Management of stage III non-small-cell lung cancer: rays of hope.

Lung cancer remains the most common cause of cancer death across the world. Non-small-cell lung cancer (NSCLC) represents the most frequent type of lung cancer and is frequently diagnosed at an advanced stage. Stage III NSCLC, which encompasses 30% of cases, refers to a state between localized and metastatic disease, and is associated with poor prognosis. As highlighted in this review, stage III represents a heterogenous group, whose complex management includes multimodal treatment, discussed below, and requires discussion in multidisciplinary teams. The goal of this approach is a maximalist attitude in these patients with locally advanced and non-metastatic disease. However, many issues remain under debate including the optimal sequences of treatment between different treatment modalities, patient selection particularly for surgery, the duration of perioperative treatments and the identification of biomarkers to determine which patients might benefit of specific treatment like immunotherapy and targeted therapies. This review describes the current landscape of management of stage III NSCLC, discussing the critical issue of resectability, and highlighting the recent advancements in the field, particularly the incorporation of immune-checkpoint inhibitors (ICIs) and targeted therapies in this setting.

Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice.

Background: Liver metastasis is the major cause of colorectal cancer related death. Mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T-cell therapy has been illustrated effective and safe through regional delivery of breast cancer, ovarian cancer and malignant mesothelioma tumors. Herein, we investigated the safety, efficacy, and immune microenvironment of regional delivery of MSLN (CAR) T-cell in the treatment of colorectal carcinoma liver metastases (CRLM). Methods: Second-generation MSLN CAR T-cells were administered by portal vein (PV) or caudal vein (CV, systemic administration) delivery in an orthotopic MSLN+ CRLM nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/γc-/- (NSG) mouse model. A total of 20 mice were randomly divided into control group, non-transduced T cell (NT)-CV group, NT-PV group, MSLN CAR T-cell CV (MSLN-CV) group, and MSLN CAR T-cell PV (MSLN-PV) group, with each group containing four mice to examine the safety and efficacy. The bioluminescence intensity (BLI) of tumor burden, tumor tissue macroscopic and microscopic observation were used to evaluate treatment efficacy. The safety was examined by body weight, survival time, and vital organ damage of mice. CAR T-cell infiltration and cytokine concentration were analyzed by flow cytometry, and immunostaining. The change of immune microenvironment between regional delivery and systemic delivery was investigated on an immune reconstructed CRLM patient-derived xenograft (PDX) model. Additionally, T cell subsets and immunosuppressive markers were examined. Results: PV administration of 1×107/100 µL MSLN CAR T-cells in 20 NSG mice was well tolerated, and no overt toxicity was observed. The tumor burden in the PV group was obviously alleviated. The BLI was (0.73±0.52)×109 in PV group and (1.97±0.11)×109 in CV group (P<0.05), CD8+ granzyme B (GB)+ T cell percentage (MSLN-CV 4.42%±0.47% vs. MSLN-PV 13.5%±4.67%, P<0.01) and cytokine concentration were obviously increased in the MSLN-PV group. In the immune reconstituted CRLM PDX model, intratumor (IT) delivery of MSLN CAR T-cells exhibited much more infiltration of CD4+ and CD8+ T cells accompanied with elevated expression levels of PD-1, LAG-3, and TIM-3. Conclusions: Regional delivery of MSLN-targeted CAR T-cell therapy has encouraging results in the orthotopic CRLM NSG mouse model and PDX model, and converts the tumor microenvironment from cold to hot. This study may provide a new therapeutic approach for CRLM. Further clinical study is needed.

Oncogenic alterations in advanced NSCLC: a molecular super-highway.

Lung cancer ranks among the most common cancers world-wide and is the first cancer-related cause of death. The classification of lung cancer has evolved tremendously over the past two decades. Today, non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, comprises a multitude of molecular oncogenic subsets that change both the prognosis and management of disease.Since the first targeted oncogenic alteration identified in 2004, with the epidermal growth factor receptor (EGFR), there has been unprecedented progress in identifying and targeting new molecular alterations. Almost two decades of experience have allowed scientists to elucidate the biological function of oncogenic drivers and understand and often overcome the molecular basis of acquired resistance mechanisms. Today, targetable molecular alterations are identified in approximately 60% of lung adenocarcinoma patients in Western populations and 80% among Asian populations. Oncogenic drivers are largely enriched among non-smokers, east Asians, and younger patients, though each alteration has its own patient phenotype.The current landscape of druggable molecular targets includes EGFR, anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirstin rat sarcoma virus (KRAS), human epidermal receptor 2 (HER2), c-MET proto-oncogene (MET), neurotrophic receptor tyrosine kinase (NTRK), rearranged during transfection (RET), neuregulin 1 (NRG1). In addition to these known targets, others including Phosphoinositide 3-kinases (PI3K) and fibroblast growth factor receptor (FGFR) have garnered significant attention and are the subject of numerous ongoing trials.In this era of personalized, precision medicine, it is of paramount importance to identify known or potential oncogenic drivers in each patient. The development of targeted therapy is mirrored by diagnostic progress. Next generation sequencing offers high-throughput, speed and breadth to identify molecular alterations in entire genomes or targeted regions of DNA or RNA. It is the basis for the identification of the majority of current druggable alterations and offers a unique window into novel alterations, and de novo and acquired resistance mechanisms.In this review, we discuss the diagnostic approach in advanced NSCLC, focusing on current oncogenic driver alterations, through their pathophysiology, management, and future perspectives. We also explore the shortcomings and hurdles encountered in this rapidly evolving field.

Novel targets for immune-checkpoint inhibition in cancer.

Immune-checkpoint inhibitors have revolutionized cancer therapy, yet many patients either do not derive any benefit from treatment or develop a resistance to checkpoint inhibitors. Intrinsic resistance can result from neoantigen depletion, defective antigen presentation, PD-L1 downregulation, immune-checkpoint ligand upregulation, immunosuppression, and tumor cell phenotypic changes. On the other hand, extrinsic resistance involves acquired upregulation of inhibitory immune-checkpoints, leading to T-cell exhaustion. Current data suggest that PD-1, CTLA-4, and LAG-3 upregulation limits the efficacy of single-agent immune-checkpoint inhibitors. Ongoing clinical trials are investigating novel immune-checkpoint targets to avoid or overcome resistance. This review provides an in-depth analysis of the evolving landscape of potentially targetable immune-checkpoints in cancer. We highlight their biology, emphasizing the current understanding of resistance mechanisms and focusing on promising strategies that are under investigation. We also summarize current results and ongoing clinical trials in this crucial field that could once again revolutionize outcomes for cancer patients.

Cellular Therapy in NSCLC: Between Myth and Reality.

PURPOSE OF REVIEW: In this paper, we review the current state and modalities of adoptive cell therapies (ACT) in non-small cell lung carcinoma (NSCLC). We also discuss the challenges hampering the use of ACT and the approaches to overcome these barriers. RECENT FINDINGS: Several trials are ongoing investigating the three main modalities of T cell-based ACT: tumor-infiltrating lymphocytes (TILs), genetically engineered T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells. The latter, in particular, has revolutionized the treatment of hematologic malignancies. However, the efficacy against solid tumor is still sparse. Major limitations include the following: severe toxicities, restricted infiltration and activation within the tumors, antigen escape and heterogeneity, and manufacturing issues. ACT is a promising tool to improve the outcome of metastatic NSCLC, but significant translational and clinical research is needed to improve its application and expand the use in NSCLC.

Neoadjuvant Immunotherapy: A Promising New Standard of Care.

Neoadjuvant immunotherapy has emerged as a promising approach in the treatment of various malignancies, with preclinical studies showing improved immune responses in the preoperative setting. FDA-approved neoadjuvant-immunotherapy-based approaches include triple-negative breast cancer and early non-small cell lung cancer on the basis of improvement in pathological response and event free survival. Nevertheless, current trials have only shown benefits in a fraction of patients. It is therefore crucial to identify predictive biomarkers to improve patient selection for such approaches. This review aims to provide an overview of potential biomarkers of neoadjuvant immunotherapy in early triple-negative breast cancer, bladder cancer, melanoma, non-small cell lung cancer, colorectal cancer and gastric cancer. By the extrapolation of the metastatic setting, we explore known predictive biomarkers, i.e., PD-L1, mismatch repair deficiency and tumour mutational burden, as well as potential early-disease-specific biomarkers. We also discuss the challenges of identifying reliable biomarkers and the need for standardized protocols and guidelines for their validation and clinical implementation.

Pleural Mesothelioma in the Era of Immunotherapy.

Over the course of the last decade, immunotherapy has revolutionised the management of a great number of cancer types. The treatment of pleural mesothelioma, a rare and highly aggressive cancer, is also being transformed by immunotherapy. The recent combination of ipilimumab and nivolumab improved overall survival compared with platinum-based chemotherapy, irrespective of the histology, establishing immunotherapy as a front-line standard of care in advanced pleural mesothelioma. Yet, most patients do not derive long-term benefit from any of the available therapies, and we note a significant lack of predictive and prognostic biomarkers. After progressing on first-line therapy, patients have limited therapeutic options, and data are scarce about optimal sequencing. In this perspective, we discuss the current management of pleural mesothelioma, defining what we consider to be the therapeutic sequence based on performance status and tumour histology. We also highlight promising ongoing trials that could further shape the management of this rare disease.

Precision Oncology in Gastrointestinal Stromal Tumors.

