Germline mutations in high penetrance genes are associated with worse clinical outcomes in patients with non-small cell lung cancer.

Objective: To determine the frequency of pathogenic mutations in high-penetrance genes (HPGs) in patients with non-small cell lung cancer (NSCLC) and identify whether such mutations are associated with clinicopathologic outcomes. Methods: Patients with NSCLC who had consented to participate in a linked clinical database and biorepository underwent germline DNA sequencing using a next-generation sequencing panel that included cancer-associated HPGs and cancer risk-associated single nucleotide polymorphisms (SNPs). These data were linked to the clinical database to assess for associations between germline variants and clinical phenotype using Fisher's exact test and multivariable logistic and Cox regression. Results: We analyzed 151 patients, among whom 33% carried any pathogenic HPG mutation and 23% had a genetic risk score (GRS) >1.5. Among the patients without any pathogenic mutation, 31% were at cancer stage II or higher, compared with 55% of those with 2 types of HPG mutations (P = .0293); 40% of patients with both types of HPG mutations had cancer recurrence, compared with 21% of patients without both types (P = .0644). In multivariable analysis, the presence of 2 types of HPG mutations was associated with higher cancer stage (odds ratio [OR], 3.32; P = .0228), increased recurrence of primary tumor (OR, 2.93; P = .0527), shorter time to recurrence (hazard ratio [HR], 3.03; P = .0119), and decreased cancer-specific (HR, 3.53; P = .0039) and overall survival (HR, 2.44; P = .0114). Conclusions: The presence of mutations in HPGs is associated with higher cancer stage, increased risk of recurrence, and worse cancer-specific and overall survival in patients with NSCLC. Further large studies are needed to better delineate the role of HPGs in cancer recurrence and the potential benefit of adjuvant treatment in patients harboring such mutations.

Alliance Foundation Trial 09: A Randomized, Multicenter, Phase 2 Trial Evaluating Two Sequences of Pembrolizumab and Standard Platinum-Based Chemotherapy in Patients With Metastatic NSCLC.

INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a "pick a winner" design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively (p = 0.93). The progression-free survival in arms A and B was as follows: hazard ratio of B versus A equals to 1.06, 95 % CI: 0.68-1.66, p value equals to 0.84, and median progression-free survival of 5.8 months and 4 months, respectively. The overall survival was as follows: hazard ratio of B versus A equals to 1.04, 95 % CI: 0.63-1.74, p value equals to 0.85, and median overall survival of 15.5 months and 14 months, respectively. CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted.

Safe Transitions and Congregate Living in the Age of COVID-19: A Retrospective Cohort Study.

BACKGROUND: COVID-19 represents a grave risk to residents in skilled nursing facilities (SNFs). OBJECTIVE: To determine whether establishment of an appropriate-use committee was associated with a reduction in SNF utilization. DESIGNS, SETTING, AND PARTICIPANTS: Retrospective cohort study at NorthShore University HealthSystem, a multihospital integrated health system in northern Illinois. Participants were patients hospitalized from March 19, 2019, to July 16, 2020. INTERVENTION: Creation of a multidisciplinary committee to assess appropriateness of discharge to SNF following hospitalization. MAIN OUTCOME AND MEASURES: Primary outcome was total discharges to SNFs. Secondary outcomes were new discharges to SNFs, readmissions, length of stay (LOS), and COVID-19 incidence following discharge. RESULTS: Matched populations pre and post intervention were each 4424 patients. Post intervention, there was a relative reduction in total SNF discharges of 49.7% (odds ratio [OR], 0.42; 95% CI, 0.38-0.47) and in new SNF discharges of 66.9% (OR, 0.29; 95% CI, 0.25-0.34). Differences in readmissions and LOS were not statistically significant. For patients discharged to a SNF, 2.99% (95% CI, 1.59%-4.39%) developed COVID-19 within 30 days, compared with 0.26% (95% CI, 0.29%-0.93%) of patients discharged to other settings (P < .001). CONCLUSION: Implementing a review committee to assess for appropriateness of SNF use after a hospitalization during the COVID-19 pandemic is highly effective. There was no negative impact on safety or efficiency of hospital care, and reduced SNF use likely prevented several cases of COVID-19. This model could serve as a template for other hospitals to reduce the risks of COVID-19 in SNFs and as part of a value-based care strategy.

Docetaxel, Oxaliplatin, and 5-Fluorouracil (DOF) in Metastatic and Unresectable Gastric/Gastroesophageal Junction Adenocarcinoma: A Phase II Study with Long-Term Follow-Up.

