(1) Objective: Late-line chemotherapy rechallenge in recurrent cervical cancer is associated with modest therapy response but significant side effects. As mTOR pathways modulate cellular growth via estrogen receptor (ER) signaling and combined mTOR and ER inhibition previously demonstrated survival benefits in breast cancer, this exploratory study evaluates mTOR pathway and ER expression interactions in a preclinical cervical cancer model. (2) Methods: Immunostaining of a 126-tumor core tissue microarray was performed to assess phosphorylated-mTOR and ER expression. To identify tumor subsets with different clinical behavior, expression results were matched with clinicopathologic patient characteristics, and both univariate and multivariable survival statistics were performed. (3) Results: phosphorylated-mTOR correlates with ER (r = 0.309, p < 0.001) and loss of PTEN expression (r = −2.09, p = 0.022) in tumor samples across stages but not in matched negative controls. Positive ER expression is observed significantly more often in phosphorylated-mTOR positive samples (30.0% vs. 6.3%, p = 0.001). In the subgroup of phosphorylated-mTOR positive tumors (n = 60), ER expression is associated with improved survival (p = 0.040). (4) Conclusion: ER expression appears closely intertwined with EGFR/PTEN/mTOR-pathway activation and seems to define a subgroup with clinically distinct behavior. Considering limited therapeutic options in recurrent cervical cancer, further validation of combined mTOR and ER inhibition in selected patients could appear promising.

BackgroundInducing recovery in myocardial ischemia is limited to a timely reopening of infarct vessels and clearing the cardiac microcirculation, but additional molecular factors may impact recovery.ObjectiveIn this scoping review, we identify the paradigm shifts decoding the branching points of experimental and clinical evidence of pressure-controlled intermittent coronary sinus occlusion (PICSO), focusing on myocardial salvage and molecular implications on infarct healing and repair.DesignThe reporting of evidence was structured chronologically, describing the evolution of the concept from mainstream research to core findings dictating a paradigm change. All data reported in this scoping review are based on published data, but new evaluations are also included.ResultsPrevious findings relate hemodynamic PICSO effects clearing reperfused microcirculation to myocardial salvage. The activation of venous endothelium opened a new avenue for understanding PICSO. A flow-sensitive signaling molecule, miR-145-5p, showed a five-fold increase in porcine myocardium subjected to PICSO.Verifying our theory of "embryonic recall," an upregulation of miR-19b and miR-101 significantly correlates to the time of pressure increase in cardiac veins during PICSO (r(2) = 0.90, p < 0.05; r(2 )= 0.98, p < 0.03), suggesting a flow- and pressure-dependent secretion of signaling molecules into the coronary circulation. Furthermore, cardiomyocyte proliferation by miR-19b and the protective role of miR-101 against remodeling show another potential interaction of PICSO in myocardial healing.ConclusionMolecular signaling during PICSO may contribute to retroperfusion toward deprived myocardium and clearing the reperfused cardiac microcirculation. A burst of specific miRNA reiterating embryonic molecular pathways may play a role in targeting myocardial jeopardy and will be an essential therapeutic contribution in limiting infarcts in recovering patients.

<p>Supplementary table legend</p>

<p>Patients characteristics of the overall population</p>

AbstractBottlebrush polymers are highly promising as unimolecular nanomedicines due to their unique control over the critical parameters of size, shape and chemical function. However, since they are prepared from biopersistent carbon backbones, most known bottlebrush polymers are non‐degradable and thus unsuitable for systemic therapeutic administration. Herein, we report the design and synthesis of novel poly(organo)phosphazene‐g‐poly(α‐glutamate) (PPz‐g‐PGA) bottlebrush polymers with exceptional control over their structure and molecular dimensions (Dh ≈ 15–50 nm). These single macromolecules show outstanding aqueous solubility, ultra‐high multivalency and biodegradability, making them ideal as nanomedicines. While well‐established in polymer therapeutics, it has hitherto not been possible to prepare defined single macromolecules of PGA in these nanosized dimensions. A direct correlation was observed between the macromolecular dimensions of the bottlebrush polymers and their intracellular uptake in CT26 colon cancer cells. Furthermore, the bottlebrush macromolecular structure visibly enhanced the pharmacokinetics by reducing renal clearance and extending plasma half‐lives. Real‐time analysis of the biodistribution dynamics showed architecture‐driven organ distribution and enhanced tumor accumulation. This work, therefore, introduces a robust, controlled synthesis route to bottlebrush polypeptides, overcoming limitations of current polymer‐based nanomedicines and, in doing so, offers valuable insights into the influence of architecture on the in vivo performance of nanomedicines.

