Monica Giovannini

Activity of epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations.

Introduction: Mutations of the epidermal growth factor receptor (EGFR) have been proven to predict activity of the EGFR-tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib. Although the “common” EGFR mutations, such as the L858R point mutation in exon 21 and the in-frame deletional mutation in exon 19, have been definitively associated with response to EGFR-TKIs, the correlation with response to treatment for many other rarer mutations is still unclear. In this study, we report the results of treating patients with advanced non-small cell lung cancer harboring rare EGFR mutations treated with EGFR-TKIs. Methods: The frequency of rare mutations has been investigated in 681 cases of non-small cell lung cancer screened between 2006 and 2010. Mutations in exons 18 and 20, uncommon mutations in exons 19 and 21, and/or the presence of different mutations in a single tumor (complex mutations) were considered rare. Results: EGFR mutations were detected in 99 tumors (14.5%). Eighteen cases carried rare mutations, and 10 of these patients were treated with erlotinib or gefitinib. The clinical outcome was described case by case with references to the literature. Of note, we found two EGFR mutations never identified before and one of unknown response to EGFR-TKIs. Conclusions: Gefitinib and erlotinib have different antitumor activity according to the type of the EGFR mutation borne. Report of cases harboring rare mutations can support the decision-making process in this subset of patients.

Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): A critical view

Neuroendocrine tumors (NET) are classified according to the Ki67 in low-intermediate grade (Ki67<20%) and high grade (Ki67>20%). The NET of the latter group are also known as neuroendocrine carcinoma (NEC), and their prognosis is dismail. While in the former group biotherapy and radionuclide therapy can be proposed, chemotherapy represents the only treatment usually proposed for NEC. Cisplatin/etoposide combination is usually chosen based on the rationale that NEC are clinically similar to small cell lung cancer. However, evidence for cisplatin/etoposide in NEC is poor and controversial, and different schedules and response rate have been published so far. These aspects, combined with the heterogeneous characteristics of NEC, prompt us to have some doubt in considering cisplatin/etoposide as the gold standard. Some evidence exists that carboplatin can be used instead of cisplatin and irinotecan instead of etoposide without reducing efficacy. Furthermore other drugs, as gemcitabine, oxaliplatin or temozolomide can be evaluated in NEC with non-neuroendocrine component or in mixed adenoneuroendocrine carcinomas. NEC are a category of NET that should be deeply studied to verify if the response to cisplatin/etoposide is homogeneous related to the different Ki67, different morphology and/or different primary site.

Malignant pleural mesothelioma: current treatments and emerging drugs

Background: Malignant pleural mesothelioma (MPM) is an uncommon disease whose incidence is increasing worldwide over the past 30 years. Surgical resection and radiotherapy represent the standard treatment in patient with resectable MPM. Chemotherapy is also necessary to reduce incidence of distant metastases, but the optimal setting of treatment (neoadjuvant, adjuvant and intrapleural) is not clarified. For the patients with unresectable MPM, the combination cisplatin and pemetrexed or ralitrexed is the standard treatment as supported by a Phase III study. Better understanding of molecular pathways involved in MPM has enabled inclusion of new drugs targeted against pathways responsible for proliferation, cell survival and angiogenesis. Objective: This review discusses the current treatment option, the specific signal pathways activated in MPM and the novel agents under evaluation in clinical trials. Methods: We use for this article abstracts, papers, oral presentations from ASCO and the website http://www.clinical-trials.gov. Results/ conclusion: This review summarizes the activity of chemotherapy and of new agents under evaluation in clinical trials. The better understanding of molecular pathways activated in MPM will hopefully provide new therapeutic options for these patients in the future.

Vaccines in non-small cell lung cancer: Rationale, combination strategies and update on clinical trials

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer related mortality worldwide and despite some advances in therapy the overall prognosis remains disappointing. New therapeutic approaches like vaccination have been proposed and several clinical trials are ongoing. Many tumor antigens have been identified so far and specific tumor vaccines targeting these antigens have been developed. Even if the ideal setting for vaccine therapy might be the adjuvant one, vaccines seem to be potentially beneficial also in advanced disease and combination therapy could be a promising treatment option. In the advanced setting anti-MUC-1 vaccine (belagenpumatucel) and anti-TGF-β(2) vaccine (BPL-25) have entered in phase III trials as maintenance therapy after first line chemotherapy. In the adjuvant setting the most relevant and promising vaccines are directed against MAGE-A3 and PRAME, respectively. We will review the key points for effective active immunotherapies and combination therapies, giving an update on the most promising vaccines developed in NSCLC.

