Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer.

BACKGROUND: The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC). RESEARCH QUESTION: How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC? METHODS: We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution. RESULTS: A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples. INTERPRETATION: Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.

An early look at selective RET inhibitor resistance: new challenges and opportunities.

Two RET inhibitors, selpercatinib and pralsetinib, recently received approval for the treatment of advanced RET fusion-positive lung cancer. Acquired resistance to these inhibitors will be a major challenge. We have shown that resistance can emerge due to recurrent RET kinase domain mutations and, in most cases, due to RET-independent mechanisms.

A retrospective analysis of actionable pharmacogenetic/genomic biomarker language in FDA labels.

The primary goal of precision medicine is to maximize the benefit-risk relationships for individual patients by delivering the right drug to the right patients at the right dose. To achieve this goal, it has become increasingly important to assess gene-drug interactions (GDIs) in clinical settings. The US Food and Drug Administration (FDA) periodically updates the table of pharmacogenetic/genomic (PGx) biomarkers in drug labeling on their website. As described herein, an effort was made to categorize various PGx biomarkers covered by the FDA-PGx table into certain groups. There were 2 major groups, oncology molecular targets (OMT) and drug-metabolizing enzymes and transporters (DMETs), which constitute ~70% of all biomarkers (~33% and ~35%, respectively). These biomarkers were further classified whether their labeling languages could be actionable in clinical practice. For OMT biomarkers, ~70% of biomarkers are considered actionable in clinical practice as they are critical for the selection of appropriate drugs to individual patients. In contrast, ~30% of DMET biomarkers are considered actionable for the dose adjustments or alternative therapies in specific populations, such as CYP2C19 and CYP2D6 poor metabolizers. In addition, the GDI results related to some of the other OMT and DMET biomarkers are considered to provide valuable information to clinicians. However, clinical GDI results on the other DMET biomarkers can possibly be used more effectively for dose recommendation. As the labels of some drugs already recommend the precise doses in specific populations, it will be desirable to have clear language for dose recommendation of other (or new) drugs if appropriate.

Post-treatment cell-free DNA as a predictive biomarker in molecular-targeted therapy of hepatocellular carcinoma.

BACKGROUND: Liquid biopsies, particularly those involving circulating tumor DNA (ctDNA), are rapidly emerging as a non-invasive alternative to tumor biopsies. However, clinical applications of ctDNA analysis in hepatocellular carcinoma (HCC) have not been fully elucidated. METHODS: We measured the amount of plasma-derived cell-free DNA (cfDNA) in HCC patients before (n = 100) and a few days after treatment (n = 87), including radiofrequency ablation, transarterial chemoembolization, and molecular-targeted agents (MTAs), and prospectively analyzed their associations with clinical parameters and prognosis. TERT promoter mutations in cfDNA were analyzed using droplet digital PCR. Furthermore, we performed a comprehensive mutational analysis of post-treatment cfDNA via targeted ultra-deep sequencing (22,000× coverage) in a panel of 275 cancer-related genes in selected patients. RESULTS: Plasma cfDNA levels increased significantly according to HCC clinical stage, and a high cfDNA level was independently associated with a poor prognosis. TERT promoter mutations were detected in 45% of all cases but were not associated with any clinical characteristics. cfDNA levels increased significantly a few days after treatment, and a greater increase in post-treatment cfDNA levels was associated with a greater therapeutic response to MTAs. The detection rate of TERT mutations increased to 57% using post-treatment cfDNA, suggesting that the ctDNA was enriched. Targeted ultra-deep sequencing using post-treatment cfDNA after administering lenvatinib successfully detected various gene mutations and obtained promising results in lenvatinib-responsive cases. CONCLUSIONS: Post-treatment cfDNA analysis may facilitate the construction of biomarkers for predicting MTA treatment effects.

Challenges of the current precision medicine approach for pancreatic cancer: A single institution experience between 2013 and 2017.

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

Targeting HER2 in Breast Cancer: Latest Developments on Treatment Sequencing and the Introduction of Biosimilars.

Approximately 20% of all breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). Targeting breast cancer through this vital oncogenic protein has been a major step towards improved patient outcomes. Today, several anti-HER2 agents are in clinical use including: the monoclonal antibodies trastuzumab and pertuzumab; the small molecule inhibitors lapatinib, neratinib, and tucatinib; and the antibody-drug conjugates ado-trastuzumab emtansine and trastuzumab deruxtecan, in some jurisdictions. In addition, several trastuzumab biosimilars have recently been granted regulatory approval in North America and the EU, and are enhancing patient access to HER2-directed therapy. The various agents differ greatly in their side-effect profiles and approved indications, from neoadjuvant and adjuvant use in early disease, to first- and later-line use in metastatic disease. This review discusses the current treatment recommendations for the use of anti-HER2 agents alone and in combination, examines the latest advances in HER2-targeted drugs and how they may be best applied in clinical practice, and provides guidance on optimal sequencing of the growing array of therapeutic options for HER2-positive breast cancer.

