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The COVID‐19 pandemic had a severe impact on medical care. Our study aims to investigate the impact of COVID‐19 on advanced melanoma care in the Netherlands. We selected patients diagnosed with irresectable stage IIIc and IV melanoma during the first and second COVID‐19 wave and compared them with patients diagnosed within the same time frame in 2018 and 2019. Patients were divided into three geographical regions. We investigated baseline characteristics, time from diagnosis until start of systemic therapy and postponement of anti‐PD‐1 courses. During both waves, fewer patients were diagnosed compared to the control groups. During the first wave, time between diagnosis and start of treatment was significantly longer in the southern region compared to other regions (33 vs 9 and 15 days, P‐value, What's new? Little is known about the effects of COVID‐19 on advanced melanoma care. In this study, the authors examined several quality indicators of care. They observed a worsening in baseline characteristics, longer time between diagnosis and start of treatment and more postponed anti‐PD‐1 antibody courses with differences between the northern, middle and southern regions. Future studies are necessary to assess the long‐term consequences of our observed changes in advanced melanoma care.

Inadequate margins continue to occur frequently in patients who undergo surgical resection of a tumor, suggesting that current intraoperative methods are not sufficiently reliable in determining the margin status. This clinical demand has inspired the development of many novel imaging techniques that could help surgeons with intraoperative margin assessment. This systematic review provides an overview of novel imaging techniques for intraoperative margin assessment in surgical oncology, and reports on their technical properties, feasibility in clinical practice and diagnostic accuracy. PubMed, Embase, Web of Science and the Cochrane library were systematically searched (2013‐2018) for studies reporting on imaging techniques for intraoperative margin assessment. Patient and study characteristics, technical properties, feasibility characteristics and diagnostic accuracy were extracted. This systematic review identified 134 studies that investigated and developed 16 groups of techniques for intraoperative margin assessment: fluorescence, advanced microscopy, ultrasound, specimen radiography, optical coherence tomography, magnetic resonance imaging, elastic scattering spectroscopy, bio‐impedance, X‐ray computed tomography, mass spectrometry, Raman spectroscopy, nuclear medicine imaging, terahertz imaging, photoacoustic imaging, hyperspectral imaging and pH measurement. Most studies were in early developmental stages (IDEAL 1 or 2a, n = 98); high‐quality stage 2b and 3 studies were rare. None of the techniques was found to be clearly superior in demonstrating high feasibility as well as high diagnostic accuracy. In conclusion, the field of imaging techniques for intraoperative margin assessment is highly evolving. This review provides a unique overview of the opportunities and limitations of the currently available imaging techniques., What's new? While surgical resection is critical in the treatment of primary solid tumors, resection at tumor margins remains problematic, with inadequately resected margins facilitating tumor recurrence. In this systematic review, the authors collected information on novel imaging techniques applied to the intraoperative assessment of tumor margins across cancer types. A total of 16 groups of techniques were identified, with many in early stages of clinical application. Following comparison, no single technique was clearly superior in clinical feasibility or diagnostic accuracy. The review highlights the evolving nature of imaging techniques for intraoperative margin assessment and identifies opportunities and limitations in the field.

Pancreatic cancer (PC) survival is poor, as detection usually occurs late, when treatment options are limited. Screening of high‐risk individuals may enable early detection and a more favorable prognosis. Knowledge gaps prohibit establishing the effectiveness of screening. We developed a Microsimulation Screening Analysis model to analyze the impact of relevant uncertainties on the effect of PC screening in high‐risk individuals. The model simulates two base cases: one in which lesions always progress to PC and one in which indolent and faster progressive lesions coexist. For each base case, the effect of annual and 5‐yearly screening with endoscopic ultrasonography/magnetic resonance imaging was evaluated. The impact of variance in PC risk, screening test characteristics and surgery‐related mortality was evaluated using sensitivity analyses. Screening resulted in a reduction of PC mortality by at least 16% in all simulated scenarios. This reduction depended strongly on the natural disease course (annual screening: −57% for “Progressive‐only” vs −41% for “Indolent Included”). The number of screen and surveillance tests needed to prevent one cancer death was impacted most by PC risk. A 10% increase in test sensitivity reduced mortality by 1.9% at most. Test specificity is important for the number of surveillance tests. In conclusion, screening reduces PC mortality in all modeled scenarios. The natural disease course and PC risk strongly determines the effectiveness of screening. Test sensitivity seems of lesser influence than specificity. Future research should gain more insight in PC pathobiology to establish the true value of PC screening in high‐risk individuals., What's new? About 10 percent of pancreatic cancers occur in individuals with inherited risk factors. While screening such high‐risk individuals can facilitate the detection of precursor lesions and early‐stage cancer, the extent to which benefits outweigh harms, including overdiagnosis, remains unknown. Here, using a microsimulation model, the authors explored uncertainties concerning the early detection of pancreatic cancer and analyzed the impact of these uncertainties on the effect of screening. In all simulated scenarios, screening was associated with reduced pancreatic cancer mortality. The effectiveness of screening was most strongly impacted by characteristics of natural disease course and level of pancreatic cancer risk

Chemotherapy-induced myelosuppression is an acute, dose-limiting toxicity of chemotherapy regimens used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib protects haematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). To assess the totality of the myeloprotective benefits of trilaciclib, including analysis of several clinically relevant but low-frequency events, an exploratory composite endpoint comprising five major adverse haematological events (MAHE) was prospectively defined: all-cause hospitalisations, all-cause chemotherapy dose reductions, febrile neutropenia (FN), prolonged severe neutropenia (SN) and red blood cell (RBC) transfusions on/after week 5. MAHE and its individual components were assessed in three randomised, double-blind, placebo-controlled Phase 2 trials in patients receiving a platinum/etoposide or topotecan-containing chemotherapy regimen for ES-SCLC, and in data pooled from the three trials. A total of 242 patients were randomised across the three trials (trilaciclib, n = 123; placebo, n = 119). In the individual trials and the pooled analysis, administering trilaciclib prior to chemotherapy resulted in a statistically significant reduction in the cumulative incidence of MAHE compared with placebo. In the pooled analysis, the cumulative incidences of all-cause chemotherapy dose reductions, FN, prolonged SN and RBC transfusions on/after week 5 were significantly reduced with trilaciclib versus placebo; however, no significant difference was observed in rates of all-cause hospitalisations. Additionally, compared with placebo, trilaciclib significantly extended the amount of time patients remained free of MAHE. These data support the myeloprotective benefits of trilaciclib and its ability to improve the overall safety profile of myelosuppressive chemotherapy regimens used to treat patients with ES-SCLC. This article is protected by copyright. All rights reserved.

Incorporating dual human epidermal growth factor receptor 2 (HER2) blockade into neoadjuvant systemic therapy (NST) led to higher response in patients with HER2‐positive breast cancer. However, axillary response to treatment regimens, including single or dual HER2 blockade, in patients with clinically node‐positive breast cancer remains uncertain. Our study aimed to examine the pathologic axillary response according to the type of NST, that is, single or dual HER2 blockade. In our study, 546 patients with clinically node‐positive, HER2‐positive breast cancer who received NST followed by axillary surgery were retrospectively selected and divided into three groups: chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab. The primary outcome was the axillary pathologic complete response (pCR). Among 471 patients undergoing axillary lymph node dissection, the axillary pCR rates were 43.5%, 74.5% and 68.8% in patients who received chemotherapy alone, chemotherapy + trastuzumab and chemotherapy + trastuzumab with pertuzumab, respectively. There was no difference in axillary pCR rates between patients who received single or dual HER2 blockade (P = .379). Among patients receiving chemotherapy + trastuzumab, patients without breast pCR had the greatest risk for residual axillary metastases (relative risk, 9.8; 95% confidence interval, 3.2‐14.9; P, What's new? Dual blockade of the human epidermal growth factor receptor 2 (HER2) with trastuzumab and pertuzumab is the preferred option for neoadjuvant systemic therapy (NST) against node‐positive, HER2‐positive breast cancer. Whether this approach effectively improves pathologic complete response (pCR), however, remains unclear. Here, comparison of pCR for single or dual HER2 blockade shows that trastuzumab effectively increases axillary pCR rate in clinically node‐positive, HER2‐positive breast cancer. The addition of pertuzumab to trastuzumab did not further elevate pCR rate. The findings are relevant to decisions regarding axillary surgery in breast cancer patients with pCR after NST with HER2 targeted agents.

Aloe-emodin (1,8-dihydroxy-3-(hydroxymethyl)-anthraquinone), AE, is one of the active constituents of a number of plant species used in traditional medicine. We have previously identified, for the first time, AE as a new antitumor agent and shown that its selective in vitro and in vivo killing of neuroblastoma cells was promoted by a cell-specific drug uptake process. However, the molecular mechanism underlying the cell entry of AE has remained elusive as yet. In this report, we show that AE enters tumor cells via two of the five somatostatin receptors: SSTR2 and SSTR5. This observation was suggested by gene silencing, receptor competition, imaging and molecular modeling experiments. Furthermore, SSTR2 was expressed in all surgical neuroblastoma specimens we analyzed by immunohistochemistry. The above findings have strong implications for the clinical adoption of this natural anthraquinone molecule as an antitumor agent. This article is protected by copyright. All rights reserved.

