Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards

BACKGROUND: Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. METHODS: High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0-1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. RESULTS: A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician's choice. CONCLUSIONS: Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts

The emergence of the multidimensional organization

A field research, commissioned by the Dutch Foundation for Management Studies, on the state of the application of the concept of business unit-organization (M-form) in the Netherlands, has produced some noteworthy results. Through interviews with 36 organizations, most for-profit companies (including Dutch subsidiaries of multinationals), two non-profit institutions and two government agencies, the following was found. The concept of unit management, that is to organize the firm in a number of self-contained business units as profit centers, is still very strong in the theory-in-use of managers and as a basis for accounting systems. However virtual no business unit any longer is self-contained organized, contrary to the definition of the M-form. All business units, in varying degree, depend on resources outside the unit to achieve their objectives. In at least five cases the mental anchoring to the unit-concept has resulted in debilitating problems with respect to account management and with project management, organizational entities which are needed to satisfy the Chandlerian criteria of fit-to-market and fit-to-strategy. A small number of companies have overcome this problem and similar dilemmas by defining accountability for turnover and profit & loss simultaneously over multiple dimensions (product, region, account, market segment, industry), for each dimension a separate manager is accountable, contrary to what is assumed in the literature on economic organization theory, accounting theory and management control. Examples of firms doing so are ABN AMRO, IBM, Microsoft, ASML, PwC and some others. Those companies have commensurate multidimensional management reporting, management information, and coordination & control processes, and are successful companies (except ABN AMRO which is unbundled by three other banks). The reason to operate a multidimensional organization seems to be the emergence of multidimensional markets, to need to exploit economies of scope, especially with respect to knowledge, to have higher effectiveness in management control, to be more flexible, to reduce resource biased risk averse target setting, and to appropriate more value from the market in the case of network industries. The concept of the multidimensional organization was presaged by Ackoff (1977) and Prahalad & Doz (1979) and Prahalad (1980) but has virtual disappeared from the literature since then. Its present emerging can be explained by using Arrow's (1974) The Limits of Organization, especially Arrow's prediction of the consequences of a fall in costs of information for the agenda of the firm. This paper will describe the multidimensional organization as an empirical phenomenon, explaining its workings and its raison d'être in operational terms. In addition to that, using Williamson's efficiency hypothesis, the efficiency of the multidimensional organization is discussed whether the multidimensional organization is more efficient as is the M-form. This paper does not in the first place aim, as is common, to make a contribution to existing literature. Its first purpose is to report on a new empirical phenomenon