是指肿瘤的雌激素，孕激素受体和HER-2 均为阴性。
免疫抑制剂派姆单抗（pembrolizumab）联合化疗作为新辅助治疗高危早期三阴性乳腺癌 Pembrolizumab in combination with chemotherapy for high-risk early-stage triple-negative breast cancer (8/15/2021)
FDA 批准派姆单抗联合化疗用于新辅助治疗高危早期三阴性乳腺癌, 然后继续单药作为手术后的辅助治疗。
KEYNOTE-522 (NCT03036488) 是一项随机、多中心、双盲、安慰剂对照试验，在 1,174 名患有新诊断的未经治疗的高危早期三阴性乳腺癌（肿瘤 > 1 厘米 但直径 ≤ 2 厘米 且淋巴结受累, 或肿瘤 > 2 cm，无论淋巴结受累情况如何）。无论肿瘤 PD-L1 表达如何，患者都被纳入研究。 患者随机 (2:1) 接受派姆单抗联合化疗或安慰剂联合化疗。派姆单抗（每 3 周 200 毫克）加紫杉醇（每周）和卡铂（每周或每三周）共四个周期，然后是派姆单抗加环磷酰胺和阿霉素（每 3 周）共四个周期作为手术前的新辅助治疗。手术后再接受九个周期的 派姆单抗（每三周）作为辅助治疗。派姆单抗与化疗联合给药用于新辅助治疗 24 周，然后作为单药用于辅助治疗长达 27 周。主要疗效结果指标是病理完全响应率和无事件生存率。
派姆单抗联合化疗患者的病理完全响应率为 63%（95% CI：59.5、66.4），而单独接受化疗的患者病理完全响应率率为 56%（95% CI：50.6、60.6）。经历无事件生存率事件的患者人数分别为 123 (16%) 和 93 (24%)（HR 0.63；95% CI：0.48, 0.82；p = 0.00031）。 在派姆单抗联合化疗的试验中，≥20% 的患者报告的最常见不良反应是疲劳/乏力、恶心、便秘、腹泻、食欲下降、皮疹、呕吐、咳嗽、呼吸困难、发热、脱发、周围神经病变、粘膜炎症、口腔炎、头痛、体重减轻、腹痛、关节痛、肌痛和失眠。
这种联合疗法改变了治疗高危早期三阴性乳腺癌的实践。
FDA approved, on July 26, 2021, pembrolizumab in combination with chemotherapy for neoadjuvant treatment of high-risk early-stage triple-negative breast cancer, and then as a single drug for adjuvant therapy.
KEYNOTE-522 (NCT03036488) is a randomized, multicenter, double-blind, placebo-controlled trial of 1,174 newly diagnosed untreated high-risk early-stage triple-negative breast cancer (tumor diameter > 1 cm but ≤ 2 cm with lymph node involvement, or tumor diameter > 2 cm, no matter whether lymph node is involved). Regardless tumor PD-L1 expression, patients were included in the study. The patients were randomized (2:1) to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. As neoadjuvant treatment before surgery, pembrolizumab (200 mg every 3 weeks) plus paclitaxel (weekly) and carboplatin (weekly or every three weeks) for four cycles, followed by pembrolizumab plus cyclophosphamide and doxorubicin (every 3 weeks) for four cycles. After surgery, patients received nine cycles of pembrolizumab (every three weeks) as adjuvant therapy. In total, pembrolizumab was administered in combination with chemotherapy for neoadjuvant therapy for 24 weeks, and then as a single agent for adjuvant therapy for up to 27 weeks. The main efficacy outcome indicators were pathological complete response rate and event-free survival rate.
The pathological complete response rate of patients with pembrolizumab combined with chemotherapy was 63% (95% CI: 59.5, 66.4), while the pathological complete response rate of patients receiving chemotherapy alone was 56% (95% CI: 50.6, 60.6). The number of patients who experienced event-free survival events were 123 (16%) and 93 (24%) (HR 0.63; 95% CI: 0.48, 0.82; p = 0.00031) respectively.
The most common adverse reactions (>20%) reported in the combination arm, were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, fever, hair loss, peripheral Neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.
This combination therapy is practice-changing in managing high-risk early-stage triple-negative breast cancer.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer July 26, 2021 Schmid P et al. N Engl J Med 2020; 382: 810
雄激素受体拮抗剂Enzalutamide 用于晚期三阴性乳腺癌 (2015.8.16)
大约有30％的三阴性乳腺癌为雄激素受体阳性。在2015年的ASCO年会上，有一個2期临床试验报道，共有118位三阴性的乳腺癌病人參加。主要的目标是临床受益率（完全或部分响应率，疾病稳定率）可以维持至少16個星期。参加者的原来的肿瘤标本至少有10％的雄激素受体。有75位病人可以评价，16星期的临床受益率为35％（包括8％的完全或部分响应率）；〉＝24星期的受益率为29％。中位无进展生存期为14.7星期。 另外，有一组病人称为意图治疗者（Intent-to-treat, III），她们的雄激素受体可以是阳性或阴性，她们至少服用过一次Enzalutamide。在这组病人中，16星期受益率为25％（包括6％的完全或部分响应率）。24星期受益率为20％。中位无进展生存期为12.6星期。 后来对lTT一组的病人进行了基因测定，用此法测定为雄激素受体阳性的病人，16和24小时受益率分别为39％和36％；而阴性者则为11％和6％。雄激素受体阳性者的中位无进展生存期为16.1星期，而阴性者仅为8.1星期。 总体来说，在lTT一组中，雄激素受体阳性者，若Enzalutamide是第一线或第二线治疗中位无进展生存期为40.4星期（尚未达到），而阴性者则为8.9星期。
参考文献 ASCO June 2015铂类化疗和三阴性乳房癌
Platinum and Triple-negative breast cancer
有两个随机的第二阶段试验，三阴性乳房癌患者手术前化疗中若加上卡铂，完全缓解率比不含卡铂的化疗有显著性地提高。一個是CALGB40603试验，对第二和第三期的乳房肿瘤病人，在结束剂量密集型AC（阿霉素和环磷酰胺）之后，每三周一次的紫杉醇同时加上卡铂，一共四次。完全缓解率从41％增加到54％（p＝0.029）。还有一個是GeparSixto试验，病人随机分为两组，一组接受每周紫杉醇和脂质体阿霉素（liposomal doxorubicin），共18周；另一组同时接受三种化疗，即再加上毎周卡铂。所有病人都接受每三周一次的阿瓦斯汀。完全缓解率分别为36.9％（三种药）和53.2％（四种药）（p＝0.005）。
由于以上的试验随访尚短，至今尚未有数据证明加上卡铂可以延长复发生存率或生存率，但笔者认为对高风险的三阴性乳房癌患者，若不能参加临床试验，在充分认识到数据的有限性，卡铂的付作用后，也可以考虑使用。
另外，也有报道紫杉醇纳米制剂用于术前比紫杉醇更有效，可以取得更高的病理完全缓解率（见＂最近进展＂2015年2月22日）。
There were two randomized phase II trials that showed when carboplatin was added to the preoperative chemotherapy in triple-negative breast cancer patients, the complete remission rate was significantly higher than the regime of chemotherapy without carboplatin. One was CALGB40603 trial. For patients with stage II and III breast cancer, at the end of dose-intensive AC (doxorubicin and cyclophosphamide), paclitaxel and carboplatin were added once every three weeks for a total of four cycles. The complete remission rate increased from 41% to 54% (p=0.029). Another trial was GeparSixto trial. Patients were randomly divided into two groups. One group received weekly paclitaxel and liposomal doxorubicin for 18 weeks; the other group received three types of chemotherapy at the same time, that is weekly carboplatin. All patients received Avastin every three weeks. The complete remission rate was 36.9% (three drugs) and 53.2% (four drugs) (p=0.005). Due to the short follow-up of the above trials, there was no data to prove that adding carboplatin can prolong survival or recurrence-free survival. In those high-risk triple-negative breast cancer patients, if they can not participate clinical trial, carboplatin can be considered after discussion about the pros and cons. In addition, it has also been reported that nanoparticle albumin-bound paclitaxel is more effective than paclitaxel before surgery and can achieve a higher pathological complete remission rate (see “Recent Progress” on February 22, 2015).
参考文献 J Clin Onc 2015. 35: 1-4. San Antonio Breast Cancer Symposium, December, 2014.
病例讨论 1:
55岁幼儿园教师， 身高170 公分，体重180斤。二周前发现左乳外上方有一亇硬块，约蚕豆大小。她做了乳腺钼靶摄像 和超声，在左乳1：00 发现2公分的肿块。右侧乳腺无异常。她约了外科医生做了一个活检，证实为分化三级的乳腺癌。接着，她做了一个乳腺部分切除术和前哨淋巴结活检。术后病理为2 .1公分的乳腺癌，分化三级，无血管和淋巴管浸润，上下内外前深切缘肿瘤切缘都大于扵3毫米。另有1.8 公分的低分化原位癌伴中央性坏死。雌孕激素受体均为阴性，HER-2 组化也为阴性。 病人血常规，肝肾功能，血淸钙及胸部平片均为正常。病人无高血压，糖尿病。心肺功能良好。
问： 接下来应该怎么办？
答； 她患的是所谓的＂三阴性乳腺癌＂，术后应该做辅助化疗。化疗前要测心脏射血分数。可釆用的化疗包括密集型AC–>T。毎两週一次Adriamycin 和Cyclophosphamide（阿霉素和环磷酰胺），共4次。然后毎週一次Paclitaxel （紫杉醇），共12次。在每一次化疗后需皮下注射白细胞生长素来维持体内中性白细胞的数量。也有人主张用卡铂，但迄今尚无临床 数据可以推荐。 化疗结束后，开始放疗。
问： 放疗结束后还应做些什么？
答：治疗己经结束。术后两年内，应每三个月去肿瘤科随访。她的体重偏高，应该设法减肥。这对减少肿瘤复发有益。
病例讨论 2 (3/3/2019):
问：一位82岁的女性，她刚进行了改良的乳房切除术。病理学鉴定了2.5 cm低分化的浸润性导管癌，为三阴性。 15/15左侧腋窝淋巴结都有转移。她素来健康，没有重要的内科疾病。她的家人不希望她因化疗而病得太重。接下来怎么做？
答：她需要进行全身扫描，以确定她是否有全身转移。
问：她做了PET扫描，显示右侧骨盆骨有单一转移灶。但她否认有任何疼痛。接下来应该做些什么?
答：如果可能的话，应该努力对骨病变进行活组织检查。 若在技术上具有挑战性，考虑她有如此之多转移的淋巴结，转移可能很大。她属于所谓的孤独转移灶（见1/13/2019最近进展）的病人。术后治疗首先仍应以治愈为目的。在她这个年龄，使用阿霉素/紫杉烷/卡铂的剂量密集化疗可能受不了。她的家人不希望她因化疗而病得太重。建议用单药卡铂，并开始zometa。三阴性乳腺癌可能对铂类非常敏感。
问：她接受单剂量的卡铂，AUC为6，每3周一次，共6个周期。她每隔4周接受一次Zometa。她没有任何并发症。接下来做什么？
答：她应该重复PET扫描。
问：重复PET扫描显示右侧骨盆的阳性信号完全消失。
答：太好了。她应该见放疗科医生以讨论右侧骨盆区放辐射治疗。对于仅有孤独性转移灶的病人，治疗应该十分积极，以争取治愈。
附注 : 2021 年 7 月 26 日FDA 批准 pembrolizumab 与化疗联合用于治疗局部复发性不可切除或转移性三阴性乳腺癌患者，其肿瘤表达 PD-L1（综合阳性评分 [CPS] ≥10）。
Case Discussion 2 (3/3/2019):
Question: An 82-year-old woman just had a modified mastectomy. Pathology identified 2.5 cm poorly differentiated invasive ductal carcinoma, which was triple-negative. Fifteen out of 15 left axillary lymph nodes were involved. She had always been healthy and had no major medical comorbidity. Her family did not want her to be too ill due to chemotherapy. What to do next?
Answer: She needs a full body scan to determine if she has systemic metastases.
Q: She had a PET scan which showed a single focus of suspicious metastasis in the right pelvic bone. But she denied any pain. What should be done next?
Answer: If possible, efforts should be made to biopsy bone lesions. If it is technically challenging, the lesion should be dealt with as a metastasis considering that she has so many involved lymph nodes. She may belong to the so-called solitary metastasis (see recent progress on 1/13/2019). Postoperative treatment should still be aimed to cure. At her age, dose-dense doxorubicin/taxane/carboplatin chemotherapy may not be tolerable. Single agent of carboplatin can be considered and zometa be added Triple negative breast cancer may be very sensitive to platinum.
Q: She received single drug of carboplatin with an AUC of 6, once every 3 weeks, for a total of 6 cycles. She received Zometa every 4 weeks. She did not have any complications. What’s next?
Answer: She should repeat the PET scan.
Q: Repeated PET scans showed that the PET-avid signal on the right pelvis completely disappeared.
Answer: That’s great. She should see a radiation oncologist to discuss radiation therapy in the right pelvic area. For patients with solitary lesion of metastasis, treatment should be aggressive aiming for cure.
Addenda: On July 7, 2021, FDA approved pembrolizumab for the treatment of unresectable locally-advanced or metastatic triple-negative breast cancer while PD-L1 expression is positive (comprehensive score [CPS] ≥10).