指南标题：Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline
发布机构：美国临床肿瘤学会(ASCO, American Society of Clinical Oncology)
指南发表：J Clin Oncol. 2015 Jul 20.
临床问题1
什么情况下（对哪些患者）应进行转移灶活检或取样以检测原发灶激素受体或HER2状态的改变？
Clinical Question 1
Under what circumstances (ie, for which patients) should metastases be biopsied or otherwise sampled to test for changes from the primary tumor with respect to endocrine receptor or HER2 status?
指南推荐1
乳腺癌首次出现转移时，对可获取的病灶进行活检以确认诊断。需要注意的是，当评估转移灶时，ER、PR和HER2的状态可能与原发灶不同，这些结果可为治疗决策提供参考信息。因此，专家组推荐对一个转移部位进行ER、PR和HER2的状态及性能检测，尤其对于骨转移病灶。然而，对于转移部位生物标记物改变的患者，尚缺乏足够数据证明根据此结果更改系统治疗方案是否对疗效有影响。专家组非正式共识认为：符合临床状况及患者治疗目标的情况下，当原发灶与转移灶ER、PR和HER2表达不一致时，应根据转移灶的检测结果指导治疗。（证据来源：基于原发灶与转移灶之间的生物标志物转变的证据，尚无证据说明生物标志物的改变与系统治疗的选择影响预后。证据级别：欠充分。推荐等级：中度。）
Recommendation 1
At initial presentation of metastasis from breast cancer, it is standard of care to biopsy an accessible lesion to confirm metastatic breast cancer. When evaluating the metastatic site(s), it is important to note that the results of ER, PR, and/or HER2 status may have changed from the primary tumor, and these results may inform treatment decisions. Therefore, this Panel recommends restesting for ER, PR, and HER2 on one metastasis with careful attention to assayper formance, particularly for bone metastases. However, for patients with documented changes in these biomarkers, data are lacking to determine whether outcomes from systemic therapy are altered when guided by biomarker test results from the metastases. The Panel informal consensus for the management of care when there is discordance of ER, PR, or HER2 results between primary and metastatic tissues is to use the ER, PR, or HER2 status from the metastasis to direct therapy, if supported by the clinical scenario and the patient’s goals for care. (Type: evidence based for biomarker change from primary to metastasis, but no evidence to demonstrate that systemic therapy choices affect health outcomes when biomarker change occurs. Evidence quality: insufficient. Strength of recommendation: moderate.)
临床解读
对转移病灶的诊断，可从良性到恶性病变进行鉴别，包括新发恶性病变。因此，在可能的情况下，专家组建议对病灶进行活检。若确诊转移病变，则可在对现状有足够把握的情况下制定后续治疗计划。专家组根据现有数据，发现转移灶ER、PR及HER2改变并不常见，在综合统计的病例中＜10%。这些数据代表了相当数量的患者，故具有临床意义。对于这些受体状态的改变有一些可能的解释，包括性能分析、肿瘤异质性及肿瘤生物进化。虽然不同改变都有其各自不同的潜在因素，但目前的治疗决策多根据这些生物标记物来确定，对转移灶再活检及评估ER、PR及HER2状态在所有病例中都被认为是合理的。专家组认为，由于现有病理学条件下检测到的ER、PR及HER2结果可靠度不高，故应对发生骨转移的患者这种特殊情况提高警惕。
骨活检标本的脱钙作用可能会影响ER、PR及HER2检测结果。因此只要有可能，应使标本在检测前的处理过程中不进行脱钙。应用ethylenedi-aminetetra-acetic acid以及减少甲酸脱钙时间为可行方法；然而，这两种方法都有缺陷，并且在临床应用前均需进行验证。将有活性的肿瘤组织从宿主骨骼物理分离，可使至少一部分肿瘤组织不必经过脱钙处理，但可能细针活检标本不能实现。对于乳腺癌骨转移病灶的穿刺活检，将伴有血凝块的组织与骨组织碎片分别用标本容器送检可能不必经过脱钙处理，且可用于检测乳腺癌骨转移灶的HER2状态。若无法检测到未经脱钙的标本，应谨慎解读阴性结果，并考虑对额外或更合适的标本进行检测。
在原发灶与转移灶受体表达不一致的情况下，临床医生应确保应用了恰当的检测程序，因其潜在影响着患者的治疗。新证据表明，肿瘤之间及肿瘤内部的异质性要比既往所认为的更重要，不同的转移部位可能包含不同的生物标记表达谱，肿瘤内的细胞克隆分子谱也不同。专家组非正式共识认为：符合临床状况及患者治疗目标的情况下，当原发灶与转移灶ER、PR和HER2表达不一致时，应根据转移灶的检测结果指导治疗。医生需进行临床判断。
Clinical Interpretation
The differential diagnosis for a lesion suggestive of a metastatic focus ranges from benign to malignant, including a new malignancy. Hence, when possible, this Panel recommends a biopsy be performed. If metastatic disease is confirmed, subsequent treatment planning can be made with confidence of the condition at hand. The Expert Panel reviewed the available data and found that the frequency of change from the primary tumor to the metastasis for ER, PR, orHER2 was uncommon,10% in all cases of pooled estimates. This represents a significant number of patients and is therefore clinically meaningful. There are several potential explanations for these changes, including variability in assay performance, tumor heterogeneity, and biologic evolution of the tumor.Although each reason for change may have its own potential significance, performing rebiopsy and retesting for ER, PR, and HER2 was believed to be justified in all cases, given that the choice of current therapy is largely determined by these biomarkers. The Panel believed that special circumstances should be noted in patients with bone metastases for whom results of ER, PR, and HER2 maybe unreliable with current pathology practices.
The decalcification of bone biopsy material for the analysis of ER, PR, and HER2 may alter the outcome of the tumor analysis. Whenever possible, testing of bone metastases should be performed using a validated assay with a sample that has not been decalcified during preanalytic processing. Using ethylenedi-aminetetra-acetic acid-based decalcification solutions and trying to limit the time in formic acid decalcification represent possible options; however, both approaches have disadvantages and should be validated before being offered clinically for breast cancer biomarker analysis. The ability to physically separate viable tumor from host skeletal tissue, so that at least some of the tumor can be processed without having to undergo decalcification, would be clearly advantageous, but may not be practical on small-needle biopsy specimens. For needle biopsies of metastatic breast cancer to bone, submitting the accompanying blood clot in the specimen container separately from the fragments of bony tissue may yield viable tumor that would not have to undergo decalcification and could be used for the analysis of HER2 in breast cancer metastatic to skeletal tissue. If it is not possible to test a sample that has not undergone decalcification, a negative result should be interpreted with caution, and consideration should be given to an additional and more suitable biopsy sample for testing.
In cases of discordance between the primary and metastatic site, the clinician should ensure that appropriate assay procedures were performed, given that this has the potential to affect treatment of the patient. Finally, emerging evidence suggests a greater importance of both inter-and intratumoral heterogeneity than previously appreciated. Studies have shown that different metastatic sites may contain different biomarker profiles, and clones within tumors may vary by molecular profile. The clinical consequences ofthese findings are as yet unknown. The Panel informal consensus for the management of care when there is discordance of ER, PR, or HER2 results between primary and metastatic tissues is to use the ER, PR, or HER2 status from the metastasis to direct therapy, if supported by the clinical scenario and the patient’s goals for care. Clinical judgment must be exercised.
