Identification Of New Predictive Markers Research Articles

Can the presence of aortic or coronary artery calcifications in the standard of care baseline CT or PET-CT scan of patients with Hodgkin or non-Hodgkin lymphoma be used as a predictor of MACE?

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR <60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

Functional roles of long noncoding RNA MALAT1 in gynecologic cancers.

Gynecologic cancers are reproductive disorders characterized by pelvic pain and infertility. The identification of new predictive markers and therapeutic targets for the treatment of gynecologic cancers is urgently necessary. One of the recent successes in gynecologic cancers research is identifying the role of signaling pathways in the pathogenesis of the disease. Recent experiments showed long noncoding RNAs (lncRNA) can be novel therapeutic approaches for the diagnosis and treatment of gynecologic cancers. LncRNA are transcribed RNA molecules that play pivotal roles in multiple biological processes by regulating the different steps of gene expression. Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) is a well-known lncRNA that plays functional roles in gene expression, RNA processing, and epigenetic regulation. High expression of MALAT1 is closely related to numerous human diseases. It is generally believed that MALAT1 expression is associated with cancer cell growth, autophagy, invasion, and metastasis. MALAT1 by targeting multiple signaling pathways and microRNAs (miRNAs) could contribute to the pathogenesis of gynecologic cancers. In this review, we will summarize functional roles of MALAT1 in the most common gynecologic cancers, including endometrium, breast, ovary, and cervix.

387TiP - Palbociclib rechallenge in hormone receptor (HR)[+]/HER2[-] advanced breast cancer (ABC). PALMIRA trial

BackgroundThe combination of a CDK4/6 inhibitor (CDK4/6i) with letrozole (LET) or fulvestrant (FUL) is the most active first–line (1L) treatment for patients (pts) with HR[+]/HER2[-] ABC. Although endocrine sensitivity persists beyond progression, preliminary findings suggest more adaptive resistance mechanisms to endocrine therapy (ET) than to CDK4/6i. At present, there are no data about prolonging CDK4/6 blockade beyond progression on a CDK4/6i. The aim of this study is to determine whether palbociclib rechallenge combined with second–line ET upon progression to a prior palbociclib–based therapy will improve progression–free survival (PFS) over ET alone in HR[+]/HER2[-] ABC pts. Trial designThis is an international, open–label, randomized phase II trial. A total of 198 pts will be randomized (2:1) to palbociclib plus ET (LET or FUL) or ET alone, until progressive disease (PD) or unacceptable toxicity. Pts will be stratified by 1L ET and presence of visceral metastasis. Main selection criteria include: (1) Pre– and post–menopausal women with HR[+]/HER2[-] ABC; (2) Evidence of PD on a 1L combination of palbociclib plus LET or FUL after obtaining clinical benefit (secondary resistance); (3) Pts relapsing on or within the first year of a palbociclib–based adjuvant regimen; (4) Measurable and biopsable disease or non–measurable disease with bone lesion. The primary objective is to assess PFS of palbociclib plus ET versus ET alone. The 1st co-primary endpoint is the PFS in the combination arm only. If this objective is achieved, we will compare PFS between the two arms (2nd co-primary endpoint). With 128 events, the 1st and 2nd analyses have an 80% power to detect a 1.4–month (hazard ratio [HR]=0.74) or 2.74–month (HR=0.6) increase over 4–month median PFS for ET arm, respectively. The nominal alpha level is 5% for two-sided log-rank tests. Secondary objectives evaluate: Safety–related outcomes, objective response rate, 6–month clinical benefit rate, overall survival, quality of life, and time to first chemotherapy. Exploratory objectives include: Correlation between the intrinsic molecular subtypes and efficacy/safety findings, and identification of new predictive markers. Clinical trial identificationNCT03809988. First Posted: January 18, 2019. Legal entity responsible for the studyMedica Scientia Innovation Research (MedSIR). FundingPfizer S.L.U. DisclosureA. Llombart Cussac: Honoraria (institution), Advisory / Consultancy: Roche, GlaxoSmithKline, Novartis, Celgene, Eisai, AstraZeneca; Research grant / Funding (institution): GlaxoSmithKline, Sanofi, Puma Biotechnology; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). P. Schmid: Advisory / Consultancy: Pfizer, AstraZeneca, Novartis, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, Puma; Research grant / Funding (institution): AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas; Spouse / Financial dependant, Spouse is consulting for Genentech/Roche: Genentech/Roche. I. Macpherson: Honoraria (self): Celldex, Daiichi Sankyo, Eisai, Genomic Health, Novartis, Pfizer, Roche; Travel / Accommodation / Expenses: Eisai, Roche. J. Gligorov: Advisory / Consultancy: Daïchi, EISAI, Genomic Health, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer, Roche Genentech; Travel / Accommodation / Expenses: EISAI, Genomic Health, MSD, Novartis, Pfizer, Roche Genentech; Non-remunerated activity/ies: Daichi, EISAI, Genomic Health, Immunomedics, Novartis, Pfizer, Roche Genentech. M. Sampayo: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). F. Riva: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). A. Malfettone: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J.M. Pérez-García: Advisory / Consultancy: Roche, Lilly; Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J. Cortés: Advisory / Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Honoraria (institution): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung; Research grant / Funding (institution): Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). All other authors have declared no conflicts of interest.

