卡培他滨辅助治疗乳腺癌之争
前情提要
2017年8月24日，美国麻省医学会《新英格兰医学杂志》正式发表美国佛蒙特大学医学中心、纽约迈蒙尼德医疗中心、土耳其安卡拉巴耶塞特一世大学、日本京都大学、大阪国立医院、东京中央大学对卡培他滨辅助治疗乳腺癌研究（CREATE-X）的争议。
佛蒙特大学、迈蒙尼德医疗中心：
此前，日本和韩国于2017年6月1日在《新英格兰医学杂志》正式发表卡培他滨用于残留癌症辅助治疗（CREATE-X）研究结果【1】，认为对于新辅助化疗后仍有残留病变的HER2阴性乳腺癌患者，使用卡培他滨可延长无病生存和总生存，并且未发生预料之外的毒性作用。该研究为改变临床实践提供了证据，尤其对于三阴性乳腺癌女性。然而，卡培他滨对于激素受体阳性病变患者的价值仍不明确。激素受体阳性癌发生于大约70%的残留病变患者，与激素受体阴性癌相比，对化疗的反应较差【2,3】。
抑制卵巢功能研究（SOFT）和他莫昔芬对比依西美坦研究（TEXT）显示，接受化疗后仍未绝经的激素受体阳性乳腺癌绝经前患者，属于非常高风险亚组患者，可获益于卵巢抑制＋他莫昔芬或芳香酶抑制剂的内分泌疗法【4,5】。在CREATE-X研究的患者中，接受辅助内分泌疗法的绝经前女性占41%。亚组分析根据是否使用内分泌疗法进行，但是未对疗法进行分类。
卡培他滨可能通过增加化疗所致绝经率，从而有利于绝经前激素受体阳性病变患者。如果安慰剂组与卡培他滨组相比，使用卵巢抑制较多，那么可能抵消观察到的卡培他滨获益。试问各个亚组的内分泌疗法＋卵巢抑制分布是否均衡？
参考文献
Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376:2147-2159.
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-172.
Ruades Ninfea JI, Burdette-Radoux S, Sands M, et al. Low dose metronomic cyclophosphamide, methotrexate (LDCM) and aspirin for patients with residual disease after neoadjuvant chemotherapy for stage II-III breast cancer. J Clin Oncol. 2016;34(15)Suppl:e12040.
Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372:436-446.
Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107-118.
安卡拉巴耶塞特一世大学：
根据CREATE-X研究报告，对于标准新辅助化疗后残留浸润病变的三阴性乳腺癌患者，卡培他滨辅助疗法可显著延长无病生存和总生存。然而，激素受体阳性亚组未见显著获益。
激素受体阳性乳腺癌的两种不同分子亚型，被称为管腔A型（HER2阴性且Ki67低，对内分泌疗法敏感、对化疗不敏感）和管腔B型（HER2阴性且Ki67高、HER2阳性无论Ki67高低，对内分泌疗法不敏感、对化疗敏感），与不同的化疗反应率相关。已知管腔B型与管腔A型的患者相比，新辅助化疗和辅助化疗的获益较大、反应率更高【1】。因此，如果根据管腔A型和管腔B型进行亚组分析，该研究的无病生存和总生存结果可能十分有趣。
有研究在患者接受化疗前根据病理评估对激素受体状态进行分类，多达30%的患者新辅助化疗前后激素受体状态不一致【2】。据此，了解手术前后激素受体状态的不一致率及其对无病生存和总生存的影响也将十分有趣。
参考文献
Ades F, Zardavas D, Bozovic-Spasojevic I, et al. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32:2794-2803.
van de Ven S, Smit VT, Dekker TJ, Nortier JW, Kroep JR. Discordances in ER, PR and HER2 receptors after neoadjuvant chemotherapy in breast cancer. Cancer Treat Rev. 2011;37:422-430.
