising novel therapeutic agents were briefly described. Finally, a ‘question and answer’ format was adopted to report results of interesting studies on some hot topics.