Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors
Abstract
:1. Introduction
2. Materials and Methods
2.1. FFPE Tissue Collection
2.2. DNA and RNA Isolation
2.3. High-Throughput Sequencing
2.4. Microsatellite Instability
2.5. HPV Genotyping
2.6. Immunohistochemistry
2.7. ERBB2 Fluorescent in situ (FISH) Hybridization
2.8. Statistical Analysis
3. Results
3.1. Clinicopathological Characteristics of Cohort
3.2. Detection of Genomic Alterations across the Cohort
3.3. Characterization of Histological Subtypes
3.4. Immune Characterization of Gynecological Tumors and Detected Altered Genes
3.5. Clinical Impact
3.6. Total Cost and Cost Difference versus NGS
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
- Galceran, J.; Ameijide, A.; Carulla, M.; Mateos, A.; Quirós, J.R.; Rojas, D.; Alemán, A.; Torrella, A.; Chico, M.; Vicente, M.; et al. Cancer incidence in Spain, 2015. Clin. Transl. Oncol. 2017, 19, 799–825. [Google Scholar] [CrossRef]
- Lovly, C.M.; Shaw, A.T. Molecular Pathways: Resistance to Kinase Inhibitors and Implications for Therapeutic Strategies. Clin. Cancer Res. 2014, 20, 2249–2256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Roock, W.; Claes, B.; Bernasconi, D.; De Schutter, J.; Biesmans, B.; Fountzilas, G.; Kalogeras, K.T.; Kotoula, V.; Papamichael, D.; Laurent-Puig, P.; et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol. 2010, 11, 753–762. [Google Scholar] [CrossRef]
- Evans, T.; Matulonis, U. Next-generation sequencing: Role in gynecologic cancers. J. Natl. Compr. Cancer Netw. 2016, 14, 1165–1173. [Google Scholar] [CrossRef] [PubMed]
- Prendergast, E.N.; Elvin, J.A. Genomic profiling of gynecologic cancers and implications for clinical practice. Curr. Opin. Obstet. Gynecol. 2017, 29, 18–25. [Google Scholar] [CrossRef]
- Roddy, E.; Chapman, J. Genomic insights in gynecologic cancer. Curr. Probl. Cancer 2017, 41, 8–36. [Google Scholar] [CrossRef]
- Kandoth, C.; Schultz, N.; Cherniack, A.; Akbani, R.; Liu, Y. Integrated genomic characterization of endometrial carcinoma. Nature 2013, 497, 67–73. [Google Scholar] [CrossRef] [Green Version]
- Urick, M.E.; Bell, D.W. Clinical actionability of molecular targets in endometrial cancer. Nat. Rev. Cancer 2019, 19, 510–521. [Google Scholar] [CrossRef]
- Bell, D.; Berchuck, A.; Birrer, M.; Chien, J.; Cramer, D. Integrated genomic analyses of ovarian carcinoma. Nature 2011, 474, 609–615. [Google Scholar] [CrossRef]
- Rojas, V.; Hirshfield, K.M.; Ganesan, S.; Rodriguez-Rodriguez, L. Molecular characterization of epithelial ovarian cancer: Implications for diagnosis and treatment. Int. J. Mol. Sci. 2016, 17, 2113. [Google Scholar] [CrossRef] [Green Version]
- Kurman, R.J.; Shih, I. The Dualistic Model of Ovarian Carcinogenesis Revisited, Revised, and Expanded. Am. J. Pathol. 2016, 186, 733–747. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tiezzi, D.G.; Vellano, C.P.; Andrade, K. Integrated genomic and molecular characterization of cervical cancer. Nature 2017, 543, 378–384. [Google Scholar] [CrossRef]
