Therapeutic Decisions For Individual Patients Research Articles

Development and validation of a nomogram for predicting survival of breast cancer patients with ipsilateral supraclavicular lymph node metastasis.

Background:Breast cancer patients with ipsilateral supraclavicular lymph node metastasis (ISLNM) but without distant metastasis are considered to have a poor prognosis. This study aimed to develop a nomogram to predict the overall survival (OS) of breast cancer patients with ISLNM but without distant metastasis.Methods:Medical records of breast cancer patients who received surgical treatment at the Affiliated Cancer Hospital of Zhengzhou University, Jiyuan People's Hospital and Huaxian People's Hospital between December 21, 2012 and June 30, 2020 were reviewed retrospectively. Overall, 345 patients with pathologically confirmed ISLNM and without evidence of distant metastasis were identified. They were further randomized 2:1 and divided into training (n = 231) and validation (n = 114) cohorts. A nomogram to predict the probability of OS was constructed based on clinicopathologic variables identified by the univariable and multivariable analyses. The predictive accuracy and discriminative ability were measured by calibration plots, concordance index (C-index), and risk group stratification.Results:Univariable analysis showed that estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), human epidermal growth factor receptor 2-positive (HER2+) with Herceptin treatment, and a low axillary lymph node ratio (ALNR) were prognostic factors for better OS. PR+, HER2+ with Herceptin treatment, and a low ALNR remained independent prognostic factors for better OS on multivariable analysis. These variables were incorporated into a nomogram to predict the 1-, 3-, and 5-year OS of breast cancer patients with ISLNM. The C-indexes of the nomogram were 0.737 (95% confidence interval [CI]: 0.660–0.813) and 0.759 (95% CI: 0.636–0.881) for the training and the validation cohorts, respectively. The calibration plots presented excellent agreement between the nomogram prediction and actual observation for 3 and 5 years, but not 1 year, OS in both the cohorts. The nomogram was also able to stratify patients into different risk groups.Conclusions:In this study, we established and validated a novel nomogram for predicting survival of patients with ISLNM. This nomogram may, to some extent, allow clinicians to more accurately estimate prognosis and to make personalized therapeutic decisions for individual patients with ISLNM.

A review of systemic therapy in biliary tract carcinoma.

Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surgery, chemotherapy and other treatment modalities have improved, surgery remains the only potential curative treatment and is appropriate for only those few patients who present with localized, resectable disease. However, for the majority of patients, unresectable disease is evident at diagnosis and about 95% of patients die within 10 years, despite the majority receiving chemotherapy. Long-term survival is significantly greater for patients with resected BTC compared to those with unresectable disease. In unresected disease, life expectancy is limited, with first-line gemcitabine/cisplatin (GEM/CIS) accepted as standard of care. Currently no standard second-line regimen which provides significant improvement of clinical outcomes exists for those who present with refractory disease or who relapse after first-line treatment. Of particular importance is establishing the impact of best supportive care (BSC) as a benchmark for survival outcomes to which the impact of treatment modalities can be compared. Survival outcome often differs significantly for patients with different prognostic factor profiles even when receiving the same therapy so that it can be difficult to predict which patient subgroup might benefit most from which therapy. Therefore, the influence of prognostic factors on survival under different therapies as well as under BSC needs to be further assessed in order to arrive at truly evidence-based, best therapeutic decisions for individual patients. Encouraging new research into the genomic landscape of BTC may help to further subdivide the BTC population into molecular-genetic clusters likely to be sensitive to different targeted therapy approaches leading to further improvements in survival. Consequently, an unmet need exists not only to develop new and more effective therapies for this devastating disease, but also to integrate original research findings into a more complex, dynamic, individualized therapeutic decision model to aid clinicians in making evidence-based, best therapeutic decisions for individual patients.

Comprehensive genomic and transcriptomic profiling in advanced-stage cancers and rare malignancies: Clinical results from the MASTER trial of the German Cancer Consortium

Abstract Background Precision oncology, guided by high-resolution molecular diagnostics, refers to the ability to identify patients that are likely to respond to specific anticancer therapies. Although recent studies demonstrated the utility of comprehensive molecular profiling based on whole-exome/genome sequencing and transcriptome sequencing to guide therapeutic decisions in individual patients, many questions remain unanswered. Methods We report the clinical results of MASTER, a multicenter, cross-entity registry trial for prospective, biology-driven stratification of younger adults with advanced-stage cancer and patients with rare tumors conducted by NCT Heidelberg/Dresden and the German Cancer Consortium. From 2013 to 2018, we discussed the molecular profiles from 1,311 poor-prognosis patients in a cross-institutional molecular tumor board. Results Evaluation of the data based on a standardized bioinformatics workflow and manual curation by a team of translational oncologists allowed categorization into 7 intervention baskets and formulation of evidence-based recommendations for clinical management in more than 80% of patients, which could be acted upon in approximately one third of cases. Overall response and disease control rates on molecularly guided treatment were improved compared to prior systemic therapies, which translated into a progression-free survival ratio of greater than 1.3 in more than 30% of cases. Comprehensive genomic profiling also provided relevant diagnostic information that led to categorization of some tumors based on genotype and subsequent histopathologic reevaluation. Conclusions Our experience demonstrates that comprehensive molecular profiling in a multi-institutional clinical setting is feasible, complements and advances routine molecular diagnostics, and creates clinically meaningful therapeutic opportunities. Current and future initiatives of the MASTER network are focused on the standardization of variant classification and evidence levels in molecular tumor boards; the implementation of molecularly stratified basket trials; and the integration of additional layers of patient characterization. Legal entity responsible for the study The authors. Funding German Cancer Consortium, Heidelberg Institute for Personalized Oncology. Disclosure W. Weichert: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Research grant / Funding (self): Bruker. All other authors have declared no conflicts of interest.

Abstract 468: Clinical relevance of comprehensive genomic analysis in advanced-stage cancers and rare malignancies: Results from the MASTER trial of the German Cancer Consortium

Abstract Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on high-resolution molecular diagnostics. The value of comprehensive molecular profiling based on whole-exome/genome sequencing (WES/WGS) and global RNA sequencing to guide therapeutic decisions in individual patients remains to be established. We report the results of MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a multicenter registry trial for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors conducted under the auspices of NCT Heidelberg/Dresden and the German Cancer Consortium (DKTK). Based on a standardized workflow for selection and consenting of patients, sample processing, WES/WGS and RNA sequencing, bioinformatic analysis, and technical validation of potentially actionable findings, we have analyzed more than 1300 poor-prognosis (median overall survival, 12 months) patients representing a broad spectrum of entities. Evaluation of the data by a cross-institutional molecular tumor board has allowed categorization into 7 different intervention baskets and formulation of evidence-based recommendations for clinical management in more than 80% of patients, which were implemented in approximately one third of cases. Overall response and disease control rates on molecularly guided treatment were significantly improved compared to prior systemic therapies, which translated into a progression-free survival (PFS) ratio of greater than 1.3 in more than 40% of cases. In 5% of patients, comprehensive genomic profiling allowed to refine the clinical diagnosis, as exemplified by several soft-tissue sarcomas not otherwise specified and carcinomas of unknown primary site that could be categorized based on their genotypes and subsequent histopathologic re-evaluation. Finally, systematic analysis of germline alterations revealed that 11% of patients had pathogenic (ACMG Class 4 or 5) variants in known tumor predisposition genes, and that 4% were carriers for autosomal recessive disorders. This prospective trial demonstrates that molecular profiling based on WES/WGS and RNA sequencing in a multi-institutional clinical setting is feasible, complements and advances routine molecular diagnostics, and creates clinically meaningful therapeutic opportunities in a significant proportion of patients. To improve clinical translation, the MASTER platform is now linked to a growing portfolio of cross-institutional basket trials. In the intermediate term, genomic profiling within MASTER will be integrated with additional layers of patient characterization and extended to additional treatment modalities (e.g. radiotherapy and surgical interventions). Citation Format: Peter Horak, Christoph Heining, Simon Kreutzfeldt, Christoph E. Heilig, Lino Möhrmann, Laura Gieldon, Martina Fröhlich, Sebastian Uhrig, Daniel Hübschmann, Katja Beck, Daniela Richter, Stephan Wolf, Katrin Pfütze, Christina Geörg, Bettina Meißburger, Frederick Klauschen, Sebastian Ochsenreither, Gunnar Folprecht, Jens Siveke, Sebastian Bauer, Thomas Kindler, Christian Brandts, Melanie Börries, Nikolas von Bubnoff, Karsten Spiekermann, Philipp J. Jost, Klaus Schulze-Osthoff, Michael Bitzer, Peter Schirmacher, Christof von Kalle, Richard Schlenk, Barbara Klink, Barbara Hutter, Wilko Weichert, Albrecht Stenzinger, Evelin Schröck, Benedikt Brors, Hanno Glimm, Stefan Fröhling. Clinical relevance of comprehensive genomic analysis in advanced-stage cancers and rare malignancies: Results from the MASTER trial of the German Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 468.

