Breast Contrast Enhanced MR Imaging: Semi-Automatic Detection of Vascular Map and Predominant Feeding Vessel.

PURPOSE: To obtain breast vascular map and to assess correlation between predominant feeding vessel and tumor location with a semi-automatic method compared to conventional radiologic reading. METHODS: 148 malignant and 75 benign breast lesions were included. All patients underwent bilateral MR imaging. Written informed consent was obtained from the patients before MRI. The local ethics committee granted approval for this study. Semi-automatic breast vascular map and predominant vessel detection was performed on MRI, for each patient. Semi-automatic detection (depending on grey levels threshold manually chosen by radiologist) was compared with results of two expert radiologists; inter-observer variability and reliability of semi-automatic approach were assessed. RESULTS: Anatomic analysis of breast lesions revealed that 20% of patients had masses in internal half, 50% in external half and the 30% in subareolar/central area. As regards the 44 tumors in internal half, based on radiologic consensus, 40 demonstrated a predominant feeding vessel (61% were supplied by internal thoracic vessels, 14% by lateral thoracic vessels, 16% by both thoracic vessels and 9% had no predominant feeding vessel-p<0.01), based on semi-automatic detection, 38 tumors demonstrated a predominant feeding vessel (66% were supplied by internal thoracic vessels, 11% by lateral thoracic vessels, 9% by both thoracic vessels and 14% had no predominant feeding vessel-p<0.01). As regards the 111 tumors in external half, based on radiologic consensus, 91 demonstrated a predominant feeding vessel (25% were supplied by internal thoracic vessels, 39% by lateral thoracic vessels, 18% by both thoracic vessels and 18% had no predominant feeding vessel-p<0.01), based on semi-automatic detection, 94 demonstrated a predominant feeding vessel (27% were supplied by internal thoracic vessels, 45% by lateral thoracic vessels, 4% by both thoracic vessels and 24% had no predominant feeding vessel-p<0.01). An excellent agreement between two radiologic assessments (k = 0.81) and between radiologic consensus and semi-automatic assessment (k = 0.80) was found to identify origin of predominant feeding vessel. An excellent reliability for semi-automatic assessment (Cronbach's alpha = 0.96) was reported. CONCLUSIONS: Predominant feeding vessel location was correlated with breast lesion location: internal thoracic artery supplied the highest proportion of breasts with tumor in internal half and lateral thoracic artery supplied the highest proportion of breasts with lateral tumor.

Trastuzumab and target-therapy side effects: Is still valid to differentiate anthracycline Type I from Type II cardiomyopathies?

The improvement in cancer therapy and the increasing number of long term survivors unearth the issue of cardiovascular side effects of anticancer treatments. As a paradox in cancer survivors, delayed cardiotoxicity has emerged as a significant problem. Two categories of cardiotoxic side effects of antineoplastic drugs have been previously proposed: Type I cardiotoxicity, defined as permanent cardiotoxicity, is usually caused by anthracyclines; Type II cardiotoxicity, considered as reversible cardiotoxicity, has been mainly related to monoclonal antibodies. The cardiotoxicity of antibodies has been associated to trastuzumab, a humanized anti-ErbB2 monoclonal antibody currently in clinical use for the therapy of breast carcinomas, which induces cardiac dysfunction when used in monotherapy, or in combination with anthracyclines. Furthermore, recent retrospective studies have shown an increased incidence of heart failure and/or cardiomyopathy in patients treated with trastuzumab, that can persist many years after the conclusion of the therapy, thus suggesting that the side toxic effects are not always reversible as it was initially proposed. On the other hand, early detection and prompt therapy of anthracycline associated cardiotoxicity can lead to substantial recovery of cardiac function. On the basis of these observations, we propose to find a new different classification for cardiotoxic side effects of drugs used in cancer therapy.

Integration of DCE-MRI and DW-MRI Quantitative Parameters for Breast Lesion Classification.

