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Background: CUPISCO is an ongoing randomized phase II trial (NCT03498521) comparing molecularly guided therapy versus platinum‐based chemotherapy in patients newly diagnosed with "unfavorable" cancer of unknown primary (CUP). Materials and Methods: Patients with an unfavorable CUP diagnosis, as defined by the European Society of Medical Oncology (ESMO), and available cancer tissue for molecular sequencing are generally eligible. Potential patients with CUP entering screening undergo a review involving reference histopathology and clinical work‐up by a central eligibility review team (ERT). Patients with "favorable" CUP, a strongly suspected primary site of origin, lack of tissue, or unmet inclusion criteria are excluded. Results: As of April 30, 2020, 628 patients had entered screening and 346 (55.1%) were screen failed. Screen fails were due to technical reasons (n = 89), failure to meet inclusion and exclusion criteria not directly related to CUP diagnosis (n = 89), and other reasons (n = 33). A total of 124 (35.8%) patients were excluded because unfavorable adeno‐ or poorly differentiated CUP could not be confirmed by the ERT. These cases were classified into three groups ineligible because of (a) histologic subtype, such as squamous and neuroendocrine, or favorable CUP; (b) evidence of a possible primary tumor; or (c) noncarcinoma histology. Conclusion: Experience with CUPISCO has highlighted challenges with standardized screening in an international clinical trial and the difficulties in diagnosing unfavorable CUP. Reconfirmation of unfavorable CUP by an ERT in a clinical trial can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding of diagnostic challenges and improve diagnostic pathology and clinical CUP algorithms. Implications for Practice: A high unmet need exists for improved treatment of cancer of unknown primary (CUP); however, study in a trial setting is faced with the significant challenge of definitively distinguishing CUP from other cancer types. This article reports the authors' experience of this challenge so far in the ongoing CUPISCO trial, which compares treatments guided by patients' unique genetic signatures versus standard chemotherapy. The data presented will aid future decision‐making regarding diagnosing true CUP cases; this will have far‐reaching implications in the design, execution, and interpretation of not only CUPISCO but also future clinical studies aiming to find much‐needed treatment strategies. Effective therapeutic regimens are lacking for patients with cancers of unknown primary (CUP). This article reports the clinic‐pathological challenges associated with diagnosis of unfavorable CUP in the CUPSICO trial and suggests refinements for diagnostic algorithms. [ABSTRACT FROM AUTHOR]

Background: Carcinoma of unknown primary origin (CUP) accounts for 2%–5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. Materials and Methods: Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture‐based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death‐ligand 1 (PD‐L1) positivity were determined. Results: A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD‐L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%. Conclusions: Thirty‐two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD‐L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP‐informed treatment. Clinical trial identification number. NCT03498521 Implications for Practice: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death‐ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling‐informed treatment. This article focuses on the ability of comprehensive genomic profiling to identify potentially targetable genetic alterations in cancers of unknown primary, based on the inclusion criteria for the CUPISCO clinical trial and aiming for more effective therapeutic options for patients. [ABSTRACT FROM AUTHOR]

Background: The coronavirus disease 2019 (COVID‐19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). Materials and Methods: To depict the state‐of‐the‐art management of GCTs during the COVID‐19 pandemic, a survey including 26 questions was circulated by e‐mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network–Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. Results: Fifty‐three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID‐19–positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony‐stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. Conclusion: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID‐19 pandemic. Implications for Practice: Despite the chaos, disruptions, and fears fomented by the COVID‐19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity. This article focuses on state‐of‐the‐art management of testicular germ cell tumors during the COVID‐19 pandemic, highlighting different approaches based on the pandemic experience in each individual country. [ABSTRACT FROM AUTHOR]