Advancements in Diagnostics and Therapeutics for Cancer of Unknown Primary in the Era of Precision Medicine

Ting Zhao; Xiaowei Zhang; Xin Liu; Qifeng Wang; Xichun Hu; Zhiguo Luo

doi:10.1002/mco2.70161

MedComm ›› 2025, Vol. 6 ›› Issue (5) : e70161 DOI: 10.1002/mco2.70161

REVIEW

Advancements in Diagnostics and Therapeutics for Cancer of Unknown Primary in the Era of Precision Medicine

Ting Zhao ¹^,²
, Xiaowei Zhang ¹^,²
, Xin Liu ¹^,²
, Qifeng Wang ²^,³
, Xichun Hu ¹^,²
, Zhiguo Luo ¹^,²

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Abstract

Cancer of unknown primary (CUP), a set of histologically confirmed metastases that cannot be identified or traced back to its primary despite comprehensive investigations, accounts for 2–5% of all malignancies. CUP is the fourth leading cause of cancer-related deaths worldwide, with a median overall survival (OS) of 3–16 months. CUP has long been challenging to diagnose principally due to the occult properties of primary site. In the current era of molecular diagnostics, advancements in methodologies based on cytology, histology, gene expression profiling (GEP), and genomic and epigenomic analysis have greatly improved the diagnostic accuracy of CUP, surpassing 90%. Our center conducted the world's first phase III trial and demonstrated improved progression-free survival and favorable OS by GEP-guided site-specific treatment of CUP, setting the foundation of site-specific treatment in first-line management for CUP. In this review, we detailed the epidemiology, etiology, pathogenesis, as well as the histologic, genetic, and clinical characteristics of CUP. We also provided an overview of the advancements in the diagnostics and therapeutics of CUP over the past 50 years. Moving forward, we propose optimizing diagnostic modalities and exploring further-line treatment regimens as two focus areas for future studies on CUP.

Keywords

cancer of unknown primary / molecular diagnostics / empirical chemotherapy / site-specific therapy / molecularly guided therapy

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Ting Zhao, Xiaowei Zhang, Xin Liu, Qifeng Wang, Xichun Hu, Zhiguo Luo. Advancements in Diagnostics and Therapeutics for Cancer of Unknown Primary in the Era of Precision Medicine. MedComm, 2025, 6(5): e70161 DOI:10.1002/mco2.70161

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References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	N. Pavlidis and G. Pentheroudakis, “Cancer of Unknown Primary Site,” Lancet 379 (2012): 1428-1435.

[2]	A. Kramer, T. Bochtler, C. Pauli, et al., “Cancer of Unknown Primary: ESMO Clinical Practice Guideline for Diagnosis, Treatment and Follow-up,” Annals of Oncology 34 (2023): 228-246.

[3]	A. Kramer, T. Bochtler, C. Pauli, et al., “Molecularly Guided Therapy versus Chemotherapy After Disease Control in Unfavourable Cancer of Unknown Primary (CUPISCO): An Open-label, Randomised, Phase 2 Study,” Lancet 404 (2024): 527-539.

[4]	C. Binder, K. L. Matthes, D. Korol, S. Rohrmann, and H. Moch, “Cancer of Unknown Primary-Epidemiological Trends and Relevance of Comprehensive Genomic Profiling,” Cancer Medicine 7 (2018): 4814-4824.

[5]	E. Rassy and N. Pavlidis, “The Currently Declining Incidence of Cancer of Unknown Primary,” Cancer Epidemiology 61 (2019): 139-141.

[6]	M. S. Lee and H. K. Sanoff, “Cancer of Unknown Primary,” Bmj 371 (2020): m4050.

[7]	K. Hemminki, J. Ji, J. Sundquist, and X. Shu, “Familial Risks in Cancer of Unknown Primary: Tracking the Primary Sites,” Journal of Clinical Oncology 29 (2011): 435-440.

[8]	N. Pavlidis and G. Pentheroudakis, “Cancer of Unknown Primary Site: 20 Questions to be Answered,” Annals of Oncology 21, no. Suppl 7 (2010): vii303-vii307.

[9]	E. Rassy and N. Pavlidis, “Progress in Refining the Clinical Management of Cancer of Unknown Primary in the Molecular Era,” Nature Reviews Clinical Oncology 17 (2020): 541-554.

[10]	G. R. Varadhachary and M. N. Raber, “Cancer of Unknown Primary Site,” New England Journal of Medicine 371 (2014): 757-765.

[11]	E. Rassy, P. Parent, F. Lefort, S. Boussios, G. Baciarello, and N. Pavlidis, “New Rising Entities in Cancer of Unknown Primary: Is There a Real Therapeutic Benefit?,” Critical Reviews in Oncology/Hematology 147 (2020): 102882.

[12]	J. Vikesa, A. K. Moller, B. Kaczkowski, et al., “Cancers of Unknown Primary Origin (CUP) Are Characterized by Chromosomal Instability (CIN) Compared to Metastasis of Know Origin,” BMC Cancer 15 (2015): 151.

[13]	K. Hermans, F. Kazemzadeh, C. Loef, et al., “Risk Factors for Cancer of Unknown Primary: A Literature Review,” BMC Cancer 23 (2023): 314.

[14]	K. Hemminki, K. Sundquist, J. Sundquist, and J. Ji, “Risk of Cancer of Unknown Primary After Hospitalization for Autoimmune Diseases,” International Journal of Cancer 137 (2015): 2885-2895.

[15]	N. Pavlidis, E. Rassy, and J. Smith-Gagen, “Cancer of Unknown Primary: Incidence Rates, Risk Factors and Survival Among Adolescents and Young Adults,” International Journal of Cancer 146 (2020): 1490-1498.

[16]	K. Hemminki, B. Chen, O. Melander, J. Manjer, G. Hallmans, and A. Hemminki, “Smoking and Body Mass Index as Risk Factors for Subtypes of Cancer of Unknown Primary,” International Journal of Cancer 136 (2015): 246-247.

[17]	E. Rassy, J. Kattan, and N. Pavlidis, “Familial Cancer of Unknown Primary,” International Journal of Clinical Oncology 24 (2019): 1328-1331.

[18]	R. W. Tothill, J. Li, L. Mileshkin, et al., “Massively-parallel Sequencing Assists the Diagnosis and Guided Treatment of Cancers of Unknown Primary,” Journal of Pathology 231 (2013): 413-423.

[19]	J. S. Ross, K. Wang, L. Gay, et al., “Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies,” JAMA Oncology 1 (2015): 40-49.

[20]	W. M. Chiang, M. Kapadia, N. V. Laver, and J. S. Nystrom, “Cancer of Unknown Primary: From Immunohistochemistry to Gene Expression Profiling,” Journal of Clinical Oncology 30 (2012): e300-302.

[21]	C. R. Handorf, “Gene Expression Analysis and Immunohistochemistry in Evaluation of Cancer of Unknown Primary: Time for a Patient-centered Approach,” Journal of the National Comprehensive Cancer Network: JNCCN 9 (2011): 1415-1420.

[22]	E. B. Stelow and H. Yaziji, “Immunohistochemistry, Carcinomas of Unknown Primary, and Incidence Rates,” Seminars in Diagnostic Pathology 35 (2018): 143-152.

[23]	J. R. Conner and J. L. Hornick, “Metastatic Carcinoma of Unknown Primary: Diagnostic Approach Using Immunohistochemistry,” Advances in Anatomic Pathology 22 (2015): 149-167.

[24]	D. Dum, A. Menz, C. Volkel, et al., “Cytokeratin 7 and Cytokeratin 20 Expression in Cancer: A Tissue Microarray Study on 15,424 Cancers,” Experimental and Molecular Pathology 126 (2022): 104762.

[25]	F. A. Greco, W. J. Lennington, D. R. Spigel, and J. D. Hainsworth, “Molecular Profiling Diagnosis in Unknown Primary Cancer: Accuracy and Ability to Complement Standard Pathology,” JNCI: Journal of the National Cancer Institute 105 (2013): 782-790.

[26]	S. E. Kerr, C. A. Schnabel, P. S. Sullivan, et al., “Multisite Validation Study to Determine Performance Characteristics of a 92-gene Molecular Cancer Classifier,” Clinical Cancer Research 18 (2012): 3952-3960.

[27]	S. Moran, A. Martinez-Cardus, S. Sayols, et al., “Epigenetic Profiling to Classify Cancer of Unknown Primary: A Multicentre, Retrospective Analysis,” The Lancet Oncology 17 (2016): 1386-1395.

[28]	Y. Zhao, Z. Pan, S. Namburi, et al., “CUP-AI-Dx: A Tool for Inferring Cancer Tissue of Origin and Molecular Subtype Using RNA Gene-expression Data and Artificial Intelligence,” EBioMedicine 61 (2020): 103030.

[29]	C. R. Handorf, A. Kulkarni, J. P. Grenert, et al., “A Multicenter Study Directly Comparing the Diagnostic Accuracy of Gene Expression Profiling and Immunohistochemistry for Primary Site Identification in Metastatic Tumors,” American Journal of Surgical Pathology 37 (2013): 1067-1075.

[30]	Q. Ye, Q. Wang, P. Qi, et al., “Development and Clinical Validation of a 90-Gene Expression Assay for Identifying Tumor Tissue Origin,” The Journal of Molecular Diagnostics 22 (2020): 1139-1150.

[31]	Y. Shen, Q. Chu, X. Yin, et al., “TOD-CUP: A Gene Expression Rank-based Majority Vote Algorithm for Tissue Origin Diagnosis of Cancers of Unknown Primary,” Briefings in Bioinformatics 22 (2021): 2106-2118.

[32]	M. Y. Lu, T. Y. Chen, D. F. K. Williamson, et al., “AI-based Pathology Predicts Origins for Cancers of Unknown Primary,” Nature 594 (2021): 106-110.

[33]	I. Moon, J. LoPiccolo, S. C. Baca, et al., “Machine Learning for Genetics-based Classification and Treatment Response Prediction in Cancer of Unknown Primary,” Nature Medicine 29 (2023): 2057-2067.

[34]	L. Nguyen, A. Van Hoeck, and E. Cuppen, “Machine Learning-based Tissue of Origin Classification for Cancer of Unknown Primary Diagnostics Using Genome-wide Mutation Features,” Nature Communications 13 (2022): 4013.

[35]	F. Tian, D. Liu, N. Wei, et al., “Prediction of Tumor Origin in Cancers of Unknown Primary Origin With Cytology-based Deep Learning,” Nature Medicine 30 (2024): 1309-1319.

[36]	S. Zhang, S. He, X. Zhu, et al., “DNA Methylation Profiling to Determine the Primary Sites of Metastatic Cancers Using Formalin-fixed Paraffin-embedded Tissues,” Nature Communications 14 (2023): 5686.

[37]

J. D. Hainsworth, M. S. Rubin, D. R. Spigel, et al., “Molecular Gene Expression Profiling to Predict the Tissue of Origin and Direct Site-specific Therapy in Patients With Carcinoma of Unknown Primary Site: A Prospective Trial of the Sarah Cannon Research Institute,” Journal of Clinical Oncology 31 (2013): 217-223.

[38]	H. Hayashi, T. Kurata, Y. Takiguchi, et al., “Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling with Carboplatin and Paclitaxel for Patients with Cancer of Unknown Primary Site,” Journal of Clinical Oncology 37 (2019): 570-579.

[39]	H. Hayashi, Y. Takiguchi, H. Minami, et al., “Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial,” JAMA Oncology 6 (2020): 1931-1938.

[40]	M. J. Fusco, T. C. Knepper, J. Balliu, et al., “Evaluation of Targeted Next-Generation Sequencing for the Management of Patients Diagnosed With a Cancer of Unknown Primary,” The Oncologist 27 (2022): e9-e17.

[41]	Z. L. XL, X. Zhang, S. Jiang, et al., “A Randomized Phase III Trial of Site-specific Therapy Guided by the 90-gene Expression Assay versus Empiric Chemotherapy in Patients With Cancer of Unknown Primary,” Annals of Oncology 34 (2023): S711-S731.

[42]	X. Liu, X. Zhang, S. Jiang, et al., “Site-specific Therapy Guided by a 90-gene Expression Assay versus Empirical Chemotherapy in Patients With Cancer of Unknown Primary (Fudan CUP-001): A Randomised Controlled Trial,” The Lancet Oncology (2024).

[43]	E. Rassy, C. Labaki, R. Chebel, et al., “Systematic Review of the CUP Trials Characteristics and Perspectives for next-generation Studies,” Cancer Treatment Reviews 107 (2022): 102407.

[44]	D. Urban, A. Rao, M. Bressel, Y. R. Lawrence, and L. Mileshkin, “Cancer of Unknown Primary: A Population-based Analysis of Temporal Change and Socioeconomic Disparities,” British Journal of Cancer 109 (2013): 1318-1324.

[45]	D. H. Brewster, J. Lang, L. A. Bhatti, C. S. Thomson, and K. A. Oien, “Descriptive Epidemiology of Cancer of Unknown Primary Site in Scotland, 1961-2010,” Cancer Epidemiology 38 (2014): 227-234.

[46]	M. Randen, L. E. Rutqvist, and H. Johansson, “Cancer Patients Without a Known Primary: Incidence and Survival Trends in Sweden 1960-2007,” Acta Oncologica 48 (2009): 915-920.

[47]	E. Mnatsakanyan, W. C. Tung, B. Caine, and J. Smith-Gagen, “Cancer of Unknown Primary: Time Trends in Incidence, United States,” Cancer Causes & Control 25 (2014): 747-757.