OBJECTIVE: The purpose of our study was to evaluate the diagnostic value of an imaging protocol combining dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI) in patients with suspicious breast lesions. MATERIALS AND METHODS: A total of 31 breast lesions (15 malignant and 16 benign proved by histological examination) in 26 female patients were included in this study. For both DCE-MRI and DW-MRI model free and model based parameters were computed pixel by pixel on manually segmented ROIs. Statistical procedures included conventional linear analysis and more advanced techniques for classification of lesions in benign and malignant. RESULTS: Our findings indicated no strong correlation between DCE-MRI and DW-MRI parameters. Results of classification analysis show that combining of DCE parameters or DW-MRI parameter, in comparison of single feature, does not yield a dramatic improvement of sensitivity and specificity of the two techniques alone. The best performance was obtained considering a full combination of all features. Moreover, the classification results combining all features are dominated by DCE-MRI features alone. CONCLUSION: The combination of DWI and DCE-MRI does not show a potential to dramatically increase the sensitivity and specificity of breast MRI. DCE-MRI alone gave the same performance as in combination with DW-MRI.

BMI and breast cancer prognosis benefit: mammography screening reveals differences between normal weight and overweight women.

OBJECTIVES: Few studies are available on the potential impact of body weight on breast cancer prognosis in screen-detected patients. Moreover, it is not known whether body mass index (BMI) could have a different prognostic impact in screen-detected versus symptomatic breast cancer patients. To investigate these unsolved issues, we carried out a retrospective study evaluating the effect of BMI on breast cancer prognosis in screen-detected vs symptomatic breast cancer patients. MATERIALS AND METHODS: We conducted a follow-up study on 448 women diagnosed with incident, histologically-confirmed breast cancer. Patients were categorized according to their BMI as normal weight, overweight and obese. Disease free survival (DFS), overall survival (OS), and BMI curves were compared according to mode of cancer detection. RESULTS: Among screen-detected patients, higher BMI was associated with a significant lower DFS, whereas no significant difference was observed among symptomatic patients. OS showed similar results. In the multivariate analysis adjusting for age, education, tumor size, nodal status, estrogen receptor (ER), progesterone receptor (PR) and menopausal status, the risk for high level of BMI among screen-detected patients did not reach the statistical significance for either recurrence or survival. CONCLUSION: Our study highlights the potential impact of high bodyweight in breast cancer prognosis, the findings confirm that obesity plays a role in women breast cancer prognosis independently from diagnosis mode.

Anthropometric, metabolic and molecular determinants of human epidermal growth factor receptor 2 expression in luminal B breast cancer.

Genomic and trascriptomic profiling has recently contributed details to the characterization of luminal B breast cancer. We explored the contribution of anthropometric, metabolic, and molecular determinants to the multifaceted heterogeneity of this breast cancer subtype, with a specific focus on the association between body mass index (BMI), pre-treatment fasting glucose, hormone receptors, and expression of human epidermal growth factor receptor 2 (HER2). Extensively annotated specimens were obtained from 154 women with luminal B breast cancer diagnosed at two Italian comprehensive cancer centres. Participants' characteristics were descriptively analyzed overall and by HER2 status (positive vs. negative). BMI (<25 vs ≥25), pre-treatment fasting glucose (

Metabolic syndrome-breast cancer link varies by intrinsic molecular subtype.

BACKGROUND: Metabolic syndrome (MS) has been shown to increase the risk of breast cancer. Existing data suggest that the strength of metabolic syndrome-breast cancer link varies by intrinsic molecular subtype, but results from worldwide literature are controversial. Primary endpoint of the study was to assess whether MS is a predictor of specific breast cancer (BC) subtype. Secondary endpoint was to determine whether components of MS can individually increase the risk of specific breast cancer subtype. METHODS: Anthropometric and metabolic variables were correlated to breast cancer specific subgroups, retrospectively. Statistical significance was considered when p ≤ 0.05 and 95% CI. RESULTS: Data analysis suggests that MS per se represents a modifiable risk factor for BC in postmenopausal [OR 6.28 (95% CI 2.79-14.11) p < 0.00001]. MS per se prevalence is higher among Luminal breast cancers in postmenopausal [OR 1.37 (95% CI 1.07-2.80) p = 0.03]. Body Mass Index (BMI) alone is associated to Luminal A subtype breast cancer risk [OR 1.12 (95% CI 0.96-2.196 p = 0.2]. Waist Circumference > 88 cm has been shown to be specifically and statistically significant associated to HER-2+ breast cancer subtypes in postmenopausal [OR 2.72 (95% CI 1.69- 10.72) p = 0.01], whilst in Luminal B it was only marginally statistical associated [OR 2.21 (95% CI 0.77-2.60) p = 0.1]. Insulin resistance showed statistical significant association to HER-2+ and Luminal B tumors [OR 2.11 (95% CI 1.66-6.69) p = 0.05] and [OR 2.33 (95% CI 1.2-4.2) p = 0.006], respectively. Hence, it has emerged that BMI is weakly associated to Luminal A breast cancers in this case series, whereas visceral obesity and insulin resistance are likely to be linked to more aggressive breast cancer subtypes. CONCLUSIONS: New molecular biomarkers unveiling metabolic syndrome related breast carcinogenesis need to be detected to further stratify breast cancer risk by subtypes.