Abstract Aims Mechanochemical signalling drives organogenesis and is highly conserved in mammal evolution. Regaining recovery in myocardial jeopardy by inducing principles linking cardiovascular therapy and clinical outcome has been the dream of scientists for decades. Concepts involving embryonic pathways to regenerate adult failing hearts became popular in the early millennium. Since then, abundant data on stem cell research have been published, never reaching widespread application in heart failure therapy. Another conceptual access, using mechanotransduction in cardiac veins to limit myocardial decay, is pressure‐controlled intermittent coronary sinus occlusion (PICSO). Recently, we reported acute molecular signs and signals of PICSO activating regulatory miRNA and inducing cell proliferation mimicking cardiac development in adult failing hearts. According to a previously formulated hypothesis, ‘embryonic recall’, this study aimed to define molecular signals involved in endogenous heart repair during PICSO and study their relation to patient survival. Methods and results We previously reported a study on the acute molecular effects of PICSO in an observational non‐randomized study. Eight out of the thirty‐two patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) were treated with PICSO. Survival was monitored over 10 years, and coronary sinus blood samples were collected during intervention before and after 20 min and tested for miRNA signalling and proliferation when co‐cultured with cardiomyocytes. A numerically lower death rate post‐CRT and PICSO as compared with control CRT only, and a non‐significant reduction in all‐cause mortality risk of 42% was observed (37.5% vs. 54.0%, relative risk = 0.58, 95% confidence interval: 0.17–2.05; P = 0.402). Four miRNAs involved in cell cycle, proliferation, morphogenesis, embryonic development, and apoptosis significantly increased concomitantly in survivors and PICSO compared with a decrease in non‐survivors (hsa‐miR Let7b, P < 0.01; hsa‐miR‐ 421, P < 0.006; hsa‐miR 363‐3p, P < 0.03 and hsa‐miR 19b‐3p P < 0.01). In contrast, three miRNAs involved in proliferation and survival, determining cell fate, and recycling endosomes decreased in survivors and PICSO (hsa miR 101‐3p, P < 0.03; hsa‐miR 25‐3p, P < 002; hsa‐miR 30d‐5p P < 0.04). In vitro cellular proliferation increased in survivors and lowered in non‐survivors showing a pattern distinction, discriminating longevity according to up to 10‐year survival in heart failure patients. Conclusions This study proposes that generating regenerative signals observed during PICSO intervention relate to patient outcomes. Morphogenetic pathways induced by periods of flow reversal in cardiac veins in a domino‐like pattern transform embryonic into regenerative signals. Studies supporting the conversion of mechanochemical signals into regenerative molecules during PICSO are warranted to substantiate predictive power on patient longevity, opening new therapeutic avenues in otherwise untreatable heart failure.

In this analysis, we examined the efficacy, feasibility, and limitations of the application of mTOR inhibitors based on the individual molecular profiles of pretreated cancer patients after the failure of all standard treatments in the palliative setting. In this single-center, real-world analysis of our platform for precision medicine, we analyzed the molecular characteristics of 71 cancer patients. The tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite stability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after a consensus discussion. Seventy-one cancer patients with activation of the mTOR pathway were offered an mTORC1-inhibitor-based targeted therapy, and twenty-three (32.4%) of them eventually received the targeted therapy. Only three patients (4.2%) achieved stable disease, of whom one experienced progressive disease again after 9.1 months. The median time to treatment failure was 2.8 months. In total, 110 mutations were detected in 60 patients (84.5%). The three most frequent mutations were found in TP53, PTEN, and KRAS, which accounted for over 50% (56.4%) of all mutations. In sum, in selected patients with heavily pretreated solid tumors with activation of the mTOR pathway, the antitumoral activity of mTORC1 inhibition was weak.

