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## Non–Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

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## Optimize Local Therapy for Oligometastatic and Oligoprogressive Non–Small Cell Lung Cancer to Enhance Survival

Metastatic non–small cell lung cancer (NSCLC) is highly heterogeneous, and there are patients with limited areas of metastases (oligometastases) or progression (oligoprogression) whose natural history and prognosis can be considerably more favorable. As a result, local therapy may offer these patients a chance at clinically meaningful disease control and/or cure. This review begins by describing the current status of the existing prospective data, including evidence of overall survival improvements from multiple randomized trials. Given the nascence of this realm, the review then examines ongoing controversies and unresolved issues regarding local therapy for oligometastatic and oligoprogression. First, the role of local therapy in the setting of targeted therapies and immunotherapy is discussed, because most published randomized trials of local therapy have been performed in the context of chemotherapy, which is no longer the standard of care for most patients with metastatic NSCLC. Refining patient selection for local therapy is then reviewed, including clinical factors (such as control of the primary and regional lymph node sites, the heterogeneous definitions of oligometastases/oligoprogression, and the underrepresentation of brain metastases in existing randomized data) and novel pathologic/molecular biomarkers. Next, because there also remains no consensus regarding the optimal modality of local therapy, the advantages and disadvantages of stereotactic radiotherapy, surgery, and other ablative techniques are discussed. Subsequently, methods to optimize radiotherapy are examined, including controversies regarding the optimal dose/fractionation and timing/sequencing scheme. A discussion regarding potentially extending the existing data to polymetastatic NSCLC follows. The review concludes with remarks regarding prudently designing randomized trials of local therapy going forward, including the benefits and drawbacks of specific endpoints meriting further testing in this unique population.

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## Randomized Trial of a Supportive Psychotherapy for Parents of Adolescents and Young Adults With Hematologic Malignancies

Background: Cancer regularly disrupts health and developmental trajectories in adolescents and young adults (AYAs). Parents have been shown to have a substantial impact on the health and cancer survivorship activities of AYA patients in the form of symptom management. However, no randomized controlled trial has evaluated a coping support intervention (CSI) program for parents of AYAs with cancer aged 18 to 40 years. Patients and Methods: From November 30, 2012, to August 29, 2016, parents of AYAs with hematologic malignancies were randomized in a phase III controlled trial (1:1 ratio, stratified sampling) to either the research-based CSI AYA-Parents group (CSI group; n=82) or the standard care (SC) group (n=70). CSI consisted of 5 sessions to achieve the enhancement of parental adaptive coping as the primary outcome (per the adaptive coping scale of the 28-item Brief COPE, a validated multidimensional self-assessment-questionnaire recommended for clinical cancer research). Measures of adaptive coping, depression, and mental health were collected at pre-CSI (measurement date T1), at the end of the intervention sessions (measurement date T2), and at follow-up (3 months). We calculated mean change scores in outcomes and estimated intervention effect sizes (Cohen’s d) for changes from T1 to T2/T3, with 0.2 indicating a small effect, 0.5 a medium effect, and 0.8 a large effect. All statistical tests were 2-sided. Results: In the intention-to-treat analysis, the CSI group significantly improved their adaptive coping compared with the SC group (95% CI, 0.30–2.54; P=.013; d=0.405), whereas adaptive coping in the SC group deteriorated. The CSI group also experienced a significant decrease in depressive symptoms and improved mental health with clinical significance (95% CI, –1.98 to –0.30; P=.008; d=0.433, and 95% CI, –0.19 to 3.97; P=.074; d=0.292, respectively). Sensitivity analyses confirmed the robustness of the main intention-to-treat analysis. Conclusions: CSI improved effectively adaptive coping and depression in parents of AYAs with hematologic malignancies. It may represent a novel family-based approach in AYA oncology care.

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## Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report

Metastatic breast cancer demonstrates HER2/neu amplification approximately 15% of the time. However, HER2 mutations, which often stimulate tumor growth, occur in only 3% to 5% of patients, and are seen more frequently in metastatic versus primary tumors. They are more frequent in lobular carcinoma, including triple-negative lobular cancer. Many of these variants are resistant to trastuzumab and lapatinib. However, neratinib can be efficacious, and recent data suggest that antibody–drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan may also be helpful. Laboratory and clinical data raise the possibility that simultaneous treatment with ADCs plus neratinib may be even more efficacious. Tucatinib, which has demonstrated significant activity in the central nervous system, has also been shown in vitro to be active against a number of these HER2 variants. This report describes a patient with metastatic estrogen receptor–positive, HER2-nonamplified breast cancer with an activating HER2 mutation whose tumor became resistant to neratinib as well as capecitabine, but whose subsequent leptomeningeal disease had a dramatically successful response to tucatinib plus capecitabine. As the frequency of HER2 mutations increases during the evolution of metastatic breast cancer, it is important to obtain genomic evaluation on these tumors with either repeat tissue or liquid biopsy as they progress over time.