Combination of inositol and alpha lipoic acid in metabolic syndrome-affected women: a randomized placebo-controlled trial.

BACKGROUND: Inositol has been reported to improve insulin sensitivity since it works as a second messenger achieving insulin-like effects on metabolic enzymes. The aim of this study was to evaluate the inositol and alpha lipoic acid combination effectiveness on metabolic syndrome features in postmenopausal women at risk of breast cancer. METHODS: A six-month prospective, randomized placebo-controlled trial was carried out on a total of 155 postmenopausal women affected by metabolic syndrome at risk of breast cancer, the INOSIDEX trial. All women were asked to follow a low-calorie diet and were assigned randomly to daily consumption of a combination of inositol and alpha lipoic acid (77 pts) or placebo (78 pts) for six months. Primary outcomes we wanted to achieve were both reduction of more than 20% of the HOMA-IR index and of triglycerides serum levels. Secondary outcomes expected were both the improvement of high-density lipoprotein cholesterol levels and the reduction of anthropometric features such as body mass index and waist-hip ratio. RESULTS: A significant HOMA-IR reduction of more than 20% was evidenced in 66.7% (P <0.0001) of patients, associated with a serum insulin level decrease in 89.3% (P <0.0000). A decrease in triglycerides was evidenced in 43.2% of patients consuming the supplement (P <0.0001). An increase in HDL cholesterol (48.6%) was found in the group consuming inositol with respect to the placebo group. A reduction in waist circumference and waist-hip ratio was found in the treated group with respect to the placebo group. CONCLUSIONS: Inositol combined with alpha lipoic acid can be used as a dietary supplement in insulin-resistant patients in order to increase their insulin sensitiveness. Daily consumption of inositol combined with alpha lipoic acid has a significant bearing on metabolic syndrome. As metabolic syndrome is considered a modifiable risk factor of breast tumorigenesis, further studies are required to assess whether inositol combined with alpha lipoic acid can be administered as a dietary supplement in breast cancer primary prevention. TRIAL REGISTRATION: Current Controlled Trial ISRCTN74096908.

Surgical impact of preoperative breast MRI in women below 40 years of age.

Our aim was to evaluate the surgical impact of preoperative MRI in young patients. We reviewed a single-institution database of 283 consecutive patients below 40 years of age and who were treated for breast cancer. Thirty-seven (13 %) patients who received neoadjuvant chemotherapy were excluded. The remaining 246 patients included 124 (50 %) who preoperatively underwent conventional imaging (CI), i.e., mammography/ultrasonography (CI-group), and 122 (50 %) who underwent CI and dynamic MRI (CI + MRI-group). Pathology of surgical specimens served as a reference standard. Mann-Whitney, χ (2), and McNemar statistics were used. There were no significant differences between groups in terms of age, tumor pathologic subtype, stage, receptor, or nodal status. The mastectomy rate was 111/246 (45 %) overall but was significantly different between groups (46/124, 37 %, for the CI group and 65/122, 53 %, for the CI + MRI group; p = 0.011). Of 122 CI + MRI patients, 46 (38 %) would have undergone mastectomy due to CI alone, while MRI determined 19 additional mastectomies, increasing the mastectomy rate from 38 % to 53 % (p < 0.001). The number of patients with multifocal, multicentric, synchronous, or bilateral cancers was significantly different between groups (10/124, 8 %, for the CI group and 33/122, 27 %, for the CI + MRI group; p < 0.001). In the CI + MRI group, multifocal, multicentric, or synchronous bilateral cancers were detected with mammography in 5/33 (15 %) patients, with ultrasonography in 15/33 (45 %) patients, and with MRI in 32/33 (97 %) patients (p < 0.005). Two mastectomies were due to false positives at both conventional tests in the CI group (2/124, 1.6 %) and two mastectomies were due to MRI false positives in the CI + MRI group (2/122, 1.6 %). In conclusion, breast cancer in young patients was treated with mastectomy in 37-38 % of cases on the basis of CI only and in these patients MRI was more sensitive than CI for multifocal, multicentric, or synchronous bilateral cancers, resulting in an additional mastectomy rate of 15 %. A low probability of inappropriate imaging-based decision-making for mastectomy exists for both CI alone and for CI + MRI, making presurgical needle biopsy mandatory for findings that suggest a need for mastectomy.