Preclinical studies have shown synergistic effects when combining PARP1/2 inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. After a formulation change of olaparib from capsules to tablets, we initiated a dose finding study of olaparib tablets bidaily (BID) continuously with carboplatin to prepare comparative studies in this patient group. Patients were included in a 3 + 3 dose‐escalation schedule: olaparib 25 mg BID and carboplatin area under the curve (AUC) 3 mg*min/mL d1/d22, olaparib 25 mg BID and carboplatin AUC 4 mg*min/mL d1/d22, followed by increasing dose‐levels of olaparib from 50 mg BID, 75 mg BID, to 100 mg BID with carboplatin at AUC 4 mg*min/mL d1/d22. After two cycles, patients continued olaparib 300 mg BID as monotherapy. Primary objective was to assess the maximum tolerable dose (MTD). Twenty‐four patients with a confirmed diagnosis of advanced cancer were included. Most common adverse events were nausea (46%), fatigue (33%) and platelet count decrease (33%). Dose‐level 3 (olaparib 75 mg BID and carboplatin AUC 4 mg*min/mL; n = 6) was defined as MTD. Fourteen out of 24 patients (56%) had a partial response as best response (RECIST 1.1). Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with olaparib tablet AUC0‐12 of 16.3 μg/mL*h at MTD. Polymers of ADP‐ribose levels in peripheral blood mononuclear cells were reduced by 98.7% ± 0.14% at Day 8 compared to Day 1 for dose‐level 3. Olaparib tablets 75 mg BID and carboplatin AUC 4 mg*min/mL for two cycles preceding olaparib monotherapy 300 mg is a feasible and tolerable treatment schedule for patients with advanced cancer., What's new? Preclinical studies have shown synergistic effects when combining PARP1/2‐inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. This phase I trial of olaparib tablets combined with carboplatin in advanced cancer patients showed that the combination has an acceptable side‐effect profile. The maximum tolerable dose was olaparib tablets 75 mg BID and carboplatin AUC 4 mg*min/ml. The observed preliminary anti‐tumor activity was encouraging, with 58% of patients having a decrease in tumor volume of more than 30%. This study shows that the tablet formulation of olaparib can be administered safely in combination with carboplatin, compared to the previous capsule formulation.

This cross‐sectional and longitudinal descriptive analysis aimed to track the evolving landscape of global immuno‐oncology (IO) trials and provide insight into the resolution of IO‐related controversies. Clinical trials (n = 4510) registered on ClinicalTrials.gov in 2007 to 2019 studying immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), cancer vaccines and immune modulators were included. Most of IO trials are Phase 2 and focus on ICIs and multiple IO therapies. The United States leads global IO research, with stable growth and the best methodological quality. Mainland China ranks first in the number of ACT trials but has the lowest article publication rate (6.2%). A multiple‐arm comparative design is often adopted in multiple IO therapies trials (44.0%). Trials studying ICIs and multiple IO therapies are likely to use early registration (80.0% and 86.6%) and stringent corticosteroid‐/infection‐related criteria. Hospitals have provided the most extensive and strongest support for all IO categories. Big pharma prefers to fund Phase 3‐4 ICI trials (6.98%), while small pharma has a wider sponsorship favoring Phase 1‐2 trials. The “partial‐use‐of‐corticosteroids” strategy is generally well accepted in ICI trials with a definitive trend (32.5%; P, What's new? In recent decades, immunotherapy has emerged and advanced to become a key part of cancer‐fighting strategies. The rapid growth of immuno‐oncology, however, has been accompanied by controversy in suitable interventions and trial design. In this cross‐sectional and longitudinal analysis, disparities in design were found to be common in immuno‐oncology trials, with differences influenced by factors such as cancer type and trial sponsor. Trials with strict limitations on corticosteroid use had significantly higher publications rates than trials permitting partial corticosteroid administration. The data further suggest that timely publication of immuno‐oncology trials is the third year after trial completion.

We conducted a study to document the impact of COVID‐19 pandemic on cancer screening continuum in selected low‐ and middle‐income countries (LMICs). LMICs having an operational cancer control plan committed to screen eligible individuals were selected. Managers/supervisors of cancer screening programs were invited to participate in an online survey and subsequent in‐depth interview. Managers/supervisors from 18 programs in 17 countries participated. Lockdown was imposed in all countries except Brazil. Screening was suspended for at least 30 days in 13 countries, while diagnostic‐services for screen‐positives were suspended in 9 countries. All countries except Cameroon, Bangladesh, India, Honduras and China managed to continue with cancer treatment throughout the outbreak. The participants rated service availability compared to pre‐COVID days on a scale of 0 (no activities) to 100 (same as before). A rating of ≤50 was given for screening services by 61.1%, diagnostic services by 44.4% and treatment services by 22.2% participants. At least 70% participants strongly agreed that increased noncompliance of screen‐positive individuals and staff being overloaded or overwhelmed with backlogs would deeply impact screening programs in the next 6 months at least. Although many of the LMICs were deficient in following the “best practices” to minimize service disruptions, at least some of them made significant efforts to improve screening participation, treatment compliance and program organization. A well‐coordinated effort is needed to reinitiate screening services in the LMICs, starting with a situational analysis. Innovative strategies adopted by the programs to keep services on‐track should be mutually shared., What's new? Reductions in non‐emergency health services and diversion of resources during the coronavirus disease (COVID‐19) pandemic have greatly affected all areas of health care, including cancer care. Here, the authors investigated the impact of the COVID‐19 pandemic specifically on cancer screening in low‐ and middle‐income countries. Nearly all countries investigated experienced suspensions in cancer screening lasting at least one month, owing to lockdown restrictions, changes in health priorities, and reduced patient visits. Upon reopening, cancer services generally operated at significantly reduced capacities, emphasizing a need for highly coordinated re‐initiation efforts to ensure continuity of cancer care following lockdown.

In the global KEYNOTE‐042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD‐L1)‐positive locally advanced/metastatic non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE‐042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD‐L1 tumor proportion score [TPS] ≥50% vs 1%‐49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD‐L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty‐two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow‐up, 33.0 [range, 25.6‐41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD‐L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43‐0.94]), TPS ≥20% (0.66 [0.47‐0.92]) and TPS ≥1% (0.67 [0.50‐0.89]). Grade 3 to 5 treatment‐related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE‐042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD‐L1 TPS ≥1%, supporting first‐line pembrolizumab monotherapy for PD‐L1‐positive advanced/metastatic NSCLC in China., What's new? The global KEYNOTE‐042 clinical study helped establish single‐agent pembrolizumab, an anti‐PD‐1 monoclonal antibody, as a standard first‐line treatment option in patients with previously untreated PD‐L1‐positive locally advanced/metastatic non–small‐cell lung cancer (NSCLC) without EGFR/ALK aberrations. Because disease characteristics and responses to anticancer therapy may differ between Asian and other populations, there is a need to evaluate these treatments specifically in Asian patients. Here, the authors show that pembrolizumab also improved overall survival and was better tolerated than chemotherapy among Chinese patients with PD‐L1 TPS ≥1% in the KEYNOTE‐042 study. These data support first‐line pembrolizumab monotherapy for PD‐L1‐positive advanced/metastatic NSCLC in China.

Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti‐programmed death‐1 (anti‐PD‐1) and anti‐cytotoxic T‐lymphocyte antigen‐4 (anti‐CTLA‐4) immune checkpoint inhibitors. Treatment with the T‐cell growth factor interleukin‐2 (IL‐2) has shown some clinical benefit but has limitations due to poor tolerability. Therefore, we evaluated the efficacy of bempegaldesleukin (BEMPEG; NKTR‐214), a first‐in‐class CD122‐preferential IL‐2 pathway agonist, alone and in combination with anti‐PD‐1 or anti‐CTLA‐4 immune checkpoint inhibitors in metastatic and orthotopic murine models of osteosarcoma. Treatment with BEMPEG delayed tumor growth and increased overall survival of mice with K7M2‐WT osteosarcoma pulmonary metastases. BEMPEG also inhibited primary tumor growth and metastatic relapse in lungs and bone in the K7M3 orthotopic osteosarcoma mouse model. In addition, it enhanced therapeutic activity of anti‐CTLA‐4 and anti‐PD‐1 checkpoint blockade in the DLM8 subcutaneous murine osteosarcoma model. Finally, BEMPEG strongly increased accumulation of intratumoral effector T cells and natural killer cells, but not T‐regulatory cells, resulting in improved effector:inhibitory cell ratios. Collectively, these data in multiple murine models of osteosarcoma provide a path toward clinical evaluation of BEMPEG‐based regimens in human osteosarcoma., What's new? Despite treatment, many patients with osteosarcoma are at high risk for metastatic disease. Such cases of advanced osteosarcoma present significant therapeutic challenges, owing largely to a lack of novel and optimized treatment strategies. Here, the authors investigated the efficacy of bempegaldesleukin (BEMPEG; NKTR‐214), a novel CD122‐preferential interleukin‐2 pathway agonist, in murine models of osteosarcoma. Experiments show that BEMPEG monotherapy decreases metastatic relapse in lung and bone tissue and prolongs survival in mice. Durable tumor growth was achieved with combined BEMPEG and anti‐CTLA‐4 or anti‐PD‐1 checkpoint inhibition. The data provide a scientific rationale for clinical evaluation of BEMPEG for osteosarcoma treatment.

Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti‐PD‐1/PD‐L1 therapeutic biomarkers and protein markers of potential chemotherapy response. Data were extracted from a clinical‐grade testing database (Caris Life Sciences; February 2015 through November 2017): immunotherapy response markers (microsatellite instability‐high [MSI‐H], tumor mutational burden‐high [TMB‐H], and PD‐L1 protein expression) and protein chemotherapy response markers (excision repair complementation group 1 [ERCC1], topoisomerase 1 [TOPO1], topoisomerase 2 [TOP2A], thymidylate synthase [TS], tubulin beta 3 [TUBB3], ribonucleotide reductase regulatory subunit M1 [RRM1] and O‐6‐methyl guanine DNA methyltransferase [MGMT]). Relationships were determined by the Mantel‐Haenszel chi‐squared test or Fischer's exact tests. Overall, 28,034 patients representing a total of 40 tumor types were assessed. MSI‐H was found in 3.3% of patients (73% were also TMB‐H), TMB‐H, 8.4% (28.3% were also MSI‐H) and PD‐L1 expression in 11.0% of patients (5.1% were also MSI‐H; 16.4% were also TMB‐H). Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin or etoposide (TOP2A positivity) have a higher probability of response, whereas combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI‐H but not TMB‐H or PD‐L1‐expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD‐L1 is frequently coexpressed, but MSI‐H and TMB‐H are not associated. Protein markers of potential chemotherapy response along with next‐generation sequencing for immunotherapy response markers can help support rational combinations as part of an individualized, precision oncology approach., What's new? With the emerging success of immunotherapy of cancers, combinations with conventional chemotherapies are increasingly being tested in clinical trials. Here the authors examined concurrent biomarker expression of checkpoint (PD‐1/PD‐L1) blockade immunotherapy and various cytotoxic chemotherapies to determine which chemotherapeutic agents will best synergize with immunotherapy. They predict that combining platinum or doxorubicin, epirubicin, or etoposide treatments with PD‐1/PD‐L1 inhibitors would have a higher probability of response than other treatments, supporting a rational combination strategy in a possibly individualized treatment approach.

