Molecular predictors of post-mastectomy breast cancer loco-regional recurrence

描述(申请人提供)：乳腺癌是一种不同的疾病过程，尽管临床分期相似，但治疗结果明显不同。即使采用最激进和最现代的治疗，也有高达15%的患者出现局部区域复发(LRR)，这增加了远处疾病和死亡的风险。个体风险因素，如年龄、肿瘤大小和分级，在临床上预测预后的能力有限；因此，识别分子图谱以更准确地评估风险仍然是一个重要的目标。这一资料有助于确定LRR作为局部治疗选择评估的一部分，特别是当传统风险分层参数支持的辅助治疗建议导致较窄的风险：收益比时。先前对LRR基因图谱的评估因患者数量较少、临床特征和治疗方案不同而受到阻碍。有必要进行进一步的研究，以开发一种不仅可以预测LRR，而且无论肿瘤大小或年龄等临床因素都适用于患者的配置文件。对这种工具的需求最大的是目前被描述为中等风险的患者，即T1-T3期乳腺癌，有0-3个阳性结节。在没有新辅助治疗和术后没有放射治疗的情况下接受乳房切除术的患者将提供最均匀的患者亚群，因为他们的病理分期不会因新辅助治疗而改变。我们假设LRR患者的分子谱不同于没有复发的患者的分子谱。将进行一项回顾性病例对照研究，将两名没有LRR的对照患者与每个乳腺癌切除术后的LRR配对。我们的目标是1)确定与中低危乳腺癌术后患者LRR风险升高相关的分子突变(DNA、RNA、IHC)；2)确定PIK3CA突变和/或PTEN缺失引起的PI3K通路激活是否与LRR相关；3)确定Ki-67所确定的肿瘤增殖是否与LRR相关。我们的长期目标是创建一种新的分子图谱来预测这个队列中的LRR，然后在1)后续研究中的单独的TBCRC(转化型乳腺癌研究联盟)队列中进一步验证这一签名，2)在适当的合作小组试验中存储石蜡块，3)将未来的TBCRC患者试验作为相关和翻译组件。在独立队列中验证后，我们将进行一项前瞻性研究，以使用我们的LRR签名来确定是否需要辅助放射治疗。分子图谱可能为指导乳腺癌个体化治疗提供更多信息。然后，临床治疗将基于女性的个体预后，使用肿瘤的分子特征来确定最佳治疗方案。

DESCRIPTION (provided by applicant): Breast cancer represents a heterogeneous disease process with markedly different treatment outcomes despite similar clinical staging. Even with the most aggressive and modern therapy as much as 15 percent of patients develop local-regional recurrences (LRR) which increase the risk of distant disease and death. Individual risk factors such as age, tumor size and grade are clinically limited in ability to predict outcome; therefore, the identification of a molecular profile to more accurately assess risk remains an important goal. This profile can help determine LRR as part of the evaluation for local therapeutic options, particularly when adjuvant treatment recommendations supported by traditional risk stratification parameters result in a narrow risk: benefit ratio. Previous evaluation of a genetic profile for LRR has been hindered by smaller patient numbers with heterogeneous clinical characteristics and treatment regimens. Additional study is warranted to develop a profile that would not only predict LRR but be applicable to patients regardless of clinical factors such as tumor size or age. The need for such a tool is greatest, in patients currently characterized as being at intermediate risk, i.e. stage T1-T3 breast cancer with 0-3 positive nodes. Patients treated with mastectomy without neoadjuvant therapy and without postoperative radiation therapy would provide the most uniform subset of patients since their pathologic staging is not altered by neoadjuvant therapy. We hypothesize that the molecular profile of patients with a LRR differ than the molecular profile of patients who do not have a recurrence. A retrospective case-control study will be performed, matching two control patients without LRR for each patient with a post-mastectomy LRR. Our aims are 1) To determine molecular aberrations (DNA, RNA, IHC) associated with an elevated risk of LRR in otherwise low to intermediate risk post-mastectomy patients; 2) To determine whether PI3K pathway activation by PIK3CA mutation and/or PTEN loss is associated with LRR; 3) To determine if tumor proliferation, as determined by Ki-67, is associated with LRR. Our long-term goal is to create a novel molecular profile that would predict LRR in this cohort and then further validate this signature in 1) a separate TBCRC (Translational Breast Cancer Research Consortium) cohort in a follow-up study, 2) in paraffin blocks stored from appropriate cooperative group trials, 3) with future TBCRC patient trials as a correlative and translational component. Upon validation in an independent cohort, we will pursue a prospective study to use our LRR signature for determining the need for adjuvant radiation therapy. A molecular profile may provide more information to guide an individualized therapeutic approach to breast cancer therapy. Then clinical management would be based on a women's individual prognosis using the tumor's molecular profile to define the best therapy.