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Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well-differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although GEP-NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP-NETs is surgery, which offers the best chance for a cure. However, because GEP-NETs are often slow-growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide-receptor radionuclide therapy with α and ß emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies.

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Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

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Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody-drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody-drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

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Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice.

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Breast cancer is the most frequent malignancy in women. However, in the middle and late stages, some people develop distant metastases, which considerably lower the quality of life and life expectancy. The brain is one of the sites where metastasis frequently happens. According to epidemiological research, brain metastases occur at a late stage in 30-50% of patients with HER2-positive breast cancer, resulting in a poor prognosis. Additionally, few treatments are available for HER2-positive brain metastatic breast cancer, and the mortality rate is remarkable owing to the complexity of the brain's anatomical structure and physiological function. In this review, we described the stages of the brain metastasis of breast cancer, the relationship between the microenvironment and metastatic cancer cells, and the unique molecular and cellular mechanisms. It involves cancer cells migrating, invading, and adhering to the brain; penetrating the blood-brain barrier; interacting with brain cells; and activating signal pathways once inside the brain. Finally, we reviewed current clinically used treatment approaches for brain metastasis in HER2-positive breast cancer; summarized the traditional treatment, targeted treatment, immunotherapy, and other treatment modalities; compared the benefits and drawbacks of each approach; discussed treatment challenges; and emphasized the importance of identifying potential targets to improve patient survival rates and comprehend brain metastasis in breast cancer.

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BACKGROUND: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing. METHODS: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes. RESULTS: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days). CONCLUSION: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing.

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Several novel agents (e.g., molecularly targeted drug, bispecific antibody, antibody-drug conjugate, chimeric antigen receptor T-cell therapy) have successively emerged in clinical practice and are occasionally used in allogeneic hematopoietic cell transplantation (allo-HCT) settings. These drugs are expected to reduce pretransplant tumors, lower the risk of relapse with posttransplant maintenance therapy, and consequently improve transplant outcomes. Additionally, some molecularly targeted drugs could be adapted to treat steroid-refractory acute and/or chronic graft-versus-host disease (GVHD), which remained the leading cause of nonrelapse mortality after allo-HCT. However, these agents develop an excessive immune reaction, including GVHD, or presented an increased risk of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) as their "off-target" effects. Thus, this review aimed to summarize the risk assessment and management of post-posttransplant complications, focusing on GVHD and SOS/VOD, in the era of molecularly targeted therapy. Moreover, recent advances in GVHD or SOS/VOD prophylaxis and treatment using novel agents/devices are also discussed.

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The management of advanced renal cell carcinoma has advanced tremendously over the past decade, but most patients still do not receive durable clinical benefit from current therapies. Renal cellcarcinoma is an immunogenic tumor, historically with conventional cytokine therapies, such as interleukin-2 and interferon-α, and contemporarily with the introduction of immune checkpoint inhibitors. Now the central therapeutic strategy in renal cell carcinoma is combination therapies including immunecheckpoint inhibitors. In this Review, we look back on the historical changes in systemic therapy for advanced renal cell carcinoma, and focus on the latest developments and prospects in this field.

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BACKGROUND: Human malignancies are composed of heterogeneous subpopulations of cancer cells with phenotypic and functional diversity. Among them, a unique subset of cancer stem cells (CSCs) has both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties. As such, CSCs are promising cellular targets for effective cancer therapy. At the molecular level, hyper-activation of multiple stemness regulatory signaling pathways and downstream transcription factors play critical roles in controlling CSCs establishment and maintenance. To regulate CSC properties, these stemness pathways are controlled by post-translational modifications including, but not limited to phosphorylation, acetylation, methylation, and ubiquitination. CONCLUSION: In this review, we focus on E3 ubiquitin ligases and their roles and mechanisms in regulating essential hallmarks of CSCs, such as self-renewal, invasion and metastasis, metabolic reprogramming, immune evasion, and therapeutic resistance. Moreover, we discuss emerging therapeutic approaches to eliminate CSCs through targeting E3 ubiquitin ligases by chemical inhibitors and proteolysis-targeting chimera (PROTACs) which are currently under development at the discovery, preclinical, and clinical stages. Several outstanding issues such as roles for E3 ubiquitin ligases in heterogeneity and phenotypical/functional evolution of CSCs remain to be studied under pathologically and clinically relevant conditions. With the rapid application of functional genomic and proteomic approaches at single cell, spatiotemporal, and even single molecule levels, we anticipate that more specific and precise functions of E3 ubiquitin ligases will be delineated in dictating CSC properties. Rational design and proper translation of these mechanistic understandings may lead to novel therapeutic modalities for cancer procession medicine.

