Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the ‘mutation dose’) of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV 600E and PIK3CA than for KRAS,NRAS, and BRAF non‐V600 variants. TP53 and BRAFV 600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild‐type primary tumors previously exposed to EGFR antibodies. Patients with RAS‐ or BRAFV 600E‐mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS,BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV 600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV 600E‐ and KRAS‐resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20–8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

Opinion statementCancer-associated pain has traditionally been treated with opioid analgesics, often in escalating doses. Opioid-induced constipation (OIC) is a common problem associated with chronic use of opioid analgesics. Typical treatment strategies to alleviate constipation are based on dietary changes, exercise, and laxatives. However, laxatives have a nonspecific action and do not target underlying mechanisms of OIC. This article will review prevalent, clinical presentation and recommendations for the treatment of OIC. An independent literature search was carried out by the authors. We reviewed the literature for randomized controlled trials that studied the efficacy of laxatives, naloxone, and naloxegol in treating OIC. Newer strategies addressing the causal pathophysiology of OIC are needed for a more effective assessment and management of OIC. Finally, traditional recommended therapies are appraised and compared with the latest pharmacological developments. Future research should address whether naloxegol is more efficacious by its comparison directly with first-line treatments, including laxatives.

Background Bevacizumab, a VEGF‐A inhibitor, in combination with chemotherapy, has proven to increase progression‐free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin‐2 (Ang‐2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF‐A and Ang‐2, suggesting that the dual VEGF‐A and Ang‐2 blocker vanucizumab (RO5520985 or RG‐7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX‐6 (folinic acid (leucovorin), fluorouracil (5‐FU) and oxaliplatin) versus bevacizumab/mFOLFOX‐6 for first‐line mCRC. Patients and Methods All patients received mFOLFOX‐6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles; other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator‐assessed PFS. Results One hundred eighty‐nine patients were randomized (vanucizumab, n = 94; bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39; bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64–1.58; p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang‐2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%); gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. Conclusion Vanucizumab/mFOLFOX‐6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX‐6. Our results suggest that Ang‐2 is not a relevant therapeutic target in first‐line mCRC. Implications for Practice This randomized phase II study demonstrates that additional angiopoietin‐2 (Ang‐2) inhibition does not result in superior benefit over anti–VEGF‐A blockade alone when each added to standard chemotherapy. Moreover, the performed pharmacokinetic and pharmacodynamic analysis revealed that vanucizumab was bioavailable and affected its intended target, thereby strongly suggesting that Ang‐2 is not a relevant therapeutic target in the clinical setting of treatment‐naïve metastatic colorectal cancer. As a result, the further clinical development of the dual VEGF‐A and Ang‐2 inhibitor vanucizumab was discontinued.

Biomarkers play an important role in the detection and management of cancer patients. In gastrointestinal cancer, there is increasing interest in their development and validation according to specific tumor type. Prognostic biomarkers enable identification of patients with a more aggressive tumor evolution, while predictive biomarkers permit the identification of patients with a higher probability of responding or not to a specific treatment. Several biomarkers are currently widely employed in gastrointestinal cancers. These include rat sarcoma-2 virus () which is used to identify colorectal cancer (CRC) patients who will not respond to anti-epidermal growth factor receptor (EGFR) agents, while in gastric cancer, anti-human epidermal growth factor receptor 2 (HER2) therapy has been shown to only be active in HER2-positive patients. In pancreatic cancer, is a tool used to differentiate patients who are likely to respond to platinum-based combination therapies and to benefit from poly (ADP-ribose) polymerase (PARP) inhibitors. This review provides an update of the main biomarkers currently used in colorectal, gastric and pancreatic cancers, and reviews those that are being developed.

Background: Trastuzumab combined with cisplatin and fluoropyrimidines, either capecitabine or 5-fluorouracile (XP/FP), is the standard first-line treatment for advanced, HER2-positive, gastric cancer patients based on the ToGA trial. Despite the lack of phase III trials, many clinicians administer trastuzumab with alternative regimens. One meta-analysis suggests that substituting cisplatin for oxaliplatin might lead to greater efficacy and less toxicity. Methods: 594 patients with HER2-positive gastroesophageal adenocarcinoma were recruited from the AGAMENON-SEOM registry. The objective was to evaluate the external validity of clinical trials with chemotherapy and trastuzumab. Results: The regimens used in at least 5% of the patients were XP (27%), oxaliplatin and capecitabine (CAPOX) (26%), oxaliplatin and 5-fluorouracil (FOLFOX) (14%), FP (14%), triplet with anthracycline/docetaxel (7%), and carboplatin-FU (5%). Median exposure to trastuzumab was longer with FOLFOX (11.4 months, 95% CI, 9.1–21.0) versus ToGA regimens (7.5, 6.4–8.5), p < 0.001. Patients with HER2-IHC 3+ cancers had higher response rates than those with IHC 2+/FISH+, odds-ratio 1.97 (95% CI, 1.25–3.09). The results achieved with CAPOX–trastuzumab were comparable to those attained with ToGA regimens. FOLFOX–trastuzumab was superior to ToGA schemes in terms of overall survival (OS), with a greater magnitude of effect in IHC 2+/FISH+ tumors (HR 0.47, 0.24–0.92) compared with IHC 3+ (HR 0.69, 0.49–0.96), and in diffuse (HR 0.37, 0.20–0.69) versus intestinal-type tumors (HR 0.76, 0.54–1.06). Conclusion: We have updated the external validity of clinical trials with trastuzumab in first-line treatment of gastric cancer. Our data confirm the comparable outcomes of ToGA regimens and CAPOX–trastuzumab in clinical practice and point toward a possible benefit of FOLFOX–trastuzumab, contingent on the subtypes typically less sensitive to trastuzumab, to be confirmed in clinical trials.

In our opinion research is moving forward on a good path; we have seen the recent approval of aflibercept, and in the following years we might have newer standard treatment options among the latest compounds under development.

Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in the last decade. Surgical resection remains the cornerstone therapy for CCA. Unfortunately, complete resection is only possible in less than 15–35% of cases, with a risk of recurrence greater than 60%. Liver transplantation (LT) has been postulated as an effective therapeutic strategy in those intrahepatic CCA (iCCA) smaller than 3 cm. However, the low rate of early diagnosis in non-resectable patients justifies the low applicability in clinical practice. The evidence regarding LT in locally advanced iCCA is scarce and based on small, retrospective, and, in most cases, single-center case series. In this setting, the response to neoadjuvant chemotherapy could be useful in identifying a subgroup of patients with biologically less aggressive tumors in whom LT may be successful. The results of LT in pCCA are promising, however, we need a very careful selection of patients and adequate experience in the transplant center. Locoregional therapies may be relevant in unresectable, liver-only CCA. In iCCA smaller than 2 cm, particularly those arising in patients with advanced chronic liver disease in whom resection or LT may not be feasible, thermal ablation may become a reliable alternative. The greatest advances in the management of CCA occur in systemic treatment. Immunotherapy associated with chemotherapy has emerged as the gold standard in the first-line treatment. Likewise, the most encouraging results have been obtained with targeted therapies, where the use of personalized treatments has shown high rates of objective and durable tumor response, with clear signs of survival benefit. In conclusion, the future of CCA treatment seems to be marked by the development of new treatment strategies but high-quality, prospective studies that shed light on their use and applicability are mandatory.