ALK-Rearranged Non-Small Cell Lung Cancer in 2020: Real-World Triumphs in an Era of Multigeneration ALK-Inhibitor Sequencing Informed by Drug Resistance Profiling.

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.

Correction to: The role of proteomics in the age of immunotherapies.

Some parts of the Abstract, Introduction and Discussion included uncited text from the following previously published chapter.

The role of proteomics in the age of immunotherapies.

The antigenic landscape of the adaptive immune response is determined by the peptides presented by immune cells. In recent years, a number of immune-based cancer therapies have been shown to induce remarkable clinical responses through the activation of the patient's immune system. As a result, there is a need to identify immune biomarkers capable of predicting clinical response. Recent advances in proteomics have led to considerable developments in the more comprehensive profiling of the immune response. "Immunoproteomics" utilises a rapidly increasing collection of technologies in order to identify and quantify antigenic peptides or proteins. This includes gel-based, array-based, mass spectrometry (MS), DNA-based, or computer-based (in silico) approaches. Immunoproteomics is yielding an understanding of disease and disease progression, vaccine candidates, and biomarkers to a depth not before understood. This review gives an overview of the emerging role of proteomics in improving personalisation of immunotherapy treatment.

From mice to men: GEMMs as trial patients for new NSCLC therapies.

Given the large socio-economic burden of cancer, there is an urgent need for in vivo animal cancer models that can provide a rationale for personalised therapeutic regimens that are translatable to the clinic. Recent developments in establishing mouse models that closely resemble human lung cancers involve the application of genetically engineered mouse models (GEMMs) for use in drug efficacy studies or to guide patient therapy. Here, we review recent applications of GEMMs in non-small cell lung cancer research for drug development and their potential in aiding biomarker discovery and understanding of biological mechanisms behind clinical outcomes and drug interactions.

CA9, CYFIP2 and LGALS3BP-A Novel Biomarker Panel to Aid Prognostication in Glioma.

Brain cancer is a devastating and life-changing disease. Biomarkers are becoming increasingly important in addressing clinical issues, including in monitoring tumour progression and assessing survival and treatment response. The goal of this study was to identify prognostic biomarkers associated with glioma progression. Discovery proteomic analysis was performed on a small cohort of astrocytomas that were diagnosed as low-grade and recurred at a higher grade. Six proteins were chosen to be validated further in a larger cohort. Three proteins, CA9, CYFIP2, and LGALS3BP, were found to be associated with glioma progression and, in univariate analysis, could be used as prognostic markers. However, according to the results of multivariate analysis, these did not remain significant. These three proteins were then combined into a three-protein panel. This panel had a specificity and sensitivity of 0.7459 for distinguishing between long and short survival. In silico data confirmed the prognostic significance of this panel.

Optimal Upfront Treatment in Surgically Resectable Pancreatic Cancer Candidates: A High-Volume Center Retrospective Analysis.

Pancreatic adenocarcinoma is a devastating disease with only 15-20% of patients resectable at diagnosis. Neoadjuvant chemotherapy for this cohort is becoming increasingly popular; however, there are no published randomized trials that support the use of neoadjuvant chemotherapy over upfront surgery in resectable disease. This retrospective cohort analysis was conducted to compare both treatment pathways and to identify any potential prognostic markers. Medical records from one large volume pancreatic cancer center from 2013-2019 were reviewed and 126 patients with upfront resectable disease were analyzed. Due to a change in practice in our center patients treated prior to December 2016 received upfront surgery and those treated after this date received neoadjuvant chemotherapy. Of these, 86 (68%) patients were treated with upfront surgery and 40 (32%) of patients were treated with neoadjuvant chemotherapy. Our results demonstrated that patients treated with upfront surgery with early-stage (1a) disease had a longer median OS compared to those treated with neoadjuvant chemotherapy (24 vs. 21 months, p = 0.028). This survival difference was not evident for all patients (regardless of stage). R0 resections were similar between groups (p = 0.605). We identified that both tumor viability (in neoadjuvant chemotherapy-treated patients) and tumor grade were useful prognostic markers. Upfront surgery for certain patients with low volume disease may be suitable despite the global trend towards neoadjuvant chemotherapy for all upfront resectable patients. A prospective clinical trial in this cohort incorporating biomarkers is needed to determine optimal therapy pathway.

Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK.

Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of FGFR family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1-4 was detected in 8%-19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.

Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer.

Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell division cycle-associated protein 3 (CDCA3) is elevated in adenocarcinoma (LUAD) and correlates with sensitivity to platinum-based chemotherapy. Herein, we explored whether CDCA3 levels were associated with EGFR mutant LUAD and TKI response. We demonstrate that in a small-cohort tissue microarray and in vitro LUAD cell line panel, CDCA3 protein levels are elevated in EGFR mutant NSCLC as a result of increased protein stability downstream of receptor tyrosine kinase signalling. Here, CDCA3 protein levels correlated with TKI potency, whereby CDCA3high EGFR mutant NSCLC cells were most sensitive. Consistently, ectopic overexpression or inhibition of casein kinase 2 using CX-4945, which pharmacologically prevents CDCA3 degradation, upregulated CDCA3 levels and the response of T790M(+) H1975 cells and two models of acquired resistance to TKIs. Accordingly, it is possible that strategies to upregulate CDCA3 levels, particularly in CDCA3low tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients.

A multicenter study of thromboembolic events among patients diagnosed with ROS1-rearranged non-small cell lung cancer.

OBJECTIVES: This study aimed to describe the longitudinal thromboembolism (TE) risk relative to the natural history of disease and clinical course of ROS1 rearranged non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Cases of ROS1-rearranged NSCLC from six Australian hospitals were pooled and evaluated for incidence, timing, predictors and outcomes of venous or arterial TE, as well as objective response rate (ORR) to active therapy and overall survival (OS). RESULTS: Of 42 patients recruited, 20 (48%) experienced TE; one (2%) arterial, 13 (31%) a pulmonary emboli (PE), and 12 (29%) a deep vein thrombosis. Among those with TE, six (30%) experienced multiple events, three as concurrent and three as recurrent diagnoses. The cumulative incidence of TE over time, adjusted for death as a competing risk factor, approached 50%. TE occurred prior to, during and post the peri-diagnostic period and occurred irrespective of treatment strategy. A thrombophilia was identified in n = 3/10 (30%) cases screened: in two factor V Leiden and in one anti-thrombin III (ATIII) deficiency. Median OS was 21.3 months in those with TE vs. 28.8 months in those without; hazard ratio 1.16 (95%CI 0.43-3.15). Respective ORR to first-line therapy with TE was 50% vs. 44% without TE in the chemotherapy arm and 67% vs. 50% in the targeted therapy arm. CONCLUSION: In the rare cancer subtype, ROS1, these real-world data demonstrate sustained TE risk beyond the diagnostic period irrespective of therapeutic strategy. High incidence of PE, concurrent TE, and recurrent TE warrant validation in larger cohorts. Consideration of primary thromboprophylaxis in ROS1 populations is recommended.

The pattern of subjective anxiety during in-session exposures over the course of cognitive-behavioral therapy for clients with social anxiety disorder.

Exposure-based therapies are efficacious treatments for social anxiety disorder (i.e., Gould et al., 1997). Much of the theory behind these treatments is derived from Foa and colleagues' (Foa, Huppert, & Cahill, 2005; Foa & Kozak, 1986) work on emotional processing. However, there has been little research examining individual differences in emotional processing patterns within and between treatment sessions among clients with social anxiety disorder. This study utilized longitudinal data analytic methods to examine changes in subjective anxiety during the first 3 exposure sessions in group and individual cognitive-behavioral therapy for social anxiety disorder. The results of this study provide preliminary evidence that, although anxiety generally decreases across exposures, some individuals experience considerable fluctuations in anxiety during a single exposure. Although anxiety during the first exposure was not significantly related to outcome, the relationship between anxiety during exposure and outcome became stronger during subsequent exposures. Overall, this study highlights the need to conduct more fine-grained analyses to better understand the mechanisms underlying exposure-based therapies for social anxiety disorder.

Assessing Client Progress Session by Session in the Treatment of Social Anxiety Disorder: The Social Anxiety Session Change Index.

Frequent assessment during therapy can improve treatments and provide accountability. However, clinicians often do not monitor progress because of the time it takes to administer and score assessments. In response, the Social Anxiety Session Change Index (SASCI) was developed. The SASCI is a short, easily administered rating of subjective improvement that asks clients with social anxiety disorder how much they have changed since the beginning of therapy. Change on the SASCI was related to change in fear of negative evaluation, a core aspect of social anxiety, and to clinician-rated improvement, but not to ratings of anxiety sensitivity or depression. Because it is brief and easily interpretable, the SASCI can be used in a variety of clinical settings to monitor change across therapy. The SASCI is presented along with examples of how the information gathered from frequent administration can inform clinical practice.

Pattern of care and survival of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALK+ NSCLC) in an Australian Metropolitan Tertiary Referral Centre: A retrospective cohort analysis.