Precision medicine strives to optimize health by delivering care tailored to each person’s unique biology. The striking heterogeneity of inflammatory bowel disease (IBD) in phenotypic presentation, disease course, and treatment response renders it ideally suited to benefit from precision medicine approaches. Despite recent innovative research, implementations of truly tangible precision medicine applications in IBD are few. Although the past 20 years have ushered in a slew of novel therapies, our ability to use them in a rational, biology-driven fashion remains fairly crude. Although the limitations of a one-size-fits-all approach in IBD are widely acknowledged, clinical practice has struggled to move meaningfully beyond them. In this regard, the IBD community must cover substantial ground to catch up with other fields, such as oncology. Despite the important differences between cancer and IBD, including the clonal nature of malignancy, the IBD community can still glean important lessons from the successes of precision oncology. Here, we review some of the major barriers to progress in precision IBD and propose calls to action while drawing on precision oncology for insights. We have omitted certain generic challenges, such as the need for harmonization, global data sharing, and ethical/privacy considerations, which are reviewed elsewhere,1Denson L.A. Curran M. McGovern D.P.B. et al.Challenges in IBD research: precision medicine.Inflamm Bowel Dis. 2019; 25: S31-S39Crossref PubMed Scopus (39) Google Scholar,2Liu X. Luo X. Jiang C. et al.Difficulties and challenges in the development of precision medicine.Clin Genet. 2019; 95: 569-574Crossref PubMed Scopus (20) Google Scholar focusing on challenges specific to precision IBD (Figure 1). A fundamental first challenge is that current IBD diagnostic and classification schemes, such as the Lennard-Jones criteria and Montreal classification,3Silverberg M.S. Satsangi J. Ahmad T. et al.Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol. 2005; 19: 5A-36ACrossref PubMed Scopus (2350) Google Scholar do not capture the significant heterogeneity of IBD. Even the segregation of IBD into Crohn’s disease (CD), ulcerative colitis (UC), and the ill-defined entity IBD-unclassified is a vast oversimplification of complex pathophysiologic processes. More than 240 genetic risk variants interact with epigenetic, immunologic, and microbial factors, under the influence of dynamic environmental exposures, to elicit the rich array of clinical manifestations of IBD.4Chang J.T. Pathophysiology of inflammatory bowel diseases.N Engl J Med. 2020; 383: 2652-2664Crossref PubMed Scopus (138) Google Scholar The narrow focus of existing diagnostic/classification systems on phenotypic features, such as disease location and behavior, and their constraint by categorical definitions of CD as discontinuous and transmural and of UC as continuous and mucosal prevent them from encompassing and meaningfully describing the full breadth of IBD. One potential approach is to reorganize the clinical criteria that make up existing classification systems. For example, a novel index including a subset of the Lennard-Jones criteria was shown to better distinguish CD from UC than the original criteria.5Reinisch S. Schweiger K. Pablik E. et al.An index with improved diagnostic accuracy for the diagnosis of Crohn’s disease derived from the Lennard-Jones criteria.Aliment Pharmacol Ther. 2016; 44: 601-611Crossref PubMed Scopus (2) Google Scholar However, a solution that leverages molecular characterization will almost certainly be better equipped to capture and delineate the numerous distinct IBD subtypes. Work from the International IBD Genetics Consortium, which examined associations between genetic risk scores and IBD subphenotypes, supported a continuum of disorders better explained by three IBD subgroups (ileal CD, colonic CD, and UC) compared with the traditional 2 subgroups (CD and UC).6Cleynen I. Boucher G. Jostins L. et al.Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study.Lancet. 2016; 387: 156-167Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar Here, there are lessons to take from oncology’s playbook. At comprehensive cancer centers, systematic molecular tumor characterization, especially for genetic aberrations using next-generation sequencing, is the standard of care. Malignancies are not solely defined by qualitative descriptors but also by their genetic architecture. In many cases, these molecular signatures can be used to risk-stratify patients and to select biology-specific treatment regimens.7Malone E.R. Oliva M. Sabatini P.J.B. et al.Molecular profiling for precision cancer therapies.Genome Med. 2020; 12: 8Crossref PubMed Scopus (187) Google Scholar The success of this approach in oncology has hinged on the availability of large numbers of novel targeted drugs; in 2020 alone, 21 therapeutic compounds were approved by the US Food and Drug Administration.8New oncology drug approvals in 2020.Clinical Oncology News. December 15, 2020; (Available at:) (Accessed December 11, 2021)https://www.clinicaloncology.com/FDA-Watch/Article/12-20/New-Oncology-Drug-Approvals-in-2020/61464Google Scholar It is time to move beyond our current phenotypically driven IBD classification to outline the molecular blueprint of IBD and to reveal all its subtypes, each likely with a distinct disease trajectory and treatment response profile. Thus, molecularly defined subphenotypes can be explored for their ability to predict prognosis and likelihood of treatment response, which are central goals in precision IBD. Although past studies have largely sought to identify biomarkers that align with conventional IBD types/phenotypes (eg, CD vs UC, ileal vs colonic CD), we must instead define novel IBD subtypes that align with molecular biomarkers. Important tools to accomplish this will include unsupervised clustering methods9Shen R. Mo Q. Schultz N. et al.Integrative subtype discovery in glioblastoma using iCluster.PLoS One. 2012; 7e35236Crossref Scopus (162) Google Scholar and systems biology methods that conceptualize IBD pathogenesis as a network rather than linear interactions, thus emphasizing nodes amenable to therapeutic interventions. Broad racial/ethnic representation and longitudinal assessment will be vital to capture the heterogeneity of IBD. Any novel biomarkers or precision medicine tools, whether for classification or other purposes (eg, prognosis, treatment response), will need to be the product of processes that ensure reproducibility. Industry collaborations can facilitate standardized access to samples under monitored conditions. Classic endoscopic, histologic, and radiographic assessment will continue to play an important, but perhaps complementary, role in IBD classification. Emerging approaches, such as artificial intelligence (AI) methods, including computer vision and deep learning/neural networks, can help to automate, standardize, and enhance the reproducibility of these traditional assessments and aid in identifying novel subgroups by detecting patterns not previously discernible.10Chahal D. Byrne M.F. A primer on artificial intelligence and its application to endoscopy.Gastrointest Endosc. 2020; 92: 813-820Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,11van der Laak J. Litjens G. Ciompi F. Deep learning in histopathology: the path to the clinic.Nat Med. 2021; 27: 775-784Crossref PubMed Scopus (64) Google Scholar The big data multiomics approach advocated here is not without its own inherent challenges, including the small effect sizes of many analytic measures, such as the majority of genetic variants,12McGovern D.P.B. Kugathasan S. Cho J.H. Genetics of inflammatory bowel diseases.Gastroenterology. 2015; 149: 1163-1176Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar relative to intersubject heterogeneity. This mandates processes to reconcile statistical and clinical significance (one should not be equated with the other) and to integrate numerous—at times, seemingly disparate—effects into a cohesive model that explains biological phenomena. In addition, although current technologies allow us to probe many multiomics facets of IBD, modalities to quantify the exposome remain limited—a real challenge given the very significant effect of the environment on IBD pathophysiology and likely on treatment response. A second challenge is the lack of criterion standard, precision medicine–appropriate endpoints. Such endpoints must be objective, clearly defined, reproducible, attainable within a sensible timeframe, and deeply rooted in disease biology and, thus, causally associated with clinically meaningful long-term outcomes. Clinical activity indices, despite being highly relevant for patients and regulatory agencies, are not suitable, given their subjective nature and imperfect correlation with inflammatory activity. Even seemingly “hard” outcomes, such as surgery, hospitalization, and treatment escalation, are suboptimal because they lack standardized definitions and may reflect physician practices and/or patient preferences. Regulatory agencies are increasingly embracing objective outcomes, such as endoscopy and histology in trial design, but have simultaneously mandated patient-reported outcomes (PROs) as coprimary endpoints.13Williet N. Sandborn W.J. Peyrin-Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease.Clin Gastroenterol Hepatol. 