A multicenter high-quality data registry for advanced proton therapy approaches: the POWER registry.

BACKGROUND: Paucity and low evidence-level data on proton therapy (PT) represent one of the main issues for the establishment of solid indications in the PT setting. Aim of the present registry, the POWER registry, is to provide a tool for systematic, prospective, harmonized, and multidimensional high-quality data collection to promote knowledge in the field of PT with a particular focus on the use of hypofractionation. METHODS: All patients with any type of oncologic disease (benign and malignant disease) eligible for PT at the European Institute of Oncology (IEO), Milan, Italy, will be included in the present registry. Three levels of data collection will be implemented: Level (1) clinical research (patients outcome and toxicity, quality of life, and cost/effectiveness analysis); Level (2) radiological and radiobiological research (radiomic and dosiomic analysis, as well as biological modeling); Level (3) biological and translational research (biological biomarkers and genomic data analysis). Endpoints and outcome measures of hypofractionation schedules will be evaluated in terms of either Treatment Efficacy (tumor response rate, time to progression/percentages of survivors/median survival, clinical, biological, and radiological biomarkers changes, identified as surrogate endpoints of cancer survival/response to treatment) and Toxicity. The study protocol has been approved by the IEO Ethical Committee (IEO 1885). Other than patients treated at IEO, additional PT facilities (equipped with Proteus®ONE or Proteus®PLUS technologies by IBA, Ion Beam Applications, Louvain-la-Neuve, Belgium) are planned to join the registry data collection. Moreover, the registry will be also fully integrated into international PT data collection networks.

Outcome of patients with metastatic triple negative breast cancer treated with first-line chemotherapy: a single institution retrospective analysis.

PURPOSE: Metastatic triple negative breast cancer (mTNBC) is associated with poor prognosis and limited treatment options. It is known to be high immunogenic, with a high level of programmed cell death-ligand 1 (PD-L1) expression. PD-L1 expression in TNBC does not have a clear prognostic relevance. In this study, we aimed to assess survival outcomes according to PD-L1 expression in the real world. METHODS: We retrospectively analyzed mTNBC patients treated with first-line chemotherapy at European Institute of Oncology with evaluable PD-L1 expression. Primary endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) according to PD-L1 expression. RESULTS: From January 2000 to December 2018, 190 patients fulfilled the inclusion criteria for final analysis. PD-L1 positive (≥ 1%) subgroup showed a median PFS of 6.8 vs 5.6 months in PD-L1 negative subgroup (PFS-HR 1.25, 95% CI 0.89-1.74, p-value = 0.191), while at data cutoff we had 120 deaths in the PD-L1 < 1% population with a median OS of 22.1 months and 42 deaths in PD-L1 positive patients with a median OS of 20.8 months (OS-HR 1.09, 95% CI 0.76-1.55, p-value = 0.64). No difference in PFS and OS was related to the choice of chemotherapy (p-value for PFS: 0.19, p-value for OS: 0.53). CONCLUSION: No differences in clinical outcome were found according to PD-L1 status or chemotherapy regimen chosen. In "unselected" patients, single agent or combination chemotherapy could be appropriate, although in the immunotherapy era patients with newly diagnosed mTNBC should be routinely tested for PD-L1 status. The variability in PD-L1 expression by metastatic site warrants further investigation.

The prolonged clinical benefit with metronomic chemotherapy (VEX regimen) in metastatic breast cancer patients.

Metronomic chemotherapy is a treatment option for metastatic breast cancer (MBC) patients who require prolonged disease control without cumulative toxicity. Data available on the efficacy and tolerability of prolonged usage of metronomic therapy are limited. We analyzed patients with MBC, enrolled in a clinical trial, who obtained a prolonged clinical benefit for a duration of at least 12 months with vinorelbine 30 or 40 mg orally three times a week, cyclophosphamide 50 mg daily and capecitabine 500 mg three times a day (VEX regimen). The patients were treated at the European Institute of Oncology, Milan. We identified 67 MBC patients. The median age before starting the VEX regimen was 53 years. There were 59 patients (88%) who had hormone-receptors positive and HER2 negative BC. We had 37 patients who received VEX as the first-line treatment for MBC, while 30 patients were pretreated. The objective response rate was 49% (95% CI, 37-62). The median duration of VEX treatment after the first year was 14 months (min-max range 0.3-81.3 months). The progression-free survival at 3 years was 25.4% (95% CI, 15.7-36.2) and at 4 years was 18.5% (95% CI, 10.1-28.8 time 0 corresponds to 1 year after starting VEX). A total of 25 patients required a dose reduction, 7% of patients experienced G3 hand and foot syndrome. Metronomic VEX regimen can induce prolonged clinical benefit in MBC. On the basis of this long-term safety evaluation, there is no evidence of specific cumulative or delayed toxicities with metronomic chemotherapy.