AIM: To report on the pattern of care and survival of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALK+NSCLC) in a real-world retrospective cohort from an Australian tertiary referral center. METHODS: Individuals with a pathological diagnosis of ALK+NSCLC via immunohistochemistry and fluorescence in situ hybridization and a radiological diagnosis of stage IV disease were eligible. Patients were identified via the Pathology Department specimen database and electronic patient chart review. Data were collected and analyzed for baseline demographics, radiological pattern of disease and response to treatment, treatment sequencing, toxicity and survival. RESULTS: Thirty-five patients were identified over a 7-year period from 2010 to 2016 and followed for a median of 23 months. Median overall survival (OS) in the entire cohort was immature at data cut, 46.0 months (95% confidence interval [CI], 22.53-69.47 months), with the longest surviving patient was alive 62.1 months since diagnosis. Objective radiological response rate overall across six potential treatments and six treatment lines (range 1-6) was 58.2%. Almost 50% received at-least two lines of ALK inhibitor therapy with median OS in this group estimated to be 53.4 months (95% CI, 35.1 months-not reached). Toxicity was manageable with a low rate of ≥ grade 3 toxicity (n = 7). Forty-eight percent relapsed within the CNS and 43% overall died due to CNS progression. In those with CNS diagnosis at baseline and/or progression within the CNS (n = 32), median OS was also 46.0 months (95% CI, 24.22-66.78 months). CONCLUSION: This retrospective cohort analysis of a single tertiary institution experience in treating ALK+NSCLC demonstrates impressive OS and the importance and impact of careful management of CNS disease in this patient population.

Retrospective assessment of childhood sexual and physical abuse: a comparison of scaled and behaviorally specific approaches.

This study compared retrospective reports of childhood sexual and physical abuse as assessed by two measures: the Childhood Trauma Questionnaire (CTQ), which uses a Likert-type scaling approach, and the Computer Assisted Maltreatment Inventory (CAMI), which employs a behaviorally specific means of assessment. Participants included 1,195 undergraduate students recruited from three geographically diverse universities. Agreement was high across the two measures in the classification of victim status (92% and 80% for sexual and physical abuse, respectively). However, the CTQ classified more participants as sexually abused than did the CAMI, whereas the opposite trend was found for physical abuse. For child physical abuse, many participants reporting abusive acts on the CAMI scored below the cut-point for physical abuse on the CTQ. Classification differences for both types of abuse were largely unrelated to demographic factors, socially desirable responding, or self-reported withholding of information. The implications of these results are discussed in light of future research using retrospective methods of assessing childhood abuse.

Exhaled breath condensate for lung cancer protein analysis: a review of methods and biomarkers.

Lung cancer is a leading cause of cancer-related deaths worldwide, and is considered one of the most aggressive human cancers, with a 5 year overall survival of 10-15%. Early diagnosis of lung cancer is ideal; however, it is still uncertain as to what technique will prove successful in the systematic screening of high-risk populations, with the strongest evidence currently supporting low dose computed tomography (LDCT). Analysis of exhaled breath condensate (EBC) has recently been proposed as an alternative low risk and non-invasive screening method to investigate early-stage neoplastic processes in the airways. However, there still remains a relative paucity of lung cancer research involving EBC, particularly in the measurement of lung proteins that are centrally linked to pathogenesis. Considering the ease and safety associated with EBC collection, and advances in the area of mass spectrometry based profiling, this technology has potential for use in screening for the early diagnosis of lung cancer. This review will examine proteomics as a method of detecting markers of neoplasia in patient EBC with a particular emphasis on LC, as well as discussing methodological challenges involving in proteomic analysis of EBC specimens.

Changes in proposed mechanisms of action during an acceptance-based behavior therapy for generalized anxiety disorder.

Based on the theory that generalized anxiety disorder (GAD) is maintained through a reactive and fused relationship with one's internal experiences and a tendency towards experiential avoidance and behavioral restriction, an acceptance-based behavior therapy (ABBT) was developed to specifically target these elements. Since ABBT has been shown to be an efficacious treatment in previous studies, the current study focuses on proposed mechanisms of change over the course of therapy. Specifically, the current study focuses on session-by-session changes in two proposed mechanisms of change: acceptance of internal experiences and engagement in meaningful activities. Overall, clients receiving ABBT reported an increase in the amount of time spent accepting internal experiences and engaging in valued activities. Change in both acceptance and engagement in meaningful activities was related to responder status at post-treatment and change in these two proposed mechanisms predicted outcome above and beyond change in worry. In addition, change in acceptance was related to reported quality of life at post-treatment.

Efficacy of a manualized and workbook-driven individual treatment for social anxiety disorder.

Social anxiety disorder is a prevalent and impairing disorder for which viable cognitive-behavioral therapies exist. However, these treatments have not been easily packaged for dissemination and may be underutilized as a result. The current study reports on the findings of a randomized controlled trial of a manualized and workbook-driven individual cognitive-behavioral treatment for social anxiety disorder (Hope, Heimberg, Juster, & Turk, 2000; Hope, Heimberg, & Turk, 2006). This treatment package was derived from an empirically supported group treatment for social anxiety disorder and intended for broad dissemination, but it has not previously been subjected to empirical examination on its own. As a first step in that examination, 38 clients seeking treatment for social anxiety disorder at either the Adult Anxiety Clinic of Temple University or the Anxiety Disorders Clinic of the University of Nebraska-Lincoln were randomly assigned to receive either immediate treatment with this cognitive-behavioral treatment package or treatment delayed for 20 weeks. Evaluation at the posttreatment/postdelay period revealed substantially greater improvements among immediate treatment clients on interviewer-rated and self-report measures of social anxiety and impairment. Three-month follow-up assessment revealed maintenance of gains. Clinical implications and directions for future research are discussed.

Working alliance for clients with social anxiety disorder: relationship with session helpfulness and within-session habituation.

It has been suggested that a strong working alliance encourages clients to take risks during therapy (Raue, Castonguay, & Goldfried, 1993). This encouragement may be important for clients who fear negative evaluations as they engage in risk-taking elements of therapy. This study examined the relationship between working alliance, session helpfulness and measures of emotional processing in 18 clients undergoing cognitive behavior therapy (CBT) for social anxiety disorder. Results indicate a positive correlation between client-rated, but not observer-rated, working alliance and session helpfulness. Moderate levels of working alliance were associated with higher initial anxiety and deeper within-session habituation. Overall, a strong alliance was associated with clients engaging with the session and finding the session helpful. Implications for the use of CBT for social anxiety are discussed.

Discriminating between cognitive and supportive group therapies for chronic mental illness.

This descriptive and comparative study employed a Q-sort process to describe common factors of therapy in two group therapies for inpatients with chronic mental illness. While pharmacological treatments for chronic mental illness are prominent, there is growing evidence that cognitive therapy is also efficacious. Groups examined were part of a larger study comparing the added benefits of cognitive versus supportive group therapy to the treatment milieu. In general, items described the therapist's attitudes and behaviors, the participants' attitudes and behaviors, or the group interactions. Results present items that were most and least characteristic of each therapy and items that discriminate between the two modalities. Therapists in both groups demonstrated good therapy skills. However, the cognitive group was described as being more motivated and active than the supportive group, indicating that the groups differed in terms of common as well as specific factors of treatment.

Gender differences in social support for socially anxious individuals.

Given that social anxiety disorder is a common, chronic, debilitating disorder and socially anxious women appear to have different experiences related to social development and social support than men, it is essential that the gender differences in social anxiety and social support be understood. The present study examined perceived social support quantity and satisfaction in 23 women and 28 men seeking treatment for social anxiety disorder. Contrary to expectations, men and women did not differ on measures of social support. However, younger, unmarried women reported having smaller social support networks and less satisfaction with their social support networks than older, married women. Analyses of socially anxious men did not reveal such a pattern. The current study provides preliminary evidence that younger, single women have social support networks that are less satisfying than the social support networks of older, married women. Inclusion of social support modules within a cognitive behavioral treatment approach for social anxiety disorder may be warranted, particularly for young, unmarried women.

Exposure utilization and completion of cognitive behavioral therapy for PTSD in a "real world" clinical practice.

This study assessed rates of imaginal exposure therapy (ET) utilization and completion of cognitive behavioral therapy (CBT) for posttraumatic stress disorder (PTSD) in a clinical setting and examined variables associated with CBT completion. Using a clinical definition, the completion rate of CBT was markedly lower than rates reported in randomized trials. CBT completion was inversely related to severity of overall pretreatment measures of PTSD, avoidance, hyperarousal, depression, impaired social functioning, and borderline personality disorder. Regression yielded avoidance and depression as unique predictors of completion. Most dropouts occurred before starting imaginal ET, although initiating ET was associated with greater likelihood of completion. Results highlight methodological differences between research and practice notions of treatment completion and the need for further study of variables influencing CBT completion in practice settings.