Editta Baldini

Mutational Analysis in Cytological Specimens of Advanced Lung Adenocarcinoma: A Sensitive Method for Molecular Diagnosis

Introduction: The discovery that somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with sensitivity to the EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinomas, whereas Kras mutations are associated with resistance, has generated excitement among both clinicians and researchers studying non-small cell lung cancer (NSCLC). Mutational analysis may soon be very useful in choosing among a wide range of targeted therapies to individualize treatment to tumor characteristics. This analysis would be even more useful in patients with advanced NSCLC, in whom cytological specimens are often the only material available. Methods: We analyzed 23 archived cytologic specimens of advanced/metastatic lung adenocarcinomas for mutations in EGFR exons 18 to 21, and Kras exon 2. Results: Our data show that our cytological specimens were perfectly adequate for the molecular analysis of EGFR and Kras mutations. EGFR TK domain mutations were found in three cases (13.04%) and were associated with both female gender (p = 0.02) and a nonsmoking history (p = 0.008). Moreover, we explored the relationship between EGFR mutation status and the presence of Kras mutations. Kras mutations involving codon 12 in exon 2 were found in 5 (21.73%) of the 23 adenocarcinomas and were associated, where known, with smoking habits. We never found EGFR alterations in tumors with Kras mutations. Conclusions: Our results provide oncologists with a highly accurate laboratory method to identify biological predictors of the efficacy of different therapies, and they may have an important impact on clinical practice. This method may be particularly useful in patients with advanced/metastatic NSCLC.

Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: Results from the gruppo oncologico nord ovest randomized trial

The authors performed a randomized trial comprising patients with metastatic breast carcinoma (MBC). They used a noninferiority design to evaluate whether the results of sequential administration of epirubicin and paclitaxel were not markedly worse than the concomitant administration in terms of objective response rates (ORRs). Toxicity profile, quality of life (QOL), and pharmacoeconomic evaluations were evaluated as well.

Gemcitabine plus epirubicin plus taxol (GET) in advanced breast cancer: a phase II study*

AbstractPurpose. To investigate the activity of the combination of gemcitabine (G) plus epirubicin (E) and taxol (T), (GET), in metastatic breast cancer, to evaluate the feasibility of this regimen as induction before high dose chemotherapy and to study the pharmacokinetic interactions of these three drugs. Patients and methods. Metastatic breast cancer patients, with bidimensionally measurable disease were eligible. Treatment consisted of G 1000mg/sqm days 1 and 4 plus E 90 mg/sqm day 1 plus T 175mg/sqm/3h day 1, every 21 days. After six courses of GET, patients aged less than 60 years, in complete or partial remission or stable disease entered a programme of high dose chemotherapy (HDCT), as consolidation treatment. Results. Thirtysix patients were included in this study. Grade 4 neutropenia was observed in 64% of the patients, with four episodes of febrile neutropenia; 39% of the patients experienced mild to moderate peripheral neuropathy; grade 2 and 3 mucositis occurred respectively in 9 (25%) and 6 (17%) patients. The overall response rate to GET was 92% (95% CI, 77.53%–98.25%); CR 31% and PR 61%. After six courses of GET, 25 patients received HDCT, leading to an overall response rate of 96% with 58% CR. At a median follow up of 25 months (range 8–39), 13 out of 36 patients are progression free and 26 alive. Median progression free survival is 21 months, while median overall survival has not yet been reached. The pharmacokinetic data show that G does not influence the interactions between E and T, while gemcitabine kinetics remains unchanged. Conclusions. The results of the present study indicate that the addition of G to E plus T as front line treatment for advanced breast cancer is well tolerated with an ORR of 92%. On the basis of the high activity and interesting progression free and overall survival rates, the GET combination deserves further evaluation in randomized trials.