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## Adjuvant Hormone Therapy–Related Hot Flashes Predict Treatment Discontinuation and Worse Breast Cancer Prognosis

Background: Clinical trials have shown that adjuvant hormone therapy (AHT)–related hot flashes can predict better breast cancer outcomes. This population-based cohort study investigated whether this result can be generalized to a real-world setting. Patients and Methods: By linking the National Quality Registry for Breast Cancer, Prescribed Drug Register, and Cause-of-Death Register, we identified 7,152 chemotherapy-free patients with breast cancer who initiated AHT in Stockholm from 2006 through 2019, and followed them until 2020. Hot flashes were defined as new use of drugs for hot flashes within 6 months after initiating AHT. We used Cox models to compare disease-free survival and treatment discontinuation among patients with and without hot flashes. Results: Patients who newly used drugs for hot flashes shortly after AHT initiation had worse disease-free survival (adjusted hazard ratio [HR], 1.67; 95% CI, 1.11–2.52) and a higher treatment discontinuation rate (adjusted HR, 1.47; 95% CI, 1.21–1.78). The association between drugs for hot flashes and discontinuation of AHT differed by patient characteristics, with stronger associations among low-income patients (HR, 1.91; 95% CI, 1.41–2.59) and those without first-degree relatives who had cancer (HR, 1.81; 95% CI, 1.39–2.35) or died from cancer (HR, 1.71; 95% CI, 1.37–2.12). Conclusions: AHT-related hot flashes predict worse, rather than better, breast cancer outcomes among patients in clinical routine practice. The identification of adverse effects by the initiation of hot flash medications may identify a subset of patients with more severe hot flashes who are more likely to discontinue AHT and need more support for treatment adherence.

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## Economic Analysis of Exclusionary EGFR Test Versus Up-Front NGS for Lung Adenocarcinoma in High EGFR Mutation Prevalence Areas

Background: This study sought to determine whether exclusionary EGFR mutation testing followed by next-generation sequencing (NGS) is a cost-efficient and timely strategy in areas with high prevalence rates of EGFR mutation. Methods: We developed a decision tree model to compare exclusionary EGFR testing followed by NGS and up-front NGS. Patients entered the model upon diagnosis of metastatic lung adenocarcinoma. Gene alterations with FDA-approved targeted therapies included EGFR, ALK, ROS1, BRAF, RET, MET, NTRK, and KRAS. Model outcomes were testing-related costs; time-to-test results; monetary loss, taking both costs and time into consideration; and percentage of patients who could be treated by FDA-approved therapies. Stacked 1-way and 3-way sensitivity analyses were performed. Results: Exclusionary EGFR testing incurred testing-related costs of US $1,387 per patient, a savings of US$1,091 compared with the costs of up-front NGS. The time-to-test results for exclusionary EGFR testing and up-front NGS were 13.0 and 13.6 days, respectively. Exclusionary EGFR testing resulted in a savings of US $1,116 in terms of net monetary loss, without a reduction of patients identified with FDA-approved therapies. The EGFR mutation rate and NGS cost had the greatest impact on minimizing monetary loss. Given that the tissue-based NGS turnaround time was shortened to 7 days, up-front NGS testing would become the best strategy if its price could be reduced to US$568 in Taiwan. Conclusions: In areas with high prevalence rates of EGFR mutation, exclusionary EGFR testing followed by NGS, rather than up-front NGS, is currently a cost-efficient strategy for metastatic lung adenocarcinoma.

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## Personalizing First-Line Management of Metastatic Renal Cell Carcinoma: Leveraging Current and Novel Therapeutic Options

The treatment of metastatic renal cell carcinoma (RCC) has been revolutionized by advances in immunotherapeutic and targeted agents. Therapeutic approaches to RCC in these categories have recently evolved to include immune checkpoint inhibitors, novel vascular endothelial growth factor receptor–targeting tyrosine kinase inhibitors, and combinations of those agents. Multiple regimens within each category have been approved for use in the first-line treatment of clear cell and non–clear cell RCC. However, few of these regimens have been directly compared, leading to a new clinical challenge for physicians: how to select a first-line treatment regimen for an individual patient from among multiple approved options. In the modern era of RCC management, the initial treatment selection therefore becomes highly personalized and depends on numerous patient-specific factors, including histopathologic and clinical features of the disease, comorbid conditions, and psychosocial and economic factors. This review details current first-line treatment options for the management of metastatic RCC and proposes a framework whereby treatment selection can be optimized for individual patients.