优化早期和晚期乳腺癌的辅助化疗和手术

　　2016年9月15日，《美国医学会杂志肿瘤学分册》在线发表哈佛大学达纳法伯癌症研究所内科肿瘤学家的述评：优化早期和晚期乳腺癌的辅助化疗和手术，重点讨论了蒽环类和卡培他滨在高风险三阴性乳腺癌中的地位、手术在乳腺癌尤其是晚期乳腺癌中的地位。

　　1　引言

　　2016年美国临床肿瘤学会（ASCO）年会发表的研究结果将进一步提高我们对乳腺癌的认识和治疗能力。

　　蒽环类和紫杉类为基础的化疗是目前高风险、早期、局部晚期乳腺癌辅助治疗的标准方案。2006年，美国肿瘤学研究组织（USOR）9735研究表明，TC方案（多西他赛＋环磷酰胺）与4个周期AC方案（多柔比星＋环磷酰胺）相比，无病生存率显著提高【1】。这些数据，与雌激素受体（ER）阳性乳腺癌根据基因组特征确定化疗方案的模式转变、HER2阳性乳腺癌无蒽环类方案的可用性相呼应，已使蒽环类辅助治疗的应用有所减少。

　　2　优化高风险HER2阴性肿瘤的辅助化疗：蒽环类对比卡培他滨

　　ABC（蒽环类用于早期乳腺癌）Ⅲ期辅助治疗研究【2】由USOR与国家外科辅助治疗乳腺肠道研究组织（NSABP）共同开展，检查了对HER2阴性乳腺癌有效的紫杉类＋烷化剂方案再加用蒽环类可否提供额外获益。他们在4130例女性中比较了6个周期TC与TaxAC（AC＋多西他赛或紫杉醇）方案。该研究结果发现TaxAC比TC相比，无病生存优势＞20%，绝对差为2.5%，并且排除了无蒽环类方案非劣效性的可能性。蒽环类方案获益多见于高风险病例（ER阴性和/或淋巴结阳性）而未见于ER阳性病例。这些数据再次确认蒽环类＋紫杉类＋烷化剂方案可用于治疗高风险HER2阴性患者，尤其是那些ER阴性和大量淋巴结受累的患者（见表）。

表：HER2阴性乳腺癌辅助化疗方案

　　高风险、ER阴性、HER2阴性乳腺癌女性仍然面临复发风险，有研究已经解决了蒽环类和紫杉类以外的额外化疗是否可能产生临床获益。其中一项研究即FinXX研究【3】，该研究随机分配患者接受蒽环类＋紫杉类±卡培他滨，随访10年结局无显著差异。但是，在202例三阴性乳腺癌患者中，加用卡培他滨提高了无复发生存（风险比：0.43，95%置信区间：0.24～0.79）和总生存。

　　FinXX研究【3】并非检查卡培他滨辅助治疗作用的唯一研究。2015年发表结果的CREATE-X研究【4】，将蒽环类＋紫杉类新辅助化疗后残留病灶的患者随机分配接受标准治疗或标准治疗＋卡培他滨辅助治疗。2年时，卡培他滨辅助治疗使无病生存和总生存显著获益，尤其对于三阴性病变患者【4】。但是，其他辅助研究对于蒽环类＋烷化剂＋紫杉类化疗后卡培他滨能否提供临床优势的结论不一。

　　总之，这些数据有趣地表明，某些高风险三阴性病变患者可以考虑将卡培他滨加入蒽环类＋紫杉类方案，尽管这些数据都来自亚组分析，并且卡培他滨仍不应作为常规疗法（见表）。

　　3　优化早期和晚期乳腺癌的辅助手术

　　对于早期乳腺癌，前哨淋巴结清扫术（SLND）是淋巴结阴性肿瘤患者的标准腋窝手术。美国外科医师学院肿瘤学组（ACOSOG）的研究Z0011【5】解答了对于哪些局限性淋巴结病变需要完成腋窝淋巴结清扫（ALND）：接受保乳手术、放疗和标准辅助治疗的1或2个前哨淋巴结阳性以及淋巴结临床阴性的T1/T2肿瘤患者。2011年，Z011研究显示完成腋窝淋巴结清扫并不影响5年总生存、无病生存率或局部复发【5】。虽然这些结果重新定义了临床实践，但是已有关于Z011研究随访相对较短和放疗存在变量的质疑。在2016年ASCO年会上，这些问题在Z011研究10年生存报告中得到解答，其中早期结果被充分验证：ALND与SLNB的总生存、无病生存、局部或区域复发无统计学显著差异；此外，各组放疗变量分布均匀。这些结果再次肯定了单用SNLB作为T1/T2和淋巴结临床阴性但有1或2个淋巴结病理阳性患者的现行治疗标准。

