Enrica Capelletto

L718Q Mutation as New Mechanism of Acquired Resistance to AZD9291 in EGFR-Mutated NSCLC

Abstract With the advent of third-generation epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitors, such as AZD9291 and CO-1686, new mechanisms of drug resistance are emerging, like C797S and L884V EGFR mutations, in patients with EGFR T790M-positive non-small cell lung cancer (NSCLC). Here we present a case of advanced NSCLC with coexisting primary L585R and secondary T790M EGFR mutations that acquired resistance to AZD9291 (osimertinib) due to the occurrence of the tertiary L718Q mutation. This is the first clinical report for this new mutation as EGFR-dependent mechanism of resistance to AZD9291.

Updated clinical information on multitargeted antifolates in lung cancer.

Pemetrexed, a third-generation antifolate already indicated in combination with cisplatin for the systemic treatment of malignant pleural mesothelioma and, as a single agent, for the second-line treatment of non-small-cell lung cancer was in 2008 granted approval for histologically based first-line treatment by both the EMEA and FDA. Thymidylate synthase, the main molecular target of pemetrexed, has higher mRNA and protein expression in squamous- and small-cell lung cancer compared with adenocarcinoma. This differential expression might well molecularly explain the differential clinical activity of pemetrexed in the various histotypes of lung cancer, including the marginal activity in small-cell lung cancer. These hypothesis-generating findings are currently validated in prospective studies.

Emerging new agents for the management of patients with non-small cell lung cancer.

Lung cancer is one of the leading causes of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for at least 87% of all lung cancers and most cases present at an advanced stage, with metastatic, locally advanced or recurrent disease. With a greater understanding of tumour biology, a number of targeted agents have been investigated for the treatment of advanced NSCLC. These include insulin-like growth factor inhibitors, c-MET inhibitors, poly(adenosine diphosphate-ribose) polymerase inhibitors, histone deacetylase inhibitors, proapoptotic agents, epidermal growth factor receptor inhibitors, vaccines, immunotherapy and hedgehog inhibitors. This article aims to provide an overview of some of the emerging molecules for NSCLC that have demonstrated interesting results in the past couple of years, including descriptions of the molecular pathways of these drugs and their main location of action.

Impact of Non–Small-Cell Lung Cancer-Not Otherwise Specified Immunophenotyping on Treatment Outcome

Introduction: The vast majority of non–small-cell lung cancers (NSCLCs) presents as advanced disease, and histological diagnosis is widely based on small samples. The differential activity and toxicity profile of new cytotoxic and molecular-targeted therapies according to histotypes requires a precise subtyping of NSCLC. Immunohistochemistry (IHC) contributes to define the most probable histotype; however, the real impact of IHC characterization of NSCLC-not otherwise specified (NOS) in terms of outcome is not well established. Methods: A large series of 224 advanced “nonsquamous” NSCLC diagnosed on small biopsy or cytological samples and homogeneously treated was retrospectively selected, all having adequate follow-up data available. Reviewed diagnoses resulted into two groups: adenocarcinoma (ADC) and NSCLC-NOS. The latter was further characterized by IHC (TTF-1, Napsin-A, p40, and Desmocollin-3) –identify a possible, most probable differentiation lineage. Results: Sixty-seven percentage of cases were classified as ADC based on morphological examination only (“morphological ADC”) and 33% as NSCLC-NOS. IHC profiling of NSCLC-NOS identified 43.2% of cases with an ADC immunophenotype (“NSCLC favor ADC”), 10.8% with a phenotype favoring squamous lineage, and 46% lacking differentiation features. Survival curves confirmed no difference in terms of outcome between the morphological ADC and the NSCLC favor ADC groups, while a significantly poorer outcome was found in the “null” group in terms of best response, progression-free survival or overall survival (OS). Conclusion: Tumors with an IHC profile ADC-like had an OS comparable with that of morphological ADCs. These findings support the use of IHC to optimize lung cancer histological typing and therapy.

Fetal Adenocarcinoma of the Lung in a 25-Year-Old Woman

We report the case of a 25-year-old woman with a chance detection at x-ray of a well-defined mass in the right upper lobe during a medical examination. The patient suffered from a modest flu syndrome, with cough and fever. She was a current smoker. CT scan showed a homogeneous well-defined perihilar mass without calcifications, located in the right upper lobe and fully surrounded by aerated parenchyma. A right upper lobectomy with mediastinal lymph node sampling was performed. A pathologic diagnosis of well-differentiated fetal adenocarcinoma of the lung was made and staged as T2N0. Few cases of this type of malignancy have been reported in literature.

