三阴性乳腺癌新辅助治疗：无突变者加卡铂可获益
2014年，德国乳腺癌研究协作组在《柳叶刀肿瘤学分册》发表的GBG66研究（GeparSixto）结果表明，将卡铂加入蒽环类＋紫杉类＋贝伐珠单抗的新辅助治疗联合方案，可提高三阴性乳腺癌（TNBC）患者的病理完全缓解（pCR）率（57%比42.7%，P=0.015）。TNBC约占所有乳腺癌的17%，其中乳腺癌易感基因（BRCA1、BRCA2）突变携带者分别约占70%、23%，那么TNBC患者BRCA突变状态是否影响（能否预测）上述治疗方案的效果？
2017年7月13日，《美国医学会杂志肿瘤学分册》在线发表德国乳腺癌研究协作组、科隆大学医院、奥芬巴赫萨纳医院、海德堡大学医院、柏林大学医院、纽伦堡大学医院、慕尼黑技术大学医院、罗斯托克大学医院、埃森米特医院、基尔大学医院、乌尔姆大学医院、马格德堡大学医院、慕尼黑红十字会医院、汉堡大学医院、法兰克福大学医院、柏林布赫赫利俄斯医院的GBG66随机临床研究二次分析报告，通过调查TNBC患者的DNA样本和家族史，以确定铂类＋蒽环类＋紫杉类＋贝伐珠单抗的新辅助治疗效果和生存转归。结果发现，在对291例TNBC患者进行的随机临床研究二次分析中：有BRCA突变者的缓解率较高，加入卡铂未见获益；无BRCA突变者可获益于将卡铂加入紫杉醇＋低剂量多柔比星＋贝伐珠单抗方案。因此，对于有BRCA突变者，可考虑使用不加卡铂的简化治疗方案，但是需要进一步前瞻研究以确定最佳方案。
该二次分析利用2011年8月1日～2012年12月31日入组多中心前瞻随机临床研究（GBG66）的315例TNBC患者存档DNA样本和癌症家族史，对其中291例女性患者（占92.4%，平均年龄48±11岁）DNA样本的BRCA1、BRCA2以及16种其他癌症易感基因种系突变进行分析，对有卡铂组和无卡铂组的pCR（ypT0/ypN0）和无病生存（DFS）患者比例进行比较。基因分析在德国科隆家族性乳腺癌卵巢癌中心进行，数据分析于2015年11月1日～12月31日进行。
结果发现：
有、无卡铂组的pCR率分别为56.8%、41.4%（优势比：1.87，95%置信区间：1.17～2.97，P=0.009）
致病BRCA突变率为17.2%
无卡铂组：有、无突变者的pCR率分别为66.7%、36.4%（优势比：3.50，95%置信区间：1.39～8.84，P=0.008）
有卡铂组：有、无突变者的pCR率分别为65.4%、55.0%（优势比：1.55，95%置信区间：0.64～3.74，P=0.33）
有突变者：有、无卡铂组的pCR率分别为65.4%、66.7%（优势比：0.94，95%置信区间：0.29～3.05，P=0.92）
无突变者：有、无卡铂组的pCR率分别为55.0%、36.4%（优势比：2.14，95%置信区间：1.28～3.58，P=0.004）
有、无卡铂组的复发风险减少45%（风险比：0.55，95%置信区间：0.32～0.95，P=0.03）
无突变者：有、无卡铂组的DFS率分别为85.3%、73.5%（风险比：0.53，95%置信区间：0.29～0.96，P=0.04）
有突变者：有、无卡铂组的DFS率分别为86.3%、82.5%
因此，在GBG66研究的非标准（多柔比星剂量低且无环磷酰胺）多药联合方案下，无BRCA突变患者可获益于加入卡铂，有BRCA突变患者缓解率较高而加入卡铂并无获益。
对此，旧金山加利福尼亚大学综合癌症中心、加拿大不列颠哥伦比亚癌症中心、不列颠哥伦比亚大学发表同期述评：铂类新辅助治疗之未解难题。
虽然GBG66研究二次分析提供了进一步证据表明BRCA相关TNBC可能与散发疾病不同，但是仍然不足以改变临床实践。虽然铂类药物可以改善TNBC的整体pCR率，但是仍然不清楚这类药物应该如何以及何时加入新辅助化疗方案。此外，有待确定是否可以使用铂类取代蒽环类，或者这些药物是否应该优先用于标准新辅助化疗未达pCR的患者，以及各种检测同源重组缺陷的方法是否有助于确定最有可能获益的患者亚组，所有这些问题都在进行积极的临床调查。
TNBC治疗方案需要改进，并且需要深入了解不同治疗选择对亚组的影响。未来的研究必须将新方法与已被接受的标准进行比较，如同GBG66研究所证实的，包括对标志的前瞻分析，以揭示最佳的未来疗法。铂类药物可以提高疗效，但是也可增加毒性，对于结局的益处仍不确定。迫切需要对疗法进行个体化。
JAMA Oncol. 2017 Jul 13. [Epub ahead of print]
Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial.