GIST (gastrointestinal stromal tumors) represent 20% of sarcomatous tumors and 1-2% of primary gastrointestinal cancers. They have an excellent prognosis when localized and resectable, though their prognosis is poor in the metastatic setting, with limited options after the second line until recently. Four lines are now standard in KIT-mutated GIST and one in PDGFRA-mutated GIST. An exponential growth of new treatments is expected in this era of molecular diagnostic techniques and systematic sequencing. Currently, the main challenge remains the emergence of resistance linked to secondary mutations caused by selective pressure induced by TKIs. Repeating biopsies to tailor treatments might be a step in the right direction, and liquid biopsies at progression may offer a non-invasive alternative. New molecules with wider KIT inhibition are under investigation and could change the catalog and the sequence of existing treatments. Combination therapies may also be an approach to overcome current resistance mechanisms. Here, we review the current epidemiology and biology of GIST and discuss future management options, with an emphasis on genome-oriented therapies.

Current Approaches to Neoadjuvant Immunotherapy in Resectable Non-small Cell Lung Cancer.

PURPOSE OF REVIEW: For decades, early-stage resectable non-small cell lung cancer (NSCLC), while potentially curable, has been marred by unacceptably high recurrence rates. RECENT FINDINGS: Anti-PD(L)1 immune checkpoint blockade (ICB) has revolutionized the treatment of advanced NSCLC, and with recent approvals in the peri-operative space, is now poised to transform the systemic treatment paradigm for localized and locally-advanced NSCLC. In this review, we focus on neoadjuvant ICB in resectable NSCLC, highlighting the pre-clinical rationale for neoadjuvant ICB, early clinical trials, randomized phase 3 trial data, and future directions for resectable NSCLC.

Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study.

BACKGROUND: Carriers of germline pathogenic variants of the BRCA1 gene (gBRCA1) tend to have a higher incidence of haematological toxicity upon exposure to chemotherapy. We hypothesised that the occurrence of agranulocytosis during the first cycle of (neo-)adjuvant chemotherapy (C1) in breast cancer (BC) patients could predict gBRCA1 pathogenic variants. PATIENTS AND METHODS: The study population included non-metastatic BC patients selected for genetic counselling at Hôpitaux Universitaires de Genève (Jan. 1998 to Dec. 2017) with available mid-cycle blood counts performed during C1. The BOADICEA and Manchester scoring system risk-prediction models were applied. The primary outcome was the predicted likelihood of harbouring gBRCA1 pathogenic variants among patients presenting agranulocytosis during C1. RESULTS: Three hundred seven BC patients were included: 32 (10.4%) gBRCA1, 27 (8.8%) gBRCA2, and 248 (81.1%) non-heterozygotes. Mean age at diagnosis was 40 years. Compared with non-heterozygotes, gBRCA1 heterozygotes more frequently had grade 3 BC (78.1%; p = 0.014), triple-negative subtype (68.8%; p <0.001), bilateral BC (25%; p = 0.004), and agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy (45.8%; p = 0.002). Agranulocytosis and febrile neutropenia that developed following the first cycle of chemotherapy were independently predictive for gBRCA1 pathogenic variants (odds ratio: 6.1; p = 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value for agranulocytosis predicting gBRCA1 were 45.8% (25.6-67.2%), 82.8% (77.5-87.3%), 22.9% (6.1-37.3%), and 93.4% (88.9-96.4%), respectively. Agranulocytosis substantially improved the positive predictive value of the risk-prediction models used for gBRCA1 evaluation. CONCLUSION: Agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy is an independent predictive factor for gBRCA1 detection in non-metastatic BC patients.

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature.

BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7-14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4-4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

The Evolving Role of Immune-Checkpoint Inhibitors in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare cancer usually caused by asbestos exposure and associated with a very poor prognosis. After more than a decade without new therapeutic options, immune checkpoint inhibitors (ICIs) demonstrated superiority over standard chemotherapy, with improved overall survival in the first and later-line settings. However, a significant proportion of patients still do not derive benefit from ICIs, highlighting the need for new treatment strategies and predictive biomarkers of response. Combinations with chemo-immunotherapy or ICIs and anti-VEGF are currently being evaluated in clinical trials and might change the standard of care in the near future. Alternatively, some non-ICI immunotherapeutic approaches, such as mesothelin targeted CAR-T cells or denditric-cells vaccines, have shown promising results in early phases of trials and are still in development. Finally, immunotherapy with ICIs is also being evaluated in the peri-operative setting, in the minority of patients presenting with resectable disease. The goal of this review is to discuss the current role of immunotherapy in the management of malignant pleural mesothelioma, as well as promising future therapeutic directions.

Evolution of biological features of invasive lobular breast cancer: Comparison between primary tumour and metastases.