　　对于晚期乳腺癌，手术治疗长期存在这个问题：手术治疗原发性乳腺癌是否影响转移性乳腺癌女性的临床结局？十多年前，一项回顾性分析表明，接受乳房切除术的Ⅳ期乳腺癌女性有较好生存【6】。虽然其他研究和一项荟萃分析支持这些结果，但是存在方法学质疑：回顾性分析无法完全解决临床选择偏倚或分期变动偏倚（例如在乳房手术后发现有Ⅳ期癌症的患者中评估结局）。

　　为了回答这些质疑，美国、土耳其【7】、印度、日本（日本临床肿瘤学组研究JCOG1017）和荷兰（SUBMIT）的研究者开展了手术或全身疗法作为Ⅳ期乳腺癌初始治疗的多项前瞻研究。印度塔塔纪念医院的初始转移性乳腺癌女性随机研究显示，先行局部区域疗法与初始全身疗法相比，未见生存获益。

　　有两组研究者报道了初始转移性病变女性乳房手术的前瞻经验：

　　土耳其MF07-01研究【7】随机分配Ⅳ期乳腺癌患者接受原发灶手术后适当全身疗法或单用全身疗法。中位3年随访期间，研究者发现手术组患者有生存优势（风险比：0.66，95%置信区间：0.49～0.88，中位总生存：46比37个月）。值得注意的是，该研究各组临床特征不平衡，均有利于手术组的预后。手术组较少患者有三阴性病变或内脏病变，而更多患者仅有骨骼病变【7】。

　　乳腺癌转化研究联盟（TBCRC）013多中心前瞻登记研究【8】通过分析对一线疗法有效并被建议择期手术患者的结局，也评估了原发性乳腺癌手术对转移性病变的的作用。选择手术与未手术的女性相比，生存并未改善。有趣的是，极少对全身治疗有效的患者需要局部姑息治疗。

　　虽然研究设计大不相同，这些研究【7,8】的结果意味着，肿瘤生物特性和全身疗法效果是Ⅳ期乳腺癌结局的主要驱动因素，并且质疑任何原发手术的必要性。因此，来信前瞻研究的大量证据表明，全身治疗（而非局部区域治疗）应为作为晚期乳腺癌和乳腺肿瘤女性的初始方案。在那些对治疗有效的患者中，外科姑息治疗几乎没有必要，并且在原发肿瘤对全身疗法耐药的患者中，不同的全身治疗往往仍然是首要需求。在少数情况下，手术或放疗可能为胸部病变（非乳腺病变部位）提供有效的局部姑息作用，患者应被密切监测是否出现这种情况。

JAMA Oncol. 2016 Sep 15. [Epub ahead of print]

Optimizing Adjuvant Chemotherapy and Surgery for Early- and Late-Stage Breast Cancer.

Vaz-Luis I, Burstein HJ.

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.

Introduction

The findings presented during the 2016 American Society of Clinical Oncology (ASCO) meeting will further advance our understanding of, and ability to treat, breast cancer. Anthracycline- and taxane-based chemotherapy are the current standard for adjuvant treatment in high-risk, early-stage, and locally advanced breast cancer. In 2006, the United States Oncology Research (USOR) Trial 9735 showed that treatment with docetaxel and cyclophosphamide (TC) resulted in a significantly higher disease-free survival rate than 4 cycles of doxorubicin and cyclophosphamide (AC). [1] These data—in concert with the paradigm shift in chemotherapy use for estrogen receptor (ER)-positive breast cancer prompted by genomic signatures and the availability of non-anthracycline options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer—have precipitated a decline in the use of adjuvant anthracyclines.

