Circulating plasma tumor DNA as a biomarker for early stage breast cancer

 描述（由申请人提供）：乳腺肿瘤学的个性化药物正在发展中。目前，肿瘤学家使用先前的临床试验数据，根据肿瘤的特征和患者的临床阶段推荐多种疗法。这种方法的局限性在于 这些数据是从大量患者中平均得到的，然后应用于每个人。这就产生了不确定性，因为目前还没有可靠的方法来识别在初级治疗后真正具有显微镜残留疾病的个体患者和已经治愈的患者。因此，肿瘤学家倾向于用多种疗法治疗大多数患者，从过去的临床试验中知道大多数患者不需要这些额外的疗法，导致过度治疗。该项目提出了一种替代模式，将导致肿瘤学家如何推荐和遵循治疗反应的范式转变。研究小组提出，使用液滴数字PCR（ddPCR）和下一代测序（NGS）的新技术，可以可靠地检测和测量从癌细胞脱落到循环中的血浆肿瘤DNA（ptDNA）分子。他们已经证明了使用这些技术在早期乳腺癌患者中检测微观残留疾病的能力。该团队提出了一个转型项目，以解决早期（治疗意图）乳腺癌的特定未满足的需求。众所周知，有一部分乳腺癌患者在完成术前化疗（新辅助治疗; NAT）后没有乳腺癌和淋巴结癌的证据。这被称为病理完全反应（pCR），并与良好的预后相关。这就提出了这些患者在NAT后是否需要手术的问题，然而，患者必须接受手术才能知道他们已经实现了pCR。该团队将通过确定NAT后可检测的ptDNA的缺失是否会预测pCR来解决这个难题，因此他们将定义“液体pCR”。根据他们的数据，研究小组假设NAT后>95%没有检测到ptDNA的患者将具有pCR。这将为未来的研究奠定基础，以确定NAT后无法检测到ptDNA的患者是否可以安全地放弃手术和/或放射治疗，类似于几十年前治疗肛门癌的范式转变。这项工作的第二个长期目标是在未来的研究中确定NAT后ptDNA的存在是否识别出未来复发风险显著的患者子集，因此可以作为临床试验的平台，为具有可检测ptDNA的患者提供新的靶向治疗。最终，测量ptDNA将使个体治疗选择成为可能，并改变目前在早期疾病中过度治疗的做法。

 DESCRIPTION (provided by applicant): Personalized medicine for breast oncology is in evolution. Currently, oncologists use prior clinical trials data to recommend multiple therapies based upon features of the tumor and clinical stage of the patient. A limitation with this approach is that these data are averaged from large groups of patients that are then applied to each individual. This creates uncertainty as there is currently no reliable method to identify individua patients who truly have microscopic residual disease after primary therapy from those that are already cured. Thus, oncologists tend to treat the majority of patients with multiple therapies knowing from past clinical trials that most patients do not need these additional therapies, resulting in overtreatment. This project proposes an alternative model that will lead to a paradigm shift in how oncologists recommend and follow responses to therapy. The research team proposes that using the newer technologies of droplet digital PCR (ddPCR) and next generation sequencing (NGS), plasma tumor DNA (ptDNA) molecules shed into the circulation from cancer cells can be reliably detected and measured. They have already demonstrated the ability to detect microscopic residual disease using these technologies in early stage breast cancer patients. The team proposes a transforming project to address specific unmet needs in early stage (curative intent) breast cancer. It is well known that there are subsets of breast cancer patients who upon completion of preoperative chemotherapy (neoadjuvant therapy; NAT) have no evidence of cancer in the breast and lymph nodes. This is termed a pathologic complete response (pCR), and is associated with a favorable prognosis. This raises the question of whether these patients need surgery after NAT, however, patients must undergo surgery to know that they have achieved a pCR. The team will solve this conundrum by determining if the absence of detectable ptDNA after NAT will predict for a pCR and they will therefore define a "liquid pCR". Based on their data, the team hypothesizes that >95% of patients without detectable ptDNA after NAT will have a pCR. This will set the stage for future studies to determine if patients without detectable ptDNA after NAT can safely forego surgery and/or radiation therapy, similar to the paradigm shift in treating anal cancer decades ago. A second long-term goal of this work is to determine in future studies whether the presence of ptDNA after NAT identifies a subset of patients with significant risk for future recurrence, which could therefore serve as a platform for clinical trials with new targeted therapies for patients wih detectable ptDNA. Ultimately measuring ptDNA will enable individual therapy options and change the current practice of overtreatment in early stage disease.