Tumor Diameter for Hepatocellular Carcinoma: Why Should Size Matter?

PURPOSE: There are two main goals in hepatocellular carcinoma management, the first is long term survival and the second is the low recurrence rate after the treatment. Therefore, a lot of selection criteria defined for each treatment method and tumor size is one of the most important parameter in almost all of them. METHODS: In this review, importance of diamater in hepatocellular carcinoma is reviewed. RESULTS: Many reports showed a significant association between increase in maximum tumor diameter and microvascular invasion. Patients with larger tumors are more likely to have poorly differentiated tumors. Increased regional and distant metastasis of tumors were observed in the larger size hepatocellular carcinoma. Liver transplantation represents the best treatment option for patients with decompensated liver cirrhosis and hepatocellular carcinoma. CONCLUSIONS: Combined with biological, inflammatory, radiological, pathological and genetic markers that predict the biological behavior of the tumor, today, tumor size is one of the best aggressiveness markers until new markers are found. So, tumor size is matter.

Frontline PARP inhibitor maintenance therapy in ovarian cancer: A Society of Gynecologic Oncology practice statement.

PARP inhibitors (PARPi) have shown have activity in the treatment of ovarian cancer. Previous studies documented activity in patients with germline (gBRCA) and tumor (tBRCA) BRCA mutations (BRCAm) for treatment in lieu of chemotherapy as well as in recurrent ovarian cancer as maintenance therapy. The recent data from four randomized phase 3 trials have established an important role for frontline PARPi maintenance therapy in ovarian cancer. While SOLO-1 only included BRCAm patients, PRIMA, VELIA, and PAOLA-1 enrolled broader patient populations. The magnitude of benefit of PARPi in these studies was consistently greatest in the BRCAm patients (germline or tumor). PARPi treatment also improved PFS in the HRD cohort but to a lesser degree than in patients with BRCAm. In secondary analyses, the overall impact of PARPi treatment in HR proficient patients, which comprise about 50% of ovarian cancers, was more limited than in the other subgroups. Data for overall survival, also a secondary endpoint, is currently immature for these four trials. Fatigue, hematologic, and GI toxicities are the most commonly noted adverse events with PARPi therapy. The recent FDA approvals of PARPi in the maintenance setting will enable clinicians to incorporate these into frontline armamentarium of ovarian cancer treatment.

Patients with BRAF-Mutant Advanced/Metastatic Melanoma: Original Research on the Treatment Reality in Germany and Austria in the Era of Choice.

INTRODUCTION: Cutaneous melanoma is one of the most aggressive forms of skin neoplasms and represents a major cause of neoplastic or cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15% when the disease metastasizes to distant organs. The objective of our study was to evaluate the status quo of the current treatment standards in stage IV melanoma and rationale for therapy decisions in Germany and Austria between January 2016 and September 2018. METHODS: In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in the first, second, and third line with registered substances were analyzed using descriptive statistics. RESULTS: Ninety-nine patients (50.5% male) received a total of 172 treatment lines. The first (99 patients), second (56 patients), and third (17 patients) treatment lines were documented. Within the 80.8% of patients with stage IV melanoma, targeted therapy (TT) was more frequently administered as a first-line treatment than immunotherapy (IO) with checkpoint inhibitors (59.6% TT vs. 40.4% IO). Across all lines, patients received TT in 54.7% and IO in 43.0% of the cases. As targeted agents, dabrafenib plus trametinib was predominantly prescribed (72.3%), whereas the monotherapy with anti-programmed cell death protein 1 and anti-cytotoxic T lymphocyte-associated protein 4 antibodies or their combination was prescribed similarly often (50.0% vs. 47.3%). Most commonly, the treatment type was switched from TT to IO or vice versa upon disease progression. The most frequent rationales for prescribing either TT or IO were remission pressure (72.9%) or physician's preference (45.0%), respectively. Disease progression was a more frequent cause of treatment discontinuation than undesired events. CONCLUSION: Patients in Germany and Austria with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. TT was more frequently administered than IO while the rationale for prescribing a specific treatment type differed between the two.

Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group 'Molecular Diagnostics and Therapy'.

Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force 'Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality.

Precision oncology: the intention-to-treat analysis fallacy.