Homeostasis model assessment to detect insulin resistance and identify patients at high risk of breast cancer development: National Cancer Institute of Naples experience.

BACKGROUND: Metabolic Syndrome (MS) has been correlated to breast carcinogenesis. MS is common in the general population (34%) and increases with age and body mass index. Although the link between obesity, MS and hormone related cancer incidence is now widely recognized, the molecular mechanisms at the basis of such increase are still poorly characterized. A crucial role is supposed to be played by the altered insulin signalling, occurring in obese patients, which fuels cancer cell growth, proliferation and survival. Therefore we focused specifically on insulin resistance to investigate clinically the potential role of insulin in breast carcinogenesis. METHODS: 975 patients were enrolled and the association between MS, insulin resistance, and breast cancer was evaluated. Women were stratified by age and menopausal status. Insulin resistance was measured through the Homeostasis Model Assessment score (HOMA-IR). The cut off value to define insulin resistance was HOMA-IR ≥ 2.50. RESULTS: Higher prevalence of MS (35%) was found among postmenopausal women with breast cancer compared to postmenopausal healthy women (19%) [OR 2.16]. A broad range of BMI spanning 19-48 Kg/m2 was calculated. Both cases and controls were characterized by BMI ≥ 25 Kg/m2 (58% of cases compared to 61% of controls). Waist circumference >88 cm was measured in 53% of cases - OR 1.58- (95% CI 0.8-2.8) and in 46% of controls. Hyperinsulinemia was detected in 7% of cases - OR 2.14 (95% CI 1.78-2.99) and only in 3% of controls. HOMA-IR score was elevated in 49% of cases compared to 34% of controls [OR 1.86], suggesting that insulin resistance can nearly double the risk of breast cancer development. Interestingly 61% of women operated for breast cancer (cases) with HOMA-IR ≥ 2.5 presented subclinical insulin resistance with fasting plasma glucose levels and fasting plasma insulin levels in the normal range. Both android fat distribution and insulin resistance correlated to MS in the subgroup of postmenopausal women affected by breast cancer. CONCLUSIONS: Our results further support the hypothesis that MS, in particular insulin resistance and abdominal fat, can be considered as risk factors for developing breast cancer after menopause. We suggest that HOMA-IR, rather than fasting plasma glucose and fasting plasma insulin levels alone, could be a valuable tool to identify patients with subclinical insulin resistance, which could be relevant for primary prevention and for high risk patient screening.

Molecular profiles of screen detected vs. symptomatic breast cancer and their impact on survival: results from a clinical series.

BACKGROUND: Stage shift is widely considered a major determinant of the survival benefit conferred by breast cancer screening. However, factors and mechanisms underlying such a prognostic advantage need further clarification. We sought to compare the molecular characteristics of screen detected vs. symptomatic breast cancers and assess whether differences in tumour biology might translate into survival benefit. METHODS: In a clinical series of 448 women with operable breast cancer, the Kaplan-Meier method and the log-rank test were used to estimate the likelihood of cancer recurrence and death. The Cox proportional hazard model was used for the multivariate analyses including mode of detection, age at diagnosis, tumour size, and lymph node status. These same models were applied to subgroups defined by molecular subtypes. RESULTS: Screen detected breast cancers tended to show more favourable clinicopathological features and survival outcomes compared to symptomatic cancers. The luminal A subtype was more common in women with mammography detected tumours than in symptomatic patients (68.5 vs. 59.0%, p=0.04). Data analysis across categories of molecular subtypes revealed significantly longer disease free and overall survival for screen detected cancers with a luminal A subtype only (p=0.01 and 0.02, respectively). For women with a luminal A subtype, the independent prognostic role of mode of detection on recurrence was confirmed in Cox proportional hazard models (p=0.03). An independent role of modality of detection on survival was also suggested (p=0.05). CONCLUSIONS: Molecular subtypes did not substantially explain the differences in survival outcomes between screened and symptomatic patients. However, our results suggest that molecular profiles might play a role in interpreting such differences at least partially.Further studies are warranted to reinterpret the efficacy of screening programmes in the light of tumour biology.

