New insights into the biology and development of lung cancer in never smokers-implications for early detection and treatment.

Lung cancer is the leading cause of cancer deaths worldwide. Despite never smokers comprising between 10 and 25% of all cases, lung cancer in never smokers (LCNS) is relatively under characterized from an etiological and biological perspective. The application of multi-omics techniques on large patient cohorts has significantly advanced the current understanding of LCNS tumor biology. By synthesizing the findings of multi-omics studies on LCNS from a clinical perspective, we can directly translate knowledge regarding tumor biology into implications for patient care. Primarily focused on never smokers with lung adenocarcinoma, this review details the predominance of driver mutations, particularly in East Asian patients, as well as the frequency and importance of germline variants in LCNS. The mutational patterns present in LCNS tumors are thoroughly explored, highlighting the high abundance of the APOBEC signature. Moreover, this review recognizes the spectrum of immune profiles present in LCNS tumors and posits how it can be translated to treatment selection. The recurring and novel insights from multi-omics studies on LCNS tumor biology have a wide range of clinical implications. Risk factors such as exposure to outdoor air pollution, second hand smoke, and potentially diet have a genomic imprint in LCNS at varying degrees, and although they do not encompass all LCNS cases, they can be leveraged to stratify risk. Germline variants similarly contribute to a notable proportion of LCNS, which warrants detailed documentation of family history of lung cancer among never smokers and demonstrates value in developing testing for pathogenic variants in never smokers for early detection in the future. Molecular driver subtypes and specific co-mutations and mutational signatures have prognostic value in LCNS and can guide treatment selection. LCNS tumors with no known driver alterations tend to be stem-like and genes contributing to this state may serve as potential therapeutic targets. Overall, the comprehensive findings of multi-omics studies exert a wide influence on clinical management and future research directions in the realm of LCNS.

Development and early-stage evaluation of a patient portal to enhance familial communication about hereditary cancer susceptibility testing: A patient-driven approach.

INTRODUCTION: Genetic testing for hereditary cancer syndromes (HCSs) can improve health outcomes through cancer risk mitigation strategies. Effective communication between tested individuals and their family members is key to reducing the hereditary cancer burden. Our objective was to develop a patient portal to improve familial communication for patients undergoing HCS genetic testing, followed by an early-phase evaluation. METHODS: The portal was developed following the completion of 25 semistructured interviews with individuals having undergone HCS susceptibility testing at BC Cancer. Following initial development, we recruited patients and healthcare providers to provide critical feedback informing portal refinement. Quantitative feedback was summarized using descriptive statistics, and qualitative feedback was synthesized by two reviewers who engaged in iterative discussion within the research team to prioritize recommendations for integration. RESULTS: The patient portal includes four key components consisting of (a) targeted educational information about hereditary cancer and HBOC syndrome associated risks and testing process overview, (b) a general frequently asked questions 'FAQ' page informed by the qualitative interviews, patient partner feedback, and consultation with the HCP, (c) guidance to support familial communication including a video developed with a patient partner describing their lived experience navigating the communication process and (d) a series of lay summaries of genetic test findings to support information transfer among family members. Thirteen healthcare providers and seven patients participated in user testing. Domains within which participant recommendations were provided included presentation, educational content and process clarification. CONCLUSIONS: This investigation demonstrates the value of continual integration of patient and provider preferences through the development of tools endeavouring to assist with complex genomics-informed decision-making. Our work aims to broaden the population-wide impact of HCS testing programs by improving communication processes between probands and their potentially affected family members. PATIENT OR PUBLIC CONTRIBUTION: This work involved a patient partner who was actively engaged in all aspects of the research investigation including protocol development, review and editing of all study documentation (including that of the previously published qualitative investigation), interpretation of results, as well as reviewing and editing the manuscript. Patient partners and healthcare professionals were recruited as research participants to provide critical feedback on the patient portal.

What competencies do European general practice trainees value the most? A prioritisation exercise using a Delphi-informed approach.