LESSONS LEARNED: Adding docetaxel to the modified FOLFOX7 backbone (DOF) is a feasible three-drug combination therapy for advanced gastric cancer with high activity, providing evidence that leucovorin is not necessary in this setting.The DOF regimen represents an alternative to the FLOT (5-FU 2,600 mg/m2 as 24-hour infusion with leucovorin 200 mg/m2, oxaliplatin 85 mg/m2, and docetaxel 50 mg/m2) regimen that can be considered in select patients with advanced gastric cancer and is a potential choice in the curative setting. BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) demonstrates high response rates in advanced gastric cancer, albeit with increased toxicity. Given the efficacy of platinum-taxane-fluoropyrimidine regimens, this phase II study evaluated the efficacy and toxicity of docetaxel, oxaliplatin, and 5-FU (DOF) for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. METHODS: Patients with metastatic or unresectable gastric or GEJ adenocarcinoma with no prior therapy for metastatic disease received docetaxel 50 mg/m2 on day 1, oxaliplatin 85 mg/m2 on day 1, and 5-FU 2,400 mg/m2 continuous intravenous infusion over 46 hours; cycles were repeated every 2 weeks. The primary endpoint was overall response rate (ORR). RESULTS: Forty-four patients were enrolled. Assessment of treatment response and toxicity was feasible in 41 and 43 patients, respectively. ORR was 73.2% (68.3% partial response; 4.9% complete response). Therapy was discontinued for progressive disease in 53%, toxicity in 26%, and death on treatment in 16%. Two patients underwent surgical resection. Thirty-three patients (76.7%) received at least seven cycles (7-34). Grade 3-4 toxicities occurred in 31 patients (72.1%), including neutropenia (23.3%), neurologic (20.9%), and diarrhea (14.0%). Median overall survival was 10.3 months. CONCLUSION: DOF demonstrates a high response rate, expected safety profile, and prolonged survival and remains an option for select patients with unresectable or metastatic gastric or GEJ adenocarcinoma.

A Predictive 7-Gene Assay and Prognostic Protein Biomarkers for Non-small Cell Lung Cancer.

PURPOSE: This study aims to develop a multi-gene assay predictive of the clinical benefits of chemotherapy in non-small cell lung cancer (NSCLC) patients, and substantiate their protein expression as potential therapeutic targets. PATIENTS AND METHODS: The mRNA expression of 160 genes identified from microarray was analyzed in qRT-PCR assays of independent 337 snap-frozen NSCLC tumors to develop a predictive signature. A clinical trial JBR.10 was included in the validation. Hazard ratio was used to select genes, and decision-trees were used to construct the predictive model. Protein expression was quantified with AQUA in 500 FFPE NSCLC samples. RESULTS: A 7-gene signature was identified from training cohort (n = 83) with accurate patient stratification (P = 0.0043) and was validated in independent patient cohorts (n = 248, P < 0.0001) in Kaplan-Meier analyses. In the predicted benefit group, there was a significantly better disease-specific survival in patients receiving adjuvant chemotherapy in both training (P = 0.035) and validation (P = 0.0049) sets. In the predicted non-benefit group, there was no survival benefit in patients receiving chemotherapy in either set. The protein expression of ZNF71 quantified with AQUA scores produced robust patient stratification in separate training (P = 0.021) and validation (P = 0.047) NSCLC cohorts. The protein expression of CD27 quantified with ELISA had a strong correlation with its mRNA expression in NSCLC tumors (Spearman coefficient = 0.494, P < 0.0088). Multiple signature genes had concordant DNA copy number variation, mRNA and protein expression in NSCLC progression. CONCLUSIONS: This study presents a predictive multi-gene assay and prognostic protein biomarkers clinically applicable for improving NSCLC treatment, with important implications in lung cancer chemotherapy and immunotherapy.

Clinical and molecular features of innate and acquired resistance to anti-PD-1/PD-L1 therapy in lung cancer.

HYPOTHESIS: The majority of non-small cell lung cancer (NSCLC) patients treated with anti-PD-1/PD-L1 therapy develop either innate or acquired resistance. Across tumor types, the "T cell-inflamed" tumor microenvironment correlates with clinical response to immunotherapy. We hypothesize that clinical characteristics may be predictive of resistance and that "T cell-inflamed" NSCLC tumors can be identified by gene expression profiling. RESULTS: Of 93 patients, 36 (38.7%) had innate resistance and 57 (61.3%) had initial benefit to immunotherapy. Innate resistance was associated with non-smokers (p = 0.013), more involved disease sites (p = 0.011), more prior therapy (p = 0.001), and a lower albumin level (p = 0.014). Among patients with initial benefit, factors associated with subsequent progression-free survival included higher Karnofsky Performance Status (KPS) (p = 0.004) and lower depth of response to anti-PD-1 therapy (p = 0.003). A "T cell-inflamed" microenvironment was identified in 42% of TCGA adenocarcinoma samples versus 21.0% of squamous cell. DISCUSSION: Specific clinical characteristics appear to be predictive of either innate or acquired resistance to anti-PD-1/PD-L1 therapy. A "T cell-inflamed" tumor was more common in adenocarcinoma than squamous histology. METHODS: A retrospective review of NSCLC patients treated with anti-PD-1/PD-L1 monotherapy. Patients with innate resistance to anti-PD-1/PD-L1 therapy (defined as progression at first CT evaluation) were compared to patients with initial clinical benefit. Among those with initial clinical benefit, we identified prognostic factors for time to progression (acquired resistance) or death. To further corroborate our findings on limited numbers, immune gene expression profiling of all NSCLC samples from the TCGA database was also pursued.

Targeting pathways mediating resistance to anti-EGFR therapy in squamous cell carcinoma of the head and neck.

INTRODUCTION: As epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of squamous cell carcinomas of the head and neck (SCCHN), several therapeutic agents that target EGFR have been evaluated for the treatment of SCCHN. Although patients with SCCHN derive clinical benefit from anti-EGFR agents, most notably the EGFR monoclonal antibody cetuximab, these patients eventually become resistant to EGFR-based therapies; preclinical studies have shown activation of secondary signaling pathways that lead to resistance to EGFR inhibition and, as such, serve as potential therapeutic targets to overcome resistance to EGFR inhibitors. AREAS COVERED: This review summarizes the results of recently completed trials of anti-EGFR agents in SCCHN, highlights the various mechanisms that drive resistance to EGFR inhibitors in SCCHN, and focuses on several novel targeted agents that could potentially help overcome resistance to EGFR-based therapies in SCCHN. Expert commentary: Due to the development of resistance to EGFR-targeted therapies, novel treatment approaches to overcome resistance are a key unmet need for SCCHN.

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization.

INTRODUCTION: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care. MATERIALS AND METHODS: Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements. RESULTS: A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months. CONCLUSION: Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.

The Chicago Thoracic Oncology Database Consortium: A Multisite Database Initiative.

OBJECTIVE: An increasing amount of clinical data is available to biomedical researchers, but specifically designed database and informatics infrastructures are needed to handle this data effectively. Multiple research groups should be able to pool and share this data in an efficient manner. The Chicago Thoracic Oncology Database Consortium (CTODC) was created to standardize data collection and facilitate the pooling and sharing of data at institutions throughout Chicago and across the world. We assessed the CTODC by conducting a proof of principle investigation on lung cancer patients who took erlotinib. This study does not look into epidermal growth factor receptor (EGFR) mutations and tyrosine kinase inhibitors, but rather it discusses the development and utilization of the database involved. METHODS:  We have implemented the Thoracic Oncology Program Database Project (TOPDP) Microsoft Access, the Thoracic Oncology Research Program (TORP) Velos, and the TORP REDCap databases for translational research efforts. Standard operating procedures (SOPs) were created to document the construction and proper utilization of these databases. These SOPs have been made available freely to other institutions that have implemented their own databases patterned on these SOPs. RESULTS: A cohort of 373 lung cancer patients who took erlotinib was identified. The EGFR mutation statuses of patients were analyzed. Out of the 70 patients that were tested, 55 had mutations while 15 did not. In terms of overall survival and duration of treatment, the cohort demonstrated that EGFR-mutated patients had a longer duration of erlotinib treatment and longer overall survival compared to their EGFR wild-type counterparts who received erlotinib. DISCUSSION: The investigation successfully yielded data from all institutions of the CTODC. While the investigation identified challenges, such as the difficulty of data transfer and potential duplication of patient data, these issues can be resolved with greater cross-communication between institutions of the consortium. CONCLUSION: The investigation described herein demonstrates the successful data collection from multiple institutions in the context of a collaborative effort. The data presented here can be utilized as the basis for further collaborative efforts and/or development of larger and more streamlined databases within the consortium.

Prognostic and Predictive Value in KRAS in Non-Small-Cell Lung Cancer: A Review.

