Nsaid Effects on Clinical and Imaging Breast Biomarkers

说明(申请人提供)：雌激素受体阳性(ER+)或管腔型肿瘤占所有乳腺癌的60%-75%，死亡人数超过所有其他类型乳腺癌的总和。芳香酶抑制剂(AI)被推荐作为绝经后妇女激素反应性肿瘤的一线辅助治疗。尽管激素治疗取得了显著的成功，但大约20%-25%的ER+疾病患者的病情会在10年内恶化，复发的患者最终会死于他们的疾病。药物依从性差，主要是由于对副作用不耐受，仍然是实现最大药物效益的主要挑战。显然，有必要最大限度地提高人工智能的效率。非类固醇抗炎药(NSAIDs)，特别是舒林酸，在临床前模型中显示出强大的和机械支持的抗癌活性。我们假设舒林酸联合AIS可以协同作用于乳房密度和乳房组织生物标记物，作为复发风险的替代物。在人工智能治疗中加入舒林酸还可能有额外的好处，即减少与人工智能使用相关的肌肉和骨骼疼痛，从而改善依从性和长期疗效。为了验证我们的假设，150名接受人工智能治疗ER+肿瘤的乳腺癌患者将被随机分为两个干预组之一，为期12个月：1)AI+舒林酸150 mg Bid或2)AI+安慰剂Bid。我们的具体目标是：1.比较核磁共振成像(MRI)测量的乳房密度的变化-获得性脂水比(FWR)(主要试验终点)在个体内和治疗组之间。我们假设，接受AI+舒林酸150 mg BID治疗的女性在12个月内乳房密度将下降(即增加FWR)，而接受AI+安慰剂治疗的女性的乳房密度不会改变。2.比较个体内和治疗臂之间水的表观扩散系数(ADC)。我们假设，在接受AI+舒林酸150 mg Bid治疗的女性患者中，扩散加权磁共振(DW-MRI)测量的ADC值将在12个月内发生显著变化，而接受AI+安慰剂治疗的女性患者的ADC值不会改变。3.使用简明疼痛问卷简表(BPI-SF)比较个体内和治疗组之间的疼痛评分。我们假设，接受AI+舒林酸150 mg Bid治疗的女性在12个月内疼痛评分将会降低，而接受AI+安慰剂治疗的女性疼痛评分不会改变。此外，由于前体药物舒林酸亚磺酸(Clinoril“)已被证明可以避免肾功能正常的患者肾脏合成扩张血管的前列腺素，我们假设每天使用舒林酸不会增加肾清除正常的AIS女性的血压(BP)，因此不会增加通过药物引起的高血压介导的心血管毒性的风险。舒林酸联合AI的II期生物标记物试验的成功将为更大规模的癌症特定结果试验提供依据。 公共卫生相关性： 雌激素受体阳性或管腔型肿瘤占乳腺癌的大多数，是乳腺癌相关发病率和死亡率的主要原因。由于对副作用，特别是肌肉骨骼疼痛的不耐受，芳香酶抑制剂治疗早期中断的比率很高(到第3年估计为30%)，现在与乳腺癌复发率较高的临床益处减少有关。非类固醇抗炎药(NSAIDs)在治疗与前列腺素相关的炎症相关的肌肉骨骼疼痛方面显示出强大的疗效。非甾体抗炎药在乳腺癌模型中也显示出抗癌活性，观察证据表明，在经常使用的人中，乳腺癌复发的几率较低。我们提出了新的磁共振成像(MRI)和组织生物标记物研究，以评估舒林酸-一种有效的、非选择性的非甾体抗炎药与芳香化酶抑制剂联合使用-对雌激素受体阳性乳腺癌妇女的“高危”乳房组织的影响。此外，我们将测试舒林酸在减少肌肉骨骼症状方面的作用，作为提高患者对人工智能治疗依从性的一种方法。心血管风险将通过系列血压测量进行检查，为接受非类固醇抗炎药治疗的女性提供重要的安全数据。这些风险大多是通过抑制COX-2明确定义的，但在理论上也适用于非类固醇抗炎药。

DESCRIPTION (provided by applicant): Estrogen receptor positive (ER+), or luminal type, tumors account for 60-75% of all breast cancers and for more deaths than all other types of breast cancer combined. Aromatase inhibitors (AI) are recommended as first-line adjuvant therapy for hormone responsive tumors in postmenopausal women. In spite of significant success with hormonal therapies, ~20-25% of patients with ER+ disease will progress by 10 years with relapsed patients ultimately succumbing to their disease. Poor drug adherence, principally due to intolerance to side effects, remains a major challenge for achieving greatest drug benefit. A need to maximize AI efficacy is evident. Non-steroidal anti-inflammatory agents (NSAIDs), particularly sulindac, demonstrate potent and mechanistically supported anti-cancer activity for breast tumors in preclinical models. We hypothesize that sulindac, combined with AIs may act synergistically on breast density and breast tissue biomarkers as surrogates for relapse risk. The addition of sulindac to AI therapy may also have the added benefit of decreasing muscle and skeletal pain associated with AI use and thus improved adherence and long-term efficacy. To test our hypotheses, 150 breast cancer patients, stable on AI therapy for ER+ tumors, will be randomized to one of two intervention arms for 12 months: 1) AI + sulindac 150 mg bid or 2) AI + placebo bid. Our specific aims are: 1. To compare change in breast density as measured by Magnetic Resonance Imaging (MRI)-acquired fat-to-water ratio (FWR) (primary trial endpoint) within individuals and between treatment arms. We hypothesize that women treated with AI + sulindac 150 mg bid will show decreased breast density (i.e., increased FWR) over 12 months, whereas breast density in women receiving AI + placebo will not change. 2. To compare the apparent diffusion coefficient (ADC) of water within individuals and between treatment arms. We hypothesize that ADC values measured by diffusion weighted MRI (DW-MRI) will significantly change in women treated with AI + sulindac 150 mg bid over 12 months, whereas they will not change in women receiving AI + placebo. 3. To compare pain scores using the Brief Pain Inventory-Short form (BPI-SF) within individuals and between treatment arms. We hypothesize that women treated with AI + sulindac 150 mg bid will experience reduced pain scores over 12 months, whereas they will not change in women receiving AI + placebo. In addition, because the prodrug sulindac sulfoxide (Clinoril") has been shown to spare renal synthesis of the vasodilatory prostaglandins in patients with normal renal function, we hypothesize that daily sulindac use will not increase blood pressure (BP) in women on AIs with normal renal clearance and thus, will not elevate risk of CV toxicity mediated through drug-induced hypertension. Success in this phase II biomarker trial of sulindac combined with AI will serve as justification for a larger trial with cancer specific outcomes. PUBLIC HEALTH RELEVANCE: Estrogen receptor positive, or luminal type, tumors comprise the majority of breast cancers and account for most breast cancer-related morbidity and death. High rates of early discontinuation of aromatase inhibitor therapy (estimated at 30% by year 3) due to intolerance to side effects, notably musculoskeletal pain are now linked to reduced clinical benefit as higher rates of breast cancer recurrence. Non-steroidal anti-inflammatory drugs (NSAIDs) demonstrate potent efficacy for the management of musculoskeletal pain associated with prostanoid-related inflammation. NSAIDs also demonstrate anti-cancer activity in breast cancer models, with observational evidence that supports lower odds of breast cancer recurrences among regular users. We propose novel magnetic resonance imaging (MRI) and tissue biomarker studies to assess the effect of sulindac, a potent, non-selective NSAID in combination with aromatase inhibitors on 'high-risk' breast tissue of women with estrogen receptor positive breast cancer. In addition, we will test the role of sulindac on decreasing musculoskeletal symptoms as an approach to improve patient adherence to AI therapy. Cardiovascular risks, mostly clearly defined with COX-2 inhibition, but also theoretically plausible with NSAID use will be examined with serial blood pressure measurements to provide important safety data for women receiving NSAID therapy.