Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, ...functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN. This landscape reveals distinct genomic subpopulations of aNEN based on primary localization and differentiation grade; we observe relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (average 5.45 somatic mutations per megabase) with TP53, KRAS, RB1, CSMD3, APC, CSMD1, LRATD2, TRRAP and MYC as major drivers versus an overall low TMB in neuroendocrine tumors (1.09). Furthermore, we observe distinct drivers which are enriched in somatic aberrations in pancreatic (MEN1, ATRX, DAXX, DMD and CREBBP) and midgut-derived neuroendocrine tumors (CDKN1B). Finally, 49% of aNEN patients reveal potential therapeutic targets based upon actionable (and responsive) somatic aberrations within their genome; potentially directing improvements in aNEN treatment strategies.
The incorporation of molecular profiling into routine clinical practice has already been adopted in some tumor types, such as human epidermal growth factor receptor 2 (HER2) testing in breast cancer ...and KRAS genotyping in colorectal cancer, providing a guide to treatment selection that is not afforded by histopathologic diagnosis alone. It is inevitable that over time, with rapid advances in scientific knowledge, bioinformatics, and technology to identify oncogenic drivers, molecular profiling will complement histopathologic data to influence management decisions. Emerging technologies such as multiplexed somatic mutation genotyping and massive parallel genomic sequencing have become increasingly feasible at point-of-care locations to classify cancers into molecular subsets. Because these molecular subsets may differ substantially between each other in terms of sensitivity or resistance to systemic agents, there is consensus that clinical trials should be more stratified for or be performed only in such molecularly defined subsets. This approach, however, poses challenges for clinical trial designs because smaller numbers of patients would be eligible for such trials, while the number of novel anticancer drugs warranting further clinical exploration is rapidly increasing. This article provides an overview of the emerging methodologic challenges in the cancer genome era and offers some potential solutions for transforming clinical trial designs so they can identify new active anticancer regimens in molecularly defined subgroups as efficiently as possible.
The cytotoxic agent bleomycin is feared for its induction of sometimes fatal pulmonary toxicity, also known as bleomycin-induced pneumonitis (BIP). The central event in the development of BIP is ...endothelial damage of the lung vasculature due to bleomycin-induced cytokines and free radicals. Ultimately, BIP can progress in lung fibrosis. The diagnosis is established by a combination of clinical symptoms, radiographic alterations, and pulmonary function test results, while other disorders resembling BIP have to be excluded. Pulmonary function assessments most suitable for detecting BIP are those reflecting lung volumes. The widely used transfer capacity of the lungs for carbon monoxide appeared recently not to be specific when bleomycin is used in a polychemotherapeutic regimen. There are no proven effective treatments for BIP in humans, although corticosteroids are widely applied. When patients survive BIP, they almost always recover completely with normalization of radiographic and pulmonary function abnormalities. This review focuses on BIP, especially on the pathogenesis, risk factors, and its detection.
In several diseases, low muscle mass has been revealed as an unfavorable prognostic factor for outcome. Whether this holds true in patients with solid malignancies as well has increasingly been ...explored recently. However, this research field is severely hampered by a lack of consensus on how to determine muscle mass in cancer patients and on the definition of low muscle mass. Consequently, the prevalence of low muscle mass varies widely across several studies. Nevertheless, most studies show that, in patients with solid malignancies, low muscle mass is associated with a poor outcome. In the future, more research is needed to get better insight into the best method to determine muscle mass, the exact prognostic value of low muscle mass in diverse tumor types and stages, pathophysiology of low muscle mass in patients with cancer, and ways to intervene and improve muscle mass in patients. This review addresses the current literature on the importance of muscle mass in cancer patients and the methods of muscle measurement.
Implications for Practice:
An increasing number of studies underline the clinical value of low muscle mass as a prognostic factor for adverse outcomes in cancer patients. However, studies show large heterogeneity because of the lack of a standardized approach to measure muscle mass and the lack of reference populations. As a result, the interpretation of data and further progress are severely hampered, hindering the implementation of muscle measurement in oncological care. This review summarizes the methods of diagnosing low muscle mass in cancer patients, the difference between underlying syndromes such as sarcopenia and cachexia, and the association with clinical outcomes described so far.
Many studies underline the clinical value of low muscle mass as a prognostic factor for adverse outcomes in cancer patients, but there is no standardized approach for measuring muscle mass. This review summarizes the methods of diagnosing low muscle mass in cancer patients, the difference between underlying syndromes (sarcopenia and cachexia), and the association with clinical outcomes.
In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients ...participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.
Highlights • CTC enumeration has grade A clinical validity in metastatic breast cancer. • CTC enumeration is ready to be used in certain clinical cases. • The combination of CTC enumeration and ...characterization has great potential.
A phase II study with sorafenib in patients with angiosarcoma conducted by the French Sarcoma Group, and published in this issue of The Oncologist, is evaluated. The importance of proper design and ...conduct of phase II trials is stressed.
Pazopanib is a recently approved, novel tyrosine kinase inhibitor specifically designed to impair angiogenesis by abrogating vascular endothelial growth factor receptor 2 (VEGFR‐2) to exert its ...function. Pazopanib inhibits VEGF‐induced endothelial cell proliferation in vitro and angiogenesis in vivo and demonstrates antitumor activity in mouse models. Furthermore, the pazopanib concentration resulting in maximal inhibition of VEGFR‐2 phosphorylation in vivo was in line with the steady‐state concentration required to inhibit growth of tumor xenografts, suggesting that pazopanib's mechanism of action is indeed through VEGFR‐2 inhibition.
In a phase I trial, a generally well‐tolerated dose was identified at which the majority of patients achieved pazopanib plasma concentrations above the concentration required for maximal in vivo inhibition of VEGFR‐2 phosphorylation in preclinical models. Administered as monotherapy, evidence of antitumor activity was observed in phase II studies in several tumor types, including soft tissue sarcoma, renal cell cancer (RCC), ovarian cancer, and non‐small cell lung cancer. Recently, the U.S. Food and Drug Administration granted approval for treatment with pazopanib in patients with RCC based on the longer progression‐free survival time observed with this agent in a placebo‐controlled, randomized trial. This review summarizes the preclinical and clinical pharmacokinetics and pharmacodynamics of pazopanib, as well as data on clinical activity, that ultimately resulted in its recent approval.
This review summarizes the preclinical and clinical pharmacokinetics and pharmacodynamics of pazopanib, as well as data on clinical activity, that ultimately resulted in its recent approval.
From February 7-11, 2011, the multidisciplinary Lorentz Workshop Circulating Tumor Cell (CTC) Isolation and Diagnostics: Toward Routine Clinical Use was held in Leiden (The Netherlands) to discuss ...progress and define challenges and potential solutions for development of clinically useful circulating tumor cell (CTC) diagnostics. CTCs, captured as "liquid biopsy" from blood, for counting and characterization using pathology and molecular assays, are expected to replace metastatic tissue biopsies to be used to predict drug response and resistance and to monitor therapy response and cancer recurrence. CTCs are highly heterogeneous; therefore, cancer type-specific isolation technologies, as well as complex clinical interpretation software, are required.
Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we ...present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12
and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12
and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups.
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