IMPORTANCE: Lung cancer is the leading cause of cancer deaths worldwide, with non-small-cell lung cancer (NSCLC) constituting more than 80% of all lung cancers. Non-small-cell lung cancer is a heterogenous disease, with multiple different oncogenic driver mutations representing possible therapeutic targets. The vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) represents one of the most common oncogenic driver mutations. Unfortunately, targeted therapies thus far have been unsuccessful. OBJECTIVE: To discuss current advancements in understanding the prognostic and predictive value of KRAS in NSCLC and explaining the treatment advancements in both the preclinical and clinical setting. EVIDENCE REVIEW: PubMed, Cochrane Library, and Google Scholar databases were searched through February 1, 2016. English-language peer-reviewed articles published between 1964 and 2016 were found using the keywords "RAS," "KRAS," "NSCLC," "synthetic lethality," "oncogenic driver mutations," "clinical trials," and "phase 3 clinical trials." Abstracts at scientific meetings were not excluded. Of 112 records idetified, 61 articles or studies were included in qualitative synthesis for this review. FINDINGS: The KRAS oncogenic driver mutation is noted in 15% to 25% of patients with NSCLC. While there has been limited success in inhibiting the protein directly, phase 2 and phase 3 clinical trials have demonstrated success in inhibiting downstream effectors, specifically MEK1 and/or MEK2 with selumetinib and trametinib (albeit with poor tolerability). Current clinical trials are evaluating inhibiting downstream effector pathways for improved efficacy. In the laboratory, the success of synthetic lethal approaches suggests another possible direction for future clinical trials. CONCLUSIONS AND RELEVANCE: KRAS is one of the most common oncogenic driver mutations in NSCLC, with prior attempts at direct inhibition being unsuccessful. In recent years, there has been significant advancement in the understanding of the biology of KRAS and its downstream effectors. This has translated into a multitude of important preclinical studies and clinical trials that are currently underway to find effective therapeutic drugs for KRAS mutant lung cancer. Ultimately, better therapeutics need to be engineered to arrive at RAS-driven precision medicine.

Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation.

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future.

Promotion of self-management for post treatment cancer survivors: evaluation of a risk-adapted visit.

PURPOSE: The LIFE Cancer Survivorship Program at NorthShore University HealthSystem provides risk-adapted visits (RAV) facilitated by an oncology nurse during which a survivorship care plan (SCP) is provided and discussed. In this report, we describe and evaluate RAV in promoting individualized health care and self-management during survivorship transition. METHODS: Patients complete a post-RAV questionnaire at their RAV and another ≥1 year after their RAV. RESULTS: One thousand seven hundred thirteen (1713) RAVs, majority for breast cancer, occurred from January 2007 to March 2014. One thousand six hundred fifteen (1615) "day-of" post-RAV questionnaires were completed. Respondents scaled statements as strongly agree/agree/disagree/strongly disagree. Combined strongly agree/agree ratings are 94 % felt more confident in communicating information about their treatments to other health care providers, 90 % felt more comfortable recognizing signs/symptoms to report to providers, and 98 % had a better appreciation for community programs/services. Of 488 respondents (RAV January 2007 to December 2012 n = 1366) to a questionnaire at least 1 year after the RAV, nearly 100 % found SCP useful to summarize medical information, 97 % to reinforce follow-up, 85 % to recognize symptoms of recurrence, 93 % to identify healthy lifestyle practices, 91 % to assist in identifying resources for support, 72 % discussed their SCP with their healthcare provider, and 97 % made at least one positive lifestyle change. CONCLUSIONS: Participation in LIFE RAV following treatment helps survivors to guide future self-care behavior. Data suggest that benefits may persist 1 year after the visit and support the feasibility of a nurse-led RAV to establish a SCP in cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Combined provision and discussion of SCPs help survivors construct a useful understanding of their cancer experience and may promote long-term self-management.

Lung cancer-a fractal viewpoint.

Fractals are mathematical constructs that show self-similarity over a range of scales and non-integer (fractal) dimensions. Owing to these properties, fractal geometry can be used to efficiently estimate the geometrical complexity, and the irregularity of shapes and patterns observed in lung tumour growth (over space or time), whereas the use of traditional Euclidean geometry in such calculations is more challenging. The application of fractal analysis in biomedical imaging and time series has shown considerable promise for measuring processes as varied as heart and respiratory rates, neuronal cell characterization, and vascular development. Despite the advantages of fractal mathematics and numerous studies demonstrating its applicability to lung cancer research, many researchers and clinicians remain unaware of its potential. Therefore, this Review aims to introduce the fundamental basis of fractals and to illustrate how analysis of fractal dimension (FD) and associated measurements, such as lacunarity (texture) can be performed. We describe the fractal nature of the lung and explain why this organ is particularly suited to fractal analysis. Studies that have used fractal analyses to quantify changes in nuclear and chromatin FD in primary and metastatic tumour cells, and clinical imaging studies that correlated changes in the FD of tumours on CT and/or PET images with tumour growth and treatment responses are reviewed. Moreover, the potential use of these techniques in the diagnosis and therapeutic management of lung cancer are discussed.