Patients' Attitudes and Physicians' Perceptions Toward Maintenance Therapy for Advanced Non–Small-cell Lung Cancer: A Multicenter Italian Survey

Introduction Pemetrexed maintenance therapy (MT) after induction with platinum‐based chemotherapy has recently become a common treatment strategy for advanced nonsquamous non–small‐cell lung cancer (NSCLC). However, the benefits of MT should be weighed with consideration of the patients’ perceptions and preferences. The aim of the present study was to evaluate patients’ attitudes toward MT and to describe physicians’ awareness of their patients’ inclinations. Materials and Methods We administered a 12‐question anonymous survey and the Distress Thermometer Questionnaire to patients with advanced or recurrent nonsquamous NSCLC. The survey was also distributed to the referring physicians. Results From December 2014 to July 2015, 92 patients and 37 physicians were enrolled. All 92 patients completed the questionnaire at T0 (before starting chemotherapy) and 56.5% also did so at T1 (after completion of induction). The physicians completed the survey only at T0. Most patients had a positive attitude toward MT at both T0 (78.9%) and T1 (86.5%), and 100% of the physicians thought their patients would be in favor of MT. The physicians believed that their patients’ attitudes toward MT would decrease proportionally with the reduction in the magnitude of the overall survival increase and expected benefits. The decrease expected by the physicians was much greater than that reported by the patients. This was especially true for an overall survival increase as small as 1 month (51.9% of patients accepting MT vs. 13.5% supposed by physicians) or when the only treatment benefit was radiologic tumor stabilization (69.3% of patients accepting MT vs. 37.8% supposed by physicians). Conclusion NSCLC patients have a generally positive attitude toward MT, which is not directly proportional to the expected benefits and greater than the attitude expected by physicians. Micro‐Abstract One question is how long patients with advanced non–small‐cell lung cancer wish to receive therapy. The perceptions of > 100 patients and physicians were analyzed to compare different prognostic conditions. The patients’ attitudes were generally positive and not directly linked to the expected benefits, suggesting that other factors in conjunction with the clinical assessment, such as the doctor–patient relationship, should be considered to understand patients’ motivations.

First-line therapeutic options for advanced non-small-cell lung cancer in the molecular medicine era

Lung cancer is the leading cause of cancer-related mortality worldwide in both sexes, expected to account, in the near future, for more than 30% of all cancer-related deaths. Recently, improvements in the systemic therapy of non-small-cell lung cancer according to histology and tumor molecular characteristics led to a progressive prolongation of survival, more clinically meaningful in selected groups of patients with tumors harboring specific genomic alterations. As the search for individualized therapeutic approaches could represent one of the potential ways to improve survival expectancy of non-small-cell lung cancer patients with advanced disease stage, the aim of this review is to discuss how currently to select the best front-line therapeutic strategy.

Final data of an Italian multicentric survey about counseling for smoking cessation in patients with diagnosis of a respiratory disease

Smoking is the major risk factor for cancer and several respiratory diseases. Quitting smoking at any point of life may increase the effectiveness of treatments and improve prognosis of patients with any pulmonary disease, including lung cancer. However, few institutions in Europe offer to patients adequate counseling for smoking cessation.

NGR‐hTNF and Doxorubicin as Second‐Line Treatment of Patients with Small Cell Lung Cancer

Abstract Lessons Learned. NGR‐hTNF was safely combined with doxorubicin, showing a promising antitumor activity in unselected patients with relapsed small cell lung cancer. Similar antitumor activity was observed in platinum‐sensitive and platinum‐resistant patient cohorts. Background. Relapsed small cell lung cancer (SCLC) patients have limited treatment options and poor outcomes. NGR‐hTNF is a vascular‐targeting agent, which increases intratumoral chemotherapy penetration and T‐lymphocyte infiltration. Methods. Twenty‐eight patients relapsing after at least one platinum‐based regimen with a treatment‐free interval shorter (n = 16; platinum‐resistant) or longer (n = 12; platinum‐sensitive) than 3 months received NGR‐hTNF 0.8 μg/m2 plus doxorubicin 75 mg/m2 every 3 weeks. The primary endpoint of this single‐arm phase II trial was progression‐free survival (PFS), and safety, response rate, and survival were secondary endpoints. Results. The most common grade 3–4 toxicities were neutropenia (53%) and anemia (21%). Median PFS was 3.2 months for all patients, 2.7 months for platinum‐resistant patients, and 4.1 months for platinum‐sensitive patients. Seven patients had partial responses (25%), including four (25%) with platinum‐resistant and three (25%) with platinum‐sensitive relapse. Mean changes from baseline in tumor burden (after two, four, and six cycles) did not differ between platinum‐resistant (−9%, −29%, and −32%) and platinum‐sensitive (−11%, −20%, and −43%) cohorts. Overall survival was associated only with baseline lymphocyte counts, with median survival times of 13.1 and 5.2 months for lymphocyte counts above or below the median, respectively. Conclusion. NGR‐hTNF plus doxorubicin showed manageable toxicity and promising activity in patients with relapsed SCLC.

Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal

Introduction: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials. Methods: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (&kgr; > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM. Conclusions: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1–2 = 0 points, 3–5 = 1 point, 6–9 = 2 points, or ≥10 = 4 points), and Ki‐67 labeling index based on 2000 cells (<30% = 0 points versus ≥30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki‐67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1‐point increase in score being 1.46 (95% confidence interval: 1.36–1.56) in the training set and 1.28 (95% confidence interval: 1.22–1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors). Discussion: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM.