The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer

Lung cancer is the most common cancer diagnosed in the UK. Outcomes for patients with this disease remain poor and new strategies to treat this disease require investigation. One potential option is to combine novel agents with radiotherapy in clinical studies. Here we discuss some of the important issues to consider when combining novel agents with radiotherapy, together with potential solutions as discussed at a recent Clinical Translational Radiotherapy Group (CTRad) workshop.

Radiotherapy and Immunotherapy Combinations in Non-small Cell Lung Cancer: A Promising Future?

The goal of re-programming the host immune system to target malignancy with durable anti-tumour clinical responses has been speculated for decades. In the last decade such speculation has been transformed into reality with unprecedented and durable responses to immune checkpoint inhibitors seen in solid tumours. This mini-review considers the mechanism of action of immune modulating agents and the potential for combination with radiotherapy in the treatment of non-small cell lung cancer.

Surgical results and survival of older patients with unsuspected N2 (stage IIIA) non-small cell lung cancer

Purposes. The optimal treatment of N2 non-small cell lung cancer (NSCLC) in older patients is still debate and represent an important treatment and ethical problem. Patients and methods. Between January 2000 to December 2010, 273 older patients underwent lung resection for (NSCLC). Results. The overall-operative mortality was 9.5%. Risk factors for in-hospital mortality were pneumonectomy and poli-vasculopathy. One, 3 and 5-year survival were 73%, 23% and 16% respectively. Conclusions. In potentially operable older patients with NSCLC we need to make every effort to exclude N2 involvement because very poor long-term survival. Pneumonectomy in older patients gains prohibitive in-hospital mortality.

Handgrip dynamometry and patient-generated subjective global in patients with non-resectable lung cancer

Rationale: Undernutrition is frequently associated with advanced lung cancer. Accurate nutritional assessment tools are important to provide the proper nutritional therapy. Hand grip strength (HGS) has already been used in these patients and the findings suggest it is a good indicator of nutritional status. The aim of this study was to evaluate the association between nutritional status and hand grip strength in patients with nonresectable lung cancer.

LUNG CANCER IN NEPAL: THE ROLE OF TRADITIONAL TOBACCO PRODUCTS AND COMBUSTION RELATED HOUSEHOLD AIR POLLUTION

The burden of chronic diseases such as cancer is increasing in low and middle income countries around the globe. Nepal, one of the world’s poorest countries, is no exception to this trend, with lung cancer as the leading causes of cancer deaths. Despite this, limited data is available on the environmental and behavioral risk factors that contribute to the lung cancer etiology in Nepal. The objectives of this dissertation are to: 1) investigate the ethnic differences in consumption of local tobacco products and their role in lung cancer risk in Nepal; 2) evaluate urinary metabolite of 1,3-butadiene as a biomarker of exposure to combustion related household air pollution (CRHAP); 3) investigate the association between CRHAP exposure and lung cancer risk using urinary metabolite of 1,3-butadiene as a biomarker of exposure; 4) investigate the association between CRHAP exposure and lung cancer risk using questionnaire based measure of exposure. Lung cancer cases (n=606) and frequency matched controls (N=606) were recruited from B.P. Koirala Memorial Cancer Hospital. We obtained biological samples and information on lifestyles including cooking habits and type of fuels used. We used liquid chromatograph tandem mass spectrometer (LC-MS/MS) to quantify urinary metabolites of 1,3-butadiene in urine samples. We employed a combination of logistic and linear regression models to detect any exposure-disease associations while controlling for known confounding variables. Overall, we found that ethnic groups in Nepal use different tobacco products that have different differing cancer potency -we observed the highest odds ratios for the traditional tobacco products. The biomarker analysis showed strong evidence that monohydroxybutyl mercapturic acid is associated with biomass fuel use among participants. However, we did not find significant association between urinary MHMBA and lung cancer risk. When we used questionnaire based measure of exposure to household air pollution, we observed significant, dose-response associations between CRHAP exposure and lung cancer risk, particularly among never-smokers. Our results show that important role of local tobacco products in lung cancer risk in Nepal. Furthermore, we demonstrate that CRHAP exposure is a risk factor for lung cancer risk, independent of tobacco smoking.