Metabolic syndrome affects breast cancer risk in postmenopausal women: National Cancer Institute of Naples experience.

Postmenopausal women show the highest incidence of breast cancer in the female population and are often affected by metabolic syndrome. Metabolic syndrome (MS)--characterized by central adiposity, insulin resistance, low serum high-density lipoprotein cholesterol (HDL-C), high serum triglyceride and high blood pressure--seems to be strictly correlated to breast carcinogenesis. We enrolled 777 healthy women and women with breast cancer in our nested case-control study to evaluate the association between MS and breast cancer, analyzing anthropometric parameters (weight, height, BMI, waist and hip circumference), blood pressure, serum HDL-C, triglyceride, fasting plasma glucose, insulin, testosterone and uric acid levels and administering a questionnaire about physical activity, food intake, tobacco use, alcohol abuse, personal and familial history of disease. We found an higher prevalence of metabolic syndrome (30%) in postmenopausal breast cancer patients compared to healthy women (19%). None of the individual MS features was strong enough to be considered responsible for breast carcinogenesis alone. However, of the 63 postmenopausal breast cancer cases associated to MS, 30% presented three or more MS features, suggesting that the activation of multiple molecular pathways underlying MS might contribute to tumorigenesis. Our data support the hypothesis that MS may be an indicator of breast cancer risk in postmenopausal women. The unsettlement of the hormonal arrangement in postmenopausal, along with an increase in visceral adiposity, probably favour the hormone-dependent cell proliferation, which drives tumorigenesis. Adjustments in lifestyle with physical activity intensification and healthy diet could represent modifiable factors for the primary prevention of sporadic breast cancer.

Gail model risk factors: impact of adding an extended family history for breast cancer.

An approach commonly used in estimating breast cancer risk is the Gail model. The objective of this study was to evaluate the feasibility and impact of adding extended family history as a new breast cancer risk factor into the Gail model. The data of the present study include cases with breast cancer and hospitalized controls recruited in the National Cancer Institute of Naples (southern Italy) between 1997 and 2000. We compared the first-degree relative (FDR) risk factor (standard Gail model) with the second-degree relative (SDR) information; and the FDR risk factor (standard Gail model) with the combination of FDR and SDR. We computed the c-statistic by comparing the risks found in our population to those in Gail-US population. The concordance for the model with FDR was 0.55 (95% CI 0.53-0.58), the model with SDR shows a modest but significant discriminatory accuracy (0.56, 95% CI 0.53-0.59), and the combination of FDR+SDR gave the concordance statistic of 0.57 (95% CI 0.54-0.60), indicating a good comparison between the two models. The results of our study show that extended family history information could be useful to improve the discriminatory power of the Gail model risk factors.

Compliance and toxicity of adjuvant CMF in elderly breast cancer patients: a single-center experience.

BACKGROUND: Few data are available on compliance and safety of adjuvant chemotherapy when indicated in elderly breast cancer patients; CMF (cyclophosphamide, methotrexate, fluorouracil) can be reasonably considered the most widely accepted standard of treatment. METHODS: We retrospectively reviewed compliance and safety of adjuvant CMF in patients older than 60. The treatment was indicated if patients had no severe comorbidity, a high-risk of recurrence, and were younger than 75. Toxicity was coded by NCI-CTC. Toxicity and compliance were compared between two age subgroups (< 65, > or = 65) by Fisher exact test and exact Wilcoxon rank-sum test. RESULTS: From March 1991 to March 2002, 180 patients were identified, 100 older than 60 and younger than 65, and 80 aged 65 or older. Febrile neutropenia was more frequent among older patients (p = 0.05). Leukopenia, neutropenia, nausea, cardiac toxicity and thrombophlebitis tended to be more frequent or severe among elderlies, while mucositis tended to be more evident among younger patients, all not significantly. Almost one half (47%) of the older patients receiving concomitant radiotherapy experienced grade 3-4 haematological toxicity. Compliance was similar in the two groups, with 6 cycles administered in 86% and 79%, day-8 chemotherapy omitted at least once in 36% and 39%, dose reduction in 27% and 38%, prolonged treatment duration (> or = 29 weeks) in 10% and 11% and need of G-CSF in 9% and 18%, among younger and older patients, respectively. CONCLUSION: Our data show that, in a highly selected population of patients 65 or more years old, CMF is as feasible as in patients older than 60 and younger than 65, but with a relevant burden of toxicity. We suggest that prospective trials in elderly patients testing less toxic treatment schemes are mandatory before indicating adjuvant chemotherapy to all elderly patients with significant risk of breast cancer recurrence.

Biweekly docetaxel-irinotecan with filgrastim support in pretreated breast and non-small-cell lung cancer patients. A phase I study.

BACKGROUND: Docetaxel (DTX) has been shown to be a very active drug in both breast cancer (BC) and non-small-cell lung cancer (NSCLC). Irinotecan (CPT-11) is also active in NSCLC, and has shown promising antitumor activity in pretreated BC. PURPOSE. To define the MTDs of these two drugs given together every other week with the use of filgrastim support in pretreated BC and NSCLC patients. PATIENTS AND METHODS: Patients (aged 18-70 years, performance status < or =2) with advanced NSCLC or BC who had received at least one prior chemotherapy regimen were candidates for this phase I study. The starting DTX and CPT-11 doses were 60 mg/m(2) and 80 mg/m(2). Doses were alternately escalated at each step by 10 mg/m(2) for both drugs. Filgrastim 300 microg/day was given subcutaneously from days 4 through 7 of each cycle. RESULTS: From April 2000, 41 patients were included in the trial (27 BC, 14 NSCLC). All BC patients had received epirubicin plus paclitaxel (with or without cisplatin) as first-line treatment. Of the 14 NSCLC patients, 12 had received cisplatin-based first-line therapy, and 8 patients had been pretreated with paclitaxel. The dose escalation proceeded through five dose levels up to DTX and CPT-11 doses of 80 mg/m(2) and 100 mg/m(2), respectively. Overall, ten patients showed dose-limiting toxicity during the first cycle, diarrhea in seven and neutropenia in the remaining three. Considering all 218 cycles delivered, grade 3 or 4 neutropenia occurred in 14 patients (34%), with only one episode of neutropenic fever, while severe diarrhea was observed in 9 patients (23%). A total of 21 objective responses were registered (four complete) for an overall response rate of 51% [95% CI 35-67]. A major response was seen in 16 of the 27 BC patients (59%) and in 5 of the 14 NSCLC patients (36%). CONCLUSIONS: DTX and CPT-11 can be safely given together biweekly at adequate doses, with filgrastim support. In view of the promising activity data in both groups, phase II studies testing this combination in pretreated BC and NSCLC patients are ongoing.

Intragenic amplification and formation of extrachromosomal small circular DNA molecules from the PIP gene on chromosome 7 in primary breast carcinomas.

The PIP gene is expressed in exocrine glands and, in pathologic conditions, in breast cysts and breast cancers exhibiting apocrine features. It is localized on the long arm of chromosome 7, a region frequently alterated in mammary tumors. We previously described an abnormal restriction pattern of the PIP gene in 33% of prostate carcinomas analyzed. Here, we analyze the structure of the PIP gene in primary breast carcinomas. We report that part of the 3' end, including exon 3, intron C, two-thirds of exon 4 and a small portion of intron B, is amplified and involved in the formation of extrachromosomal spcDNA molecules in 3/14 (21.4%) breast cancers analyzed. The involvement of a well-defined intragenic region of a gene in the formation of spcDNA appears to be unprecedented. Since spcDNA has been suggested to serve as an enhancer of genetic instability, the PIP gene may be the target of genomic variability processes in breast cancer.

A phase I-II study on a gemcitabine-cyclophosphamide-fluorouracil/folinic acid triplet combination in anthracycline- and taxane-refractory breast cancer patients.

PURPOSE: To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes. METHODS: Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned. RESULTS: Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61). CONCLUSIONS: The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients.