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Biomedical subjects

Filippo Montemurro

Publications and source records attributed to Filippo Montemurro.

At least 19 recordsLinked to original sources
PubMed2006

Relationship between DCE-MRI morphological and functional features and histopathological characteristics of breast cancer.

We studied whether dynamic contrast-enhanced MRI (DCE-MRI) could identify histopathological characteristics of breast cancer. Seventy-five patients with breast cancer underwent DCE-MRI followed by core biopsy. DCE-MRI findings were evaluated following the scoring system published by Fischer in 1999. In this scoring system, five DCE-MRI features, three morphological (shape, margins, enhancement kinetic) and two functional (initial peak of signal intensity (SI) increase and behavior of signal intensity curve), are defined by 14 parameters. Each parameter is assigned points ranging from 0 to 1 or 0 to 2, with higher points for those that are more likely to be associated with malignancy. The sum of all the points defines the degree of suspicion of malignancy, with a score 0 representing the lowest and 8 the highest degree of suspicion. Associations between DCE-MRI features and tumor histopathological characteristics assessed on core biopsies (histological type, grading, estrogen and progesterone receptor status, Ki67 and HER2 status) were studied by contingency tables and logistic regression analysis. We found a significant inverse association between the Fischer's score and HER2-overexpression (odds ratio-OR 0.608, p = 0.02). Based on our results, we suggest that lesions with intermediate-low suspicious DCE-MRI parameters may represent a subset of tumor with poor histopathological characteristics.

Adult↗
PubMed2006

Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy.

We sought to describe patterns of treatment and clinical outcome in patients with HER2-positive advanced breast cancer progressing on trastuzumab-based therapy. One hundred eighty-four consecutive HER2-positive advanced breast cancer patients received trastuzumab-based therapy between September 1999 and September 2004. Patients were followed up until death or May 2005. For patients progressing on trastuzumab-based therapy, we calculated the response rate (RR) to the first post-progression treatment, overall survival (OS) from the first administration of trastuzumab, time to second progression (TT-SP), and post-progression survival (PPS), according to treatment. At the time of this analysis, 132 patients had progressed on trastuzumab-based therapy, and 89 had died. Of the progressing patients, 21 experienced rapid progression and could not receive additional anticancer treatments;40 patients continued trastuzumab either alone (12 patients with isolated central nervous system progression), with chemotherapy (23 patients), or with endocrine therapy (5 patients); and 71 stopped trastuzumab and received chemotherapy (61 patients) or endocrine therapy (10 patients) as the first post-progression treatment. Excluding patients with rapid progression, clinical outcomes were similar whether trastuzumab was continued or not, in terms of RR (18% and 27%, respectively), OS (31 and 30 months, respectively), TT-SP (6 and 7 months, respectively), and PPS (21 and 19 months, respectively). The clinical outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy might not be influenced by continuing trastuzumab. The optimal therapeutic strategy in this setting of patients needs evaluation in randomized trials.

Adult↗
PubMed2005

TGFalpha expression impairs Trastuzumab-induced HER2 downregulation.

The HER2 gene encodes a tyrosine kinase receptor overexpressed in 25-30% of human breast cancers. Clinical trials have shown the efficacy of the anti-HER2 monoclonal antibody Trastuzumab in metastatic breast cancer patients. Nevertheless, 70% of patients are unresponsive from start of treatment and nearly all become unresponsive during treatment. Possible mechanisms for these failures could depend on impairment of the machinery responsible for receptor downregulation. To test this hypothesis, we analysed the genomic sequences encoding regions known to be critical for HER2 downregulation, of both HER2 and of the ubiquitin ligase Cbl. We investigated 63 breast cancers, and found no mutations in these regions. We thus considered alternative mechanisms -- such as TGFalpha production -- possibly interfering with HER2 downregulation. In selected cases, by comparing breast cancer neoplastic tissue before and after Trastuzumab treatment, we found induction of TGFalpha expression. Moreover, by in vitro expression of exogenous TGFalpha in breast cancer cells, we observed a dramatic reduction in Trastuzumab-induced HER2 endocytosis, downregulation and cell growth inhibition. Our results suggest that unresponsiveness to Trastuzumab may not be due to intrinsic defects in the machinery responsible for HER2 downregulation, but can be associated with a TGFalpha-related mechanism of escape to HER2 downregulation.

Antibodies, Monoclonal↗
PubMed2005

Dynamic contrast-enhanced MRI and sonography in patients receiving primary chemotherapy for breast cancer.