[48]	P. Qi, Y. Sun, X. Liu, et al., “Clinicopathological, Molecular and Prognostic Characteristics of Cancer of Unknown Primary in China: An Analysis of 1420 Cases,” Cancer Medicine 12 (2023): 1177-1188.

[49]	E. El Rassy, J. Kattan, and N. Pavlidis, “A New Entity of Abdominal Squamous Cell Carcinoma of Unknown Primary,” European Journal of Clinical Investigation 49 (2019): 13111.

[50]	A. M. Chen, “Management of Unknown Primary Head and Neck Cancer With Radiation Therapy in the Era of human Papillomavirus (HPV): No Longer Cutting Down the Tree to Get an Apple,” Radiotherapy and Oncology 189 (2023): 109952.

[51]	D. M. Filippini, E. Broseghini, F. Carosi, et al., “A Systematic Review of Diagnostic and Prognostic Biomarkers for Head and Neck Cancer of Unknown Primary: An Unmet Clinical Need,” Diagnostics (Basel) 13 (2023).

[52]	R. Kaaks, D. Sookthai, K. Hemminki, et al., “Risk Factors for Cancers of Unknown Primary Site: Results From the Prospective EPIC Cohort,” International Journal of Cancer 135 (2014): 2475-2481.

[53]	K. Hermans, P. A. van den Brandt, C. Loef, R. L. H. Jansen, and L. J. Schouten, “Alcohol Consumption, Cigarette Smoking and Cancer of Unknown Primary Risk: Results From the Netherlands Cohort Study,” International Journal of Cancer 148 (2021): 1586-1597.

[54]	K. Hemminki, N. Pavlidis, K. K. Tsilidis, K. Sundquist, and J. Ji, “Age-Dependent Metastatic Spread and Survival: Cancer of Unknown Primary as a Model,” Scientific Reports 6 (2016): 23725.

[55]	K. Hemminki, M. Bevier, A. Hemminki, and J. Sundquist, “Survival in Cancer of Unknown Primary Site: Population-based Analysis by Site and Histology,” Annals of Oncology 23 (2012): 1854-1863.

[56]	K. Hermans, P. A. van den Brandt, C. Loef, R. L. H. Jansen, and L. J. Schouten, “Anthropometry, Physical Activity and Cancer of Unknown Primary (CUP) Risk: Results From the Netherlands Cohort Study,” Cancer Epidemiology 69 (2020): 101836.

[57]	K. Hermans, P. A. van den Brandt, C. Loef, R. L. H. Jansen, and L. J. Schouten, “Vegetable and Fruit Consumption and Cancer of Unknown Primary Risk: Results From the Netherlands Cohort Study on Diet and Cancer,” BMC Cancer 22 (2022): 399.

[58]	M. Lopez-Lazaro, “The Migration Ability of Stem Cells Can Explain the Existence of Cancer of Unknown Primary Site. Rethinking Metastasis,” Oncoscience 2 (2015): 467-475.

[59]	T. Olivier, E. Fernandez, I. Labidi-Galy, et al., “Redefining Cancer of Unknown Primary: Is Precision Medicine Really Shifting the Paradigm?,” Cancer Treatment Reviews 97 (2021): 102204.

[60]	E. Rassy, T. Assi, and N. Pavlidis, “Exploring the Biological Hallmarks of Cancer of Unknown Primary: Where Do We Stand Today?,” British Journal of Cancer 122 (2020): 1124-1132.

[61]	S. A. Joosse and K. Pantel, “Genetic Traits for Hematogeneous Tumor Cell Dissemination in Cancer Patients,” Cancer and Metastasis Reviews 35 (2016): 41-48.

[62]	A. M. Conway, C. Mitchell, E. Kilgour, G. Brady, C. Dive, and N. Cook, “Molecular Characterisation and Liquid Biomarkers in Carcinoma of Unknown Primary (CUP): Taking the ‘U’ out of ‘CUP’,” British Journal of Cancer 120 (2019): 141-153.

[63]	C. Massard, Y. Loriot, and K. Fizazi, “Carcinomas of an Unknown Primary Origin-Diagnosis and Treatment,” Nature Reviews Clinical Oncology 8 (2011): 701-710.

[64]	S. Boussios, E. Rassy, E. Samartzis, et al., “Melanoma of Unknown Primary: New Perspectives for an Old Story,” Critical Reviews in Oncology/Hematology 158 (2021): 103208.

[65]	J. S. Ross, E. S. Sokol, H. Moch, et al., “Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design,” The Oncologist 26 (2021): e394-e402.

[66]	A. M. Varghese, A. Arora, M. Capanu, et al., “Clinical and Molecular Characterization of Patients With Cancer of Unknown Primary in the Modern Era,” Annals of Oncology 28 (2017): 3015-3021.

[67]	H. A. Es, H. Mahdizadeh, A. A. H. Asl, and M. Totonchi, “Genomic Alterations and Possible Druggable Mutations in Carcinoma of Unknown Primary (CUP),” Scientific Reports 11 (2021): 15112.

[68]	X. Wang, A. Beharry, B. S. Sheffield, and P. K. Cheema, “Feasibility of Point-of-Care Genomic Profiling in the Diagnosis and Treatment of Cancer of Unknown Primary,” The Oncologist 28 (2023): 474-478.

[69]	C. B. Westphalen, J. Federer-Gsponer, C. Pauli, et al., “Baseline Mutational Profiles of Patients With Carcinoma of Unknown Primary Origin Enrolled in the CUPISCO Study,” ESMO Open 8 (2023): 102035.

[70]	F. Verginelli, A. Pisacane, G. Gambardella, et al., “Cancer of Unknown Primary Stem-Like Cells Model Multi-organ Metastasis and Unveil Liability to MEK Inhibition,” Nature Communications 12 (2021): 2498.

[71]	L. Mohrmann, M. Werner, M. Oles, et al., “Comprehensive Genomic and Epigenomic Analysis in Cancer of Unknown Primary Guides Molecularly-informed Therapies Despite Heterogeneity,” Nature Communications 13 (2022): 4485.

[72]	H. M. Kim and J. S. Koo, “Programmed Death-ligand 1 Expression in Carcinoma of Unknown Primary,” BMC Cancer 24 (2024): 689.

[73]	A. Posner, T. Sivakumaran, A. Pattison, et al., “Immune and Genomic Biomarkers of Immunotherapy Response in Cancer of Unknown Primary,” Journal for ImmunoTherapy of Cancer 11 (2023).

[74]	Z. Gatalica, J. Xiu, J. Swensen, and S. Vranic, “Comprehensive Analysis of Cancers of Unknown Primary for the Biomarkers of Response to Immune Checkpoint Blockade Therapy,” European Journal of Cancer 94 (2018): 179-186.

[75]	A. Chebly, T. Yammine, S. Boussios, N. Pavlidis, and E. Rassy, “Chromosomal Instability in Cancers of Unknown Primary,” European Journal of Cancer 172 (2022): 323-325.

[76]	J. Li, M. J. Hubisz, E. M. Earlie, et al., “Non-cell-autonomous Cancer Progression From Chromosomal Instability,” Nature 620 (2023): 1080-1088.

[77]	I. Vitale, C. Galassi, and L. Galluzzi, “Chromosomal Instability Drives Immunosuppression and Metastatic Dissemination,” Cell Research 34 (2024): 7-8.

[78]	D. H. Al-Rawi, E. Lettera, J. Li, M. DiBona, and S. F. Bakhoum, “Targeting Chromosomal Instability in Patients With Cancer,” Nature Reviews Clinical Oncology 21 (2024): 645-659.

[79]	J. D. Hainsworth, W. J. Lennington, and F. A. Greco, “Overexpression of Her-2 in Patients With Poorly Differentiated Carcinoma or Poorly Differentiated Adenocarcinoma of Unknown Primary Site,” Journal of Clinical Oncology 18 (2000): 632-635.

[80]	E. Briasoulis, M. Tsokos, G. Fountzilas, et al., “Bcl2 and p53 Protein Expression in Metastatic Carcinoma of Unknown Primary Origin: Biological and Clinical Implications. A Hellenic Co-operative Oncology Group Study,” Anticancer Research 18 (1998): 1907-1914.

[81]	N. Pavlidis, E. Briassoulis, M. Bai, G. Fountzilas, and N. Agnantis, “Overexpression of C-myc, Ras and C-erbB-2 Oncoproteins in Carcinoma of Unknown Primary Origin,” Anticancer Research 15 (1995): 2563-2567.

[82]	V. Karavasilis, V. Malamou-Mitsi, E. Briasoulis, et al., “Matrix Metalloproteinases in Carcinoma of Unknown Primary,” Cancer 104 (2005): 2282-2287.

[83]	L. Qin, S. Tian, L. Yang, J. Fan, and J. Zhang, “Liver Failure as the Initial Presentation in Cancer of Unknown Primary: A Case Report,” BMC Infectious Diseases [Electronic Resource] 23 (2023): 363.

[84]	S. Kolling, F. Ventre, E. Geuna, et al., “Metastatic Cancer of Unknown Primary” or “Primary Metastatic Cancer?,” Frontiers in Oncology 9 (2019): 1546.

[85]	W. Sun, W. Wu, Q. Wang, et al., “Clinical Validation of a 90-gene Expression Test for Tumor Tissue of Origin Diagnosis: A Large-scale Multicenter Study of 1417 Patients,” Journal of Translational Medicine 20 (2022): 114.

[86]	Y. Shao, X. Liu, S. Hu, et al., “Sentinel Node Theory Helps Tracking of Primary Lesions of Cancers of Unknown Primary,” BMC Cancer 20 (2020): 639.

[87]	T. J. Galloway and J. A. Ridge, “Management of Squamous Cancer Metastatic to Cervical Nodes with an Unknown Primary Site,” Journal of Clinical Oncology 33 (2015): 3328-3337.

[88]	G. Pentheroudakis, V. Golfinopoulos, and N. Pavlidis, “Switching Benchmarks in Cancer of Unknown Primary: From Autopsy to Microarray,” European Journal of Cancer 43 (2007): 2026-2036.

[89]	N. Laprovitera, M. Riefolo, E. Ambrosini, C. Klec, M. Pichler, and M. Ferracin, “Cancer of Unknown Primary: Challenges and Progress in Clinical Management,” Cancers (Basel) 13 (2021).

[90]

I. Hanzalova and M. Matter, “Peripheral Lymphadenopathy of Unknown Origin in Adults: A Diagnostic Approach Emphasizing the Malignancy Hypothesis,” Swiss Medical Weekly: Official Journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology 154 (2024): 3549.

[91]	M. Milovic, I. Popov, and S. Jelic, “Tumor Markers in Metastatic Disease From Cancer of Unknown Primary Origin,” Medical Science Monitor 8 (2002): MT25-30.

[92]	P. N. Nikolova, V. H. Hadzhiyska, K. B. Mladenov, et al., “The Impact of 18F-FDG PET/CT in the Clinical Management of Patients With Lymph Node Metastasis of Unknown Primary Origin,” Neoplasma 68 (2021): 180-189.

[93]	G. Zaun, M. Weber, M. Metzenmacher, et al., “SUV(max) above 20 in (18)F-FDG PET/CT at Initial Diagnostic Workup Associates With Favorable Survival in Patients With Cancer of Unknown Primary,” Journal of Nuclear Medicine 64 (2023): 1191-1194.

[94]	K. E. Rusthoven, M. Koshy, and A. C. Paulino, “The Role of Fluorodeoxyglucose Positron Emission Tomography in Cervical Lymph Node Metastases From an Unknown Primary Tumor,” Cancer 101 (2004): 2641-2649.

[95]	F. Eilsberger, F. E. Noltenius, D. Librizzi, et al., “Real-Life Performance of F-18-FDG PET/CT in Patients With Cervical Lymph Node Metastasis of Unknown Primary Tumor,” Biomedicines 10 (2022).

[96]

J. R. J. Willemse, D. M. J. Lambregts, S. Balduzzi, et al., “Identifying the Primary Tumour in Patients With Cancer of Unknown Primary (CUP) Using [(18)F]FDG PET/CT: A Systematic Review and Individual Patient Data Meta-analysis,” European Journal of Nuclear Medicine and Molecular Imaging 52 (2024): 225-236.

[97]	T. Sivakumaran, A. Cardin, J. Callahan, et al., “Evaluating the Utility of (18)F-FDG PET/CT in Cancer of Unknown Primary,” Journal of Nuclear Medicine 65 (2024): 1557-1563.

[98]	C. P. Reinert, J. Sekler, C. la Fougere, C. Pfannenberg, and S. Gatidis, “Impact of PET/CT on Clinical Management in Patients With Cancer of Unknown Primary-a PET/CT Registry Study,” European Radiology 30 (2020): 1325-1333.

[99]	C. van der Leest, E. F. Smit, J. Baas, et al., “SUVmax During 18FDG-PET Scanning in Small Cell Lung Cancer: Similar Information as in Non-small Cell Lung Cancer?,” Lung Cancer 76 (2012): 67-71.

[100]

N. M. Cheng, C. E. Hsieh, C. T. Liao, et al., “Prognostic Value of Tumor Heterogeneity and SUVmax of Pretreatment 18F-FDG PET/CT for Salivary Gland Carcinoma with High-Risk Histology,” Clinical Nuclear Medicine 44 (2019): 351-358.

[101]

S. Liu, Z. Feng, H. Wen, et al., “(18)F-FDG PET/CT Can Predict Chemosensitivity and Proliferation of Epithelial Ovarian Cancer via SUVmax Value,” Japanese Journal of Radiology 36 (2018): 544-550.

[102]

T. F. Cermik, N. Ergul, B. Yilmaz, and G. Mercanoglu, “Tumor Imaging with 68Ga-DOTA-FAPI-04 PET/CT: Comparison with 18F-FDG PET/CT in 22 Different Cancer Types,” Clinical Nuclear Medicine 47 (2022): e333-e339.

[103]

B. Gu, Z. Yang, X. Du, et al., “Imaging of Tumor Stroma Using (68)Ga-FAPI PET/CT to Improve Diagnostic Accuracy of Primary Tumors in Head and Neck Cancer of Unknown Primary: A Comparative Imaging Trial,” Journal of Nuclear Medicine 65 (2024): 365-371.

[104]

B. Gu, X. Xu, J. Zhang, et al., “The Added Value of (68)Ga-FAPI PET/CT in Patients With Head and Neck Cancer of Unknown Primary With (18)F-FDG-Negative Findings,” Journal of Nuclear Medicine 63 (2022): 875-881.

[105]

G. Rossi, N. Nannini, and M. Costantini, “Morphology and More Specific Immunohistochemical Stains Are Fundamental Prerequisites in Detection of Unknown Primary Cancer,” Journal of Clinical Oncology 27 (2009): 649-650. author reply 650-642.

[106]

K. Beauchamp, B. Moran, T. O'Brien, et al., “Carcinoma of Unknown Primary (CUP): An Update for Histopathologists,” Cancer and Metastasis Reviews 42 (2023): 1189-1200.

[107]

T. Seidlitz, Y. T. Chen, H. Uhlemann, et al., “Mouse Models of Human Gastric Cancer Subtypes with Stomach-Specific CreERT2-Mediated Pathway Alterations,” Gastroenterology 157 (2019): 1599-1614. e1592.

[108]

J. Selves, E. Long-Mira, M. C. Mathieu, P. Rochaix, and M. Ilie, “Immunohistochemistry for Diagnosis of Metastatic Carcinomas of Unknown Primary Site,” Cancers (Basel) 10 (2018).

[109]

E. Rassy, R. Abou-Jaoude, S. Boussios, et al., “Sarcoma of Unknown Primary: Myth or Reality?,” Journal of the Egyptian National Cancer Institute 34 (2022): 27.

[110]

R. Odze, “Cytokeratin 7/20 Immunostaining: Barrett's Oesophagus or Gastric Intestinal Metaplasia?,” Lancet 359 (2002): 1711-1713.

[111]

K. A. Oien and J. L. Dennis, “Diagnostic Work-up of Carcinoma of Unknown Primary: From Immunohistochemistry to Molecular Profiling,” Annals of Oncology 23, no. Suppl 10 (2012): x271-277.

[112]

H. Vidarsdottir, L. Tran, B. Nodin, et al., “Immunohistochemical Profiles in Primary Lung Cancers and Epithelial Pulmonary Metastases,” Human Pathology 84 (2019): 221-230.

[113]

J. D. Hainsworth and F. A. Greco, “Gene Expression Profiling in Patients With Carcinoma of Unknown Primary Site: From Translational Research to Standard of Care,” Virchows Archiv 464 (2014): 393-402.

[114]

J. K. Dermawan and B. P. Rubin, “The Role of Molecular Profiling in the Diagnosis and Management of Metastatic Undifferentiated Cancer of Unknown Primary(*): Molecular Profiling of Metastatic Cancer of Unknown Primary,” Seminars in Diagnostic Pathology 38 (2021): 193-198.

[115]

H. M. Horlings, R. K. van Laar, J. M. Kerst, et al., “Gene Expression Profiling to Identify the Histogenetic Origin of Metastatic Adenocarcinomas of Unknown Primary,” Journal of Clinical Oncology 26 (2008): 4435-4441.

[116]

J. Bridgewater, R. van Laar, A. Floore, and T. V. L. Van, “Gene Expression Profiling May Improve Diagnosis in Patients With Carcinoma of Unknown Primary,” British Journal of Cancer 98 (2008): 1425-1430.

[117]

G. R. Varadhachary, D. Talantov, M. N. Raber, et al., “Molecular Profiling of Carcinoma of Unknown Primary and Correlation With Clinical Evaluation,” Journal of Clinical Oncology 26 (2008): 4442-4448.

[118]

S. Moran, A. Martinez-Cardus, S. Boussios, and M. Esteller, “Precision Medicine Based on Epigenomics: The Paradigm of Carcinoma of Unknown Primary,” Nature Reviews Clinical Oncology 14 (2017): 682-694.

[119]

H. Hasegawa, M. Ando, Y. Yatabe, et al., “Site-specific Chemotherapy Based on Predicted Primary Site by Pathological Profile for Carcinoma of Unknown Primary Site,” Clinical Oncology (Royal College of Radiologists (Great Britain)) 30 (2018): 667-673.

[120]

R. K. van Laar, X. J. Ma, D. de Jong, et al., “Implementation of a Novel Microarray-based Diagnostic Test for Cancer of Unknown Primary,” International Journal of Cancer 125 (2009): 1390-1397.

[121]

R. Pillai, R. Deeter, C. T. Rigl, et al., “Validation and Reproducibility of a Microarray-based Gene Expression Test for Tumor Identification in Formalin-fixed, Paraffin-embedded Specimens,” The Journal of Molecular Diagnostics 13 (2011): 48-56.

[122]

F. A. Monzon, F. Medeiros, M. Lyons-Weiler, and W. D. Henner, “Identification of Tissue of Origin in Carcinoma of Unknown Primary With a Microarray-based Gene Expression Test,” Diagnostic Pathology 5 (2010): 3.

[123]

J. D. Hainsworth, C. A. Schnabel, M. G. Erlander, D. W. Haines, and F. A. Greco, “A Retrospective Study of Treatment Outcomes in Patients With Carcinoma of Unknown Primary Site and a Colorectal Cancer Molecular Profile,” Clinical Colorectal Cancer 11 (2012): 112-118.

[124]

Y. Zhang, L. Xia, D. Ma, J. Wu, X. Xu, and Y. Xu, “90-Gene Expression Profiling for Tissue Origin Diagnosis of Cancer of Unknown Primary,” Frontiers in Oncology 11 (2021): 722808.

[125]

P. Qi, Y. Sun, Y. Pang, et al., “Diagnostic Utility of a 90-Gene Expression Assay (Canhelp-Origin) for Patients With Metastatic Cancer With an Unclear or Unknown Diagnosis,” Molecular Diagnosis & Therapy (2024).

[126]

Q. Wang, F. Li, Q. Jiang, et al., “Gene Expression Profiling for Differential Diagnosis of Liver Metastases: A Multicenter, Retrospective Cohort Study,” Frontiers in Oncology 11 (2021): 725988.

[127]

M. Ferracin, M. Pedriali, A. Veronese, et al., “MicroRNA Profiling for the Identification of Cancers With Unknown Primary Tissue-of-origin,” Journal of Pathology 225 (2011): 43-53.

[128]

G. R. Varadhachary, Y. Spector, J. L. Abbruzzese, et al., “Prospective Gene Signature Study Using microRNA to Identify the Tissue of Origin in Patients With Carcinoma of Unknown Primary,” Clinical Cancer Research 17 (2011): 4063-4070.

[129]

N. Laprovitera, M. Riefolo, E. Porcellini, et al., “MicroRNA Expression Profiling With a Droplet Digital PCR Assay Enables Molecular Diagnosis and Prognosis of Cancers of Unknown Primary,” Molecular Oncology 15 (2021): 2732-2751.

[130]

E. Meiri, W. C. Mueller, S. Rosenwald, et al., “A Second-generation microRNA-based Assay for Diagnosing Tumor Tissue Origin,” The Oncologist 17 (2012): 801-812.

[131]

M. O. Sanden, R. Wassman, K. Ashkenazi, H. Benjamin, Y. Spector, and E. Goren, “Observational Study of Real World Clinical Performance of Microrna Molecular Profiling for Cancer of Unknown Primary (CUP),” Journal of Clinical Oncology (2013): abstr e22173.

[132]

R. W. Tothill, A. Kowalczyk, D. Rischin, et al., “An Expression-based Site of Origin Diagnostic Method Designed for Clinical Application to Cancer of Unknown Origin,” Cancer Research 65 (2005): 4031-4040.

[133]

L. Morawietz, A. Floore, L. Stork-Sloots, et al., “Comparison of Histopathological and Gene Expression-based Typing of Cancer of Unknown Primary,” Virchows Archiv 456 (2010): 23-29.

[134]

C. I. Dumur, C. E. Fuller, T. L. Blevins, et al., “Clinical Verification of the Performance of the Pathwork Tissue of Origin Test: Utility and Limitations,” American Journal of Clinical Pathology 136 (2011): 924-933.

[135]

A. F. Fernandez, Y. Assenov, J. I. Martin-Subero, et al., “A DNA Methylation Fingerprint of 1628 human Samples,” Genome Research 22 (2012): 407-419.

[136]

F. Ades, E. de Azambuja, G. Daugaard, et al., “Comparison of a Gene Expression Profiling Strategy to Standard Clinical Work-up for Determination of Tumour Origin in Cancer of Unknown Primary (CUP),” Journal of Chemotherapy 25 (2013): 239-246.

[137]

R. W. Tothill, F. Shi, L. Paiman, et al., “Development and Validation of a Gene Expression Tumour Classifier for Cancer of Unknown Primary,” Pathology 47 (2015): 7-12.

[138]

A. Posner, O. W. Prall, T. Sivakumaran, et al., “A Comparison of DNA Sequencing and Gene Expression Profiling to Assist Tissue of Origin Diagnosis in Cancer of Unknown Primary,” Journal of Pathology 259 (2023): 81-92.

[139]

B. G. Mathew, F. Aliyuda, D. Taiwo, et al., “From Biology to Diagnosis and Treatment: The Ariadne's Thread in Cancer of Unknown Primary,” International Journal of Molecular Sciences 24 (2023).

[140]

J. De Wilde, R. Van Paemel, A. De Koker, et al., “A Fast, Affordable, and Minimally Invasive Diagnostic Test for Cancer of Unknown Primary Using DNA Methylation Profiling,” Laboratory Investigation 104 (2024): 102091.

[141]

L. Stark, A. Kasajima, F. Stogbauer, et al., “Head and Neck Cancer of Unknown Primary: Unveiling Primary Tumor Sites Through Machine Learning on DNA Methylation Profiles,” Clinical Epigenetics 16 (2024): 47.

[142]

J. Hwang, Y. Lee, S. K. Yoo, and J. I. Kim, “Image-based Deep Learning Model Using DNA Methylation Data Predicts the Origin of Cancer of Unknown Primary,” Neoplasia 55 (2024): 101021.

[143]

Epigenetic Profiling of CUP. Cancer Discovery 2016, 6: 1203.

[144]

M. L. Stackpole, W. Zeng, S. Li, et al., “Cost-effective Methylome Sequencing of Cell-free DNA for Accurately Detecting and Locating Cancer,” Nature Communications 13 (2022): 5566.

[145]

K. Swanson, E. Wu, A. Zhang, A. A. Alizadeh, and J. Zou, “From Patterns to Patients: Advances in Clinical Machine Learning for Cancer Diagnosis, Prognosis, and Treatment,” Cell 186 (2023): 1772-1791.

[146]

X. Wang, J. Zhao, E. Marostica, et al., “A Pathology Foundation Model for Cancer Diagnosis and Prognosis Prediction,” Nature 634 (2024): 970-978.

[147]

M. K. Gould, B. Z. Huang, M. C. Tammemagi, Y. Kinar, and R. Shiff, “Machine Learning for Early Lung Cancer Identification Using Routine Clinical and Laboratory Data,” American Journal of Respiratory and Critical Care Medicine 204 (2021): 445-453.

[148]

D. Dong, M. J. Fang, L. Tang, et al., “Deep Learning Radiomic Nomogram Can Predict the Number of Lymph Node Metastasis in Locally Advanced Gastric Cancer: An International Multicenter Study,” Annals of Oncology 31 (2020): 912-920.

[149]

Y. Liu, A. Jain, C. Eng, et al., “A Deep Learning System for Differential Diagnosis of Skin Diseases,” Nature Medicine 26 (2020): 900-908.

[150]

S. W. Lorkowski, J. K. Dermawan, and B. P. Rubin, “The Practical Utility of AI-assisted Molecular Profiling in the Diagnosis and Management of Cancer of Unknown Primary: An Updated Review,” Virchows Archiv 484 (2024): 369-375.

[151]

J. Michuda, A. Breschi, J. Kapilivsky, et al., “Validation of a Transcriptome-Based Assay for Classifying Cancers of Unknown Primary Origin,” Molecular Diagnosis & Therapy 27 (2023): 499-511.

[152]

A. M. Conway, S. P. Pearce, A. Clipson, et al., “A cfDNA Methylation-based Tissue-of-origin Classifier for Cancers of Unknown Primary,” Nature Communications 15 (2024): 3292.

[153]

F. A. Greco, J. B. Erland, L. H. Morrissey, et al., “Carcinoma of Unknown Primary Site: Phase II Trials With Docetaxel plus Cisplatin or Carboplatin,” Annals of Oncology 11 (2000): 211-215.

[154]

F. A. Greco, J. Gray, H. A. Burris, J. B. Erland, L. H. Morrissey, and J. D. Hainsworth, “Taxane-based Chemotherapy for Patients With Carcinoma of Unknown Primary Site,” Cancer Journal (Sudbury, Mass.) 7 (2001): 203-212.

[155]

E. Briasoulis, H. Kalofonos, D. Bafaloukos, et al., “Carboplatin plus Paclitaxel in Unknown Primary Carcinoma: A Phase II Hellenic Cooperative Oncology Group Study,” Journal of Clinical Oncology 18 (2000): 3101-3107.

[156]

B. F. El-Rayes, A. F. Shields, M. Zalupski, et al., “A Phase II Study of Carboplatin and Paclitaxel in Adenocarcinoma of Unknown Primary,” American Journal of Clinical Oncology 28 (2005): 152-156.

[157]

E. Briasoulis, G. Fountzilas, A. Bamias, et al., “Multicenter Phase-II Trial of irinotecan plus Oxaliplatin [IROX regimen] in Patients With Poor-prognosis Cancer of Unknown Primary: A Hellenic cooperative Oncology Group Study,” Cancer Chemotheraphy and Pharmacology 62 (2008): 277-284.

[158]

S. Culine, A. Lortholary, J. J. Voigt, et al., “Cisplatin in Combination With either Gemcitabine or Irinotecan in Carcinomas of Unknown Primary Site: Results of a Randomized Phase II Study-trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01),” Journal of Clinical Oncology 21 (2003): 3479-3482.

[159]

A. Piga, R. Nortilli, G. L. Cetto, et al., “Carboplatin, Doxorubicin and Etoposide in the Treatment of Tumours of Unknown Primary Site,” British Journal of Cancer 90 (2004): 1898-1904.

[160]

G. Pentheroudakis, E. Briasoulis, H. P. Kalofonos, et al., “Docetaxel and Carboplatin Combination Chemotherapy as Outpatient Palliative Therapy in Carcinoma of Unknown Primary: A Multicentre Hellenic Cooperative Oncology Group Phase II Study,” Acta Oncologica 47 (2008): 1148-1155.

[161]

R. L. Woods, R. M. Fox, M. H. Tattersall, J. A. Levi, and G. N. Brodie, “Metastatic Adenocarcinomas of Unknown Primary Site: A Randomized Study of Two Combination-chemotherapy Regimens,” New England Journal of Medicine 303 (1980): 87-89.

[162]

R. M. Goldberg, F. P. Smith, W. Ueno, J. D. Ahlgren, and P. S. Schein, “5-fluorouracil, Adriamycin, and Mitomycin in the Treatment of Adenocarcinoma of Unknown Primary,” Journal of Clinical Oncology 4 (1986): 395-399.

[163]

D. J. Wagener, P. H. de Mulder, J. T. Burghouts, and J. J. Croles, “Phase II Trial of Cisplatin for Adenocarcinoma of Unknown Primary Site. IKZ/IKO Clinical Research Group,” European Journal of Cancer 27 (1991): 755-757.

[164]

J. D. Hainsworth, J. B. Erland, L. A. Kalman, M. T. Schreeder, and F. A. Greco, “Carcinoma of Unknown Primary Site: Treatment With 1-hour Paclitaxel, Carboplatin, and Extended-schedule Etoposide,” Journal of Clinical Oncology 15 (1997): 2385-2393.

[165]

F. A. Greco and J. D. Hainsworth, “One-hour Paclitaxel, Carboplatin, and Extended-schedule Etoposide in the Treatment of Carcinoma of Unknown Primary Site,” Seminars in Oncology 24, no. S19-S119 (1997): 101-105.

[166]

E. Briasoulis, N. Tsavaris, G. Fountzilas, et al., “Combination Regimen With Carboplatin, Epirubicin and Etoposide in Metastatic Carcinomas of Unknown Primary Site: A Hellenic Co-Operative Oncology Group Phase II Study,” Oncology 55 (1998): 426-430.

[167]

E. Warner, R. Goel, J. Chang, et al., “A Multicentre Phase II Study of Carboplatin and Prolonged Oral Etoposide in the Treatment of Cancer of Unknown Primary Site (CUPS),” British Journal of Cancer 77 (1998): 2376-2380.

[168]

C. I. Falkson and G. L. Cohen, “Mitomycin C, Epirubicin and Cisplatin versus Mitomycin C Alone as Therapy for Carcinoma of Unknown Primary Origin,” Oncology 55 (1998): 116-121.

[169]

F. J. Lofts, H. Gogas, and J. L. Mansi, “Management of Adenocarcinoma of Unknown Primary With a 5-fluorouracil-cisplatin Chemotherapy Regimen (CFTam),” Annals of Oncology 10 (1999): 1389-1392.

[170]

J. E. Dowell, A. M. Garrett, Y. Shyr, D. H. Johnson, and K. R. Hande, “A Randomized Phase II Trial in Patients With Carcinoma of an Unknown Primary Site,” Cancer 91 (2001): 592-597.

[171]

F. A. Greco, H. A. Burris, S. Litchy, et al., “Gemcitabine, Carboplatin, and Paclitaxel for Patients With Carcinoma of Unknown Primary Site: A Minnie Pearl Cancer Research Network Study,” Journal of Clinical Oncology 20 (2002): 1651-1656.

[172]

C. Balana, J. L. Manzano, I. Moreno, et al., “A Phase II Study of Cisplatin, Etoposide and Gemcitabine in an Unfavourable Group of Patients With Carcinoma of Unknown Primary Site,” Annals of Oncology 14 (2003): 1425-1429.

[173]

D. Pouessel, S. Culine, C. Becht, et al., “Gemcitabine and docetaxel as front-line Chemotherapy in Patients With Carcinoma of an Unknown Primary Site,” Cancer 100 (2004): 1257-1261.

[174]

F. A. Greco, G. I. Rodriguez, D. W. Shaffer, et al., “Carcinoma of Unknown Primary Site: Sequential Treatment With Paclitaxel/Carboplatin/Etoposide and Gemcitabine/Irinotecan: A Minnie Pearl Cancer Research Network Phase II Trial,” The Oncologist 9 (2004): 644-652.

[175]

Y. H. Park, B. Y. Ryoo, S. J. Choi, S. H. Yang, and H. T. Kim, “A Phase II Study of paclitaxel plus Cisplatin Chemotherapy in an Unfavourable Group of Patients With Cancer of Unknown Primary Site,” Japanese Journal of Clinical Oncology 34 (2004): 681-685.

[176]

J. D. Hainsworth, D. R. Spigel, E. L. Raefsky, et al., “Combination Chemotherapy With Gemcitabine and Irinotecan in Patients With Previously Treated Carcinoma of an Unknown Primary Site: A Minnie Pearl Cancer Research Network Phase II Trial,” Cancer 104 (2005): 1992-1997.

[177]

H. Carlson, R. Lenzi, M. N. Raber, and G. R. Varadhachary, “A Phase II Study to Evaluate the Efficacy and Toxicity of Oxaliplatin in Combination With Gemcitabine in Carcinoma of Unknown Primary,” International Journal of Clinical Oncology 18 (2013): 226-231.

[178]

S. Palmeri, V. Lorusso, L. Palmeri, et al., “Cisplatin and Gemcitabine With either Vinorelbine or Paclitaxel in the Treatment of Carcinomas of Unknown Primary Site: Results of an Italian Multicenter, Randomized, Phase II Study,” Cancer 107 (2006): 2898-2905.

[179]

J. D. Hainsworth, D. R. Spigel, D. S. Thompson, et al., “Paclitaxel/Carboplatin plus Bevacizumab/Erlotinib in the First-line Treatment of Patients With Carcinoma of Unknown Primary Site,” The Oncologist 14 (2009): 1189-1197.

[180]

K. Schuette, G. Folprecht, A. Kretzschmar, et al., “Phase II Trial of Capecitabine and Oxaliplatin in Patients With Adeno- and Undifferentiated Carcinoma of Unknown Primary,” Onkologie 32 (2009): 162-166.

[181]

G. Huebner, H. Link, C. H. Kohne, et al., “Paclitaxel and Carboplatin vs Gemcitabine and Vinorelbine in Patients With Adeno- or Undifferentiated Carcinoma of Unknown Primary: A Randomised Prospective Phase II Trial,” British Journal of Cancer 100 (2009): 44-49.

[182]

J. D. Hainsworth and D. R. Spigel, “Oxaliplatin and Capecitabine in the Treatment of Patients With Recurrent or Refractory Carcinoma of Unknown Primary Site: A Phase 2 Trial of the Sarah Cannon Oncology Research Consortium,” Cancer 116 (2010): 2448-2454.

[183]

M. Gross-Goupil, A. Fourcade, E. Blot, et al., “Cisplatin Alone or Combined With Gemcitabine in Carcinomas of Unknown Primary: Results of the Randomised GEFCAPI 02 Trial,” European Journal of Cancer 48 (2012): 721-727.

[184]

J. D. Hainsworth, G. Daugaard, T. Lesimple, et al., “Paclitaxel/Carboplatin With or Without Belinostat as Empiric First-line Treatment for Patients With Carcinoma of Unknown Primary Site: A Randomized, Phase 2 Trial,” Cancer 121 (2015): 1654-1661.

[185]

D. Y. Shin, Y. H. Choi, L. HR, et al., “A Phase II Trial of Modified FOLFOX6 as First-line Therapy for Adenocarcinoma of an Unknown Primary Site,” Cancer Chemotheraphy and Pharmacology 77 (2016): 163-168.

[186]

M. Martin, A. Villar, A. Sole-Calvo, et al., “Doxorubicin in Combination With Fluorouracil and Cyclophosphamide (i.v. FAC regimen, day 1, 21) versus Methotrexate in Combination With Fluorouracil and Cyclophosphamide (i.v. CMF regimen, day 1, 21) as Adjuvant Chemotherapy for Operable Breast Cancer: A Study by the GEICAM Group,” Annals of Oncology 14 (2003): 833-842.

[187]

M. Reck, J. Remon, and M. D. Hellmann, “First-Line Immunotherapy for Non-Small-Cell Lung Cancer,” Journal of Clinical Oncology 40 (2022): 586-597.

[188]

M. Pinter, B. Scheiner, and D. J. Pinato, “Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Emerging Challenges in Clinical Practice,” The Lancet Gastroenterology and Hepatology 8 (2023): 760-770.

[189]

X. Liu, X. Zhang, S. Jiang, et al., “Site-specific Therapy Guided by a 90-gene Expression Assay versus Empirical Chemotherapy in Patients With Cancer of Unknown Primary (Fudan CUP-001): A Randomised Controlled Trial,” The Lancet Oncology 25 (2024): 1092-1102.

[190]

X. Hu, S. Jiang, and X. Liu, “Site-specific or Empirical Chemotherapy for Cancer of Unknown Primary: The Right Answer?—Authors' reply,” The Lancet Oncology 25 (2024): e530.

[191]

C. Aggarwal, M. E. Marmarelis, W. T. Hwang, et al., “Association between Availability of Molecular Genotyping Results and Overall Survival in Patients with Advanced Nonsquamous Non-Small-Cell Lung Cancer,” JCO Precision Oncology 7 (2023): e2300191.

[192]

M. B. Nierengarten, “Molecularly Guided Therapy Improves Survival Outcomes for Patients With a Cancer of Unknown Primary,” Cancer 130 (2024): 4165.

[193]

K. Haratani, H. Hayashi, T. Takahama, et al., “Clinical and Immune Profiling for Cancer of Unknown Primary Site,” Journal for ImmunoTherapy of Cancer 7 (2019): 251.

[194]

E. Rassy, S. Boussios, and N. Pavlidis, “Genomic Correlates of Response and Resistance to Immune Checkpoint Inhibitors in Carcinomas of Unknown Primary,” European Journal of Clinical Investigation 51 (2021): e13583.

[195]

J. D. Hainsworth, H. A. Burris, S. W. Calvert, et al., “Gemcitabine in the Second-line Therapy of Patients With Carcinoma of Unknown Primary Site: A Phase II Trial of the Minnie Pearl Cancer Research Network,” Cancer Investigation 19 (2001): 335-339.

[196]

J. D. Hainsworth, D. R. Spigel, C. Farley, et al., “Phase II Trial of Bevacizumab and Erlotinib in Carcinomas of Unknown Primary Site: The Minnie Pearl Cancer Research Network,” Journal of Clinical Oncology 25 (2007): 1747-1752.

[197]

A. K. Moller, K. D. Pedersen, J. Abildgaard, B. L. Petersen, and G. Daugaard, “Capecitabine and Oxaliplatin as Second-line Treatment in Patients With Carcinoma of Unknown Primary Site,” Acta Oncologica 49 (2010): 431-435.

[198]

J. Tanizaki, K. Yonemori, K. Akiyoshi, et al., “Open-label Phase II Study of the Efficacy of nivolumab for Cancer of Unknown Primary,” Annals of Oncology 33 (2022): 216-226.

[199]

K. P. Raghav, B. Stephen, D. D. Karp, et al., “Efficacy of pembrolizumab in Patients With Advanced Cancer of Unknown Primary (CUP): A Phase 2 Non-randomized Clinical Trial,” Journal for ImmunoTherapy of Cancer 10 (2022).

[200]

M. Pouyiourou, B. N. Kraft, T. Wohlfromm, et al., “Nivolumab and ipilimumab in Recurrent or Refractory Cancer of Unknown Primary: A Phase II Trial,” Nature Communications 14 (2023): 6761.

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