The purpose of this prospective phase II clinical trial was to investigate the efficacy and safety of anlotinib in patients with relapsed small cell lung cancer (SCLC). Forty‐five patients with relapsed SCLC were enrolled and treated with anlotinib (one cycle of 12 mg daily for 14 days, discontinued for 7 days, and repeated every 21 days) until disease progression or intolerance of treatment. The primary end point was progression‐free survival (PFS). Secondary end points were overall survival (OS), disease control rate (DCR), objective control rate (ORR) and toxicity. The median PFS was 4.1 months (95% confidence interval [CI] 2.4‐5.8) and the median OS was 6.1 months (95% CI 2.2‐10.0). The OS for the limited‐stage subgroup was significantly longer than that of the extensive‐stage subgroup (P = .02). The DCR was 67%, and the ORR was 11%. The most common adverse event was hypertension (13%), which was controlled well with antihypertensive drugs. In conclusion, anlotinib has likely efficacy in patients with relapsed SCLC, and the side effects can be well tolerated. A longer OS was observed in limited‐stage SCLC patients treated with anlotinib., What's new? Although untreated small cell lung cancer (SCLC) patients are usually sensitive to chemotherapy, they are prone to relapse. Anlotinib is a novel multi‐target small molecule tyrosine kinase inhibitor with both anti‐angiogenesis and anti‐tumor growth effects. While anlotinib became the first drug approved for third‐line and further‐line treatment of SCLC in China, few studies have focused on anlotinib treatment in relapsed SCLC. This one‐arm, prospective phase II clinical study reports a median progression‐free survival of 4.1 months (95% CI 2.4‐5.8) and median overall survival of 6.1 months (95% CI 2.2‐10.0) for anlotinib treatment in relapsed SCLC, with relatively mild side effects.

Obesity adversely impacts overall and cancer‐specific survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, feasibility and effects in patients are unknown. A two‐arm, single‐blinded, randomized controlled weight‐loss trial was undertaken presurgery among 32 overweight/obese, Stage 0–II breast cancer patients. The attention control arm (AC) received basic nutritional counseling and upper‐body progressive resistance training whereas the weight loss intervention (WLI) arm received identical guidance, plus counseling on caloric restriction and aerobic exercise to promote 0.68–0.92 kg/week weight loss. Anthropometrics, body composition, blood and survey data were collected at baseline and presurgery ∼30 days later. Tumor markers (e.g., Ki67) and gene expression were assessed on biopsy and surgical specimens; sera were analyzed for cytokines, growth and metabolic factors. Significant WLI vs. AC differences were seen in baseline‐to‐follow‐up changes in weight (−3.62 vs. −0.52 kg), %body fat (−1.3 vs. 0%), moderate‐to‐vigorous physical activity (+224 vs. +115 min/week), caloric density (−0.3 vs. 0 kcal/g), serum leptin (−12.3 vs. −4.0 ng/dl) and upregulation of tumor PI3Kinase signaling and cell cycle‐apoptosis related genes (CC‐ARG; all p‐values, What's new? Obesity adversely impacts survival among breast cancer patients. Preclinical studies demonstrate negative energy balance inhibits cancer progression; however, effects in patients are unknown. This is the first randomized controlled trial to assess the impact of a pre‐surgical weight loss intervention among early‐stage breast cancer patients. Results show the effects of acute negative energy balance on tumor biology, circulating biomarkers, and quality‐of‐life. Short‐term weight loss interventions are feasible; however, mixed effects on tumor biology suggest unclear benefit to pre‐surgical caloric restriction. Such interventions may be better timed after surgical resection, though cell cycle‐apoptosis and DNA damage‐repair scores support increasing physical activity.

Ponatinib is a small molecule multi‐tyrosine kinase inhibitor clinically approved for anticancer therapy. Molecular mechanisms by which cancer cells develop resistance against ponatinib are currently poorly understood. Likewise, intracellular drug dynamics, as well as potential microenvironmental factors affecting the activity of this compound are unknown. Cell/molecular biological and analytical chemistry methods were applied to investigate uptake kinetics/subcellular distribution, the role of lipid droplets (LDs) and lipoid microenvironment compartments in responsiveness of FGFR1‐driven lung cancer cells toward ponatinib. Selection of lung cancer cells for acquired ponatinib resistance resulted in elevated intracellular lipid levels. Uncovering intrinsic ponatinib fluorescence enabled dissection of drug uptake/retention kinetics in vitro as well as in mouse tissue cryosections, and revealed selective drug accumulation in LDs of cancer cells. Pharmacological LD upmodulation or downmodulation indicated that the extent of LD formation and consequent ponatinib incorporation negatively correlated with anticancer drug efficacy. Co‐culturing with adipocytes decreased ponatinib levels and fostered survival of cancer cells. Ponatinib‐selected cancer cells exhibited increased LD levels and enhanced ponatinib deposition into this organelle. Our findings demonstrate intracellular deposition of the clinically approved anticancer compound ponatinib into LDs. Furthermore, increased LD biogenesis was identified as adaptive cancer cell‐defense mechanism via direct drug scavenging. Together, this suggests that LDs represent an underestimated organelle influencing intracellular pharmacokinetics and activity of anticancer tyrosine kinase inhibitors. Targeting LD integrity might constitute a strategy to enhance the activity not only of ponatinib, but also other clinically approved, lipophilic anticancer therapeutics., What's new? Ponatinib is a small‐molecule multi‐tyrosine kinase inhibitor clinically approved for anticancer therapy. However, to date, the intracellular pharmacokinetics of this compound and the molecular mechanisms underlying resistance in cancer cells remain largely unknown. Here, the authors found that ponatinib was selectively scavenged by lipid droplets in cancer cells. Ponatinib accumulation into lipid droplets emerged as a critical determinant of intrinsic and acquired drug resistance. The findings suggest that lipid droplets represent an underestimated organelle influencing intracellular pharmacokinetics and anticancer tyrosine kinase inhibitor activity. Moreover, co‐targeting of lipogenic cancer cell phenotypes might enhance the efficacy of ponatinib and other lipophilic pharmaceuticals.

The ALSYMPCA study established a 3.6 month Overall Survival (OS) benefit in metastatic Castration Resistant Prostate Cancer (mCRPC) patients treated with Radium‐223 dichloride (Ra‐223) over placebo. Here we report clinical outcomes of Ra‐223 treatment in a nonstudy population. In this prospective registry, patients from 20 Dutch hospitals were included prior to Ra‐223 treatment. Clinical parameters collected included previous treatments and Adverse Events. Primary outcome was 6 months Symptomatic Skeletal Event (SSE)‐free survival, while secondary outcomes included Progression‐Free Survival (PFS) and Overall Survival (OS). Of the 305 patients included, 300 were evaluable. The mean age was 73.6 years, 90% had ≥6 bone metastases and 74.1% were pretreated with Docetaxel, 19.5% with Cabazitaxel and 80.5% with Abiraterone and/or Enzalutamide. Of all patients, 96.7% were treated with Ra‐223 and received a median of 5 cycles. After a median follow‐up of 13.2 months, 6 months SSE‐free survival rate was 83%, median PFS was 5.1 months and median OS was 15.2 months. Six months SSE‐free survival rate and OS were comparable with those reported in ALSYMPCA. “Previous Cabazitaxel treatment” and “bone‐only metastases” were independent predictors of a shorter and longer PFS, respectively, while above‐median LDH and “bone‐only metastases” were independent predictors of shorter and longer OS, respectively. Toxicity was similar as reported in the ALSYMPCA trial. These results suggest that in a nonstudy population, Ra‐223 treatment is well‐tolerated, equally effective as in the ALSYMPCA population and that patients not previously treated with Cabazitaxel benefit most from Ra‐223., What's new? The ALSYMCA phase III trial reported a survival benefit from Radium‐223 treatment in patients with metastatic castration‐resistant prostate cancer (mCRPC). These patients, however, were not treated previously with newer life‐prolonging drugs, raising questions about whether the ALSYMCA population reflects current populations of mCRPC patients. In this prospective study, men with mCRPC who were pretreated with newer generation drugs prior to receiving Radium‐223 experienced improvements in disease‐free and overall survival that were comparable to those reported in the ALSYMPCA study. Prior treatment with cabazitaxel independently predicted shorter progression‐free survival. The findings suggest that, overall, Radium‐233 is effective in men with mCRPC.

Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient‐derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP‐ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double‐stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP‐inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies., What's new? Treatment options and outcomes for osteosarcoma have changed very little in decades. New treatment strategies are thus urgently needed. In this study, the authors found that the checkpoint inhibitor ‘prexasertib’ increased apoptosis and DNA damage in patient‐derived osteosarcoma cells, at very low concentrations. In addition, when combined with cisplatin and talazoparib, prexasertib acted in a synergistic fashion. This drug thus represents a promising therapeutic candidate for further preclinical and clinical development in osteosarcoma.

