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Background: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are overprescribed in patients with cancer; there is increasing evidence of their effects on cancer development and survival. The objective of this narrative review is to comprehensively identify cancer medications that have clinically meaningful drug–drug interactions (DDIs) with PPIs, including loss of efficacy or adverse effects, and to explore the association between PPIs and cancer. Methods: A PubMed search of English language studies published from 1 January 2016, to 1 June 2021 was conducted. The search terms included “proton pump inhibitors,” “cancer,” “chemotherapy,” “immunotherapy,” “hormonotherapies,” “targeted therapies,” “tyrosine kinase inhibitors,” and “gut microbiome”. Recent and relevant clinical trials, meta-analyses, and reviews were included. Results: PPIs may have pro-tumor activity by increasing plasma gastrin levels or anti-tumor activity by inhibiting V-ATPases. However, their impact on cancer survival remains unclear. PPIs may decrease the efficacy of some antineoplastic agents through direct DDIs (e.g., some tyrosine kinase inhibitors, capecitabine, irinotecan, methotrexate). More complex DDIs seem to exist for immunotherapies with indirect interactions through the microbiome. PPIs worsen hypomagnesemia, bone loss, iron, and vitamin B12 deficiencies but may have a protective effect on the renal system. Discussion/Conclusions: PPIs may interact with the cancer microbiome and the efficacy of various antineoplastic agents, although only a few DDIs involving PPIs are clinically significant. Further pharmaco-epidemiological studies are warranted, but physicians should be aware of the potential consequences of PPI use, which should be dose appropriate and prescribed according to guidelines.

Abstract Cholangiocarcinoma is the second most common liver cancer after hepatocellular carcinoma. In case of metastatic or unresectable disease, the recommended first-line treatment is gemcitabine-based doublet, most commonly gemcitabine and cisplatin. There is no standard treatment for further lines. MET fusions are rare alterations described in many cancers. The efficacy of specific MET inhibitors is poorly studied. We present the case of a patient with chemotherapy-refractory metastatic cholangiocarcinoma harboring a CAPZA-2-MET fusion along with MET amplification who dramatically responded to capmatinib, a specific MET tyrosine kinase inhibitor. The efficacy of specific MET inhibitors is poorly studied. This article presents the case of a patient with chemotherapy-refractory metastatic cholangiocarcinoma harboring a CAPZA-2-MET fusion along with MET amplification who dramatically responded to capmatinib, a specific MET tyrosine kinase inhibitor.

Immune checkpoint inhibitors (ICIs) are commonly used to treat patients with advanced urothelial cancer. However, a significant number of patients do not respond to ICI, and the lack of validated predictive biomarkers impedes the success of the ICI strategy alone or in combination with chemotherapy or targeted therapies. In addition, some patients experience potentially severe adverse events with limited clinical benefit. Therefore, identifying biomarkers of response to ICI is crucial to guide treatment decisions. The most evaluated biomarkers to date are programmed death ligand 1 expression, microsatellite instability/defective mismatch repair phenotype, and tumor mutational burden. Other emerging biomarkers, such as circulating tumor DNA and microbiota, require evaluation in clinical trials. This review aims to examine these biomarkers for ICI response in urothelial cancer and assess their analytical and clinical validation.

Background Adjuvant chemotherapy (AC) improves the prognosis after pancreatic ductal adenocarcinoma (PDAC) resection. However, previous studies have shown that a large proportion of patients do not receive or complete AC. This national study examined the risk factors for the omission or interruption of AC. Methods Data of all patients who underwent pancreatic surgery for PDAC in France between January 2012 and December 2017 were extracted from the French National Administrative Database. We considered “omission of adjuvant chemotherapy” (OAC) all patients who failed to receive any course of gemcitabine within 12 postoperative weeks and “interruption of AC” (IAC) was defined as less than 18 courses of AC. Results A total of 11 599 patients were included in this study. Pancreaticoduodenectomy was the most common procedure (76.3%), and 31% of the patients experienced major postoperative complications. OACs and IACs affected 42% and 68% of the patients, respectively. Ultimately, only 18.6% of the cohort completed AC. Patients who underwent surgery in a high-volume centers were less affected by postoperative complications, with no impact on the likelihood of receiving AC. Multivariate analysis showed that age ≥ 80 years, Charlson comorbidity index (CCI) ≥ 4, and major complications were associated with OAC (OR = 2.19; CI 95% [1.79–2.68]; OR = 1.75; CI 95% [1.41–2.18] and OR = 2.37; CI 95% [2.15–2.62] respectively). Moreover, age ≥ 80 years and CCI 2–3 or ≥ 4 were also independent risk factors for IAC (OR = 1.54, CI 95% [1.1–2.15]; OR = 1.43, CI 95% [1.21–1.68]; OR = 1.47, CI 95% [1.02–2.12], respectively). Conclusion Sequence surgery followed by chemotherapy is associated with a high dropout rate, especially in octogenarian and comorbid patients.