It has recently been suggested that precision oncology studies should be reanalysed using the intention-to-treat (ITT) methodology developed for randomized controlled clinical trials. This reanalysis dramatically decreases response rates in precision medicine studies. We contend that the ITT analysis of precision oncology trials is invalid. The ITT methodology was developed three decades ago to mitigate the problems of randomized trials, which try to ensure that both arms have an unselected patient population free from confounders. In contrast, precision oncology trials specifically select patients for confounders (that is biomarkers) that predict response. To demonstrate the issues inherent in an ITT reanalysis for precision cancer medicine studies, we take as an example the drug larotrectinib (TRK inhibitor) approved because of remarkable responses in malignancies harbouring NTRK fusions. Based on large-scale studies, NTRK fusions are found in ~0.31% of tumours. In a non-randomized pivotal study of larotrectinib, 75% of the 55 treated patients responded. Based upon the prevalence of NTRK fusions, ~18,000 patients would need to be screened to enrol the 55 treated patients. Utilizing the ITT methodology, the revised response rate to larotrectinib would be 0.23%. This is, of course, a dramatic underestimation of the efficacy of this now Food and Drug Administration (FDA)-approved drug. Similar issues can be shown for virtually any biomarker-based precision clinical trial. Therefore, retrofitting the ITT analysis developed for unselected patient populations in randomized trials yields misleading conclusions in precision medicine studies.

Utilizing Real-World Evidence (RWE) to Improve Care in Chronic Lymphocytic Leukemia: Challenges and Opportunities.

PURPOSE OF REVIEW: This review discusses important findings from real-world evidence (RWE) studies impacting the field of chronic lymphocytic leukemia (CLL), from prognostication to long-term management and sequencing of novel agents. RECENT FINDINGS: RWE data, which represents a heterogeneous cohort of patients treated at non-academic centers and off-clinical trial, demonstrate several key differences between findings in randomized controlled trials (RCT) of novel agents in CLL. While toxicity and discontinuation rates are higher, survival outcomes are encouraging in clinical practice, with often equivalent outcomes from reduced-dose or time-limited therapy of drug. Though sequencing of novel agents lacks robust RCT data, RWE data provide important guidance for selection and sequencing of novel agents. RWE has critically informed our practice by providing diverse patient data and real-time analysis for important clinical questions outpacing the rapidly growing field of CLL.

[Neuropilins: relevant therapeutic targets to improve the treatment of cancers]. / Les neuropilines - Des cibles pertinentes pour améliorer le traitement des cancers.

Exacerbated angiogenesis is one of the hallmarks of cancer defined by Hanahan and Weinberg. However, targeting the signaling pathway of the "Vascular Endothelial Growth Factor (VEGF)" or its receptors has shown its therapeutic limits. Despite short term benefits for patients, tumors always relapse and generally become metastatic and incurable. Neuropilins 1 and 2 (NRP1, 2) whose activity was originally described in the nervous system, stimulate many parameters involved in tumor aggressiveness including cell proliferation, angiogenesis and lymphangiogenesis, and immune tolerance. Thus, an overexpression of NRP1 or 2 in many tumors, is correlated with a short survival of the patients. The purpose of this review is to describe the mechanisms of action involved in stimulating NRP1, 2 and to take stock of therapeutic strategies in preclinical studies or in early phase trials in patients with different cancers.

TITLE: Les neuropilines - Des cibles pertinentes pour améliorer le traitement des cancers. ABSTRACT: Une angiogenèse exacerbée est une des caractéristiques (« hallmarks ¼) du cancer, définies par Hanahan et Weinberg1. Cependant, le ciblage de la voie de signalisation du VEGF (vascular endothelial growth factor) ou de ses récepteurs a montré ses limites thérapeutiques. Après un bénéfice thérapeutique indéniable pour les patients, les tumeurs récidivent après quelques mois, et deviennent généralement métastatiques et incurables. Les neuropilines 1 et 2 (NRP1, 2) dont l'activité a été décrite initialement dans le système nerveux, stimulent de nombreuses fonctions impliquées dans l'agressivité tumorale, notamment la prolifération cellulaire, l'angiogenèse et la lymphangiogenèse, ainsi que la tolérance immunitaire. Ainsi, une surexpression de NRP1 ou 2 dans de nombreuses tumeurs, est corrélée à une survie courte des patients. Cette revue a pour objectif de décrire les mécanismes d'action impliqués dans la stimulation de NRP1 et NRP2 et de faire le point sur les stratégies thérapeutiques en études précliniques ou en essais de phase précoces chez des patients atteints de différents cancers.

Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.