We studied effectiveness of the AS04‐adjuvanted HPV‐16/18 (AS04‐HPV‐16/18) vaccine against human papillomavirus (HPV) oropharyngeal infections associated with the increase of head/neck cancers in western countries. All 38,631 resident adolescents from 1994 to 1995 birth cohorts of 33 Finnish communities were invited in this community‐randomized trial (NCT00534638). During 2008–2009, 11,275 girls and 6,129 boys were enrolled in three arms of 11 communities each. In Arm A, 90% of vaccinated girls/boys, and in Arm B, 90% of vaccinated girls received AS04‐HPV‐16/18 vaccine. Other Arm A/B and all Arm C vaccinated participants received control vaccine. All Arm A participants and Arm B female participants were blinded to vaccine allocation. Oropharyngeal samples were analyzed from 4,871 18.5‐year‐old females who attended follow‐up visit 3–6 years postvaccination. HPV DNA prevalence was determined by SPF‐10 LiPA and Multiplex type‐specific PCR. Total vaccine effectiveness (VE) was defined as relative reduction of oropharyngeal HPV prevalence in pooled Arms A/B HPV‐vaccinated females vs. all Arm C females. VE against oropharyngeal HPV‐16/18, HPV‐31/45 and HPV‐31/33/45 infections were 82.4% (95% confidence intervals [CI]: 47.3–94.1), 75.3% (95%CI: 12.7–93.0) and 69.9% (95% CI: 29.6–87.1), respectively. In conclusion, the AS04‐HPV‐16/18 vaccine showed effectiveness against vaccine and nonvaccine HPV‐types oropharyngeal infections in adolescent females up to 6 years postvaccination., What's new? The incidence of oropharyngeal cancers due to human papillomavirus (HPV) infection is increasing in Western countries. However, the efficacy of HPV vaccines against oropharyngeal infection is not well documented. Based on a large community‐randomized trial in Finland, the authors report high effectiveness (82.4%) of Cervarix vaccine against oropharyngeal HPV‐16/18 infection and moderate effectiveness against non‐vaccine types HPV‐31/33/45 infection in female adolescents. The protective effects were observed up to 6 years after vaccination. These results provide further evidence that HPV vaccination holds the potential to reduce oral HPV infection, thereby offering protection against HPV‐related head and neck cancers.

Delayed time to chemotherapy (TTC) is associated with decreased outcomes of breast cancer patients. Recently, studies suggested that the association might be subtype‐dependent and that TTC within 30 days should be warranted in patients with triple‐negative breast cancer (TNBC). The aim of the current study is to determine if TTC beyond 30 days is associated with reduced 10‐year overall survival in TNBC patients. We identified all TNBC patients diagnosed between 2006 and 2014 who received adjuvant chemotherapy in the Netherlands. We distinguished between breast‐conserving surgery (BCS) vs. mastectomy given the difference in preoperative characteristics and outcomes. The association was estimated with hazard ratios (HRs) using propensity‐score matched Cox proportional hazard analyses. In total, 3,016 patients were included. In matched patients who underwent BCS (n = 904), 10‐year overall survival was favorable for patients with TTC within 30 days (84.4% vs. 76.9%, p = 0.001). Patients with TTC beyond 30 days were more likely than those with TTC within 30 days to die within 10 years after surgery (HR 1.69 (95% CI 1.22–2.34), p = 0.002). In matched patients who underwent mastectomy (n = 1,568), there was no difference in 10 years overall survival between those with TTC within or beyond 30 days (74.5% vs. 74.7%, p = 0.716), nor an increased risk of death for those with TTC beyond 30 days (HR 1.04 (95% CI 0.84–1.28), p = 0.716). Initiation of adjuvant chemotherapy beyond 30 days is associated with decreased 10 years overall survival in TNBC patients who underwent BCS. Therefore, timelier initiation of chemotherapy in TNBC patients undergoing BCS seems warranted., What's new? Current breast cancer treatment guidelines recommend that chemotherapy is initiated between 6‐12 weeks after surgery. Delayed treatment can lead to poorer outcome, but there's no precise definition of the optimal window. Recent work suggests that for patients with triple negative breast cancer (TNBC), it's best to initiate chemotherapy within 30 days. Here, the authors evaluated outcomes for TNBC patients correlated with time to chemotherapy. They found that in patients undergoing breast‐conserving surgery, an interval of more than 30 days before chemotherapy was associated with decreased survival. If the patient had undergone a mastectomy, a longer delay before chemotherapy did not impact survival.

Non‐clear cell renal cell carcinoma is a very rare malignancy that includes several histological subtypes. Each subtype may need to be addressed separately regarding prognosis and treatment; however, no Phase III clinical trial data exist. Thus, treatment recommendations for patients with non‐clear cell metastatic RCC (mRCC) remain unclear. We present first prospective data on choice of first‐ and second‐line treatment in routine practice and outcome of patients with papillary mRCC. From the prospective German clinical cohort study (RCC‐Registry), 99 patients with papillary mRCC treated with systemic first‐line therapy between December 2007 and May 2017 were included. Prospectively enrolled patients who had started first‐line treatment until May 15, 2016, were included into the outcome analyses (n = 82). Treatment was similar to therapies used for clear cell mRCC and consisted of tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors and recently checkpoint inhibitors. Median progression‐free survival from start of first‐line treatment was 5.4 months (95% confidence interval [CI], 4.1–9.2) and median overall survival was 12.0 months (95% CI, 8.1–20.0). At data cutoff, 73% of the patients died, 6% were still observed, 12% were lost to follow‐up, and 9% were alive at the end of the individual 3‐year observation period. Despite the lack of prospective Phase III evidence in patients with papillary mRCC, our real‐world data reveal effectiveness of systemic clear cell mRCC therapy in papillary mRCC. The prognosis seems to be inferior for papillary compared to clear cell mRCC. Further studies are needed to identify drivers of effectiveness of systemic therapy for papillary mRCC., What's new? Over the past decade, the treatment landscape for locally advanced or metastatic renal cell carcinoma (mRCC) has dramatically changed. To date, however, guideline recommendations mainly address patients with clear cell mRCC, due to a lack of prospective Phase III evidence for the rarer, non‐clear cell mRCC subtypes. This is the first longitudinal, prospective cohort study evaluating treatment and survival of patients with papillary mRCC outside a prospective clinical trial setting. The presented real‐world data help bridge the evidence gap by revealing the frequent use and effectiveness of systemic clear cell mRCC therapy in papillary mRCC, with a seemingly inferior prognosis.

Between January 1, 2011, and December 31, 2016, we studied the incidence, management and outcome of high‐risk breast lesions in a consecutive series of 376,519 screens of women who received biennial screening mammography. During the 6‐year period covered by the study, the proportion of women who underwent core needle biopsy (CNB) after recall remained fairly stable, ranging from 39.2% to 48.1% (mean: 44.2%, 5,212/11,783), whereas the proportion of high‐risk lesions at CNB (i.e., flat epithelial atypia, atypical ductal hyperplasia, lobular carcinoma in situ and papillary lesions) gradually increased from 3.2% (25/775) in 2011 to 9.5% (86/901) in 2016 (p, What's new? Screening mammography aims to catch breast cancer early to reduce associated morbidity and mortality. Women with suspect findings at mammography frequently are recalled for further testing with core needle biopsy (CNB). In this investigation, the proportion of high‐risk lesions detected at CNB was found to have tripled among women in the Netherlands who underwent mammographic screening between 2011 and 2016. This increase was accompanied by an increase in lesion excision rates. Of excised lesions, little more than 14% proved to be malignant at two‐year follow‐up. The remainder of lesions exhibited benign pathology, suggesting that many women underwent potentially unnecessary surgery.

Due to the increasing incidence and prevalence of neuroendocrine tumors (NETs), there is a need to assess any gaps in awareness and care. A survey was undertaken in 2017 to identify perceived unmet needs from the perspectives of patients/families, patient advocates and health care professionals (HCPs). The survey consisted of 33–37 questions (depending on type of respondent) across four areas: information, care, treatments and research. In total, 443 participants from 26 countries responded: 338 patients/families, 35 advocates and 70 HCPs. Perceived unmet needs regarding provision of information at diagnosis differed between groups. While 59% of HCPs believed they provided sufficient information, informational needs were mostly/fully met for only 30% of patients and 18% of advocates. Additionally, 91% of patients and 97% of advocates felt that patients had to search for information themselves. Availability of Gallium‐68‐Dotatate PET/CT scan was limited for the majority of patients (patients: 73%; advocates: 85%; HCP: 86%), as was access to treatments, particularly peptide receptor radionuclide therapy (patients: 42%; advocates: 95%; HCPs: 77%). All groups felt that standards of care, including psychological needs and diagnosis of mental health, were not fully met. Although about two‐thirds of patients were managed by a multidisciplinary team, 14% of patients reportedly did not have enough contact. All groups supported more patient involvement in research; patients and advocates prioritized improvement in diagnosis and HCPs focused on clinical trials. This survey revealed significant unmet needs but differing perceptions regarding these among the groups. There is a need for investigation and collaboration to improve standards of care for NET patients., What's new? Even though the incidence of neuroendocrine tumors (NETs) has been rising worldwide, the current management of patients varies considerably, potentially leaving many with suboptimal care. An international survey was carried out in 2017 to investigate unmet needs in the NET patient community. The survey revealed that patients perceive numerous unmet needs in key areas including provision of information, diagnostics and treatment access, care standards, and research involvement. While healthcare professionals were aware of these gaps, they generally underestimated their magnitude. Patients and healthcare professionals need to work together to improve the lives and prospects of the increasing numbers of patients.

Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)‐negative and HPV‐positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups. Here, we searched for optimal radiosensitization approaches for HPV‐positive and HPV‐negative HNSCCs by performing a targeted CRISPR‐Cas9 screen. We found that inhibition of base excision repair resulted in a better radiotherapy response in HPV‐positive HNSCC, which is correlated with upregulation of genes involved in base excision repair. In contrast, inhibition of nonhomologous end‐joining and mismatch repair showed strong effects in both HNSCC groups. We validated the screen results by combining radiotherapy with targeted inhibition of DNA repair in several preclinical models including primary and recurrent patient‐derived HNSCC xenografts. These findings underline the importance of stratifying HNSCC patients for combination treatments., What's new? The combination of radiotherapy and targeted inhibition of DNA repair pathways can potentially improve therapeutic response in patients with head and neck squamous cell carcinoma (HNSCC). Here, a targeted CRISPR‐Cas9 screen was used to identify optimal radiosensitization approaches for human papillomavirus (HPV)‐positive and HPV‐negative HNSCC. Inhibition of base excision repair was associated with improved radiotherapy response in HPV‐positive HNSCC cells. By comparison, inhibition of non‐homologous end‐joining and mismatch repair was effective in both HPV‐positive and HPV‐negative cells. The screen results were validated in patient‐derived xenograft models, suggesting that stratification of HNSCC patients by HPV status may benefit therapeutic outcome.