Background Advanced pancreatic ductal adenocarcinoma (aPDAC) is often accompanied by significant muscle mass loss, contributing to poor prognosis. SarcAPACaP, an ancillary study of the GERCOR‐APACaP phase III trial, evaluated the role of adapted physical activity (APA) in aPDAC Western patients receiving first‐line chemotherapy. The study aimed to assess (1) the potential impact of computed tomography (CT)–quantified muscle mass before and during treatments on health‐related quality of life (HRQoL) and overall survival (OS) and (2) the role of APA in mitigating muscle mass loss. Methods In the APACaP trial, aPDAC patients with ECOG performance status (PS) 0–2 were randomized 1:1 to usual care including first‐line chemotherapy or usual care plus a 16‐week home‐based APA program. In the SarcAPACaP study, the surface muscular index (SMI) was determined from L3 CT scan slices. Two patient populations were analysed: those with CT scan available at baseline (modified[m] intent‐to‐treat [ITT]1‐W0) and those with CT scans available at both W0 and W16 (mITT2 W0–W16). Low muscle mass was defined by low SMI with SMI < 41 cm2/m2 for women and < 43 and < 53 cm2/m2 for men with body max index < 25.0 and ≥ 25.0 kg/m2, respectively. Muscle loss was defined by the relative difference of SMI between W0 and W16 (100*[SMI W16–SMI W0]/SMI W0). In mITT2 W0–W16, patients were stratified into three groups based on the severity of muscle loss: none, moderate (0%–10%) and high (≥ 10%). Associations between muscle mass loss and OS, time until definitive deterioration (TUDD) of HRQoL and the effect of APA on loss of muscle mass were assessed. Results Between October 2014 and May 2020, 313 patients were prospectively enrolled, with 225 in mITT1 W0 and 128 in mITT2 W0–W16, with 65 assigned to the APA arm. Both groups had similar baseline characteristics with comparable OS and TUDD. A low SMI at W0 was not associated with OS and TUDD of HRQoL in either group. Among mITT2 W0–W16 patients, high muscle mass loss (n = 27) independently predicted OS (p = 0.012) and showed a trend toward negatively affecting TUDD of HRQoL. Notably, APA did not mitigate muscle loss in our study population. Conclusions Longitudinal muscle mass loss emerged as a predictive factor for both OS and HRQoL in aPDAC patients undergoing chemotherapy, while a low SMI at diagnosis did not provide prognostic value. APA did not impact muscle mass loss in this population.

BackgroundDespite improvement in colorectal liver metastasis (CLM) treatment, survival after liver surgery remains highly variable. Several clinicopathologic prognostic factors have been reported, but their validity in the era of more effective perioperative chemotherapy remains to be defined. The aim of this study is to analyze the prognostic factors associated with survival after CLM resection.MethodsClinicopathologic data of patients included in the MIROX phase III trial who underwent surgery for isolated CLMs were analyzed. The primary endpoints were 5-year overall survival (OS) and disease-free survival (DFS). Univariate Cox analysis was performed to identify associations with OS and DFS and select variables for inclusion in a multivariate model to determine their independent prognostic value.ResultsA total of 181 patients were analyzed. The median follow-up period was 6.42 years [95% confidence interval (CI) 5.15–8.71 years], and the 5-year OS and DFS rates were 67.1% and 35.4%, respectively. On multivariate analysis, Fong’s clinical risk score (CRS) as a categorical variable (CRS 0–1 vs. 2–3 vs. 4–5, p = 0.036) and polymorphonuclear neutrophil (PMN) count (> 6000/mm3 vs. ≤ 6000/mm3, p = 0.006) before chemotherapy were found to be independent prognostic factors for OS. However, only Fong’s CRS remained significantly associated with DFS (p = 0.027). The final OS model was used to establish a nomogram that allows individual OS estimations at 1, 3, 5, and 10 years.ConclusionsFong’s CRS was independently associated with DFS and poor OS after CLM resection with FOLFOX-based chemotherapy regimen. It could be useful in daily practice and future trials to select patients more accurately.

