PURPOSE: To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva. METHODS: We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore. RESULTS: Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in PIK3CA (n = 9; 35%), ERBB2 (4 mutations and 3 copy number alterations; 27%), and TP53 (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a PIK3CA p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION: EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.
PURPOSE: To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva. METHODS: We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore. RESULTS:Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in PIK3CA (n = 9; 35%), ERBB2 (4 mutations and 3 copy number alterations; 27%), and TP53 (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a PIK3CAp.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION: EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.
Authors: Ahmet Zehir; Ryma Benayed; Ronak H Shah; Aijazuddin Syed; Sumit Middha; Hyunjae R Kim; Preethi Srinivasan; Jianjiong Gao; Debyani Chakravarty; Sean M Devlin; Matthew D Hellmann; David A Barron; Alison M Schram; Meera Hameed; Snjezana Dogan; Dara S Ross; Jaclyn F Hechtman; Deborah F DeLair; JinJuan Yao; Diana L Mandelker; Donavan T Cheng; Raghu Chandramohan; Abhinita S Mohanty; Ryan N Ptashkin; Gowtham Jayakumaran; Meera Prasad; Mustafa H Syed; Anoop Balakrishnan Rema; Zhen Y Liu; Khedoudja Nafa; Laetitia Borsu; Justyna Sadowska; Jacklyn Casanova; Ruben Bacares; Iwona J Kiecka; Anna Razumova; Julie B Son; Lisa Stewart; Tessara Baldi; Kerry A Mullaney; Hikmat Al-Ahmadie; Efsevia Vakiani; Adam A Abeshouse; Alexander V Penson; Philip Jonsson; Niedzica Camacho; Matthew T Chang; Helen H Won; Benjamin E Gross; Ritika Kundra; Zachary J Heins; Hsiao-Wei Chen; Sarah Phillips; Hongxin Zhang; Jiaojiao Wang; Angelica Ochoa; Jonathan Wills; Michael Eubank; Stacy B Thomas; Stuart M Gardos; Dalicia N Reales; Jesse Galle; Robert Durany; Roy Cambria; Wassim Abida; Andrea Cercek; Darren R Feldman; Mrinal M Gounder; A Ari Hakimi; James J Harding; Gopa Iyer; Yelena Y Janjigian; Emmet J Jordan; Ciara M Kelly; Maeve A Lowery; Luc G T Morris; Antonio M Omuro; Nitya Raj; Pedram Razavi; Alexander N Shoushtari; Neerav Shukla; Tara E Soumerai; Anna M Varghese; Rona Yaeger; Jonathan Coleman; Bernard Bochner; Gregory J Riely; Leonard B Saltz; Howard I Scher; Paul J Sabbatini; Mark E Robson; David S Klimstra; Barry S Taylor; Jose Baselga; Nikolaus Schultz; David M Hyman; Maria E Arcila; David B Solit; Marc Ladanyi; Michael F Berger Journal: Nat Med Date: 2017-08-04 Impact factor: 53.440
Authors: D Crawford; M Nimmo; P B Clement; T Thomson; J L Benedet; D Miller; C B Gilks Journal: Int J Gynecol Pathol Date: 1999-10 Impact factor: 2.762
Authors: Britta Weigelt; Rui Bi; Rahul Kumar; Pedro Blecua; Diana L Mandelker; Felipe C Geyer; Fresia Pareja; Paul A James; Fergus J Couch; Diana M Eccles; Fiona Blows; Paul Pharoah; Anqi Li; Pier Selenica; Raymond S Lim; Gowtham Jayakumaran; Nic Waddell; Ronglai Shen; Larry Norton; Hannah Y Wen; Simon N Powell; Nadeem Riaz; Mark E Robson; Jorge S Reis-Filho; Georgia Chenevix-Trench Journal: J Natl Cancer Inst Date: 2018-09-01 Impact factor: 13.506
Authors: Debyani Chakravarty; Jianjiong Gao; Sarah M Phillips; Ritika Kundra; Hongxin Zhang; Jiaojiao Wang; Julia E Rudolph; Rona Yaeger; Tara Soumerai; Moriah H Nissan; Matthew T Chang; Sarat Chandarlapaty; Tiffany A Traina; Paul K Paik; Alan L Ho; Feras M Hantash; Andrew Grupe; Shrujal S Baxi; Margaret K Callahan; Alexandra Snyder; Ping Chi; Daniel Danila; Mrinal Gounder; James J Harding; Matthew D Hellmann; Gopa Iyer; Yelena Janjigian; Thomas Kaley; Douglas A Levine; Maeve Lowery; Antonio Omuro; Michael A Postow; Dana Rathkopf; Alexander N Shoushtari; Neerav Shukla; Martin Voss; Ederlinda Paraiso; Ahmet Zehir; Michael F Berger; Barry S Taylor; Leonard B Saltz; Gregory J Riely; Marc Ladanyi; David M Hyman; José Baselga; Paul Sabbatini; David B Solit; Nikolaus Schultz Journal: JCO Precis Oncol Date: 2017-05-16
Authors: K Kashiwada-Nakamura; T M Myangat; I Kajihara; Y Kusaba; K Tanaka; R Sakamoto; S Maeda-Otsuka; S Yamada-Kanazawa; S Sawamura; H Kanemaru; Y Nishimura; N Honda; K Makino; A Miyashita; J Aoi; T Igata; T Makino; S Masuguchi; S Fukushima; H Ihn Journal: Skin Health Dis Date: 2021-05-05