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BACKGROUND: The emergence of molecularly targeted agents (MTAs) has altered the treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) /metastatic breast cancer (MBC). Multiple guidelines recommend molecularly targeted therapy as first-line treatment for HR+/HER2- ABC/MBC. However, optimal treatment for disease progression during MTA therapy remains undetermined. This study evaluated the suitability of different MTA types for this patient subgroup. METHODS: In this retrospective study, we analyzed the electronic health records of 56 patients with HR+/HER2- ABC/MBC receiving treatment with palbociclib, abemaciclib, or everolimus in our center between April 2014 and June 2021. RESULTS: Overall, 39, 14, and 35 regimens using palbociclib, abemaciclib, and everolimus, respectively, were identified. Three and 53 patients were premenopausal and postmenopausal, respectively. MTAs were included in the 1st-11th lines of treatment. Time to failure (TTF) was significantly different among the three MTAs. In contrast, TTF did not significantly differ among the 50 regimens that included CDK4/6 inhibitors, with/without prior mTOR inhibitor use, and the 35 regimens that included mTOR inhibitors, with/without prior CDK4/6 inhibitor use. CONCLUSIONS: The sequential use of different MTA classes did not affect the TTF of another MTA. mTOR inhibitor + exemestane is a favorable treatment option after CDK4/6 inhibitor + hormone therapy, and CDK4/6 inhibitor + hormone therapy is suitable for patients previously treated with mTOR inhibitor + exemestane. Although this study was retrospective and conducted at a single center, the present findings are useful for treatment selection in clinical practice.

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BACKGROUND: We previously reported the feasibility and efficacy of neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer. Here, we report the results of a long-term follow-up study. METHODS: This was a multi-institutional, prospective phase 2 study of patients with locally advanced rectal cancer. Patients received neoadjuvant chemotherapy with molecularly targeted agents before undergoing total mesorectal excision. Six cycles of modified FOLFOX (mFOLFOX6) with bevacizumab were administered to KRAS-mutant patients, and mFOLFOX6 with cetuximab was administered to KRAS-wild-type patients. Here, we report the secondary end points of overall survival, relapse-free survival, and local recurrence rate. RESULTS: Sixty patients were enrolled in this study. R0 resection was achieved in 98.3% (59/60) patients, and pathological complete response was achieved in 16.7% (10/60) patients. After a median follow-up of 5.4 years, the 5 year overall survival was 81.6%, the 5 year relapse-free survival was 71.7%, and the 5 year local recurrence rate was 12.6%. None of the patients who achieved pathological complete response developed recurrence within 5 years. CONCLUSIONS: The use of molecularly targeted agents in the neoadjuvant setting for locally advanced rectal cancer has an acceptable prognosis.

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The off-target toxicity of molecular targeted drug hinders its clinical transformation. Herein, we report a new molecular targeted drug oHA-GX1 constructed by oligomeric hyaluronan (oHA) and peptide GX1 (CGNSNPKSC). The oHA-GX1 can not only suppress the tumor growth by interacting with overexpressed VEGF and CD44 receptors inside tumor tissues, but also reduce the likelihood of off-target toxicity due to the multiple VEGF and CD44 receptors binding sites. The cytotoxicity study shows that the IC50oHA-GX1 against co-SGC-7901 and co-HUVEC cells fell in the range of common cytotoxic drugs. The animal experiment results reveal that the tumor inhibition rate of oHA-GX1 (100 mg/kg) against SGC-7901 tumor-bearing mice were 78.4 %, which was comparable to that of front-line chemotherapy drugs. Also, the cytotoxicity study on normal cells, hemolysis test, hemagglutination assay and the acute toxicity test demonstrate that oHA-GX1 exhibited excellent biosafety. This molecular targeted drug that utilizes the multiple receptor-binding sites to get rid of the side effects caused by off-target paves a new direction for the discovery of anticancer drugs with high efficacy and low adverse effects.

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BACKGROUND: COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. PATIENTS AND METHODS: At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. RESULTS: In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. CONCLUSIONS: While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.

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For many years, researchers have been trying to develop the most effective ways to fight lung cancer, which is the cause of the largest number of cancer-related deaths among men and women worldwide. The most advanced treatments for nearly all non-small-cell lung cancer (NSCLC) types include immunotherapy with immune checkpoint inhibitors (ICIs), mainly anti-programmed death 1/anti-programmed death ligand 1 monoclonal antibodies (anti-PD-1/PD-L1 mAbs) in monotherapy or in combination with other strategies. Despite significant advances, long survival is not achievable in most cases, so new solutions are constantly being sought. One of the questions raised by oncologists is the efficacy of ICIs in patients with molecular driver alterations, especially when the possibilities of using molecularly targeted therapies are exhausted (e.g., due to resistance to tyrosine kinase inhibitors). There are studies investigating this problem, but it is still poorly described. Among probable immunotherapy' failures reasons, low immunogenicity of tumors with one driver mutation is listed. Nevertheless, in some cases, the therapy is efficient, and more research is required to establish the management of NSCLC patients with oncogenic driver abnormalities. The aim of this article is to review current discoveries in this matter.

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Biliary cancer (BC) is a rare disease. It is formed from the biliary epithelium of the small ducts in the liver periphery (intrahepatic) and the main ducts of the hilum (extrahepatic). The incidence of intrahepatic carcinoma is rising in the western world, and the incidence of gallbladder cancer is declining. Surgical treatment is the primary treatment option for localized forms of these tumors, but only a small group of patients is eligible for it. Palliative therapy is the standard treatment option for those with advanced cases, and it mainly relies on chemotherapy. The advanced form's five-year survival of BC does not exceed 5%. However, targeted therapy aimed at tumors with fusion mutations of the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH) 1 and 2, the genes encoding the B-Raf protein (BRAF), breast cancer (BRCA1/2), epidermal growth factor receptor 2 (HER2), and the neurotrophic receptor tyrosine kinase gene (NTRK), is gradually changing the paradigm in the treatment of this disease. This can be seen especially in approaches to treating intrahepatic cholangiocarcinoma, which is associated with a high incidence of mutations. This literature review aims to provide the latest scientific evidence regarding targeted therapy in treating cholangiocarcinoma.

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BACKGROUND: Targeted therapy, especially the use of poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors (PARPis), has improved the outcome of patients with ovarian cancer. However, most high-grade serous ovarian cancer (HGSOC) patients have wild-type BRCA1/2, and it is necessary to disclose more potential novel targets for other available targeted drugs. So, detection of genetic alterations beyond BRCA1/2 is critical to screen HGSOC patients for personalized therapy. In this study, a broad, hybrid capture-based next-generation sequencing (NGS) assay was used to identify actionable genetic alterations from HGSOC cancer tissues. METHODS: Sixty-eight patients with HGSOC were enrolled, including 6 International Federation of Gynecology and Obstetrics (FIGO) stage I, 15 stage II, 37 stage III and 10 stage IV patients. All patients signed informed consent forms. Potentially actionable genetic alterations, including base substitutions, indels, copy number alterations, and gene fusions, were identified using targeted NGS. RESULTS: In our study, 14.7% (10/68) of the tumors harbored actionable genetic alterations in patients with BRCA1. A total of 25.0% (17/68) of patients without BRCA1 mutations harbored other actionable genetic alterations, such as homologous recombination repair (HRR) pathway-related genes (ATM, CDK12, FANCA, and FANCD2), PI3K/AKT/mTOR pathway genes (NF1, FBXW7, PIK3CA, PTEN, TSC1, and TSC2), and some other genes (ARID1A, FGFR1, KRAS, and NRAS). Furthermore, some patients harboring ARID1A or NF1 actionable genetic alterations showed good clinical efficacy to immune checkpoint inhibitors (ICIs) and everolimus, respectively. CONCLUSIONS: Our research indicates that 39.7% (27/68) of patients with HGSOC harbored at least one actionable genetic alteration. 25.0% (17/68) of patients had somatic mutations or copy number variations beyond BRCA1 mutations and might be treated with off-label therapy or to be allocated into clinical trial. NGS assays of HGSOC patients are necessary to screen actionable genetic alterations to guide personalized and precise treatment.

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Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.

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Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. ESCC predominantly affects African and Asian populations, which is closely related to chronic smoking and alcohol consumption. EAC typically arises in Barrett's esophagus with a predilection for Western countries. While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer, molecularly targeted therapy is still at the early stages. With the development of large-scale next-generation sequencing, various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied. Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer. In this review, we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer. Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.

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Background: Young gastric cancer (YGC) has been indicated as having a worse prognosis than in elderly gastric cancer (EGC). It has been reported that YGC and EGC patients show different genomic profiles; however, there has been no comparative study conducted to reveal their mutational characteristics. Methods: Firstly, we divided and analyzed the mutational landscape and 50 cancer-related genes characters of YGC (n=18) and EGC (n=18) patients from The Cancer Genome Atlas-Stomach Adenocarcinoma (TCGA-STAD). A total of 8 gastric cancer samples including 4 YGC and 4 EGC patients were collected to detect 50 cancer-related genes by multiplex polymerase chain reaction (PCR) next generation sequencing. The R/maftools package was used to describe the mutational characteristics. Results: Our results showed that the EGC group harbored more mutations than the YGC group. In 50 cancer-related genes in our cohort, the YGC group tended to be different from the EGC group using multiplex PCR next generation sequencing. In the YGC group, candidate mutations were identified within the following genes: IDH2, PDGFRA, KRAS, FLT3, FGFR2, and FGFR3. The YGC group showed less tumor mutational burden (TMB) level then EGC. Conclusions: The YGC group tended to be more sensitive to molecularly targeted therapy because of it having more somatic mutations in 50 cancer-related genes using targeted next-generation sequencing.

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Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. ESCC predominantly affects African and Asian populations, which is closely related to chronic smoking and alcohol consumption. EAC typically arises in Barrett's esophagus with a predilection for Western countries. While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer, molecularly targeted therapy is still at the early stages. With the development of large-scale next-generation sequencing, various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied. Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer. In this review, we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer. Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.