Опухоли головы и шеи. 2020; 10: 69-78
MASC-карцинома околоушной слюнной железы: современные возможности диагностики и таргетной терапии при транслокациях (слияниях) в гене NTRK
https://doi.org/10.17650/2222-1468-2020-10-2-69-78Аннотация
MASC-карцинома слюнной железы, аналог секреторной карциномы молочной железы (mammary analogue secretory carcinoma) – редкая злокачественная опухоль слюнной железы, которая по гистологическому строению похожа на секреторную карциному молочной железы. В 2017 г. Всемирная организация здравоохранения выделила эти опухоли в отдельный подтип в гистологической классификации опухолей слюнных желез.
В данной работе обобщены данные научной литературы о MASC-карциноме слюнных желез, в частности о ее гистологических, молекулярно-генетических особенностях, возможностях ее диагностики и лекарственной терапии. На клиническом примере продемонстрирована успешность применения энтректиниба (ингибитора тирозинкиназ при слияниях в генах NTRK1, NTRK2, NTRK3) у пациента со слиянием ETV6-NTRK3, выявленным при секвенировании нового поколения (next-generation sequencing).
Секвенирование нового поколения позволяет определить молекулярно-генетические особенности редких опухолей, что открывает возможности для эффективной индивидуализированной терапии. Верификация MASC-карцином и определение их молекулярно-генетических характеристик имеет большое значение для прогноза, так как выявление характерного для данного подтипа слияния генов ETV6-NTRK3 и, соответственно, назначение таргетной терапии ингибиторами тирозинкиназ (энтректинибом, ларотректинибом) улучшает прогноз. В приведенном клиническом случае, несмотря на высокую клиническую эффективность таргетной терапии и быстрый ответ опухоли, наблюдалось постепенное развитие резистентности вследствие появления мутации G623R в гене NTRK3, которая снизила чувствительность опухоли к препарату. Таким образом, актуально дальнейшее изучение эффективности таргетной терапии, в том числе 2-го поколения, у пациентов с редкими опухолями и слияниями NTRK.
Список литературы
1. Skálová A., Vanecek T., Sima R. et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6- NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010;34(5):599–608. DOI: 10.1097/PAS.0b013e3181d9efcc.
2. Ito Y., Ishibashi K., Masaki A. et al. Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic and molecular study including 2 cases harboring ETV6-X fusion. Am J Surg Pathol 2015;39(5):602–10. DOI: 10.1097/PAS.0000000000000392.
3. Escalante D.A., Wang H., Fundakowski C.E. Fusion proteins in head and neck neoplasms: clinical implications, genetics, and future directions for targeting. Cancer Biol Ther 2016;17(10):995–1002. DOI: 10.1080/15384047.2016.1219823.
4. Skálová A., Vanecek T., Majewska H. et al. Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes. Am J Surg Pathol 2014;38(1):23–33. DOI: 10.1097/PAS.0000000000000088.
5. Cai Y., Cai F., Qiao H., Wang Z. The significance of the morphological and immunological characteristics in the diagnosis of parotid mammary analogue secretory carcinoma: five case reports and a review of the literature. Int J Clin Exp Pathol 2019;12(6):2233–40.
6. Skálová A., Vanecek T., Martinek P. et al. Molecular profiling of mammary analog secretory carcinoma revealed a subset of tumors harboring a novel ETV6-RET translocation: report of 10 cases. Am J Surg Pathol 2018;42(2):234–46. DOI: 10.1097/PAS.0000000000000972.
7. Skálová A., Vanecek T., Simpson R.H. et al. Mammary analogue secretory carcinoma of salivary glands: molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6-NTRK3 fusion transcript by standard RT-PCR: report of 4 cases harboring ETV6-X gene fusion. Am J Surg Pathol 2016;40(1):3–13. DOI: 10.1097/PAS.0000000000000537.
8. Stransky N., Cerami E., Schalm S. et al. The landscape of kinase fusions in cancer. Nat Commun 2014;5:4846. DOI: 10.1038/ncomms5846.
9. Amatu A., Sartore-Bianchi A., Bencardino K. et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol 2019;30(Suppl 8):viii5–15. DOI: 10.1093/annonc/mdz383.
10. Amatu A., Sartore-Bianchi A., Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 2016;1(2):e000023. DOI: 10.1136/esmoopen-2015-000023.
11. Vaishnavi A., Le A.T., Doebele R.C. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015;5(1):25–34.
12. Gatalica Z., Xiu J., Swensen J., Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol 2019;32(1):147–53. DOI: 10.1038/s41379-018-0118-3.
13. Solomon J.P., Linkov I., Rosado A. et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol 2020;33(1):38–46. DOI: 10.1038/s41379-019-0324-7.
14. Marchiò C., Scaltriti M., Ladanyi M. et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol 2019;30(9):1417–27. DOI: 10.1093/annonc/mdz204.
15. Connor A., Perez-Ordoñez B., Shago M. et al. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol 2012;36(1):27–34. DOI: 10.1097/PAS.0b013e318231542a.
