Carcinoma of Unknown Primary Site: Outcomes in Patients with a Colorectal Molecular Profile Treated with Site Specific Chemotherapy
Author(s)
F. Anthony Greco*,
Wayne J. Lennington,
David R. Spigel,
Gauri R. Varadhachary,
John D. Hainsworth
ABSTRACT
Purpose: Accurate identification of carcinoma of unknown primary site (CUP) patients with colorectal sites of origin may improve outcomes by directing colorectal chemotherapy rather than empiric chemotherapy. Clinical features, standard pathologic evaluation, treatment response, and survival of CUP patients whose tumors had colorectal genetic signatures were examined. Patients and Methods: We prospectively tested paraffin-embedded biopsies from 213 CUP patients using mRNA-based RT-PCR assays, and identified patients with colorectal genetic signatures. Results: Assays were successful in 185 specimens (87%); 32 (17%) had colorectal genetic signatures. All 32 patients had carcinoma; colonoscopy was normal in 30 patients studied; 29 patients (90%) had typical metastatic sites; 17 (53%) had consistent IHC profiles (CK20+, CDX2+). Twenty-nine patients (90%) received first- and/or second-line colorectal chemotherapy regimens (response rates of 69% and 54%, respectively). Median, 2- and 4-year survivals for all 32 patients were 21 months, 42%, and 35%, respectively. Conclusion: The majority of CUP patients with colorectal molecular profile diagnoses responded to site-specific chemotherapy; median survival was similar to patients with known advanced colorectal carcinoma and superior to expected survival of CUP patients receiving empiric chemotherapy. Molecular profile assays can identify CUP patients with colorectal carcinoma; colorectal chemotherapy appears to improve outcomes.
Purpose: Accurate identification of carcinoma of unknown primary site (CUP) patients with colorectal sites of origin may improve outcomes by directing colorectal chemotherapy rather than empiric chemotherapy. Clinical features, standard pathologic evaluation, treatment response, and survival of CUP patients whose tumors had colorectal genetic signatures were examined. Patients and Methods: We prospectively tested paraffin-embedded biopsies from 213 CUP patients using mRNA-based RT-PCR assays, and identified patients with colorectal genetic signatures. Results: Assays were successful in 185 specimens (87%); 32 (17%) had colorectal genetic signatures. All 32 patients had carcinoma; colonoscopy was normal in 30 patients studied; 29 patients (90%) had typical metastatic sites; 17 (53%) had consistent IHC profiles (CK20+, CDX2+). Twenty-nine patients (90%) received first- and/or second-line colorectal chemotherapy regimens (response rates of 69% and 54%, respectively). Median, 2- and 4-year survivals for all 32 patients were 21 months, 42%, and 35%, respectively. Conclusion: The majority of CUP patients with colorectal molecular profile diagnoses responded to site-specific chemotherapy; median survival was similar to patients with known advanced colorectal carcinoma and superior to expected survival of CUP patients receiving empiric chemotherapy. Molecular profile assays can identify CUP patients with colorectal carcinoma; colorectal chemotherapy appears to improve outcomes.
Cite this paper
F. Greco, W. Lennington, D. Spigel, G. Varadhachary and J. Hainsworth, "Carcinoma of Unknown Primary Site: Outcomes in Patients with a Colorectal Molecular Profile Treated with Site Specific Chemotherapy," Journal of Cancer Therapy, Vol. 3 No. 1, 2012, pp. 37-43. doi: 10.4236/jct.2012.31005.
F. Greco, W. Lennington, D. Spigel, G. Varadhachary and J. Hainsworth, "Carcinoma of Unknown Primary Site: Outcomes in Patients with a Colorectal Molecular Profile Treated with Site Specific Chemotherapy," Journal of Cancer Therapy, Vol. 3 No. 1, 2012, pp. 37-43. doi: 10.4236/jct.2012.31005.
References
[1] F. A. Greco amd J. D. Hainsworth, “Cancer of Unknown Primary Site,” In: V. T. J. DeVita, S. Hellman, S. A. Rosenberg, Eds., Cancer: Principles and Practice of Oncology, 8th Editon, Lippincott, Philadelphia, 2008, pp. 2363-2387. [2] F. A. Greco and M. G Erlander, “Molecular Classification of Cancers of Unknown Primary Site,” Molecular Diagnosis Therapy, Vol. 13, No. 6, 2009, pp. 367-737. [3] X. J. Ma, R. Patel, X. Wang, et al., “Molecular Classification of Human Cancers Using a 92-Gene Real-Time Quantitative Polymerase Chain Reaction Assay,” Archives of Pathology & Laboratory Medicine, Vol. 130, No. 4, 2006, pp. 465-472. [4] N. Rosenfeld, R. Aharonov, E. Meiril, et al., “MicroRNAs Accurately Identify Cancer Tissue Origin,” Nature Biotechnology, Vol. 26, No. 4, 2008, pp. 462-469. doi:10.1038/nbt1392 [5] F. A. Monzon, M. Lyons-Weiler, L. J. Buturovic, et al., “Multicenter Validation of a 1500-Gene Expression Profile for Identification of Tumor Tissue of Origin,” Journal of Clinical Oncology, Vol. 27, No. 15, 2009, pp. 2503-2509. doi:10.1200/JCO.2008.17.9762 [6] R. Pilllai, R. Deeler, C. T. Rigl, et al., “Validation and Reproducibility of a Microarray-Based Gene Expression Test for Tumor Indentification in Formalin-Fixed, Paraffin-Embedded Specimens,” The Journal of Molecular Diagnostics, Vol. 13, No. 1, 2011, pp. 48-56. doi:10.1016/j.jmoldx.2010.11.001 [7] G. Varadhachary, D. Talantov, M. Raber, et al., “Molecular Profiling of Carcinoma of Unknown Primary and Correlation with Clinical Evaluation,” Journal of Clinical Oncology, Vol. 26, No. 27, 2008, pp. 4442-4450. doi:10.1200/JCO.2007.14.4378 [8] J. Bridgewater, R. van Laar, A. Floore, et al., “Gene Expression Profiling May Improve Diagnosis in Patients with Carcinoma of Unknown Primary,” British Journal of Cancer, Vol. 98, No. 8, 2008, pp. 1425-1430. doi:10.1038/sj.bjc.6604315 [9] H. M. Horlings, R. 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, Vol. 26, No. 27, 2008, pp. 4435-4439. doi:10.1200/JCO.2007.14.6969 [10] F. A. Monzon, F. Medeiros, M. Lyons-Weiler, et al., “Identification of Tissue of Origin in Carcinoma of Unknown Primary with a Microarray-Based Gene Expression Test,” Diagnostic Pathology, Vol. 5, 2010, pp. 3-7. doi:10.1186/1746-1596-5-3 [11] F. A. Greco, D. R. Spigel, D. A. Yardley, et al., “Molecular Profiling in Unknown Primary Cancer Tissue of Origin Prediction,” The Oncologist, Vol. 15, No. 5, 2010, pp. 500-506. doi:10.1634/theoncologist.2009-0328 [12] F. A. Greco and N. Pavlidis, “Treatment for Patients with Unknown Primary Carcinoma and Unfavorable Prognostic Factors,” Seminars in Oncology, Vol. 36, No. 1, 2009, pp. 35-74. doi:10.1053/j.seminoncol.2008.10.005 [13] L. B. Saltz, S. Clarke, E. Diaz-Rubio, W. Scheithauer, et al., “Bevacizumab in Combination with Oxaliplatin-Based Chemotherapy as First-Line Therapy in Metastatic Colorectal cancer: A Randomized Phase III Study,” Journal of Clinical Oncology, Vol. 26, No. 12, 2008, pp. 2013-2019. doi:10.1200/JCO.2007.14.9930 [14] F. F. Kabbinavar, H. I. Hurwitz, J. Yi, et al., “Addition of Bevacizumab to Fluorouracil-Based First-Line Treatment of Metastatic Colorectal Cancer: Pooled Analysis of Cohorts of Older Patients from Two Randomized Clinical Trials,” Journal of Clinical Oncology, Vol. 27, No. 2, 2000, pp. 199-205. doi:10.1200/JCO.2008.17.7931 [15] D. Talantov, J. Baden and T. Jaktoe, “A Quantitative Reverse Transcriptase-Polymerase Chain Reaction Array to Identify Metastatic Carcinoma Tissue of Origin,” The Journal of Molecular Diagnostics, Vol. 8, No. 3, 2006, pp. 320. doi:10.2353/jmoldx.2006.050136 [16] S. Y. Park, B. H. Kim, S. H. Kim, et al., “Panels of Immunohistochemical Markers Help Determine Primary Sites of Metastatic Adenocarcinomas,” Archives of Pathology & Laboratory Medicine, Vol. 131, No. 10, 2007, pp. 1561-1567. [17] K. A. Oien, “Pathologic Evaluation of Unknown Primary Cancer,” Seminars in Oncology, Vol. 36, No. 1, 2009, pp. 8-37. doi:10.1053/j.seminoncol.2008.10.009 [18] P. J. Zhang, M. hah, G. W. Spiegel, et al., “Cytokeratin 7 Immunoreactivity in Rectal Adenocarcinoma,” Applied Immunohistochemistry & Molecular Morphology, Vol. 11, No. 4, 2003, pp. 306-310. doi:10.1097/00129039-200312000-00005 [19] G. R. Varadhachary, M. N. Raber, A. Matamoros, et al., “Carcinoma of Unknown Primary with a Colon-Cancer Profile-Changing Paradigm and Emerging Definitions,” The Lancet Oncology, Vol. 9, No. 6, 2008, pp. 596-600. doi:10.1016/S1470-2045(08)70151-7
[1] F. A. Greco amd J. D. Hainsworth, “Cancer of Unknown Primary Site,” In: V. T. J. DeVita, S. Hellman, S. A. Rosenberg, Eds., Cancer: Principles and Practice of Oncology, 8th Editon, Lippincott, Philadelphia, 2008, pp. 2363-2387. [2] F. A. Greco and M. G Erlander, “Molecular Classification of Cancers of Unknown Primary Site,” Molecular Diagnosis Therapy, Vol. 13, No. 6, 2009, pp. 367-737. [3] X. J. Ma, R. Patel, X. Wang, et al., “Molecular Classification of Human Cancers Using a 92-Gene Real-Time Quantitative Polymerase Chain Reaction Assay,” Archives of Pathology & Laboratory Medicine, Vol. 130, No. 4, 2006, pp. 465-472. [4] N. Rosenfeld, R. Aharonov, E. Meiril, et al., “MicroRNAs Accurately Identify Cancer Tissue Origin,” Nature Biotechnology, Vol. 26, No. 4, 2008, pp. 462-469. doi:10.1038/nbt1392 [5] F. A. Monzon, M. Lyons-Weiler, L. J. Buturovic, et al., “Multicenter Validation of a 1500-Gene Expression Profile for Identification of Tumor Tissue of Origin,” Journal of Clinical Oncology, Vol. 27, No. 15, 2009, pp. 2503-2509. doi:10.1200/JCO.2008.17.9762 [6] R. Pilllai, R. Deeler, C. T. Rigl, et al., “Validation and Reproducibility of a Microarray-Based Gene Expression Test for Tumor Indentification in Formalin-Fixed, Paraffin-Embedded Specimens,” The Journal of Molecular Diagnostics, Vol. 13, No. 1, 2011, pp. 48-56. doi:10.1016/j.jmoldx.2010.11.001 [7] G. Varadhachary, D. Talantov, M. Raber, et al., “Molecular Profiling of Carcinoma of Unknown Primary and Correlation with Clinical Evaluation,” Journal of Clinical Oncology, Vol. 26, No. 27, 2008, pp. 4442-4450. doi:10.1200/JCO.2007.14.4378 [8] J. Bridgewater, R. van Laar, A. Floore, et al., “Gene Expression Profiling May Improve Diagnosis in Patients with Carcinoma of Unknown Primary,” British Journal of Cancer, Vol. 98, No. 8, 2008, pp. 1425-1430. doi:10.1038/sj.bjc.6604315 [9] H. M. Horlings, R. 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, Vol. 26, No. 27, 2008, pp. 4435-4439. doi:10.1200/JCO.2007.14.6969 [10] F. A. Monzon, F. Medeiros, M. Lyons-Weiler, et al., “Identification of Tissue of Origin in Carcinoma of Unknown Primary with a Microarray-Based Gene Expression Test,” Diagnostic Pathology, Vol. 5, 2010, pp. 3-7. doi:10.1186/1746-1596-5-3 [11] F. A. Greco, D. R. Spigel, D. A. Yardley, et al., “Molecular Profiling in Unknown Primary Cancer Tissue of Origin Prediction,” The Oncologist, Vol. 15, No. 5, 2010, pp. 500-506. doi:10.1634/theoncologist.2009-0328 [12] F. A. Greco and N. Pavlidis, “Treatment for Patients with Unknown Primary Carcinoma and Unfavorable Prognostic Factors,” Seminars in Oncology, Vol. 36, No. 1, 2009, pp. 35-74. doi:10.1053/j.seminoncol.2008.10.005 [13] L. B. Saltz, S. Clarke, E. Diaz-Rubio, W. Scheithauer, et al., “Bevacizumab in Combination with Oxaliplatin-Based Chemotherapy as First-Line Therapy in Metastatic Colorectal cancer: A Randomized Phase III Study,” Journal of Clinical Oncology, Vol. 26, No. 12, 2008, pp. 2013-2019. doi:10.1200/JCO.2007.14.9930 [14] F. F. Kabbinavar, H. I. Hurwitz, J. Yi, et al., “Addition of Bevacizumab to Fluorouracil-Based First-Line Treatment of Metastatic Colorectal Cancer: Pooled Analysis of Cohorts of Older Patients from Two Randomized Clinical Trials,” Journal of Clinical Oncology, Vol. 27, No. 2, 2000, pp. 199-205. doi:10.1200/JCO.2008.17.7931 [15] D. Talantov, J. Baden and T. Jaktoe, “A Quantitative Reverse Transcriptase-Polymerase Chain Reaction Array to Identify Metastatic Carcinoma Tissue of Origin,” The Journal of Molecular Diagnostics, Vol. 8, No. 3, 2006, pp. 320. doi:10.2353/jmoldx.2006.050136 [16] S. Y. Park, B. H. Kim, S. H. Kim, et al., “Panels of Immunohistochemical Markers Help Determine Primary Sites of Metastatic Adenocarcinomas,” Archives of Pathology & Laboratory Medicine, Vol. 131, No. 10, 2007, pp. 1561-1567. [17] K. A. Oien, “Pathologic Evaluation of Unknown Primary Cancer,” Seminars in Oncology, Vol. 36, No. 1, 2009, pp. 8-37. doi:10.1053/j.seminoncol.2008.10.009 [18] P. J. Zhang, M. hah, G. W. Spiegel, et al., “Cytokeratin 7 Immunoreactivity in Rectal Adenocarcinoma,” Applied Immunohistochemistry & Molecular Morphology, Vol. 11, No. 4, 2003, pp. 306-310. doi:10.1097/00129039-200312000-00005 [19] G. R. Varadhachary, M. N. Raber, A. Matamoros, et al., “Carcinoma of Unknown Primary with a Colon-Cancer Profile-Changing Paradigm and Emerging Definitions,” The Lancet Oncology, Vol. 9, No. 6, 2008, pp. 596-600. doi:10.1016/S1470-2045(08)70151-7