- Miller, E.M.; Patterson, N.E.; Gressel, G.M.; Karabakhtsian, R.G.; Sagie, M.B.; Ravi, N.; Maslov, A.; Tintaya, W.Q.; Wang, T.; Lin, J.; et al. Utility of a custom designed next generation DNA sequencing gene panel to molecularly classify endometrial cancers according to The Cancer Genome Atlas subgroups. BMC Med. Genom. 2020, 13, 179. [Google Scholar] [CrossRef] [PubMed]
- Leskela, S.; Romero, I.; Rosa-Rosa, J.M.; Caniego-casas, T.; Cristobal, E.; Pérez-mies, B.; Gutierrez-pecharroman, A.; Santón, A.; Ojeda, B.; López-reig, R.; et al. Molecular Heterogeneity of Endometrioid Ovarian Carcinoma An Analysis of 166 Cases Using the Endometrial Cancer Subrogate Molecular Classification. Am. J. Surg. Pathol. 2020, 44, 982–990. [Google Scholar] [CrossRef]
- Nie, Q.; Omerza, G.; Chandok, H.; Prego, M.; Hsiao, M.C.; Meyers, B.; Hesse, A.; Uvalic, J.; Soucy, M.; Bergeron, D.; et al. Molecular profiling of gynecologic cancers for treatment and management of disease–demonstrating clinical significance using the AMP/ASCO/CAP guidelines for interpretation and reporting of somatic variants. Cancer Genet. 2020, 242, 25–34. [Google Scholar] [CrossRef]
- Taghizadeh, H.; Mader, R.M.; Müllauer, L.; Aust, S.; Polterauer, S.; Kölbl, H.; Seebacher, V.; Grimm, C.; Reinthaller, A.; Prager, G.W. Molecular Guided Treatments in Gynecologic Oncology: Analysis of a Real-World Precision Cancer Medicine Platform. Oncol. 2020, 25, e1060–e1069. [Google Scholar] [CrossRef]
- Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [Green Version]
- Pinto, M.P.; Balmaceda, C.; Bravo, M.L.; Kato, S.; Villarroel, A.; Owen, G.I.; Roa, J.C.; Cuello, M.A.; Ibañez, C. Patient inflammatory status and CD4+/CD8+ intraepithelial tumor lymphocyte infiltration are predictors of outcomes in high-grade serous ovarian cancer. Gynecol. Oncol. 2018, 151, 10–17. [Google Scholar] [CrossRef] [Green Version]
- Martin de la Fuente, L.; Westbom-Fremer, S.; Arildsen, N.S.; Hartman, L.; Malander, S.; Kannisto, P.; Måsbäck, A.; Hedenfalk, I. PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma. Virchows Arch. 2020, 477, 83–91. [Google Scholar] [CrossRef] [Green Version]
- Chen, P.; Zhang, Y.; Liang, C.; Yang, Y.; Li, Y.; Wan, J. Classification of serous ovarian carcinoma based on immunogenomic profiling. Int. Immunopharmacol. 2021, 91, 107274. [Google Scholar] [CrossRef] [PubMed]
- Gotoh, O.; Kiyotani, K.; Chiba, T.; Sugiyama, Y.; Takazawa, Y.; Nemoto, K.; Kato, K.; Tanaka, N.; Nomura, H.; Hasegawa, K.; et al. Immunogenomic landscape of gynecologic carcinosarcoma. Gynecol. Oncol. 2021, 160, 547–556. [Google Scholar] [CrossRef] [PubMed]
- Prieto-Potin, I.; Carvajal, N.; Plaza-Sánchez, J.; Manso, R.; Aúz-Alexandre, C.L.; Chamizo, C.; Zazo, S.; López-Sánchez, A.; Rodríguez-Pinilla, S.M.; Camacho, L.; et al. Validation and clinical application of a targeted next-generation sequencing gene panel for solid and hematologic malignancies. PeerJ 2020, 8, e10069. [Google Scholar] [CrossRef] [PubMed]
- Li, M.M.; Datto, M.; Duncavage, E.J.; Kulkarni, S.; Lindeman, N.I.; Roy, S.; Tsimberidou, A.M.; Vnencak-Jones, C.L.; Wolff, D.J.; Younes, A.; et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J. Mol. Diagn. 2017, 19, 4–23. [Google Scholar] [CrossRef] [Green Version]
- Goel, A.; Nagasaka, T.; Hamelin, R.; Boland, C.R. An optimized pentaplex PCR for detecting DNA mismatch repair-deficient colorectal cancers. PLoS ONE 2010, 5, e9393. [Google Scholar] [CrossRef]
- Luchini, C.; Bibeau, F.; Ligtenberg, M.J.L.; Singh, N.; Nottegar, A.; Bosse, T.; Miller, R.; Riaz, N.; Douillard, J.-Y.; Andre, F.; et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: A systematic review-based approach. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2019, 30, 1232–1243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salgado, R.; Denkert, C.; Demaria, S.; Sirtaine, N.; Klauschen, F.; Pruneri, G.; Wienert, S.; Van den Eynden, G.; Baehner, F.L.; Penault-Llorca, F.; et al. The evaluation of tumor-infiltrating lymphocytes (TILS) in breast cancer: Recommendations by an International TILS Working Group 2014. Ann. Oncol. 2015, 26, 259–271. [Google Scholar] [CrossRef]
- Hendry, S. Assessing tumor infiltrating lymphocytes in solid tumors: A practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group. Adv. Anat. Pathol. 2017, 24, 311–335. [Google Scholar] [CrossRef]
- Zong, L.; Sun, Z.; Mo, S.; Lu, Z.; Yu, S.; Xiang, Y.; Chen, J. PD-L1 expression in tumor cells is associated with a favorable prognosis in patients with high-risk endometrial cancer. Gynecol. Oncol. 2021, 162, 631–637. [Google Scholar] [CrossRef]
- Köbel, M.; Ronnett, B.M.; Singh, N.; Soslow, R.A.; Gilks, C.B.; Mccluggage, W.G. Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility. Int. J. Gynecol. Pathol. 2018, 38, s123–s131. [Google Scholar] [CrossRef]
- Buza, N. HER2 testing and reporting in endometrial serous carcinoma: Practical recommendations for HER2 immunohistochemistry and fluorescent in situ hybridization: Proceedings of the ISGyP companion society session at the 2020 USCAP annual meeting. Int. J. Gynecol. Pathol. 2021, 40, 17–23. [Google Scholar] [CrossRef] [PubMed]
- Zazo, S.; González-Alonso, P.; Martín-Aparicio, E.; Chamizo, C.; Cristóbal, I.; Arpí, O.; Rovira, A.; Albanell, J.; Eroles, P.; Lluch, A.; et al. Generation, characterization, and maintenance of trastuzumab-resistant HER2+ breast cancer cell lines. Am. J. Cancer Res. 2016, 6, 2661–2678. [Google Scholar] [PubMed]
- Dion, L.; Carton, I.; Jaillard, S.; Timoh, K.N.; De, T.; Rouge, M.; Brousse, S.; Lavou, V. The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer. J. Clin. Med. 2020, 9, 2239. [Google Scholar] [CrossRef] [PubMed]
- Konstantinopoulos, P.A.; Norquist, B.; Lacchetti, C.; Armstrong, D. Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. J. Clin. Oncol. 2020, 38, 1222. [Google Scholar] [CrossRef] [PubMed]
- Köbel, M.; Piskorz, A.M.; Lee, S.; Lui, S.; LePage, C.; Marass, F.; Rosenfeld, N.; Masson, A.M.M.; Brenton, J.D. Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma. J. Pathol. Clin. Res. 2016, 2, 247–258. [Google Scholar] [CrossRef]
- Kuhn, E.; Wang, T.L.; Doberstein, K.; Bahadirli-Talbott, A.; Ayhan, A.; Sehdev, A.S.; Drapkin, R.; Kurman, R.J.; Shih, I.M. CCNE1 amplification and centrosome number abnormality in serous tubal intraepithelial carcinoma: Further evidence supporting its role as a precursor of ovarian high-grade serous carcinoma. Mod. Pathol. 2016, 29, 1254–1261. [Google Scholar] [CrossRef]
- Gorski, J.W.; Ueland, F.R.; Kolesar, J.M. CCNE1 amplification as a predictive biomarker of chemotherapy resistance in epithelial ovarian cancer. Diagnostics 2020, 10, 279. [Google Scholar] [CrossRef]
- Harbin, L.M.; Gallion, H.H.; Allison, D.B.; Kolesar, J.M. Next Generation Sequencing and Molecular Biomarkers in Ovarian Cancer—An Opportunity for Targeted Therapy. Diagnostics 2022, 12, 842. [Google Scholar] [CrossRef]
- Vermij, L.; Smit, V.; Nout, R.; Bosse, T. Incorporation of molecular characteristics into endometrial cancer management. Histopathology 2020, 76, 52–63. [Google Scholar] [CrossRef]
- Murali, R.; Davidson, B.; Fadare, O.; Carlson, J.A.; Crum, C.P.; Gilks, C.B.; Irving, J.A.; Malpica, A.; Matias-guiu, X.; McCluggage, W.G.; et al. High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations. Int. J. Gynecol. Cancer 2018, 38, 40–63. [Google Scholar] [CrossRef]
- Lee, E.K.; Fader, A.N.; Santin, A.D.; Liu, J.F. Uterine serous carcinoma: Molecular features, clinical management, and new and future therapies. Gynecol. Oncol. 2021, 160, 322–332. [Google Scholar] [CrossRef] [PubMed]
- Zhao, S.; Choi, M.; Overton, J.D.; Bellone, S.; Roque, D.M.; Cocco, E.; Guzzo, F.; English, D.P.; Varughese, J.; Gasparrini, S.; et al. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc. Natl. Acad. Sci. USA 2013, 110, 2916–2921. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ross, D.S.; Devereaux, K.A.; Jin, C.; Lin, D.Y.; Zhang, Y.; Marra, A.; Makker, V.; Weigelt, B.; Ellenson, L.H.; Chui, M.H. Histopathologic features and molecular genetic landscape of HER2-amplified endometrial carcinomas. Mod. Pathol. 2021, 35, 962–971. [Google Scholar] [CrossRef]
- Fader, A.N.; Roque, D.M.; Siegel, E.; Buza, N.; Hui, P.; Abdelghany, O.; Chambers, S.K.; Secord, A.A.; Havrilesky, L.; O’Malley, D.M.; et al. Randomized Phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J. Clin. Oncol. 2018, 36, 2044–2051. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hong, J.H.; Cho, H.W.; Ouh, Y.-T.; Lee, J.K.; Chun, Y.; Gim, J.-A. Genomic landscape of advanced endometrial cancer analyzed by targeted next-generation sequencing and the cancer genome atlas (TCGA) dataset. J. Gynecol. Oncol. 2022, 33, e29. [Google Scholar] [CrossRef]
- Arend, R.C.; Goel, N.; Roane, B.M.; Foxall, M.E.; Dholakia, J.; Londoño, A.I.; Wall, J.A.; Leath, C.A.; Huh, W.K. Systematic Next Generation Sequencing is feasible in clinical practice and identifies opportunities for targeted therapy in women with uterine cancer: Results from a prospective cohort study. Gynecol. Oncol. 2021, 163, 85–92. [Google Scholar] [CrossRef]
- Mori, S.; Gotoh, O. Genomic alterations in gynecological malignancies: Histotype-associated driver mutations, molecular subtyping schemes, and tumorigenic mechanisms. J. Hum. Genet. 2021, 66, 853–868. [Google Scholar] [CrossRef]
- Maruthi, V.K.; Khazaeli, M.; Jeyachandran, D.; Desouki, M.M. The Clinical Utility and Impact of Next Generation Sequencing in Gynecologic Cancers. Cancers 2022, 14, 1352. [Google Scholar] [CrossRef]
- Goebel, E.A.; Vidal, A.; Matias-Guiu, X.; Blake Gilks, C. The evolution of endometrial carcinoma classification through application of immunohistochemistry and molecular diagnostics: Past, present and future. Virchows Arch. 2018, 472, 885–896. [Google Scholar] [CrossRef]
- Qiu, L.; Feng, H.; Yu, H.; Li, M.; You, Y.; Zhu, S.; Yang, W.; Jiang, H.; Wu, X. Characterization of the Genomic Landscape in Cervical Cancer by Next Generation Sequencing. Genes 2022, 13, 287. [Google Scholar] [CrossRef]
- Hilal, T.; Nakazawa, M.; Hodskins, J.; Villano, J.L.; Mathew, A.; Goel, G.; Wagner, L.; Arnold, S.M.; Desimone, P.; Anthony, L.B.; et al. Comprehensive genomic profiling in routine clinical practice leads to a low rate of benefit from genotype-directed therapy. BMC Cancer 2017, 17, 602. [Google Scholar] [CrossRef] [PubMed]
- Temko, D.; Van Gool, I.C.; Rayner, E.; Glaire, M.; Makino, S.; Brown, M.; Chegwidden, L.; Palles, C.; Depreeuw, J.; Beggs, A.; et al. Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response. J. Pathol. 2018, 245, 283–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Billingsley, C.; Cohn, D.; Mutch, D.; Hade, E.; Goodfellow, P. Prognostic significance of POLE exonuclease domain mutations in high grade endometrioid endometrial cancer on survival and recurrence: A sub-analysis. Int. J. Gynecol. Cancer 2016, 26, 933–938. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Garmezy, B.; Gheeya, J.; Lin, H.Y.; Huang, Y.; Kim, T.; Jiang, X.; Thein, K.Z.; Pilié, P.G.; Zeineddine, F.; Wang, W.; et al. Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers. JCO Precis. Oncol. 2022, 6, e2100267. [Google Scholar] [CrossRef]
- André, F.; Ciruelos, E.; Rubovszky, G.; Campone, M.; Loibl, S.; Rugo, H.S.; Iwata, H.; Conte, P.; Mayer, I.A.; Kaufman, B.; et al. Alpelisib for PIK3CA -Mutated, Hormone Receptor–Positive Advanced Breast Cancer. N. Engl. J. Med. 2019, 380, 1929–1940. [Google Scholar] [CrossRef]
- Mills, A.M.; Bullock, T.N.; Ring, K.L. Targeting immune checkpoints in gynecologic cancer: Updates & perspectives for pathologists. Mod. Pathol. 2022, 35, 142–151. [Google Scholar] [CrossRef]
- Twomey, J.D.; Zhang, B. Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics. AAPS J. 2021, 23, 39. [Google Scholar] [CrossRef]
- Green, A.K.; Feinberg, J.; Makker, V. A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am. Soc. Clin. Oncol. Educ. B. 2020, 40, 238–244. [Google Scholar] [CrossRef]
- Cao, W.; Ma, X.; Fischer, J.V.; Sun, C.; Kong, B.; Zhang, Q. Immunotherapy in endometrial cancer: Rationale, practice and perspectives. Biomark. Res. 2021, 9, 49. [Google Scholar] [CrossRef]
- Musacchio, L.; Boccia, S.M.; Caruso, G.; Santangelo, G.; Fischetti, M.; Tomao, F.; Perniola, G.; Palaia, I.; Muzii, L.; Pignata, S.; et al. Immune checkpoint inhibitors: A promising choice for endometrial cancer patients? J. Clin. Med. 2020, 9, 1721. [Google Scholar] [CrossRef]
- Aravantinou-Fatorou, A.; Andrikopoulou, A.; Liontos, M.; Fiste, O.; Georgakopoulou, V.E.; Dimopoulos, M.A.; Gavriatopoulou, M.; Zagouri, F. Pembrolizumab in endometrial cancer: Where we stand now (Review). Oncol. Lett. 2021, 22, 821. [Google Scholar] [CrossRef] [PubMed]
- Oaknin, A.; Gilbert, L.; Tinker, A.; Brown, J.; Mathews, C.; Press, J.; Sabatier, R.; O’Malley, D.; Samouelian, V.; Boni, V.; et al. Analysis of antitumor activity of dostarlimab by tumor mutational burden (TMB) in patients with endometrial cancer (EC). Ann. Oncol. 2021, 32, S388–S389. [Google Scholar] [CrossRef]
- Buza, N. Immunohistochemistry in gynecologic carcinomas: Practical update with diagnostic and clinical considerations based on the 2020 WHO classification of tumors. Semin. Diagn. Pathol. 2022, 39, 58–77. [Google Scholar] [CrossRef] [PubMed]
- Chung, H.C.; Schellens, J.H.M.; Delord, J.-P.; Perets, R.; Italiano, A.; Shapira-Frommer, R.; Manzuk, L.; Piha-Paul, S.A.; Wang, J.; Zeigenfuss, S.; et al. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study. J. Clin. Oncol. 2018, 18, 5522. [Google Scholar] [CrossRef]
- Colombo, N.; Dubot, C.; Lorusso, D.; Caceres, M.V.; Hasegawa, K.; Shapira-Frommer, R.; Tewari, K.S.; Salman, P.; Hoyos Usta, E.; Yañez, E.; et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N. Engl. J. Med. 2021, 385, 1856–1867. [Google Scholar] [CrossRef] [PubMed]
- Köbel, M.; Kang, E.Y. The Evolution of Ovarian Carcinoma Subclassification. Cancers 2022, 14, 416. [Google Scholar] [CrossRef]
- Palaia, I.; Tomao, F.; Sassu, C.M.; Musacchio, L.; Panici, P.B. Immunotherapy for ovarian cancer: Recent advances and combination therapeutic approaches. Onco. Targets. Ther. 2020, 13, 6109–6129. [Google Scholar] [CrossRef]
- Santandrea, G.; Piana, S.; Valli, R.; Zanelli, M.; Gasparini, E.; de Leo, A.; Mandato, V.D.; Palicelli, A. Immunohistochemical Biomarkers as a Surrogate of Molecular Analysis in Ovarian Carcinomas: A Review of the Literature. Diagnostics 2021, 11, 199. [Google Scholar] [CrossRef]
- Yi, M.; Zheng, X.; Niu, M.; Zhu, S.; Ge, H.; Wu, K. Combination strategies with PD-1/PD-L1 blockade: Current advances and future directions. Mol. Cancer 2022, 21, 28. [Google Scholar] [CrossRef]
- Peres, L.C.; Cushing-Haugen, K.L.; Anglesio, M.; Wicklund, K.; Bentley, R.; Berchuck, A.; Kelemen, L.E.; Nazeran, T.M.; Gilks, C.B.; Harris, H.R.; et al. Histotype classification of ovarian carcinoma: A comparison of approaches. Gynecol. Oncol. 2018, 151, 53–60. [Google Scholar] [CrossRef]
- Haunschild, C.; Tewari, K. The current landscape of molecular profiling in the treatment of epithelial ovarian cancer. Gynecol. Oncol. 2021, 160, 333–345. [Google Scholar] [CrossRef] [PubMed]
- McCluggage, W.G.; Singh, N.; Gilks, C.B. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology 2022, 80, 762–778. [Google Scholar] [CrossRef] [PubMed]
Feature, n (%) | Tumor Site | |||
---|---|---|---|---|
Ovary, n = 22 | Uterus, n = 15 | Cervix, n = 11 | Vagina, n = 1 | |
Median age (range) | 56 (46–65) | 61 (37–64) | 53 (36–58) | 46 |
Family history of malignancy | 9 (18) | 3 (6) | 1 (2) | 0 |
Metastatic disease | 2 (4) | 2 (4) | 4 (8) | 0 |
Histological diagnosis | ||||
High grade serous carcinoma | 18 (37) | 0 | 0 | 0 |
Endometrioid carcinoma | 0 | 6 (12) | 0 | 0 |
Serous carcinoma | 0 | 5 (10) | 0 | 0 |
Atypical polypoid adenomyoma | 0 | 2 (4) | 0 | 0 |
Clear cell carcinoma | 3 (6) | 1 (2) | 0 | 0 |
Neuroendocrine carcinoma | 1 (2) | 1 (2) | 0 | 0 |
Squamous cell carcinoma | 0 | 0 | 5 (10) | 1 (2) |
Mucinous carcinoma | 0 | 0 | 3 (6) | 0 |
Adenocarcinoma | 0 | 0 | 3 (6) | 0 |
FIGO stage * | ||||
I | 1 (2) | 5 (10) | 1 (2) | 1 (2) |
II | 0 | 1 (2) | 0 | 0 |
III | 15 (31) | 2 (4) | 1 (2) | 0 |
IV | 5 (10) | 4 (8) | 8 (16) | 0 |
Unknown | 1 (2) | 3 (6) | 1 (2) | 0 |
Treatment scheme | ||||
Neo-adjuvant | 12 (24) | 2 (4) | 6 (12) | 0 |
Adjuvant | 9 (18) | 5 (10) | 3 (6) | 1 (2) |
None | 0 | 7 (14) | 0 | 0 |
Unknown | 1(2) | 1 (2) | 2 (4) | 0 |
Treatment regimen | ||||
Platinum | 0 | 0 | 4 (8) | 1 (2) |
Platinum+taxane | 19 (39) | 7 (14) | 3 (6) | 0 |
Platinum+taxane+bevacizumab | 1 (2) | 0 | 2 (4) | 0 |
Others | 1 (2) | 1 (2) | 2 (4) | 0 |
None | 0 | 6 (12) | 0 | 0 |
Unknown | 1 (2) | 1 (2) | 0 | 0 |
Adjuvant radiotherapy | 1 (2) | 6 (12) | 10 (20) | 0 |
Surgery debulking | 19 (39) | 13 (26) | 7 (14) | 0 |
Recurrence | 17 (35) | 9 (18) | 7 (14) | 1 (2) |
Radiological response | ||||
Complete response | 6 (12) | 0 | 1 (2) | 0 |
Partial response | 15 (31) | 5 (10) | 6 (12) | 1 (2) |
Progressive disease | 0 | 2 (4) | 3 (6) | 0 |
Unknown | 1 (2) | 8 (16) | 1 (2) | 0 |
Molecular Pathway | Tumor Site (Histological Subtype) | |||||||
---|---|---|---|---|---|---|---|---|
Ovary | Uterus | Cervix | ||||||
H-G Serous Carcinoma | Clear Cell Carcinoma | Serous Carcinoma | Clear Cell Carcinoma | Endometrioid Carcinoma | Squamous Cell Carcinoma | Adenocarcinoma | Mucinous Carcinoma | |
HPV | - | - | - | - | - | associated | independent | |
TP53 | TP53 mut | - | TP53 mut | TP53 mut | - | - | - | - |
Wnt-beta-catenin | - | - | CTNNB1 mut | - | CTNNB1 mut | - | - | - |
SOX17 CNA | ||||||||
PiK3CA-PTEN-AKT-mTOR | PiK3CA CNA | PiK3CA mut | PiK3CA mut+CNA | PiK3CA mut | PiK3CA mut | PiK3CA mut | PiK3CA mut | - |
PTEN loss | PTEN mut | PTEN loss | PTEN mut | |||||
PiK3R1 mut | PiK3R1 mut | |||||||
MAP kinase | NF1 mut | KRAS mut | - | - | KRAS mut | - | KRAS mut | - |
Tyrosine kinase receptors | - | - | ERBB2 CNA | ERBB2 mut+CNA | ERBB3 mut | - | ERBB2 CNA | |
FGFR2 mut | FGFR2 mut | |||||||
FGFR1 CNA | ||||||||
FGFR3 CNA | ||||||||
Homologous recombination deficiency | BRCA1 mut | - | - | - | - | - | - | - |
BRCA2 mut | ||||||||
CDK12 mut | ||||||||
EMSY mut | ||||||||
BRIP mut | ||||||||
PALB2 mut | ||||||||
RAD51 mut | ||||||||
BARD1 mut | ||||||||
ATM mut | ||||||||
ATR mut | ||||||||
Mismatch repair | - | - | - | MSI-H | MSI-H | - | - | - |
Base excision repair | - | - | - | - | POLE mut | - | - | - |
SWI/SNF nucleosome remodeling complex | - | ARID1A mut | - | ARID1A mut | ARID1A mut | - | - | - |
Cell cycle | CCNE1 CNA | - | CCNE1 CNA | - | - | - | - | MDM2 CNA |
RB1 mut+CNA | MYC mut | |||||||
CDKN2A mut | PPP2R1A mut | |||||||
Other genomic aberrations | TERT mut | TERT mut | - | CASP8, HLA-A, SHKBP1, TGBR2, TGFbeta | - | |||
FOXM1 CNA | FBXW7 mut | STK11 mut | ||||||
NOTCH1 CNA | LRPB1 loss |
Patient | Tumor Site | Histological Subtype | MMR Status | Microsatellite Instability | Repair Altered Genes | PD-L1 by CPS (%) | TiLs (%) |
---|---|---|---|---|---|---|---|
384 | Uterus | Endometrioid | - | MSS | POLE | - | - |
375 | Uterus | Serous | pMMR | MSS | MSH6 | - | 0 |
163 | Uterus | Serous | pMMR | MSS | PMS2 | 0 | 0 |
317 | Ovary | HGSC | pMMR | MSS | PMS2/POLE | 10 | 90 |
189 | Ovary | HGSC | pMMR | MSI-L | PMS2 | 10 | 10 |
370 | Ovary | HGSC | pMMR | MSS | PMS2 | 18 | 20 |
144 | Ovary | HGSC | pMMR | MSS | MSH6 | 20 | 1 |
393 | Ovary | HGSC | pMMR | - | POLE | 35 | 20 |
201 | Uterus | Endometrioid | pMMR | MSS | POLE | 35 | 90 |
272 | Uterus | Serous | pMMR | MSS | MSH2 | 53 | 0 |
65 | Uterus | Serous | dMMR | MSI-L | NONE | 55 | 90 |
37 | Cervix | SCC | dMMR | MSI-L | NONE | 58 | 75 |
403 | Ovary | CCC | dMMR | MSI-H | NONE | 63 | 15 |
294 | Ovary | HGSC | - | MSS | POLE | 68 | 95 |
Patient | Gene | Variant Categorization | Variant Type | Tumor Site | Histological Subtype | Targeted Therapy | Radiological Response |
---|---|---|---|---|---|---|---|
11 | BRCA1 | Tier IA | INDEL | Ovary | HGSC | None | CR |
163 | PPP2R1A | Tier IID | SNV | Uterus | Serous | Olaparib | PR |
178 | WT | - | - | Ovary | HGSC | Niraparib | CR |
189 | BRCA1 | Tier III | SNV | Ovary | HGSC | None | PR |
201 | BRCA2 | Tier IA | SNV | Uterus | Endometrioid | None | Lost to follow-up |
261 | BRCA1 | Tier III | SNV | Ovary | HGSC | Olaparib | PR |
276 | BRCA2 | Tier III | SNV | Cervix | Endocervical | None | CR |
294 | BRCA1 | Tier IA | SNV | Ovary | HGSC | Olaparib | PR |
370 | RAD51B | Tier III | SNV | Ovary | HGSC | Niraparib | CR |
375 | ATM | Tier III | SNV | Uterus | Serous | Olaparib | Lost to follow-up |
381 | ATM | Tier III | SNV | Vagina | SSC | Pembrolizumab * | PR |
390 | WT | - | - | Cervix | SSC | Pembrolizumab * | PR |
436 | BRCA1-BRCA2 | Tier IA- Tier III | INDEL-SNV | Ovary | HGSC | Olaparib | PR |
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Prieto-Potin, I.; Idrovo, F.; Suárez-Gauthier, A.; Díaz-Blázquez, M.; Astilleros-Blanco de Córdova, L.; Chamizo, C.; Zazo, S.; Carvajal, N.; López-Sánchez, A.; Pérez-Buira, S.; et al. Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors. Diagnostics 2022, 12, 1903. https://doi.org/10.3390/diagnostics12081903
Prieto-Potin I, Idrovo F, Suárez-Gauthier A, Díaz-Blázquez M, Astilleros-Blanco de Córdova L, Chamizo C, Zazo S, Carvajal N, López-Sánchez A, Pérez-Buira S, et al. Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors. Diagnostics. 2022; 12(8):1903. https://doi.org/10.3390/diagnostics12081903
Chicago/Turabian StylePrieto-Potin, Iván, Franklin Idrovo, Ana Suárez-Gauthier, María Díaz-Blázquez, Laura Astilleros-Blanco de Córdova, Cristina Chamizo, Sandra Zazo, Nerea Carvajal, Almudena López-Sánchez, Sandra Pérez-Buira, and et al. 2022. "Comprehensive Approach to Genomic and Immune Profiling: Insights of a Real-World Experience in Gynecological Tumors" Diagnostics 12, no. 8: 1903. https://doi.org/10.3390/diagnostics12081903