Endocrine-responsive lobular carcinoma of the breast: features associated with risk of late distant recurrence.

BACKGROUND: Invasive lobular carcinomas (ILCs) account for 10-15% of all breast cancers. They are characterized by an elevated endocrine responsiveness and by a long lasting risk of relapse over time. Here we report for the first time an analysis of clinical and pathological features associated with the risk of late distant recurrence in ILCs. PATIENTS AND METHODS: We retrospectively analyzed all consecutive patients with hormone receptor-positive ILC operated at the European Institute of Oncology (EIO) between June 1994 and December 2010 and scheduled to receive at least 5 years of endocrine treatment. The aim was to identify clinical and pathological variables that provide prognostic information in the period beginning 5 years after definitive surgery. The cumulative incidence of distant metastases (CI-DM) from 5 years after surgery was the prospectively defined primary endpoint. RESULTS: One thousand eight hundred seventy-two patients fulfilled the inclusion criteria. The median follow-up was 8.7 years. Increased tumor size and positive nodal status were significantly associated with higher risk of late distant recurrence, but nodal status had a significant lower prognostic value in late follow-up period (DM-HR, 3.21; 95% CI, 2.06-5.01) as compared with the first 5 years of follow-up (DM-HR, 9.55; 95% CI, 5.64-16.2; heterogeneity p value 0.002). Elevated Ki-67 labeling index (LI) retained a significant and independent prognostic value even after the first 5 years from surgery (DM-HR, 1.81; 95% CI 1.19-2.75), and it also stratified the prognosis of ILC patients subgrouped according to lymph node status. A combined score, obtained integrating the previously validated Clinical Treatment Score post 5 years (CTS5) and Ki-67 LI, had a strong association with the risk of late distant recurrence of ILCs. CONCLUSION: We identified factors associated with the risk of late distant recurrence in ER-positive ILCs and developed a simple prognostic score, based on data that are readily available, which warrants further validation.

Presence and activities of clinical research coordinators at Italian Health Care Institutions: A national cross-sectional survey.

BACKGROUND: Clinical Research Coordinators (CRCs) are key members of research teams who ensure rigorous conduction of clinical studies and quality standard compliance. Yet, their roles and responsibilities are still not well defined, and formal recognition of their professional profile is lacking in Italy. This survey of Italian healthcare institutions collected data on centers' research activities number of CRCs and tasks they performed and explored factors associated with CRC employment. METHODS: Cross-sectional study using a brief questionnaire. Data were analyzed by means of graphical representations, histogram, scatter, and polar plots. Multivariable linear regression was specified to test the association between the number of CRCs and a subset of factors. RESULTS: Data collection took place from February to December 2020. 62/143 institutions (43.4%) responded. Median number of ongoing studies reported by centers was 65 (IQR 29-205); of these, median of sponsored and interventional studies was 32 and 35, respectively. Median number of CRCs employed at each center was 6 (IQR 2-9). The frequency with which activities were reported to be performed by CRCs overlapped with those of Data Managers. Linear multivariable regression analysis revealed a statistically significant association between the number of employed CRCs and the number of sponsored studies (P = 0.01), but not with the total number of studies, geographical location, or institution type. CONCLUSIONS: The association between industry funding and the number of CRCs observed in this study should be further explored to understand the direction of this relationship and to verify whether this may influence compliance with quality standards.

No impact of central venous insertion site on oncology patients' quality of life and psychological distress. A randomized three-arm trial.