Molecularly targeted therapies in non-small-cell lung cancer annual update 2014.

There have been significant advances in the understanding of the biology and treatment of non-small-cell lung cancer (NSCLC) during the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC. We are beginning to understand the mechanisms of acquired resistance after exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next-generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies, and immunotherapy.

Outpatient advance care planning for patients with metastatic cancer: a pilot quality improvement initiative.

BACKGROUND: Despite American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines recommending that oncologists discuss advance care planning (ACP) with patients with stage IV cancer early in treatment, in standard practice ACP remains a late step of a terminal illness. ACP preserves comfort and dignity at the end of life, ensuring patients receive the care that they desire. METHODS AND MATERIALS: A feasibility study in patients with stage IV cancer was developed to test whether incorporating ACP immediately after a stage IV cancer diagnosis is feasible. Inclusion criteria were consecutive new gastrointestinal and thoracic oncology patients treated by one of two oncologists. The project included creation of new workflow; development of an ACP patient education guidebook; training seminars for oncology staff; and enhancements to the electronic health record (EHR) to improve ACP documentation. RESULTS: The oncologists recorded 33 of 48 (69%) advance directive notes (ADNs) and 22 of 48 (46%) code status orders (CSOs) in the EHR of patients newly diagnosed with stage IV cancer by following ACP protocol during the 6-month trial period. Twenty-one of 33 ADNs were entered within 7 days of first consultation. The median time to ADN placement was 1 day after consultation. Twenty-two of 33 patients with ADNs had CSOs placed, of which 16 were do-not-resuscitate (DNR) and 6 were full code. One year prior to the feasibility study, only 1 of 75 deceased patients of the two oncologists had outpatient ADNs and CSOs. CONCLUSIONS: Outpatient ACP is feasible early in the care of patients with stage IV cancer through systematic improvement in workflow and motivated providers. Education and infrastructure were pivotal to routine development of advance care plans.

Buccal spectral markers for lung cancer risk stratification.

Lung cancer remains the leading cause of cancer deaths in the US with >150,000 deaths per year. In order to more effectively reduce lung cancer mortality, more sophisticated screening paradigms are needed. Previously, our group demonstrated the use of low-coherence enhanced backscattering (LEBS) spectroscopy to detect and quantify the micro/nano-architectural correlates of colorectal and pancreatic field carcinogenesis. In the lung, the buccal (cheek) mucosa has been suggested as an excellent surrogate site in the "field of injury". We, therefore, wanted to assess whether LEBS could similarly sense the presence of lung. To this end, we applied a fiber-optic LEBS probe to a dataset of 27 smokers without diagnosed lung cancer (controls) and 46 with lung cancer (cases), which was divided into a training and a blinded validation set (32 and 41 subjects, respectively). LEBS readings of the buccal mucosa were taken from the oral cavity applying gentle contact. The diagnostic LEBS marker was notably altered in patients harboring lung cancer compared to smoking controls. The prediction rule developed on training set data provided excellent diagnostics with 94% sensitivity, 80% specificity, and 95% accuracy. Applying the same threshold to the blinded validation set yielded 79% sensitivity and 83% specificity. These results were not confounded by patient demographics or impacted by cancer type or location. Moreover, the prediction rule was robust across all stages of cancer including stage I. We envision the use of LEBS as the first part of a two-step paradigm shift in lung cancer screening in which patients with high LEBS risk markers are funnelled into more invasive screening for confirmation.

Buccal microRNA dysregulation in lung field carcinogenesis: gender-specific implications.

MicroRNAs (miRNAs) have been shown to be reliable early biomarkers in a variety of cancers including that of lung. We ascertained whether the biomarker potential of miRNAs could be validated in microscopically normal and easily accessible buccal epithelial brushings from cigarette smokers as a consequence of lung cancer linked 'field carcinogenesis'. We found that compared to neoplasia-free subjects, a panel of 68 miRNAs were upregulated and 3 downregulated in the normal appearing buccal mucosal cells collected from patients harboring lung cancer (n=76). The performance characteristics of selected miRNAs (with ≥ 1-fold change) were excellent with an average under the receiver operator characteristic curve (AUROC) of >0.80. Several miRNAs also displayed gender specificity between the groups. These results provide the first proof-of-concept scenario in which minimally intrusive cheek brushings could provide an initial screening tool in a large at-risk population.

Molecular pathways and therapeutic targets in lung cancer.

Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.