Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G.A. Amadeo, 42, 20133 Milan, Italy.
Semin Cancer Biol. 2017 Jun;44:106-116. doi: 10.1016/j.semcancer.2017.04.007. Epub 2017 Apr 22.
Breast cancer ranks first among female cancer-related deaths in Western countries. As the primary tumor can often be controlled by surgical resection, the survival of women with breast cancer is closely linked to the incidence of distant metastases. Molecular screening by next generation sequencing highlighted the spatial and temporal heterogeneity of solid tumors as well as the clonal evolution of cancer cells during progression and under treatment pressure. Such findings question whether an optimal assessment of disease progression and a screening for druggable mutations should be based on molecular features of primary or recurrent/metastatic lesions and therefore represent a crucial element for failure or success of personalized medicine. In fact, new targeted therapies may induce only short-term benefit annulled by the emergence of resistant clones with new driver mutations which would need to be rapidly and reliably identified. Serial tissue sampling is therefore essential but, unfortunately, also represents a problem since biopsies from solid lesions, which are invasive and potentially painful and risky, cannot be easily repeatedly sampled, are inaccessible or may not fully reflect tumor heterogeneity. The need to early detect and strike this "moving target" is now directing the scientific community toward liquid biopsy-based biomarkers, which include circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA), can be repeatedly assessed through non-invasive and easy-to-perform procedures and may act as reliable read-outs of functional and molecular features of recurrent/metastatic lesions. In this review we summarize the outcome of CTCs and ctDNA in breast cancer, with special reference on their role on unveiling and overcoming tumor heterogeneity, on their potential relevance for tumor surveillance and monitoring, and for the selection of therapeutic options. Finally, we propose integration between blood-based molecular and clinical approaches for monitoring disease progression according to the specific pattern of recurrence of the most aggressive breast cancer molecular subtypes.
在西方国家，乳腺癌在女性癌症相关死亡中位居第一。由于原发肿瘤通常可以通过手术切除来控制，因此乳腺癌患者的生存与远处转移的发生率密切相关。下一代测序的分子筛选突出了实体瘤的空间和时间异质性以及癌细胞在进展过程中和在治疗压力下的克隆进化。这些发现引发了这样一个问题，即是否应该根据原发性或复发性/转移性病变的分子特征来最佳评估疾病进展并筛选可用药突变，这代表了个体化医疗成败的关键因素。事实上，新的靶向治疗可能仅带来短期获益，而新的驱动突变会导致耐药克隆的出现，这些克隆需要快速可靠地识别。因此，连续组织采样至关重要，但不幸的是，这也是一个问题，因为实体病变的活检是侵入性的，可能会带来疼痛和风险，而且不易重复采样，无法获取或可能无法完全反映肿瘤异质性。早期检测和打击这个“移动目标”的需求，促使科学界转向基于液体活检的生物标志物，包括循环肿瘤细胞（CTC）和游离循环肿瘤 DNA（ctDNA），可以通过非侵入性和易于执行的程序进行重复评估，并可能作为复发性/转移性病变功能和分子特征的可靠指标。在这篇综述中，我们总结了 CTC 和 ctDNA 在乳腺癌中的结果，特别提到了它们在揭示和克服肿瘤异质性、在肿瘤监测和监测方面的潜在相关性，以及在选择治疗方案方面的作用。最后，我们提出根据最具侵袭性的乳腺癌分子亚型的特定复发模式，将血液分子和临床方法进行整合，以监测疾病进展。