General Practice has changed over the past decade. Expansion of clinicians' roles may create uncertainty, stress, and overload - particular for those at the start of their career. The WONCA Europe network for medical education, EURACT, has published competency-based aims and requirements for speciality training in general practice. Greater understanding of the trainee perspective would support planning and delivery of postgraduate training curricula. This two-step study aims to provide a competency priority list, created by European early career general practitioners, to highlight skills that this generation considers highly essential in future speciality training. A competency list was drafted with trainee- and early career general practitioners from across Europe at the Vasco da Gama Movement Forum (Edinburgh, January 2022). Participants identified competencies that they regarded as most relevant for future speciality training in their respective national contexts. Competencies were coded into categories and ranked in two consecutive rounds, the first taking place online and the second at WONCA Europe (London, June 2022). After two rounds, a consensual list of three main competencies for each category was drafted. The top three competencies for each category remained the same throughout both rounds and may be considered competencies that early career general practitioners in Europe consider important for training. Prioritisation of these competencies by institutions and educators within general practice training programmes may support trainees' satisfaction and perceived preparedness for practice.

"Game Changer": Health Professionals' Views on the Clinical Utility of Circulating Tumor DNA Testing in Hereditary Cancer Syndrome Management.

BACKGROUND: We explored health professionals' views on the utility of circulating tumor DNA (ctDNA) testing in hereditary cancer syndrome (HCS) management. MATERIALS AND METHODS: A qualitative interpretive description study was conducted, using semi-structured interviews with professionals across Canada. Thematic analysis employing constant comparison was used for analysis. 2 investigators coded each transcript. Differences were reconciled through discussion and the codebook was modified as new codes and themes emerged from the data. RESULTS: Thirty-five professionals participated and included genetic counselors (n = 12), geneticists (n = 9), oncologists (n = 4), family doctors (n = 3), lab directors and scientists (n = 3), a health-system decision maker, a surgeon, a pathologist, and a nurse. Professionals described ctDNA as "transformative" and a "game-changer". However, they were divided on its use in HCS management, with some being optimistic (optimists) while others were hesitant (pessimists). Differences were driven by views on 3 factors: (1) clinical utility, (2) ctDNA's role in cancer screening, and (3) ctDNA's invasiveness. Optimists anticipated ctDNA testing would have clinical utility for HCS patients, its role would be akin to a diagnostic test and would be less invasive than standard screening (eg imaging). Pessimistic participants felt ctDNA testing would add limited utility; it would effectively be another screening test in the pathway, likely triggering additional investigations downstream, thereby increasing invasiveness. CONCLUSIONS: Providers anticipated ctDNA testing will transform early cancer detection for HCS families. However, the contrasting positions on ctDNA's role in the care pathway raise potential practice variations, highlighting a need to develop evidence to support clinical implementation and guidelines to standardize adoption.

Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.

Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52-0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54-0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12-0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10-1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Large-scale group genetic counseling: Evaluation of a novel service delivery model in a Canadian hereditary cancer clinic.

Increasing demand for genetic services has led to the development of streamlined genetic counseling (GC) models. We piloted large-scale group pre-test GC with up to 50 patients per group and compared this to a traditional one-on-one approach. Patients referred to the British Columbia (BC) Cancer Hereditary Cancer Program were eligible if they had: (a) family history meeting our program's referral criteria; (b) no relevant personal history of cancer; (c) no prior genetic testing in the family; and (d) no living testable relative in BC. Patient-reported outcome measures included: (a) Genetic Counselling Outcome Scale (GCOS) prior to pre-test GC (T1) and at 4 weeks post-test GC (T2); (b) Satisfaction Survey after pre-test GC; and (c) the Multidimensional Impact of Cancer Risk Assessment (MICRA) for patients undergoing testing (4 weeks after post-test GC). In total, 391 patients underwent GC, 184 by group and 207 by one-on-one appointments. Between May 2018 and May 2019, 6 pre-test group sessions were conducted (median number of patients per group = 28; range 15-48). 8% of patients (n = 32) declined large group GC due to personal preference for one-on-one GC. There were no statistically significant differences in MICRA and GCOS survey results when comparing the pre-test large group versus traditional pre-test one-on-one models (based on 3 MICRA subscales: p = 0.063, p = 0.612, p = 0.842; and GCOS p = 0.169). Overall, the large group pre-test counseling approach was more time-efficient with 15-48 patient group sessions conducted over a mean duration of 80 min as compared to 42 min per patient with the traditional one-on-one GC model. Large-scale group GC was feasible and acceptable to patients and represents a novel streamlined model for GC to enable timely access to cancer genetic services.

Barriers and Facilitators to Participation in Health Screening: an Umbrella Review Across Conditions.