Optimizing Adjuvant Chemotherapy for High-Risk HER2-Negative Tumors: Anthracyclines vs Capecitabine

The ABC (anthracyclines in early breast cancer) phase III adjuvant trials, [2] developed by USOR and the National Surgical Adjuvant Breast and Bowel Project (NSABP), examined whether anthracyclines provided additional benefit in the era of effective taxane-alkylator-based regimens for HER2-negative breast cancer. They compared 6 cycles of TC vs AC with docetaxel or paclitaxel (TaxAC) in 4130 women. The trials disclosed a greater than 20% disease-free survival advantage for TaxAC vs TC, translating into a 2.5% absolute difference, and excluded the possibility of noninferiority for the non-anthracycline option. The numerical benefit of anthracycline-based regimens was more pronounced in higher-risk cases—those that were ER negative and/or node positive—and not observed in node-negative, ER-positive cases. These data reaffirm anthracycline-taxane-alkylator therapy as appropriate treatment for patients with high-risk HER2-negative disease, particularly those with ER-negative disease and substantial nodal involvement (Table).

Table. Adjuvant Chemotherapy Options for HER2-Negative Breast Cancer Warranting Chemotherapy Treatment

Women with higher-risk, ER-negative, HER2-negative breast cancers still face risk of recurrence, and studies have addressed whether additional chemotherapy beyond anthracyclines and taxanes might yield clinical benefit. One such study was the FinXX trial, [3] which randomly assigned patients to an anthracycline-taxane regimen with or without the addition of capecitabine. Overall, with 10 years of follow-up, there were no differences in outcomes found between arms. However, among the 202 patients with triple-negative breast cancer, the addition of capecitabine improved relapse-free survival (hazard ratio [HR], 0.43; 95% CI, 0.24-0.79) and overall survival.

The FinXX trial [3] is not the only study to examine the role of adjuvant capecitabine. In 2015, Toi et al [4] presented the results of the CREATE-X trial, which randomized patients with residual disease after neoadjuvant anthracycline-taxane chemotherapy to standard treatment alone or standard treatment with postadjuvant capecitabine. At 2 years, there were significant disease-free and overall survival benefits for adjuvant capecitabine, particularly among patients with triple-negative disease. [4] However, other adjuvant trials have yielded mixed signals on whether capecitabine offers clinical advantage beyond anthracycline-alkylator-taxane based chemotherapy.

Collectively, these data intriguingly suggest that some patients with high-risk triple-negative disease might consider adding capecitabine to anthracycline-taxane regimens, though these are subset analyses, and capecitabine should not yet be considered a routine therapy (Table).

Optimizing Adjuvant Surgery for Early- and Late-Stage Breast Cancer

Sentinel lymph node dissection (SLND) is the standard axillary surgery for patients with node-negative tumors. The American College of Surgeons Oncology Group (ACOSOG) study Z0011 [5] addressed the need for completion of axillary lymph node dissection (ALND) for those with limited nodal disease: women who were clinically node negative with T1/T2 tumors and 1 or 2 positive sentinel lymph nodes who underwent conserving surgery, radiotherapy, and standard adjuvant treatment. In 2011, Z011 demonstrated that completion axillary dissection did not affect 5-year overall survival, disease-free survival, or local recurrence. [5] While these results redefined clinical practice, there have been concerns related to relatively short follow-up and variation in the radiation therapy delivered. At the ASCO 2016 meeting, these concerns were addressed in the 10-year survival report, in which the earlier findings were fully validated: there were with no statistically significant differences in overall survival, disease-free survival, or local or regional recurrence between ALND and SLNB. Moreover, it was shown that variations in radiation therapy were equally distributed among the arms. These results reinforce SNLB, alone, as the prevailing standard for treatment of patients with T1/T2 and clinically negative disease but with 1 or 2 pathologically involved nodes.