Overuse of antibiotic drugs alters the composition of gut microbiota and has detrimental effects on the host. In our study, we investigated association of gut flora and antibiotics in the prognosis of patients with liver cancer who have undergone chemotherapy by analyzing two independent clinical studies. We retrospectively subanalyzed a previously reported randomized controlled trial (RCT) on hepatic arterial infusion chemotherapy in patients with hepatocellular carcinoma (HCC) to investigate the association between use of antibiotics and prognosis. In the other study, we prospectively determined the abundance of specific bacterial genus in patients with HCC by sequencing 16S ribosomal RNA and assessed its association with survival. Subanalysis of the RCT data showed that, of 26 types of antibiotics used, administration of carbapenem before or during chemotherapy was associated with poor progression‐free survival (PFS) and overall survival (OS) of patients with HCC (carbapenem + vs. −; median PFS, 78 days vs. 154 days, p = 0.0053; median OS, 177 days vs. 475 days, p = 0.0003). Multivariate analysis revealed that antianaerobic drug use is an independent predictor of poor prognosis. In the prospective study, the abundance of Blautia in fecal microbiota correlated positively with both PFS and OS of patients with HCC who underwent chemotherapy. Use of antibiotics targeting anaerobes is associated with a poor prognosis in patients with HCC who have undergone chemotherapy, whereas the intestinal anaerobic bacteria, Blautia is associated with a good prognosis. These findings might indicate the need for caution regarding overuse of broad‐spectrum antibiotics targeting anaerobes in patients with HCC., What's new? Overuse of antibiotic drugs alters the composition of gut microbiota and can have detrimental effects on the host. However, it remains unclear whether antibiotics impair the anti‐cancer effects of cytotoxic drugs in cancer patients. Using data from two independent clinical studies, here the authors reveal that use of antibiotics targeting anaerobes is associated with a poor prognosis in patients with hepatocellular carcinoma (HCC) who have undergone chemotherapy, whereas the intestinal anaerobic bacteria, Blautia is associated with a good prognosis. These findings might indicate the need for caution regarding overuse of broad‐spectrum antibiotics targeting anaerobes in patients with HCC.

Gastrin‐releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclide therapy (TRT). We optimized the bombesin‐derived GRPR‐antagonist PEG2‐RM26 for labeling with 177Lu and further determined the effect of treatment with 177Lu‐labeled peptide alone or in combination with the anti‐HER2 antibody trastuzumab in a murine model. The PEG2‐RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide‐chelator conjugates were labeled with 177Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC‐3 xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA‐PEG2‐RM26, (C) 177Lu‐DOTAGA‐PEG2‐RM26, (D) trastuzumab or (E) 177Lu‐DOTAGA‐PEG2‐RM26 in combination with trastuzumab. 177Lu‐DOTAGA‐PEG2‐RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% of radioligand remained when coinjected with phosphoramidon), high affinity to GRPR (K D = 0.4 ± 0.2 nM), and favorable biodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu‐DOTAGA‐PEG2‐RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorter than for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantly improved survival. No treatment‐related toxicity was observed. In conclusion, based on in vitro and in vivo characterization of the four 177Lu‐labeled PEG2‐RM26 analogs, we concluded that 177Lu‐DOTAGA‐PEG2‐RM26 was the most promising analog for TRT. Radiotherapy using 177Lu‐DOTAGA‐PEG2‐RM26 effectively inhibited tumor growth in vivo in a murine prostate cancer model. Anti‐HER2 therapy additionally improved survival., What's new? Targeted radionuclide therapy (TRT) using radiolabeled peptides seeking gastrin‐releasing peptide receptors (GRPRs) in tumors is a promising approach to treat disseminated prostate cancer. The possibility to improve the therapeutic index via combination therapies also warrants further investigation. Here, the authors developed and characterized a promising GRPR‐targeting radioligand and demonstrated its therapeutic efficacy in prostate cancer xenografts. Moreover, this study using the anti‐HER2 antibody trastuzumab presents the first in vivo proof‐of‐principle that the effects of anti‐GRPR radiotherapy can be amplified by co‐administration of anti‐HER2 treatment leading to prolonged survival.

Aberrant activation in fibroblast growth factor signaling has been implicated in the development of various cancers, including squamous cell lung cancer, squamous cell head and neck carcinoma, colorectal and bladder cancer. Thus, fibroblast growth factor receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated the activity of a novel pan‐FGFR inhibitor, rogaratinib, in biochemical, cellular and in vivo efficacy studies in a variety of preclinical cancer models. In vitro kinase activity assays demonstrate that rogaratinib potently and selectively inhibits the activity of FGFRs 1, 2, 3 and 4. In line with this, rogaratinib reduced proliferation in FGFR‐addicted cancer cell lines of various cancer types including lung, breast, colon and bladder cancer. FGFR and ERK phosphorylation interruption by rogaratinib treatment in several FGFR‐amplified cell lines suggests that the anti‐proliferative effects are mediated by FGFR/ERK pathway inhibition. Furthermore, rogaratinib exhibited strong in vivo efficacy in several cell line‐ and patient‐derived xenograft models characterized by FGFR overexpression. The observed efficacy of rogaratinib strongly correlated with FGFR mRNA expression levels. These promising results warrant further development of rogaratinib and clinical trials are currently ongoing (ClinicalTrials.gov Identifiers: NCT01976741, NCT03410693, NCT03473756)., What's new? Deregulated fibroblast growth factor receptor (FGFR) signaling is involved in tumorigenesis and cancer progression. Here, the authors report on a novel pan‐FGFR inhibitor, rogaratinib, that potently and highly selectively prevents the activity of FGFRs 1, 2, 3, and 4. Rogaratinib inhibits cell proliferation in various FGFR‐addicted cancers in vitro, including colon, lung, and bladder cancer. Rogaratinib also exhibits strong in vivo efficacy in several cell line‐ and patient‐derived xenograft models characterized by FGFR mRNA overexpression with good tolerability. Altogether, these data warrant the further development of rogaratinib for treatment of cancers with FGFR alterations, and clinical trials are currently ongoing.

Panitumumab is approved for RAS wild‐type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first‐line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab‐based maintenance after oxaliplatin discontinuation in RAS wild‐type patients. First‐line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression‐free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5‐fluorouracil/leucovorin (5‐FU/LV) maintenance was 21 (interquartile range: 11–41) weeks; that of 5‐FU/LV ± bevacizumab maintenance was 16 (6–31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3–50.4) and 39.1 (34.2–63.0) months for panitumumab plus 5‐FU/LV maintenance and 24.1 (17.7–33.0) and 28.9 (21.0–32.0) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3–23.6) and 15.4 (11.6–18.4) months for panitumumab plus 5‐FU/LV maintenance and 12.6 (9.4–16.2) and 13.1 (9.5–16.6) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7–42.8) and 33.5 (24.5–54.9) months for panitumumab plus 5‐FU/LV maintenance and 16.4 (12.4–24.1) and 23.3 (15.7–26.3) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8–19.2) and 9.7 (5.8–14.8) months and 7.1 (5.6–10.2) and 7.0 (3.9–10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5‐FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first‐line treatment. Prospective studies are warranted., What's new? Panitumumab is an anti‐EGFR antibody used in the treatment of RAS wild‐type metastatic colorectal cancer. But is it useful for long‐term therapy in these patients, especially after more toxic therapies like oxaliplatin are discontinued? In this retrospective analysis, the authors found that a maintenance regimen including panitumumab was well tolerated and may be associated with better outcomes than non‐panitumumab strategies. Patients who received panitumumab‐based maintenance therapy were also more likely to have had a good response to first‐line treatment. The results from this study indicate that further, prospective studies are warranted.

Osimertinib is the only Food and Drug Administration‐approved third‐generation epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitor (TKI). A meta‐analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment‐naïve patients with EGFR‐TKI‐sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6‐month PFS 83% (95% CI 80–87%), and 12‐month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier‐generation EGFR‐TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6‐month PFS 63% (95% CI 58–69%), and 12‐month PFS 32% (95% CI 17–47%). EGFR‐TKI‐naïve patients with EGFR‐positive mutations tend to have longer median PFS than EGFR‐TKI‐pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation‐positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation‐positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients., What's new? Epidermal growth factor receptor (EGFR) tyrosine‐kinase inhibitors (TKIs) have shown significant promise in treating advanced non‐small‐cell lung cancer (NSCLC). In this meta‐analysis, the authors found that osimertinib, a third‐generation EGFR‐TKI, is an especially favorable treatment option. Outcomes were encouraging for previously‐treated, advanced NSCLCs that carried T790M mutations. In addition, treatment‐naïve patients whose advanced NSCLC had EGFR‐TKI‐sensitizing mutations tended to have a better response with osimertinib than did previous patients treated with earlier‐generation EGFR‐TKIs. These results indicate that further clinical trials are warranted for optimizing the use of osimertinib in advanced NSCLC.

High‐risk neuroblastoma, a predominantly TP53 wild‐type (wt) tumour, is incurable in >50% patients supporting the use of MDM2 antagonists as novel therapeutics. Idasanutlin (RG7388) shows in vitro synergy with chemotherapies used to treat neuroblastoma. This is the first study to evaluate the in vivo efficacy of the intravenous idasanutlin prodrug, RO6839921 (RG7775), both alone and in combination with temozolomide in TP53 wt orthotopic neuroblastoma models. Detection of active idasanutlin using liquid chromatography‐mass spectrometry and p53 pathway activation by ELISA assays and Western analysis showed peak plasma levels 1 h post‐treatment with maximal p53 pathway activation 3–6 h post‐treatment. RO6839921 and temozolomide, alone or in combination in mice implanted with TP53 wt SHSY5Y‐Luc and NB1691‐Luc cells showed that combined RO6839921 and temozolomide led to greater tumour growth inhibition and increase in survival compared to vehicle control. Overall, RO6839921 had a favourable pharmacokinetic profile consistent with intermittent dosing and was well tolerated alone and in combination. These preclinical studies support the further development of idasanutlin in combination with temozolomide in neuroblastoma in early phase clinical trials., What's new? Long‐term survival of high‐risk neuroblastoma patients currently averages than 50%. New therapies that both improve survival and reduce treatment toxicity are urgently needed. MDM2 antagonists are a novel class of anti‐cancer agents that stabilize the p53 pathway and lead to tumour suppression. In this preclinical study, the authors tested a prodrug of the MDM2 inhibitor idasanutlin in mice. They found that this compound inhibited tumour growth and increased survival, especially in combination with temozolomide. These results support the further development of idasanutlin plus temozolomide in clinical trials for neuroblastoma.

