Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers.

Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.

Liquid Biopsy Snapshots of Key Phosphoproteomic Pathways in Lung Cancer Patients for Diagnosis and Therapy Monitoring.

Phosphorylation is a post-translational modification in proteins that changes protein conformation and activity for regulating signal transduction pathways. This mechanism is frequently impaired in lung cancer, resulting in permanently active constitutive phosphorylation to initiate tumor growth and/or reactivate pathways in response to therapy. We developed a multiplexed phosphoprotein analyzer chip (MPAC) that enables rapid (detection time: 5 min) and sensitive (LOD: 2 pg/µL) detection of protein phosphorylation and presents phosphoproteomic profiling of major phosphorylation pathways in lung cancer. We monitored phosphorylated receptors and downstream proteins involved in mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR pathways in lung cancer cell line models and patient-derived extracellular vesicles (EV). Using kinase inhibitor drugs in cell line models, we found that the drug can inhibit the phosphorylation and/or activation of the kinase pathway. We then generated a phosphorylation heatmap by EV phosphoproteomic profiling of plasma samples isolated from 36 lung cancer patients and 8 noncancer individuals. The heatmap showed a clear difference between the noncancer and cancer samples and identify the specific proteins that are activated in the cancer samples. Our data also showed that MPAC could monitor immunotherapy responses by assessment of the phosphorylation states of the proteins, particularly for PD-L1. Finally, with a longitudinal study, we found that the phosphorylation levels of the proteins were indicative of a positive response to therapy. We believe that this study will lead to personalized treatment by providing a better understanding of the active and resistant pathways and will provide a tool for selecting combined and targeted therapies for precision medicine.

Prognostic value of integrating circulating tumour cells and cell-free DNA in non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC) often presents at an incurable stage, and majority of patients will be considered for palliative treatment at some point in their disease. Despite recent advances, the prognosis remains poor, with a median overall survival of 12-18 months. Liquid biopsy-based biomarkers have emerged as potential candidates for predicting prognosis and response to therapy in NSCLC patients. This pilot study evaluated whether combining circulating tumour cells and clusters (CTCs) and cell-free DNA (cfDNA) can predict progression-free survival (PFS) in NSCLC patients. Methods: CTC and cfDNA/ctDNA from advanced stage NSCLC patients were measured at study entry (T0) and 3-months post-treatment (T1). CTCs were enriched using a spiral microfluidic chip and characterised by immunofluorescence. ctDNA was assessed using an UltraSEEK® Lung Panel. Kaplan-Meier plots were generated to investigate the contribution of the presence of CTC/CTC clusters and cfDNA for PFS. Cox proportional hazards analysis compared time to progression versus CTC/CTC cluster counts and cfDNA levels. Results: Single CTCs were found in 14 out of 25 patients, while CTC clusters were found in 8 out of the 25 patients at T0. At T1, CTCs were found in 7 out of 18 patients, and CTC clusters in 1 out of the 18 patients. At T0, CTC presence and the combination of CTC cluster counts with cfDNA levels were associated with shorter PFS, p = 0.0261, p = 0.0022, respectively. Conclusions: Combining CTC cluster counts and cfDNA levels could improve PFS assessment in NSCLC patients. Our results encourage further investigation on the combined effect of CTC/cfDNA as a prognostic biomarker in a large cohort of advanced stage NSCLC patients.

Pembrolizumab-induced toxic epidermal necrolysis: case report.

A 63-year-old man with metastatic lung adenocarcinoma presented with biopsy confirmed toxic epidermal necrolysis (TEN). Symptoms commenced following 3 cycles of carboplatin, pemetrexed and pembrolizumab, with the first cycle given ~9.5 weeks prior to presentation. The patient was managed with immunosuppressive therapy including high dose methylprednisolone, cyclosporine, intravenous immunoglobulin, antibiotics and optimal skin care, and achieved excellent recovery of the skin lesions with minimal sequelae. This rare occurrence of pembrolizumab-induced TEN has only been reported previously in a few cases with limited evidence on management. Given the increasing use of immune checkpoint inhibitors and the long half-life of these agents, our case highlights the importance of recognizing this complication and of a multidisciplinary approach to management.

The identification of circulating tumour DNA using MassARRAY technology in non-small-cell lung cancer (NSCLC).

