Molecular Characterization Of Tumors Research Articles

Reprogramming of VEGF-mediated extracellular matrix changes through autocrine signaling

ABSTRACT Vascular endothelial growth factor (VEGF) plays key roles in angiogenesis, vasculogenesis, and wound healing. In cancers, including triple negative breast cancer (TNBC), VEGF has been associated with increased invasion and metastasis, processes that require cancer cells to traverse through the extracellular matrix (ECM) and establish angiogenesis at distant sites. To further understand the role of VEGF in modifying the ECM, we characterized VEGF-mediated changes in the ECM of tumors derived from TNBC MDA-MB-231 cells engineered to overexpress VEGF. We established that increased VEGF expression by these cells resulted in tumors with reduced collagen 1 (Col1) fibers, fibronectin, and hyaluronan. Molecular characterization of tumors identified an increase of MMP1, uPAR, and LOX, and a decrease of MMP2, and ADAMTS1. α-SMA, a marker of cancer associated fibroblasts (CAFs), increased, and FAP-α, a marker of a subset of CAFs associated with immune suppression, decreased with VEGF overexpression. Analysis of human data from The Cancer Genome Atlas Program confirmed mRNA differences for several molecules when comparing TNBC with high and low VEGF expression. We additionally characterized enzymatic changes induced by VEGF overexpression in three different cancer cell lines that clearly identified autocrine-mediated changes, specifically uPAR, in these enzymes. Unlike the increase of Col1 fibers and fibronectin mediated by VEGF during wound healing, in the TNBC model, VEGF significantly reduced key protein components of the ECM. These results further expand our understanding of the role of VEGF in cancer progression and identify potential ECM-related targets to disrupt this progression.

PIK3CA copy-number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer.

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of ∼10%-15%. Considering the well-established predictive role of PIK3CA mutations for response to agents targeting the PI3K/AKT/mTOR pathway, several clinical trials are currently evaluating these drugs in patients with advanced TNBC. However, much less is known regarding the actionability of PIK3CA copy-number gains, which represent a thoroughly common molecular alteration in TNBC, with a prevalence estimated at 6%-20%, and are listed as "likely gain-of-function" alterations in the OncoKB database. In the present paper, we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy-number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.

Brain metastasis screening in the molecular age.

The incidence of brain metastases (BM) amongst cancer patients has been increasing due to improvements in therapeutic options and an increase in overall survival. Molecular characterization of tumors has provided insights into the biology and oncogenic drivers of BM and molecular subtype-based screening. Though there are currently some screening and surveillance guidelines for BM, they remain limited. In this comprehensive review, we review and present epidemiological data on BM, their molecular characterization, and current screening guidelines. The molecular subtypes with the highest BM incidence are epithelial growth factor receptor-mutated non-small cell lung cancer (NSCLC), BRCA1, triple-negative (TN), and HER2+ breast cancers, and BRAF-mutated melanoma. Furthermore, BMs are more likely to present asymptomatically at diagnosis in oncogene-addicted NSCLC and BRAF-mutated melanoma. European screening standards recommend more frequent screening for oncogene-addicted NSCLC patients, and clinical trials are investigating screening for BM in hormone receptor+, HER2+, and TN breast cancers. However, more work is needed to determine optimal screening guidelines for other primary cancer molecular subtypes. With the advent of personalized medicine, molecular characterization of tumors has revolutionized the landscape of cancer treatment and prognostication. Incorporating molecular characterization into BM screening guidelines may allow physicians to better identify patients at high risk for BM development and improve patient outcomes.

