Orphan Tumors Research Articles

Prospective study of the real impact of fusion centered genomic assays in patient management in a national collaborative group: the GETHI-XX-16 study.

Precision medicine represents a paradigm shift in oncology. Access to genetic testing and targeted therapies is frequently limited. Assays based on DNA sequencing can miss druggable alterations. We aimed to determine the impact of a free access program to RNA tests in patient management. We designed a multicenter prospective observational study within the Spanish National Group for Translational Oncology and Rare and Orphan Tumors (GETTHI). Eligible patients were adults with solid cancers that had progressed on standard therapies. Tumor samples were analyzed using two RNA sequencing assays (Trailblaze PharosTM and Archer FusionPlex Solid TumorTM). A central committee evaluated the actionability of genetic alterations and reported the findings to attending physicians, who made the final clinical management decisions. Between November 2016 and April 2019, 395 patients with 41 different tumors across 30 hospitals were included. Molecular analysis revealed actionable genetic alterations in 57 individuals (14.4%). Targeted therapies were advised for 23 and seven received a matched targeted therapy: two lung cancers (EML4-ALK and CD74-ROS1 fusion), three glioblastomas (EGFR point mutations), one oligodendroglioma (FGFR3-TACC3 fusion) and a prostate cancer (SND1-BRAF fusion). The outcomes included two tumor responses, one disease stabilization, one early withdrawal due to toxicity, one progression, and one unknown. Despite the growing knowledge of cancer biology and its translation to drug development, the overall impact of personalized treatments remains low. Access to comprehensive molecular tests covering properly all known actionable alterations and programs for a wide access to targeted therapies seem to be critical steps.

Phase II clinical trial assessing the efficacy of enzalutamide in advanced non-resectable granulosa cell ovarian tumors: The GREKO III study (GETHI2016–01)

BackgroundGranulosa cell ovarian tumors (GCT) are orphan disease with limited treatments. Hormone therapy is a potential treatment, due to the overexpression of hormone receptors in most tumors. This study explores the activity of the antiandrogen, enzalutamide, in metastatic cases. MethodsWe designed a phase II clinical trial under the Spanish Collaborative Group for Transversal Oncology and Rare and Orphan Tumors (GETTHI). Eligible participants were adult women with advanced GCT. Primary endpoint was objective response rate. Secondary endpoints included clinical benefit rate, progression-free survival, overall survival, and safety profile. Patients received enzalutamide 160 mg once daily. ResultsFrom April 2018 to March 2020, eighteen patients were screened, and sixteen were included across nine institutions. Median age was 56.4 years (range 45–71), and most were Caucasian (14 cases), one Arabian and one Latin. ECOG performance status was zero in 13 cases (81 %) and one in three (19 %). Six patients (38 %) had previously received hormone therapy as adjuvant treatment or for advanced disease, and 15 (94 %) chemotherapy. Median time from metastasis to study entry was 96 months (range 4.5–198).No objective response was observed, but the clinical benefit rate reached 68.8 % (95 % CI [46 %–91.5 %]). Median progression-free survival was 3.8 months (95 % CI [1.36–6.14]). Median overall survival was not reached, with a median follow-up of 6 months (range 2.2–19).At the time of database closure, 14 patients had discontinued treatment, 13 due to disease progression and one by personal choice. Two deaths attributed to disease progression were recorded.Five grade 3 adverse events were reported, with only one (asthenia) deemed related to the therapy. ConclusionsAlthough enzalutamide demonstrated modest activity in GCT, durable stabilization was observed in some cases.Trial Registration:ClinicalTrials.gov Identifier: NCT03464201

Therapeutic inhibition of isocitrate dehydrogenase mutations in glioma and cholangiocarcinoma: new insights and promises-a narrative review.

The identification of mutation hot spots in the isocitrate dehydrogenase (IDH) genes is one of the most important cancer genome-wide sequencing discoveries with relevant impact in the treatment of some orphan tumors. These genes were mostly found mutated in lower-grade gliomas (LGGs), acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and in cholangiocarcinoma. This aberrant genomic condition represents a therapeutic target of great interest in cancer research, especially in AML, given the limitations of currently approved therapies in this field. In this review, we investigate the role of IDH mutation and the mutant IDH (mIDH)-targeted therapies for cholangiocarcinoma and glioma. Here, we provide an overview of the IDH mutation role and discuss its role in tumorigenesis and progression of some solid cancers, in which the therapeutic strategy can be completely changed thanks to these brand-new therapeutic options. The encouraging early clinical data demonstrated to be a proof of concept for investigational mIDH1/2 inhibitors in tumors with a paucity of therapeutic possibilities. Moreover, we list the most important randomised clinical trials still active with their preliminary results.

