Frequency and Prognostic Value of Circulating Tumor Cells in Cancer of Unknown Primary.

BACKGROUND: Cancer of unknown primary (CUP) is defined as a primary metastatic malignancy, in which the primary tumor remains elusive in spite of a comprehensive diagnostic workup. The frequency and prognostic value of circulating tumor cells (CTCs), which are considered to be the source of metastasis, has not yet been systematically evaluated in CUP. METHODS: A total of 110 patients with a confirmed diagnosis of CUP according to the European Society for Medical Oncology (ESMO) guidelines, who presented to our clinic between July 2021 and May 2023, provided blood samples for CTC quantification using CellSearch methodology. CTC counts were correlated with demographic, clinical, and molecular data generated by comprehensive genomic profiling of tumor tissue. RESULTS: CTCs were detected in 26% of all patients at initial presentation to our department. The highest CTC frequency was observed among patients with unfavorable CUP (35.5%), while patients with single-site/oligometastatic CUP harbored the lowest CTC frequency (11.4%). No statistically significant association between CTC positivity and the number of affected organs (P = 0.478) or disease burden (P = 0.120) was found. High CTC levels (≥5 CTCs/7.5 mL; 12/95 analyzed patients) predicted for adverse overall survival compared to negative or low CTC counts (6-months overall survival rate 90% vs 32%, log-rank P < 0.001; HR 5.43; 95% CI 2.23-13.2). CTC dynamics were also prognostic for overall survival by landmark analysis (log-rank P < 0.001, HR 10.2, 95% CI 1.95-52.9). CONCLUSIONS: CTC frequency is a strong, independent predictor of survival in patients with CUP. CTC quantification provides a useful prognostic tool in the management of these patients.

Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial.

Cancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMBhigh vs. TMBlow stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size (n = 194). Among 31 evaluable patients, 16% had a high TMB ( > 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMBlow and TMBhigh, respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response.

[Cancer of unknown primary (CUP)-single-site, oligometastatic, and in the head and neck region]. / Cancer of unknown primary (CUP) ­ lokal begrenzt, oligometastatisch und im Kopf-Hals-Bereich.

INTRODUCTION: About 20% of all cancer of unknown primary (CUP) cases can be classified into favorable subgroups, which are defined by either obvious analogies to certain cancers with a known primary or amenability to local ablative treatment. In the updated European Society for Medical Oncology (ESMO) guidelines for diagnosis and treatment of CUP, the definition of favorable subgroups has been revised according to the latest scientific findings. In particular, the definition and treatment of oligometastatic CUP have undergone considerable changes in recent years. Thus, we delineate the current diagnostic and therapeutic standards for the two favorable CUP subtypes single-site/oligometastatic and head/neck CUP. METHODS: The classification, diagnostic workup, and treatment of single-site and oligometastatic CUP are summarized based on the current ESMO and American Society of Clinical Oncology (ASCO) guidelines together with a literature review. CONCLUSIONS: Single-site and oligometastatic CUP is defined by the presence of a maximum of five metastases that are amenable to local ablative treatment. Median overall survival is favorable and exceeds 4 years after local ablation of all detectable metastases. Lymph node metastases in the head and neck region represent a frequent scenario of single-site CUP. They usually originate from human papillomavirus (HPV)-associated squamous cell carcinoma in the oropharynx. Diagnostic workup comprises computed tomography (CT), magnetic resonance imaging (MRI) if necessary, and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), followed by panendoscopy and biopsies of suspicious mucosal sites. Neck dissection, potentially followed by adjuvant radiotherapy, and definitive radiotherapy represent equally effective oncological treatment options with respect to a favorable prognosis.

[Cancer of unknown primary-The new ESMO guidelines]. / CUP-Syndrom ­ die neue ESMO-Leitlinie.

BACKGROUND: The European Society of Medical Oncology (ESMO) recently published extensively revised guidelines on cancer of unknown primary (CUP). The new version contains the following relevant amendments: with respect to diagnostics of CUP, the current guidelines aim for a more precise and standardized definition of CUP by establishing diagnostic algorithms. Recommendations for molecular diagnostics of cancer tissue have also been implemented. With respect to CUP classification, the favorable category has been revised. A carcinoma with immunohistochemistry typical for renal cell carcinoma (renal-like CUP) was introduced in the new definition of favorable subtypes, for which a specific treatment is indicated. Based on a newly defined oligometastatic situation a subgroup with localized cancer potentially curatively treatable with surgery and/or radiotherapy was introduced into the CUP classification. With respect to treatment of CUP, the current guidelines present options beyond empirical chemotherapy, which is still the standard of care treatment, and pinpoint indications and predictive biomarkers for targeted and immune checkpoint inhibitor treatment. RELEVANT UPDATES: The European Society of Medical Oncology (ESMO) recently published extensively revised guidelines on the CUP syndrome. The new version contains the following relevant amendments: the current guidelines aim for a more precise and standardized definition of CUP by establishing diagnostic algorithms with respect to the diagnostics of CUP syndrome. Recommendations for molecular diagnostics of cancer tissue have also been implemented. The classification of the CUP syndrome has also been revised. A carcinoma with immunohistochemistry typical for renal cell carcinoma (renal-like CUP) was introduced in the new definition of favorable subtypes, for which a specific treatment is indicated. Based on a newly defined oligometastatic situation a local potentially curatively treatable with surgery and/or radiotherapy subgroup was introduced into the CUP classification. With respect to treatment of the CUP syndrome, the current guidelines present options beyond empirical chemotherapy, which is still the gold standard treatment, and pinpoint indications and predictive biomarkers for targeted and immune checkpoint inhibitor treatment. SCHLUSSFOLGERUNG: The aim of this review is to present the current state of diagnostics, classification and treatment of CUP syndrome, with a focus on recent developments and revisions implemented in the current ESMO guidelines.

Prognostic impact of copy number alterations and tumor mutational burden in carcinoma of unknown primary.

INTRODUCTION: Chromosomal aberrations are known to drive metastatic spread, but their profile is still elusive in carcinoma of unknown primary (CUP). Therefore, the aim of this study was to characterize the chromosomal aberration pattern in CUP depending on histological and clinical features and to assess its prognostic impact together with chromothripsis, tumor mutational burden (TMB), microsatellite instability (MSI), and mutational profiles as potential prognostic biomarkers. METHODS: Chromosomal aberrations and chromothripsis were detected by methylation-based copy number variation (CNV) analysis, whereas TMB and MSI were calculated based on large next-generation sequencing (NGS) panels. Putative primaries were assigned by consensus between two independent oncologists. RESULTS: CNV losses varied depending on putative primaries and were more abundant in patients harboring TP53 mutations and/or deletions 17p. CNV loss was prognostically adverse in localized CUP treated with surgery and/or radiotherapy, but not in disseminated poor-risk CUP treated with palliative chemotherapy. CNV loss also worsened the prognosis in squamous cell CUP. Chromothripsis was detected in 18/59 (30.5%) patients without prognostic effect. TMB was highest in cases with MSI, squamous cell histology, and with lung, anal or cervical putative primaries. CONCLUSION: Overall, CNV, chromothripsis, TMB, and MSI profiles in CUP are reminiscent of biological characteristics known from other cancer entities without a unifying CUP-specific signature. Markedly, high-level CNV loss is an adverse predictive biomarker in localized but not disseminated chemotherapy-treated CUP. This implies that chromosomal losses drive CUP progression, but also increase susceptibility to chemotherapy, with both effects apparently leveling out in disseminated CUP.

Local ablative treatment with surgery and/or radiotherapy in single-site and oligometastatic carcinoma of unknown primary.

BACKGROUND: Single-site carcinoma of unknown primary (CUP) is recognised as a distinct favourable subtype in the European Society of Medical Oncology (ESMO) classification. There is broad consensus that these patients are candidates for local ablative treatment strategies with surgery and/or radiotherapy, but data on their outcomes are scarce. PATIENTS AND METHODS: In this study, we have addressed the prospects of cure and prognostic factors in a retrospective cohort of 63 patients who were eligible for local treatment at our centre. RESULTS: Median event-free (EFS) and overall survival (OS) were 15.6 months and 52.5 months, respectively. Of 61 patients who received local treatment, 20 (32.8%) remained event-free over a median follow-up of 28 months. Baseline clinical parameters including affected organ, number, volume and histology of metastases had no significant impact on prognosis, whereas deleterious TP53 mutations and DNA copy number loss emerged as independent adverse risk factors with respect to EFS. Surgical treatment was associated with improved OS as compared to radiation-based therapy. CONCLUSION: Our study advocates to pursue localised treatment with surgery and/or radiotherapy whenever feasible and implies that genetic parameters might additionally determine the clinical course of single-site CUP patients.