Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget's Disease of the Vulva.
Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget's Disease of the Vulva.
复制标题
基因组改变作为外阴乳房外佩吉特病的潜在治疗靶点。
作者：
M. Stasenko;G. Jayakumaran;R. Cowan;V. Broach;D. Chi;A. Rossi;T. Hollman;A. Zehir;N. Abu;M. Leitao
目的
确定基因组改变作为外阴乳房外佩吉特病（EMPD）的潜在治疗靶点。
方法
我们确定了所有在我们机构接受治疗的原发性外阴EMPD患者，并进行了410-468个癌症相关基因的配对肿瘤-正常大规模平行测序（MSK-IMPACT测定）。对2014年至2019年测序的外阴样本的EMPD进行了审查，并确定了体细胞突变，特别关注潜在治疗靶点的突变。临床数据从电子病历中提取。微卫星不稳定性（MSI）通过MSIscore评估。
结果
26例EMPD患者的肿瘤进行了基因组测序。诊断时，所有患者均为非侵入性或微创（< 1 mm）疾病; 2例患者最终发展为侵入性疾病。19名患者（73%）的主要治疗是手术，7名患者（27%）是咪喹莫特局部治疗。7例患者在临床过程中接受了≥ 2次手术（1例患者接受了5次外阴切除术）。样品在分析的基因中具有2个编码突变的中值（范围，0-29）。最常见的突变是PIK 3CA（n = 9; 35%）、ERBB 2（4个突变和3个拷贝数改变; 27%）和TP 53（n = 7; 27%）。MSIscore可用于23个样品;所有样品都是微卫星稳定的。在肿瘤基因组分析后，发现一名最初接受多次切除和咪喹莫特治疗的患者有PIK 3CA p.E542K突变。她在疾病进展前接受了18个月的PI 3 K抑制剂治疗。
结论
外阴EMPD有一个慢性和复发的过程，往往需要多次手术切除。缺乏有效的局部治疗。我们在> 25%的真实世界临床队列中确定了靶向突变（PIK 3CA或ERBB 2）。实施EMPD治疗靶向疗法的额外前瞻性研究是必要的。
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.
影响因子：
4.1
作者：
Cheng, Donavan T.;Mitchell, Talia N.;Berger, Michael F.
通讯作者：
Berger, Michael F.