Utilizing nullomers in cell-free RNA for early cancer detection.

Early detection of cancer can significantly improve patient outcomes; however, sensitive and highly specific biomarkers for cancer detection are currently missing. Nullomers are the shortest sequences that are absent from the human genome but can emerge due to somatic mutations in cancer. We examine over 10,000 whole exome sequencing matched tumor-normal samples to characterize nullomer emergence across exonic regions of the genome. We also identify nullomer emerging mutational hotspots within tumor genes. Finally, we provide evidence for the identification of nullomers in cell-free RNA from peripheral blood samples, enabling detection of multiple tumor types. We show multiple tumor classification models with an AUC greater than 0.9, including a hepatocellular carcinoma classifier with an AUC greater than 0.99.

Peptide absent sequences emerging in human cancers.

Early diagnosis of cancer can significantly improve survival of cancer patients; however sensitive and highly specific biomarkers for cancer detection are currently lacking for most cancer types. Nullpeptides are short peptides that are absent from the human proteome. Here, we examined the emergence of nullpeptides during cancer development. We analyzed 3,600,964 somatic mutations across 10,064 whole exome sequencing tumor samples spanning 32 cancer types. We analyze RNA-seq data from primary tumor samples to identify the subset of nullpeptides that emerge in highly expresed genes. We show that nullpeptides, and particularly the subset that is highly recurrent across cancer patients, can be identified in tumor biopsy samples. We find that cancer genes show an excess of nullpeptides and detect nullpeptide hotspots in specific loci of oncogenes and tumor suppressors. We also observe that recurrent nullpeptides are more likely to be found in neoantigens, which have been shown to be effective targets for immunotherapy, suggesting that they can be used to prioritize candidates. Our findings provide evidence for the utility of nullpeptides as cancer detection and therapeutic biomarkers.

Nab-Paclitaxel and Gemcitabine as First-Line Treatment of Metastatic Ampullary Adenocarcinoma with a Novel R-Spondin2 RNA Fusion and NTRK3 Mutation.

Ampullary adenocarcinoma is a rare malignancy that lacks standard systemic treatment. We describe a case of recurrent metastatic ampullary adenocarcinoma of the pancreaticobiliary subtype treated with nanoparticle albumin-bound (nab)-paclitaxel and gemcitabine as first-line treatment. This report also highlights the molecular profile of the ampullary adenocarcinoma and circulating tumor DNA (ctDNA). This is a case of pancreaticobiliary ampullary adenocarcinoma in a 67-year-old woman who initially presented with painless jaundice. Endoscopic and imaging evaluation revealed biliary ductal dilation secondary to an ampullary mass. Pathology confirmed the diagnosis of ampullary adenocarcinoma of the pancreaticobiliary subtype. She underwent surgical resection of the tumor, followed by adjuvant chemotherapy with gemcitabine and capecitabine. The tumor subsequently recurred in the liver. She received palliative chemotherapy with nab-paclitaxel and gemcitabine, resulting in an objective tumor response for 14 months. Molecular profiling of the tumor and ctDNA revealed a novel MATN2-RSPO RNA fusion and a novel NTRK3 mutation, respectively. Our report suggests that long-term durable response can be achieved in metastatic pancreaticobiliary ampullary adenocarcinoma using nab-paclitaxel and gemcitabine. Molecular profiling of the tumor identified a novel R-Spondin2 RNA fusion and NTRK3 mutation that can be potentially targeted for treatment.

Impact of Colorectal Cancer Sidedness and Location on Therapy and Clinical Outcomes: Role of Blood-Based Biopsy for Personalized Treatment.

Colorectal cancer is one of the most common malignant diseases in the United States and worldwide, and it remains among the top three causes of cancer-related death. A new understanding of molecular characteristics has changed the profile of colorectal cancer and its treatment. Even controlling for known mutational differences, tumor side of origin has emerged as an independent prognostic factor, and one that impacts response to therapy. Left- and right-sided colon cancers differ in a number of key ways, including histology, mutational profile, carcinogenesis pathways, and microbiomes. Moreover, the frequency of certain molecular features gradually changes from the ascending colon to rectum. These, as well as features yet to be identified, are likely responsible for the ongoing role of tumor sidedness and colorectal subsites in treatment response and prognosis. Along with tumor molecular profiling, blood-based biopsy enables the identification of targetable mutations and predictive biomarkers of treatment response. With the application of known tumor characteristics including sidedness and subsites as well as the utilization of blood-based biopsy, along with the development of biomarkers and targeted therapies, the field of colorectal cancer continues to evolve towards the personalized management of a heterogeneous cancer.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Locoregional Gastric Adenocarcinoma: Systematic Review and Guidelines.

OBJECTIVE: The objective of this study was to systematically evaluate the data regarding the use of neoadjuvant, perioperative, surgical, and adjuvant treatment options in localized gastric cancer patients and to develop Appropriate Use Criteria recommended by a panel of experts convened by the American Radium Society. METHODS: Preferred reporting items for systematic reviews and meta-analyses methodology was used to develop an extensive analysis of peer-reviewed phase 2/2R/3 trials, as well as meta-analyses found within the Ovid Medline database between 2010 and 2020. The expert panel then rated the appropriateness of various treatments in 5 representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: For patients with medically operable locally advanced gastric cancer, the strongest recommendation was for perioperative chemotherapy based on high-quality data. Acceptable alternatives included surgery followed by either chemotherapy or concurrent chemoradiotherapy (CRT). For patients with upfront resection of stages I to III gastric cancer (no neoadjuvant therapy), the group strongly recommended adjuvant therapy with either chemotherapy alone or CRT, based on high-quality data. For patients with locally advanced disease who received preoperative chemotherapy without tumor regression, the group strongly recommended postoperative chemotherapy or postoperative CRT. Finally, for medically inoperable gastric cancer patients, there was moderate consensus recommending definitive concurrent CRT. CONCLUSIONS: The addition of chemotherapy and/or radiation, either in the neoadjuvant, adjuvant, or perioperative setting, results in improved survival rates for patients compared with surgery alone. For inoperable patients, definitive CRT is a reasonable treatment option, though largely palliative.

Drug-Microbiota Interaction in Colon Cancer Therapy: Impact of Antibiotics.

Colon adenocarcinoma is one of the most common malignancies, and it is highly lethal. Chemotherapy plays an important role in the treatment of colon cancer at various stages of the disease. The gut microbiome has emerged as a key player in colon cancer development and progression, and it can also alter the therapeutic agent's efficacy and toxicities. Antibiotics can directly and/or indirectly affect the balance of the gut microbiome and, therefore, the clinical outcomes. In this article, we provided an overview of the composition of the gut microbiome under homeostasis and the mechanistic links between gut microbiota and colon cancer. The relationship between the use of oral antibiotics and colon cancer, as well as the impact of the gut microbiome on the efficacy and toxicities of chemotherapy in colon cancer, are discussed. Potential interventions to modulate microbiota and improve chemotherapy outcomes are discussed. Further studies are indicated to address these key gaps in the field and provide a scientific basis for the design of novel microbiota-based approaches for prevention/use as adjuvant therapeutics for patients with colon cancer.

The exercise in all chemotherapy trial.

BACKGROUND: Multiple international organizations have called for exercise to become standard practice in the setting of oncology care. The feasibility of integrating exercise within systemic chemotherapy has not been investigated. METHODS: Patients slated to receive infusion therapy between April 2017 and October 2018 were screened for possible inclusion. The study goal was to establish the acceptability and feasibility of embedding an exercise professional into the chemotherapy infusion suite as a method of making exercise a standard part of cancer care. The exercise prescriptions provided to patients were individualized according to results of brief baseline functional testing. RESULTS: In all, 544 patients were screened, and their respective treating oncologists deemed 83% of them to be medically eligible to participate. After further eligibility screening, 226 patients were approached. Nearly 71% of these patients (n = 160) accepted the invitation to participate in the Exercise in All Chemotherapy trial. Feasibility was established because 71%, 55%, 69%, and 63% of the aerobic, resistance, balance, and flexibility exercises prescribed to patients were completed. Qualitative data also supported the acceptability and feasibility of the intervention from the perspective of patients and clinicians. The per-patient cost of the intervention was $190.68 to $382.40. CONCLUSIONS: Embedding an exercise professional into the chemotherapy infusion suite is an acceptable and feasible approach to making exercise standard practice. Moreover, the cost of the intervention is lower than the cost of other common community programs. Future studies should test whether colocating an exercise professional with infusion therapy could reach more patients in comparison with not colocating. LAY SUMMARY: Few studies have tested the implementation of exercise for patients with cancer by embedding an exercise professional directly into the chemotherapy infusion suite. The Exercise in All Chemotherapy trial shows that this approach is both acceptable and feasible from the perspective of clinicians and patients.

Trends and patterns in the use of opioids among metastatic breast cancer patients.

Opioid use among metastatic breast cancer (MBC) patients has not been well-studied. This study examined the trends and patterns of opioid use among working-age, privately insured patients diagnosed with MBC. Using MarketScan data, we identified female patients diagnosed with MBC in 2006-2015. We determined the proportion of patients who filled a prescription for an opioid and calculated days' supply and daily morphine milligram equivalents (MMEs) from 1 year prior to diagnosis till 1 year after. We assessed the trend in opioid use over the 10-year study period and examined opioid usage patterns after the diagnosis of MBC. Among 24,752 patients included, 11,579 (46.8%) had an opioid prescription within 1 year before diagnosis of MBC, and 20,416 (81.4%) had an opioid prescription within 1 year after diagnosis. The proportion of patients with opioid prescriptions after diagnosis was relatively stable from 2006 to 2015. However, both the median daily MME and median days' supply decreased over time with most of the decline from the subgroup of patients with prior prescription opioid use. Most patients received an opioid prescription in the first month after diagnosis (57.3%), dropping to approximately 20% from 3 to 12 months after diagnosis. Also, the median days' supply increased substantially during the year after diagnosis for patients who received opioids (from 7 to 19). Most women with MBC require opioid analgesia within the first month after diagnosis. Judicious, long-term management of pain after diagnosis of MBC will continue to be necessary for many patients.

Extracellular Vesicles as Potential Biomarkers for Early Detection and Diagnosis of Pancreatic Cancer.

Pancreatic carcinoma (PC) is highly metastatic, and it tends to be detected at advanced stages. Identifying and developing biomarkers for early detection of PC is crucial for a potentially curative treatment. Extracellular vesicles (EVs) are bilayer lipid membrane-structured nanovesicles found in various human bodily fluids, and they play important roles in tumor biogenesis and metastasis. Cancer-derived EVs are enriched with DNA, RNA, protein, and lipid, and they have emerged as attractive diagnostic biomarkers for early detection of PC. In this article, we provided an overview of the cell biology of EVs and their isolation and analysis, and their roles in cancer pathogenesis and progression. Multiplatform analyses of plasma-based exosomes for genomic DNA, micro RNA, mRNA, circular RNA, and protein for diagnosis of PC were critically reviewed. Numerous lines of evidence demonstrate that liquid biopsy with analysis of EV-based biomarkers has variable performance for diagnosis of PC. Future investigation is indicated to optimize the methodology for isolating and analyzing EVs and to identify the combination of EV-based biomarkers and other clinical datasets, with the goal of improving the predictive value, sensitivity, and specificity of screening tests for early detection and diagnosis of PC.

Contrast-Enhanced Ultrasonography for Screening and Diagnosis of Hepatocellular Carcinoma: A Case Series and Review of the Literature.

Background: Contrast-enhanced ultrasound (CEUS) is a safe and noninvasive imaging technique that can characterize and evaluate liver lesions, and has been approved for this use in the Unites States since 2016. CEUS has been shown to be similar in accuracy to computed tomography (CT) and magnetic resonance imaging (MRI) for noninvasive diagnosis of hepatocellular carcinoma (HCC) and offers several advantages in certain patient populations who have contraindications for CT or MRI. However, CEUS has inherent limitations and has not been widely employed for evaluation of HCC. Methods: We present three retrospective cases of liver lesions in patients with cirrhosis, who underwent screening for HCC using concurrent, well-timed CT and CEUS. Results: In these cases, the liver lesions were better visualized and then diagnosed as malignancy via CEUS, whereas the lesions were best appreciated on CT only in retrospect. Conclusions: In some cirrhotic patients, a focal lesion may be more easily identifiable via CEUS than on CT and thus accurately characterized, suggesting an important and complementary role of CEUS with CT or MRI. Further studies are indicated to support the use of CEUS for the diagnosis and characterization of liver lesions in screening patients at risk for developing HCC.

Recurrent Superior Vena Cava Syndrome in a Patient with Sarcoidosis and Pancreatic Adenocarcinoma: A Case Report and Literature Review.

