正确解读乳腺癌新辅助化疗耐药
2017年12月7日，美国麻省医学会《新英格兰医学杂志》发表宾夕法尼亚大学、明尼苏达大学、旧金山加利福尼亚大学对乳腺癌新辅助化疗耐药最新基础研究临床意义的解读，澄清了一些对乳腺癌新辅助化疗的误解、困惑、质疑和顾虑。
转移性乳腺癌发生于30%的乳腺癌女性，其中某些类型乳腺癌比其他类型乳腺癌更容易复发（图1）。复发性乳腺癌被认为是由原发性乳腺癌逃逸并进入淋巴系统和（或）血液的肿瘤细胞产生，这些细胞可能通过特定机制进行转移并逃避标准疗法。
图1、乳腺癌：肿瘤类型不同，结局不同。
对患者进行适当治疗并获得无病结局的关键，在于了解疾病诊断时的生物学特性。2017年6月29日，《美国医学会杂志肿瘤学分册》在线发表的随机临床研究二次分析报告，发现有的肿瘤复发风险超低，并且可以通过多基因检测进行诊断【1】。
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对于有远处转移风险的女性，可以被归类为晚期复发风险女性（主要为激素受体阳性女性），其化疗效果可能很小；对于早期复发风险女性，标准治疗方案仍以化疗为主【2】。对于新辅助化疗后肿瘤完全消失的女性，长期生存情况良好。
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2017年7月5日，美国科学促进会《科学》旗下《转化医学》在线发表爱因斯坦医学院和康奈尔大学医学院的乳腺癌小鼠模型研究报告，发现原发性乳腺癌微环境可以影响新辅助化疗敏感性【3】。因此，肿瘤转移微环境是新辅助化疗效果不佳（根据标准治疗后残余肿瘤判断）的决定因素，这可以为针对耐药机制、提高完全缓解和无转移生存机会的策略奠定基础。
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该研究揭示了来自原发性乳腺癌的肿瘤细胞，可以在显微解剖结构部位“肿瘤转移微环境”内浸润和扩散的机制，了解该机制对于设计避免新辅助化疗耐药的手段具有临床意义。如图1所示，早期复发风险肿瘤的繁殖速度较高，与不可太能复发的肿瘤相比，更有可能破坏其DNA修复机制。晚期发展为转移性乳腺癌的残余肿瘤细胞，可以通过以繁殖停止为特征的“休眠期”并激活求生机制进行转化。通过标准辅助化疗手段，在诊断时消灭肿瘤细胞，已经显示可以减少复发的可能性，不过重要的是，需要注意作为新辅助疗法（外科手术之前）实施的化疗，可以发现哪些肿瘤有效以及哪些无效（图1）。但是，标准疗法还不够完善，而且对于耐药肿瘤细胞的求生机制，也知之甚少。
“成功”发生转移的微环境，可能为肿瘤逃避治疗提供了一个保护罩。根据该研究报道，化疗通过血管周围巨噬细胞表达高水平的血管生成素受体TIE2和血管内皮生长因子（二者均为进入血管所需）从而增加乳腺癌小鼠模型肿瘤浸润。化疗还提高了血管的通透性，并提高了游走细胞的比例，游走细胞可以表达哺乳激活蛋白（MENA）调节肌动蛋白结构和细胞活动能力；既往研究曾经观察到MENA表达于小鼠模型容易发生转移的肿瘤细胞。这些效应可见于新辅助化疗标准方案药物紫杉醇、多柔比星、环磷酰胺。
该研究还对20例新辅助化疗后残余肿瘤患者新辅助化疗前后肿瘤标本的转移微环境和MENA表达情况进行了分析，发现新辅助化疗后肿瘤微环境密度和MENA基因表达均有提高，由此推断对于新辅助化疗未完全缓解的肿瘤，肿瘤微环境内在机制可能起了作用。
既往研究已经描述了其他转移机制。例如，早期原发病灶孕激素受体阳性肿瘤细胞表达HER2后不久，可以分泌Wnt家族成员4（Wnt4）和核因子κB配体受体激活物（RANKL），从而促进骨髓转移【4】。该过程与肿瘤细胞从更多晚期原发性肿瘤转移同时发生，具有不同的遗传学改变以及与微环境的相互作用。
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综上所述，这些数据推进了乳腺原发性肿瘤非常早期阶段即可散播转移种子的假说。
某些媒体错误报道了上述研究数据，声称新辅助化疗引起乳腺癌转移【5-7】，造成患者可能困惑新辅助化疗是否增加她们死于乳腺癌的机会，并质疑新辅助化疗是否应该作为医疗标准之一。以下临床证据应该能够减轻此类顾虑。
根据2014年《柳叶刀》发表的乳腺癌新辅助化疗研究汇总分析，接受标准新辅助化疗后，13～50%的高风险乳腺癌女性获得病理学完全缓解；获得与未获完全缓解的女性相比，长期无病生存结局较好【8】。此外，根据2008年美国临床肿瘤学会《临床肿瘤学杂志》发表的NSABP乳腺癌新辅助化疗前瞻随机研究（B-18和B-27）表明，加入蒽环类＋紫杉类为主的新辅助化疗方案，可以提高病理学完全缓解和无远处转移生存的可能性，尤其对于侵袭性较强的肿瘤类型【9】。事实上，新辅助治疗已经成为药物开发的重点之一。
相反，术后残余病变是不良结局的预测指标；根据多项研究和荟萃分析，残余病变与转移性乳腺癌风险增加有关。由于爱因斯坦医学院和康奈尔大学医学院的研究仅仅评估了残余病变女性，故比较合理的结论应该是：他们发现了一种容易被解决的新辅助化疗耐药机制，抑制血管生成素受体TIE2的一类实验药物可能有效。因此，该研究应该激发患者和临床医师坚持而非避免标准疗法，并积极参与尝试新治疗方案的临床研究，克服在乳腺癌诊断时可能就已发生的治疗耐药，因为那时转移尚可预防，正如中国春秋时代名医扁鹊所言：疾在腠理，汤熨之所及也；在肌肤，针石之所及也；在肠胃，火齐之所及也；在骨髓，司命之所属，无奈何也。
参考文献
Esserman LJ, Yau C, Thompson CK, et al. Use of molecular tools to identify patients with indolent breast cancers with ultralow risk over 2 decades. JAMA Oncol. 2017;3:1503-1510.
Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375:717-729.
Karagiannis GS, Pastoriza JM, Wang Y, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med. 2017;9:eaan0026.
Schwartz RS, Erban JK. Timing of metastasis in breast cancer. N Engl J Med. 2017;376:2486-2488.
Begley S. Chemotherapy before breast cancer surgery might fuel metastasis. STAT. July 10, 2017. www.statnews.com/2017/07/10/breast-cancer-chemotherapy
Knapton S. Chemotherapy may spread cancer and trigger more aggressive tumours, warn scientists. The Telegraph. July 6, 2017. www.telegraph.co.uk/science/2017/07/05/chemotherapy-may-spread-cancer-trigger-aggressive-tumours-warn
Yirka B. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Medical Press. July 6, 2017. www.medicalxpress.com/news/2017-07-neoadjuvant-chemotherapy-breast-cancer-metastasis.html
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-172.