Screening is an essential prevention practice for a number of health conditions. However, screening coverage remains generally low. Studies that investigate determinants of screening participation are becoming more common, but oftentimes investigate screening for health conditions in an individualized rather than integrated fashion. In routine clinical practice, however, healthcare professionals are often confronted with situations in which several screening procedures are recommended for the same patient. The consideration of their common determinants may support a more integrated screening approach. The objectives of this umbrella review were therefore to examine: 1) the determinants (barriers and facilitators) that have been identified in relation to recommended health screening procedures; and 2) the modifiable determinants (in primary care) common across health conditions or specific to individual procedures. Results were presented through a narrative synthesis. PubMed, PsycInfo and Cochrane were searched up to January 2022. Systematic reviews reporting determinants of participation in health screening procedures with grade A or B recommendation according to the US Preventive Services Task Force were included. A total of 85 systematic reviews were included, most which contained both qualitative and quantitative studies on determinants that describe individual factors (961 occurrences), social factors (113 occurrences, healthcare professional factors (149 occurrences), health system factors (105 occurrences) and screening procedure factors (99 occurrences). The most studied screening procedures concerned cervical cancer/human papillomavirus (n = 33), breast cancer (n = 28), colorectal cancer (n = 25) and the human immunodeficiency virus (n = 12). Other conditions have been under-studied (e.g. cardiovascular problems, lung cancer, syphilis). The individual domain, including determinants such as knowledge, beliefs and emotions, was the most covered across health conditions. Healthcare professional's recommendations and the quality of patient-provider communication were identified to have a strong influence on screening participation in most conditions. The other three domains included determinants which were more specific to a condition or a population. Various determinants modifiable in primary care were found in the individual domain and in the health system, healthcare professional and screening procedure domains. Quality was assessed as low for most systematic reviews included. The identification of various modifiable determinants common across conditions highlights the potential of an integrated screening participation approach. Interventions may address common determinants in a broader person-centred framework within which tailoring to specific procedures or populations can be considered. This approach needs to be explored in intervention studies. The systematic review registration is PROSPERO CRD42019126709.

Comparing algorithms for characterizing treatment effect heterogeneity in randomized trials.

The identification and estimation of heterogeneous treatment effects in biomedical clinical trials are challenging, because trials are typically planned to assess the treatment effect in the overall trial population. Nevertheless, the identification of how the treatment effect may vary across subgroups is of major importance for drug development. In this work, we review some existing simulation work and perform a simulation study to evaluate recent methods for identifying and estimating the heterogeneous treatments effects using various metrics and scenarios relevant for drug development. Our focus is not only on a comparison of the methods in general, but on how well these methods perform in simulation scenarios that reflect real clinical trials. We provide the R package benchtm that can be used to simulate synthetic biomarker distributions based on real clinical trial data and to create interpretable scenarios to benchmark methods for identification and estimation of treatment effect heterogeneity.

An evaluation of memory and attention in BRCA mutation carriers using an online cognitive assessment tool.

BACKGROUND: The objective of this study was to evaluate the impact of various surgical, hormonal, and lifestyle factors on memory and attention in women with a BRCA1 or BRCA2 mutation. METHODS: BRCA mutation carriers enrolled in a longitudinal study were invited to complete an online brain health assessment tool designed to screen for cognitive deficits. Four measures of memory and executive attention were assessed individually, and an overall score was compiled adjusting for age. Exposures, including preventive surgery, hormone use, and lifestyle factors, were captured by questionnaire. Performance on each of the 5 subtasks was analyzed according to various exposures. Analysis of covariance was used to compare overall scores. RESULTS: In total, 880 women completed the online cognitive assessment. The average age of the participants was 54 years (range, 23-86 years). The mean overall test score was 54.4 (range, 0-93). The individual subtask scores declined with age at test completion (P < .0001) and increased with level of education (P ≤ .01). Women who underwent a preventive oophorectomy had a significantly higher overall score compared with women who did not undergo this surgery (55.5 vs 50.5; P = .01). Reconstructive breast surgery was also associated with a higher overall score (56.5 vs 52.3; P = .005). Chemotherapy and hormone-replacement therapy were not predictive of the overall score. CONCLUSIONS: These findings are reassuring to high-risk women who undergo early surgical menopause for their cancer predisposition. Further studies are needed to evaluate cognitive function over time when memory deficits become more prevalent.

Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers.

PURPOSE: It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80. METHODS: Subjects had no history of cancer and both breasts intact at age 60 (n = 699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk. RESULTS: Over a mean follow-up of 7.9 years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk. CONCLUSIONS: Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.

Improved structural variant interpretation for hereditary cancer susceptibility using long-read sequencing.

PURPOSE: Structural variants (SVs) may be an underestimated cause of hereditary cancer syndromes given the current limitations of short-read next-generation sequencing. Here we investigated the utility of long-read sequencing in resolving germline SVs in cancer susceptibility genes detected through short-read genome sequencing. METHODS: Known or suspected deleterious germline SVs were identified using Illumina genome sequencing across a cohort of 669 advanced cancer patients with paired tumor genome and transcriptome sequencing. Candidate SVs were subsequently assessed by Oxford Nanopore long-read sequencing. RESULTS: Nanopore sequencing confirmed eight simple pathogenic or likely pathogenic SVs, resolving three additional variants whose impact could not be fully elucidated through short-read sequencing. A recurrent sequencing artifact on chromosome 16p13 and one complex rearrangement on chromosome 5q35 were subsequently classified as likely benign, obviating the need for further clinical assessment. Variant configuration was further resolved in one case with a complex pathogenic rearrangement affecting TSC2. CONCLUSION: Our findings demonstrate that long-read sequencing can improve the validation, resolution, and classification of germline SVs. This has important implications for return of results, cascade carrier testing, cancer screening, and prophylactic interventions.

Genetic testing for hereditary cancer syndromes: patient recommendations for improved risk communication.

BACKGROUND: Multi-gene panel testing is replacing single-gene testing for patients with suspected hereditary cancer syndromes. The detection of a hereditary cancer syndrome allows tested individuals to initiate enhanced primary and secondary prevention efforts-where available-with a view to reduce disease burden. Current policy prevents testing programmes from communicating genetic test results with potentially affected family members, yet it is well documented that tested individuals face multiple challenges in initiating such discussions with relatives. OBJECTIVE: In response to this challenge, we sought patient recommendations about how to improve genetic risk communication to enhance interfamilial discussions about primary and secondary disease prevention. DESIGN: We conducted 25 semi-structured interviews with individuals who received genetic testing through British Columbia's Hereditary Cancer Program between 2017 and 2018. Interviews were professionally transcribed and analysed using a constant comparative approach. RESULTS: Participants described difficulty engaging in conversations with relatives who were resistant to receiving genetic risk information, when communicating with younger relatives and where participants reported strained familial relationships. Participants recommended that testing facilities provide a summary of results and implications and that resources be made available to prepare patients for challenging discussions with family members. DISCUSSION: Our study demonstrates that individuals undergoing genetic testing for suspected hereditary cancer syndromes would benefit from additional supportive resources alongside genetic counselling. Providing this on-going support will enhance the accurate and transparent communication of risk to facilitate the uptake of cascade testing and enhanced prevention strategies.

BRCA mutation testing for first-degree relatives of women with high-grade serous ovarian cancer.

BACKGROUND: Women with high-grade serous ovarian cancer (HGSC) have a 20% chance of carrying a BRCA1 or 2 mutation. Not all undergo genetic testing, and there is a large legacy group of untested patients. Their female first-degree relatives (FDR) may not qualify for testing unless they have specific ethnicity, or personal/family cancer history. We conducted a cost-effectiveness analysis to evaluate risk-reducing strategies for these FDR who are ineligible for testing. METHODS: A Markov Monte Carlo simulation model estimated the costs and benefits of 3 strategies for female FDR of HGSC patients whose BRCA status is unknown: (1) no BRCA testing; (2) universal BRCA testing, followed by risk-reducing bilateral salpingo-oophorectomy (RRBSO) for mutation carriers; (3) universal RRBSO, without BRCA testing. Effectiveness was estimated in quality-adjusted life year (QALY) gains over a 50-year time horizon. Sensitivity analyses accounted for uncertainty around various parameters. RESULTS: Universal BRCA testing for female FDR of women with HGSC yielded a higher average QALY gain at acceptable cost compared to no BRCA testing, with an incremental cost-effectiveness ratio of $7888 per QALY. Universal BRCA testing was more effective and less costly than universal RRBSO (19.20 QALYs vs. 18.52 QALYs, and $10,135 vs. $14,231, respectively). Results were stable over wide ranges of plausible costs and estimates. Compliance with hormone replacement therapy had to exceed 79.3% for universal RRBSO to be the most effective strategy. CONCLUSION: BRCA mutation testing should be offered to all female first-degree relatives of women with high-grade serous ovarian cancer when BRCA mutation status is unknown.