At the other extreme of surgical care for breast cancer lingers this question: would surgical treatment of a primary breast cancer affect outcomes for women with known metastatic breast cancer? More than a decade ago, a retrospective analysis suggested that women undergoing mastectomy for stage IV breast cancer had better survival. [6] Despite additional studies and a meta-analysis corroborating these results, there have been methodological concerns that retrospective analyses could not fully account for clinical selection bias or evaluate outcomes among women found to have stage IV cancer after breast surgery, an example of stage migration bias.

To answer these concerns, investigators in the US, Turkey, [7] India, Japan (Japan Clinical Oncology Group Study JCOG1017), and the Netherlands (SUBMIT) embarked on multiple, prospective studies of surgery or systemic therapy as initial treatment for stage IV breast cancer. The randomized trial among women with de novo metastatic breast cancer at Tata Memorial Hospital in India showed no survival benefit for upfront local-regional therapy compared with initial treatment with systemic therapy.

Two teams of investigators reported on prospective experiences with breast surgery among women with de novo metastatic disease. The Turkish MF07-01 trial [7] randomized patients with stage IV breast cancer to primary surgery followed by appropriate systemic therapy or systemic therapy alone. During a median of 3 years' follow-up, the researchers found a survival advantage among patients in the surgical arm (HR, 0.66; 95% CI, 0.49-0.88; median overall survival, 46 vs 37 months). Of note, there were imbalances among clinical characteristics between arms, all favoring the prognosis in the surgery group. Fewer patients in the surgery group had triple-negative disease or visceral disease, while more patients had bone-only disease. [7]

The Translational Breast Cancer Research Consortium (TBCRC) 013 multicenter prospective registry [8] also evaluated the role of primary breast surgery in metastatic disease by charting outcomes among patients who responded to first-line therapy and were referred to discuss elective surgery. Women who opted for surgery had no better survival than those who did not have surgery. Interestingly, few patients responding to systemic treatment needed local palliation.

While differing substantially in study designs, the findings of these trials [7,8] imply that tumor biology and systemic therapy results are the major drivers of outcomes in stage IV breast cancer, and they call into question any need for primary surgery. Thus, there is substantial evidence from prospective studies that systemic treatment, not local-regional therapy, should be the initial plan for women with advanced breast cancer and tumor in the breast. Among those patients responding to therapy, surgical palliation is rarely necessary, and in patients with primary tumor resistance to systemic therapy, different systemic treatment often remains the paramount need. In uncommon instances, surgery or radiotherapy may provide effective local palliation for chest disease, as they may for nonbreast sites of disease, and patients should be monitored expectantly to see if such circumstances arise.

REFERENCES

1. Jones S, Holmes FA, O'Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with overall survival benefit compared with doxorubicin and cyclophosphamide: 7 year follow-up of US Oncology Research Trial 9735. J Clin Oncol. 2009;27(8):1177-1183.

2. Blum JL, Flynn PJ, Yothers G, et al. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. ASCO Meeting Abstracts; June 3-7, 2016; Chicago, IL: abstract 1000.

3. Joensuu H, Kellokumpu-Lehtinen P-L, Huovinen R, et al. Adjuvant capecitabine in combination with docetaxel (T), epirubicin (E), and cyclophosphamide (C) in the treatment of early breast cancer (BC): 10-year survival results from the randomized FinXX trial. ASCO Meeting Abstracts; June 3-7, 2016; Chicago, IL: abstract 1001.

4. Toi M, Lee S-J, Lee ES, et al. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Paper presented at the 2015 Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX.

5. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305(6):569-575.

6. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival in metastatic breast cancer? Surgery. 2002;132(4):620-626.

7. Soran A, Ozmen V, Ozbas S, et al. A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer: Turkish Study (Protocol MF07-01). ASCO Meeting Abstracts; June 3-7, 2016; Chicago, IL: abstract 1005.

8. King TA, Lyman J, Gonen M, et al. A prospective analysis of surgery and survival in stage IV breast cancer (TBCRC 013). ASCO Meeting Abstracts; June 3-7, 2016; Chicago, IL: abstract 1006.

9. Jones et al. A prospective analysis of surgery and survival in stage IV breast cancer (TBCRC 013). ASCO Meeting Abstracts; June 3-7, 2016; Chicago, IL: abstract 1006.

PMID: 27631400

DOI: 10.1001/jamaoncol.2016.3631