京都大学、大阪国立医院、中央大学：
SOFT和TEXT为绝经前激素受体阳性病变患者的个体化辅助内分泌疗法提供了重要临床数据【1】。在我们的研究中，18%的激素受体阳性病变患者接受了促黄体激素释放激素类似物，对照组（56%）多于卡培他滨组（44%）。我们未对激素受体阳性病变患者亚组进行统计学分析。英国TACT2（早期乳腺癌卡培他滨加速辅助化疗研究）术后辅助治疗研究【2】比较了表柔比星→环磷酰胺＋甲氨蝶呤＋氟尿嘧啶联合方案、表柔比星→卡培他滨（2500mg/m²体表面积，每3周×4），该研究表明，环磷酰胺＋甲氨蝶呤＋氟尿嘧啶与卡培他滨相比，化疗期间卵巢功能紊乱或月经周期中断的发生率显著较高（86%比73%，P＜0.001）。但是，卡培他滨对曾经接受新辅助化疗（尤其是蒽环类、紫杉类、环磷酰胺）患者的卵巢功能抑制情况知之甚少。
已知管腔A型癌与管腔B型癌相比，对细胞毒性化疗诸如蒽环类和紫杉类的敏感性较差【3】。对于曾经接受新辅助化疗的患者，根据多基因检测评分为高风险与低风险的癌症相比，病理完全反应率较高【4】。目前，尚不清楚管腔亚型和多基因检测能否预测卡培他滨单药辅助疗法的反应。
新辅助化疗后的雌激素受体状态变化并不常见，但是从管腔B型癌转为管腔A型癌也不少见。有项研究根据基线时的21基因（Oncotype DX）分子检测发现，约30%的高风险评分患者残留癌为低风险或中风险评分【5】。发生与未发生这些变化的肿瘤相比，术后卡培他滨辅助治疗的效果可能不同。此外，基线时和新辅助治疗后的配对分析，可能有助于确定新的卡培他滨疗效预测生物标志。
参考文献
Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372:436-446
Cameron D, Morden JP, Canney P, et al. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017;18:929-945.
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-172.
Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23:7265-7277.
Yardley DA, Peacock NW, Shastry M, et al. A phase II trial of ixabepilone and cyclophosphamide as neoadjuvant therapy for patients with HER2-negative breast cancer: correlation of pathologic complete response with the 21-gene Recurrence Score. Breast Cancer Res Treat. 2015;154:299-308.
N Engl J Med. 2017 Aug 24;377(8):790-792.
Adjuvant Capecitabine for Breast Cancer.
Jose I. Ruades Ninfea; Susan Burdette-Radoux; Marie E. Wood; Mutlu Hizal; Mehmet A.N. Sendur; Bülent Yalcin; Masakazu Toi; Norikazu Masuda; Yasuo Ohashi.
University of Vermont Medical Center, Burlington, VT; Maimonides Medical Center, Brooklyn, NY; Ankara Yildirim Beyazit University, Ankara, Turkey; Kyoto University, Kyoto, Japan; National Hospital Organization Osaka National Hospital, Osaka, Japan; Chuo University, Tokyo, Japan.
Masuda et al. (June 1 issue)[1] report the results of the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial. They conclude that the use of capecitabine in patients who have human epidermal growth factor receptor 2 (HER2)-negative breast cancer with residual disease after neoadjuvant chemotherapy prolonged disease-free survival and overall survival and was associated with expected toxic effects. This trial provides practice-changing evidence, predominantly for women with triple-negative disease. However, the value of capecitabine in patients with hormone-receptor-positive disease remains uncertain. Hormone-receptor-positive cancers, which occur in approximately 70% of patients with residual disease, are less responsive to chemotherapy than hormone-receptor-negative cancers.[2,3]
The Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT) showed that premenopausal patients with hormone-receptor-positive breast cancer who remained premenopausal after receiving chemotherapy constituted a particularly high-risk subgroup of patients who benefited from endocrine therapy with ovarian suppression plus tamoxifen or an aromatase inhibitor.[4,5] Premenopausal women who received adjuvant endocrine therapy constituted 41% of the patients in the CREATE-X trial. A subgroup analysis was performed according to the use of endocrine therapy, but the type of therapy was not specified.
Capecitabine may have benefited premenopausal patients with hormone-receptor-positive disease by increasing the rate of chemotherapy-induced menopause. If the use of ovarian suppression was more common in the placebo group than in the capecitabine group, it may have offset the observed benefit of capecitabine. Was the use of endocrine therapy combined with ovarian suppression well distributed among the subgroups?
REFERENCES
Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376:2147-2159.
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-172.
Ruades Ninfea JI, Burdette-Radoux S, Sands M, et al. Low dose metronomic cyclophosphamide, methotrexate (LDCM) and aspirin for patients with residual disease after neoadjuvant chemotherapy for stage II-III breast cancer. J Clin Oncol. 2016;34(15)Suppl:e12040.
Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372:436-446.
Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371:107-118.
Masuda and colleagues report that adjuvant capecitabine therapy significantly prolonged disease-free survival and overall survival among patients who had triple-negative residual invasive disease after standard neoadjuvant chemotherapy. However, no significant benefit was shown in the hormone-receptor-positive subgroup.
The two different molecular subtypes of hormone-receptor-positive breast cancer, termed luminal A and luminal B, are associated with different rates of response to chemotherapy. Patients with the luminal B subtype have been shown to have a greater benefit from and better rates of response to both neoadjuvant chemotherapy and adjuvant chemotherapy than those with the luminal A subtype.[1] Thus, it would be intriguing to know the results of this trial with respect to disease-free survival and overall survival according to the luminal A and B subtypes.
The trial classified the hormone-receptor status of the patients according to pathological evaluation before they received chemotherapy. In up to 30% of the patients, discordance between the hormone-receptor status before and after neoadjuvant chemotherapy was reported.[2] On these grounds, it would also be interesting to know the rate of discordance between hormone-receptor status before and after surgery as well as its effect on the rates of disease-free survival and overall survival.
REFERENCES
Ades F, Zardavas D, Bozovic-Spasojevic I, et al. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32:2794-2803.
van de Ven S, Smit VT, Dekker TJ, Nortier JW, Kroep JR. Discordances in ER, PR and HER2 receptors after neoadjuvant chemotherapy in breast cancer. Cancer Treat Rev. 2011;37:422-430.
SOFT and TEXT provided clinically significant data to personalize adjuvant endocrine therapy for premenopausal patients with hormone-receptor-positive disease.[1] In our trial, 18% of the patients with hormone-receptor-positive disease received a luteinizing hormone-releasing hormone analogue, and it was used slightly more often in the control group (56%) than in the capecitabine group (44%). We did not conduct a statistical analysis in the subgroup of patients with hormone-receptor-positive disease. The UK TACT2 (United Kingdom, Trial of Accelerated Adjuvant Chemotherapy with Capecitabine in Early Breast Cancer) trial of postoperative adjuvant therapy[2] compared epirubicin followed by a combined regimen of cyclophosphamide, methotrexate, and fluorouracil with epirubicin followed by capecitabine (at a dose of 2500 mg per square meter of body-surface area, every 3 weeks for four cycles). The UK TACT2 trial showed that the rate of disruption of ovarian function or discontinuation of menstrual periods during chemotherapy was significantly higher with cyclophosphamide, methotrexate, and fluorouracil than with capecitabine (86% vs. 73%, P<0.001). Yet little is known about the suppression of ovarian function by capecitabine in patients who have received neoadjuvant chemotherapy, particularly with anthracycline, taxane, and cyclophosphamide.
As compared with luminal B-like cancers, luminal A-like cancers are known to be less sensitive to cytotoxic chemotherapy such as an anthracycline and a taxane.[3] Among patients who have received neoadjuvant chemotherapy, those with cancers scored as high risk by a multigene assay tend to have a higher rate of pathological complete response than those with cancers scored as low risk.[4] At the moment, it is unclear how luminal subtyping and the multigene assay are predictive of the response to adjuvant capecitabine monotherapy.
A change in estrogen-receptor status after neoadjuvant chemotherapy is infrequent, but it is not rare to have a conversion from luminal B-like cancer to luminal A-like cancer. In one trial, approximately 30% of the patients with a high-risk score according to the Oncotype DX molecular assay at baseline had a low-risk or an intermediate-risk score in the residual cancers.[5] The therapeutic effect of postoperative adjuvant capecitabine may differ between tumors that have these changes and tumors that do not. In addition, paired analyses, at baseline and after neoadjuvant therapy, may be helpful in the development of new predictive biomarkers for capecitabine.
REFERENCES
Francis PA, Regan MM, Fleming GF, et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372:436-446
Cameron D, Morden JP, Canney P, et al. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017;18:929-945.
Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164-172.
Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23:7265-7277.
Yardley DA, Peacock NW, Shastry M, et al. A phase II trial of ixabepilone and cyclophosphamide as neoadjuvant therapy for patients with HER2-negative breast cancer: correlation of pathologic complete response with the 21-gene Recurrence Score. Breast Cancer Res Treat. 2015;154:299-308.
PMID: 28834474
DOI: 10.1056/NEJMc1708487