Versatile strategy for controlling the specificity and activity of engineered T cells.

The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR-T--cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as "switch" molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a "universal" anti-FITC-directed CAR-T cell. Optimization of this CAR-switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR-T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy.

Willingness of breast cancer patients to undergo biopsy and breast cancer clinicians' practices around seeking biopsy at the time of breast cancer relapse.

PURPOSE: The practice of seeking a biopsy to confirm a metastatic relapse of a prior breast cancer is individualized. Tumor samples have well-recognized importance in clinical and translational research, but also an increasing role in routine care. We sought to determine the attitudes of patients and breast cancer clinicians about biopsy at breast cancer relapses. METHODS: Consenting breast cancer patients and clinicians completed questionnaires with scenarios of decreasing personal benefit and increasing discomfort or inconvenience associated with biopsy at relapse of a prior breast cancer. For each scenario, patients were asked whether they would, would not, or were unsure about agreeing to a biopsy. Clinicians provided information about their practice, research activities, and usual biopsy habits. They were asked to estimate how often patients would agree to a biopsy under each of the conditions presented to patient participants. RESULTS: The majority of patients expressed a willingness to undergo a biopsy procedure of modest inconvenience and discomfort to establish an uncertain diagnosis, guide treatment, to participate in a trial, or for research purposes only. About 50% of patients indicated that they would undergo an invasive biopsy procedure requiring IV sedation or general anesthetic for purely altruistic reasons. In spite of being a largely academic group, clinician respondents underestimated patient willingness to have a biopsy in all scenarios, particularly when there was no attached personal benefit. CONCLUSION: Breast cancer patients were very willing to undergo biopsy at breast cancer relapse for their routine care, clinical trials, or for research only. Clinicians act as the intermediary between patients and tumor tissue repositories, and clinician perceptions and practices should shift to match the altruistic attitudes of breast cancer patients.

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial.

BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING: Canadian Cancer Society Research Institute and Pfizer.

A genetically encoded aza-Michael acceptor for covalent cross-linking of protein-receptor complexes.

Selective covalent bond formation at a protein-protein interface potentially can be achieved by genetically introducing into a protein an appropriately "tuned" electrophilic unnatural amino acid that reacts with a native nucleophilic residue in its cognate receptor upon complex formation. We have evolved orthogonal aminoacyl-tRNA synthetase/tRNACUA pairs that genetically encode three aza-Michael acceptor amino acids, N(ε)-acryloyl-(S)-lysine (AcrK, 1), p-acrylamido-(S)-phenylalanine (AcrF, 2), and p-vinylsulfonamido-(S)-phenylalanine (VSF, 3), in response to the amber stop codon in Escherichia coli. Using an αErbB2 Fab-ErbB2 antibody-receptor pair as an example, we demonstrate covalent bond formation between an αErbB2-VSF mutant and a specific surface lysine ε-amino group of ErbB2, leading to near quantitative cross-linking to either purified ErbB2 in vitro or to native cellular ErbB2 at physiological pH. This efficient biocompatible reaction may be useful for creating novel cell biological probes, diagnostics, or therapeutics that selectively and irreversibly bind a target protein in vitro or in living cells.

Therapeutic applications of an expanded genetic code.

To date, over 100 noncanonical amino acids (ncAAs) have been genetically encoded in living cells in order to expand the functional repertoire of the canonical 20 amino acids. More recently, this technology has been expanded to the field of protein therapeutics, where traditional chemical methods typically result in heterogeneous mixtures of proteins. The site-specific incorporation of ncAAs with orthogonal chemical groups allows unprecedented control over the site of conjugation and the stoichiometry, thus facilitating the rational optimization of the biological functions and/or pharmacokinetics of biologics. Herein, we discuss the recent contribution of ncAA technology in enhancing the pharmacological properties of current protein therapeutics as well as developing novel therapeutic modalities.

Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.

OBJECTIVES: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. METHODS: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. RESULTS: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. CONCLUSION: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients.