Towards precision oncology in angiosarcomas using next generation “omic” technologies

Angiosarcomas are a group of aggressive tumors of vascular origin. Although thought to be a rare cancer constituting just 1–2% of all soft tissue sarcomas, recent observations suggest that angiosarcomas are more common amongst Asian populations as compared to the West, suggesting the possibility of distinct genetic or environmental triggers influencing its pathogenesis. Advances in genomic sequencing efforts have led to the discovery of ultraviolet mutation signatures and high tumor mutation burden as common features of angiosarcoma of the head and neck. In addition, multi-omic analyses integrated with clinical data identified 3 subtypes characterized by distinctive etiological and biological phenotypes, with potential implications on precision therapy. The systemic and local immune milieu, as well as the presence of “giant” tumor cells, was also recently demonstrated to influence clinical behavior and patient outcomes, further highlighting complexities of this disease. Improvements in next generation “omic”-based technologies are expected to improve our understanding of angiosarcoma and guide the development of precision oncology in this rare cancer.     

Prognostic impact of circulating tumor cells detected with the microfluidic “universal CTC‐chip” for primary lung cancer

Detecting rare circulating tumor cells (CTCs) in the bloodstream is extremely challenging. We had previously developed a novel polymeric microfluidic device, “CTC‐chip,” for capturing CTCs and have shown high capture efficiency in lung cancer cell lines by conjugating Abs against epithelial cell adhesion molecules (EpCAM). This study aimed to optimize the EpCAM‐chip and clarify the prognostic impact of CTCs in lung cancer patients. Of 123 patients with pathologically proven lung cancer, both progression‐free survival (P = .037) and cancer‐specific survival (P = .0041) were predominantly poor when CTCs were detected before treatment. After classification into surgical and chemotherapy groups, progression‐free survival was worse in CTC‐positive patients in both groups (surgery, P = .115; chemotherapy, P = .012), indicating that the detection of baseline CTCs is a risk factor for recurrence and progression. Furthermore, we recovered captured CTCs using micromanipulators and undertook mutation analysis using PCR. Thus, the EpCAM‐chip is a highly sensitive system for detecting CTCs that contributes to the prediction of recurrence and progression and enables genetic analysis of captured CTCs, which could open new diagnostic, therapeutic, and prognostic options for lung cancer patients.     

PD-L1-expressing extranodal diffuse large B-cell lymphoma,NOS with and without PD-L1 3’-UTR structural variations

Immune evasion mediated by PD-L1 plays an important role in the development of B-cell malignancies. However, PD-L1 expression is infrequently observed in tumor cells of extranodal diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Other than copy number alterations, PD-L1 is aberrantly upregulated by structural variations in the 3′-UTR of PD-L1. We report four cases with PD-L1 expression on tumor cells, including two with structural variations in the 3′-UTR of PD-L1 and two without. Our report demonstrates the presence of a small number of “immune evasion-type” extranodal DLBCL, NOS cases.     

Factors Associated with “Survivor Identity” in Men with Breast Cancer

Cancer patients vary in their comfort with the label “survivor”. Here, we explore how comfortable males with breast cancer (BC) are about accepting the label cancer “survivor”. Separate univariate logistic regressions were performed to assess whether time since diagnosis, age, treatment status, and cancer stage were associated with comfort with the “survivor” label. Of the 70 males treated for BC who participated in the study, 58% moderately-to-strongly liked the term “survivor”, 26% were neutral, and 16% moderately-to-strongly disliked the term. Of the factors we explored, only a longer time since diagnosis was significantly associated with the men endorsing a survivor identity (OR = 1.02, p = 0.05). We discuss how our findings compare with literature reports on the comfort with the label “survivor” for women with BC and men with prostate cancer. Unlike males with prostate cancer, males with BC identify as “survivors” in line with women with BC. This suggests that survivor identity is more influenced by disease type and treatments received than with sex/gender identities.     

Prospective genomically guided identification of “early/evolving” and “undersampled” IDH-wildtype glioblastoma leads to improved clinical outcomes

BackgroundGenomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma.MethodsClinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” per cIMPACT-NOW criteria.ResultsWe identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term “early/evolving” and “undersampled” glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone.ConclusionsThese results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.     

Diagnosis of “cribriform” prostatic adenocarcinoma: an interobserver reproducibility study among urologic pathologists with recommendations

Accurate diagnosis of cribriform Gleason pattern 4 (CrP4) prostate adenocarcinoma (PCa) is important due to its independent association with adverse clinical outcomes and as a growing body of evidence suggests that it impacts clinical decision making in PCa management. To identify reproducible features for diagnosis of CrP4, we assessed interobserver agreement among 27 experienced urologic pathologists of 60 digital images from 44 radical prostatectomies (RP) that represented a broad spectrum of potential CrP4. The following morphologic features were correlated with the consensus diagnosis (defined as 75% agreement) for each image: partial vs. transluminal glandular bridging, intraglandular stroma, <12 vs. ≥12 lumina, well vs. poorly formed lumina, mucin (mucinous fibroplasia, extravasation, or extracellular pool), size (compared to benign glands and number of lumina), number of attachments with gland border by tumor cells forming a “glomeruloid-like” pattern, a clear luminal space along the periphery of gland occupying <50% of glandular circumference, central nerve, dense (cell mass occupying >50% of luminal space) vs. loose, and regular vs. irregular contour. Interobserver reproducibility for the overall diagnostic agreement was fair (k=0.40). Large CrP4 had better agreement (k=0.49) compared to small CrP4 (k=0.40). Transluminal bridging, dense cellular proliferation, a clear luminal space along the periphery of gland occupying <50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were significantly associated with consensus for CrP4. In contrast, partial bridging, majority of intraglandular cells in contact with stroma, mucinous fibroplasia, only one attachment to the gland border by tumor cells forming a “glomeruloid-like” pattern, and a clear luminal space along the periphery of gland accounting for >50% of the glandular circumference were associated with consensus against CrP4. In summary, we identified reproducible morphological features for and against CrP4 diagnosis, which could be used to refine and standardize the diagnostic criteria for CrP4.     

Molecularly profiled trials: toward a framework of actions for the “nil actionables”

The sequencing of tumour or blood samples is increasingly used to stratify patients into clinical trials of molecularly targeted agents, and this approach has frequently demonstrated clinical benefit for those who are deemed eligible. But what of those who have no clear and evident molecular driver? What of those deemed to have “nil actionable” mutations? How might we deliver better therapeutic opportunities for those left behind in the clamour toward stratified therapeutics? And what significant learnings lie hidden in the data we amass but do not interrogate and understand? This Perspective article suggests a holistic approach to the future treatment of such patients, and sets a framework through which significant additional patient benefit might be achieved. In order to deliver upon this framework, it encourages and invites the clinical community to engage more enthusiastically and share learnings with colleagues in the early drug discovery community, in order to deliver a step change in patient care.Subject terms: Drug development, Target identification, Drug development     

Surrogacy Beyond Prognosis: The Importance of “Trial-Level” Surrogacy

Many candidate surrogate endpoints are currently assessed using a 2-level statistical approach, which consists in checking whether (1) the potential surrogate is associated with the final endpoint in individual patients and (2) the effect of treatment on the surrogate can be used to reliably predict the effect of treatment on the final endpoint. In some situations, condition (1) is fulfilled but condition (2) is not. We use concepts of causal inference to explain this apparently paradoxical situation, illustrating this review with 2 contrasting examples in operable breast cancer: the example of pathological complete response (pCR) and that of disease-free survival (DFS). In a previous meta-analysis, pCR has been shown to be a strong and independent prognostic factor for event-free survival (EFS) and overall survival (OS) after neoadjuvant treatment of operable breast cancer. Yet, in randomized trials, the effects of experimental treatments on pCR have not translated into predictable effects on EFS or OS, making pCR an “individual-level” surrogate, but not a “trial-level” surrogate. In contrast, DFS has been shown to be an acceptable surrogate for OS at both the individual and trial levels in early, HER2-positive breast cancer. The distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint.

Many candidate surrogate endpoints are currently assessed using a two-level statistical approach. This article explores tentative surrogates versus actual outcomes, focusing on the “surrogate paradox”.

Implications for PracticeThe distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint.     

Molecular biology and genetics of lymphomas

This article summarizes molecular and genetic features of B-cell non-Hodgkin lymphoma and focuses on diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and mantle cell lymphoma. In each of these entities, hallmark genetic aberrations, cytogenetic characteristics, and alterations of single genes that might be involved in the pathogenesis and molecular evolution of the tumor are described. Recent results from gene-expression profiling studies are incorporated that are relevant for the classification of lymphoma entities, the prediction of their clinical behavior, and the identification of deregulated signal-transduction pathways that might represent potential targets in future therapeutic approaches.     

“We’re on a Merry-Go-Round”: Reflections of Patients and Carers after Completing Treatment for Sarcoma

Sarcoma is a rare cancer that has a significant impact on patients’ and carers’ quality of life. Despite this, there has been a paucity of research exploring the diverse experiences of patients and carers following sarcoma treatment. The aim of this study was to explore patients’ and carers’ reflections on life after treatment for sarcoma. A qualitative research design with a social constructionist epistemology was used. Participants included patients previously treated for sarcoma (n = 21) and family carers of patients treated for sarcoma (n = 16). Participants completed semi-structured interviews which were analysed using thematic analysis. Three primary themes were identified: “This journey is never going to be over”, “But what happens when I am better?”, and finding a silver lining. Participants represented sarcoma as having a long-term, and sometimes indefinite, threat on their life that they had limited control over. Conclusions: This study highlight the heterogeneous and ongoing needs of sarcoma survivors and their families. Patients and carers strove to translate their experiences in a meaningful way, such as by improving outcomes for other people affected by sarcoma. Parental carers in particular attempted to protect the patient from the ongoing stress of managing the disease.     

Establishment of an HLA-A*0201 human papillomavirus type 16 tumor model to determine the efficacy of vaccination strategies in HLA-A*0201 transgenic mice

With the increasing generation of new cancer vaccine strategies, there is also an increasing demand for preclinical models that can carefully predict the efficacy of these vaccines in humans. However, the only tumor models available to study vaccines against human papillomavirus (HPV) 16 have been developed in C57BL/6 mice. To test the HLA-restricted capabilities of vaccination strategies, it is important to establish a tumor model in HLA-A*0201 transgenic mice. By transfecting heart lung fibroblasts from HLA-A*0201 mice with HPV16 E6 and E7 oncogenes and H-Ras V12, we have generated a transgenic cell line that is tumorigenic in HLA-A*0201 mice. The dominant H-2D(b) HPV16 E7 epitope was removed from the E7 construct to ensure that all antitumor responses were mediated through the HLA-A*0201-restricted epitopes. We used this tumor model to test the efficacy of two genetic vaccines: a plasmid DNA multi-epitope vaccine encoding human epitopes of HPV16, and a Venezuelan equine encephalitis (VEE) virus-based vector to deliver HPV16 E6 and E7 RNA. We show that both our multi-epitope DNA- and VEE-based vaccines protect 100% of HLA-A*0201 transgenic mice from tumor challenge and elicit a specific T-cell response against multiple HLA-A*0201-restricted HPV16 epitopes. Furthermore, both vaccines significantly decreased tumor burden when tested therapeutically. In conclusion, this is the first tumor model that allows for the assessment of the potential of a vaccine to induce HPV-directed, HLA-A*0201-restricted, antitumor responses in mice. These results pave the way for the clinical evaluation of these vaccines.     

