Nsaid Effects on Clinical and Imaging Breast Biomarkers

描述（由申请人提供）：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。芳香化酶抑制剂（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。尽管激素疗法取得了显著成功，但约20-25%的ER+疾病患者将进展10年，复发患者最终死于疾病。药物依从性差，主要是由于对副作用的不耐受，仍然是实现最大药物获益的主要挑战。显然，需要最大限度地提高人工智能的功效。非甾体抗炎药（NSAID），特别是舒林酸，在临床前模型中显示出对乳腺肿瘤的强效和机制支持的抗癌活性。我们假设舒林酸与人工免疫制剂联合使用可能对乳腺密度和乳腺组织生物标志物起协同作用，作为复发风险的替代物。在AI治疗中添加舒林酸还可能具有减少与AI使用相关的肌肉和骨骼疼痛的额外益处，从而改善依从性和长期疗效。为了检验我们的假设，150例接受AI治疗ER+肿瘤稳定的乳腺癌患者将随机分配至两个干预组之一，持续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.比较个体内和治疗组间通过磁共振成像（MRI）获得的脂肪-水比（FWR）（主要试验终点）测量的乳腺密度变化。我们假设接受AI +舒林酸150 mg bid治疗的女性将显示乳腺密度降低（即，增加FWR），而接受AI +安慰剂的女性的乳腺密度不会改变。2.比较个体内和治疗组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12个月的女性中，通过弥散加权MRI（DW-MRI）测量的ADC值将显著改变，而在接受AI +安慰剂治疗的女性中，ADC值不会改变。3.使用简明疼痛量表-简表（BPI-SF）比较个体内和治疗组间的疼痛评分。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，由于前药舒林酸亚砜（Clinoril”）已显示在肾功能正常的患者中减少血管舒张性肾上腺素的肾合成，我们假设每日使用舒林酸不会增加肾清除率正常的AI女性的血压（BP），因此不会增加药物诱导的高血压介导的CV毒性风险。舒林酸与AI联合的II期生物标志物试验的成功将成为一项具有癌症特异性结果的更大规模试验的理由。

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.