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778-785.
N Engl J Med. 2017 Dec 7;377(23):2287-2289.
Mechanisms of Resistance to Neoadjuvant Chemotherapy in Breast Cancer.
DeMichele A, Yee D, Esserman L.
University of Pennsylvania, Philadelphia; University of Minnesota, Minneapolis; University of California, San Francisco, San Francisco.
A study of mouse models of breast cancer suggests that the microenvironment of an established primary breast cancer affects susceptibility to neoadjuvant chemotherapy.
Metastatic cancer occurs in 30% of women who receive a diagnosis of breast cancer, although some types of breast cancer are more likely to recur than others (Figure 1). Recurrent cancer is thought to arise from tumor cells that escape from the primary breast lesion and enter the lymphatic system, the blood, or both; these cells probably use specific mechanisms to metastasize and evade standard therapies.
Figure 1: Breast Cancer -- Many Tumor Types, Many Outcomes.
The key to administering appropriate therapy and attaining disease-free outcomes in patients lies in understanding the biology of the disease at the time of diagnosis. Emerging evidence suggests that there are tumors that have an ultralow risk of recurrence, which can be identified at diagnosis by a multigene test[1]. Women at risk for distant spread of their disease can be classified as those at risk for late recurrence (primarily women with hormone receptor [HR]-positive disease), for whom chemotherapy may have little effect, and those at risk for early recurrence, for whom chemotherapy-based regimens are the standard treatment[2]. Women whose tumors completely disappear in response to neoadjuvant treatment have excellent long-term survival. A recent study by Karagiannis et al[3]. implicates the tumor microenvironment of metastasis (TMEM) as a determinant of poor response to neoadjuvant chemotherapy (as indicated by residual tumor after standard treatment), which may inform strategies to target mechanisms of resistance and improve chances for complete response and metastasis-free survival. HER2 denotes human epidermal growth factor receptor 2.
A recent study by Karagiannis et al[3]. sheds light on a mechanism by which tumor cells from primary breast lesions may intravasate and disseminate at sites of microanatomical structures called "tumor microenvironment of metastases"; understanding this mechanism has implications for devising a means to circumvent resistance to neoadjuvant chemotherapy. As shown in Figure 1, tumors that pose an early threat of recurrence have higher proliferative rates and are more likely to have had an insult to their DNA repair machinery than tumors that are unlikely to recur. Residual tumor cells that later develop into metastatic tumors may transition through a "dormant phase" that is characterized by cessation of proliferation and activation of survival mechanisms. The ability to eradicate tumor cells at the time of diagnosis by means of standard adjuvant chemotherapy has been shown to reduce the likelihood of recurrence, but it is important to note that chemotherapy administered as neoadjuvant therapy (before surgical resection) reveals which tumors respond and which do not (Figure 1). However, the standard therapy is far from perfect, and the survival mechanisms of resistant tumor cells are poorly understood.
The microenvironment of "successful" metastases probably provides a protective niche in which tumors evade treatment. Karagiannis et al. reported that in mouse models of breast cancer, chemotherapy increased intratumoral infiltration by perivascular macrophages that express high levels of the angiopoietin receptor TIE2 and the vascular endothelial growth factor (both of which are required for intravasation). Treatment also promoted vascular permeability and increased the proportion of migratory cells expressing the mammalian-enabled protein (MENA), which regulates actin structure and cell motility; Karagiannis et al. observed previously that MENA is expressed on tumor cells that are prone to metastasis in mouse models. These effects were seen with the drugs paclitaxel, doxorubicin, and cyclophosphamide, which are part of standard regimens of neoadjuvant chemotherapy.
Karagiannis et al. also studied the metastasis microenvironment and MENA expression in tumor samples obtained before and after neoadjuvant chemotherapy in 20 women, all of whom had a residual tumor after neoadjuvant chemotherapy. They found that both the density of the tumor microenvironment and expression of the MENA gene had increased from the pretherapy levels and inferred that a mechanism inherent to the tumor niche may be at play in some tumors that do not fully respond to neoadjuvant chemotherapy.
Other mechanisms for metastases have been described. For example, it has been shown that progesterone receptor-positive tumor cells in early primary lesions secrete Wnt family member 4 (Wnt4) and receptor activator of nuclear factor-κB ligand (RANKL) shortly after expression of human epidermal growth factor receptor 2 (HER2), thus facilitating dissemination to the bone marrow[4] -- a process that parallels the dissemination of tumor cells from more established primary tumors that have distinct genetic changes and interactions with the microenvironment. Taken together, these data advance the hypothesis that the seeds of metastasis are sown at a very early stage in primary tumor development in the breast.
Some have interpreted the data reported by Karagiannis et al. to suggest that neoadjuvant chemotherapy causes metastases in patients with breast cancer[5-7], and patients may wonder whether neoadjuvant chemotherapy increases their chance of dying from breast cancer and question whether it should be part of the standard of care. Clinical evidence should allay such concerns.
Overall, 13 to 50% of women with high-risk breast cancers have a pathological complete response after standard neoadjuvant chemotherapy; long-term disease-free outcome is better in women who have a complete response than in women who do not[8]. Moreover, prospective, randomized trials have shown that the addition of a taxane to anthracycline-based regimens increases the odds of both a pathological complete response and survival free of distant metastasis, especially among women with more aggressive tumor types.9 In fact, the relationship between complete pathological response and improved survival is one of the primary reasons that neoadjuvant treatment has become a focus of drug development.
Conversely, residual disease after surgery is a predictor of poor outcome; in multiple trials and meta-analyses, residual disease has been associated with an increased risk of metastatic disease. Given that Karagiannis et al. evaluated only women with residual disease, a more appropriate conclusion is that they identified a tractable mechanism of resistance to neoadjuvant chemotherapy, for which a class of experimental drugs (those that inhibit TIE2) may prove effective. Thus, the study by Karagiannis et al. should motivate patients and clinicians to adhere to standard therapies rather than to avoid them and to participate in trials that test new treatment regimens designed to overcome resistance to therapy that may be developing around the time of diagnosis, when metastases can be prevented.
REFERENCES
Esserman LJ, Yau C, Thompson CK, et al. Use of molecular tools to identify patients with indolent breast cancers with ultralow risk over 2 decades. JAMA Oncol. 2017;3:1503-1510.
Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375:717-729.
Karagiannis GS, Pastoriza JM, Wang Y, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med. 2017;9:eaan0026.
Schwartz RS, Erban JK. Timing of metastasis in breast cancer. N Engl J Med. 2017;376:2486-2488.
Begley S. Chemotherapy before breast cancer surgery might fuel metastasis. STAT. July 10, 2017. www.statnews.com/2017/07/10/breast-cancer-chemotherapy
Knapton S. Chemotherapy may spread cancer and trigger more aggressive tumours, warn scientists. The Telegraph. July 6, 2017. www.telegraph.co.uk/science/2017/07/05/chemotherapy-may-spread-cancer-trigger-aggressive-tumours-warn
Yirka B. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Medical Press. July 6, 2017. www.medicalxpress.com/news/2017-07-neoadjuvant-chemotherapy-breast-cancer-metastasis.html
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-172.
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778-785.
PMID: 29211674
DOI: 10.1056/NEJMcibr1711545