PURPOSE: Though totally implantable access ports (TIAP) are extensively used, information from randomized trials about the impact of insertion site on patient's quality of life (QoL) and psychological distress is unavailable. PATIENTS AND METHODS: Four hundred and three patients eligible for receiving intravenous chemotherapy for solid tumours were randomly assigned to implantation of a single type of TIAP, either through a percutaneous landmark access to the internal jugular or an ultrasound-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Patients' QoL and psychological distress were investigated at regular intervals by means of EORTC QLQ-C30 and HADS (Hospital Anxiety and Depression Scale) questionnaires, using univariate and multivariate repeated measure linear mixed models. A post hoc analysis investigated the impact of type of administered chemotherapy (adjuvant vs palliative). RESULTS: Three hundred and eighty-four patients (95.2%) were evaluable, 126 with the internal jugular, 132 with the subclavian and 126 with the cephalic vein access. The median follow-up was 361 days (range, 0-1,087). Mean score changes for the items of the EORTC QLQ-C30 scales were significantly associated with type of administered chemotherapy only (P < 0.001), and not with implantation site. Frequency distribution of patients with depression and anxiety score greater than 10 at HADS was not significantly different, with respect either to type of administered chemotherapy or TIAP implantation site. CONCLUSION: Central venous insertion sites had no impact on patients' QoL and psychological distress. Patients undergoing palliative therapies showed worse EORTC QLQ-C30 scales.

Biological and clinical features of triple negative Invasive Lobular Carcinomas of the breast. Clinical outcome and actionable molecular alterations.

BACKGROUND: We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) METHODS: We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012. Primary objective was to assess the invasive disease-free survival(iDFS). Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene. Additionally, DNA mutational status of an independent cohort of 45 TN-ILCs from three databases were analyzed, to confirm mutations in ERBB2-gene and to identify other recurrently mutated genes. RESULTS: Among 4152 ILCs, 74(1.8%) were TN and were analyzed. The iDFS at 5 and 10 years of FUP were 50.4%(95%CI,38.0-61.6) and 37.2%(95%CI,25.5-48.8), respectively. The molecular subtype was defined through PAM50-classifier for 31 out of 74 TN-ILCs: 48% were Luminal-A(15/31), 3% luminal-B(1/31), 32% HER2-enriched (10/31), and only 16% basal-like(5/31). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 94% of luminal tumors versus 53% in non-luminal tumors; p-value = 0.001). 20% of TN-ILCs analyzed(7/35), harbored a pathogenetic and actionable mutation in the ERBB2-gene. Analysis of the independent cohort of 45 TN-ILCs from three different databases, confirmed similar percentage of pathogenetic and actionable mutations in ERBB2-gene(20%; 9/45). Among the top 10 molecular pathways significantly enriched for recurrently mutated genes in TN-ILCs(FDR<0.05), there were ErbB-signaling and DNA-damage-response pathways. CONCLUSIONS: TN-ILCs are rare tumors with poor prognosis. Their specific biological features require newly defined targeted therapeutic strategies.

Continuity of Cancer Care: The Surgical Experience of Two Large Cancer Hubs in London and Milan.

The SARS-CoV-2 (COVID-19) pandemic is having a large effect on the management of cancer patients. This study reports on the approach and outcomes of cancer patients receiving radical surgery with curative intent between March and September 2020 (in comparison to 2019) in the European Institute of Oncology, IRCCS (IEO) in Milan and the South East London Cancer Alliance (SELCA). Both institutions implemented a COVID-19 minimal pathway where patients were required to self-isolate prior to admission and were swabbed for COVID-19 within 72 h of surgery. Positive patients had surgery deferred until a negative swab. At IEO, radical surgeries declined by 6% as compared to the same period in 2019 (n = 1477 vs. 1560, respectively). Readmissions were required for 3% (n = 41), and <1% (n = 9) developed COVID-19, of which only one had severe disease and died. At SELCA, radical surgeries declined by 34% (n = 1553 vs. 2336). Readmissions were required for 11% (n = 36), <1% (n = 7) developed COVID-19, and none died from it. Whilst a decline in number of surgeries was observed in both centres, the implemented COVID-19 minimal pathways have shown to be safe for cancer patients requiring radical treatment, with limited complications and almost no COVID-19 infections.

Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy.

The predictive role of the degree of endocrine responsiveness to preoperative chemotherapy (PCT) is unclear. We reviewed pretreatment biopsies of 553 patients with locally advanced breast cancer who were treated with PCT. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to the degree of estrogen (ER) and progesterone receptor (PgR) expression (ER and PgR absent, vs. ER or PgR 0-49%, vs. ER and PgR >or=50% of the cells positive). A statistically significant higher pCR rate was observed at the multivariate analysis for patients with ER and PgR absent tumors (17.7%) versus patients with tumors expressing high ER and PgR (0%) (OR 14.4 P < 0.001). Despite the higher incidence of pCR, a statistically significant worse disease-free survival (DFS), and overall survival (OS) was observed for patients with ER and PgR absent tumors versus patients with tumors expressing high ER and PgR (HR 6.4, 95% CI 3.5-11.6, for DFS; HR 3.6 95% CI 2.4-5.6 for OS). Response and outcome after PCT are correlated with the degree of expression of steroid hormone receptors. Studies on tailored preoperative therapies are needed.