Safe lipid nanocapsule-based gel technology to target lymph nodes and combat mediastinal metastases from an orthotopic non-small-cell lung cancer model in SCID-CB17 mice

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Alcohol consumption and lung cancer risk in never smokers

Objective: The main objective of this study is to analyse the role of alcohol consumption on lung cancer risk in people who have never smoked. Methods: We conducted a systematic review of the scientific literature following the PRISMA statement. We searched Medline, EMBASE and CINAHL using different combinations of MeSH terms and free text. We included cohort studies, pooled cohort studies and case-control studies comprising at least 25 anatomopathologically-confirmed diagnoses of lung cancer cases, a sample size larger than 100 individuals and more than five years of follow-up for cohort studies. We excluded studies that did not specifically report results for never smokers. We developed a quality score to assess the quality of the included papers and we ultimately included 14 investigations with a heterogeneous design and methodology. Results: Results for alcohol consumption and lung cancer risk in never smokers are inconclusive; however, several studies showed a dose-response pattern for total alcohol consumption and for spirits. Heterogeneous results were found for wine and beer. Conclusion: No clear effect is observed for alcohol consumption. Due to the limited evidence, no conclusion can be drawn for beer or wine consumption. There is little research available on the effect of alcohol on lung cancer risk for people who have never smoked, and more studies are urgently needed on this topic.

Clinical Studies on conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor in second-line treatment of non-small cell lung cancer

Purpose: To study the effect of conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in the second-line treatment of non-small cell lung cancer (NSCLC). Methods: A total of 316 patients attending Shanghai Pulmonary Hospital affiliated to Tongji University, were divided into two groups: 106 patients were treated with conformal radiotherapy combined with EGFR-TKI (gefitinib, 250 mg/day; or erlotinib, 150 mg/day), while 210 patients were treated with EGFRTKI alone. Some factors, including adverse reactions (AR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and one-year and two-year survival rate, were evaluated. Results: No obvious difference was observed in AR between the two groups (p > 0.05). In the combination therapy group, complete response (CR) was 5 cases, partial response (PR) 43 cases, and stable disease (SD) 47 cases, progressive disease (PD) was 11 cases, response rate (RR) was 45.3 %, and DCR 89.6 %. Median PFS in the combination therapy group and targeted therapy group was 6.5 and 5.0 months, respectively. On the other hand, median OS in the combination therapy group and targeted group was 14.1 and 12.6 months, respectively. One-year survival rate of the combination therapy group and EGFR-TKI group was 60.3 and 50.0 %, respectively, while the two-year survival rate was 26.3 and 19.0 %, respectively. Conclusion: Conformal radiotherapy combined with EGFR-TKI can be used as an effective second-line treatment for NSCLC.

Inhibition of proliferation, migration and invasion of human non-small cell lung cancer cell line A549 by phlomisoside F from Phlomis younghusbandii Mukerjee

Purpose: To determine the effect of phlomisoside F (PMF) on the proliferation, migration and invasion of human non-small cell lung cancer cell line A549 and explore the possible mechanisms. Methods: The anti-proliferative effect of PMF on A549 cells was determined by CCK-8. Subsequently, migration and invasion were evaluated by Transwell and Transwell with matrigel assays, respectively. Furthermore, cell cycle and apoptosis were assessed by flow cytometry, while the mechanisms of action were determined by Western blotting. Results: PMF exhibited significant anti-proliferative effect on A549 cells in concentration-dependent and time-dependent manners, with half maximal inhibitory concentration (IC50) of 54.51 μM. Treatment with PMF (10, 20 and 40 μM) for 48 h resulted in significantly decreased migration and invasion in A549 cells. In addition, PMF at concentrations of 25, 50 and 75 μM induced cell cycle arrest in G0/G1phase and enhanced cell apoptosis in A549 cells. Furthermore, caspase-3, caspase-9 and Bax protein expressions were up-regulated while Bacl-2 and COX-2 protein expressions were significantly downregulated at 10, 20 and 40 μM concentrations of PMF. Conclusion: PMF suppresses A549 cell growth, migration and invasion. The mechanism may be related to the induction of mitochondria-mediated apoptosis pathway via regulation of caspase-3, caspase-9, Bcl-2 and Bax expressions, and inhibition of PGE2 synthesis by reducing COX-2 expression.