We compared dynamic contrast-enhanced MRI (DCE-MRI) and sonography (US) for monitoring tumour size in 21 patients with breast cancer undergoing primary chemotherapy (PCT) followed by surgery. The correlation between DCE-MRI and US measurements of tumour size, defined as the product of the two major diameters, was 0.555 (P=0.009), 0.782 (P<0.001), and 0.793 (P<0.001) at baseline, and after two and four cycles of PCT, respectively. The median tumour size was significantly larger when measured by DCE-MRI than by US at baseline (1472 vs 900 mm(2), P<0.001) and after two cycles of PCT (600 vs 400 mm(2), P=0.009). After PCT, the median tumour size measured by the two techniques was similar (256 vs 289 mm(2) for DCE-MRI and US, respectively, P=0.859). The correlation with the histopathological major tumour diameter was 0.824 (P<0.001) and 0.705 (P<0.001) for post-treatment DCE-MRI and US, respectively. Measurements of the final major tumour diameter by DCE-MRI tended to be more precise, including cases achieving a pathological complete response. Randomized trials are warranted to establish the clinical impact of the initial discrepancy in tumour size estimates between DCE-MRI and US, and the trend towards a better definition of the final tumour size provided by DCE-MRI in this clinical setting.

Adult↗
PubMed2005

The 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, FL, USA, 13-17 May, 2005.

Nearly 29,000 scientists from all over the world gathered at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). The programme included the presentation of new data encompassing all the fields of cancer research, including cancer prevention, treatment and biology. Special sessions were added to summarise and discuss achievements in the field of translational research on biologically targeted therapies. Rational drug design based on tumour biology and genetics represents a promising strategy to overcome the limitations of conventional chemotherapy. Increased knowledge in the field of molecular oncology, genetics and progress in technology are revolutionising tumour classification, prognostication, prediction and therapy. However, at present, for most of the diseases, improvements brought about by the newer therapies are small, although clinically meaningful. This review will briefly address some of the most interesting data presented at ASCO 2005.

Humans↗
PubMed2005

Target achieved.

Explore the source record for details and available documents.

Antibodies, Monoclonal↗
PubMed2005

Controversies in breast cancer: adjuvant and neoadjuvant therapy.

Initial randomised studies of chemotherapy and endocrine therapy showed that systemic treatments had a substantial impact on the survival of women with early breast cancer. The original assumption was that the efficacy of these treatments was limited to those patients presenting with more adverse prognostic features. Subsequently, meta-analyses of randomised trials revealed that the benefits of chemotherapy and endocrine therapy are not mutually exclusive and extend to all the prognostic subgroups. However, the absolute benefit varies according to baseline characteristics such as tumour stage and other biological factors. Over the last 10 years, considerable progress has been made with the introduction of new drugs into the adjuvant and neoadjuvant treatment of women with breast cancer. Taxanes and third-generation aromatase inhibitors are providing proof of additional benefits compared with standard reference treatments. In parallel, research on the biology of breast cancer is establishing novel prognostic and predictive factors, which may allow better treatment tailoring. Currently, however, women with early breast cancer and their doctors face the difficult task of making therapeutic decisions often based on early results from positive studies. In a disease where follow up is crucial to fully assess the benefit and long-term toxicities of an intervention, current knowledge leaves unanswered questions that generate debate and controversy. This review will summarise recent results from randomised trials of adjuvant and neoadjuvant therapy in women with early breast cancer and focus on the current controversies.

Age Factors↗
PubMed2005

Incorporating trastuzumab into the neoadjuvant treatment of HER2-overexpressing breast cancer.

We sought to provide a brief overview of the available results of trastuzumab in the neoadjuvant treatment of women with locally advanced, HER2-overexpressing breast cancer. A review of published reports was conducted by the use of Medline computer searching and manual searching of abstracts presented at the Annual Meeting of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium between 2002 and 2004. Several phase II trials and one phase III trial show that trastuzumab-containing regimens are feasible and yield high rates of clinical and pathologic complete response in women with locally advanced HER2-overexpressing breast cancer. Moreover, the neoadjuvant approach allows serial monitoring of biologic phenomena that occur during the administration of therapy, which acquires particular importance in the case of targeted therapies like trastuzumab. The incorporation of trastuzumab into neoadjuvant therapy for breast cancer appears promising. However, no data on long-term survival and safety are available at present. Well-designed clinical trials are needed to establish the optimal trastuzumab-based neoadjuvant strategy.

Adult↗
PubMed2005

HER2 gene-amplified breast cancers with monosomy of chromosome 17 are poorly responsive to trastuzumab-based treatment.

