美国国家综合癌症网络更新乳腺癌临床实践指南（V1.2017）

2017年03月17日 15:07 金港医药

　　2017年3月10日，美国国家综合癌症网络（NCCN）在线发表乳腺癌临床实践指南2017年第1版，全文共201页。

NCCN为非营利联盟组织（注：非政府机构，故不宜按照台湾习惯译为国立），由23个居世界领导地位的美国知名癌症中心组成，其宗旨在于全心致力对癌症患者医疗管理品质及效率的提升，通过成员机构临床人才的专业知识及领导能力, NCCN发展出之临床资源提供给医疗保健系统决策者极具价值之重要资讯。

　　与其他指南几年更新一次有所不同，NCCN指南每年更新几次。

　　按照惯例，NCCN通常在每年下半年发表次年第1版指南，当年再发表第2、3版指南。例如，NCCN乳腺癌临床实践指南分别于2015年7月16日、2015年11月18日、2016年5月6日发表2015年第3版、2016年第1版、2016年第2版。

　　此次，NCCN一反常态，2016年5月6日后未再更新，时隔308天后，跳过2016年第3版，直接公布2017年第1版。

　　关于上版（2016年第2版）NCCN乳腺癌临床实践指南，请参阅国内非NCCN官方微信公众号（订阅号：NCCN指南，服务号：NCCN指南者）2017年3月8日推出的非官方中文版，译者：任倩楠（中山大学肿瘤防治中心）。

　　关于本版（2017年第1版）NCCN乳腺癌临床实践指南，更新内容如下：

小叶原位癌（LCIS-1）

诊断项下，删除0期TisN0M0
Under diagnosis, removed Stage 0 Tis, N0, M0
根据粗针穿刺活检分为三种
Biopsy was core needle biopsy, divided pathway into three

经典型LCIS（Classic LCIS）
多形性LCIS（Pleomorphic LCIS）
与摄片不一致（Non-concordant with imaging）

修改脚注b：LCIS某些亚型（多形性LCIS）可能有与导管原位癌（DCIS）相似的生物学行为。对于多形性LCIS，临床医师可以考虑完全切除并且切缘阴性，增加：但这可能导致乳房切除率高而无临床获益证据（删除：但是缺乏关于手术切除并且切缘阴性的有效性结局数据），无数据支持在这种情况下使用放射疗法。
Modified footnote b: "Some variants of LCIS (pleomorphic LCIS) may have a similar biological behavior to that of DCIS. Clinicians may consider complete excision with negative margins for pleomorphic LCIS, but this may lead to high mastectomy rate without proven clinical benefit. but outcomes data regarding the efficacy of surgical excision to negative margins are lacking. There are no data to support using radiotherapy in this setting."

导管原位癌（DCIS-1）

删除NCCN乳腺筛查与诊断指南的链接
Removed link to NCCN Guidelines for Breast Screening and Diagnosis

导管原位癌（DCIS-A）

增加以下声明：
Added the following statements:
NCCN专家组同意2016年SSO/ASTRO/ASCO切缘共识指南将阴性切缘定义为“肿瘤无墨染”
The NCCN Panel accepts the definition of a negative margin as "No ink on the tumor," from the 2016 SSO/ASTRO/ASCO Consensus Guidelines on Margins
对于单纯DCIS，阴性切缘至少2mm与＜2mm相比，接受全乳放疗（WBRT）患者的同侧乳腺肿瘤复发（IBTR）风险较低。阴性切缘＞2mm的常规做法不被证据支持。当考虑最佳切缘宽度时，微浸润DCIS（定义为无＞1mm的浸润病灶）应当被认为DCIS。
For pure DCIS, margins of at least 2 mm are associated with a reduced risk of ipsilateral breast tumor recurrence (IBTR) relative to narrower negative margin widths in patients receiving WBRT. The routine practice of obtaining negative margin widths wider than 2 mm is not supported by the evidence. DCIS with microinvasion (defined as no invasive focus >1 mm in size) should be considered as DCIS when considering the optimal margin width.
对于单纯切除治疗（未放疗）的患者，无论切缘宽度如何，IBTR的风险显著高于乳房切除术＋全乳放疗（即使原先认为低风险的患者）。单纯切除治疗的最佳切缘宽度未知，但至少应为2mm。一些证据表明，切缘宽度＞2mm的IBTR率较低。
For patients treated with excision alone (without radiation), regardless of margin width, the risk of IBTR is substantially higher than treatment with excision and whole breast radiation therapy (even in predefined low-risk patients). The optimal margin width for treatment with excision alone is unknown, but should be at least 2 mm. Some evidence suggests lower rates of IBTR with margin widths wider than 2 mm.
删除以下声明：
Removed the following statements:
关于DCIS阴性病理学切缘的定义存在很大争议，争议源于：疾病异质性、难以区分不同增生病变、切缘位置的解剖学考虑、缺乏关于DCIS预后因素的前瞻数据。
Substantial controversy exists regarding the definition of a negative pathologic margin in DCIS. Controversy arises out of the heterogeneity of the disease, difficulties in distinguishing the spectrum of hyperplastic conditions, anatomic considerations of the location of the margin, and inadequate prospective data on prognostic factors in DCIS.
切缘＞10mm普遍被认为阴性（但是可能过大，并且可能导致美观效果不佳）
Margins greater than 10 mm are widely accepted as negative (but may be excessive and may lead to a less optimal cosmetic outcome).
切缘＜1mm被认为太少
Margins less than 1 mm are considered inadequate.
病理学切缘在1～10mm之间时，越大复发风险越小。虽然对于乳腺（胸壁或皮肤）纤维腺体交界部位＜1mm的手术切缘不强求再次手术切除，但是有指征对乳房肿块切除术涉及部位进行较大剂量的增强放疗（2B类）
With pathologic margins between 1-10 mm, wider margins are generally associated with lower local recurrence rates. However, close surgical margins (<1 mm) at the fibroglandular boundary of the breast (chest wall or skin) do not mandate surgical re-excision but can be an indication for higher boost dose radiation to the involved lumpectomy site (category 2B).

浸润性乳腺癌（BINV-1、10、14、17）炎性乳腺癌（IBC-1）

检查
Workup
增加综合代谢专家组
Added Comprehensive metabolic panel
摄片推荐意见加入“造影剂增强”
Clarified "with contrast" to imaging recommendations
删除FDG PET/CT后的“2B类”
Removed "category 2B" from FDG PET/CT

浸润性乳腺癌（BINV-1）

增加链接：术前全身疗法（BINV-10和BINV-14）
Added links to preoperative systemic therapy pages BINV-10 and BINV-14）

浸润性乳腺癌（BINV-2）

阴性腋窝淋巴结
Negative axillary nodes
修改：“全乳±瘤床增强放疗”后增加“并对中央区/内象限肿瘤或肿瘤＞2cm伴有其他高风险特征（年轻或广泛淋巴血管间浸润[LVSI]）患者考虑区域淋巴结放疗”
Modified - "Radiation therapy to whole breast with or without boost to tumor bed, and consider regional nodal radiation in patients with central/medial tumors or tumors >2 cm with other high-risk features (young age or extensive lymphovascular space invasion [LVSI])."
修改：在有选择性的低风险患者中考虑部分乳房加速放疗（APBI）
Modified - "Consideration of accelerated partial breast irradiation (APBI) in selected low-risk patients."
统一修改脚注“q”删除FDG PET/CT后的“2B类”并细化：“考虑摄片检查进行全身分期，包括胸/腹±盆腔诊断性造影剂增强CT、骨扫描、可选FDG PET/CT（2B类）（见BINV-1）”
Modified footnote "q" for consistency: "Consider imaging for systemic staging, including chest/abdominal ± pelvic diagnostic CT with contrast, bone scan, and optional FDG PET/CT (category 2B) (See BINV-1)."

浸润性乳腺癌（BINV-3）

修改：“阴性腋窝淋巴结和肿瘤≤5cm且切缘阴性但＜1mm：考虑胸壁放疗”后增加“，对中央区/内象限肿瘤或肿瘤＞2cm伴有其他高风险特征（年轻或广泛LVSI）患者±区域淋巴结放疗”
Negative axillary nodes and tumor ≤5 cm and negative margins but <1 mm: Modified "Consider radiation therapy to chest wall, ±regional nodal radiation in patients with central/medial tumors or tumors >2 cm with other high-risk features (young age or extensive LVSI)."
修改脚注“u”：“乳房切除术后放疗可以考虑用于多种高风险复发因素的患者”后增加“，包括中央区/内象限肿瘤或肿瘤＞2cm伴有其他高风险特征如年轻或广泛LVSI”
Modified footnote "u": "Postmastectomy radiation therapy may be considered for patients with multiple high-risk recurrence factors, including central/medial tumors or tumors >2 cm with other highrisk features such as young age and/or extensive LVSI."

浸润性乳腺癌（BINV-5）

“肿瘤≤0.5cm包括微浸润：考虑辅助内分泌疗法＋辅助化疗＋曲妥珠单抗”增加脚注
Tumor ≤0.5 cm including microinvasive - consider adjuvant endocrine therapy ± adjuvant chemotherapy with trastuzumab, added a footnote
新增脚注cc：“对于HER2阳性T1aN0乳腺癌，如果原发癌为ER阴性并且肿瘤大小接近T1b（＞5mm），可以考虑每周紫杉醇辅助化疗＋曲妥珠单抗（Tolaney et al. NEJM 2015）。对于ER阳性乳腺癌和肿瘤大小接近T1mic（＜1mm）的患者，当估计复发风险＜5%并且内分泌疗法仍为全身治疗的可行选择时，全身化疗＋抗HER2的绝对获益可能微不足道”（BINV-7也新增该脚注）
New footnote: "Adjuvant chemotherapy with weekly paclitaxel and trastuzumab (Tolaney et al. NEJM 2015) can be considered for HER2-positive T1a N0 cancers, if the primary cancer is ER negative, and the tumor size borders on T1b (> 5mm). The absolute benefit of HER2-based systemic chemotherapy is likely negligible in patients with ER-positive cancers and tumor size bordering on T1mic (< 1mm), when the estimated recurrence risk is less than 5% and endocrine therapy remains a viable option for systemic treatment." (footnote also included on BINV-7)

浸润性乳腺癌（BINV-5、6、7、8）

修改脚注“w”：“对于小叶导管混合癌、化生癌，应根据导管成分进行分级，并根据该分级进行治疗。化生或混合成分不改变预后”改为“对于小叶导管混合癌，应根据导管成分进行分级，并根据该分级进行治疗。对于化生癌，组织学分级的预后价值不确定。然而，当化生癌特定组织学亚型存在并占肿瘤10%以上时，亚型为独立预后变量”
Changed footnote "w": "Mixed lobular and ductal carcinoma should be graded based on the ductal component and treated based on this grading. For metaplastic carcinoma, the prognostic value of the histologic grading is uncertain. However, when a specific histologic subtype of metaplastic carcinoma is present and accounts for more than 10% of the tumor, the subtype is an independent prognostic variable."

浸润性乳腺癌（BINV-13）

乳房肿块切除术
Lumpectomy
删除第一点的内分泌疗法，放入第二点放疗后的第三、四点进行详细描述
Removed the endocrine therapy in the first bullet, since this is covered in detail in bullets 3 and 4, following the radiation bullet.
修改第二点：“乳房肿块切除术后，根据来自化疗前肿瘤初诊特征和化疗后病理学结果的最高疾病分期进行辅助放疗。建议辅助放疗用于：BINV-2的指征；cT3-4、cN2-3、III期、残留病变＞2cm的任何ypN+”
Changed: "Adjuvant radiation therapy post-lumpectomy is based on maximal disease stage from pre-chemotherapy tumor characteristics at diagnosis and post-chemotherapy pathology results. Adjuvant radiation therapy is recommended: As indicated on BINV-2; For cT3-4, cN2-3, stage III, residual disease >2 cm any ypN+"

浸润性乳腺癌（BINV-16）

新增：“定期筛查家族史变化，并转诊至遗传咨询，参见NCCN遗传性/家族性高风险评估指南：乳腺癌和卵巢癌”
Added: "Periodic screening for changes in family history and referral to genetic counseling as indicated, added see NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian."
修改脚注“pp”：不鼓励使用雌激素、孕激素、选择性雌激素受体调节剂治疗乳腺癌女性的骨质疏松或骨质减少。使用双膦酸盐（口服/静脉）或地诺单抗（狄诺塞麦）可以维持或改善骨矿物质密度，并降低绝经后（自然或诱发）患者接受辅助内分泌疗法的骨折风险。任何一种治疗的最佳持续时间尚未确定，持续3年以上仍未可知。抗骨质疏松疗法持续时间的考虑因素包括：骨矿物质密度、对治疗的反应、骨质继续流失或骨折的风险因素。女性开始双膦酸盐或地诺单抗治疗前应进行牙科检查和预防性牙科手术，并应服用钙和维生素D补充剂。
Modified footnote "pp": The use of estrogen, progesterone, or selective estrogen receptor modulators to treat osteoporosis or osteopenia in women with breast cancer is discouraged. The use of a bisphosphonate (oral/IV) or denosumab is acceptable to maintain or to improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) patients receiving adjuvant endocrine therapy. Optimal duration of either therapy has not been established. Duration beyond 3 y is not known. Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. Women treated with a bisphosphonate or denosumab should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D."

浸润性乳腺癌（BINV-20）

修改脚注“ddd”：尚不清楚在初诊时表现为完全原发性和转移性疾病的女性能否获益于姑息性局部乳房手术和/或放疗。通常，姑息性局部治疗应仅在初始全身疗法有效后才予以考虑。
Modified footnote "ddd": It is unclear that women presenting at time of initial diagnosis with an intact primary and metastatic disease will benefit from the performance of palliative local breast surgery and/or radiation therapy. Generally this palliative local therapy should only be considered only after response to initial systemic therapy.
各项治疗选择增加脚注“ddd”。
Added footnote "ddd" to each treatment option.
新增脚注“ggg”：帕泊昔布联合来曲唑可以考虑用于HER2阴性转移性乳腺癌
Added footnote "ggg": Palbociclib in combination with letrozole may be considered in HER2-negative, metastatic breast cancer.

浸润性乳腺癌（BINV-23、N）

新增脚注：如果帕泊昔布＋来曲唑治疗期间疾病进展，无数据支持其他帕泊昔布方案继续治疗。同样，如果依西美坦＋依维莫司治疗期间疾病进展，无数据支持其他依维莫司方案继续治疗。
Added a new footnote: "If there is disease progression while on palbociclib + letrozole there are no data to support an additional line of therapy with another palbociclib regimen. Likewise, if there is disease progression while on exemestane + everolimus, there are no data to support an additional line of therapy with another everolimus regimen."

浸润性乳腺癌（BINV-B）

修改：乳腺专用MRI检查可能有助于确定乳腺钼靶、超声波或体检无法确定腋窝淋巴结腺癌、原发灶隐匿性（或未确定）癌、佩吉特病（乳头乳晕或乳房外湿疹样癌）、浸润性小叶癌女性的原发癌。
Modified: "May be useful for identifying primary cancer in women with axillary nodal adenocarcinoma and occult (or unidentified) primary cancer, with Paget's disease, or with invasive lobular carcinoma poorly (or inadequately) defined on mammography, ultrasound, or physical examination."

浸润性乳腺癌（BINV-G）

保乳疗法＋放疗的禁忌证包括：
Contraindications for breast-conserving therapy requiring radiation therapy include:
绝对禁忌证新增：ATM突变纯合子（2B类）
Absolute: Homozygous for ATM mutation (category 2B)
相对禁忌证新增：p53突变综合征（2B类）
Relative: Li-Fraumeni syndrome (category 2B)

浸润性乳腺癌（BINV-H）

第二点修改：通常，为了治疗癌症，保留皮肤的乳房切除术需要切除乳头乳晕复合体（NAC）。但是，通过有经验团队严格选择的癌症患者也可以选择NAC保留术式。回顾性数据支持在治疗乳头累及程度低和复发率低的早期、生物学类型良好（例如诺丁汉1或2级、淋巴结阴性、HER2/neu阴性、无淋巴血管浸润）的乳腺癌、位于乳房外周（距离乳头＞2cm）的浸润性癌和/或DCIS时，使用NAC保留术式。乳头累及的术前临床证据，包括佩吉特病、乳头恶性溢液和/或摄片结果提示乳头或乳晕下组织恶性病变，为乳头保留禁忌证。术中位于乳房外周（距离乳头＞2cm）。必须进行乳头切缘评定，并且清楚标示乳头切缘。
2nd bullet: "In general, the nipple-areolar complex (NAC) is sacrificed with skin-sparing mastectomy for cancer therapy. However, NAC-sparing procedures may be an option in cancer patients who are carefully selected by experienced multidisciplinary teams. Retrospective data support the use of NAC-sparing procedures for breast cancer therapy with low nipple-involvement rates and low local recurrence rates for early-stage, and select advanced biologically favorable (eg, Nottingham grade 1 or 2, node-negative, HER2/neu negative, no lymphovascular invasion), invasive cancers and/or DCIS. Preoperative clinical evidence of nipple involvement including Paget's disease, nipple discharge associated with malignancy, and/or imaging findings suggesting malignant involvement of the nipple or subareolar tissues contraindicates nipple preservation. Intraoperative that is peripherally located in the breast (>2 cm from nipple). Nipple margin assessment is mandatory, and the nipple margin should be clearly designated."

浸润性乳腺癌（BINV-I）

更新了APBI部分以下声明：
Updated the following statement in the APBI section:
NCCN专家组同意ASTRO更新后的2016版APBI指南，现将APBI的“适合”患者定义为以下之一：a）浸润性导管癌且年龄≥50岁，测量≤2cm（T1病变）且阴性切缘宽度≥2mm，无LVSI，ER阳性且BRCA阴性；b）细胞核分级低/中、筛查检出DCIS测量尺寸≤2.5cm且阴性切缘宽度≥3mm。
The NCCN Panel accepts the updated 2016 version of the ASTRO APBI guideline, which now defines patients "suitable" for APBI to be one of the following:a) 50 years or older with invasive ductal carcinoma measuring ≤2cm (T1 disease) with negative margin widths of ≥2mm, no LVSI, ER-positive, and BRCA negative or b) Low/ intermediate nuclear grade, screen-detected DCIS measuring size ≤2.5 cm with negative margin widths of ≥3 mm.
删除：如不合适临床试验，根据ASTRO共识声明，可能适合APBI的患者：女性≥60岁且非BRCA1/2突变携带者且单灶T1N0ER阳性癌症已接受手术，组织学应为浸润性导管癌或预后较好的导管亚型，且不伴广泛导管内成分（EIC）或LCIS且切缘应为阴性
Removed: If not trial eligible, per the consensus statement from the American Society for Radiation Oncology (ASTRO), patients who may be suitable for APBI are women 60 y and older who are not carriers of BRCA 1/2 mutation treated with primary surgery for a unifocal T1N0 ER-positive cancer. Histology should be infiltrating ductal or a favorable ductal subtype and not associated with EIC or LCIS, and margins should be negative.

浸润性乳腺癌（BINV-J）

诊断时已绝经，增加：考虑额外5年芳香酶抑制剂
Postmenopausal at diagnosis, added "Consider aromatase inhibitor for an additional 5 y."
脚注2，增加：权衡卵巢抑制疗法相关利弊的讨论至关重要
Footnote 2, added: "A balanced discussion of the risks and benefits associated with ovarian suppression therapy is critical."

浸润性乳腺癌（BINV-K1/7）

HER2阴性病变治疗方案：删除“FEC/CEF→T”，删除“FAC→T”
Regimens for HER2-negative disease: Removed "FEC/CEF followed by T", Removed "FAC followed by T"
新增脚注：由于医学上的必要性（减少过敏反应），纳米白蛋白结合（NAB）紫杉醇可以替代紫杉醇或多西他赛。如果替代每周紫杉醇或多西他赛，那么NAB紫杉醇每周剂量不应超过125mg/m²
Added a new footnote: "Nab-paclitaxel may be substituted for paclitaxel or docetaxel due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of nab-paclitaxel should not exceed 125 mg/m²."

浸润性乳腺癌（BINV-K7/7）

删除以下参考文献：
Removed the following references:
Roche H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 001 trial. J Clin Oncol 2006;24:5664-5671.
Martin M, Rodriguez-Lescure A, Ruiz A, et al: Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst 2008;100:805-814.

浸润性乳腺癌（BINV-L1/2）

删除：内分泌疗法（芳香酶抑制剂【绝经后女性首选，或接受卵巢抑制疗法的绝经前女性】或他莫昔芬）可考虑单独用于激素受体阳性患者
Removed: "Endocrine therapy alone (aromatase inhibitor [preferred for postmenopausal women; given with ovarian suppression for premenopausal women] or tamoxifen) may be considered for patients with hormone-receptor positive disease."
增加：术前内分泌疗法可考虑单独用于有合并症或低风险管腔型ER阳性患者
Added "Preoperative endocrine therapy alone may be considered for patients with ER-positive disease based on comorbidities or low-risk luminal biology."

浸润性乳腺癌（BINV-N）

绝经前患者：选择性ER调节剂（他莫昔芬或托瑞米芬）或卵巢切除或抑制，绝经后女性加用内分泌疗法。
Premenopausal Patients: Selective ER modulators, added "(tamoxifen or toremifene)" to "or ovarian ablation or suppression, plus endocrine therapy as for postmenopausal women."
绝经后患者：帕泊昔布＋来曲唑,，增加（1类）
Postmenopausal Patients: Palbociclib + letrozole, added (category 1).
修改脚注1：对于符合BOLERO-2研究标准的患者，可以考虑依西美坦＋依维莫司（非甾体AI或12个月内进展）删除：或任何时间他莫昔芬。
Modified footnote 1: "A combination of exemestane with everolimus can be considered for patients who meet the eligibility criteria for BOLERO-2 (progressed within 12 mo or on non-steroidal AI)," removed or any time on tamoxifen.
修改脚注4：对于女性绝经后女性或绝经前接受LHRH激动剂抑制卵巢且激素受体阳性且HER2阴性转移性乳腺癌既往辅助或转移性内分泌疗法期间或之后进展。
Modified footnote 4: "For postmenopausal women or for premenopausal women receiving ovarian suppression with an LHRH agonist, with hormone-receptor positive and HER2-negative metastatic breast cancer that has progressed on or after prior adjuvant or metastatic endocrine therapy."
“氟维司群”改为“选择性ER下调剂（氟维司群）”
Added selective ER down-regulator to fulvestrant

浸润性乳腺癌（BINV-O）

新增脚注：由于医学上的必要性（减少过敏反应），纳米白蛋白结合（NAB）紫杉醇可以替代紫杉醇或多西他赛。如果替代每周紫杉醇或多西他赛，那么NAB紫杉醇每周剂量不应超过125mg/m²
·Added a new footnote: "Nab-paclitaxel may be substituted for paclitaxel or docetaxel due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of nab-paclitaxel should not exceed 125 mg/m²."

浸润性乳腺癌（BINV-P3/3）

建议转移性疾病患者随访PET/CT：将化疗和内分泌疗法后的“未知”改为“可选”
Changed the suggested follow-up with PET/CT for patients with metastatic disease from "unknown" to "optional" following chemotherapy and endocine therapy.