Exposure to Stressful Life Events and Lung Cancer Risk

Objectif: Examiner l’association entre l'exposition aux évènements stressants de la vie et le cancer du poumon. Méthodes: Les données proviennent d’une étude cas-témoins, menée chez les hommes et les femmes vivant dans la région métropolitaine de Montréal entre 1996 et 2001. Le cancer du poumon d’un cas éligible devait être confirmé histologiquement à l’un des 18 hôpitaux de cette région. Les témoins ont été sélectionnés aléatoirement de la liste électorale du Québec et ont été appariés au cas par fréquence de groupes d'âge et par sexe. Un questionnaire a été administré en entrevue pour recueillir les données, dont l’évaluation de huit évènements stressants de la vie par le participant. Si le participant avait vécu un évènement stressant ciblé durant les six dernières années, il devait aussi coter cet évènement sur une échelle de trois points. La régression logistique non conditionnelle a été utilisée pour estimer les rapports de cotes ainsi que leurs intervalles de confiance à 95%. Des analyses par sexe, niveau de tabagisme et par type histologique ont été réalisées. Nous avons aussi analysé l’association entre le cancer du poumon et le nombre total d'évènements, les évènements de perte et les évènements socioéconomiques, ainsi que chaque évènement individuellement. Les analyses des scores d'impact autoévalués et avec un score externe de perception, ont également été menées. Résultats: La population de ce projet comprend 1061 cas et 1422 témoins, âgés de 35 à 70 ans. Les participants inclus avaient répondu aux sections du questionnaire portant sur les facteurs de style de vie et sur l'historique de tabagisme. Dans l'ensemble, nous n’avons pas observé d’association entre le cancer du poumon et l'exposition aux évènements stressants de la vie. Nous avons observé une diminution du risque pour les évènements socioéconomiques autoévalués comme peu stressants (RC=0,50; IC 95%= 0,31 - 0,81). Conclusion: Nos résultats suggèrent que les évènements socioéconomiques sont associées à un risque réduit si ces évènements sont considérés comme peu stressant.

Exposure to Stressful Life Events and Lung Cancer Risk

Objectif: Examiner l’association entre l'exposition aux évènements stressants de la vie et le cancer du poumon. Méthodes: Les données proviennent d’une étude cas-témoins, menée chez les hommes et les femmes vivant dans la région métropolitaine de Montréal entre 1996 et 2001. Le cancer du poumon d’un cas éligible devait être confirmé histologiquement à l’un des 18 hôpitaux de cette région. Les témoins ont été sélectionnés aléatoirement de la liste électorale du Québec et ont été appariés au cas par fréquence de groupes d'âge et par sexe. Un questionnaire a été administré en entrevue pour recueillir les données, dont l’évaluation de huit évènements stressants de la vie par le participant. Si le participant avait vécu un évènement stressant ciblé durant les six dernières années, il devait aussi coter cet évènement sur une échelle de trois points. La régression logistique non conditionnelle a été utilisée pour estimer les rapports de cotes ainsi que leurs intervalles de confiance à 95%. Des analyses par sexe, niveau de tabagisme et par type histologique ont été réalisées. Nous avons aussi analysé l’association entre le cancer du poumon et le nombre total d'évènements, les évènements de perte et les évènements socioéconomiques, ainsi que chaque évènement individuellement. Les analyses des scores d'impact autoévalués et avec un score externe de perception, ont également été menées. Résultats: La population de ce projet comprend 1061 cas et 1422 témoins, âgés de 35 à 70 ans. Les participants inclus avaient répondu aux sections du questionnaire portant sur les facteurs de style de vie et sur l'historique de tabagisme. Dans l'ensemble, nous n’avons pas observé d’association entre le cancer du poumon et l'exposition aux évènements stressants de la vie. Nous avons observé une diminution du risque pour les évènements socioéconomiques autoévalués comme peu stressants (RC=0,50; IC 95%= 0,31 - 0,81). Conclusion: Nos résultats suggèrent que les évènements socioéconomiques sont associées à un risque réduit si ces évènements sont considérés comme peu stressant.

TAZ role in lung cancer: resistance to BET inhibitors and functional interaction with lncRNA

Despite extensive research and introduction of innovative therapy, lung cancer prognosis remains poor, with a five years survival of only 17%. The success of pharmacological treatment is often impaired by drug resistance. Thus, the characterization of response mechanisms to anti-cancer compounds and of the molecular mechanisms supporting lung cancer aggressiveness are crucial for patient’s management. In the first part of this thesis, we characterized the molecular mechanism behind resistance of lung cancer cells to the Inhibitors of the Bromodomain and Extraterminal domain containing Proteins (BETi). Through a CRISPR/Cas9 screening we identified three Hippo Pathway members, LATS2, TAOK1 and NF2 as genes implicated in susceptibility to BETi. These genes confer sensitivity to BETi inhibiting TAZ activity. Conversely, TAZ overexpression increases resistance to BETi. We also displayed that BETi downregulate both YAP, TAZ and TEADs expression in several cancer cell lines, implying a novel BETi-dependent cytotoxic mechanism. In the second part of this work, we attempted to characterize the crosstalk between the TAZ gene and its cognate antisense long-non coding RNA (lncRNA) TAZ-AS202 in lung tumorigenesis. As for TAZ downregulation, TAZ-AS202 silencing impairs NSCLC cells proliferation, migration and invasion, suggesting a pro-tumorigenic function for this lncRNA during lung tumorigenesis. TAZ-AS202 regulates TAZ target genes without altering TAZ expression or localization. This finding implies an uncovered functional cooperation between TAZ and TAZ-AS202. Moreover, we found that the EPH-ephrin signaling receptor EPHB2 is a downstream effector affected by both TAZ and TAZ-AS202 silencing. EPHB2 downregulation significantly attenuates cells proliferation, migration and invasion, suggesting that, at least in part, TAZ-AS202 and TAZ pro-oncogenic activity depends on EPH-ephrin signaling final deregulation. Finally, we started to dissect the mechanism underlying the TAZ-AS202 regulatory activity on EPHB2 in lung cancer, which may involve the existence of an intermediate transcription factor and is the object of our ongoing research.

