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

乳房切除术后乳腺癌局部区域复发的分子预测因子

• 批准号: 8243214
• 负责人: Kimberly Keene
• 金额: $ 14.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243214
• 关键词: Address; Adjuvant; Age; Apoptosis; Automobile Driving; Cancer Patient; Caring; Case-Control Studies; Cell Proliferation; Cessation of life; Characteristics; Classification; Cleaved cell; Clinical; Clinical Management; DNA; Disease; Distant; Distant Metastasis; Economic Burden; Evaluation; Future; Goals; Healthcare Systems; Immunohistochemistry; Individual; Learning; Local Therapy; Malignant Neoplasms; Mastectomy; Medical Oncology; Molecular; Molecular Profiling; Morbidity - disease rate; Mutation; Neoadjuvant Therapy; Oncologist; Operative Surgical Procedures; Outcome; PIK3CA gene; PTEN gene; Paraffin; Paraffin Embedding; Pathologic; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Positive Lymph Node; Postoperative Period; Predictive Factor; Process; Prospective Studies; RNA; Radiation; Radiation therapy; Recommendation; Recurrence; Resistance; Risk; Risk Factors; Signal Pathway; Solutions; Staging; Stratification; Therapeutic; Tissues; Treatment Protocols; Treatment outcome; Tumor Biology; United States National Institutes of Health; Validation; Woman; Work; anticancer research; base; cancer therapy; caspase-3; cohort; drug development; experience; follow-up; genetic profiling; high risk; improved; malignant breast neoplasm; novel; outcome forecast; prospective; resistance mechanism; risk benefit ratio; tool; tumor

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. PUBLIC HEALTH RELEVANCE: Breast cancer patients have markedly different treatment outcomes despite similar clinical staging. Individual risk factors such as age, tumor size and grade are 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 recurrence risk as part of the evaluation for treatment options.

描述（由申请人提供）：乳腺癌代表了一种异质性疾病过程，尽管临床分期相似，但治疗结局明显不同。即使使用最积极和最现代的治疗方法，也有多达15%的患者发生局部复发（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结果的能力有限;因此，鉴定分子谱以更准确地评估风险仍然是一个重要目标。该特征有助于确定LRR，作为局部治疗方案评价的一部分，特别是当传统风险分层参数支持的辅助治疗建议导致风险：获益比较窄时。先前对LRR遗传特征的评估受到具有异质性临床特征和治疗方案的较小患者数量的阻碍。需要进一步的研究来开发一种不仅能预测LRR，而且适用于患者的特征，而不管临床因素如肿瘤大小或年龄如何。在目前被表征为处于中等风险的患者中，即具有0-3个阳性淋巴结的T1-T3期乳腺癌，对这种工具的需求最大。接受乳房切除术治疗但未接受新辅助治疗和术后放疗的患者将提供最统一的患者亚组，因为新辅助治疗不会改变其病理分期。我们假设LRR患者的分子谱与未复发患者的分子谱不同。将进行一项回顾性病例对照研究，将两名无LRR的对照患者与每名乳房切除术后LRR的患者进行匹配。我们的目的是1）确定与低至中等风险的乳房切除术后患者中LRR风险升高相关的分子畸变（DNA，RNA，IHC）; 2）确定PIK 3CA突变和/或PTEN缺失引起的PI 3 K通路激活是否与LRR相关; 3）确定肿瘤增殖（如Ki-67所确定）是否与LRR相关。我们的长期目标是创建一种新的分子谱，预测该队列中的LRR，然后在1）随访研究中的单独TBCRC（转化乳腺癌研究联盟）队列中，2）从适当的合作组试验中储存的石蜡块中，3）未来的TBCRC患者试验作为相关和转化成分中进一步验证该特征。在一个独立的队列验证后，我们将进行一项前瞻性研究，使用我们的LRR签名来确定是否需要辅助放射治疗。分子谱可以提供更多的信息来指导乳腺癌治疗的个体化治疗方法。然后，临床管理将基于女性的个体预后，使用肿瘤的分子谱来确定最佳治疗。 公共卫生相关性：尽管临床分期相似，但乳腺癌患者的治疗结局明显不同。个体风险因素如年龄、肿瘤大小和分级在预测结果方面能力有限;因此，鉴定分子谱以更准确地评估风险仍然是一个重要目标。这种情况可以帮助确定复发风险，作为治疗方案评估的一部分。