In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri‐operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein‐1 (PD‐1, invasive front, stromal, intra‐epithelial compartments), and programmed death‐ligand 1 (PD‐L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD‐L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD‐L1 expressions on immune cells were predictive of better disease‐free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD‐L1 expression and tumor‐infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients. Here, we characterized the immune microenvironment of proficient mismatch repair/microsatellite stable oligometastatic patients with colorectal cancer (CRC) treated with the neoadjuvant FOLFOX. Primary tumor immune profiling had limited predictive value in estimating the metastatic immune context. CD3 T cells and PD‐L1 immune cells at the invasive front were predictive of disease‐free survival. In addition, the expression of CD8 and PD‐L1 was higher after FOLFOX treatment. Thus, CD8high/PD‐L1high signature could be related to chemotherapy response and could improve treatment strategies of metastatic patients with CRC.

Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.

Background BRAF V600E-mutant colorectal cancers (CRCs) are associated with shorter survival than BRAF wild-type tumors. Therapeutic decision-making for colorectal liver metastases (CRLM) harboring this mutation remains difficult due to the scarce literature. The aim was to study a large cohort of BRAF V600E-mutant CRLM patients in order to see if surgery extend overall survival among others prognostic factors. Methods BRAF V600E-mutant CRCs diagnosed with liver-only metastases, resected or not, were retrospectively identified between April 2008 and December 2017, in 25 French centers. Clinical, molecular, pathological characteristics and treatment features were collected. Overall survival (OS) was defined as the time from CRLM diagnosis to death from any cause. Cox proportional hazard models were used for statistical analysis. Results Among the 105 patients included, 79 (75%) received chemotherapy, 18 (17%) underwent upfront CRLM surgery, and 8 (8%) received exclusive best supportive care. CRLM surgery was performed in 49 (46.7%) patients. CRLM were mainly synchronous (90%) with bilobar presentation (61%). The median OS was 34 months (range, 28.9–67.3 months) for resected patients and 10.6 (6.7–12.5) months for unresected patients ( P < 0.0001). In multivariate analysis, primary tumor surgery (hazard ratio (HR) = 0.349; 95% confidence interval (CI) 0.164–0.744, P = 0.0064) and CRLM resection (HR = 0.169; 95% CI 0.082–0.348, P < 0.0001) were associated with significantly better OS. Conclusions In the era of systemic cytotoxic chemotherapies, liver surgery seems to extend OS in BRAF V600E-mutant CRCs with liver only metastases historical cohort.

Background: Biliary tract cancers (BTC) are often diagnosed after the age of 70, when comorbidities and compromised performance status (PS) are more prevalent. Objectives: This study compared clinical and disease characteristics and outcomes in BTC patients aged ⩽70 and >70 years. Design and methods: PRONOBIL-ACABI is a cohort study including 1256 BTC patients treated across 16 French centers from January 2003 to June 2021. We analyzed demographics, clinical characteristics, treatment modalities, molecular profiles, overall survival (OS) as the primary endpoint, and progression-free survival (PFS). Results: Among the 1256 BTC patients (53% male; median age: 64.5), 31% were aged >70. Patients >70 exhibited poorer PS (PS ⩾2, 17% vs 8%; p < 0.0001), a higher rate of comorbidities (⩾1, 89% vs 78%; p < 0.0001), and were less often proposed a molecular profile (43% vs 65%; p < 0.0001) than those ⩽70. Patients with unresectable BTC aged >70 had significantly shorter OS compared to younger patients (median OS: 14.6 vs 17.4 months, p < 0.0001), despite similar PFS (median PFS: 6.6 vs 5.8 months, p = 0.61). They were also less likely to receive first-line chemotherapy (87% vs 97%, p < 0.0001). In resected BTC, survival outcomes were comparable across age groups, with a median OS of 47.0 months in patients >70 vs 48.8 months in those ⩽70. Conclusion: Patients aged >70 years with unresectable BTC had a significantly shorter OS compared to those aged ⩽70, despite similar first-line PFS. In resected BTC, elderly patients achieved OS and PFS outcomes comparable to those aged ⩽70.