A phase II, single arm study of CarbopLatin plus Etoposide with Bevacizumab and Atezolizumab in patients with exTEnded-disease small-cell lung cancer (SCLC) – CeLEBrATE trial

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor diagnosed at extended disease SCLC (ES-SCLC) stage in about 70% of cases. The new standard of treatment for patients with ES-SCLC is a combination of platinum-etoposide chemotherapy and atezolizumab or durvalumab, two programmed cell death ligand 1 (PD-L1) inhibitory monoclonal antibodies (mAb). However, the benefit derived from the addition of PD-L1 inhibitors to chemotherapy in ES-SCLC was limited and restricted to a subset of patients. The vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor implicated in cancer angiogenesis, which is abundant in SCLC and associated with poor prognosis. Antiangiogenic agents, such as bevacizumab, a humanized mAb against VEGF, added to platinum-etoposide chemotherapy improved progression-free survival in SCLC in two trials, but it did not translate into a benefit in overall survival. Nevertheless, VEGF has also acts as a mediator of an immunosuppressive microenvironment and its inhibition can revert the immune-suppressive tumor microenvironment and potentially enhance the efficacy of immunotherapies. Based on available preclinical data, we hypothesized that VEGF inhibition by bevacizumab could improve atezolizumab efficacy in a synergistic way and designed a phase II single-arm trial of bevacizumab in combination with carboplatin, etoposide, and atezolizumab as first-line treatment in ES-SCLC. The trial, which is still ongoing, enrolled 53 patients, including those with treated or untreated asymptomatic brain metastases (provided criteria are met), who received atezolizumab, bevacizumab, carboplatin and etoposide for 4-6 cycles (induction phase), followed by maintenance with atezolizumab and bevacizumab for a maximum of 18 total cycles or until disease progression, patient refusal, unacceptable toxicity. The evaluation of efficacy of the experimental combination in terms of 1-year overall survival rate is not yet mature (primary objective of the trial). The combination was feasible and the toxicity profile manageable (secondary objective of the trial).

Omission of axillary clearance in patients with early breast cancer and positive sentinel node biopsy treated with conservative surgery: application of the ACOSOG Z011 trial in clinical practice

Background: Axillary lymph node dissection (ALND) in presence of sentinel lymph node (SLN) metastases has been the standard in breast cancer (BC) patients for many years. Today, after the publication of the ACOSOG Z0011 trial, ALND is a procedure restricted to a dwindling group of patients with a clearly metastatic axilla. Material and methods: This was a prospective observational trial involving two Italian Breast Units: Policlinico di Sant’Orsola and San Raffaele hospital. Objective was to evaluate that the omission of ALND in patients with cT1-2 cN0 BC undergoing breast conserving surgery (BCS) and histological finding of metastases in 1 or 2 SLN is not associated with a worse prognostic outcome. Primary endpoint was overall survival (OS). Secondary endpoints were disease free survival (DFS) and locoregional recurrence. All BC patients treated between the 1st of November 2020 and 31st of July 2023 with cT1-2 cN0 BC, preoperative negative axillary ultrasound and 1 or 2 metastatic SLN treated with sentinel node biopsy (SLNB) alone entered the study. Results: 795 cT1-2 cN0 BC patients underwent BCS and SLNB. Ninety patients were included. Median age was 60 (52-68) years. Seventy-five patients (83%) had T1 tumor and 15 (17%) T2. Median tumor size was 16 mm (11-19). The median SLN removed was 2 (1-3). Eighty-one patients had 1 positive SLN (90%), while 9 had 2 SLN metastasis (10%). 39 (43%) micrometastases were identified and 51 macrometastasis (57%). All patients underwent radiotherapy. Seventeen (19%) performed adjuvant chemotherapy. Two received immunotherapy with trastuzumab and pertuzumab. Endocrine therapy was given to 84 (93%). At a median follow-up of 19 months (IQR 13-23) OS and DFS were 100%. No loco-regional recurrence was seen. Conclusion: The preliminary results of our study confirm that omitting ALND in patients meeting Z011 criteria is oncologically safe and should be the standard of care.