Procalcitonin to guide antibiotic decision making.

There is convincing evidence linking antibiotic-stewardship efforts which include the infection marker procalcitonin (PCT) to more rational use of antibiotics with improvements in side-effects and clinical outcomes. This is particularly true in the setting of respiratory infection and sepsis. Yet, some recent trials have shown no benefit of PCT-guided care. Our aim was to discuss the benefits and limitations of using PCT for early infection recognition, severity assessment and therapeutic decisions in individual patients based on most the recent study data. Current evidence from randomized trials, and meta-analyses of these trials, indicates that PCT-guided antibiotic stewardship results in a reduction in antibiotic use and antibiotic side-effects, which translates into improved survival of patients with respiratory infections and sepsis. Notably, initial PCT levels have been found to be helpful in defining the risk for bacterial infection in the context of a low pretest probability for bacterial infections (i.e., patients with bronchitis or chronic bastructive pulmonary disease exacerbation). Monitoring of repeated PCT measurements over time has also been found helpful for estimating recovery from bacterial infection and prognosis in higher risk situations (i.e., pneumonia or sepsis) and results in early and safe discontinuation of antibiotic therapy. Some trials, however, did not find a strong effect of PCT guidance which may be explained by low protocol adherence, assessment using only a single rather than repeat PCT levels and lower antibiotic exposure in control group patients. Using PCT in the right patient population, with high-sensitivity assays and with adequate training of physicians is important to increase protocol adherence and reduce antibiotic exposure. Inclusion of PCT into antibiotic stewardship algorithms has the potential to improve the diagnostic and therapeutic management of patients presenting with respiratory illnesses and sepsis, and holds great promise to mitigate the global bacterial resistance crisis and move from a default position of standardized care to more personalized treatment decisions.

Exocrine and Endocrine Interactions in Cystic Fibrosis: A Potential Key to Understanding Insulin Secretion in Health and Disease?

The study of β-cell function in vivo has been hampered by the relative inaccessibility of the pancreas as well as the hybrid exocrine/endocrine nature of the organ. This has limited the ability to correlate structure with function, although some efforts have been made in this regard (1,2). Moreover, there are no tests available that can easily, accurately, and reproducibly measure β-cell secretion in a way that might be clinically relevant or influence therapeutic decisions for individual patients (3). The issue is further compounded by the conflation of β-cell function with β-cell mass, where the former can be taken to represent response to a “physiological” challenge and the latter is represented by the (presumed) maximal response to a “supra-physiological” challenge (4). How these relate to the numbers of functional islets or to islet “health” and integrity remains unknown, despite numerous efforts to image β-cell mass in vivo. Unfortunately in a time when an echocardiogram is routinely used for the assessment of cardiac structure and function, diabetologists are stuck with the equivalent of Laennec’s stethoscope. The response to a meal is affected by multiple factors (Fig. 1), including gastric accommodation, gastric trituration of complex food, intraluminal digestion, and subsequent absorption (5–8). In addition, the prevailing degree of insulin action will also alter β-cell secretion; indeed for glucose tolerance to be maintained, β-cell function must be able to compensate for impaired insulin action (4). This concept is embodied in the disposition index, which describes the hyperbolic relationship between the two parameters (9) (Fig. 1). Examination of insulin secretion in disease states where these parameters are directly or indirectly affected by the disease process …

Risk of serious infection in patients with rheumatoid arthritis

Studies in the pre-biologics era described elevated risk of infection in patients with rheumatoid arthritis (RA). Recently biologics have been popularized and glucocorticoids used still now in RA patients, which can lead to various infections. Incidence rates of infection in RA patients are reported to be higher than that in the general population. Several factors such as higher age, comorbidities including chronic lung disease and diabetes mellitus, and glucocorticoids are known to increase risk of serious infection. Significant correlation between methotrexate and infection is not established. Whether biologics, especially inhibitors of tumor necrosis factor alpha, increase the risk for infection is still controversial even with randomized control studies and the meta-analyses; however, time-dependent decrease of the risk was revealed. Our three-year analysis of RA patients for infections requiring hospitalization included 5441 patient-years (PY) in total and detected an incidence rate of 3.4/100 PY, of which the risk factors were higher age (70 years of age or older), male sex, progressed stage of arthritis, functional disorders, and use of glucocorticoids or biologics. Such risk factors should be kept in mind for therapeutic decisions in individual patients with RA.

Do sepsis biomarkers in the emergency room allow transition from bundled sepsis care to personalized patient care?

There is convincing evidence linking early start of fluid resuscitation and initiation of appropriate antimicrobial therapy to improved outcomes in patients with sepsis in the emergency department. Blood biomarkers measured on admission and during follow-up have the ability to guide early sepsis recognition, severity assessment and therapeutic decisions in individual patients and may allow transition from bundled sepsis care to more individualized management in single patients. Although a large number of promising diagnostic and prognostic biomarkers have been put forward in observational studies, only few have been evaluated in prospective randomized-controlled intervention trials. Markers such as lactate for risk stratification and guidance of fluid resuscitation, procalcitonin for assessing risk of bacterial infections and guiding therapeutic decisions about initiation and duration of antimicrobial therapy, and recently proadrenomedullin for early mortality prediction and site-of-care decisions in respiratory infections, have shown to improve patient management. For few biomarkers, recent study results demonstrate that well defined clinical protocols have the potential to guide decisions about the individual risk stratification and treatment of patients with suspicion of sepsis ultimately leading to improved patient care and outcomes. For other biomarkers, promising observation data have been put forward, but their potential needs to be evaluated in large-scale, well designed prospective intervention studies before clinical use can be recommended.

Role of Procalcitonin in Managing Adult Patients With Respiratory Tract Infections

Respiratory infections remain the most common reason why patients seek medical care in ambulatory and hospital settings, and they are the most frequent precursor of sepsis. In light of the limitations of clinical signs and symptoms and traditional microbiologic diagnostics for respiratory infections, blood biomarkers that correlate with the presence and extent of bacterial infections may provide additional useful information to improve diagnostic and prognostic efforts and help with therapeutic decisions in individual patients. A growing body of evidence supports the use of procalcitonin (PCT) to differentiate bacterial from viral respiratory diagnoses, to help risk stratify patients, and to guide antibiotic therapy decisions about initial need for, and optimal duration of, therapy. Although still relatively new on the clinical frontier, a series of randomized controlled trials have evaluated PCT protocols for antibiotic-related decision making and have included patients from different clinical settings and with different severities of respiratory infection. In these trials, initial PCT levels were effective in guiding decisions about the initiation of antibiotic therapy in lower-acuity patients, and subsequent measurements were effective for guiding duration of therapy in higher-acuity patients, without apparent harmful effects. Recent European respiratory infection guidelines now also recognize this concept. As with any other laboratory test, PCT should not be used on a stand-alone basis. Rather, it must be integrated into clinical protocols, together with clinical, microbiologic data and with results from clinical risk scores. The aim of this review is to summarize recent evidence about the usefulness of PCT in patients with lower respiratory tract infections and to discuss the potential benefits and limitations of this marker when used for clinical decision making.

Abstract P6-04-11: Quantitative Differences among Spectral Counts Based on LC-MS/MS Spectra Accurately Cluster Basal, Her2-Overexpressing and Luminal A Breast Carcinomas

Abstract Characterization of breast cancer subtypes at the protein-level is largely unexplored and is a powerful approach to identify novel biomarkers that may have diagnostic and prognostic utility. Shotgun proteomics analyzes mixtures at the peptide-level to generate MS/MS spectra that are then used to identify the peptides and proteins from which they were derived. We developed a method in our laboratory utilizing SDS-PAGE followed by in-gel digestion coupled with reversed-phase (RP) liquid chromatography-tandem mass spectrometry (RP-LC-MS/MS) for proteomic analysis of LCM-acquired cells. This method was then applied to a clinical sample set consisting of basal, Her2-overexpressing and luminal A frozen tumor tissues as determined by prior microarray studies. Three tumors per group were dissected in triplicate, for a total of 27 samples. Each dissection consisted of approximately 10,000 cells, corresponding to 3-5 μg protein. Following LCM, the thermoplastic membranes containing the captured cells were peeled from the cap, suspended in SDS loading buffer and gently heated for 10 minutes. The solubilized proteins were electrophoresed 2 cm into a 10-20% Tricine gel followed by in-gel trypsin digestion and peptide extraction. Replicate LC-MS/MS analysis of the tryptic peptides from each of the 27 samples was performed on a Thermo LTQ XL ion trap mass spectrometer. The resultant tandem mass spectra were searched against the human IPI database using the Myrimatch search algorithm and the results filtered using IDPicker. A spectral counting approach was applied to the data-dependent data to compare quantitative differences among the identified proteins. A total of 91,646 spectra were confidently identified, corresponding to 1671 protein groups across all biological and technical replicates. An average of 545, 543, and 610 protein groups were identified in the basal, ERBB2, and luminal A subtypes, respectively, from an equivalent of approximately 800 cells. Spectral count differences between datasets were analyzed using both a Quasi-likelihood Poisson regression model, developed in-house, and the Limma package in Bioconductor. Using a False Discovery Rate < 0.05, a total of 90 proteins showed statistically significant differences in expression among the breast tumor subtypes. Hierarchical cluster analysis generated a heat map of the protein expression patterns. Novel proteins as well as proteins corresponding to genes previously shown by gene array studies to be specific to each tumor type, including NES, ERBB2 and LGALS3BP, were represented among the differentially expressed proteins. These results demonstrate the feasability of this method to identify differential expression of protein biomarkers among breast cancer subtypes. These biomarkers should yield new insights into the pathogenesis of breast cancer and could be rapidly adapted into clinical diagnostics to guide therapeutic decisions for individual patients. The possible role in breast cancer for the novel proteins identified is currently under investigation. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-04-11.

Tumor Sclerosis but Not Cell Proliferation or Malignancy Grade Is a Prognostic Marker in Advanced-Stage Follicular Lymphoma: The German Low Grade Lymphoma Study Group

Follicular lymphoma is an indolent lymphoma with a long median overall survival. However, a considerable number of patients die within the first 2 years after the onset of the disease. Because the treatment options vary with respect to antitumor effect and potential toxic adverse effects, the identification of high-risk patients would be helpful in directing therapeutic decisions in individual patients. Several histopathologic biomarkers for risk stratification have been suggested, but most markers have not been validated in patients treated in prospective trials. We report a comprehensive approach to evaluate histopathologic biomarkers, including WHO grade, histology, and proliferation and quantitation of immune bystander cells, in 158 patients with nodal advanced-stage follicular lymphoma treated first line within a randomized trial. Tumor sclerosis was a significant prognostic marker of poor overall survival that was independent of the Follicular Lymphoma International Prognostic Index (FLIPI). WHO grade, proliferation, and total T-cell or macrophage content were not associated with overall survival. The presence of sclerosis within the lymphoma is a marker of poor overall survival that is independent of the FLIPI. The quantification of macrophage or absolute T-cell content, grading, and proliferation are of no help in predicting the outcome of FL. Future studies need to identify surrogate markers for the prognostic immune signatures identified by gene expression profiling. Most importantly, new prognostic markers need to be confirmed in patients treated within prospective trials.

The Auxometric Dimension

A system of auxometric staging for the clinical growth rate of breast cancer can be created by considering the observed duration of the tumor and the concomitant occurrence of transition events. In an inception cohort of 219 women with histologically confirmed breast cancers that had first been treated at the Yale-New Haven Hospital during the interval 1962 to 1964, the overall five-year survival rate was 63%. Within categories of the three new auxometric stages, the five-year survival rates were as follows: slow, 37/45 (82%); intermediate, 85/133 (64%); and rapid, 15/41 (37%). These auxometric categories were combined with conventional TNM anatomic categories to form a composite anatomic-auxometric system of four stages, A through D. A particularly striking feature of the new composite system was the demarcation of 22 patients in stage A who had a 100% five-year survival rate, regardless of whether mastectomy was simple or radical. In stages B, C, and D, radical mastectomy appeared superior to simple mastectomy, but the results may have been affected by bias in selecting patients according to prognostic features that are not included in the composite new stages. The results are pertinent in therapeutic decisions for individual patients, in the design of large-scale therapeutic trials, and in biologic correlation of diverse laboratory research. Because a cancer has biologic function as well as anatomic structure, both the function and the structure require appropriate analytic attention. The exclusively anatomic categories that form the basis of conventional systems of staging for breast cancer can be complemented, augmented, and improved by suitable consideration of the clinical rate of growth. (<i>JAMA</i>228:180-185, 1974)