Dysregulated PI3K/Akt/PTEN pathway is a marker of a short disease-free survival in node-negative breast carcinoma

The phosphoinositide 3-kinase/Akt pathway is involved in the pathogenesis of several human cancers. In this study, the biological and prognostic value of phosphoinositide 3-kinase/Akt pathway dysregulation was assessed by immunohistochemistry in a well-characterized series of 72 patients with node-negative breast cancer with a long-term follow-up. Phosphorylated Akt and PTEN expression was reduced in 32% and 12.5% of the tumors, respectively. Phosphorylated Akt or PTEN status was not associated with the main clinicopathologic and biological parameters, whereas their expression was tightly related to their downstream targets cyclin D1 and p27(Kip1) which are involved in cell proliferation. Survival analysis showed a strong association between a shorter disease-free survival and the dysregulated expression of phosphorylated Akt (P = .036), PTEN (P = .003), p27(Kip1) (P = .008), and Ki67 (P = .0007), or the distinct subtypes of breast tumors (luminal, HER2 overexpressing, and basal-like; P = .03). Moreover, multivariate analysis using the Cox proportional-hazards regression model showed that PTEN and Ki67 were independent predictive factors of disease recurrence and that their simultaneous dysregulation strongly increased the hazards ratio of the patients with node-negative breast cancer (hazards ratio, 38.30; P = .0014). In conclusion, our results show that the dysregulation of the phosphoinositide 3-kinase/Akt/PTEN pathway is relevant to the prognosis in node-negative breast carcinoma and that the evaluation of key components of this pathway might be a useful tool to identify the patients with node-negative breast cancer at high-risk of disease recurrence.

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer

Background. Interleukin‐2 (IL‐2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level.

Epirubicin/vinorelbine as first line therapy in metastatic breast cancer

This study was aimed at investigating the toxicity and activity of the combination epirubicin and vinorelbine in chemotherapy-naive patients with metastatic breast cancer. Fifty-one patients with measurable or evaluable metastatic breast cancer entered the study. The regimen consisted of epirubicin 90 mg/m2 as a slow i.v. infusion on day 1, followed by vinorelbine 25 mg/m2 by 30-minute intravenous infusion on days 1 and 8; the courses were repeated every 21 days for a maximum of 8 cycles. All the patients were assessable for toxicity and 47 were evaluable for response according to the World Health Organization (WHO) criteria.Objective responses were observed in 33 out of 47 evaluable patients (70.2%; 95% C.I. 55.1%–82.6%) with 4 complete (8.5%) and 29 partial responses (61.7%); 11 patients had stable disease (23.4%) and 3 patients progressed while on treatment. The median time to progression was 10 months (range 1 − 21) and the median overall survival was 23 months (range 2 − 32+). Neutropenia was the most frequent toxicity: a grade 4 neutropenia (WHO) was reported in 70% of 252 courses with a median duration of 3 days (range 1–6). Seventeen episodes of febrile neutropenia were observed but only 1 patient required hospital admission. Other hematologic toxicities were negligible. One patient experienced a paralytic ileus requiring hospitalization; no peripheral neuropathy such as muscle weakness or paresthesia was observed. No treatment-related cardiotoxicity was reported. The encouraging response rate achieved with epirubicin/vinorelbine, the easily manageable toxicities of the combination, and its feasibility in an outpatient setting make this combination worthy of further comparative trials with standard regimens.

Cyclin‐D1 expression in node‐positive (N+) and node‐negative (N−) infiltrating human mammary carcinomas

Cyclin‐D1 (CD1) expression was analyzed in human mammary carcinomas by immunohistochemical (IHC) and flow‐cytometry (FCM) methods: 52.5% and 50% of cases were strong expressors of CD1 by IHC and FCM analysis respectively. The percentage of CD1‐positive cells was especially high in node‐negative (N−) estrogen‐receptor‐positive (ER+) tumors, probably as a consequence of CD1 induction by estrogens in steroid‐responsive tissues. However, CD1 expression was not related to ER positivity in node‐positive tumors (N+). An interesting relationship between CD1 expression and H3‐thymidine labelling index (H3Td‐LI) was also found: CD1 and H3Td‐LI were unrelated in N− tumors, while high CD1 expression was observed in N+ tumors with high DNA synthesis, as assessed by H3Td‐LI. The combined measurement of DNA and CD1 showed that 27 specimens were aneuploid, 19 of them (19/27; 70%) strongly expressing CD1. Further studies are needed to clarify the role of CD1 in DNA abnormality of breast tumors. However, we cannot exclude that the CD1 may be differently de‐regulated in the last phase of tumor progression, and that CD1 over‐expression may contribute to the aneuploidy of mammary carcinomas. Int. J. Cancer (Pred. Oncol.) 84:139–144, 1999.

