A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer.

A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.

Role of CTLA Inhibition in Management of Non-Small Cell Lung Cancer.

PURPOSE OF REVIEW: The use of single-agent or combination immunotherapy strategies has revolutionized the management of patients with non-small cell lung cancer (NSCLC). Here, we review the current role for CTLA-4 inhibitors in early-stage resectable NSCLC, unresectable stage III NSCLC, and in metastatic NSCLC. RECENT FINDINGS: Immunotherapy agents alone, or in combination with chemotherapy, represent the new standard of care for the management of metastatic squamous and non-squamous NSCLC without driver mutations. Combination CTLA-4 and PD-1/L1 inhibitors can be efficacious, particularly in tumor mutation burden (TMB) high tumors, providing a chemotherapy-free strategy for metastatic patients. Early signals from neoadjuvant trials suggest a benefit for combination CTLA-4 and PD-1 inhibitions prior to surgery, with improved rates of major pathologic response (MPR). The role for CTLA4 inhibitors is currently unknown in the adjuvant and unresectable stage III setting, although clinical trials are ongoing to evaluate this approach. There is a growing role for CTLA-4 inhibition in the neoadjuvant and metastatic settings for patients with NSCLC. Biomarker selection in ongoing clinical trials will be crucial to guide patient selection for CTLA4 inhibitor therapy. Combination strategies with PD-1/L1 inhibition have demonstrated the greatest efficacy to date.

Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Locally Advanced, Unresectable Non-Small Cell Lung Cancer.

PURPOSE OF REVIEW: Treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) has recently been revolutionized by the incorporation of immunotherapy to standard platinum-based concurrent chemoradiation. This review examines the current standard practices and ongoing studies on the management of locally advanced, unresectable NSCLC. RECENT FINDINGS: Concurrent chemoradiation is the cornerstone of treatment of unresectable, locally advanced NSCLC. However, chemoradiation can be associated with high therapy-related toxicities, and risk of disease relapse remains significantly elevated despite treatment with curative intent. Durvalumab, a PD-L1 inhibitor, was recently approved as consolidation therapy following concurrent chemoradiation; this agent represents a major advancement in treatment of unresectable stage III NSCLC. Several clinical trials are currently underway to evaluate the benefit of different immunotherapy sequencing and other biomarker-driven strategies in this disease setting. Multiple trials are presently ongoing to assess novel immunotherapy and targeted therapy strategies to improve outcomes and decrease treatment-associated toxicities in patients with locally advanced NSCLC.

Subcutaneous metastasis from recurrent basaloid squamous cell carcinoma of the esophagus.

BACKGROUND: Esophageal cancer is the 11th most common cause of cancer mortality in the United States. It is aggressive in nature and has an ability to spread rapidly through direct extension, lymphatic spread, or hematogenously. With an estimated incidence of 1%, cutaneous metastases from esophageal cancer are extremely rare. CASE PRESENTATION: In this case study and review, we describe a case of recurrent esophageal basaloid squamous cell carcinoma presenting as multiple, rapidly progressing and tender subcutaneous nodules. A 69-year-old male with history of basaloid squamous cell carcinoma of the esophagus treated with concurrent chemoradiation, presented to his oncologist with complaints of a large, painful nodule at the nape of his neck approximately two years after completing treatment. On further examination, he was noted to have multiple, well circumscribed, solid, tender nodules on his abdominal wall along with a painful nodule on the pulp of his index finger. Histopathology from all sites revealed skin infiltration by high-grade invasive basaloid subtype of squamous cell carcinoma, similar to patient's prior known and treated primary esophageal cancer. Further imaging work up showed extensive metastatic disease involving lung, liver, and brain. CONCLUSION: Esophageal squamous cell carcinoma rarely metastasize to the skin. Subcutaneous nodules can be the first presentation of recurrent disease. The lesions are commonly confused with skin infections and treated inappropriately with antibiotics, leading to delay in diagnosis of recurrent disease. Early biopsy of suspicious lesions should be performed, especially in patients with history of cancer, such that prompt diagnosis and treatment can occur to maximize patient outcomes.

Immune Checkpoint Inhibitors in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer.

OPINION STATEMENT: Surgical resection ± chemotherapy ± radiation or stereotactic body radiation therapy (SBRT) are established treatment modalities for resectable stage non-small cell lung cancer (NSCLC), and concurrent chemotherapy with radiation is the therapy of choice for unresectable locally advanced disease. Despite treatment with curative intent, most patients subsequently relapse and develop distant disease. Treatment with checkpoint inhibitors represents a major advancement in the treatment of metastatic NSCLC. Therapy against programed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) is associated with a significant improvement in overall survival in stage IV disease, and these results have led to a great interest in evaluating these agents in earlier-stage NSCLC. The preliminary data from ongoing trials suggest that the integration of checkpoint blockage into the treatment of early-stage and locally advanced NSCLC is safe, tolerable, and has the potential to improve outcomes without adding substantial toxicity. In the current review, we provide an overview of the emerging data on the role of PD-1/PD-L1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors in the treatment of early-stage and locally advanced NSCLC, with a focus on ongoing clinical trials and combination strategies.