Obesity is the strongest risk factor for endometrial cancer (EC). To inform targeted screening and prevention strategies, we assessed the impact of obesity and subsequent bariatric surgery‐induced weight loss on endometrial morphology and molecular pathways implicated in endometrial carcinogenesis. Blood and endometrial tissue were obtained from women with class III–IV obesity (body mass index ≥40 and ≥50 kg/m2, respectively) immediately prior to gastric bypass or sleeve gastrectomy, and at two and 12 months’ follow up. The endometrium underwent pathological examination and immunohistochemistry was used to quantify proliferation (Ki‐67), oncogenic signaling (PTEN, pAKT, pERK) and hormone receptor (ER, PR) expression status. Circulating biomarkers of insulin resistance, reproductive function and inflammation were also measured at each time point. Seventy‐two women underwent bariatric surgery. At 12 months, the mean change in total and excess body weight was −32.7 and −62.8%, respectively. Baseline endometrial biopsies revealed neoplastic change in 10 women (14%): four had EC, six had atypical hyperplasia (AH). After bariatric surgery, most cases of AH resolved (5/6) without intervention (3/6) or with intrauterine progestin (2/6). Biomarkers of endometrial proliferation (Ki‐67), oncogenic signaling (pAKT) and hormone receptor status (ER, PR) were significantly reduced, with restoration of glandular PTEN expression, at 2 and 12 months. There were reductions in circulating biomarkers of insulin resistance (HbA1c, HOMA‐IR) and inflammation (hsCRP, IL‐6), and increases in reproductive biomarkers (LH, FSH, SHBG). We found an unexpectedly high prevalence of occult neoplastic changes in the endometrium of women undergoing bariatric surgery. Their spontaneous reversal and accompanying down‐regulation of PI3K‐AKT–mTOR signaling with weight loss may have implications for screening, prevention and treatment of this disease., What's new? Obesity is a major risk factor for endometrial cancer (EC). In this study, the authors found that, in obese women, bariatric surgery‐induced weight loss resulted in significant, beneficial changes in circulating biomarkers of insulin resistance, inflammation, and reproductive hormones, in endometrial morphology, and in molecular pathways that are implicated in endometrial carcinogenesis. The latter included changes in Ki‐67 expression and activation of the PI3K‐AKT‐mTOR oncogenic signaling pathway, including PTEN and pAKT. These results may have important implications for screening, prevention and treatment of EC.

Although immune checkpoint inhibitors (ICIs) are associated with different immune‐related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug‐event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD‐1, PD‐L1 and CTLA‐4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause‐effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines., What's new? Immune checkpoint inhibitors (ICIs), while potentially improving cancer patient survival, are associated with sometimes severe immune‐related adverse events. While these events affect all host tissues, little is known about their impact on bone in particular. Here, the authors investigated accounts of bone and joint injuries among patients taking ICIs, using clinical data and reports submitted to a pharmacovigilance database. Analyses show that ICIs may precipitate adverse skeletal events and reveal an increased reporting of serious vertebral fractures in patients lacking pre‐existing risk factors. The findings suggest that risk stratification and monitoring for skeletal lesions in patients taking ICIs is warranted.

The mechanism by which trastuzumab‐emtansine (T‐DM1) causes systemic toxicities apart from trastuzumab alone is currently unknown. We hypothesized that the systemic toxicities from T‐DM1 may have been caused by the free and active maytansine released from the lysed HER2+ tumor cells, and if so, they may correlate with the response to treatment and eventually disease‐free survival or patient outcome. In a retrospective, observational study, we evaluated 73 patients from three centers in the United States and Canada with advanced HER2+ breast cancer that received at least one dose of T‐DM1. Toxicity grades were summed to create a corresponding toxicity sum score (TSS), and its association with clinical outcomes was analyzed. A higher TSS was significantly associated with longer progression‐free survival with an HR = 0.66 [95% confidence interval [CI]: 0.47‐0.92], P = .014, for each 1‐point increase in the TSS score. Adjusted for baseline platelet count, aspartate transaminase and alanine transaminase, higher TSS remains significantly associated with longer progression‐free survival with adjusted HR = 0.67 [95% CI: 0.47‐0.93], P = .020. The analysis suggests that the systemic toxicities of T‐DM1 were significantly correlated with its clinical efficacy. This is the first report to correlate the systemic toxicities of T‐DM1 with clinical outcome. Further, this suggests that systemic toxicities of antibody‐drug conjugates (ADCs) may serve as a predictive biomarker, particularly if noncleavable linkers are used. If confirmed in larger prospective studies, the present finding is significant because most ADCs do not have a biomarker predictive of clinical outcome other than the presence or absence of the antibody target., What's new? Linkage of trastuzumab to emtansine (T‐DM1), a tumor‐antigen specific antibody, is associated with improved survival in patients with metastatic HER2+ breast cancer. Relative to trastuzumab alone, however, trastuzumab‐emtansine (T‐DM1) has unique side effects, including throbocytopenia and transaminitis. In this investigation of systemic toxicities, tumor response, and patient outcome, higher toxicity sum score for T‐DM1 was significantly associated with improved tumor response and increased progression‐free survival in metastatic HER2+ breast cancer patients. The findings suggest that emtansine freed from lysed HER2+ breast cancer cells potentially influences T‐DM1 toxicity and that systemic toxicities of antibody‐drug conjugates function as predictive biomarkers.

Interleukin (IL)‐10 has anti‐inflammatory and CD8+ T‐cell‐stimulating properties. Pegilodecakin (pegylated recombinant human IL‐10) induces intratumoral antigen‐specific CD8 + T‐cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single‐agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long‐term follow‐up with pegilodecakin + anti‐programmed cell death 1 (anti‐PD‐1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi‐cohort dose escalation IVY study enrolled 353 patients. Sixty‐six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti‐PD‐1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune‐related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression‐free survival (mPFS) of 13.9 months and 6‐month PFS probability of 60%, 76% 1‐year overall survival (OS) probability and 61% 2‐year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6‐month PFS probability 25%, 1‐year OS 50%, and 2‐year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti‐PD‐1. Most common Grade 3/4 treatment‐related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti‐PD‐1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti‐PD‐1 inhibitors was consistent as previously reported., What's new? Despite recent progress in the treatment of renal cell cancer (RCC), there is still an urgent need for treatments that will further improve the prognosis of patients with advanced RCC. Pegilodecakin is a promising IL‐10 analogue that induces CD8+T‐cell‐mediated immune activation. Does a combination regimen yield better outcomes in heavily pretreated RCC patients than pegilodecakin alone? In this study, the authors found that the most promising clinical activity was obtained using a combination of pegilodecakin plus an anti‐PD‐1 inhibitor. Combination with a tyrosine‐kinase inhibitor of VEGFR was also better than pegilodecakin monotherapy.

Contains fulltext : 235501.pdf (Publisher’s version ) (Open Access) Co-treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH-dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our study, we investigated whether a 1-hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady-state pazopanib trough concentration (C(min) ) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) C(min) levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM C(min) levels were lower in GAS users vs non-GAS users for both the 800 and 600 mg cohorts (23.7 mg/L [95% confidence interval [CI]: 21.1-26.7] vs 28.2 mg/L [95% CI: 25.9-30.5], P = .015 and 26.0 mg/L [95% CI: 22.4-30.3] vs 33.5 mg/L [95% CI: 30.3-37.1], P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non-GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub-analysis showed lower GM pazopanib C(min) in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non-users. Our research showed that a 1-hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.

Currently, all European countries offer some form of breast cancer screening. Nevertheless, disparities exist in the status of implementation, attendance and the extent of opportunistic screening. As a result, breast cancer screening has not yet reached its full potential. We examined how many breast cancer deaths could be prevented if all European countries would biennially screen all women aged 50 to 69 for breast cancer. We calculated the number of breast cancer deaths already prevented due to screening as well as the number of breast cancer deaths which could be additionally prevented if the total examination coverage (organised plus opportunistic) would reach 100%. The calculations are based on total examination coverage in women aged 50 to 69, the annual number of breast cancer deaths for women aged 50 to 74 and the maximal possible mortality reduction from breast cancer, assuming similar effectiveness of organised and opportunistic screening. The total examination coverage ranged from 49% (East), 62% (West), 64% (North) to 69% (South). Yearly 21 680 breast cancer deaths have already been prevented due to mammography screening. If all countries would reach 100% examination coverage, 12 434 additional breast cancer deaths could be prevented annually, with the biggest potential in Eastern Europe. With maximum coverage, 23% of their breast cancer deaths could be additionally prevented, while in Western Europe it could be 21%, in Southern Europe 15% and in Northern Europe 9%. Our study illustrates that by further optimising screening coverage, the number of breast cancer deaths in Europe can be lowered substantially., What's new? Breast cancer is the leading cause of death among European women. Although screening for breast cancer is available in all European countries, not all eligible women aged 50‐69 get screened. Here, the authors calculated how many deaths could be prevented if screening coverage reached 100%, considering both organized and opportunistic screening. Already, screening prevents 21 680 deaths per year, and if all countries reached full examination coverage, an additional 12 434 deaths per year could be prevented across Europe.