Perspective review: lessons from successful clinical trials and real-world studies of systemic therapy for metastatic pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are orphan tumors with the potential to spread to distant organs such as the lymph nodes, the skeleton, the lungs, and the liver. These metastatic tumors exhibit high rates of morbidity and mortality due to their frequently large tumor burden, the progression of the disease, and the excessive secretion of catecholamines that lead to cardiovascular disease and gastrointestinal dysmotility. Several molecular drivers responsible for the development of PPGLs have been described over the last 30 years. Although therapeutic options are limited, substantial progress has been made in the recognition of effective systemic therapies for these tumors. Successful clinical trials with radiopharmaceuticals such as high-specific-activity meta-iodobenzylguanidine and tyrosine kinase inhibitors such as cabozantinib and sunitinib have been recently published. This review will discuss the results of these studies and their impact on current clinical practices. In addition, this review will provide valuable information on how to design clinical trials to treat patients with metastatic PPGLs with novel medications.

Cytotoxic Pt(II) complexes containing alizarin: a selective carrier for DNA metalation.

Many efforts have been made in the last few decades to selectively transport antitumor agents to their potential target sites with the aim to improve efficacy and selectivity. Indeed, this aspect could greatly improve the beneficial effects of a specific anticancer agent especially in the case of orphan tumors like the triple negative breast cancer. A possible strategy relies on utilizing a protective leaving group like alizarin as the Pt(II) ligand to reduce the deactivation processes of the pharmacophore enacted by Pt resistant cancer cells. In this study a new series of neutral mixed-ligand Pt(II) complexes bearing alizarin and a variety of diamine ligands were synthesized and spectroscopically characterized by FT-IR, NMR and UV-Vis analyses. Three Pt(II) compounds, i.e., 2b, 6b and 7b, emerging as different both in terms of structural properties and cytotoxic effects (not effective, 10.49 ± 1.21 μM and 24.5 ± 1.5 μM, respectively), were chosen for a deeper investigation of the ability of alizarin to work as a selective carrier. The study comprises the in vitro cytotoxicity evaluation against triple negative breast cancer cell lines and ESI-MS interaction studies relative to the reaction of the selected Pt(II) complexes with model proteins and DNA fragments, mimicking potential biological targets. The results allow us to suggest the use of complex 6b as a prospective anticancer agent worthy of further investigations.

Immune checkpoint inhibitors in lung tumors with rare histologies and other thoracic malignancies.

In recent years, immunotherapy has significantly changed the treatment of locally advanced/metastatic non-small-cell lung cancer (NSCLC). Conversely, the role of immunotherapy in NSCLC with uncommon histologies remains unclear, while in other rare thoracic malignancies, such as malignant pleural mesotheliomaand thymic epithelial tumors, the use of immune checkpoint inhibitorsis modifying therapeuticstrategies with solid hopes for the future. However, larger prospective studies are urgently needed to define the best treatment strategies and the role of immunotherapy in these orphan tumors. This review provides a comprehensive overview of the emerging role of immunotherapy in the treatment of patients affected by these rare thoracic malignancies.

Cisplatin-based chemotherapy for the treatment of metastatic collecting duct carcinomas: A real-world, retrospective analysis.

Collecting duct carcinomas (CDCs) are a particularly rare subtype of kidney cancer, endowed by a particularly poor prognosis. Since no active treatments have been established for CDCs, due to similarities with upper tract urothelial carcinomas, the use of the cisplatin-gemcitabine doublet is usually recommended. Here we report a retrospective analysis of 36 metastatic CDCs treated, as everyday clinical practice, with either cisplatin-gemcitabine or cisplatin-gemcitabine-paclitaxel from 2005 to 2021. Thirty-three patients received gemcitabine (1000 mg/m2, days 1 and 8) and cisplatin (70 mg/m2, day 1), while 3 were treated with paclitaxel (80 mg/m2, days 1 and 8), gemcitabine (1000 mg/m2, days 1 and 8) and cisplatin (70 mg/m2, day 1), every 21 days for a maximum of 6 cycles. Eight out of 36 patients (22.2%) experienced a partial response, while 9 others (25%) had a disease stabilization. No benefit was observed in the only 3 patients treated with the triplet. Median PFS was just 6 months, while median OS was 8 months. The commonest grade ≥3 treatment-related adverse events were: neutropenia (75%, 11.1% of febrile neutropenia), anemia (50%), thrombocytopenia (38.8%), and vomiting (8.3%). Dose omissions and dose reductions were common, and few frail patients started the treatment with a 25% dose reduction. In conclusion, our real-world experience confirmed the modest activity and relevant toxicity of cisplatin-based chemotherapy for the treatment of CDCs. More translational studies and novel study designs are thus badly needed in these still orphan tumors.

TMC-SNPdb 2.0: an ethnic-specific database of Indian germline variants.

Cancer is a somatic disease. The lack of Indian-specific reference germline variation resources limits the ability to identify true cancer-associated somatic variants among Indian cancer patients. We integrate two recent studies, the GenomeAsia 100K and the Genomics for Public Health in India (IndiGen) program, describing genome sequence variations across 598 and 1029 healthy individuals of Indian origin, respectively, along with the unique variants generated from our in-house 173 normal germline samples derived from cancer patients to generate the Tata Memorial Centre-SNP database (TMC-SNPdb) 2.0. To show its utility, GATK/Mutect2-based somatic variant calling was performed on 224 in-house tumor samples to demonstrate a reduction in false-positive somatic variants. In addition to the ethnic-specific variants from GenomeAsia 100K and IndiGenomes databases, 305 132 unique variants generated from 173 in-house normal germline samples derived from cancer patients of Indian origin constitute the Indian specific, TMC-SNPdb 2.0. Of 305 132 unique variants, 11.13% were found in the coding region with missense variants (31.3%) as the most predominant category. Among the non-coding variations, intronic variants (49%) were the highest contributors. The non-synonymous to synonymous SNP ratio was observed to be 1.9, consistent with the previous version of TMC-SNPdb and literature. Using TMC SNPdb 2.0, we analyzed a whole-exome sequence from 224 in-house tumor samples (180 paired and 44 orphans). We show an average depletion of 3.44% variants per paired tumor and significantly higher depletion (P-value < 0.001) for orphan tumors (4.21%), demonstrating the utility of the rare, unique variants found in the ethnic-specific variant datasets in reducing the false-positive somatic mutations. TMC-SNPdb 2.0 is the most exhaustive open-source reference database of germline variants occurring across 1800 Indian individuals to analyze cancer genomes and other genetic disorders. The database and toolkit package is available for download at the following: Database URL http://www.actrec.gov.in/pi-webpages/AmitDutt/TMCSNPdb2/TMCSNPdb2.html

Translational cell biology of highly malignant osteosarcoma.

Highly malignant osteosarcoma (HMO) is the most frequent malignant bone tumor preferentially occurring in adolescents and children with a second more flat peak in patients over the age of 60. The younger patients benefit from combined neoadjuvant chemotherapy with 65-70% 5-year survival rate. In patients with metastatic HMO the 5-year survival rate is consistently poor with approximately 30%. In the last several years strategies for target therapies have been developed by using next generation sequencing (NGS) for defining targetable molecular factors. However, it has so far been challenging to establish an effective target therapy for so-called 'orphan tumors' without recognizable driver mutations, including HMO. The molecular genetic studies using NGS have shown that HMOs are genomically unstable tumors with highly complex chaotic karyotypes. Before the background of this genetic complexity more investigations should be performed in the future for defining targetable biological factors. As the prognosis could not be improved for 40 years one may expect improvements for patients only by gaining a deeper understanding of the cell and molecular biology of HMO. The cell of origin of HMO is being clarified now. The majority of studies indicate that an osteoblastic progenitor cell is probably the cell of origin of HMO and not an undifferentiated mesenchymal stem cell. This means that the established histopathological definition of HMO through verification of osteoid production by the osteoblastic cells is well justified and will probably be the cornerstone for a precise differential diagnosis of HMO also in the years to come.

Exploring the RC-106 Chemical Space: Design and Synthesis of Novel (E)-1-(3-Arylbut-2-en-1-yl)-4-(Substituted) Piperazine Derivatives as Potential Anticancer Agents.

Despite the fact that significant advances in treatment of common cancers have been achieved over the years, orphan tumors still represent an important unmet medical need. Due to their complex multifactorial origin and limited number of cases, such pathologies often have very limited treatment options and poor prognosis. In the search for new anticancer agents, our group recently identified RC-106, a Sigma receptor modulator endowed with proteasome inhibition activity. This compound showed antiproliferative activity toward different cancer cell lines, among them glioblastoma (GB) and multiple myeloma (MM), two currently unmet medical conditions. In this work, we directed our efforts toward the exploration of chemical space around RC-106 to identify new active compounds potentially useful in cancer treatment. Thanks to a combinatorial approach, we prepared 41 derivatives of the compound and evaluated their cytotoxic potential against MM and GB. Three novel potential anticancer agents have been identified.