2014; 12: 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Although the importance of the patient experience cannot be undermined, PROs capture a construct driven not only by inflammation but by myriad other influences (eg, anatomy, diet, microbiome, functional processes). As such, the juxtaposition of PROs and endpoints like mucosal healing dilutes the objectivity of the latter. The differential biological determinants of clinical activity and endoscopic healing are illustrated by the PROgECT trial, in which a colonic gene expression signature predicted mucosal healing in patients with UC treated with golimumab while showing no association with clinical response or remission.14Telesco S.E. Brodmerkel C. Zhang H. et al.Gene expression signature for prediction of golimumab response in a phase 2a open-label trial of patients with ulcerative colitis.Gastroenterology. 2018; 155: 1008-1011Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar An additional unknown is the optimal timepoint at which to assess outcomes for each therapy, reflecting our incomplete understanding of pharmacodynamics. We must also account for variability in drug exposure because this can obscure the interpretation of changes in molecular and cellular pharmacodynamic markers of treatment response. A fundamental first step is for the IBD community to achieve consensus on a core set of precision medicine–appropriate endpoints to be systematically applied across studies. Although overlap is to be expected with endpoints identified through initiatives such as Selecting Therapeutic Targets in IBD (STRIDE),15Turner D. Ricciuto A. Lewis A. et al.STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.Gastroenterology. 2021; 160: 1570-1583Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar discrepancies are anticipated (regarding PROs, for example), which must be reconciled moving forward. Although endoscopic, histologic, and radiographic endpoints are likely the most objective and appropriate of currently available outcome measures, they are far from perfect. None encapsulates the totality of the concepts of inflammatory burden, disease severity, and prognosis, and all have operational challenges, such as optimal indices/cutoffs and training standards.16Gottlieb K. Daperno M. Usiskin K. et al.Endoscopy and central reading in inflammatory bowel disease clinical trials: achievements, challenges and future developments.Gut. 2021; 70: 418-426PubMed Google Scholar As previously alluded to, AI may facilitate the reproducible interpretation of image-based outcomes and assist with the development of novel instruments. Ultimately, the IBD community must develop novel endpoints more tailored to the needs of precision medicine. Molecular biomarkers (eg, a molecular inflammatory score based on intestinal gene expression)17Argmann C. Tokuyama M. Ungaro R.C. et al.Molecular characterization of limited ulcerative colitis reveals novel biology and predictors of disease extension.Gastroenterology. 2021; 161: 1953-1968Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar warrant exploration because they have a more direct relationship to disease biology. Peripheral biomarkers from blood, stool, urine, etc represent the holy grail because their easy collection allows more frequent monitoring and treatment adjustment. In oncology, bioengineering advances in micro- and nanofluidics have enabled peripheral blood-based biomarkers, such as liquid biopsies, from which circulating tumor cells can be isolated. Biosensors and wearables offer the advantage of continuous monitoring with instantaneous feedback. Such emerging technologies hold great promise to revolutionize the way in which we measure treatment success in IBD.18Ho D. Quake S.R. McCabe E.R.B. et al.Enabling technologies for personalized and precision medicine.Trends Biotechnol. 2020; 38: 497-518Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar A major limitation of studies to date is the lack of longitudinal assessment. Prospective, longitudinal studies are needed to validate prognostic, predictive, and outcome biomarkers. In addition, longitudinal serial assessment is necessary to elucidate the temporal evolution of biomarkers in relation to disease stage and severity, as well as treatment response. A common shortcoming of studies has been a failure to account for patient differences in disease duration/severity and treatment, all of which are likely to affect disease biology and molecular profiles. Prospective longitudinal follow-up of inception cohorts, with initial sampling of treatment-naive patients and subsequent repeated sampling as the disease evolves and is treated, is likely the design best suited to address this. Serial sampling is vital because short-term changes in biomarkers may better predict long-term outcomes than single baseline parameters.19Waljee A.K. Liu B. Sauder K. et al.Predicting corticosteroid-free endoscopic remission with vedolizumab in ulcerative colitis.Aliment Pharmacol Ther. 2018; 47: 763-772Crossref PubMed Scopus (49) Google Scholar,20Waljee A.K. Liu B. Sauder K. et al.Predicting corticosteroid-free biologic remission with vedolizumab in Crohn’s disease.Inflamm Bowel Dis. 2018; 24: 1185-1192Crossref PubMed Scopus (33) Google Scholar Although inception cohort studies are the criterion standard, they are hugely resource intensive. Accordingly, we must strive to develop infrastructure and protocols to accomplish similar objectives by leveraging clinical care processes. The widespread implementation of electronic health records (EHRs) can greatly facilitate the use of routinely collected health data to ascertain longitudinal phenotypes, exposures, and outcomes, variables for which we must establish standardized definitions to optimize efficiency and accuracy. Coupling this approach to standardized biospecimen collection at key timepoints during routine follow-up presents an opportunity to democratize precision medicine studies to include more community-based centers. This recruitment strategy increases the potential “audience,” enhancing study power, and, importantly, helps include a more representative spectrum of IBD severity. Powerful tools result from the union of EHRs and machine learning, particularly deep learning. Deep learning is well suited for medical data because it can identify patterns in sparse, noisy data and requires little input-feature engineering.21Norgeot B. Glicksberg B.S. Butte A.J. A call for deep-learning healthcare.Nat Med. 2019; 25: 14-15Crossref PubMed Scopus (98) Google Scholar Nelson et al22Nelson C.A. Butte A.J. Baranzini S.E. Integrating biomedical research and electronic health records to create knowledge-based biologically meaningful machine-readable embeddings.Nat Commun. 2019; 10: 3045Crossref PubMed Scopus (17) Google Scholar have developed a method to embed clinical features from EHRs into a heterogeneous knowledge network, termed the Scalable Precision Medicine Oriented Knowledge Engine (SPOKE), which integrates data from 29 publicly available databases, effectively creating medically relevant “barcodes” for individual medical variables in EHRs that map onto SPOKE. These high-dimensional, knowledge-guided patient health signatures have been used as features in random forest modeling to recognize prodromal features of disease, such as multiple sclerosis, several years before diagnosis.23Nelson C.A. Bove R. Butte A.J. et al.Embedding electronic health records onto a knowledge network recognizes prodromal features of multiple sclerosis and predicts diagnosis.J Am Med Inform Assoc. 2022; 29: 424-434Crossref PubMed Scopus (3) Google Scholar Norgeot et al24Norgeot B. Glicksberg B.S. Trupin L. et al.Assessment of a deep learning model based on electronic health record data to forecast clinical outcomes in patients with rheumatoid arthritis.JAMA Network Open. 2019; 2e190606Crossref PubMed Scopus (76) Google Scholar have also leveraged machine learning and structured EHR data to predict future outcomes in patients with rheumatoid arthritis. The concept of repeated biological sampling, recognizing spatiotemporal disease evolution, is well established in precision oncology. When a patient’s cancer relapses, its molecular underpinnings are assumed to have shifted; the tumor is resampled and reanalyzed for molecular alterations, and therapies are adjusted accordingly. This is possible because drugs have been developed that directly target specific aberrations. Similarly, molecular characterization at a single timepoint for the purpose of treating IBD is potentially insufficient and may need to be repeated at the time of relapse. For example, such repeated sampling can help elucidate the molecular shift in patients previously responsive to an antitumor necrosis factor who have lost the response to this mechanism of action despite adequate drug exposure and the absence of immunogenicity. A significant translational gap separates precision medicine discovery and implementation in IBD. A leading contributing factor is the current model of discovery by siloed academic groups. Although this has led to numerous novel and groundbreaking discoveries, it is not a pathway that typically culminates in biomarkers that are robustly validated, reproducible according to technical standards, approved by regulatory bodies, and widely available and reimbursed, all prerequisites for global acceptance and implementation. Oncology again leads by example, having developed a model that incorporates biomarkers into drug development programs, including companion diagnostics. As an example, pembrolizumab was shown to be efficacious for non–small-cell lung cancer tumors that express the marker programmed death ligand 1 (PD-L1) in ≥50% of cells.25Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5718) Google Scholar In this randomized controlled trial, PD-L1 was measured using a commercially available companion diagnostic.25Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5718) Google Scholar As a result, both pembrolizumab and its companion diagnostic have received regulatory approval for this indication. To accommodate the inclusion of biomarkers, oncology trials have undergone a major shift in design. Several novel biomarker-focused trial designs have been developed and are reviewed elsewhere.26Hu C. Dignam J.J. Biomarker-driven oncology clinical trials: key design elements, types, features, and practical considerations.JCO Precis Oncol. 