First Detection of KRAS Mutation in Colorectal Cancer Patients in Côte d’Ivoire

Advances in molecular biology tools have made it possible to make progress in terms of therapeutics by acting specifically on the molecular mechanisms involved in the virulence of pathogens or in the development of the disease. In the case of cancer, new therapeutics have been developed thanks to these advances. This is called targeted therapy. Targeted therapy molecules specifically act as a molecule, or a molecular pathway involved in the development of the tumor. The use of targeted therapy drugs therefore requires molecular characterization of tumors. In developing countries, the reference tool is high-throughput sequencing, but due to the high cost, this strategy remains inaccessible for the majority of African populations. It is remains necessary to implement alternative molecular diagnostic tools in order to reduce the disparities currently observed in access to cancer care. The High-Resolution Melting analysis (HRM) method is based on real-time PCR and is described as a simple, rapid and specific method for the detection of somatic mutations predictive of anti-tumor therapeutic response. We demonstrated in this study that this method could be implemented in a lower middle-income country like Côte d’Ivoire, and we used it to detect KRAS mutations in colorectal cancer patients for the first time in Cote d’Ivoire.

ODP339 Nonfunctioning Giant Adenomas

Abstract Introduction Giant pituitary tumors (GA), those with 4 cm or more on the largest axis, exhibit extension beyond the sella turcica and invade structures adjacent to it. Objectives To evaluate demographic, clinical, and imaging variables in a cohort of nonfunctioning GA(NGA) patients. Methods We conducted a retrospective and observational study of patients with NGA followed in our tertiary center between 2005 and 2021. We evaluated variables related to diagnosis, treatment, and follow-up. Results We found 48 patients diagnosed with NGA. Most patients were men (n=35, 73%), and meanage at diagnosis 55.5 ± 11.8 years (35-83). Symptoms such as headache and visual alteration were present within 13 years of diagnosis. The BMI was higher than 30 in 10 cases, two with morbid obesity. Among the comorbidities, 10 patients had diabetes mellitus and one glucose intolerance; hypertension was present in 20 cases and depression in 7. Polymedication was verified in 20 patients. Pituitary MRI revealed the largest tumor axis between 4-4.9 cm in 33 patients, 5-5.9 cm in 9, and equal or greater than 6 cm in 6. In 14 cases, there was intraventricular extension, invasion of the sphenoid sinus in 11, cavernous sinus in 21, frontal lobe in 1, temporal region in 6, clivus in 3, retroclivus in 3, and rhinopharynx in one. Hyperprolactinemia was detected in 17 cases (maximum value: 70.8 ng/mL). Only three patients presented all hormonal axes intact. Respectively, 9, 15, 11, and 8 patients presented 1, 2, 3, or 4 deficient axes. Hypocortisolism was present in 18 cases, GH deficiency in 16, hypothyroidism in 32, hypogonadism in 35, and hypoprolactinemia in 3. Four patients had diabetes insipidus. Ten cases of the 44 who underwent surgery underwent two interventions and 4 cases, 3. Nine patients underwent radiotherapy. After the first surgery, 26 patients had follow-up greater than 12 months (13 to 214 months). The last image showed a giant lesion in 7 cases, macroadenoma with a larger axis less than 4 cm in 15 cases, a lesion restricted to the sella in 3 cases, and 1 case without lesion. Conclusion In our cohort, the results show the handling difficulty of NGA, determined by the complex removal of the lesion, high degree of invasion to adjacent structures, and tumor regrowth. Sequential therapeutic decisions in this group of patients require a qualified multidisciplinary team to maximize the patients’ life expectancy and quality of life while working on sharing experiences and investing in the tumor molecular characterization and new molecules that add to the poor therapeutic arsenal available. Presentation: No date and time listed

Circadian disruption enhances HSF1 signaling and tumorigenesis in Kras-driven lung cancer.

Disrupted circadian rhythmicity is a prominent feature of modern society and has been designated as a probable carcinogen by the World Health Organization. However, the biological mechanisms that connect circadian disruption and cancer risk remain largely undefined. We demonstrate that exposure to chronic circadian disruption [chronic jetlag (CJL)] increases tumor burden in a mouse model of KRAS-driven lung cancer. Molecular characterization of tumors and tumor-bearing lung tissues revealed that CJL enhances the expression of heat shock factor 1 (HSF1) target genes. Consistently, exposure to CJL disrupted the highly rhythmic nuclear trafficking of HSF1 in the lung, resulting in an enhanced accumulation of HSF1 in the nucleus. HSF1 has been shown to promote tumorigenesis in other systems, and we find that pharmacological or genetic inhibition of HSF1 reduces the growth of KRAS-mutant human lung cancer cells. These findings implicate HSF1 as a molecular link between circadian disruption and enhanced tumorigenesis.

233P Decision-making criteria for the choice of 1st line CDK4/6-inhibitor therapy for HR+/Her2- breast cancer in Germany: DECISIONext

German AGO breast recommendations 2021 propose endocrine-based therapy as the 1st therapy option for HR+, MBC, if there is no threat of organ failure. Since 2016, CDK4/6i + endocrine therapy (ET) is an option for 1st L therapy. This data collection intends to show which therapy decisions are made and why in different patient groups with 1st L MBC. Subsequent therapy may require molecular tumor characterization. How often molecular testing is done with MBC is largely unknown.

Effect of sentinel lymph node isolated tumor cells on recurrence free survival in patients with mismatch repair proficient vs. deficient stage I/II endometrioid endometrial adenocarcinoma (173)

Objectives: To assess associations between mismatch repair (MMR) status and recurrence-free survival (RFS) among early-stage endometrial cancer patients with and without isolated tumor cells (ITCs). Methods: We conducted a multi-institution, retrospective study of women with stage I/II endometrial cancer with endometrioid histology who underwent surgical staging with sentinel lymph node (SLN) mapping with or without completing the lymphadenectomy between 2016 and 2021. SLN mapping was performed following the NCCN SLN mapping guidelines. ITC patients and matched controls were identified through electronic medical records using keyword search. Patients were excluded if they had evidence of micro-or macro-metastases in any lymph node (LN). Categorical variables were analyzed using the Chi-square test and continuous variables were analyzed with Student’s t-test and the two-proportion Z-test. Kaplan–Meier method and log-rank tests were used for survival analysis. Results: Among 234 patients, 38 were found to have ITCs. The majority had grade 1 (82.1%), stage IA (67.0%), endometrioid adenocarcinoma. Overall, 22.2% of tumors were MMR deficient by immunohistochemistry. Patients with ITCs were more likely to demonstrate > 50% myometrial invasion (24.5% vs 52.5%, p=<0.001) and were more likely to receive adjuvant radiation therapy (14.8% vs 42.1%, p<0.001) and/or chemotherapy (2.6% vs 23.7%, p<0.001). Grade (p=0.923) and MMR status (p=0.850) were not significantly different between patients with ITCs and those with LN-negative disease. The Median follow-up time was 27 months. Overall, 11 patients we re diagnosed with recurrence (4.7%). The recurrence rate for patients with LN-negative disease was 4.6% (9/196) and the recurrence rate for ITC positive patients was 5.3% (2/38) (p=0.842). The 3-year RFS was 96% in patients with LN-negative disease and 88% in patients with ITC positive disease (log-rank p=0.712). Recurrence rates were comparable among patients with MMR proficient tumors, regardless of ITC status (LN-negative: 3.3% vs ITC-positive: 3.4%; p=0.975). This was also true among patients with MMR deficient tumors (LN-negative: 9.3% vs ITC-positive: 11.1%,p=0.175). RFS was not different between LN-negative and ITC-positive patients with MMR proficient tumors (log-rank p=0.846) as well as between LN-negative and ITC-positive patients with MMR deficient tumors (log-rank p=0.790). Conclusions: These preliminary data suggest that the presence of ITCs does not impact RFS in early-stage endometrial cancer patients with MMR proficient or MMR deficient tumors. However, a longer follow-up time and a larger sample size are needed to better explore the relationship between the presence of ITCs and tumor molecular characterization. Objectives: To assess associations between mismatch repair (MMR) status and recurrence-free survival (RFS) among early-stage endometrial cancer patients with and without isolated tumor cells (ITCs). Methods: We conducted a multi-institution, retrospective study of women with stage I/II endometrial cancer with endometrioid histology who underwent surgical staging with sentinel lymph node (SLN) mapping with or without completing the lymphadenectomy between 2016 and 2021. SLN mapping was performed following the NCCN SLN mapping guidelines. ITC patients and matched controls were identified through electronic medical records using keyword search. Patients were excluded if they had evidence of micro-or macro-metastases in any lymph node (LN). Categorical variables were analyzed using the Chi-square test and continuous variables were analyzed with Student’s t-test and the two-proportion Z-test. Kaplan–Meier method and log-rank tests were used for survival analysis. Results: Among 234 patients, 38 were found to have ITCs. The majority had grade 1 (82.1%), stage IA (67.0%), endometrioid adenocarcinoma. Overall, 22.2% of tumors were MMR deficient by immunohistochemistry. Patients with ITCs were more likely to demonstrate > 50% myometrial invasion (24.5% vs 52.5%, p=<0.001) and were more likely to receive adjuvant radiation therapy (14.8% vs 42.1%, p<0.001) and/or chemotherapy (2.6% vs 23.7%, p<0.001). Grade (p=0.923) and MMR status (p=0.850) were not significantly different between patients with ITCs and those with LN-negative disease. The Median follow-up time was 27 months. Overall, 11 patients we re diagnosed with recurrence (4.7%). The recurrence rate for patients with LN-negative disease was 4.6% (9/196) and the recurrence rate for ITC positive patients was 5.3% (2/38) (p=0.842). The 3-year RFS was 96% in patients with LN-negative disease and 88% in patients with ITC positive disease (log-rank p=0.712). Recurrence rates were comparable among patients with MMR proficient tumors, regardless of ITC status (LN-negative: 3.3% vs ITC-positive: 3.4%; p=0.975). This was also true among patients with MMR deficient tumors (LN-negative: 9.3% vs ITC-positive: 11.1%,p=0.175). RFS was not different between LN-negative and ITC-positive patients with MMR proficient tumors (log-rank p=0.846) as well as between LN-negative and ITC-positive patients with MMR deficient tumors (log-rank p=0.790). Conclusions: These preliminary data suggest that the presence of ITCs does not impact RFS in early-stage endometrial cancer patients with MMR proficient or MMR deficient tumors. However, a longer follow-up time and a larger sample size are needed to better explore the relationship between the presence of ITCs and tumor molecular characterization.

Update of Key Clinical, Histological and Molecular Features of Malignant Bone Tumours Arising in the Craniofacial Skeleton.

The craniofacial skeleton is a highly complex and specialized anatomic region containing and protecting the brain and sensory organs. Bone sarcomas arising here comprise a heterogeneous group of tumours, some of which differ in their biological behaviour compared to their peripheral counterparts. The reasons for this seem to lie, at least partially, in the embryonal development of the craniofacial bones. For reaching the correct diagnosis as the cornerstone of optimal personalised treatment planning, a multidisciplinary team of specialists, including pathologists, radiologists, oncologists, and head and neck surgeons needs to be involved. The most common tumours arising in the craniofacial bones are bone-forming tumours, cartilage-forming tumours, fibro-osseous lesions, giant cell-rich lesions, and notochordal tumours. While morphology remains the backbone for the diagnosis, the last decade has witnessed tremendous advances in the molecular characterization of tumours, and molecular testing is increasingly becoming a part of the diagnostic process. The integration of these new molecular markers into the diagnostic approach has undoubtedly increased the diagnostic accuracy and objectivity, and holds great promise to also identify new therapeutic targets for precision medicine in the future. Examples include HEY1-NCOA2 in mesenchymal chondrosarcoma, IDH1/2 mutations in chondrosarcoma and TFCP2 rearrangements in rhabdomyosarcoma. In this article, key clinical, histological and molecular features of malignant bone tumours arising in the craniofacial region are discussed, with a special focus on the differential diagnosis and prognostic considerations.

PATH-12. A new powerful tool to simultaneously deliver DNA methylation profile and driver fusions detection based on Nanopore Sequencing

Abstract The fast advances in molecular biology have led to the discovery of new genetic and epigenetic driver events that play a key role in the pathogenesis of central nervous system (CNS) tumors. These data showed the importance of molecular biology, and in particular methylation profiling and fusion detection, to complete the histological examination. Exploring all these complex genomic and epigenomic alterations with the technologies implemented in the routine diagnosis requires massive laboratory equipment. In addition, it could take weeks before getting data that could be important to adapt the diagnosis, prognosis, and to ultimately guide the treatment’s choice. We describe the innovative potential of a nanopore sequencing device to obtain fast and multiple information to characterize CNS tumors. Adaptive-sampling is a software-controlled enrichment unique method that allows simultaneous methylation profiling, copy number landscape assessment, and fusion gene detection. Thereby, this technology brings comprehensive molecular information that could be very important for CNS tumor classification in a very short delay (below one week) and with a relative low cost compared to the combined other molecular analysis needed to get the same information. We report ten cases of diverse CNS tumors with already known oncogenic structural variants such as YAP1-MAMLD1 fused ependymoma, CNS neuroblastoma with FOXR2 activation, CNS high-grade neuroepithelial tumor with BCOR and MEN1 alteration, and atypical teratoid rhabdoid tumors (ATRT). For these tumors, using adaptive sampling with the nanopore sequencing, we were able to detect fusion genes as driver events, while obtaining at the same time the methylation profile to corroborate the tumor classification. Our results with this combined approach, never described before, demonstrate its feasibility as a new extremely powerful tool and show remarkable perspectives for this technology to bring a fast and comprehensive tumor molecular characterization.

Treatment patterns and outcomes among patients with recurrent or advanced endometrial cancer in Europe: Endometrial Cancer Health Outcomes Europe (ECHO EU) Study.

e17627 Background: Until recently, recurrent or advanced endometrial cancer (aEC) patients in Europe had limited treatment options, with no consensus on standard of care in such settings. Approval of novel targeted therapies in 2021 are changing the treatment landscape. However, there is little real-world evidence among aEC patients in Europe. The objective of our study was to evaluate real-world treatment patterns and clinical outcomes in aEC patients who progressed following prior systemic therapy (FPST) in clinical practice in Europe. Methods: The ECHO-EU is a multicenter, retrospective chart review study in United Kingdom (UK), Germany (GE), Italy (IT) and Spain (SP). Adult women diagnosed with aEC who received at least one prior systemic therapy and progressed between July 1, 2016 – June 30, 2019, were included. De-identified patient data extracted by treating oncologists from patients’ medical records included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed to estimate real-world overall survival (OS). Results: A total of 379 (UK=101, GE=88, IT=100, SP=90) eligible aEC patients were included in the analysis. At aEC diagnosis, patients’ median age was 69 years, 97% were White/Caucasian and most prevalent histology was endometrioid carcinoma (58%). Molecular characterization of tumors including microsatellite instability/mismatch repair (MSI/MMR) status was performed in only 37% of patients. Metastases were observed in 56% of the patients at diagnosis. Median duration of follow up from aEC diagnosis was 24 months. The majority (95%) of patients initiated 1st line with chemotherapy (most commonly with platinum chemotherapy and paclitaxel). As 2nd line therapy, 81% received mono or combination chemotherapy, and 19% received hormonal therapy. Doxorubicin was the most frequently used agent (45%) in 2nd line, and 16% of patients were re-treated with platinum therapy. At last follow-up, the majority (90%) of patients discontinued 2nd line treatment, mostly due to disease progression (54%). Median duration of 2nd line therapy was 5 months (95% Confidence Interval [CI]: 4-5). Median OS from initiation of 2nd line therapy was 11 months (95% CI: 10-13). Estimated probability of OS from initiation of 2nd line therapy at 6, 12, and 24 months were 70%, 45%, and 30%, respectively. Conclusions: Our study finds thatin Europe prior to mid-2019, available treatment options were sub-optimal for aEC patients FPST, leading to poor prognosis. The utilization of MSI/MMR testing for molecular characterization of tumors was low and needs to increase. There was a significant unmet need for novel therapies that improve clinical outcomes in this patient population. Future studies evaluating treatment patterns and clinical outcomes with more recently approved treatments are warranted.

Preoperative Diagnosis and Molecular Characterization of Gliomas With Liquid Biopsy and Radiogenomics.

Gliomas are a heterogenous group of central nervous system tumors with different outcomes and different therapeutic needs. Glioblastoma, the most common subtype in adults, has a very poor prognosis and disabling consequences. The World Health Organization (WHO) classification specifies that the typing and grading of gliomas should include molecular markers. The molecular characterization of gliomas has implications for prognosis, treatment planning, and prediction of treatment response. At present, gliomas are diagnosed via tumor resection or biopsy, which are always invasive and frequently risky methods. In recent years, however, substantial advances have been made in developing different methods for the molecular characterization of tumors through the analysis of products shed in body fluids. Known as liquid biopsies, these analyses can potentially provide diagnostic and prognostic information, guidance on choice of treatment, and real-time information on tumor status. In addition, magnetic resonance imaging (MRI) is another good source of tumor data; radiomics and radiogenomics can link the imaging phenotypes to gene expression patterns and provide insights to tumor biology and underlying molecular signatures. Machine and deep learning and computational techniques can also use quantitative imaging features to non-invasively detect genetic mutations. The key molecular information obtained with liquid biopsies and radiogenomics can be useful not only in the diagnosis of gliomas but can also help predict response to specific treatments and provide guidelines for personalized medicine. In this article, we review the available data on the molecular characterization of gliomas using the non-invasive methods of liquid biopsy and MRI and suggest that these tools could be used in the future for the preoperative diagnosis of gliomas.

Predictive Biomarkers in Thyroid Cancer.

In molecular pathology, predictive biomarkers identify which patients are likely to respond to targeted drugs. These therapeutic agents block specific molecules directly involved in cancer growth, dedifferentiation and progression. Until few years ago, the only targeted drugs available for advanced thyroid cancer included multi-tyrosine kinase inhibitors, mainly targeting the MAPK pathway and the angiogenic signaling. The administration of these drugs does not necessarily require a molecular characterization of tumors to assess the presence of predictive alterations. However, the availability of new selective targeted drugs for thyroid cancer patients is changing the diagnostic strategies for the molecular characterization of these tumors. The search for targetable alterations can be performed directly on tumor tissue by using a variety of methodologies, depending also on the number and type of alterations to test (i.e. single nucleotide variation or gene rearrangement). Herein, a comprehensive review of the currently available targeted treatments for thyroid cancer, related predictive markers and testing methodologies is provided.

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

First results of the PROMPT trial: Precision oncology allocation in patients with early castration-resistant prostate cancer following routine molecular profiling.

