Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1–3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1–3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

乳房切除术后1-3个阳性淋巴结转移的乳腺癌（BC）辅助治疗一直存在争议。这项回顾性转化乳腺癌研究联合会的研究评估了与局部复发（LRR）或远处转移（DM）相关的原发性癌症中的分子畸变，与非复发性对照相比。我们确定了115例HER2阴性，初治，T 1-3和N 0-1 BC患者接受了乳房切除术，但未进行乳房切除术后放疗。其中包括32个LRR，34个DM和49个控件。对110例患者的原发肿瘤进行了RNAseq；LRR，DM或对照患者的RNA谱无差异。对57例原发肿瘤（17例LRR，15例DM和25例对照）进行的DNA分析确定了明显更多的NF1LRR（24％，47％）和DM（27％，40％）患者与对照组（0％，0％; p  <0.0001; p  = 0.0070 ）的突变和有丝分裂原活化蛋白激酶（MAPK）途径基因突变， 分别）。3例患者的主要样本和LRR样本相匹配，其中1例患者的LRR中有NF1突变。两组之间的PTEN缺失或caspase 3裂解表达没有显着差异。LRR（29.2％）和DM（26％）患者的平均Ki 67标记指数百分比高于对照组（14％，p  = 0.0045）。总之，MAPK途径中的突变，特别是NF1，与LRR和DM都相关，表明MAPK信号的改变与更具侵略性的肿瘤表型有关。来自随机试验的组织中这些关联的验证可能支持靶向治疗，以减少乳腺癌的复发。