Parents are the primary source of support for children with cancer. To inform clinical practice and health policies, the socioeconomic consequences of childhood cancer for fathers and mothers in Sweden were investigated. A total of 3865 mothers and 3865 fathers of 3865 children diagnosed with cancer in Sweden when 0 to 18 years were followed for 5 years before and 10 years after diagnosis. Socioeconomic consequences of the cancer diagnosis on earnings and employment, and mental health (number of inpatient diagnoses), were investigated exploiting variation in timing of cancer diagnosis. Data were obtained from the Swedish Childhood Cancer Registry, Intergenerational Registry and Inpatient Registry. Childhood cancer has a negative short‐term effect on fathers' and mothers' earnings; a negative long‐term effect on fathers' earnings; a positive long‐term effect on mothers' earnings; negative short‐ and long‐term effects on fathers' and mothers' employment; and no effect on the number of inpatient diagnosis of mental and behavioral disorders for fathers or mothers. Taken together, findings show that in Sweden childhood cancer has negative effects on parents' employment, a more negative impact on fathers' than mothers' earnings and no effect on inpatient diagnosis of mental and behavioral disorders. Future research should explore mechanisms possibly explaining, for example, mental health, social support and priorities regarding work and private life potentially resulting in changes from full‐time to part‐time work or vice versa. The novel findings should change clinical practice and help inform health policies for parents of children with cancer in Sweden and countries with a similar health and welfare system., What's new? Parents of children with cancer experience work disruptions both during and after treatment. However, few studies have examined the socioeconomic consequences for these parents. This study shows that, in Sweden, childhood cancer has negative short‐term effects on fathers' and mothers' earnings, with negative effects for fathers but positive effects for mothers in the long term. Negative effects were found on fathers' and mothers' employment, with stronger effects for mothers in the short term. The novel findings could help inform health policies for parents of children with cancer in Sweden and other countries with a similarly supportive health and welfare system.

The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision‐making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune‐ or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE‐006 and CHECKMATE‐067/‐066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan‐Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population‐based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3‐year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long‐term survival is possible. The prognosis of ineligible patients with advanced melanoma in real‐world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM., What's new? By necessity, randomized controlled trials (RCTs) exclude many patients. However, these ineligible patients are often still treated with new systemic therapies on an individual basis. In this study, the authors examined how various subgroups of ineligible patients fared following treatment for advanced melanoma. They found that several criteria were strongly associated with prognosis in these patients, including lactate dehydrogenase (LDH) levels. These results should provide clinicians with a decision tree of prognostic factors to help guide treatment decisions.

Vaccination against human papillomavirus (HPV) has been introduced as a public health initiative in many countries, including Denmark since October 2008. It is important to monitor postimplementation effectiveness of HPV‐vaccination at the population‐level. We studied HPV‐prevalence after first invitation to screening at age 23 years in women offered the quadrivalent HPV‐vaccine at the age of 14 years. Randomly selected screening samples from women born in 1994 in four out of five Danish regions were subjected to analysis for HPV in addition to routine cytology. Cobas4800 was used in all participating pathology departments. Data from a Danish prevaccination cross‐sectional study using Hybrid Capture 2, and a Danish split‐sample study using Cobas4800 were used for comparison. In the period from February 2017 to April 2019, 6233 screening samples from women born in 1994 were selected for HPV‐analysis; 27 samples had no HPV‐test and 3 samples had no HPV‐diagnosis, leaving 6203 samples with an HPV‐diagnosis. Prevalence of any high‐risk (HR) HPV was 35%; only 0.9% were positive for vaccine HPV types 16/18 while the remaining 34% were positive for other HR HPV. When comparing with prevaccination prevalence data, HPV‐16/18 decreased by 95%; RR = 0.05 (95% CI 0.04‐0.06), while other HR HPV remained fairly constant; RR = 0.88 (95% CI 0.82‐0.94) and RR = 0.95 (95% CI 0.88‐1.03), respectively. One‐third of women vaccinated as girls with the quadrivalent HPV‐vaccine were HR HPV‐positive at time of first invitation to screening. Vaccine HPV‐types 16 and 18 were almost eliminated, while the prevalence of nonvaccine HR HPV‐types remained constant., What's new? Vaccination against human papillomavirus (HPV) has been introduced as a public health initiative in many countries. However, data on HPV infection prevalence at screening age in HPV‐vaccinated birth cohorts remain scarce. This study found that HPV‐16 and 18 were almost eliminated in a population aged 23‐24 years where 92% of women received quadrivalent HPV vaccination at age 14. Prevalence of HPV 16 and 18 was lower in non‐vaccinated women than in previous birth cohorts not offered HPV‐vaccination. Nonetheless, one third of vaccinated women were positive for high‐risk HPV other than 16/18, with potential implications for cervical cancer prevention and screening programs.

Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T‐cell therapy for diffuse large B‐cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T‐cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post‐CAR T‐cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T‐cell therapy may lead to an increase in severity of CRS without decreasing infection rates., What's new Chimeric antigen receptor (CAR) T‐cell therapy in patients with relapsed/refractory diffuse large B‐cell lymphoma is limited by associated cytokine release syndrome, neurotoxicity, and cytopenias. Little is known about the benefits and risks of myeloid growth factor administration in CAR T‐cell therapy. This retrospective analysis reveals a significant increase in the severity but not the incidence of cytokine release syndrome in those patients that received filgrastim. There was no association of filgrastim use with the severity or incidence of neurotoxicity and infection rates. The findings call for caution in the use of myeloid growth factors in patients undergoing CAR T‐cell therapy.

Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy‐induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double‐blind, placebo‐controlled Phase II study in patients with newly diagnosed extensive‐stage small cell lung cancer (ES‐SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian‐based administration (chronoIFLO5) as either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil‐leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first‐ and second‐line settings. Primary endpoints included Grade 3‐4 toxicity rates, best objective response rate (ORR), progression‐free survival (PFS) and overall survival (OS). One‐hundred forty‐nine and 44 patients were treated in first‐line and second‐line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty‐six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2‐70.4] and resulted in median PFS and OS of 8.7 months [7.5‐9.9] and 19.9 months [15.4‐24.5]. Corresponding figures in second line were 37.5% [22.5‐52.5], 6.7 months [4.8‐8.9] and 16.3 months [11.8‐20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity., What's new? Triple chemotherapy of irinotecan, oxaliplatin and fluorouracil‐leucovorin achieves the best survival against metastatic colorectal cancer (CRC) but has worse toxicity than doublet therapy. Chronomodulation is a strategy to reduced toxicity by coordinating drug administration with the patient's circadian rhythm. Here, the authors evaluated the safety and efficacy of chronomodulated triple therapy given over a 5‐day period every 3 weeks. 149 patients received the treatment as a first‐line regimen, while 44 received it as salvage therapy. In both settings, the safety and efficacy of chronomodulated triple therapy were validated, although the optimal timing of irinotecan for minimizing toxicity remains to be determined.

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long‐term prognosis for patients with high‐risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event‐free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease‐free after completion of standard upfront therapy and did not receive DFMO. The 2‐ and 5‐year EFS were 86.4% [95% confidence interval (CI) 79.3%‐94.2%] and 85.2% [77.8%‐93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%‐88.3%] and 65.6% [55.5%‐77.5%] for the historical control group. The 2‐ and 5‐year OS were 98.8% [96.4‐100%] and 95.1% [90.5%‐99.9%] vs 94.4% [89.3%‐99.9%] and 81.6% [73.0%‐91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB., What's new? The long‐term prognosis for patients with high‐risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This phase II clinical trial update is the first study to demonstrate statistically and clinically significant improvement in event‐free and overall survival in HRNB patients as a result of DFMO administration following standard upfront therapy relative to a closely matched historical control. The findings support DFMO maintenance as a novel strategy to prevent relapse in a high‐risk population for relapse following frontline treatment.

Epacadostat is a potent and highly selective inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO1). Here we report results from the open‐label, dose‐escalation, Phase 1b ECHO‐110 study evaluating epacadostat plus atezolizumab in patients with previously treated Stage IIIB/IV nonsmall cell lung cancer (NSCLC). Eligible patients had received ≥1 prior line of platinum‐based chemotherapy (≥2 cycles) and no prior checkpoint/IDO inhibitors treatment. Oral epacadostat (25, 50, 75, 100, 200 or 300 mg) was administered twice daily (BID) with intravenous atezolizumab 1,200 mg every 3 weeks (Q3W). Primary endpoints were safety, tolerability and dose‐limiting toxicities (DLTs). Twenty‐nine patients received ≥1 dose of treatment. The maximum tolerated dose of epacadostat was not reached. Two patients had DLTs: one patient with Grade 3 dehydration and hypotension (epacadostat 200 mg BID); one patient with Grade 3 hyponatremia and Grade 4 autoimmune encephalitis (epacadostat 300 mg BID). Twenty‐three patients (79%) had treatment‐related adverse events (AEs); seven patients (24%) experienced Grade 3/4 events; five patients (17%) discontinued treatment due to treatment‐related AEs. No fatal treatment‐related AEs occurred. One patient achieved a partial response (objective response rate, 3%), which was maintained for 8.3 months; eight patients had stable disease. Baseline tumoral programmed cell death ligand 1 (PD‐L1) and IDO expression were low among patients with evaluable samples (1 of 23 expressed PD‐L1; 5 of 17 expressed IDO). Epacadostat pharmacokinetics was comparable to historical controls. Epacadostat, at doses up to 300 mg BID, combined with atezolizumab 1,200 mg Q3W was well tolerated in patients with previously treated NSCLC, although clinical activity was limited., What's new? There has been considerable interest in investigating combination treatment strategies that target separate but complementary immune‐evasion pathways, in patients with advanced non‐small‐cell lung cancer (NSCLC). The goal is to enhance the efficacy of immune checkpoint inhibitors. In this study, the authors found that combining the IDO1 enzyme inhibitor epacadostat with the PD‐L1 checkpoint inhibitor atezolizumab was generally well tolerated. However, clinical activity was limited. These results provide important insights into the challenges associated with developing combination immunotherapies in NSCLC.

The Dutch colorectal cancer (CRC) screening program started in 2014, inviting the target population biennially to perform a fecal immunochemical test (FIT). We obtained prospectively collected data from the national screening information‐system to present the results of the second round (2016) and evaluate the impact of increasing the FIT cut‐off halfway through the first round from 15 to 47 μg Hb/g feces on outcomes in the second round. Second round screening was done with a 47 μg Hb/g feces FIT cut‐off. Participants were classified based on first round participation status as either FIT (15,47) or FIT (47,47) participants, and previous nonparticipants. In total, 348,891 (75.9%) out of 459,740 invitees participated in the second round. Participation rates were 93.4% among previous participants and 21.0% among previous non‐participants. FIT(47,47) participants had a significantly higher detection rate of AN (15.3 vs. 10.4 per 1,000 participants) compared to FIT(15,47) participants in the second round, while their cumulative detection rate of AN over two rounds was significantly lower (45.6 vs. 52.6 per 1,000 participants). Our results showed that participation in the Dutch CRC screening program was consistently high and that second round detection rates depended on the first round FIT cut‐off. The cumulative detection over two rounds was higher among FIT(15,47) participants. These findings suggest that a substantial part of, but not all the missed findings in the first round due to the increased FIT cut‐off were detected in the subsequent round., What's new? In 2014, the Netherlands implemented colorectal cancer (CRC) screening based on non‐invasive fecal immunochemical testing (FIT), which offers a practical approach for population‐based CRC detection. In the Dutch program's first round, to match local resources, FIT cut‐off was increased, resulting in reduced positivity rates and reduced colonoscopy referrals, at the cost of missing advanced neoplasias. The current study shows that many of these missed advanced neoplasias were detected in subsequent screening, suggesting that increased FIT cut‐off had marginal impact on screening outcome. The findings could benefit other CRC screening programs in establishing effective FIT cut‐offs.

We analyzed data from 738 HER2‐positive metastatic breast cancer (mbc) patients treated with pertuzumab‐based regimens and/or T‐DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression‐free survival at first‐line (mPFS1) was 12 months. Pertuzumab as first‐line conferred longer mPFS1 compared to other first‐line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second‐line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T‐DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs‐negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T‐DM1 in second‐line after pertuzumab were significantly lower compared to pertuzumab‐naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment‐related outcomes of HER2‐positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2‐positive (mbc) patients., What's new? About half of breast cancers positive for human epidermal growth factor (HER2) also express hormone receptors but the impact of hormone receptor status on the success of HER2‐directed treatments is not fully explored. Here the authors retrospectively assessed tumor behavior and treatment outcomes in 738 women with HER2+ metastatic breast cancer treated with new generation anti‐HER2 agents. Distinct hormone receptor expression patterns significantly affected the progression free and overall survival, justifying further studies to define optimal treatment regimens and the interplay between hormone receptor and HER2 signaling.

Cancer stem cells (CSCs) are considered as responsible for initiation, maintenance and recurrence of solid tumors, thus representing the key for tumor eradication. The antitumor activity of extracellular vesicles (EVs) derived from different stem cell sources has been investigated with conflicting results. In our study, we evaluated, both in vitro and in vivo, the effect of EVs derived from human bone marrow mesenchymal stromal cells (MSCs) and from a population of human liver stem cells (HLSCs) of mesenchymal origin on renal CSCs. In vitro, both EV sources displayed pro‐apoptotic, anti‐proliferative and anti‐invasive effects on renal CSCs, but not on differentiated tumor cells. Pre‐treatment of renal CSCs with EVs, before subcutaneous injection in SCID mice, delayed tumor onset. We subsequently investigated the in vivo effect of MSC‐ and HLSC‐EVs systemic administration on progression of CSC‐generated renal tumors. Tumor bio‐distribution analysis identified intravenous treatment as best route of administration. HLSC‐EVs, but not MSC‐EVs, significantly impaired subcutaneous tumor growth by reducing tumor vascularization and inducing tumor cell apoptosis. Moreover, intravenous treatment with HLSC‐EVs improved metastasis‐free survival. In EV treated tumor explants, we observed both the transfer and the induction of miR‐145 and of miR‐200 family members. In transfected CSCs, the same miRNAs affected cell growth, invasion and survival. In conclusion, our results showed a specific antitumor effect of HLSC‐EVs on CSC‐derived renal tumors in vivo, possibly ascribed to the transfer and induction of specific antitumor miRNAs. Our study provides further evidence for a possible clinical application of stem cell‐EVs in tumor treatment., What's new? Stem cell‐derived extracellular vesicles (EVs) can reprogram target cells and promote tissue repair by transferring their cargo. However, the anti‐tumor activity of EVs derived from different stem cell sources has been investigated with conflicting results. Here, the authors demonstrate for the first time the anti‐tumor effect of EVs from human liver stem cells (HLSC‐EVs) in a systemic intravenous administration model. HLSC‐EVs had a selective effect on cancer stem cells that could be ascribed to the transfer and induction of anti‐tumor miRNAs. This study highlights the potential clinical use of stem cell‐derived EVs, alone or in combination with other cancer therapies.

There is uncertainty about the magnitude of the effect of screening mammography on breast cancer mortality. The relevance and validity of evidence from dated randomized controlled trials has been questioned, whereas observational studies often lack a valid comparison group. There is no estimate of the effect of one screening invitation only. We exploited the geographic rollout of the Dutch screening mammography program across municipalities to estimate the effects of one additional biennial screening invitation on breast cancer and all‐cause mortality. Population administrative data provided vital status and cause of death of a cohort of women aged 49–63 in 1995 over 17 years. Linear probability models were used to estimate the mortality effects. We estimated 154 fewer breast cancer deaths (95% confidence interval: 40–267; p = 0.01) over 17 years in a population of 100,000 women aged 49–63 who received one additional biennial screening invitation, which corresponds to an 9.6% risk reduction for a woman of age 56. The estimated effect on all‐cause mortality was negative but not close to statistical significance. Our study shows that one single invitation for breast cancer screening is effective in reducing breast cancer mortality, which is important for health policy. The effect is smaller than previous estimates of the effect of invitation for multiple screens, which further emphasizes the importance of achieving regular participation., What's new? To date, there is still uncertainty about the magnitude of the effect of screening mammography on breast cancer mortality. Here, the authors exploited the geographic rollout of the Dutch screening mammography program and high‐quality national population, cancer, and death registries to avoid limitations of observational research by comparing breast cancer mortality across groups of women of the same age who joined the mammography program at different dates. The analysis provides a unique estimate of the effect of one additional invitation for screening mammography on breast cancer mortality (around 10%) and delivers evidence in favour of the effectiveness of such screening.

In BOLERO‐2, adding everolimus to exemestane resulted in a twofold increase in median progression‐free survival (PFS) vs exemestane in postmenopausal women with hormone receptor‐positive (HR+), human epidermal growth factor receptor 2‐negative (HER2−) advanced breast cancer (aBC) after progression on a non‐steroidal aromatase inhibitor (NSAI). Here, we report on the open‐label, single‐arm, phase IIIB 4EVER trial (NCT01626222). This trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2− aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI, prior chemotherapy for advanced disease or previous exemestane. The primary endpoint was overall response rate (ORR; i.e. the percentage of patients with a best overall response of complete or partial response per RECIST 1.1) within the first 24 weeks of treatment. Secondary endpoints included PFS, overall survival, safety and health‐related quality of life. Between June 2012 and November 2013, 299 patients were enrolled at 82 German centers: 281 patients were evaluable for efficacy and 299 for safety. The ORR was 8.9% (95% confidence interval [CI]: 5.8–12.9%). Median PFS was 5.6 months (95% CI: 5.4–6.0 months). The most frequent grade 3/4 adverse events were stomatitis (8.4%), general physical health deterioration (6.7%), dyspnea (4.7%) and anemia (4.3%). The ORR in 4EVER was lower than in BOLERO‐2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal women with HR+, HER2− aBC., What's new? Current treatment guidelines for HR+, HER2– advanced breast cancer support continued endocrine therapy after progression on first‐line treatment, including the use of everolimus and exemestane combined. Here, the authors report on the phase IIIB 4EVER trial, which evaluated the efficacy, safety and quality of life effects of everolimus plus exemestane in postmenopausal women with pretreated, HR+, HER2– advanced breast cancer. The patient population was broader than that evaluated in previous major trials, and thus more reflective of real‐world practice. Overall, the results confirm the clinical benefits and known safety profile of everolimus plus exemestane in this patient population.

Breast Cancer Screening Program was introduced and rolled out in Morocco in 2010. Women between 40 and 69 years are screened at the primary health centers (PHC) with clinical breast examination (CBE). A comprehensive evaluation of the program was conducted in 2016–2017 for quality assurance and mid‐term course correction. The evaluation process involved: in‐depth interviews of program managers; focus group discussions with service‐providers of screening, diagnosis and treatment; supportive supervisory visits to randomly selected PHCs and diagnostic centers; desk review of the national guidelines and other published documents; and analysis of the performance data compiled by the program‐in‐charge. We found that the program has strong political support, a well‐organized management structure and documented national policy and protocol. In absence of a mechanism to identify and invite the eligible women individually, the program is opportunistic in nature. Every PHC is provided with an annual target to be screened. A highly visible annual campaign to educate and motivate women has a major impact on participation. Record keeping and data collection are paper‐based. In the years 2015 and 2016, 1.1 and 1.5 million women were screened, respectively. In the year 2015, 62.8% of the annual target population was covered, CBE positivity was 3.2%, a further assessment rate of screen‐positive women was 34.1% and the breast cancer detection rate was 1.0/1000 women. Systematic paper‐based data collection enabled the assessment of some of the process and outcome indicators. The screening coverage was moderate and the cancer detection rate was low., What's new? The rising incidence of breast cancer is a tremendous public health challenge in the developing world. Clinical breast examination is a promising approach provided effective diagnosis, timely treatment, and adequate resources. Here, the authors conducted a comprehensive evaluation of the Breast Cancer Screening Program in Morocco, where systematic data collection is challenging in absence of a computerized information system. They found that the program has strong political support and a well‐organized management structure. Systematic paper‐based data collection showed a moderate screening coverage and low cancer detection rate. The experience will be useful for all developing countries implementing clinical breast examination.