Vingiani, Andrea

PURPOSE The investigation of multiple molecular targets with next-generation sequencing (NGS) has entered clinical practice in oncology, yielding to a paradigm shift from the histology-centric approach to the mutational model for personalized treatment. Accordingly, most of the drugs recently approved in oncology are coupled to specific biomarkers. One potential tool for implementing the mutational model of precision oncology in daily practice is represented by the Molecular Tumor Board (MTB), a multidisciplinary team whereby molecular pathologists, biologists, bioinformaticians, geneticists, medical oncologists, and pharmacists cooperate to generate, interpret, and match molecular data with personalized treatments. PATIENTS AND METHODS Since May 2020, the institutional MTB set at Fondazione IRCCS Istituto Nazionale Tumori of Milan met weekly via teleconference to discuss molecular data and potential therapeutic options for patients with advanced/metastatic solid tumors. RESULTS Up to October 2021, among 1,996 patients evaluated, we identified >10,000 variants, 43.2% of which were functionally relevant (pathogenic or likely pathogenic). On the basis of functionally relevant variants, 711 patients (35.6%) were potentially eligible to targeted therapy according to European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets tiers, and 9.4% received a personalized treatment. Overall, larger NGS panels (containing >50 genes) significantly outperformed small panels (up to 50 genes) in detecting actionable gene targets across different tumor types. CONCLUSION Our real-world data provide evidence that MTB is a valuable tool for matching NGS data with targeted treatments, eventually implementing precision oncology in clinical practice.

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.