Although HER2 gene status determines the eligibility of breast cancer patients to trastuzumab therapy, only a fraction of HER2 gene-amplified cancers are actually responsive, indicating that complex genotypical profiles might sustain HER2-targeted therapy responsiveness. To identify genetic factors modulating the response to HER2-targeted therapy, the numerical status of chromosome 17 was evaluated in HER2 gene-amplified tumor specimens from 43 patients who received trastuzumab-based treatment for advanced breast cancer, and in 60 unamplified breast carcinomas. Archival tumor specimens were analyzed by interphase fluorescence in situ hybridization (FISH) using a centromeric probe for chromosome 17 simultaneously with the HER2/neu human gene-specific probe. In the 43 patients who received trastuzumab-based treatment, response rate and time to progression (TTP) were compared between subgroups according to chromosome 17 status. Numerical aberrations of chromosome 17 were found in 65% of HER2-amplified tumors (single centromeric signal, 44%; >3 centromeric signals, 21%) and 60% of unamplified cancers (single centromeric signal, 43%; >3 centromeric, 17%). In the 43 treated metastatic breast cancer patients, trastuzumab was combined with docetaxel (35 patients), paclitaxel (2 patients), or vinorelbine (6 patients). Response rate was 92% in patients with >2 centromeric signals (chromosome 17 eusomy/polysomy), and 53% in patients whose tumor showed a single signal (chromosome 17 monosomy) (p=0.005). Chromosome 17 numerical status was not found to affect TTP. Multivariate logistic regression analysis confirmed that the effect of chromosome 17 monosomy on tumor response was independent of other potential clinical variables. Our findings suggest that 17 monosomy defines a subgroup of HER2 gene-amplified breast cancer characterized by reduced responsiveness to trastuzumab-based treatment. Further studies on the imbalance between the amplified HER2 gene and functionally antagonist gene(s) on chromosome 17 are warranted.

Adult↗
PubMed2004

Monitoring response to primary chemotherapy in breast cancer using dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows analysis of both tumor volume and contrast enhancement pattern using a single tool. We sought to investigate whether DCE-MRI could be used to predict histological response in patients undergoing primary chemotherapy (PCT) for breast cancer. PATIENTS AND METHODS: Thirty patients with breast cancer, clinical diameter > 3 cm or stage III A/B, received anthracycline and taxane based PCT. DCE-MRI was performed at the baseline, after two cycles and after four cycles of PCT, before surgery. Histological response was assessed using a five-point scheme. Grade 4 (small cluster of dispersed residual cancer cells) and grade 5 (no residual viable cancer cell) were defined as a major histopathological response (MHR). RESULTS: Univariate analysis showed that a > 65% reduction in the tumor volume and a reduction in the early enhancement ratio (ECU) after two cycles of PCT were associated with a MHR. Multivariate analysis revealed that tumor volume reduction after two cycles of PCT was independently associated with a MHR (odds ratio [OR] 39.968, 95% confidence interval [CI] 3.438-464.962, p < 0.01). ECU reduction was still associated with a MHR (OR 2.50, 95% CI 0.263-23.775), but it did not retain statistical significance (p = 0.42). Combining tumor volume and ECU reduction after two cycles of PCT yielded a 93% diagnostic accuracy in identifying tumors achieving a pathological complete response (pCR) (histopathological grade 5). CONCLUSIONS: DCE-MRI allows prediction of the effect of neoadjuvant chemotherapy in breast cancer. Although in our study tumor volume reduction after two cycles had the strongest predictive value, DCE-MRI has the potential to provide functional parameters that could be integrated to optimize neoadjuvant chemotherapy strategies.

Adolescent↗
PubMed2004

A phase II study of three-weekly docetaxel and weekly trastuzumab in HER2-overexpressing advanced breast cancer.

BACKGROUND: To test safety and activity of 3-weekly doses of docetaxel and a weekly dose of trastuzumab in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty-two women, median age 53 years (range 36-73 years), with HER2-overexpressing advanced breast cancer were enrolled in a study of docetaxel, 75 mg/m(2) q3w for 6 cycles, and trastuzumab, 4 mg/kg loading dose, 2 mg/kg weekly thereafter. Thirty-four patients (81%) had visceral metastatic involvement. Thirty-five patients had received prior chemotherapy as part of their treatment: adjuvant/neoadjuvant (26), metastatic (2) and both (7). Thirty-one patients had been previously exposed to an anthracycline and 11 to paclitaxel. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplant. RESULTS: 226 cycles (median 6, range 1-6) were administered. The median delivered dose intensity for docetaxel was 24 mg/m(2)/week (range 16-25 mg/m(2)/week). The intent to treat overall response rate was 67% (95% confidence interval, 52-79%). Median progression-free survival, time to treatment failure, and duration of response were 9, 8 and 12 months, respectively. Symptomatic cardiotoxicity (grade 3) occurred in 1 patient. The most common grade 3/4 toxicity was neutropenia (76% of the patients), although febrile neutropenia did not occur. CONCLUSIONS: Three-weekly doses of docetaxel and a weekly dose of trastuzumab is an active and safe combination in patients with HER2-overexpressing advanced breast cancer.