Background: Superior vena cava (SVC) syndrome may result from extravascular compression or intravascular obstruction such as thrombosis. Recurrent venous thrombosis is typically associated with a hypercoagulable state such as malignancy, and inheritable or acquired coagulopathy. Sarcoidosis is a derangement of the immune system, and it has been associated with malignant diseases and hypercoagulation. The association of pancreatic cancer and sarcoidosis with SVC syndrome has not been reported previously. Here, we present a case of recurrent venous thrombosis causing SVC syndrome in a patient with pancreatic ductal adenocarcinoma and underlying thoracic sarcoidosis. Methods: The patient's electronic health record was retrospectively analyzed. Results: A 66-year-old woman with pancreatic adenocarcinoma was treated with neoadjuvant chemotherapy followed by Whipple procedure, before developing tumor recurrence in the liver. Her treatment course was complicated with repeated incidents of venous thrombosis in the presence of a central venous catheter leading to recurrent SVC syndrome, which resolved with anti-coagulation. Conclusions: This case raises a plausible inter-relationship between sarcoidosis, pancreatic cancer, and hypercoagulable state. We suggest that patients with multiple risk factors for developing venous thrombosis should be carefully monitored for any thrombotic event, and they may benefit from prophylactic anti-coagulation.

Liquid Biopsy: A Biomarker-Driven Tool towards Precision Oncology.

Liquid biopsy or the sampling of bodily fluids, mostly blood, has been intensely investigated and developed for clinical utility in medicine, especially oncology [...].

Clinical Evaluation of the Safety and Efficacy of Trifluridine/Tipiracil in the Treatment of Advanced Gastric/Gastroesophageal Junction Adenocarcinoma: Evidence to Date.

Trifluridine/tipiracil or TAS-102 (Taiho Oncology, Lonsurf®, Princeton, NJ, USA) is a combination tablet of trifluridine, a thymidine-based nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor, in a 1:0.5 molar ratio. This drug was first approved for use in metastatic colorectal cancer patients. Recently, the U S Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have granted approval of trifluridine/tipiracil for treatment of metastatic gastric and gastroesophageal junction adenocarcinoma in patients following at least two lines of chemotherapy including fluoropyrimidine and platinum chemotherapy agents, as well as taxanes or irinotecan. This approval was granted after the findings from first a Phase II trial (EPOC1201) investigating trifluridine/tipiracil, and later a global Phase III trial (TAGS trial) that compared trifluridine/tipiracil vs placebo with best supportive care. Both trials primarily utilized trifluridine/tipiracil at a dose of 35 mg/m2 twice daily. In the EPOC1201 trial, the primary end point of disease control rate was greater than 50% after eight weeks of therapy. The most common grade three or four adverse event was neutropenia; additional toxicities included leukopenia, anemia, and anorexia. In the TAGS trial, overall survival in patients treated with trifluridine/tipiracil (5.7 months) was significantly improved as compared to the placebo-controlled group (3.6 months). Treatment with trifluridine/tipiracil not only did not impair quality of life but also tended to reduce the risk of deterioration of quality of life. The results of these studies along with the subsequent FDA and EMA approval have generated an important breakthrough in regard to treatment options for patients with refractory metastatic gastric or gastroesophageal junction adenocarcinoma.

Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular matrix (ECM) generating collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in pre-treatment serum with outcome in patients with PDAC. Matrix metalloprotease (MMP)-degraded type I collagen (C1M), type III collagen (C3M), type IV collagen (C4M) and a pro-peptide of type III collagen (PRO-C3) were measured by ELISA in pre-treatment serum from a randomized phase 3 clinical trial of patients with stage III/IV PDAC treated with 5-fluorouracil based therapy (n = 176). The collagen fragments were evaluated for their correlation (r, Spearman) with serum CA19-9 and for their association with overall survival (OS) based on Cox-regression analyses. In this phase 3 PDAC trial, pre-treatment serum collagen fragment levels were above the reference range for 67%-98% of patients, with median values in PDAC approximately two-fold higher than reference levels. Collagen fragment levels did not correlate with CA19-9 (r = 0.049-0.141, p = ns). On a continuous basis, higher levels of all collagen fragments were associated with significantly shorter OS. When evaluating degradation (C3M) and formation (PRO-C3) of type III collagen further, higher PRO-C3 was associated with poor OS (>25th percentile cut-point, HR = 2.01, 95%CI = 1.33-3.05) and higher C3M/PRO-C3 ratio was associated with improved OS (>25th percentile cut-point, HR = 0.53, 95%CI = 0.34-0.80). When adjusting for CA19-9 and clinical covariates, PRO-C3 remained significant (HR = 1.65, 95%CI = 1.09-2.48). In conclusion, collagen remodeling quantified in pre-treatment serum as a surrogate measure of desmoplasia was significantly associated with OS in a phase 3 clinical PDAC trial, supporting the link between desmoplasia, tumorigenesis, and response to treatment. If validated, these biomarkers may have prognostic and/or predictive potential in future PDAC trials.

Enrichment of extracellular vesicles with lipid nanoprobe functionalized nanostructured silica.

Nanoscale extracellular vesicles (nEVs) have recently demonstrated potential value in cancer diagnostics and treatment monitoring, but translation has been limited by technical challenges in nEV isolation. Thus, we have developed a one-step nEV isolation platform that utilizes nEV size-matched silica nanostructures and a surface-conjugated lipid nanoprobe with an integrated microfluidic mixer. The reported platform has 28.8% capture efficiency from pancreatic cancer plasma and can sufficiently enrich nEVs for simpler positive identification of point mutations, particularly KRAS, in nEV DNA from the plasma of pancreatic cancer patients.

Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial.

BACKGROUND: Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed. METHODS: We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m2 doxorubicin-loaded nanoparticles (30 mg/m2 group), 20 mg/m2 doxorubicin-loaded nanoparticles (20 mg/m2 group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693. FINDINGS: Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m2 group; 130 to the 20 mg/m2 group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group. INTERPRETATION: Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed. FUNDING: Onxeo.

Special Issue: Cancer Biomarkers and Targets in Digestive Organs.

The identification and development of cancer biomarkers and targets have greatly accelerated progress towards precision medicine in oncology. [...].

Frontiers in Gastrointestinal Oncology: Advances in Multi-Disciplinary Patient Care.

Cancers of the digestive system remain highly lethal; therefore, the care of patients with malignant diseases of the digestive tract requires the expertise of providers from multiple health disciplines. Progress has been made to advance the understanding of epidemiology and genetics, diagnostic and screening evaluation, treatment modalities, and supportive care for patients with gastrointestinal cancers. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference at the Hershey Country Club in Hershey, Pennsylvania on 29 September 2017, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this oncological specialty. In this continuing medical education-certified conference, updates on the population sciences including health disparities and resistance training were presented. Progress made in various diagnostic evaluation and screening procedures was outlined. New developments in therapeutic modalities in surgical, radiation, and medical oncology were discussed. Cancer genetic testing and counseling and the supportive roles of music and arts in health and cancer were demonstrated. In summary, this disease-focused medical conference highlighted the new frontiers in gastrointestinal oncology, and showcase the multi-disciplinary care provided at the Penn State Cancer Institute.

Tumor Molecular Profiling for an Individualized Approach to the Treatment of Hepatocellular Carcinoma: A Patient Case Study.

Hepatocellular carcinoma (HCC) is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA), may produce clinical benefits to a limited extent. Systemic chemotherapy has been shown to produce a modest response, but there is no clinically valid biomarker that can be used to predict which patients may benefit. In this case study, we present two patients with metastatic HCC, they received systemic treatment using capecitabine, oxaliplatin, and either bevacizumab or sorafenib. The tumor response to treatment was determined by the progression-free survival (PFS). Molecular profiling of the tumors showed differential expression of biochemical markers and different mutational status of the TP53 and β-catenin (CTNNB1) genes. We hypothesize that the PFS correlates with the tumor molecular profiles, which may be predictive of the therapeutic response to systemic chemotherapy. Further investigation is indicated to correlate tumor biomarkers and treatment responses, with the objective of personalizing the therapies for patients with advanced HCC.

Update in Systemic and Targeted Therapies in Gastrointestinal Oncology.

Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this sub-specialty. This conference paper highlights the new development in systemic treatment of various malignant diseases in the digestive system. Results of the recent clinical trials that investigated the clinical efficacy of pegylated hyaluronidase, napabucasin, and L-asparaginase in pancreatic carcinoma are presented. The use of peri-operative chemotherapy comprised of 5-fluorouracil or capecitabine, leucovorin, oxaliplatin, and docetaxel (FLOT), and immunotherapy including pembrolizumab, nivolumab, and ipilimumab in gastroesophageal carcinoma are discussed. Data from clinical trials that investigated the targeted therapeutics including nivolumab, ramucirumab, lenvatinib, and BLU-554 are reported. The role of adjuvant capecitabine in resected biliary tract carcinoma (BTC) and nab-paclitaxel in combination with gemcitabine and cisplatin in advanced BTC are presented. In colorectal carcinoma, the efficacy of nivolumab, adjuvant FOLFOX or CAPOX, irinotecan/cetuximab/vemurafenib, and trifluridine/tipiracil/bevacizumab, is examined. In summary, some of the above systemic therapies have become or are expected to become new standard of care, while the others demonstrate the potential of becoming new treatment options.