OBJECTIVES: Attaining tumour material from lung cancer patients can be challenging with limited sample availability. Therefore, non-invasive means of assessing tumour material is becoming increasingly more important. Circulating tumour DNA (ctDNA), extracted from a blood sample is appealing for the patient, and can be performed serially over the course of treatment. MATERIALS AND METHODS: Here, we describe an approach for profiling the blood samples of 103 NSCLC patients for 73 variants in ctDNA across a panel of actionable lung cancer mutations using the UltraSEEK lung Panel (Agena Biosciences). RESULTS: Our cross-sectional study showed tumour and blood concordance in the detection of KRAS mutations (G12C, G12D, G12A/V, G12R, G12RC, Q61H) in 17/27 (63%), EGFR mutations (e746_a750del, e747_A750, T790M, L861Q) in 16/20 (80%) with additional PIK3CA_p545K mutations across both cohorts. In patients without reported tumour mutations, 11/56 (19.6%) presented with plasma mutations across EGFR, KRAS and PIK3CA. Where ctDNA mutations were measured longitudinally (n = 4 patients), the individual mutations mirrored the response to therapy/progression of disease. CONCLUSION: Whilst preliminary, this study demonstrates the utility of detecting clinically actionable mutations in the blood samples of NSCLC patients at the time of presentation, and over the course of therapy.

Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review.

Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DNA damage. This occurs by manipulating the chromatin structure and the expression of essential proteins that are critical for homologous recombination and non-homologous end joining repair pathways. Inhibitors of histone deacetylases and DNA methyltransferases have demonstrated efficacy in the clinic and represent a promising approach for cancer therapy. The aims of this review are to summarise the role of histone deacetylase and DNA methyltransferase inhibitors involved in DNA double strand break repair and explore their current and future independent use in combination with other DNA repair inhibitors or pre-existing therapies in the clinic.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer.

Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response 6for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.

High-Plex and High-Throughput Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC).

Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour-immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis (n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT (n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME (n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples, and demonstrate the power of such tools for a new generation of pathology research.

Unilateral autoimmune inner ear disease in a patient with lung cancer treated with nivolumab.

A 69-year-old male presented with early stage non-small cell lung cancer in 2016. The tumor was resected; however, the patient experienced recurrence 2 years later and subsequently received paclitaxel/carboplatin concurrently with radiotherapy. Within weeks of completing this treatment, he developed a symptomatic pancoast tumor secondary to disease progression and commenced second line nivolumab. Following the second dose of nivolumab, he developed acute unilateral right hearing loss. He commenced intravenous methylprednisolone followed by a slow taper of oral prednisolone. With steroids, he noted a gradual improvement in hearing, confirmed by audiology. Restaging imaging post-nivolumab demonstrated a complete metabolic response. Two prior cases have reported bilateral sensorineural hearing loss post-immune checkpoint inhibitor (ICI). We postulate the hearing impairment relates to the development of autoimmune inner ear disease. To our knowledge, this is the only case of a patient experiencing unilateral loss of hearing following an ICI.

Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC).

Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC). Significant developments have taken place which highlight the differences in tumor biology that exist between the mutant and wild-type subtypes of NSCLC. Patients with advanced EGFR-mutant NSCLC have a variety of EGFR-targeting agents available proven to treat their disease. This has led to superior patient outcomes when used as a monotherapy over traditional cytotoxic systemic therapy. Attempts at combining EGFR agents with other anticancer systemic treatment options, such as chemotherapy, antiangiogenic agents, and immunotherapy, have shown varied outcomes. Currently, no specific combination stands out to cause a shift away from the use of single-agent EGFR inhibitors in the first-line setting. Similarly, adjuvant EGFR inhibitors, are yet to significantly add to patient overall survival if used at earlier timepoints in the disease course. Liquid biopsy is an evolving technology with potential promise of being incorporated into the management paradigm of this disease. Data are emerging to suggest that this technique may be capable of identifying early resistance mechanisms and consequential disease progression on the basis of the analysis of blood-based circulating tumor cells.

Challenges associated with systemic therapy for older patients with inoperable non-small cell lung cancer.