The real-world performance of ThyroSeqV.2 to diagnose thyroid “neoplasm requiring surgery”

Fine-needle biopsy (FNB) predicts benign or malignant thyroid nodules. For indeterminate (ITN) FNBs, commercial molecular tests may improve the diagnostic accuracy and reduce the number of operations. These tests have had limited independent implementation studies in routine clinical practice. This is a prospective observational study. At Boston Medical Center, the 1,316 consecutive FNBs were classified to one of the six categories in the Bethesda classification system. Those ITN samples were submitted for ThyroSeqV.2 next generation sequencing panel analysis. The performance of ThyroSeqV.2 to predict “neoplasm requiring surgery” (NRS) was evaluated. ThyroSeqV.2 assay was performed in 398 FNBs on 384 cytologically ITN nodules (308 Bethesda III, 47 Bethesda IV and 29 Bethesda V). The first evaluable ThyroSeq result for each nodule was used for final analysis. Seventy-seven (72.0%) of 107 patients with a high risk molecular test underwent thyroid surgery resulting in 41 NRS (53.2%) and 36 benign nodules (46.8%). Of the 249 patients with a low risk or negative molecular analysis, 51 (20.5%) had surgery revealing 47 benign nodules (92.2%) and 4 NRS (7.8%). Based on surgical outcome of 128 ITN with evaluable ThyroSeq results, this molecular test had a sensitivity of 91% (95% CI: 79%-98%), specificity of 56% (45%-67%), positive predictive value (PPV) of 53% (42%-65%), negative predictive value (NPV) of 92% (81%-98%), and an overall accuracy of 69% (55%-85%) with a prevalence of NRS of 35% (27%-44%). ThyroSeqV.2 in this clinical use study in ITN nodules provided a similar NPV but a lower PPV than expected compared to published studies due to the detection of an array of mutations in benign nodules. The NPV of 92.0% for ITN cytology confirmed its utility as a “rule-out” test to exclude NRS.     

Consensus recommendations for MRI and PET imaging of primary central nervous system lymphoma: guideline statement from the International Primary CNS Lymphoma Collaborative Group (IPCG)

Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.     

AdAPT-001, an oncolytic adenovirus armed with a TGF-β trap,overcomes in vivo resistance to PD-L1-immunotherapy

Monoclonal antibodies targeting the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) axes have permanently changed the therapeutic landscape for multiple tumor types previously associated with a dismal prognosis such as melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma. However, only a subset of patients initially benefits from these inhibitors, and increasing clinical experience indicates that in a substantial proportion of initial responders, lethal secondary resistance ultimately develops months or years later. In this paper we evaluated combination therapy with a Phase 1 oncolytic adenovirus called AdAPT-001, armed with a TGF-β “trap” that binds to and neutralizes the immunosuppressive cytokine, TGF-β, and a checkpoint inhibitor, anti-PD-L1, in PD-L1 resistant tumors. The study, which was performed in an immunocompetent syngeneic ADS-12 mouse model, demonstrated that the combination of AdAPT-001 with PD-L1 blockade reversed PD-L1 resistance, potentially representing a future paradigm shift for patients that are primarily or secondarily resistant to checkpoint inhibitors.     

Circulating Tumor DNA in Gastric and Gastroesophageal Junction Cancer

Tumor cells shed DNA into the plasma. “Liquid biopsy” analysis of mutations or other genomic alterations in circulating cell-free DNA (cfDNA) may provide us with a tool to detect minimal residual cancer, comprehensively profile the genomic tumor landscape in search of druggable targets, and monitor cancers non-invasively over time for treatment failure or emerging treatment-resistant tumor subclones. While liquid biopsies have not yet entered routine clinical management in patients with gastric and gastroesophageal junction cancers, this group of diseases may benefit from such advanced diagnostic tools due to their pronounced genetic spatiotemporal heterogeneity and limitations in imaging sensitivity. Moreover, as the armamentarium of targeted treatment approaches and immunotherapies expands, cfDNA analyses may reveal their utility not only as a biomarker of response but also for precision monitoring. In this review, we discuss the different applications of cfDNA analyses in patients with gastric and gastroesophageal junction cancer and the technical challenges that such liquid biopsies have yet to overcome.