目的:皮肤转移(CM)占乳腺癌(BC)患者的5-30%,对治疗反应不良,预后不良。更好地了解与转移有关的分子改变至关重要,这将有助于确定CM的诊断和功效生物标志物。
方法:我们回顾性分析了13例组织学或细胞学诊断为乳腺癌和CM的患者。从病历中提取临床信息。使用425个癌症相关基因的下一代测序(NGS)分析了匹配的原发性肿瘤及其淋巴结或CM组织的突变景观。还通过免疫组织化学(IHC)分析所有组织。还评估了预后与各种临床和分子因素的关系。
结果:超过一半的患者Ki67低(<50%,53.7%)。大多数患者(12,92.3%)有皮肤以外的其他转移部位。从诊断到出现CM的中位时间(T1)为15个月(范围:0-94个月),从CM到死亡的中位时间(T2)为13个月(范围1-78)。在三种类型的组织中,最常改变的基因是TP53(69.6%,16/23),PIK3CA(34.8%,8/23),和MYC(26.1%)。CM的改变数量往往高于原发性肿瘤(中位数为8vs.6,P=0.077)。STK11中的拷贝数损失,FGFR4、TERT中的拷贝数增加,AR,FLT4和VEGFA和ATRX中的突变,SRC,AMER1和RAD51C在CM中显著富集(均P<0.05)。Ki67高组(>50%)的T1明显短于Ki67低组(≤50%)(中位数12.5vs.50.0个月,P=0.036)。TP53,PIK3CA突变,和TERT扩增组与下T2相关(中位数11vs.36个月,P=0.065;8vs.36个月,P=0.013,7vs.36个月,分别为P=0.003)。未调整所有p值。
结论:我们比较了原发性乳腺癌组织与相应的CM组织的基因组特征,并讨论了可能导致晚期乳腺癌患者皮肤转移的潜在基因和途径。TP53,PIK3CA突变体,和TERT扩增可能作为CM患者预后不良的生物标志物。
OBJECTIVE: Cutaneous metastasis (CM) accounts for 5-30% of patients with breast cancer (BC) and presents unfavorable response to treatment and poor prognosis. A better understanding of the molecular alterations involved in metastasis is essential, which would help identify diagnostic and efficacy biomarkers for CM.
METHODS: We retrospectively reviewed a total of 13 patients with histological or cytological diagnosis of breast cancer and CM. Clinical information was extracted from the medical records. The mutational landscape of matched primary tumors with their lymph nodes or CM tissues were analyzed using next-generation sequencing (NGS) of 425 cancer-relevant genes. All tissues were also analyzed by immunohistochemistry (IHC). The association of prognosis with various clinical and molecular factors was also evaluated.
RESULTS: More than half of the patients were Ki67 low (< 50%, 53.7%). Most patients (12, 92.3%) had other metastasis sites other than skin. The median time from diagnosis to the presentation of CM (T1) was 15 months (range: 0-94 months) and the median time from CM to death (T2) was 13 months (range 1-78). The most frequently altered genes across the three types of tissues were TP53 (69.6%, 16/23), PIK3CA (34.8%, 8/23), and MYC (26.1%). The number of alterations in CM tends to be higher than in primary tumors (median 8 vs. 6, P = 0.077). Copy number loss in STK11, copy number gain in FGFR4, TERT, AR, FLT4 and VEGFA and mutations in ATRX, SRC, AMER1 and RAD51C were significantly enriched in CM (all P < 0.05). Ki67 high group (> 50%) showed significantly shorter T1 than the Ki67 low group (≤ 50%) (median 12.5 vs. 50.0 months, P = 0.036). TP53, PIK3CA mutations, and TERT amplification group were associated with inferior T2 (median 11 vs. 36 months, P = 0.065; 8 vs. 36 months, P = 0.013, 7 vs. 36 months, P = 0.003, respectively). All p values were not adjusted.
CONCLUSIONS: We compared the genomic features of primary breast cancer tissues with their corresponding CM tissues and discussed potential genes and pathways that may contribute to the skin metastasis of advanced breast cancers patients. TP53, PIK3CA mutant, and TERT amplification may serve as biomarkers for poor prognosis for CM patients.