412P - Updated analysis of the national registry of nervous system tumours in Spain (RETSINE). RETSINE: National registry of nervous system tumours of the Spanish research group in neuro-oncology (GEINO) and Spanish infrequent and orphan tumours group (GETHI)

BackgroundThe Spanish Research Group in Neuro-oncology (GEINO) and Spanish Infrequent and Orphan Tumors Group (GETHI) initiated a Nervous System Tumors Registry (RETSINE) in September 2017 with the aim of evaluating accurate, basic data concerning this oncological pathology in Spain. (Spanish Agency of Medicines and Medical Devices code: GG-TIN-2017-01). MethodsThe RETSINE database collects demographic, diagnostic and treatment data from all the hospitals participating in the project. Secondarily, each researcher indicates if there is a tumor sample available for future studies that arise from the registry. ResultsFrom September 2017 to April 2019, the registry has included 1021 patients (p) from 26 different hospitals. P have been included at a rate of 60 per month. With a median age of 60 y (range: 16-89), there is a discrete predominance in males (56.1%). The main symptoms at presentation are seizures, cognitive impairment and ataxia (26.1%, 16.8% and 6.6% of p). Histology provided in 841 p=764/841 glioma (90,8%) [High Grade Glioma 618/764 (80.9%), Low Grade Glioma 146/764 (19.1%)], 77/308 no glioma (9,2%). Primary surgical treatment= 42.4% total tumor removal; 38.9% subtotal tumor removal and 7.7% biopsy. The median overall survival is 18.1 m (95% CI 15.5-20.6): 115.6 m (95% CI 38.8-192.4) in Low Grade and 17.5 m (95% CI 15.4-19.5) in High Grade Glioma. ConclusionsRETSINE is a valuable tool for analyzing the current situation of Nervous System Tumors in Spain. The possibility of carrying out clinical studies in tumors of low incidence will be increased and improved with records of cases with associated biological sample. The database provides medical information that can also assist the orientation of healthcare policies. Legal entity responsible for the studySpanish Research Group in Neuro-oncology (GEINO) and Spanish Infrequent and Orphan Tumors Group (GETHI). FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Verteporfin-Loaded Polymeric Microparticles for Intratumoral Treatment of Brain Cancer.

Glioblastoma (GBMs) is the most common and aggressive type of primary brain tumor in adults with dismal prognosis despite radical surgical resection coupled with chemo- and radiotherapy. Recent studies have proposed the use of small-molecule inhibitors, including verteporfin (VP), to target oncogenic networks in cancers. Here we report efficient encapsulation of water-insoluble VP in poly(lactic- co-glycolic acid) microparticles (PLGA MP) of ∼1.5 μm in diameter that allows tunable, sustained release. Treatment with naked VP and released VP from PLGA MP decreased cell viability of patient-derived primary GBM cells in vitro by ∼70%. Moreover, naked VP treatment significantly increased radiosensitivity of GBM cells, thereby enhancing overall tumor cell killing ability by nearly 85%. Our in vivo study demonstrated that two intratumoral administrations of sustained slow-releasing VP-loaded PLGA MPs separated by two weeks significantly attenuated tumor growth by ∼67% in tumor volume in a subcutaneous patient-derived GBM xenograft model over 26 d. Additionally, our in vitro data indicate broader utility of VP for treatment for other solid cancers, including chordoma, malignant meningioma, and various noncentral nervous system-derived carcinomas. Collectively, our work suggests that the use of VP-loaded PLGA MP may be an effective local therapeutic strategy for a variety of solid cancers, including unresectable and orphan tumors, which may decrease tumor burden and ultimately improve patient prognosis.

Comprehensive genomic profiling of appendiceal adenocarcinoma.

