Claudia Proto

Treatment of lung large cell neuroendocrine carcinoma

Lung large cell neuroendocrine carcinoma (L-LCNEC) is a rare, aggressive, and difficult-to-treat tumor. It is classified as a neuroendocrine subtype of large cell lung carcinoma (LCLC) belonging to the non-small cell lung cancer (NSCLC) group, but it is also included in the neuroendocrine tumor (NET) group. Most of the available data related to its treatment derive from retrospective analyses or small case series. For patients with L-LCNEC, prognosis is generally very poor. In early stages (I–II–III), surgery is recommended but does not seem to be sufficient. Platinum-based adjuvant chemotherapy may be useful while the role of neoadjuvant chemotherapy is still not well defined. In patients with advanced L-LCNEC, the chemotherapy regimens used in SCLC still remain the standard of treatment, but results are not satisfactory. Due to their peculiar clinical and biological features and the lack of literature data, there is an emerging need for a consensus on the best treatment strategy for L-LCNEC and for the identification of new therapeutic options. In this review, we will discuss the key aspects of L-LCNEC management with the aim to clarify the most controversial issues.

Diagnosis and management of typical and atypical lung carcinoids.

An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1-5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids.

Cognitive impairment and chemotherapy: a brief overview

Patients with cancer are experiencing long-term survival following chemotherapy, but the treatment may also be associated with short and long-term toxicity, including the possibility of cognitive dysfunction. A literature overview indicated a significant association between chemotherapy and cognitive impairment but prospective longitudinal research is warranted to examine the degree and persisting nature of this decline. Although chemotherapeutic agents are unlikely to cross the blood-brain barrier, it has been alleged that the occurrence of neurotoxicity is linked to the pro-inflammatory cytokine pathways. Moreover in most cases many other factors could play an ancillary and concomitant role. The contribution of hormone therapy as well as emotional, social, behavioural and genetic factors should always be considered. Especially physical activity and cognitive training appear promising in the management of cognitive impairment but additional studies are required to establish their efficacy.

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future.

Lung cancer is one of the major causes of cancer related mortality worldwide. Brain metastases (BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 25-40% of cases, adversely influencing quality of life (QoL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. Nevertheless, the blood-brain barrier (BBB) makes central nervous system (CNS) a sanctuary site. To date, the combination of chemotherapy with whole brain radiation therapy (WBRT), surgery and/or stereotactic radiosurgery (SRS) represents the most used treatment for patients (pts) with intracranial involvement. However, due to their clinical conditions, many pts are not able to undergo local treatments. Targeted therapies directed against epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and afatinib, achieved important improvements in EGFR mutated NSCLC with favorable toxicity profile. Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC pts with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as osimertinib and rociletinib, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review we want to highlight literature data about the use and the effectiveness of EGFR-TKIs in pts with BM from NSCLC.

Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy?

Malignant pleural mesothelioma is a rare cancer with a cause-effect relationship to asbestos exposure. The prognosis is poor and chemotherapy seems the best treatment option. In the last two decades a deeper understanding of mesothelioma carcinogenesis and invasiveness mechanisms has prompted research efforts to test new agents in patients with malignant pleural mesothelioma, but the results have been modest. Attractive preclinical data disappointed in subsequent experimental phases. Other promising agents failed to improve patient outcomes due to high toxicity. Interesting suggestions have come from preliminary data on immunotherapy. Several trials are ongoing and the results are eagerly awaited. The aim of this review is to discuss the most recent news on systemic therapy for advanced malignant pleural mesothelioma.

Uncommon mutations in epidermal growth factor receptor and response to first and second generation tyrosine kinase inhibitors: A case series and literature review

Epidermal growth factor receptor (EGFR) is the most common driver gene involved in non small cell lung cancer (NSCLC) growth, being found in approximately 10-15% of Caucasian and 40% of Asian patients. A wide variety of pathogenic mutations, deletions, insertions and duplications have been described in EGFR exons 18-21. The presence of the most common among them (e.g. exon 21 L851R and exon 19 deletions) is associated to response to first and second generation EGFR tyrosine kinase inhibitors (TKIs), which have demonstrated clear superiority over chemotherapy in terms of both progression free survival (PFS) and overall survival (OS) in all treatment lines. However, scarcity of data exists in literature about the response of rarer EGFR alterations to first and second generation TKIs, most works consisting in sporadic case reports and small case series. In this review we aim to discuss the available evidence about this topic, in order to derive suggestions for clinical practice. Furthermore, we report seven cases of patients with lung tumors harboring uncommon EGFR mutations, treated in our Institution with first or second generation TKIs.

Treatment in EGFR-mutated non-small cell lung cancer: how to block the receptor and overcome resistance mechanisms.

In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.

Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases

The discovery of EGFR mutations and EML4-ALK gene rearrangements has radically changed the therapeutic scenario for patients with advanced non-small cell lung cancer. ALK and EGFR tyrosine-kinase inhibitors showed better activity and efficacy than standard chemotherapy in the first and second line treatment settings, leading to a clear advantage in overall survival of advanced non-small cell lung cancer patients harboring these genetic alterations. Historically the coexistence of EGFR mutations and EML4-ALK rearrangements in the same tumor has been described as virtually impossible. Nevertheless many recent observations seem to show that it is not true in all cases. In this review we will discuss the available literature data regarding this rare group of patients in order to give some suggestions useful for their clinical management. Furthermore we report here two cases of concomitant presence of both alterations that will help us in the development of discussion.The discovery of EGFR mutations and EML4-ALK gene rearrangements has radically changed the therapeutic scenario for patients with advanced non-small cell lung cancer. ALK and EGFR tyrosine-kinase inhibitors showed better activity and efficacy than standard chemotherapy in the first and second line treatment settings, leading to a clear advantage in overall survival of advanced non small cell lung cancer patients harboring these genetic alterations.Historically the coexistence of EGFR mutations and EML4-ALK rearrangements in the same tumor has been described as virtually impossible. Nevertheless many recent observations seem to show that it is not true in all cases.In this review we will discuss the available literature data regarding this rare group of patients in order to give some suggestions useful for their clinical management. Furthermore we report here two cases of concomitant presence of both alterations that will help us in the development of discussion.

Small-Cell Lung Cancer: Clinical Management and Unmet Needs New Perspectives for an Old Problem

Small cell lung cancer is a highly aggressive, difficult to treat neoplasm. Among all lung tumors, small cell lung cancers account for about 20%. Patients typically include heavy smokers in 70s age group, presenting with symptoms such as intrathoracic tumors growth, distant spread or paraneoplastic syndromes at the time of diagnosis. A useful and functional classification divides small cell lung cancers into limited disease and extensive disease. Concurrent chemo-radiotherapy is the standard treatment for limited disease, with improved survival when combined with prophylactic cranial irradiation. Platinum compounds (cisplatin/carboplatin) plus etoposide remain the cornerstone for extensive disease. Nevertheless, despite high chemo- and radio-sensitivity of this cancer, nearly all patients relapse within the first two years and the prognosis is extremely poor. A deeper understanding about small cell lung cancer carcinogenesis led to develop and test a considerable number of new and targeted agents but the results are currently weak or insufficient. To date, small cell lung cancer is still a challenge for researchers. In this review, key aspects of small cell lung cancer management and controversial points of standard and new treatments will be discussed.

Abstract 3113: SMO mutation identifies a subgroup of malignant pleural mesothelioma (MPM) patients with a worse prognosis

Malignant pleural mesothelioma (MPM) is a rare malignant disease with a short prognosis and limited treatment options. However, at population level about 12% of all MPM survive more than three years. The aim of this pivotal study is to investigate whether a different gene profile could divide short versus long survivors. METHODS: A cut-off of 36 months of survival was chosen to divide patients with shorter and longer survival. Under this condition we retrospectively collected data on 32 short- and 25 long-survivors from three Italian Institutions. Paraffin-embedded tissue samples were tested for a customized panel of 21 genes (CDKN2, NF2, GSTM1, NAT2, BAP1, TERT, P53, PTCH1, SMO, LATS2, KEAP1, PI3K, KRAS, NRAS, STK11, WT1, FBXW7, CTNNB1, KIT, KDR and REV3). DNA was obtained upon manual microdissection to ensure at least 50% cancer cells. DNA was processed by PGM Ion Torrent. The major prognostic factors and mutations were described. The hazard risk of death was calculated with the Cox Model. RESULTS: The main prognostic factors were equally distributed among the two groups (age, sex, histotype, stage, and treatment). The most frequent mutations were BAP-1 (24,5%), NF-2 (17,5%), p53 (14%), SMO (8,7%) PITCH (8,8%), KEAP1 (7%) and TERT (5.3%) considering all 57 patients together. Wild-type patients for this gene panel were 31.6%. Median survival for short survivors was 13 months, while 47 for long survivors. No major differences in gene profile were observed between long and short survivors with the exception of SMO which was mutated only in short survivors (16%). SMO seems strongly associated with a poor prognosis (HR 8.01; CI95% 2.79-22.98 p CONCLUSIONS: SMO mutation was likely to identify a subset of MPM patients with worse prognosis. As SMO could be a promising target for specific inhibitors, further researches at clinical level in this subset of patients and also at preclinical level are ongoing. This study was granted by AIRC. Citation Format: Monica Ganzinelli, Claudia Proto, Diego Signorelli, Laura Botta, Giulia Pasello, Marcello Tiseo, Annalisa Trama, Gemma Gatta, Adele Busico, Alessandra Fabbri, Nadia Zaffaroni, Giuseppe Pelosi, Ugo Pastorino, Filippo De Braud, Milena Vitali, Marina C. Garassino. SMO mutation identifies a subgroup of malignant pleural mesothelioma (MPM) patients with a worse prognosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3113.