INTRODUCTION: Lung cancer is the most common cancer diagnosed worldwide. Data from several studies fall short to make appropriate conclusions on the management for elderly patients. The discovery of targeted therapy and immunotherapy has allowed these patients access to a wider array of options. AREAS COVERED: The authors review research for treating older patients with lung cancer focusing on research performed in this patient population. Data are presented relating to chemotherapy, immunotherapy, and targeted therapy in the advanced setting. EXPERT OPINION: Elderly patients particularly benefit from advances in systemic therapy. Based on the tumor profile, treatment with targeted therapy or immunotherapy should be favored over chemotherapy where possible in the elderly population. Elderly patients benefit from EGFR, ALK, and ROS-1 inhibition in the setting of these tumor alterations. These agents should be utilized early in the treatment course. Across many studies, the benefit from immunotherapy is seen irrespective of age. Favorable outcomes and toxicity profiles from immunotherapy compared to chemotherapy are well described. Chemotherapy should be offered with caution after a detailed assessment. Options include combination or single-agent chemotherapy regimens. Best supportive care alone is a reasonable option in the frailer, highly co-morbid patient.

The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer.

Despite advances in our understanding of the molecular biology of the disease and improved therapeutics, lung cancer remains the most common cause of cancer-related deaths worldwide. Therefore, an unmet need remains for improved treatments, especially in advanced stage disease. Genomic instability is a universal hallmark of all cancers. Many of the most commonly prescribed chemotherapeutics, including platinum-based compounds such as cisplatin, target the characteristic genomic instability of tumors by directly damaging the DNA. Chemotherapies are designed to selectively target rapidly dividing cells, where they cause critical DNA damage and subsequent cell death (1, 2). Despite the initial efficacy of these drugs, the development of chemotherapy resistant tumors remains the primary concern for treatment of all lung cancer patients. The correct functioning of the DNA damage repair machinery is essential to ensure the maintenance of normal cycling cells. Dysregulation of these pathways promotes the accumulation of mutations which increase the potential of malignancy. Following the development of the initial malignancy, the continued disruption of the DNA repair machinery may result in the further progression of metastatic disease. Lung cancer is recognized as one of the most genomically unstable cancers (3). In this review, we present an overview of the DNA damage repair pathways and their contributions to lung cancer disease occurrence and progression. We conclude with an overview of current targeted lung cancer treatments and their evolution toward combination therapies, including chemotherapy with immunotherapies and antibody-drug conjugates and the mechanisms by which they target DNA damage repair pathways.

Computed tomography texture analysis of response to second-line nivolumab in metastatic non-small cell lung cancer.

OBJECTIVES: Assess computed tomography texture analysis of patients likely to benefit from nivolumab. MATERIALS & METHODS: Texture analysis was used to quantify heterogeneity within the largest tumor before immunotherapy. Histogram analysis was classified as hyperdense (positive skewness) or hypodense (negative skewness) and subclassified on median standard deviation value or entropy measurement. RESULTS: 47 patients were included. At a median follow-up of 18 months, statistical significant differences in progression-free survival were observed when stratified by positive skewness with low entropy, hazard ratio: 0.43 (0.19-0.95); p = 0.036, and positive skewness with low standard deviation, hazard ratio: 0.42 (0.18-0.96); p = 0.04. CONCLUSION: Patients who derive a clinical benefit to Nivolumab show a computed tomography texture of a hyperdense yet homogenous tumor.

Professional burnout, work patterns and career satisfaction in medical oncologists in Ireland.

BACKGROUND: Burnout is an occupational syndrome frequently encountered within the healthcare profession. It is characterised by emotional exhaustion (EE), depersonalisation (DP) and a low sense of personal accomplishment (PA). Its negative impact extends to the physician, patient and overall service provision. AIMS: The aim of this study was to evaluate work patterns, the prevalence of burnout and its associations in medical oncology consultants and specialist registrars (SpRs) in Ireland. METHODS: Participants were invited to partake in an anonymised online survey. Burnout domains were measured using the validated Maslach Burnout Inventory. Associations between variables were evaluated using the Mann-Whitney U and Kruskal-Wallis tests (continuous), and chi-square and Fisher's exact testing (categorical). RESULTS: Seventy-four physicians were contacted to participate, 44 (59%) completed the survey. The majority (71%) work ≥ 50 h a week, with 57% having additional on-call commitments of ≥ 5 days/month. Burnout is defined by a high score in EE combined with a high DP and/or low PA was identified in 45% of consultants and 20% of SpRs. Longer working hours (≥ 60 h/ week) were found to be associated with both high EE (p = 0.049) and DP (p = 0.019). Higher EE scores were demonstrated in those ≥ 40 years (p = 0.04). The majority (86%) reported they would become an oncologist again. CONCLUSION: One or more of the symptoms of burnout is highly prevalent in medical oncologists in Ireland. With increasing pressure on resources, burnout is expected to increase. Attention to strategies for prevention needs to be prioritised within our healthcare system.

Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer.

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1-2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18-47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.

Targeting BRAF mutations in non-small cell lung cancer.

The management of non-small cell lung cancer (NSCLC) has changed significantly with the discovery of specific drug targets. These drugs have helped transform patient care and outcomes. BRAF mutated NSCLC is now recognised as a rare form of lung cancer. Data has begun to emerge supporting the use of BRAF/MEK inhibitors that target BRAFV600E mutations in the mitogen-activated protein kinase (MAPK) pathway. Multiple phase 2 studies have been performed assessing the effectiveness of single agent BRAF inhibition and combination BRAF/MEK inhibition in pretreated and untreated patient populations. Consistently overall response rate (ORR) and progression free survival (PFS) are improved with the addition of a MEK inhibitor. A 2-cohort phase 2 study demonstrated an ORR of 33% vs. 67% and PFS of 5.5 vs. 10.2 months in those treated with single agent dabrafenib vs. dabrafenib and trametinib respectively. A similar ORR of 63% and PFS of 10.9 months was seen in a separate phase 2 study in patients treated with Dabrafenib and Trametinib in the first line setting. Immunotherapy is beginning to show promise as an active therapy in BRAF mutated NSCLC in both V600E and non-V600E subtypes; however, this requires further study and clarification. BRAFV600E mutated NSCLC treated with chemotherapy have been widely reported to be associated with worse outcomes when compared to those without a mutation. With efficacy of combination BRAF/MEK established and early evidence of immune checkpoint inhibitor activity careful consideration should be given when choosing the most appropriate therapy in this select patient cohort.

Epidermal growth factor receptor mutated oligometastatic adeno-squamous lung cancer transformation to small cell lung cancer.

A 66-year-old non-smoker was diagnosed with stage IIIB, epidermal growth factor receptor (EGFR) mutated, squamous cell lung carcinoma. Treatment included chemotherapy, 35 fractions of radiotherapy and later Gefitinib for 3.5 years. On progression he developed a solitary brain and liver lesion. The brain lesion was excised and histology revealed adenocarcinoma of a lung primary. Afatanib was commenced for 1 further year. At the second time of progression re-biopsy identified small cell carcinoma. He completed four cycles of Carboplatin and Etoposide however deteriorated on completion of chemotherapy. EGFR directed treatment is associated with improved patient outcomes. It has been suggested that EGFR mutated squamous cell carcinoma more likely represent mixed morphology or poorly differentiated adenocarcinoma. Patients with oligometastatic progression can be treated beyond progression however the addition of a local therapy may be required. Small cell transformation is described as a rare mechanism of resistance to EGFR treatment as in our case.

Extended adjuvant endocrine therapy in hormone-receptor-positive early breast cancer.

PURPOSE OF REVIEW: The risk of relapse associated with oestrogen receptor-positive early breast cancer persists for at least 15 years after diagnosis. Several large clinical trials have examined extended adjuvant endocrine therapy. RECENT FINDINGS: The MA.17 trial demonstrated improved disease-free survival (DFS) with use of letrozole for 5 years after some years of tamoxifen and an overall survival advantage for this approach in women with node-positive oestrogen receptor-positive cancer at diagnosis. The subsequent adjuvant tamoxifen - to offer more? and adjuvant tamoxifen: longer against shorter trials demonstrated a DFS advantage for 10 years of tamoxifen over 5 years. The recently reported MA.17R trial randomized women who had already completed 5 years of aromatase inhibitor therapy with or without previous tamoxifen to further 5 years of letrozole or placebo. DFS was significantly improved in the extended letrozole group, quality of life was similar but bone fracture rates were higher. The absolute benefit in terms of reduced distant recurrences in these studies is modest, and tolerability and compliance challenges remain. SUMMARY: Physicians and patients now have multiple evidence-based treatment options for women who complete 5 years of adjuvant endocrine therapy. Extended therapy with either tamoxifen or letrozole should be considered for all and decision based on menopausal status, individual risk, tolerance and magnitude of potential benefit.