Italian, Multicenter, Phase III, Randomized Study of Cisplatin Plus Etoposide With or Without Bevacizumab as First-Line Treatment in Extensive-Disease Small-Cell Lung Cancer: The GOIRC-AIFA FARM6PMFJM Trial

Purpose Considering promising results in phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Treatment-naive patients with ED-SCLC were randomly assigned to receive either cisplatin plus etoposide (arm A) or the same regimen with bevacizumab (arm B) for a maximum of six courses. In the absence of progression, patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses. The primary end point was overall survival (OS). Results Two hundred four patients were randomly assigned and considered in intent-to-treat analyses (103 patients in arm A and 101 patients in arm B). At a median follow-up of 34.9 months in arm A and arm B, median OS times were 8.9 and 9.8 months, and 1-year survival rates were 25% and 37% (hazard ratio, 0.78; 95% CI, 0.58 to 1.06; P = .113), respectively. A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen (hazard ratio, 0.60; 95% CI, 0.40 to 0.91; P = .011). Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B, respectively ( P = .030). Regarding hematologic toxicity, no statistically significant differences were observed; for nonhematologic toxicity, only hypertension was more frequent in arm B (grade 3 or 4, 1.0% v 6.3% in arms A v B, respectively; P = .057). Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival, which, however, did not translate into a statistically significant increase in OS. Further research with novel antiangiogenic agents, particularly in the maintenance setting, is warranted.

Bevacizumab in the pre-operative treatment of locally advanced rectal cancer: A systematic review

Despite advances in the management of patients with locally advanced, non-metastatic rectal adenocarcinoma (LARC), prognosis remains largely unsatisfactory due to a high rate of distant relapse. In fact, currently available neoadjuvant protocols, represented by fluoropyrimidine-based chemo-radiotherapy (CT-RT) or short-course RT, together with improved surgical techniques, have largely reduced the risk of local relapse, with limited impact on distant recurrence. Available results of phase III trials with additional cytotoxic agents combined with standard CT-RT are disappointing, as no significant reduction in the risk of recurrence has been demonstrated. In order to improve the control of micrometastatic disease, integrating targeted agents into neoadjuvant treatment protocols thus offers a rational approach. In particular, the antiangiogenic agent bevacizumab has demonstrated synergistic activity with both CT and RT in pre-clinical and clinical models, and thus may represent a suitable companion in the neoadjuvant treatment of LARC. Preliminary results of phase I-II clinical studies are promising and suggest potential clinical parameters and molecular predictive biomarkers useful for patient selection: treatment personalization is indeed the key in order to maximize the benefit while reducing the risk of more complex neoadjuvant treatment schedules.

Differences in the availability of new anti-cancer drugs for Italian patients treated in different regions. Results of analysis conducted by the Italian Society of Medical Oncology (AIOM)

Aims and background Italy is divided into 20 regions. As a consequence of local autonomy, following marketing authorization by the Italian Medicines Agency, each drug for hospital use is not immediately available, because its approval needs to undergo further steps that can be different among regions. The Italian Society of Medical Oncology conducted the present study to describe the impact of the existence of sub-national pharmaceutical formularies on the disparity of access to new anti-cancer drugs among patients treated in different Italian regions. Methods The availability of 8 new anti-cancer drugs at a regional level and the coherence of regional authorizations compared with national authorizations approved by the Italian Medicines Agency were analyzed as of April 2009. Results Fifteen regions and autonomous province of Trento have a regional pharmaceutical formulary. In most cases, the regional pharmaceutical formularies include the eight analyzed drugs, with therapeutic indications coherent with national marketing authorization indications. Five drugs (bevacizumab, trastuzumab, rituximab, erlotinib, sunitinib) were included in all the existing regional pharmaceutical formularies, without restrictions, whereas three drugs (cetuximab, sorafenib, pemetrexed) were found to have restrictions in some regions. Conclusions The presence of multiple hierarchical levels of drug evaluation creates a potential element of disparity in the access to pharmacological therapies for Italian citizens. Free full text available at www.tumorionline.it