Antiangiogenic strategies in breast cancer management

Angiogenesis is considered one of the key mechanisms of tumour growth and survival. Therefore it represents an ideal pharmaceutical target. Many antiangiogenic agents have been developed so far in several solid tumours and also in breast cancer. Vascular endothelial growth factor (VEFG) is the main target and both monoclonal antibodies and small molecules belonging to the tyrosine kinase inhibitors directed against VEGF(R) have been developed. Some other therapeutic approaches have shown to exert some antiangiogenic activity, such as hormonal agents, metronomic chemotherapy, bisphosphonates and others. In this paper we provide an introduction of the current data supporting the angiogenesis in breast cancer and a review of the most relevant antiagiogenic therapies which have been investigated so far.

Estrogen Receptor (ER) and Epidermal Growth Factor Receptor (EGFR) as Targets for Dual Lung Cancer Therapy: Not Just a Case?

To the Editor: A 57-year-old woman never smoker with metastatic lung adenocarcinoma was treated with cisplatin and vinorelbine but progression was observed in the lung, bone, and skin. The patient had severe bone pain and multiple ulcerative bleeding skin lesions (Figure 1). Skin biopsy was performed and compared with previous lung cancer biopsies. Histologic examination confirmed to be skin metastasis of lung adenocarcinoma. The sample was thyroid transcription factor-1, carcinoembryonic antigen, cytokeratin (CK), epidermal growth factor receptor (EGFR), and estrogen receptor (ER) positive, whereas CK20, progesterone receptor and Epidermal growth factor receptor 2 were negative. Considering her never smoking status, adenocarcinoma histopatology, female gender and EGFR expression, the second line treatment with gefitinib was started in October 2005. After a few weeks of treatment with gefitinib and zoledronic acid partial recovery from bone pain and initial healing of the multiple ulcerative subcutaneous lesions was observed; the computed tomography and the bone scans performed after 3 and 6 months of treatment with gefitinib revealed disease stabilization but no further clinical improvement of bone pain and skin lesions at that time was observed. No skin rash or remarkable gastrointestinal toxicity was observed, except for mild diarrhea (grade 1 according National Cancer Institute toxicity criteria) for few days after the beginning of the therapy. Considering the persistence of clinically relevant skin lesions and the positive expression of the ER in histologic samples, treatment with aromatase inhibitor (letrozole) was added to gefitinib in June 2006. This decision was supported by data in vivo and in vitro suggesting that association of tyrosine kinase inhibitor and hormonal therapy can lead to significant suppression of tumor cell growth.1–3 After 3 weeks of therapy with gefitinib and letrozole complete recovery from bone pain was obtained and after 3 months complete remission of cutaneous lesions was observed (Figure 2). Since June 2006, no clinical and radiologic disease progression has been detected. Currently treatment with gefitinib and letrozole is well tolerated and no toxicity from these two drugs has been registered so far. There is increasing evidence of sex difference in the lung cancer risk and development. Women are more susceptible than men to the carcinogenic effects of cigarette smoke taking into account baseline exposure, body weight, height, and body mass index. Female patients are also 2.5 times more likely to suffer from adenocarcinoma which constitutes about one third of primary lung cancer cases among males and about three fourth of those among females. Serum estrogen levels are often higher in female lung cancer patients compared with female without lung cancer suggesting that estrogens may be involved in its etiology.1 In fact, they are involved in differentiation of normal lung epithelium and growth of non-small cell lung cancers (NSCLCs), especially adenoDisclosure: The author declares no conflict of interest. Address for correspondence: Monica Giovannini, MD, Department of Medical Oncology, San Raffaele Scientific Institute, Olgettina St, 60, 20132 Milan, Italy. E-mail: giovannini.monica@hsr.it Copyright

Will Antiangiogenic Agents be a Future for Mesothelioma Therapy

BACKGROUND Malignant mesothelioma (MM) is an aggressive disease that is diagnosed mostly in locally advanced or metastatic stage. In this condition chemotherapy with the combination cisplatin and pemetrexed or ralitrexed represents the standard treatment as supported by a phase III study. However, chemotherapy has very limited effect on the improvement of survival of patients and very few of the MM patients survive more than 2 years. A better understanding of molecular mechanisms and pathways involved in angiogenesis in MM is the basis for the development of new drugs targeted against these pathways responsible for the proliferation and survival of tumor cells. OBJECTIVE This review discusses the role of angiogenic factors in tumourigenesis with a particular focus on MM and it summarizes the results of clinical trials on the drugs targeting angiogenic pathways in MM. METHODS We have used original research articles, abstracts and oral presentations from ASCO (American Society of Clinical Oncology) and the website of clinical trials http://www.ClinicalTrials.gov. RESULTS/CONCLUSIONS This review summarizes the results of antiangiogenic agents under evaluation in clinical trials. A better understanding of the angiogenic pathways activated in MM will hopefully provide new therapeutic options for these patients in the future.

Features and Prognostic Factors of Large Node-Negative Non–Small-Cell Lung Cancers Shifted to Stage II

Background: During the period that randomized clinical trials were establishing the role of adjuvant therapy in tumors larger than 5 cm without lymph-node invasion, which shifted from stage IB (6th TNM) to stage II (7th TNM), we derived the rate of shifted patients in our series and analyzed the relationship between specific patient- and tumor- characteristics, and clinical outcome, to identify putative prognostic factors. Methods: We retrospectively collected data (age, sex, smoking status, type of surgery grading, and histological type) from 467 patients who underwent radical surgery for primary 6th TNM-T2N0 non–small cell lung cancer patients between 1998 and 2009 at our institute. Categorical variables were cross-tabulated by tumor staging according to the 7th TNM edition, and they were tested both for association with stage and survival. Results: One hundred and eighteen patients shifted to stage II, mainly older patients and patients with a sarcomatoid or a poorly differentiated carcinoma. Median overall survival time was significantly different across stages. Among the factors investigated, only the tumor dimension resulted in being statistically significant in multivariate analysis. Conclusions: Nearly a quarter of patients shifted from stage I (6th TNM) to stage II (7th TNM), raising a major need for information on the effects of adjuvant chemotherapy in this group of patients. Our findings suggest that randomized clinical trials aimed at addressing this topic should consider only tumor dimensions as principal selection criteria.

Safety of Systemic Chemotherapy in a Patient With Mitochondrial Myopathy and Non–Small-Cell Lung Cancer

Introduction Mitochondrial myopathies are a large, heterogeneous group of disorders that frequently present with multisystem dysfunction and have a broad variety of phenotypes and genetic etiologies. Mitochondria play important roles in cellular energy metabolism, free-radical generation, and apoptosis. They are small, semiautonomous organelles involved in cellular metabolism and the regulation of cell death. Mitochondria contain their own genetic material (mitochondrial DNA [mtDNA]) along with their own transcription, translation, and protein-assembly machinery and also encode 13 structural proteins that are all subunits of the respiratory chain. Mitochondria are genomically independent of the cell nucleus, although most mitochondrial proteins are encoded by the nuclear genome (nuclear DNA) and imported into mitochondria. It is interesting to note that the replication of mitochondria does not require the presence of mtDNA because mitochondrial biosynthesis continues even when mtDNA is deleted. The human mitochondrial genome has been completely sequenced, and each gene within it has been identified and characterized. Mitochondrial disorders are due to altered mitochondrial functions, and although each of the various mitochondrial functions may be affected, mitochondrial disorders are most frequently due to disturbances of energy production via the respiratory chain and oxidative phosphorylation. Genetically, mitochondrial disorders are due to mutations of either mtDNA or nuclear DNA. In this setting, the phenomenon of genetic heteroplasmy arises (ie, some genomes contain the mutation although the remaining genomes are wild-type genomes). mtDNA mutations may lead to the coexistence of wild-type and mutated mitochondrial genomes within a mitochondrion, cell, or tissue (heteroplasmy) or the presence of exclusively mutated mtDNA or wildtype mtDNA (homoplasmy). Heteroplasmic mtDNA mutations become symptomatic only if a certain threshold mutation load (usually 60% to 70%) is exceeded, at which point they behave as recessivelike traits. The transmission of mtDNA mutations is complex and incompletely understood; women with mtDNA mutations pass their mutations on at a level of heteroplasmy that is unpredictable and apparently random. Because mitochondria are the main source of energy production in mammalian cells, clinical manifestations of disorders of these organelles typically involve tissues with the highest energy requirements. Furthermore, the presence of mtDNA in all human tissues means that a dysfunction affects multiple organ systems. The most commonly affected organs are the nervous system (CNS and peripheral and autonomic systems as well as the optic nerve and retina), muscles (and, in particular, extraocular muscles), the cardiac apparatus, and the endocrine system. The clinical presentation is highly variable with regard to age at onset, symptoms, signs, severity, and prognosis. Mitochondrial defects have long been suspected to play an important role in the development and progression of cancer. Some mutations in mtDNA have been identified in various types of human cancer such as breast cancer, ovarian cancer, colorectal cancer, renal cell carcinoma, and lung cancer. Moreover, pathogenic mtDNA mutations seem to promote tumors by preventing apoptosis. However, it is unclear whether there are interactions between mitochondrial myopathies and cytotoxic drugs. Theoretically, and according to preclinical data, cytotoxic drugs could cause damage to mitochondria. In preclinical studies, cisplatin and carboplatin were shown to reduce L-carnitine and cause mtDNA mutations, and doxorubicin was also found to cause mtDNA mutations. Cyclophosphamide decreases the activity of enzymes of the citric acid cycle but also decreases the activity of respiratory chain complexes. There are also indications that the nephrotoxicity of ifosfamide is due to the inhibition of respiratory chain complexes. To our knowledge, there are no reports on the feasibility and safety of systemic chemotherapy in patients with mitochondrial myopathies. As a consequence, when discussing the treatment possibilities for a patient with an advanced tumor and concomitant mitochondrial myopathy, oncologists are forced to consider the option of systemic chemotherapy without being able to predict the risk of toxicity.