2019; 3 (PO.19.00086)Google Scholar By comparison, biomarker-driven trials remain rare in IBD. Although industry-partnered research programs that intertwine drug and biomarker development, with a focus on biomarker-driven trials, represent one arm of the solution, much work remains on the clinical implementation side. Decision support tools are needed to guide clinicians on which tests to perform and how to apply results. One example of this is the decision tool incorporating clinical, genetic, and serologic markers for predicting disease progression in CD.27Siegel C.A. Horton H. Siegel L.S. et al.A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables.Aliment Pharmacol Ther. 2016; 43: 262-271Crossref PubMed Scopus (66) Google Scholar Molecular tumor boards, interdisciplinary meetings during which experts achieve consensus on how to translate complex biological data into concrete clinical recommendations, have been widely adopted in oncology. An analogous approach may be of great utility in IBD, and virtual communication platforms can facilitate access to necessary experts. Mechanisms must also be put in place to migrate these data to EHRs so that they are available for health care providers and patients to make informed decisions on biomarker-aided clinical strategies. Feasibility and cost-effectiveness are not challenges to be diminished. Cost-effectiveness studies are, in fact, entirely lacking in the precision IBD space and represent an important area in need of future research. The costs of bringing precision medicine applications to the clinic can be colossal and prohibitive in some cases. This is especially true because large randomized controlled trials are the criterion standard to establish effectiveness before implementation. Nevertheless, a whole blood gene expression profile that has been associated with more severe CD is being used to stratify patients to a more aggressive treatment approach vs the standard of care in a randomized controlled trial in the first study of its kind28Biasci D. Lee J.C. Noor N.M. et al.A blood-based prognostic biomarker in IBD.Gut. 2019; 68: 1386-1395Crossref PubMed Scopus (78) Google Scholar,29Lee J.C. Lyons P.A. McKinney E.F. et al.Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis.J Clin Invest. 2011; 121: 4170-4179Crossref PubMed Scopus (201) Google Scholar (discussed later). That said, certain interventions where the balance is highly weighted toward benefit over risk and cost may be suitable for implementation even without costly randomized controlled trials. Examples that may be ready for prime time include screening for NUDT15 variants, which are associated with thiopurine-induced myelosuppression, before medication initiation, particularly in patients of East Asian ancestry as well as the use of HLA-DQA1∗05–based assays to determine people at high risk of developing immunogenicity to anti–tumor necrosis factor (TNF) therapies.30Walker G.J. Harrison J.W. Heap G.A. et al.Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease.JAMA. 2019; 321: 773-785Crossref PubMed Scopus (73) Google Scholar,31Sazonovs A. Kennedy N.A. Moutsianas L. et al.HLA-DQA1∗05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn’s disease.Gastroenterology. 2020; 158: 189-199Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar The success of precision oncology would not have been possible without access to drugs with multiple mechanisms of action. This will likely be true in IBD as well. Fortunately, numerous novel biologics and small molecules are in the IBD pipeline. However, with increasing therapeutic options comes the threat of careless cycling through medications without attempts to optimize drug performance. Even with the handful of currently available agents, it is likely that we can substantially improve outcomes by optimizing their use. To maximize drug optimization, we must deepen our limited understanding of drug mechanisms of action, including counterregulatory processes. In a study published more than 20 years ago, almost all 24 patients with CD treated with a single infliximab infusion achieved clinical remission at 1 week, and TNF secretion was undetectable within a day, suggesting almost universal efficacy of the anti-TNF mechanism.32Nikolaus S. Raedler A. Kühbacker T. et al.Mechanisms in failure of infliximab for Crohn’s disease.Lancet. 2000; 356: 1475-1479Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar However, all patients subsequently experienced a recurrence of symptoms at variable timepoints, preceded by a rise in TNF. Greater insight into the processes that prompt a loss of response in specific patients at specific timepoints, potentially even very early after treatment initiation, could enable individualized drug regimens that prevent such loss of response. Between 2008 and 2013, 26% of oncology trials investigated combination therapy to maximize efficacy, compared to <7% of nononcology trials.33Wu M. Sirota M. Butte A.J. Chen B. Characteristics of drug combination therapy in oncology by analyzing clinical trial data on ClinicalTrials.gov.Pac Symp Biocomput. 2015; : 68-79PubMed Google Scholar We have repeatedly witnessed a ceiling effect in IBD clinical trials; therapeutic regimens that combine multiple biologics and/or small molecules may represent one way to break through. Such combination therapy appears intuitive when considering the multifactorial nature of IBD and the intricacies and redundancies of the immune system. Illustrating the concept of redundancy, using single-cell RNA sequencing, Smillie et al34Smillie C.S. Biton M. Ordovas-Montanes J. et al.Intra- and inter-cellular rewiring of the human colon during ulcerative colitis.Cell. 2019; 178: 714-730Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar found that oncostatin M phenocopies TNF in UC and that this might be one of the mechanisms of anti-TNF resistance, a finding that might inform subsequent treatment strategies. The rising number of drugs greatly complicates the task of treatment selection, especially when considering combination regimens. AI-based methods could assist. One example is personalized phenotypic medicine, which can be used to predict optimal drug dosing for efficacy and safety using relatively few data points from the treated patient only.18Ho D. Quake S.R. McCabe E.R.B. et al.Enabling technologies for personalized and precision medicine.Trends Biotechnol. 2020; 38: 497-518Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Throughout this commentary, we have turned to precision oncology as a paradigm to inform steps forward in IBD. Although we acknowledge that cancer may be uniquely suited to precision medicine applications given its clonal nature and the chance to identify and to therapeutically address molecular drivers, we remain convinced that there are important lessons to learn from our oncology colleagues and that it is precisely the differences between cancer and IBD that allow these lessons to stand out. Other chronic immune-mediated diseases may appear to be more intuitive comparators, but they suffer from many of the same challenges as IBD. That said, conditions such as the inflammatory arthritides have witnessed important successes on the precision medicine front, some of which may have direct applications to IBD, such as markers of treatment response or prognostic markers. As an example, PreductSURE IBD,35PredictImmune. PredictSURE IBD.https://www.predictimmune.com/predictsureibd/Google Scholar a commercially available 17-gene quantitative polymerase chain reaction–based blood assay intended to identify IBD patients at high risk of early and frequent relapse, is based on a T-cell exhaustion signature that was first linked to prognosis in autoimmune conditions such as systemic lupus erythematosus and anti-neutrophilic cytoplasmic autoantibody–positive vasculitis.36McKinney E.F. Lee J.C. Jayne D.R.W. et al.T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.Nature. 2015; 523: 612-616Crossref PubMed Scopus (0) Google Scholar The availability of multiomics data and computational proficiency will continue to grow exponentially over the coming years, extending the boundaries of what is achievable for IBD precision medicine. A concerted effort by the IBD community to overcome the obstacles discussed here is necessary to achieve the full potential of precision medicine for patients with IBD as it concerns disease classification/prediction, endpoints, longitudinal assessment, translational commitment, and therapeutic insights. These efforts must engage all parts of the IBD family, including patients, clinicians, and scientists, and should embrace advances from other disciplines even beyond inflammation/immunity to substantiate and ensure wide reach of the benefits of precision IBD.

AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77–196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was −7.2% (95% CI [−10.4 to −3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%. Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. EudraCT: 2015-001719-11. ClinicalTrials.govIdentifier: NCT02508896.

Purpose As critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose–toxicity relation. Methods From six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject). Results After extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay. Conclusion Surgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.

Oxaliplatin is a very potent platinum(ii) drug which is frequently used in poly-chemotherapy schemes against advanced colorectal cancer. However, its benefit is limited by severe adverse effects as well as resistance development. Based on their higher tolerability, platinum(iv) prodrugs came into focus of interest. However, comparable to their platinum(ii) counterparts they lack tumor specificity and are frequently prematurely activated in the blood circulation. With the aim to exploit the enhanced albumin consumption and accumulation in the malignant tissue, we have recently developed a new albumin-targeted prodrug, which supposed to release oxaliplatin in a highly tumor-specific manner. In more detail, we designed a platinum(iv) complex containing two maleimide moieties in the axial position (KP2156), which allows selective binding to the cysteine 34. In the present study, diverse cell biological and analytical tools such as laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS), isotope labeling, and nano-scale secondary ion mass spectrometry (NanoSIMS) were employed to better understand the in vivo distribution and activation process of KP2156 (in comparison to free oxaliplatin and a non-albumin-binding succinimide analogue). KP2156 forms very stable albumin adducts in the bloodstream resulting in a superior pharmacological profile, such as distinctly prolonged terminal excretion half-life and enhanced effective platinum dose (measured by ICP-MS). The albumin-bound drug is accumulating in the malignant tissue, where it enters the cancer cells via clathrin- and caveolin-dependent endocytosis, and is activated by reduction to release oxaliplatin. This results in profound, long-lasting anticancer activity of KP2156 against CT26 colon cancer tumors in vivo based on cell cycle arrest and apoptotic cell death. Summarizing, albumin-binding of platinum(iv) complexes potently enhances the efficacy of oxaliplatin therapy and should be further developed towards clinical phase I trials.