298 Background: Appendiceal adenocarcinomas (AAs) are orphan tumors. Little is known about their molecular profile limiting understanding of their biology and development of novel targeted therapies. The purpose of this study was to delineate the molecular landscape of AAs. Methods: We performed a retrospective review of AAs patients (pts) who were evaluated at MD Anderson Cancer Center between October 2012 and April 2017 and underwent next-generation sequencing (NGS) with internal or external assays (at least 45 genes) using either tumor tissue specimens or peripheral blood for circulating cell-free DNA (cfDNA). The primary outcome was to assess the prevalence of genomic alterations (GAs) in AAs. We then performed comparative exploratory analyses of GAs using TCGA colorectal cancer (CRC) sequencing. Results: A total of 78 patients were identified of which 57 (73%) and 18 (23%) underwent tissue based and ctDNA based sequencing, respectively (3 cases had both). At least 1 GA was found in 61 (78%) of AA specimens, with a mean (SD) of 2.8 (1.6) GAs per case. Of these 44 (72%) had ≥ 2 GAs and 31 (51%) had ≥ 3 GAs. The most frequent GAs were KRAS (38 [62%]), TP53 (22 [36%]), GNAS (17 [28%]), SMAD4 (11 [18%]), PIK3CA (10 [16%]), APC (9 [15%]), ATM (8 [13%]), BRAF (5 [8%]), KIT (5 [8%]), NRAS (3 [5%]) and MET (3 [5%]). GNAS mutations frequently co-occurred with KRAS mutations (42% v 5%, OR 14.3, P &lt; 0.001). No GA was associated with grade, mucinous histology or overall survival (OS). Besides these mutations, we also found unusual cases with targetable mutations such as ALK, EGFR, MET, IDH1 and ERBB2. In our comparative analyses, mutations in KRAS (p = 0.009), TP53 (p = 0.020), GNAS (p &lt; 0.001) and APC (p &lt; 0.001) genes were significantly different from CRC whereas there was no difference in prevalence of PIK3CA, SMAD4 and ATM genes. Conclusions: To date, our analysis of one of the largest cohorts of AAs, demonstrate a majority of AAs harbor at least 1 GAs. Although treatment paradigms in AAs are extrapolated from CRC, the molecular profile of these tumors differs significantly. Molecular characterization of these rare tumors is a necessary first step towards discovery of opportunities for use of targeted therapies in these patients.

Patient-Reported Toxic Effects-The Dawn of a New Era.

Patient-Reported Toxic Effects-The Dawn of a New Era.

Cancer épidermoïde de la trachée : imagerie de l’atteinte ganglionnaire

The anatomy of the trachea lymphatics is poorly understood and the only researches date back to more than one century. Tracheal tumors are very rare, miscellaneous and variously lymphophilic. The cancers of the trachea have no TNM and their lymph node metastases are little studied despite their poor prognosis. We observed 2 cases of squamous cell carcinoma, one in the cervical and the other in the intrathoracic trachea. TDM-3D reformats demonstrated metastatic lymph nodes of the right para-tracheal lymph node chain (2R and 4R) in both patients and in the cervical lymph nodes (right recurrent nerve lymph node chain) in the patient with cervical tumor. Right location of the mediastinal metastases may be explained by the anatomy of the lymph node chain drainage of the lung segments, the right para-tracheal chain being the only one to regularly possess lymph nodes at that level. The right recurrent nerve lymph node metastases of the cervical tumor are explained by common lymph drainage of the cervical trachea towards larynx lymph centres. Besides lymph node metastases, cancers prognosis may also depends on its location in the trachea. Thus, the tracheal tumors are complex and constitute quite as many orphan tumors. Multicentric studies are mandatory to better understand their behavior. Means provided by new imaging techniques might permit establishing a veritable TNM lymph node mapping of these tumors.

Molecular markers in pediatric neuro-oncology.

Pediatric molecular neuro-oncology is a fast developing field. A multitude of molecular profiling studies in recent years has unveiled a number of genetic abnormalities unique to pediatric brain tumors. It has now become clear that brain tumors that arise in children have distinct pathogenesis and biology, compared with their adult counterparts, even for those with indistinguishable histopathology. Some of the molecular features are so specific to a particular type of tumors, such as the presence of the KIAA1549-BRAF fusion gene for pilocytic astrocytomas or SMARCB1 mutations for atypical teratoid/rhabdoid tumors, that they could practically serve as a diagnostic marker on their own. Expression profiling has resolved the existence of 4 molecular subgroups in medulloblastomas, which positively translated into improved prognostication for the patients. The currently available molecular markers, however, do not cover all tumors even within a single tumor entity. The molecular pathogenesis of a large number of pediatric brain tumors is still unaccounted for, and the hierarchy of tumors is likely to be more complex and intricate than currently acknowledged. One of the main tasks of future molecular analyses in pediatric neuro-oncology, including the ongoing genome sequencing efforts, is to elucidate the biological basis of those orphan tumors. The ultimate goal of molecular diagnostics is to accurately predict the clinical and biological behavior of any tumor by means of their molecular characteristics, which is hoped to eventually pave the way for individualized treatment.