BACKGROUND: Invasive lobular carcinoma (ILC) has unique clinical-biological features. Phenotypical differences between primary tumours (PTs) and metastases (M) have been described for invasive ductal carcinoma, but data on ILC are limited. METHODS: We retrospectively analysed patients with recurrent ILC from our institution from 2013 to 2020. We evaluated the discordance of the oestrogen receptor (ER), progesterone receptor (PgR) and HER2 between PT and M, to understand prognostic and therapeutic implications. RESULTS: Thirteen percent (n = 91) of all patients had ILC. We observed 15%, 44% and 5% of ER, PgR and HER2 status discordance between PT and M. ER/PgR discordance was related to receptor loss and HER2 mainly due to gain. PT presented a luminal-like phenotype (93%); 6% and 1% were triple-negative (TNBC) and HER2-positive. In M, there was an increase in TNBC (16%) and HER2-positive (5%). Metastasis-free survival and overall survival (OS) were different according to clinical phenotype, with poorer prognosis for HER2+ and TNBC (p < 0.001); OS after metastatic progression did not differ across phenotypes (p = 0.079). In luminal-like ILC (n = 85) at diagnosis, we found that OS after relapse was poorer in patients experiencing a phenotype switch to TNBC but improved in patients with HER2 gain (p = 0.0028). Poorer survival was reported in patients with a PgR and/or ER expression loss of ≥25%. There was HER2-low enrichment in M1 (from 37% to 58%): this change was not associated with OS (p > 0.05). CONCLUSION: Our results suggest that phenotype switch after metastatic progression may be associated with patients' outcomes. Tumour biopsy in recurrent ILC could drive treatment decision-making, with prognostic implications.

Evolving Therapeutic Scenario of Stage III Non-Small-Cell Lung Cancer.

Lung cancer remains the leading cause of cancer-related death with an incidence that continues to increase in both sexes and all ages. However, 80% to 90% of lung cancers are non-small cell lung cancer (NSCLC) and the remaining 10% to 20% are small cell lung cancer. Adenocarcinoma is the most common histologic subtype of lung cancer worldwide. More frequently, lung cancer diagnosis is made in advanced stages. Stage III NSCLC refers to locoregionally advanced disease without metastases and represents about 30% NSCLC cases. Despite the absence of metastases at diagnosis, the outcome is generally poor. Stage III comprises a heterogeneous group and optimal management requires the input of a multidisciplinary team. All modalities of oncologic treatment are involved: surgery, chemotherapy, radiotherapy, and more recently, immunotherapy and targeted therapy. We will discuss the different therapeutic options in stage III NSCLC, both in operable and inoperable scenarios, and the role of immunotherapy and targeted therapy.

RET aberrant cancers and RET inhibitor therapies: Current state-of-the-art and future perspectives.

Precision oncology informed by genomic information has evolved in leaps and bounds over the last decade. Although non-small cell lung cancer (NSCLC) has moved to center-stage as the poster child of precision oncology, multiple targetable genomic alterations have been identified in various cancer types. RET alterations occur in roughly 2% of all human cancers. The role of RET as oncogenic driver was initially identified in 1985 after the discovery that transfection with human lymphoma DNA transforms NIH-3T3 fibroblasts. Germline RET mutations are causative of multiple endocrine neoplasia type 2 syndrome, and RET fusions are found in 10-20% of papillary thyroid cases and are detected in most patients with advanced sporadic medullary thyroid cancer. RET fusions are oncogenic drivers in 2% of Non-small cell lung cancer. Rapid translation and regulatory approval of selective RET inhibitors, selpercatinib and pralsetinib, have opened up the field of RET precision oncology. This review provides an update on RET precision oncology from bench to bedside and back. We explore the impact of selective RET inhibitor in patients with advanced NSCLC, thyroid cancer, and other cancers in a tissue-agnostic fashion, resistance mechanisms, and future directions.

First-line immunotherapy in non-small cell lung cancer: how to select and where to go.

INTRODUCTION: Immunotherapy (IO) has established a new milestone in lung cancer treatment. Several registrational studies have approved immune checkpoint inhibitors (ICIs) in different settings, including the metastatic nonsmall cell lung cancer (NSCLC). As well known, responders are just a certain proportion of patients; therefore, their selection by using predictive factors has stood out as a crucial issue to address in tailoring a patient-centered care. AREAS COVERED: In our review we propose a detailed yet handy cross section on ICIs as first-line treatment in metastatic NSCLC, regarding indications, histological, clinical, and blood-based biomarkers, other than their mechanisms of resistance and new immunological actionable targets. We performed a literature search through PubMed entering keywords complying with crucial features of immunotherapy. EXPERT OPINION: IO represents the backbone of lung cancer treatment. Trials are currently testing novel immune blockade agents assessing combinatorial approaches with standard ICIs, or antibody drug conjugates (ADC), harboring immunological targets. Perfecting patients' selection is an ongoing challenge and a more and more urgent need in order to best predict responders who will consistently benefit from it.