Role of endocrine responsiveness and HER2/neu overexpression in inflammatory breast cancer treated with multimodality preoperative therapy.

We analyzed the role of endocrine responsiveness and HER2/neu overexpression in inflammatory breast cancer treated with multimodality preoperative therapy. Thirty-eight patients (estrogen receptor [ER] and/or progesterone receptor [PgR] >or=10% of the cells 21, premenopausal 14, Ki-67 expression >or=20% of the cells 30, HER2/neu overexpressed 11) were treated with six courses of epirubicin, cisplatin and fluorouracil (FU) as continuous infusion, perioperative FU as continuous infusion, mastectomy and loco-regional radiotherapy. In endocrine-responsive patients, endocrine treatment (letrozole, either alone or if premenopausal with triptorelin) was given preoperatively and as adjuvant treatment. There were 32 objective responders (84.2%; 95% CI 70.0-94.6%), three of whom had pathologic complete remission. At the multivariate analysis disease-free survival was significantly worse in patients with ER and PgR absent tumors compared with the positive expression cohort (hazards ratio [HR]: 5.91; 95% CI 1.69-20.7; p = 0.005), in particular if HER2/neu overexpression was detected (HR: 16.5; 95% CI 4.24-64.5; p < 0.0001). New multimodality and targeted strategies should be explored in endocrine nonresponsive breast cancer.

Multiple primary non-breast tumors in breast cancer survivors.

PURPOSE: The aim of this study was to assess the frequency of second primary non-breast cancer after breast cancer diagnosis and treatment, and its correlation with clinicopathological features. METHODS: Data from 21,527 patients with primary breast cancer were collected retrospectively in a single cancer centre; 4.1% of the women developed a second non-breast cancer. The most frequently observed second primary tumor affected the digestive tract (27.8%). The frequency of observed cancers was similar to that expected in the general population, excepting for an excess of melanoma [SIR 1.98 (1.52-2.53)], uterine cancers [SIR 1.44 (1.17-1.74)], ovarian cancers [SIR 1.67 (1.31-2.10)], thyroid tumors [SIR 1.54 (1.23-1.92)], and leukemia [SIR 1.57 (1.11-2.16)]. RESULTS: Clinicopathological breast cancer stratification showed a general increased risk of developing a second cancer in older patients, excluding ovarian cancer. An increased risk of developing ovarian cancer after breast cancer diagnosis was observed, in particular, in triple-negative [HR 3.47 (1.91-6.29)], G3 tumors [HR 2.54 (1.10-5.83)] and in positive breast cancer family history [HR 2.19 (1.22-3.94)]. Breast cancer survivors in hormonal therapy treatment are at higher risk for developing a second thyroid cancer [HR 4.00 (1.46-10.9)]. Conversely, adjuvant chemotherapy offered a protective effect on thyroid cancer risk development [HR 0.46 (0.28-0.76)]. CONCLUSIONS: Older age represents the major risk of developing a second primary non-breast cancer, excluding ovarian cancer. Clinical surveillance is required to prevent ovarian and thyroid cancers, respectively, in patients with positive family history, triple negative, G3 breast cancer and during hormonal therapy treatment in postmenopausal status.

Primary therapy with ECF in combination with a GnRH analog in premenopausal women with hormone receptor-positive T2-T4 breast cancer.

Patients with hormone receptor-positive tumors less often show a pathological complete response (pCR) than do those with hormone receptor-negative tumors. The addition of endocrine therapies may improve the clinical benefits of primary therapies in these patients. We investigated the efficacy of the epirubicin+cisplatin+fluorouracil (ECF) as continuous infusion) regimen in association with a gonadotropin-releasing hormone (GnRH) analog in 36 premenopausal women with T2-T4a-d N0-2 M0 ER and/or PgR-positive breast cancer. Median age was 39.5 years (range 26-53). Clinical response (complete or partial) was observed in 27 out of 36 patients (75% 95% CI 57.8-87.9%) and a pCR was observed in four patients (11%). Nine (25%) patients had stable disease and no progression was observed. Twenty-one patients (58%) were submitted for breast-conserving surgery and 15 had a radical mastectomy. No baseline clinical and biological characteristics significantly correlated with response. Thirty out of 31 patients evaluable for endocrine assessment had documented ovarian suppression, which occurred after a median of 28 days (range 20-43). We conclude that the combination of ECF and a GnRH analog is associated with a high response rate in the primary treatment of breast cancer. Further studies combining chemotherapy and endocrine agents are warranted in patients with hormone receptor-positive tumors.

Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement.

BACKGROUND: Overt ipsilateral axillary lymph node metastases of breast cancer are the most significant prognostic indicators for women who have undergone surgery, yet the clinical relevance of minimal involvement (isolated tumor cells and micrometastases) of these nodes is uncertain. PATIENTS AND METHODS: We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000. RESULTS: Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases). CONCLUSION: Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.

Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer.

BACKGROUND: HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC). METHODS: Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM). RESULTS: The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for > or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade > or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively. CONCLUSION: The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.

Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment.

PURPOSE: The purpose of this research was to identify factors predicting response to preoperative chemotherapy. EXPERIMENTAL DESIGN: In a large volume laboratory using standard immunohistochemical methods, we reviewed the pretreatment biopsies and histologic specimens at final surgery of 399 patients with large or locally advanced breast cancer (cT2-T4, N0-2, M0) who were treated with preoperative chemotherapy. The incidence of pathological complete remission and the incidence of node-negative status at final surgery were assessed with respect to initial pathological and clinical findings. Menopausal status, estrogen receptor status, progesterone receptor status [absent (0% of the cells positive) versus expressed], clinical tumor size, histologic grade, Ki-67, Her-2/neu expression, and type and route of chemotherapy were considered. RESULTS: High rates of pathological complete remission were associated with absence of estrogen receptor and progesterone receptor expression (P < 0.0001), and grade 3 (P = 0.001). Significant predictors of node-negative status at surgery were absence of estrogen receptor and progesterone receptor expression (P < 0.0001), clinical tumor size <5 cm (P < 0.001), and use of infusional regimens (P = 0.003). The chance of obtaining pathological complete remission or node-negative status for patients with endocrine nonresponsive tumors compared with those having some estrogen receptor or progesterone receptor expression was 4.22 (95% confidence interval, 2.20-8.09, 33.3% versus 7.5%) and 3.47 (95% confidence interval, 2.09-5.76, 42.9% versus 21.7%), respectively. Despite the significantly higher incidence of pathological complete remission and node-negative status achieved by preoperative chemotherapy for patients with estrogen receptor and progesterone receptor absent disease, the disease-free survival was significantly worse for this cohort compared with the low/positive expression cohort (4-year disease-free survival %: 41% versus 74%; hazard ratio 3.22; 95% confidence interval, 2.28-4.54; P < 0.0001). CONCLUSIONS: Response to preoperative chemotherapy is significantly higher for patients with endocrine nonresponsive tumors. New chemotherapy regimens or combinations should be explored in this cohort of patients with poor outcome. For patients with endocrine responsive disease, the role of preoperative endocrine therapies should be studied.

Adjuvant therapy for very young women with breast cancer: response according to biologic and endocrine features.

Incidence of breast cancer in patients aged < 20 years has been estimated to be 0.1 per 100,000 women. Reported incidences are 1.4 for women aged 20-24 years, 8.1 for women aged 25-29 years, and 24.8 for women aged 30-34 years. Younger patients have been found to have a more aggressive presentation of disease at diagnosis, which is associated with dire prognoses compared with those in premenopausal older patients. Several biologic features might explain the more aggressive behavior of breast cancer in younger patients: higher grade and higher expression of Ki67, higher occurrence of vessel invasion, and less expression of estrogen and progesterone receptors. Choice of adjuvant therapies for women aged <35 years with breast cancer is based on data derived from trials on cohorts of older patients. On average, the effect of chemotherapy for premenopausal patients is substantial: recent evidence suggested that very young women with endocrine-responsive tumors had a higher risk of relapse than older premenopausal patients with similar tumors. This was not the case for patients with endocrine-nonresponsive tumors, for which effects of chemotherapy were similar across ages. Very young women with this disease are faced with personal, family, professional, and quality-of-life issues that further complicate the phase of treatment decision-making. The development of more effective therapies for very young women with breast cancer requires tailored treatment investigations and research focused on issues specific to these patients.

Intrathecal chemotherapy in carcinomatous meningitis from breast cancer.

UNLABELLED: Meningeal metastases occur in 2-3% of patients with breast cancer, leading to neurological morbidity and increased mortality. The criteria for treatment choice are controversial and intrathecal chemotherapy (ITC) has no documented role in the management of this disorder. We therefore evaluated the efficacy of an ITC regimen for patients presenting with carcinomatous meningitis from breast cancer. PATIENTS AND METHODS: Patients with meningeal carcinomatosis with or without concomitant parenchymal brain metastasis, were treated with repeated courses of intrathecal chemotherapy according to the following alternated weekly schedule: Day 1: Thiotepa 10 mg, methotrexate 15 mg, hydrocortisone 30 mg; Day 5: cytarabine (Ara-C) 70 mg, methotrexate 15 mg, hydrocortisone 30 mg. Folinic acid 15 mg was given orally, every six hours after methotrexate on days 2-3 and 6-7. RESULTS: Thirteen consecutive patients were treated. The median age was 45 (range 30-67) years. Eleven patients had performance status (PS) 2-3. Nine patients had other metastatic sites; synchronous parenchymal brain metastasis were present in 5 patients. Concomitant systemic chemotherapy was administered in 5 patients and external whole brain radiotherapy in 7 patients. With 12 evaluable patients we observed no responses or improvement in symptoms. Side-effects were minimal. CONCLUSION: In our series of patients, ITC failed to provide objective response or relief in clinical symptoms. Despite evidence reported in the literature indicating symptomatic improvement after ITC in a number of patients with leptomeningeal metastasis, the results of our study confirm the controversial role of ITC. New drugs and new modalities of treatment should be studied in order to efficiently control meningeal involvement of breast cancer.

Preoperative concurrent chemo- and endocrine therapies for women with large operable breast cancer expressing steroid hormone receptors.

Preoperative chemotherapy and endocrine therapy yielded low pathological complete remission (pCR) rates in patients with endocrine responsive breast cancer. Patients with large operable (cT2-T3, N0-2, M0), ER > or =10% breast cancer were treated in two consecutive studies with preoperative chemotherapy (Study I: six courses of either fluorouracil, leucovorin, vinorelbine (FLN), or vinorelbine, cisplatin, and continuous infusion of fluorouracil (ViFuP), at the discretion of the treating physician; Study II: capecitabine and oral vinorelbine (CAVINO)). Concurrent letrozole (in association with triptorelin if premenopause) was given. Sixty-five (58 evaluable) and 55 (all evaluable) patients were enrolled in the two studies. In Study I there were 43 objective responders (74%, 95% CI 63-85%), three of whom had pCR. Thirty-nine objective responses (91%) and all pCR were observed in patients with tumors expressing ER > or =50%. In Study II 34 patients (62%, 95% CI 49-75%) had an objective response. Endocrine therapy administered together with new intravenous, containing regimens should be explored in the preoperative treatment of endocrine responsive breast cancer.

Low-dose aspirin for the prevention of venous thromboembolism in breast cancer patients treated with infusional chemotherapy after insertion of central vein catheter.

BACKGROUND: We previously demonstrated a high incidence (7.7%) of venous thromboembolism (VTE) in breast cancer patients treated with infusional chemotherapy after insertion of central vein catheters (CVC). The aim of this study was to evaluate the efficacy and safety of low-dose aspirin for the prevention of VTE. PATIENTS AND METHODS: In a monocentric prospective study, patients with stage II-IV breast cancer, who underwent CVC insertion for continuous infusional chemotherapy, were assigned to receive low-dose aspirin (100 mg daily). Treatment was started after CVC implantation and continued until the last day of chemotherapy. Patients were assessed for safety and for the incidence of symptomatic deep venous thrombosis (DVT) confirmed by color-Doppler ultrasonography. RESULTS: Between April 2000 and March 2004, 188 consecutive patients were included in the study. Median age was 48 years (range 22-83), 31 patients (16%) had concomitant hypertension, and 14 patients (7.4%) were smokers. Median duration of treatment with aspirin was 3.6 months (range 0.4-5.7). A DVT confirmed by color-Doppler ultrasonography was observed in four patients (2.1%; 95% confidence interval, 0.58-5.35%). Side effects included mild epistaxis (three patients, 1.5%) and mild gastric pain (two patients, 1%). No major bleeding complication or International Normal Ratio alteration occurred. CONCLUSIONS: Administration of low-dose aspirin is safe and seems to correlate with a low risk of DVT in breast cancer patients treated with infusional chemotherapy. Further randomized studies comparing low-dose aspirin with other anticoagulative agents are warranted.