Adult↗
PubMed2004

Trastuzumab-based combination therapy for breast cancer.

Trastuzumab, a humanised monoclonal antibody directed against the extracellular domain of HER-2, has been shown to be active against HER-2-overexpressing metastatic breast cancer, either as single agent or when used in combination with chemotherapy. In preclinical models, trastuzumab has shown additive and even synergistic anti-tumour activity with the most active chemotherapeutic agents used in the treatment of breast cancer. In a large, randomised, Phase III trial, the combination of trastuzumab plus chemotherapy was shown to improve response rate and survival. The high incidence of cardiotoxicity seen with the combination of trastuzumab plus anthracycline drugs prompted carrying out of several clinical studies combining trastuzumab with other chemotherapeutic agents, including docetaxel, vinorelbine, platinum salts, gemcitabine and capecitabine. This article summarises the available data on trastuzumab-based combinations for breast cancer.

Antibodies, Monoclonal↗
PubMed2004

Selected highlights from the 26th San Antonio Breast Cancer Symposium. December 3-6, 2003, San Antonio, TX, USA.

The San Antonio Breast Cancer Symposium is one of the largest international meetings devoted solely to breast cancer research. Basic scientists, translational researchers, clinical investigators and physicians share state-of-the-art information on breast cancer covering almost all the aspects of breast cancer, including prevention, aetiology, diagnosis, molecular biology and treatment. The current report describes relevant therapeutic findings that were presented at the 26 th San Antonio Breast Cancer Conference, held in San Antonio, Texas, USA, in December 2003.

Breast Neoplasms↗
PubMed2004

HER2 and central nervous system metastasis in patients with breast cancer.

We report a case of a patient who developed a central nervous system (CNS) metastasis 17 months after surgery and adjuvant therapy for stage II breast cancer. The HER2 status of the primary tumor as determined by immunohistochemistry (IHC) was 1+, and fluorescence in situ hybridization (FISH) performed retrospectively showed a borderline-negative result (ratio, 1:9), although HER2 amplification was present in a minority of breast cancer cells. By contrast, the HER2 status of the CNS metastasis was positive by IHC (3+) and FISH (ratio, 3:7). This report discusses the possibility that, for metastatic invasion into the CNS, clonal selection may occur, favoring HER2-positive cell clones.

Breast Neoplasms↗
PubMed2003

Predicting outcome based on Swenerton score in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation: implications for patient selection.

The aim of this study was to study the effectiveness of the Swenerton score in assessing extent of disease as an independent prognostic and predictive factor in patients with metastatic breast cancer (MBC) who receive high-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplant (AHSCT). Two-hundred thirty-two patients with MBC underwent HDCT. Extent of disease was assessed quantitatively using the Swenerton score. A retrospective analysis was performed using Cox proportional hazards regression and logistic regression models. One hundred three (44%) patients had a complete response (CR) after HDCT. Bone marrow as source of hematopoietic stem cells, hormone-receptor-negative status, and visceral involvement correlated with both worse overall survival (OS) and progression-free survival (PFS). Short disease-free interval, multiple sites of metastatic disease, and less than 50% reduction in the Swenerton Score during induction chemotherapy correlated with worse OS. Patients in CR at the time of HDCT had better PFS than patients in partial response, stable disease, or progressive disease. Fifty-six patients who underwent conversion to CR after HDCT had a similar median OS (not reached v 74 months; P =.51) and PFS duration (22 v 44 months; P =.15) as patients who received HDCT after a CR to standard-dose chemotherapy (SDCT). Conversion to CR was predicted by a >/=50% reduction in the Swenerton score during SDCT (odds ratio [OR] 3.32, P <.01) and soft-tissue disease (OR 4.08, P <.01). The presence of multiple metastatic sites predicted decreased probability of conversion to CR (OR 0.34, P <.01). The Swenerton score provides a thorough estimate of disease extent, and reduction of Swenerton score by SDCT is potentially useful for selecting the optimal candidates for HDCT trials who may achieve long-term disease control.

Adult↗