Current and Future Molecular Testing in NSCLC, What Can We Expect from New Sequencing Technologies?

Recent changes in lung cancer care, including new approvals in first line and the introduction of high-throughput molecular technologies in routine testing led us to question ourselves on how deeper molecular testing may be helpful for the optimal use of targeted drugs. In this article, we review recent results in the scope of personalized medicine in lung cancer. We discuss biomarkers that have a therapeutic predictive value in lung cancer with a focus on recent changes and on the clinical value of large scale sequencing strategies. We review the use of second- and third-generation EGFR and ALK inhibitors with a focus on secondary resistance alterations. We discuss anti-BRAF and anti-MEK combo, emerging biomarkers as NRG1 and NTRKs fusions and immunotherapy. Finally, we discuss the different technical issues of comprehensive molecular profiling and show how large screenings might refine the prediction value of individual markers. Based on a review of recent publications (2012–2018), we address promising approaches for the treatment of patients with lung cancers and the technical challenges associated with the identification of new predictive markers.

Genetic polymorphisms may influence the vertical growth rate of melanoma.

Background: Identification of new predictive markers in melanoma is of great clinical importance. This study was aimed to analyze association between selected common variants in the cancer susceptibility genes and melanoma progression at the time of diagnosis.Material and Method: The study included 243 consecutive patients with melanoma. Genotyping was performed using real-time PCR.Results: Our data revealed modest association between xeroderma pigmentosum complementation group D (XPD) codon 312 polymorphism and tumor thickness (as defined by Breslow score; XPD D312N CC: 3.00 ± 3.78mm, CT: 1.71 ± 2.48mm, TT: 2,53 ± 3,24mm, P=0.023). The CT genotype in XPD D312N polymorphism was more frequently represented in non-invasive melanomas compared to deeply penetrating tumors. None of the common SNPs in cyclin dependent kinase inhibitor 2A (CDKN2A), vitamin D receptor (VDR), melanocortin 1 receptor (MC1R) were associated with Breslow depth.Conclusion: These findings suggest that genetic alteration in XPD contributes to melanoma progression and may be a potential diagnostic and molecular prognostic marker.

The emergence of long non-coding RNAs in the tumorigenesis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. However, the treatments for HCC are limited, and most of them are only available to the early stage. In the later stages, traditional chemotherapy has only marginal effects and may include toxicity. Thus, the identification of new predictive markers is urgently needed. New targets for non-conventional treatments will help to accelerate research on the molecular pathogenesis of HCC. A new class of transcripts, long non-coding RNAs (lncRNAs), has recently been found to be pervasively transcribed in the human genome. Aberrant expression of several lncRNAs was found to be involved in the tumorigenesis of HCC. In this review, we describe the possible molecular mechanisms that underlie lncRNA expression changes in HCC, as well as potential future applications of lncRNA research in the diagnosis and treatment of HCC.

Lack of prognostic value of mean corpuscular volume with capecitabine therapy in metastatic breast cancer.

Capecitabine is an oral fluoropyrimidine derivative which is frequently used alone or in combination regimens for the treatment of metastatic breast cancer. Although overall and progression free survivals have increased in recent years with the use of new generation drugs, predictive factors that would further improve the outcomes are needed. Previous studies have demonstrated the relation between post-treatment increase in mean corpuscular volume (MCV) and predicting therapy response as well as survival. The present study investigated the clinical impact of MCV elevation in metastatic breast cancer patients treated with capecitabine. The data of a total of 82 patients from three centers followed between June 2005 and June 2013 were retrospectively analyzed. The demographic data and hormone receptor status of the patients, as well as initial examination before and after treatment and data concerning progression were recorded. MCV ≥ 100 fl was considered as macrocytosis. Capecitabine was given at a dose of 2500 mg/m2 daily for 14 days every three weeks. Pre-treatment and post-treatment MCV and other parameters of complete blood count were recorded. Post-treatment initial evaluation was performed after 2 cycles of therapy. The median age of the patients was 46.5 years (range 26-72 years) and 54% were premenopausal. Performance status was ECOG 0 and 1 in 81 (99%) patients. The median number of cycles for capecitabine therapy was 5 (min-max: 2-18). The median ΔMCV level (post-treatment values at sixth week - baseline) was 6.4. Whilst ΔMCV was ≥ 6.4 in 42 patients, it was <6.4 in 40 patients. Clinical benefit (complete response+partial response+stable disease) was observed in 37 (88%) of 42 patients with a median ΔMCV ≥ 6.4 and in 30 (75%) of 40 patients with ΔMCV <6.4 with no statistically significant difference (p=0.158). No significant difference was determined between the group with ΔMCV ≥ 6.4 and the group with ΔMCV <6.4 in terms of progression-free survival (11 vs 12 months) (p=0.55) and overall survival (20 months vs. 24 months) (p=0.11). The identification of new predictive markers in metastatic breast cancer is very important. In some recent studies, increase in MCV has been suggested as a marker in tumor response. In the present study, however, no significant difference was determined between tumor response and increase in MCV. Further studies including higher numbers of patients are needed to determine whether increase in MCV is a predictive marker or not.

Genexpressionsbasierte Risikoscores

The decoding of the human genome and its targeted analysis using different techniques has raised great hopes encompassing improvement in the estimation of prognosis and prediction of treatment as well as the identification of new therapeutic targets. The gene expression analysis and identification of appropriate predictive and/or prognostic gene expression signatures is a paradigm for this process. Great expectations have been placed on these new molecular markers, however, there are numerous methodological and clinical questions which need to be determined in prospective, randomized studies but which are currently in the recruiting stage. It is very much the question as to whether the new gene expression-based risk scores will bring any information gain in comparison to classical histopathology markers. However, these studies also begin to show that not only the identification of a high risk subgroup, but also reducing the risk by a specific treatment is possible. As yet it is not clear whether the practical application of this test system will actually be applicable in clinical practice.Only molecular tests which allow a dichotomous result are helpful in clinical decision-making in contrast to an intermediate risk classification which does not provide further information and only leads to uncertainty for patients and therapists. Global molecular test methods will gain in importance in the future with regards to identification of new predictive markers, because for many new substances it is not known for which patient subgroups they can be used with highest treatment success.

Emerging risk factors and markers of chronic kidney disease progression

Chronic kidney disease (CKD) is a common condition with an increasing prevalence. A number of comorbidities are associated with CKD and prognosis is poor, with many patients experiencing disease progression. Recognizing the factors associated with CKD progression enables high-risk patients to be identified and given more intensive treatment if necessary. The identification of new predictive markers might improve our understanding of the pathogenesis and progression of CKD. This Review discusses a number of emerging factors and markers for which epidemiological evidence from prospective studies indicates an association with progression of CKD. The following factors and markers are discussed: asymmetric dimethylarginine, factors involved in calcium-phosphate metabolism, adrenomedullin, A-type natriuretic peptide, N-terminal pro-brain natriuretic peptide, liver-type fatty acid binding protein, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, apolipoprotein A-IV, adiponectin and some recently identified genetic polymorphisms. Additional epidemiological and experimental data are required before these markers can be broadly used for the prediction of CKD progression and before the risk factors can be considered as potential drug targets in clinical interventional trials.