Laura Ginocchi

Anti-HER agents in gastric cancer: from bench to bedside

Despite some advances in the past few years, the search for effective treatment modalities for advanced gastric and gastro-esophageal junction cancer is far from over. Available data clearly demonstrate that the development of new drugs will have little, if any, chance of success if it is not guided by in-depth knowledge of disease biology. However, using biologic agents to target key molecular pathways, such as those regulated by human epidermal growth factor receptor (HER) family members, may be effective. Indeed, the positive results achieved by the anti-HER2 agent trastuzumab in a phase III trial in HER2-positive patients support this approach. Many new anti-HER molecules are now under evaluation for the treatment of gastric and gastro-esophageal junction cancer, but so far attempts to identify reliable predictive factors from phase I and II trials have produced inconclusive results. In addition, large phase III trials are still being conducted in molecularly unselected populations. Refining patient selection is essential to maximize the benefit of targeted agents, to avoid significant toxicities and for the development of alternative therapeutic approaches in patients who have nonresponsive disease.

Natural History of Non-Small-Cell Lung Cancer with Bone Metastases

We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival.

Second-line Treatment for Non–Small-Cell Lung Cancer: One Size Does Not Fit All

After progression following first-line treatment, many patients with advanced non-small-cell lung cancer (NSCLC) still have a good performance status and can be considered for further treatments. Based on 2 randomized phase III trials, docetaxel was the first approved second-line therapy associated with longer survival and better quality of life compared with best supportive care alone and vinorelbine or ifosfamide. Since then, other agents have been approved for the second-line treatment of NSCLC (ie, pemetrexed, erlotinib, and gefitinib). Recently, new molecular-targeted agents are being increasingly considered in this setting, above all, bevacizumab and vandetanib. The discovery and validation of predictive markers of efficacy for both chemotherapy drugs and the new targeted therapies is of primary importance for the selection of second-line treatment for all patients with advanced NSCLC.

Adjuvant chemotherapy seems beneficial for invasive intraductal papillary mucinous neoplasms

AIMS The incidence of intraductal papillary mucinous neoplasm (IPMN) is rising and these neoplasms now represent up to 25% of resected pancreatic neoplasms. The optimal postoperative management of resected invasive IPMN is still debated in the absence of large prospective clinical trials and of validated prognostic factors in this setting. The objective of our study was to identify potential prognostic factors and to investigate the role of adjuvant therapies for patients radically resected for invasive IPMN. METHODS We retrospectively reviewed clinical and pathological data regarding a large series of patients with invasive IPMN who underwent surgical resection in the last six years at University Hospital of Pisa. RESULTS Sixty-four patients were considered for the analysis, thirty-three of whom received adjuvant chemotherapy with gemcitabine. In our series node involvement and high tumoral grade emerged as the major pathologic prognostic factors. Patients treated with adjuvant chemotherapy with gemcitabine experienced a longer disease-free survival than those who received surgery alone. CONCLUSIONS Gemcitabine-based chemotherapy seems beneficial as adjuvant treatment for patients with resected invasive IPMN.

EGFR and K-Ras mutations in women with lung adenocarcinoma: implications for treatment strategy definition.

BackgroundWe aimed at investigating the outcomes of female patients with stage IIIB-IV adenocarcinoma of the lung according to EGFR and K-Ras mutational status.MethodsOne hundred and three consecutive female patients genotyped at a single Italian Institution were analyzed. Patients were planned to receive first-line platinum-based chemotherapy (CT) and a salvage treatment with anti-EGFR tyrosine-kinase inhibitors (TKIs) was proposed irrespective of tumor mutational status. EGFR (exons 18-21) and K-Ras (exon 2, codons 12-13) mutations were evaluated by real-time PCR and pyrosequencing. The association of mutational status with clinical variables and treatment benefit was investigated by chi-square test and log-rank test.ResultsEGFR and K-Ras mutations were found in 31 (30%) and 13 (15%) cases, respectively. Sixty-six patients received platinum CT: no correlation was observed between EGFR or K-Ras mutational status and response rate (RR) (p > 0.05). However, patients treated with first-line CT harboring EGFR activating mutations experienced a significantly reduced progression-free survival (PFS) in comparison with wild-type ones (4.4 vs. 6.4 months, respectively; HR 0.597, 95% CI 0.287-0.975; p=0.048). Thirty-nine patients received salvage treatment with erlotinib: EGFR activating mutations were significantly correlated with RR (60% vs. 12.5%; p=0.004) and PFS (11.4 vs. 4.5 months; HR 0.491, 95% CI 0.216-0.936; p=0.044). Responses to erlotinib were not reported among women with K-Ras mutant tumors, while 50% of those with wild-type K-Ras achieved an objective remission (p=0.296). Median PFS (3.5 vs. 8.8 months; HR 0.284, 95% CI 0.015-0.510; p=0.010) and OS (3.9 vs. 19.8 months; HR 0.158, 95% CI 0.001-0.075; p < 0.001) were significantly shorter among K-Ras mutant patients treated with TKI.ConclusionsIn our population of Caucasian women with advanced lung adenocarcinoma we observed that the presence of EGFR activating mutations correlates with a significant reduction in the benefit from first-line platinum-based CT, emphasizing the importance of an upfront use of anti-EGFR TKIs in this patient subset. K-Ras mutations seem to correlate with a detrimental effect from anti-EGFR TKI, but this finding deserves further investigation.

Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients.

VEGFR-2 and P2X7 receptor (P2X7R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X7R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94–152.96) and 65.65 months (95% CI, 52.95–76.53) for the favorable and the unfavorable genetic profile, respectively (p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis.

Not only chemotherapy in the second-line treatment of metastatic gastric cancer

ABSTRACT The role of second-line treatments after first-line chemotherapy in metastatic gastric cancer is reinforcing. Two different options, chemotherapy and anti-VEGFR therapy, are available and confirmed efficacy in this setting. The combination of the two strategies as used in other cancers is promising and could become a new standard for second-line treatment of metastatic gastric cancer. The results of the RAINBOW trial, a phase III study evaluating ramucirumab in combination with paclitaxel versus paclitaxel alone, will add new information on this topic considering that the study met its primary end point of improved overall survival.

Modified FOLFOXIRI in Advanced Pancreatic Cancer

Context The combination regimen of 5-fluorouracil, folinic acid, oxaliplatin and irinotecan named FOLFIRINOX has been proposed as a new standard of care for metastatic pancreatic cancer patients. However, FOLFIRINOX was associated with high incidence of grade 3 and 4 toxicities (neutropenia in 45.7% of patients with G-CSF use in 42.5% of patients; febrile neutropenia in 5.4%; diarrhea in 12.7%). Our group had developed a very similar schedule in colorectal cancer named FOLFOXIRI which contains no bolus 5-fluorouracil and a slight lower dose of irinotecan. Objective The objective of this study was to prospectively evaluate the tolerability and activity of a modified (m)FOLFOXIRI regimen in metastatic or locally advanced pancreatic cancer patients. Methods The regimen included a lower dose of irinotecan (administered at 150 mg/m 2 on day 1 every 14 days) and of infusional 5-fluorouracil (2,800 mg/m 2 administered as a 48-hour continuous infusion on days 1 to 3 every 14 days). Folinic acid and oxaliplatin remained unchanged. Results Thirty-nine patients with cytological or histological diagnosis of pancreatic adenocarcinoma have been treated with (m)FOLFOXIRI from August 2010 onwards; 17 had metastatic disease while 22 had locally advanced disease. A total of 260 cycles have been administered so far. The grade 3-4 toxicities reported are: neutropenia in 35.9% of patients, thrombocytopenia 2.6%, diarrhea 5.1%, stomatitis 7.7%, nausea/vomiting 5.1%, fatigue 2.6%, liver toxicity 5.1%, sensory neuropathy 5.1%. No toxic deaths and no febrile neutropenia have been occurred. G-CSF has been used in seven patients (18%). A delay in the administration of chemotherapy was required in 12 patients (31%) and a reduction of doses in 7 cases (18%). Among 30 evaluable patients 11 partial responses (36.7%) and 14 stable disease (46.7%) have been observed. Median progression-free survival (PFS) was 11.5 months and median overall survival (OS) 25.5 months. For metastatic patients only, response rate resulted 33% with a PFS and OS of 8.4 and 14.8 months, respectively. Conclusion The (m)FOLFOXIRI regimen as we used resulted feasible and quite well tolerated and it maintained its good activity in metastatic pancreatic cancer.

Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients

PURPOSE To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) combined to Cyclophosphamide (CTX) and followed by weekly Paclitaxel, in older patients (≥65 years) with diagnosis of high risk breast cancer. The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). METHODS The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. RESULTS Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. CONCLUSIONS This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings.

EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected gastric adenocarcinomas

PURPOSE The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II-III adenocarcinomas. METHODS Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. RESULTS EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). CONCLUSIONS EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers.