三阴性乳腺癌术后新白金方案问答
147天前，《美国医学会杂志》肿瘤学分册在线发表复旦大学附属肿瘤医院余科达和邵志敏等学者的PATTERN研究报告，对中国早期三阴性乳腺癌患者术后紫杉醇＋卡铂化疗方案与环磷酰胺＋氟尿嘧啶＋表柔比星→多西他赛标准化疗方案的有效性、安全性、遗传学指标进行了比较。结果发现，卡铂组与标准组相比，患者的5年无癌生存率（该研究主要结局）提高6.2个百分点（86.5%比80.3%）、发病或死亡风险相对减少35%（风险比：0.65，95%置信区间：0.44～0.96，P=0.03）。不过，患者的5年总生存率（该研究次要结局之一）仅提高3.6个百分点（93.4%比89.8%）、总死亡风险相对减少29%（风险比：0.71，95%置信区间：0.42～1.22，P=0.22）。
2021年1月7日，《美国医学会杂志》肿瘤学分册在线发表印度医学科学研究院、新德里扶轮肿瘤医院沙拉布·阿罗拉和阿图尔·巴特拉等学者的评论：早期三阴性乳腺癌术后紫杉醇＋卡铂对患者生存的影响，对PATTERN研究提出以下几点值得进一步探讨的问题：
首先，根据美国国家综合癌症网络（NCCN）乳腺癌指南，目前对于大多数三阴性乳腺癌患者，首选治疗方法为术前（新辅助）化疗，故该研究结果仅适用于术后（辅助）化疗的少数患者。对于该研究经过筛选的部分早期三阴性乳腺癌患者（包括74%的淋巴结阴性和54%的病理T1期肿瘤）而言，其结果证实了西德研究协作组PlanB研究结论，即6个周期无蒽环类化疗方案（多西他赛＋环磷酰胺）与蒽环类化疗方案（表柔比星＋环磷酰胺→多西他赛）相比，对于2449例早期HER2阴性乳腺癌患者，无癌生存率相似（89.6%比89.9%），其中445例（18.6%）三阴性乳腺癌的结局相似。不过，早期乳腺癌术后蒽环类化疗ABC研究对USOR 06-090、NSABP B-46-I/USOR 07132、NSABP B-49的联合分析表明，对于4242例HER2阴性早期乳腺癌患者，多西他赛＋环磷酰胺与蒽环类化疗相比，4年无浸润癌生存率较低（88.2%比90.7%，风险比：1.202，95%置信区间：0.97～1.49，P=0.04），对于其中947例淋巴结阴性三阴性乳腺癌患者的亚组分析表明，4年无浸润癌生存率也较低（87.0%比89.5%，风险比：1.31，95%置信区间：0.86～1.99）。因此，对于淋巴结阴性三阴性乳腺癌患者，PATTERN研究增加了术后可以考虑无蒽环类化疗方案的证据。
其次，尚不明确PATTERN研究卡铂组无癌生存获益主要由于卡铂，还是由于每周紫杉醇优于每3周多西他赛。根据E1199研究探索性分析报告，对于三阴性乳腺癌亚组患者，每周紫杉醇显著优于每3周多西他赛（10年无癌生存率：69.0%比62.3%，风险比：0.69，P=0.001；总生存率：75.1%比68.7%，风险比：0.69，P=0.02）。有理由认为，卡铂组无癌生存率的提高，可以部分归因于两个治疗组紫杉类选择和疗程的差异。
最后，印度学者对PATTERN研究心脏毒性反应发生率也很感兴趣，如果蒽环类化疗组较高，那么将进一步支持对淋巴结阴性三阴性乳腺癌术后患者进行非蒽环类化疗。
对此，2021年1月7日《美国医学会杂志》肿瘤学分册在线发表复旦大学附属肿瘤医院余科达和邵志敏等学者的答疑：
首先，PATTERN研究确实增加了淋巴结阴性三阴性乳腺癌患者术后可以考虑无蒽环类化疗方案的证据。目前，术前化疗被广泛用于三阴性乳腺癌，尤其对于淋巴结阳性患者。根据早期乳腺癌术前化疗术后残癌卡培他滨辅助化疗的CREATE-X研究结果，术前化疗被推荐用于三阴性乳腺癌患者，有助于发现未获病理完全缓解并可能获益于卡培他滨进一步治疗的患者亚组。不过，术前化疗被过度用于早期乳腺癌患者以及术前治疗弊端令人担忧，因为加用卡培他滨并非基于精准医学理念，而是基于传统概念，即三阴性乳腺癌将对加强并延长化疗方案获益。术前策略可能发现对蒽环类或紫杉类术前化疗不敏感的未获病理完全缓解肿瘤患者，但是这无助于我们找到后续有效且敏感的治疗方案。换而言之，术前治疗可以发现不敏感的亚组，但是无法揭示化疗耐药的潜在机制。
其次，6个周期紫杉醇＋卡铂方案的生存获益一定程度归因于加入了卡铂。CALGB 40101研究表明，6个周期紫杉醇单药（某些采用每周紫杉醇）并不优于6个周期多柔比星＋环磷酰胺化疗方案。根据意大利乳腺癌协作组GIM2研究，多柔比星＋环磷酰胺与氟尿嘧啶＋环磷酰胺＋多柔比星化疗方案相比，有效性可能相似，因为氟尿嘧啶并不增加治疗效果。此外，根据法国全国癌症中心联盟PACS 01研究，6个周期氟尿嘧啶＋表柔比星＋环磷酰胺的有效性不如3个周期氟尿嘧啶＋表柔比星＋环磷酰胺→3个周期多西他赛。综上所述，6个周期紫杉醇并不优于氟尿嘧啶＋表柔比星＋环磷酰胺→多西他赛。因此，紫杉醇＋卡铂优于环磷酰胺＋氟尿嘧啶＋表柔比星→多西他赛，可能归因于卡铂。对于术前患者，CALGB 40603研究结果也表明卡铂可进一步提高紫杉醇→剂量密集多柔比星＋环磷酰胺新辅助化疗的病理完全缓解率。
最后，PATTERN研究的心脏毒性事件相对较少，3～4级心脏毒性反应发生率不到1%。卡铂组322例患者的3～4级心律失常发生率为0.3%（1例）、充血性心力衰竭发生率为0；氟尿嘧啶＋表柔比星＋环磷酰胺→多西他赛组320例患者的3～4级心律失常发生率为0.9%（3例）、充血性心力衰竭发生率为0.3%（1例）。由于心脏毒性事件发生率低不足以进行统计学分析，故心脏事件详细数据有待进一步长期随访。
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JAMA Oncol. 2021 Jan 7. Online ahead of print.
Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Early Triple-Negative Breast Cancer.
Arora S, Kumar A, Batra A.
Dr. BRA Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
We read with great interest the results of the PATTERN (adjuvant Platinum and Taxane in Triple-Negative Breast Cancer) randomized clinical trial by Yu et al that compared 6 cycles of paclitaxel and carboplatin (PCb) vs anthracycline-based adjuvant chemotherapy (cyclophosphamide, epirubicin, and fluorouracil) in early triple-negative breast cancer (TNBC). Patients in the PCb arm had a 6.2% absolute benefit in disease-free survival (DFS) at 5 years (86.5% vs 80.3%; hazard ratio [HR], 0.65; 95% CI, 0.44-0.96; P=0.03). The DFS benefit did not translate into a statistically significant commensurate overall survival advantage, which was one of the secondary outcomes of the study. There are a few points that need further discussion.
First, the contemporary preferred management of most patients with TNBC is neoadjuvant chemotherapy; this limits the clinical applicability of the study results to a few patients who are treated with up-front surgery. In the select patient group of early TNBC (comprising 74% node-negative and 54% pT1 tumors), the findings strengthen the conclusions of the West German Study PlanB trial that 6 cycles of an anthracycline-free regimen (docetaxel and cyclophosphamide) were noninferior to an anthracycline-based regimen (epirubicin and cyclophosphamide followed by docetaxel) in early ERBB2-negative breast cancer. The outcomes were comparable in 445 of 2449 patients (18.2%) with TNBC and hormone-positive breast cancer. Although the ABC (Anthracycline in Early Breast Cancer) trials failed to demonstrate noninferiority of docetaxel and cyclophosphamide to anthracycline-based chemotherapy, the subgroup analysis of 947 patients with node-negative TNBC did not show any benefit of anthracyclines (HR, 1.31; 95% CI, 0.86-1.99). Thus, the PATTERN trial adds to the evidence that an anthracycline-free regimen may be considered for patients with node-negative TNBC treated with up-front surgery.
Second, it is not clear whether the DFS benefit in the PCb arm in the PATTERN trial was driven by carboplatin or weekly administration of paclitaxel compared with docetaxel administered every 3 weeks. An exploratory analysis of the E1199 trial reported that weekly paclitaxel was substantially better than every-3-weeks docetaxel in the TNBC cohort (10-year DFS: 69.0% vs 62.3%; HR, 0.69; P=0.001; overall survival: 75.1% vs 68.7%, HR, 0.69; P=0.02). It stands to reason that the improved DFS in the PCb arm could be partly attributable to the difference in choice and schedule of taxane in the 2 treatment arms.
Lastly, it will be interesting to know the incidence of cardiotoxic effects in the PATTERN trial. If it is higher in the anthracycline arm, this further supports a non-anthracycline-based adjuvant treatment in patients with node-negative TNBC.
PMID: 33410889
DOI: 10.1001/jamaoncol.2020.7157
JAMA Oncol. 2021 Jan 7. Online ahead of print.
Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Early Triple-Negative Breast Cancer-Reply.
Yu KD, Shao ZM.
Fudan University Shanghai Cancer Center, Shanghai, China; Key Laboratory of Breast Cancer in Shanghai, Shanghai, China.
We would like to thank Arora et al for their interest in our PATTERN (adjuvant Platinum and Taxane in Triple-Negative Breast Cancer) randomized clinical trial and their thoughtful comments on the article. First, we agree with their statement that "the PATTERN trial adds to the evidence that an anthracycline-free regimen may be considered for patients with node-negative TNBC [triple-negative breast cancer] treated with up-front surgery." Currently, neoadjuvant chemotherapy is widely used for patients with TNBC, especially for those with node-positive disease. Based on the results of the CREATE-X (Capecitabine for Residual Cancer as Adjuvant Therapy) trial, neoadjuvant chemotherapy is recommended for patients with TNBC because it will allow us to identify the subset of patients who do not achieve pathologic complete response (pCR) and may benefit from additional treatment with capecitabine. However, there is concern regarding the overuse of neoadjuvant chemotherapy in patients with primary breast cancer and the drawbacks of neoadjuvant therapy because the addition of capecitabine is not based on the concept of precision medicine, but on the traditional concept that a more intensive and extended chemotherapy regimen will be beneficial for TNBC. The neoadjuvant strategy may uncover patients with non-pCR tumors who are insensitive to anthracycline/taxane-containing neoadjuvant chemotherapy, but it does not help us find subsequent effective and sensitive therapeutic regimens. In other words, neoadjuvant therapy identifies the insensitive subgroup but does not reveal the underlying mechanism of chemotherapy resistance.
Second, we believe that the survival benefit of 6 cycles of the paclitaxel plus carboplatin (PCb) regimen, to some extent, is due to the addition of carboplatin. The Cancer and Leukemia Group B (CALGB) 40101 trial suggests that 6 cycles of single-agent paclitaxel (some used weekly paclitaxel) is inferior to 6 cycles of a doxorubicin and cyclophosphamide (AC) regimen. According to the Gruppo Italiano Mammella GIM2 trial, the AC and the fluorouracil, cyclophosphamide, and doxorubicin regimens might have similar efficacy because fluorouracil does not offer additional treatment efficacy. Furthermore, according to the FNCLCC PACS 01 trial, the efficacy of 6 cycles of fluorouracil, epirubicin, and cyclophosphamide (CEF) is inferior to 3 cycles of CEF followed by 3 cycles of docetaxel (CEF-T). Taken together, 6 cycles of paclitaxel should be inferior to CEF-T. Therefore, we conclude that superiority of PCb to CEF-T is likely due to the addition of carboplatin. In the neoadjuvant setting, findings of the CALGB 40603 trial have also suggested that the addition of carboplatin to neoadjuvant paclitaxel followed by dose-dense AC can further improve the pCR rate.
Finally, in the current trial, the cardiotoxic events were relatively rare, and the rate of grade 3 to 4 cardiotoxic effects was less than 1%. In the PCb group, incidence of grade 3 to 4 arrhythmia was 0.3% (1 of 322) and congestive heart failure was 0; in the CEF-T group, incidence of grade 3 to 4 arrhythmia was 0.9% (3 of 320) and congestive heart failure was 0.3% (1 of 320). Due to the low occurrence rate of cardiotoxic events and underpowered statistical analysis, detailed data regarding cardiac events will require further long-term follow-up.
PMID: 33410871
DOI: 10.1001/jamaoncol.2020.7160