16. Suehara Y., Arcila M., Wang L. et al. Identification of KIF5B-RET and GOPCROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin Cancer Res 2012;18(24):6599–608. DOI: 10.1158/1078-0432.CCR-12-0838.
17. Solomon J.P., Benayed R., Hechtman J.F., Ladanyi M. Identifying patients with NTRK fusion cancer. Ann Oncol 2019;30(Suppl 8):viii16–22. DOI: 10.1093/annonc/mdz384.
18. Drilon A., Laetsch T.W., Kummar S. et al. Efficacy of larotrectinib in TRK fusion – positive cancers in adults and children. N Engl J Med 2018;378(8):731–9. DOI: 10.1056/NEJMoa1714448.
19. Hyman D.M., Tilburg C.M., Albert C.M. et al. Durability of response with larotrectinib in adult and pediatric patients with Trk fusion cancer. Ann Oncol 2019;30:v159–93.
20. Ardini E., Menichincheri M., Banfi P. et al. Entrectinib, a pan-Trk, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther 2016;15(4):628–39. DOI: 10.1158/1535-7163.MCT-15-0758.
21. Rolfo C., De Braud F., Doebele R. et al. Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: an updated integrated analysis. J Clin Oncol 2020;38 suppl:abstr 3605.
22. Fischer H., Ullah M., de la Cruz C.C. et al. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro Oncol 2020;22(6):819–29. DOI: 10.1093/neuonc/noaa052.
23. Doebele R.C., Drilon A., Paz-Ares L. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 2019;21(2):271–82. DOI: 10.1016/S1470-2045(19)30691-6.
24. Konicek B.W., Capen A.R., Credille K.M. et al. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget 2018;9(17):13796–806. DOI: 10.18632/oncotarget.24488.
25. Drilon A., Li G., Dogan S. et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol 2016;27(5):920–26. DOI: 10.1093/annonc/mdw042.
26. Drilon A., Wang L., Arcila M.E. et al. Broad, hybrid capture-based nextgeneration sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res 2015;21(16):3631–9. DOI: 10.1158/1078-0432.CCR-14-2683.
27. Bishop J.A. Unmasking MASC: bringing to light the unique morphologic, immunohistochemical and genetic features of the newly recognized mammary analogue secretory carcinoma of salivary glands. Head Neck Pathol 2013;7(1):35–9. DOI: 10.1007/s12105-013-0429-0.
28. Takeda M., Hierro C., Krauss J. et al. Entrectinib in NTRK fusion-positive mammary analogue secretory carcinoma (MASC): a phase 1/2 integrated analysis. In: Japan Society for Head and Neck Cancer 44th Annual Meeting 2020.
Head and Neck Tumors (HNT). 2020; 10: 69-78
Mammary analogue secretory carcinoma of the salivary gland with NTRK fusions: new approaches for diagnostics and targeted therapy (review)
https://doi.org/10.17650/2222-1468-2020-10-2-69-78Abstract
Mammary analogue secretory carcinoma (MASC) of the salivary gland is a rare salivary cancer, histologically resembling to secretory carcinoma of the breast. In 2017 World Health Organization reported MASC is a new salivary cancer subtype.
The aim of this article is to collect and analyze data about MASC, particularly clinical, histological and molecular profile, to evaluate targeted therapy effects. We discuss a case report of dramatic and durable response with entrectinib and the development of acquired resistance in an NTRK3-fusion positive salivary cancer, detected by next-generation sequencing.
Next-generation sequencing as a comprehensive molecular profiling, that helps to investigate molecular profile of rare tumors and gives an opportunity to use an effective therapeutic options. Identifying ETV6-NTRK3 positive MASC provides a better prognosis for metastatic disease by using a novel effective targeted therapy with tyrosine kinase inhibitors (entrectinib, larotrectinib). Despite a durable and dramatic response, we showed an interesting case of the development of acquired resistance to tyrosine kinase inhibitors mediated by the appearance of a novel NTRK3 G623R mutation. Finally, we believe in great perspectives of comprehensive molecular profiling and targeted therapy for rare malignancies with NTRK gene fusions, including second-generation tyrosine kinase inhibitors.
References
1. Skálová A., Vanecek T., Sima R. et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6- NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010;34(5):599–608. DOI: 10.1097/PAS.0b013e3181d9efcc.
2. Ito Y., Ishibashi K., Masaki A. et al. Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic and molecular study including 2 cases harboring ETV6-X fusion. Am J Surg Pathol 2015;39(5):602–10. DOI: 10.1097/PAS.0000000000000392.
3. Escalante D.A., Wang H., Fundakowski C.E. Fusion proteins in head and neck neoplasms: clinical implications, genetics, and future directions for targeting. Cancer Biol Ther 2016;17(10):995–1002. DOI: 10.1080/15384047.2016.1219823.
4. Skálová A., Vanecek T., Majewska H. et al. Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes. Am J Surg Pathol 2014;38(1):23–33. DOI: 10.1097/PAS.0000000000000088.