Eric Hahnen; Bianca Lederer; Jan Hauke; Sibylle Loibl; Sandra Krober; Andreas Schneeweiss; Carsten Denkert; Peter A. Fasching; Jens U. Blohmer; Christian Jackisch; Stefan Paepke; Bernd Gerber; Sherko Kümmel; Christian Schem; Guido Neidhardt; Jens Huober; Kerstin Rhiem; Serban Costa; Janine Altmüller; Claus Hanusch; Holger Thiele; Volkmar Müller; Peter Nürnberg; Thomas Karn; Valentina Nekljudova; Michael Untch; Gunter von Minckwitz; Rita K. Schmutzler.
University Hospital Cologne, Cologne, Germany; German Breast Group, Neu-Isenburg, Germany; Sana Kliniken Offenbach, Offenbach, Germany; Universitat Heidelberg, Heidelberg, Germany; Charité Berlin, Berlin, Germany; University Hospital Erlangen, Erlangen, Germany; Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Charité-Universitatsmedizin Berlin, Berlin, Germany; Technischen Universitat München, München, Germany; Universitat Rostock, Rostock, Germany; Kliniken Essen-Mitte, Essen, Germany; Universitat Kiel, Kiel, Germany; Universitat Ulm, Ulm, Germany; Universitat Magdeburg, Magdeburg, Germany; University of Cologne, Cologne, Germany; Klinikum zum Roten Kreuz, München, Germany; University Hospital Hamburg-Eppendorf, Hamburg, Germany; Universitat Frankfurt, Frankfurt, Germany; Helios-Klinikum, Berlin-Buch, Berlin, Germany.
This secondary analysis of a randomized clinical trial examines DNA samples and family history of patients with triple-negative breast cancer to determine response to and survival from neoadjuvant treatment.
QUESTION: Does BRCA1 and BRCA2 germline mutation status predict therapy response in patients with triple-negative breast cancer enrolled in the GeparSixto trial?
FINDINGS: In this secondary analysis of a randomized clinical trial of 291 patients with triple-negative breast cancer, patients with BRCA1 and BRCA2 mutations showed superior response rates, without additive effects observed for carboplatin. Patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin to a regimen of paclitaxel, low-dose doxorubicin, and bevacizumab.
MEANING: A less-intense treatment regimen might be considered for BRCA1 and BRCA2 mutation carriers, but further prospective studies are needed to identify the optimal regimen.
IMPORTANCE: The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive.
OBJECTIVE: To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC.
DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015.
MAIN OUTCOMES AND MEASURES: Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point.
RESULTS: Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P=.009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P=.008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P=.004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P=.04).
CONCLUSIONS AND RELEVANCE: Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01426880
DOI: 10.1001/jamaoncol.2017.1007
JAMA Oncol. 2017 Jul 13. [Epub ahead of print]
Use of Neoadjuvant Platinum--The Ongoing Conundrum.
Hope S. Rugo; Karen Gelmon.
University of California-San Francisco Comprehensive Cancer Center, San Francisco; British Columbia Cancer Agency, Vancouver, British Columbia, Canada; University of British Columbia, Vancouver, British Columbia, Canada.
The secondary analysis of the GeparSixto trial provides further evidence that BRCA-associated TNBC may behave differently from sporadic disease, but it is not sufficient to change clinical practice. Platinum agents have improved the overall pCR rate in TNBC, but it remains unclear how and when these agents should be incorporated into neoadjuvant and adjuvant chemotherapy regimens. It also remains to be determined whether platinum can be used instead of anthracyclines, or if these agents should be used preferentially in those who do not achieve a pCR to standard neoadjuvant chemotherapy, and whether various methods of testing HRD will help to define the subset of patients most likely to benefit; all of these questions are under active clinical investigation.
Improved treatment options are needed for TNBC, and a greater understanding of the effect of subsets on choice of therapy is also needed. Future trials must compare new approaches with accepted standards and, as demonstrated in the GeparSixto trial, include prospective analysis of markers to unravel optimal future therapy. Platinum agents improve response, but toxicity is increased and benefits on outcome remain uncertain. Individualization of therapy is desperately needed.
DOI: 10.1001/jamaoncol.2017.1954