40 Background: Castration-resistant prostate cancer (CRPC) comprises distinct molecular actionable subtypes. Radboudumc, a tertiary referral center for PCa, hosts a Molecular Tumor Board (MTB), and frequently sees CRPC patients (pts) for referral for genetic testing. In the period 2017-2020, almost 50% of heavily pre-treated CRPC pts received a recommendation for a genetically matched therapy (GMT). In 2020 we initiated the PROMPT trial (NCT04746300) to prospectively study the impact of routine early molecular characterization in CRPC. Increased GMT utilization of targeted- and immunotherapy may improve outcome and quality of life of pts with metastatic CRPC, and lead to lower medical resource utilization (MRU). Here we report on first results from our observational trial. Methods: Within the PROMPT trial, prior to receiving first- or second line standard of care CRPC therapy, up to 300 pts were offered molecular tumor characterization with the TruSightOncology 500 panel (TSO500). Formalin-fixed paraffin-embedded prostate or metastatic tissue biopsies were used, preferably newly obtained. To assess both mutations and copy number alterations, the TSO500 required a minimal tumor cell percentage (TC%) of 30%. Results were discussed within the Radboudumc MTB for GMT recommendation. Actionable targets were defined per Precision Medicine Working group criteria and, when druggable, within the Drug Rediscovery Protocol trial (NCT02925234). All pts with tumor mutations carrying with a risk for cancer predisposition were referred for genetic counselling. Follow-up with patient-reported outcomes (EORTC QLQ-C30, EQ5D, BPI &amp; EPIC-26 questionnaires) and MRU was conducted every 3 months until withdrawal or death. Results: From February 2020 until October 2021 we included 284 consecutive CRPC pts with a median age of 70 years (range 46-86) with a median follow-up of 6.8 months. Newly obtained biopsies and archival material was used in 131 and 126 pts, respectively. Median TC% was 60% (range: 20-90%). TSO500 results could be reported in 254 (89%) cases, with at least one putative clinically relevant aberration in 188 evaluable pts (74%). In 100 pts (39,4%) ≥ 1 druggable target was found. Most common actionable alterations were in PTEN (19%), BRCA2 (9%) or in mismatch-repair genes or resulting in high tumor mutational burden (5%). Out of the 100 druggable pts, 31 pts (31%) initiated a form of GMT, 4 pts (4%; 2 BRCA2, 2 PTEN) died prior to receiving GMT, in 65 pts (65%) GMT is pending as they receive standard of care. Conclusions: Routine molecular profiling early in the CRPC setting is feasible in a tertiary referral center with a MTB and high volume of CRPC pts. Almost 40% CRPC pts harbored an actionable target with 31% of these pts already allocated to a GMT. Failure rates of NGS were low at 11%.

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva and vagina). To date, there is no consensus about the optimal management strategy of MM. Furthermore, the clinical rationale of molecular tumor characterization regarding BRAF, KIT or NRAS, as well as the therapeutic value of immunotherapy, chemotherapy and targeted therapy, has not yet been deeply explored and clearly established in MM. In this overview, focused on anorectal and genital MM as models of rare melanomas deserving of a multidisciplinary approach, we highlight the need of referring these patients to centers with experts in melanoma, anorectal and uro-genital cancers treatments. Taking into account the rarity, the poor outcomes and the lack of effective treatment options for MM, tailored research needs to be promptly promoted.

Building a Personalized Medicine Infrastructure for Gynecological Oncology Patients in a High-Volume Hospital

Gynecological cancers require complex intervention since patients have specific needs to be addressed. Centralization to high-volume centers improves the oncological outcomes of patients with gynecological cancers. Research in gynecological oncology is increasing thanks to modern technologies, from the comprehensive molecular characterization of tumors and individual pathophenotypes. Ongoing studies are focusing on personalizing therapies by integrating information across genomics, proteomics, and metabolomics with the genetic makeup and immune system of the patient. Hence, several challenges must be faced to provide holistic benefit to the patient. Personalized approaches should also recognize the unmet needs of each patient to successfully deliver the promise of personalized care, in a multidisciplinary effort. This may provide the greatest opportunity to improve patients’ outcomes. Starting from a narrative review on gynecological oncology patients’ needs, this article focuses on the experience of building a research and care infrastructure for personalized patient management.