Recurrent/metastatic head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and gender and molecular aspects of targeted therapy recommendations based on the patients' molecular tumor profile after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with recurrent/metastatic head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, MSI testing, immunohistochemistry, and cytogenetic analysis. In total, we detected 97 mutations in 40 patients. The five most frequent mutations were TP53 (n=21; 21.6%), CDKN2A (n=5; 5.1%), PIK3CA (n=5; 5.1%), NOTCH1 (n=4; 4.1%) and PTEN (n=4; 4.1%) that accounted for 40.2% of all mutations. 5 gene-fusions were identified, namely EIF3E - RSPO2 (n=2), FNDC3B - PIK3CA, MON2-RAP1GDS1, MYBL1-NFIB. IHC detected frequent expressions of EGFR, phosphorylated mTOR and PD-L1 in 33 (66.0%), 29 (58.0%) and 14 patients (28.0%), respectively. In 30 cases (60.0% of all patients) a molecular driven targeted therapy approach could be recommended. In over two-thirds of all recommendations (n=22/30, 73.3%), the molecular-driven treatment approach was derived from the molecular characteristics determined by immunohistochemistry. The three most recommended treatments included cetuximab (n=10), pembrolizumab (n=6), and crizotinib (n=3). Eventually, eight patients (16%) received the recommended therapy and underwent radiological assessment. Four patients (8%) experienced progressive disease and the other four patients achieved stable disease. Therapy recommendations were significantly more often issued for men (p=0.043) than for women due to gender specific differences in the molecular profile. This analysis demonstrated that precision medicine was feasible and provided molecular-driven therapy recommendations in over half of the patients. Further it underscored the relevance of immunohistochemistry in precision medicine. Our analysis revealed gender-specific differences in therapy recommendation.

Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients’ molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men (p = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome.

Advanced therapy-refractory solid tumors bear a dismal prognosis. By analyzing the molecular profile of advanced tumors, targetable molecular alterations may allow a molecular-driven treatment approach. In this analysis, we evaluated feasibility as well as gender and molecular aspects of targeted therapy recommendations based on the respective molecular tumor profile after failure of all standard treatments in patients with different types of advanced solid tumors. In this single center, real-world retrospective analysis of our precision medicine platform MONDTI, we described the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors passing a threshold of 10 patients per tumor type. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, MSI testing, immunohistochemistry, and cytogenetic analysis. In 304 cases (54.9% of all patients) a molecular driven targeted therapy approach could be recommended - mainly (in 86.2% of all cases) derived from the molecular characteristics determined by immunohistochemistry - with a recommendation rate above 50% in 12 tumor entities. The five highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), male reproductive cancers (71.4%), tumors of the central nervous system (67.8%), and head and neck cancer (65.9%). Tumor type (p=0.46), expression of p-mTOR (p=0.011), expression of EGFR (p=0.046), and expression of PD-L1 (p=0.023) had a significant impact on the targeted therapy recommendation rate. Targeted therapy recommendations were significantly more often issued for men (p = 0.015) due to gender specific differences in the molecular profile of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrated that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.