Prediction of chemotherapy-induced nausea and vomiting from patient-reported and genetic risk factors.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is common among cancer patients. Early identification of patients at risk for CINV may help to personalize anti-emetic therapies. To date, few studies have examined the combined contributions of patient-reported and genetic risk factors to CINV. The goal of this study was to evaluate these risk factors. METHODS: Prior to their first chemotherapy infusion, participants completed demographic and risk factor questionnaires and provided a blood sample to measure genetic variants in ABCB1 (rs1045642) and HTR3B (rs45460698) as well as CYP2D6 activity score. The M.D. Anderson Symptom Inventory was completed at 24 h and 5-day post-infusion to assess the severity of acute and delayed CINV, respectively. RESULTS: Participants were 88 patients (55% female, M = 60 years). A total of 23% experienced acute nausea and 55% delayed nausea. Younger age, history of pregnancy-related nausea, fewer hours slept the night prior to infusion, and variation in ABCB1 were associated with more severe acute nausea; advanced-stage cancer and receipt of highly emetogenic chemotherapy were associated with more severe delayed nausea (p values < 0.05). In multivariable analyses, ABCB1 added an additional 5% predictive value beyond the 13% variance explained by patient-reported risk factors. CONCLUSIONS: The current study identified patient-reported and genetic factors that may place patients at risk for acute nausea despite receipt of guideline-consistent anti-emetic prophylaxis. Additional studies examining other genetic variants are needed, as well as the development of risk prediction models including both patient-reported and genetic risk factors.

Physician-pharmacist collaboration for oral chemotherapy monitoring: Insights from an academic genitourinary oncology practice.

BACKGROUND: Oral chemotherapy is being routinely used in metastatic castrate-resistant prostate and renal cell cancer. Although convenient, these drugs require monitoring for adherence, toxicity, and drug interactions to maximize outcomes. Oncology pharmacists have the training and expertise that place them in an optimal position to collaboratively provide medication therapy management. METHODS: A board-certified oncology pharmacist, working in collaboration with a medical oncologist, initiated an oral chemotherapy-monitoring program. The pharmacist provided education, completed medication therapy management; monitored for adherence and toxicity; and recommended treatment of toxicity and supportive care issues. Patient encounters included one of the following: collaboration with medical oncologist visit, pharmacist visit, or telephone or email follow-up between visits. RESULTS: From December 2012 to May 2014, the pharmacist had 123 encounters with 20 patients with either metastatic prostate (n = 17) or renal cell cancer (n = 3). All patients were males (median age 80 years). Most encounters were clinic visits, in collaboration with physician visit or alone (52%); 36% were telephone encounters, and 11.3% were email follow-ups. Medication-related problems were identified in 25% of the 315 assessments made. Problems included: adverse drug reactions, 40%; inappropriate therapy, 20%; and noncompliance, 18%. Recommendations included: modification of laboratory monitoring, 25%; cancer or non-cancer therapy modification, 12%; drug discontinuation, 6.9%. Non-cancer therapy-related drug information and coordination of care accounted for 30% of recommendations. CONCLUSION: Our program led to identification of a number of potentially clinically significant issues for patients on oral chemotherapy and demonstrated the benefit of the pharmacist in the multidisciplinary team to assist in addressing them.

A matching-based machine learning approach to estimating optimal dynamic treatment regimes with time-to-event outcomes.

Observational data (e.g. electronic health records) has become increasingly important in evidence-based research on dynamic treatment regimes, which tailor treatments over time to patients based on their characteristics and evolving clinical history. It is of great interest for clinicians and statisticians to identify an optimal dynamic treatment regime that can produce the best expected clinical outcome for each individual and thus maximize the treatment benefit over the population. Observational data impose various challenges for using statistical tools to estimate optimal dynamic treatment regimes. Notably, the task becomes more sophisticated when the clinical outcome of primary interest is time-to-event. Here, we propose a matching-based machine learning method to identify the optimal dynamic treatment regime with time-to-event outcomes subject to right-censoring using electronic health record data. In contrast to the established inverse probability weighting-based dynamic treatment regime methods, our proposed approach provides better protection against model misspecification and extreme weights in the context of treatment sequences, effectively addressing a prevalent challenge in the longitudinal analysis of electronic health record data. In simulations, the proposed method demonstrates robust performance across a range of scenarios. In addition, we illustrate the method with an application to estimate optimal dynamic treatment regimes for patients with advanced non-small cell lung cancer using a real-world, nationwide electronic health record database from Flatiron Health.