Artificial intelligence for assisting cancer diagnosis and treatment in the era of precision medicine.

Over the past decade, artificial intelligence (AI) has contributed substantially to the resolution of various medical problems, including cancer. Deep learning (DL), a subfield of AI, is characterized by its ability to perform automated feature extraction and has great power in the assimilation and evaluation of large amounts of complicated data. On the basis of a large quantity of medical data and novel computational technologies, AI, especially DL, has been applied in various aspects of oncology research and has the potential to enhance cancer diagnosis and treatment. These applications range from early cancer detection, diagnosis, classification and grading, molecular characterization of tumors, prediction of patient outcomes and treatment responses, personalized treatment, automatic radiotherapy workflows, novel anti‐cancer drug discovery, and clinical trials. In this review, we introduced the general principle of AI, summarized major areas of its application for cancer diagnosis and treatment, and discussed its future directions and remaining challenges. As the adoption of AI in clinical use is increasing, we anticipate the arrival of AI‐powered cancer care.

Pre-treatment risk assessment of women with endometrial cancer: differences in outcomes of molecular and clinical classifications in the Slovenian patient cohort.

BackgroundThe aim of this study was to evaluate changes in prognostic risk profiles of women with endometrial cancer by comparing the clinical risk assessment with the integrated molecular risk assessment profiling.Patients and methodsThis prospective study recruited patients with biopsy proven endometrial cancer treated at the University Medical Centre Maribor between January 2020 to February 2021. Patient clinical data was assessed and categorized according to the currently valid European Society of Gynaecological Oncology, European SocieTy for Radiotherapy and Oncology, and European Society of Pathology (ESGO/ESTRO/ESP) guidelines on endometrial cancer. Molecular tumour characterization included determination of exonuclease domain of DNA polymerase-epsilon (POLE) mutational status by Sanger sequencing and imunohistochemical specimen evaluation on the presence of mismatch repair deficiencies (MMRd) and p53 abnormalities (p53abn).ResultsFourty-five women were included in the study. Twenty-two tumours were of non-specific mutational profile (NSMP) (56.4%), 13 were classified as MMRd (33.3%), 3 were classified as p53abn (7.7%) and 1 was classified as POLE mutated (2.6%). Six tumours (15.4%) had multiple molecular classifiers, these were studied separately and were not included in the risk assessment. The clinical risk-assessment classified 21 women (53.8%) as low-risk, 5 women (12.8%) as intermediate risk, 2 women as high-intermediate risk (5.1%), 10 women (25.6%) as high risk and 1 patient as advanced metastatic (2.6%). The integrated molecular classification changed risk for 4 women (10.3%).ConclusionsIntegrated molecular risk improves personalized risk assessment in endometrial cancer and could potentially improve therapeutic precision. Further molecular stratification with biomarkers is especially needed in the NSMP group to improve personalized risk-assessment.

The Evolving Role of Radiotherapy for Pediatric Cancers With Advancements in Molecular Tumor Characterization and Targeted Therapies.

Ongoing rapid advances in molecular diagnostics, precision imaging, and development of targeted therapies have resulted in a constantly evolving landscape for treatment of pediatric cancers. Radiotherapy remains a critical element of the therapeutic toolbox, and its role in the era of precision medicine continues to adapt and undergo re-evaluation. Here, we review emerging strategies for combining radiotherapy with novel targeted systemic therapies (for example, for pediatric gliomas or soft tissue sarcomas), modifying use or intensity of radiotherapy when appropriate via molecular diagnostics that allow better characterization and individualization of each patient’s treatments (for example, de-intensification of radiotherapy in WNT subgroup medulloblastoma), as well as exploring more effective targeted systemic therapies that may allow omission or delay of radiotherapy. Many of these strategies are still under investigation but highlight the importance of continued pre-clinical and clinical studies evaluating the role of radiotherapy in this era of precision oncology.