5. Cai Y., Cai F., Qiao H., Wang Z. The significance of the morphological and immunological characteristics in the diagnosis of parotid mammary analogue secretory carcinoma: five case reports and a review of the literature. Int J Clin Exp Pathol 2019;12(6):2233–40.
6. Skálová A., Vanecek T., Martinek P. et al. Molecular profiling of mammary analog secretory carcinoma revealed a subset of tumors harboring a novel ETV6-RET translocation: report of 10 cases. Am J Surg Pathol 2018;42(2):234–46. DOI: 10.1097/PAS.0000000000000972.
7. Skálová A., Vanecek T., Simpson R.H. et al. Mammary analogue secretory carcinoma of salivary glands: molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6-NTRK3 fusion transcript by standard RT-PCR: report of 4 cases harboring ETV6-X gene fusion. Am J Surg Pathol 2016;40(1):3–13. DOI: 10.1097/PAS.0000000000000537.
8. Stransky N., Cerami E., Schalm S. et al. The landscape of kinase fusions in cancer. Nat Commun 2014;5:4846. DOI: 10.1038/ncomms5846.
9. Amatu A., Sartore-Bianchi A., Bencardino K. et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol 2019;30(Suppl 8):viii5–15. DOI: 10.1093/annonc/mdz383.
10. Amatu A., Sartore-Bianchi A., Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 2016;1(2):e000023. DOI: 10.1136/esmoopen-2015-000023.
11. Vaishnavi A., Le A.T., Doebele R.C. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015;5(1):25–34.
12. Gatalica Z., Xiu J., Swensen J., Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol 2019;32(1):147–53. DOI: 10.1038/s41379-018-0118-3.
13. Solomon J.P., Linkov I., Rosado A. et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol 2020;33(1):38–46. DOI: 10.1038/s41379-019-0324-7.
14. Marchiò C., Scaltriti M., Ladanyi M. et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol 2019;30(9):1417–27. DOI: 10.1093/annonc/mdz204.
15. Connor A., Perez-Ordoñez B., Shago M. et al. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol 2012;36(1):27–34. DOI: 10.1097/PAS.0b013e318231542a.
16. Suehara Y., Arcila M., Wang L. et al. Identification of KIF5B-RET and GOPCROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin Cancer Res 2012;18(24):6599–608. DOI: 10.1158/1078-0432.CCR-12-0838.
17. Solomon J.P., Benayed R., Hechtman J.F., Ladanyi M. Identifying patients with NTRK fusion cancer. Ann Oncol 2019;30(Suppl 8):viii16–22. DOI: 10.1093/annonc/mdz384.
18. Drilon A., Laetsch T.W., Kummar S. et al. Efficacy of larotrectinib in TRK fusion – positive cancers in adults and children. N Engl J Med 2018;378(8):731–9. DOI: 10.1056/NEJMoa1714448.
19. Hyman D.M., Tilburg C.M., Albert C.M. et al. Durability of response with larotrectinib in adult and pediatric patients with Trk fusion cancer. Ann Oncol 2019;30:v159–93.
20. Ardini E., Menichincheri M., Banfi P. et al. Entrectinib, a pan-Trk, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther 2016;15(4):628–39. DOI: 10.1158/1535-7163.MCT-15-0758.
21. Rolfo C., De Braud F., Doebele R. et al. Efficacy and safety of entrectinib in patients (pts) with NTRK-fusion positive (NTRK-fp) solid tumors: an updated integrated analysis. J Clin Oncol 2020;38 suppl:abstr 3605.
22. Fischer H., Ullah M., de la Cruz C.C. et al. Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein. Neuro Oncol 2020;22(6):819–29. DOI: 10.1093/neuonc/noaa052.
23. Doebele R.C., Drilon A., Paz-Ares L. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 2019;21(2):271–82. DOI: 10.1016/S1470-2045(19)30691-6.
24. Konicek B.W., Capen A.R., Credille K.M. et al. Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors. Oncotarget 2018;9(17):13796–806. DOI: 10.18632/oncotarget.24488.
25. Drilon A., Li G., Dogan S. et al. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC). Ann Oncol 2016;27(5):920–26. DOI: 10.1093/annonc/mdw042.
26. Drilon A., Wang L., Arcila M.E. et al. Broad, hybrid capture-based nextgeneration sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res 2015;21(16):3631–9. DOI: 10.1158/1078-0432.CCR-14-2683.
27. Bishop J.A. Unmasking MASC: bringing to light the unique morphologic, immunohistochemical and genetic features of the newly recognized mammary analogue secretory carcinoma of salivary glands. Head Neck Pathol 2013;7(1):35–9. DOI: 10.1007/s12105-013-0429-0.
28. Takeda M., Hierro C., Krauss J. et al. Entrectinib in NTRK fusion-positive mammary analogue secretory carcinoma (MASC): a phase 1/2 integrated analysis. In: Japan Society for Head and Neck Cancer 44th Annual Meeting 2020.