Summary Background Advanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies. Methods In this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies. Results We identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p‑mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months. Conclusion A total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.

In this analysis, we examined the efficacy, feasibility, and limitations of molecular-based targeted therapies in heavily pretreated metastatic colorectal cancer (mCRC) patients after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we mapped the molecular profiles of 60 mCRC patients. Tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite instability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after consensus discussion. In total, we detected 166 mutations in 53 patients. The five most frequently found mutations were TP53, KRAS, APC, PIK3CA, and PTEN. In 28 cases (47% of all patients), a molecularly targeted therapy could be recommended. Eventually, 12 patients (20%) received the recommended therapy. Six patients (10%) had a clinical benefit. The median time to treatment failure was 3.1 months. Our study demonstrates the feasibility and applicability of using targeted therapies in daily clinical practice for heavily pretreated mCRC patients. This could be used as a targeted treatment option in half of the patients.

Introduction Advanced therapy-refractory biliary tract cancer (BTC) has poor prognosis and constitutes a major challenge for adequate treatment strategies. By mapping the molecular profiles of advanced BTC patients, precision cancer medicine may provide targeted therapies for these patients. Objective In this analysis, we aimed to show the potential of PCM in metastatic BTC. Methods In this single-center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 30 patients diagnosed with different types of metastatic BTC. Tumor samples of the patients were examined using a 161-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for chromosomal translocations. Results In total, we identified 35 molecular aberrations in 30 patients. The predominant mutations were KRAS ( n = 8), TP53 ( n = 7), IDH2 ( n = 4), and IDH1 ( n = 3) that accounted for the majority of all molecular alterations (62.86%). BRAF mutations were observed in two patients. Less frequent alterations were noted in ARID1A , CTNNB1 , ESR1 , FBXW7 , FGFR2 , MET , NOTCH2 , PIK3CA , PTCH1 , SMAD4 , and SRC1 , each in one case. FGFR fusion gene was detected in one patient. No mutations were detected in eight patients. IHC revealed EGFR and p-mTOR expression in 28 patients. Applying these results to our patients, targeted therapy was recommended for 60% of the patients ( n = 18). One patient achieved stable disease. Conclusions PCM is a feasible treatment approach and may provide molecular-guided therapy recommendations for metastatic BTC.

Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis despite systemic chemotherapy. In our platform for precision medicine, we aimed to offer molecular-guided treatments to patients without further guideline-based therapy options. In this single-center, real-world, retrospective analysis of our platform, we describe the molecular-based therapy approaches in 50 patients diagnosed with therapy refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing panel, immunohistochemistry, fluorescence in situ hybridization and RNA fusion panel. To assess the impact of the molecular portrait on the molecular guided therapy recommendation, a binary logistic regression was performed. A p-value of less than 0.05 was considered statistically significant. In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n=40; 80%), TP53 (n=29; 58%), CDKN2A (n=8; 16%), SMAD4 (n=4; 8%) and NOTCH1 (n=4; 8%), which accounted for more than half of all mutations (69.1%). BRCA2 mutation was observed in two patients. Two patients had gene-fusions, namely TBL1XR1-PIK3CA and EIF3E-RSPO2. 22 patients (44%) were found to have only one mutation and 13 patients (26%) had more than one mutation. No mutations were found in two patients. IHC detected expression of EGFR, phosphorylated mTOR and PTEN in 36 (72%), 33 (66%) and 17 patients (34%), respectively. One patient was HER2-positive. Expressions of estrogen-receptor and progesterone-receptor were seen in one patient. For 14 (28%) of the 50 patients, targeted therapy was suggested, based on the identified molecular targets. The recommended treatments included everolimus (n=3), pembrolizumab (n=3), palbociclib (n=2) and cetuximab, crizotinib, FLT3 inhibitor, nintedanib, tamoxifen, and the combination of lapatinib and trastuzumab, each in one patient. The turnaround time from biopsy to molecular profiling was around 5 weeks (36 days). The turnaround time from biopsy to therapy initiation was about 8 weeks (61 days). Eventually, 6 patients received the recommended therapy. Five patients died while receiving the therapy prior to disease restaging. One patient was treated with nintedanib and achieved stable disease for 6 months. The binary logistic regression revealed that the expression of phosphorylated mTOR significantly influenced and informed the molecular-driven treatment recommendations in our cohort (p = 0.037). The number of mutations per patient and the expressions of EGFR and PTEN were not statistically significant. Based on our observations, it seems that the expression of phosphorylated mTOR might play a clinically relevant role in the personalized treatment of therapy refractory mPDAC and should be evaluated in further clinical trials.

Introduction Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. Patients and Methods In this single-center, real-world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next-generation sequencing panel and immunohistochemistry (IHC). Results In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). Conclusion Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. Implications for Practice Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy-refractory gynecologic malignancy to offer molecular-based treatment concepts.