美国遗传性乳腺癌指南推荐意见更新
2020年4月3日，美国临床肿瘤学会、美国放射肿瘤学会和美国外科肿瘤学会联合发表遗传性乳腺癌管理指南。当时，该指南认为多腺苷二磷酸核糖聚合酶（PARP）抑制剂（奥拉帕利、他拉唑帕利）与非铂类单药化疗相比，更适合治疗晚期乳腺癌BRCA突变携带者；现有数据不足以推荐PARP抑制剂用于早期乳腺癌或中等外显基因突变携带者。2021年6月3日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》以及美国临床肿瘤学会第57届年会同时公布OlympiA研究结果，证实奥拉帕利对BRCA突变早期乳腺癌术后患者也有效。随后，美国国家综合癌症网络和美国临床肿瘤学会对乳腺癌临床实践指南、激素受体阳性HER2阴性晚期乳腺癌内分泌治疗和靶向治疗指南、激素受体阴性或内分泌治疗后HER2阴性晚期乳腺癌化疗和靶向治疗指南进行了更新。
2021年8月3日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表贝斯以色列和新英格兰女执事医疗中心、博蒙特医疗中心、美国临床肿瘤学会的高风险早期HER2阴性乳腺癌种系BRCA突变患者术后PARP抑制剂推荐意见更新。
根据OlympiA研究中位随访2.5年中期分析结果，完成局部治疗和术前新辅助或术后辅助化疗后，口服一年奥拉帕利与安慰剂相比，无浸润病变生存或无远处病变生存显著较长。该研究患者已完成至少6轮术前新辅助或术后辅助化疗，其中95%的患者接受了蒽环类和紫杉类化疗。
奥拉帕利组与安慰剂组相比：
3年无浸润病变生存率：85.9%比77.1%（风险比：0.58，99.5%置信区间：0.41～0.82，P<0.001）
3年无远处病变生存率：87.5%比80.4%（风险比：0.57，99.5%置信区间：0.39～0.83，P<0.001）
3年总生存率：92.0%比88.3%（相差3.7个百分点，95%置信区间：0.3～7.1）
奥拉帕利的安全性和耐受性可控，中期分析未见整体生活质量存在重大问题。
贫血是唯一报告的3级不良事件，发生率>5%。奥拉帕利组与安慰剂组相比，≥3级贫血发生率为8.7%比0.3%。至少一次输血发生率为5.8%比0.9%，严重不良事件（包括骨髓增生异常综合征和急性白血病）发生率并不高。
因此，2021年推荐意见更新为：
对于高复发风险早期HER2阴性乳腺癌种系BRCA1或BRCA2致病或可能致病变异患者，术前新辅助或术后辅助化疗和局部治疗（包括放疗）完成后，术后应予1年奥拉帕利辅助治疗。
对于三阴性乳腺癌肿瘤大于2厘米或任何腋窝淋巴结转移患者，术后应予1年奥拉帕利辅助治疗。
对于激素受体阳性乳腺癌至少4枚腋窝淋巴结转移患者，术后应予1年奥拉帕利辅助治疗。
对于完成术前新辅助化疗的三阴性乳腺癌和任何残留病变患者，术后应予1年奥拉帕利辅助治疗。
对于激素受体阳性乳腺癌残留病变且临床分期、病理分期、雌激素受体和肿瘤分级评分≥3分患者，术后应予1年奥拉帕利辅助治疗。
值得注意的是：
首先，OlympiA研究设计时，术前新辅助化疗后卡培他滨尚未成为标准治疗方案，故研究并未比较奥拉帕利与卡培他滨的疗效。
此外，由于PARP抑制剂是DNA相互作用药物，并且可能诱发血液系统恶性肿瘤，故需对骨髓增生异常综合征和急性髓细胞性白血病进一步随访。
最后，OlympiA研究除了种系BRCA1或BRCA2突变相关乳腺癌之外，并未评定奥拉帕利辅助治疗对任何遗传性乳腺癌的作用，亦未评定缺乏符合该研究入组条件所需高风险临床特征患者的获益。
相关链接
J Clin Oncol. 2021 Aug 3. Online ahead of print.
Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations: ASCO Hereditary Breast Cancer Guideline Rapid Recommendation Update.
Tung NM, Zakalik D, Somerfield MR; Hereditary Breast Cancer Guideline Expert Panel.
Beth Israel Deaconess Medical Center, Boston, MA; Beaumont Health, Royal Oak, MI; American Society of Clinical Oncology, Alexandria, VA.
ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.
BACKGROUND
In 2020, ASCO published a guideline on the management of hereditary breast cancer. On June 3, 2021, the OlympiA phase III, double-blind, randomized trial reported on the efficacy of adjuvant poly(ADP-ribose) polymerase (PARP) inhibitor therapy with olaparib in patients with early-stage, human epidermal growth factor receptor 2 (HER2)-negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants. A significant improvement in invasive and distant disease-free survival constituted a strong signal for an update of the 2020 ASCO-ASTRO-SSO guideline recommendation focused specifically on the role of PARP inhibitors in patients with early-stage, HER2-negative breast cancer and germline BRCA mutations.
METHODS
A targeted literature search was conducted to identify phase III clinical trials pertaining to the recommendation on PARP inhibitors in this patient population. No additional randomized trials were identified. The original Expert Panel was reconvened to review the evidence from OlympiA and to approve the updated recommendation.
EVIDENCE REVIEW
Tutt et al reported that, compared with placebo, one year of olaparib following the completion of local treatment and (neo)adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease (interim analysis with a median follow-up of 2.5 years). Patients had completed at least six cycles of neoadjuvant or adjuvant chemotherapy; 95% of patients in the trial received anthracycline- and taxane-based chemotherapy. In the olaparib group, the 3-year invasive disease-free survival was 85.9% versus 77.1% in the placebo group (hazard ratio, 0.58; 99.5% CI, 0.41 to 0.82; P < .001). In the olaparib group, the 3-year distant disease-free survival was 87.5% versus 80.4% in the placebo group (hazard ratio, 0.57; 99.5% CI, 0.39 to 0.83; P < .001). Anemia was the only grade 3 adverse event reported in > 5% of patients. In the olaparib group, 8.7% of patients had grade ≥ 3 anemia versus 0.3% of patients in the placebo group. More patients in the olaparib group had at least one blood transfusion with 5.8% versus 0.9% in the placebo group. The occurrence of serious adverse events, including myelodysplastic syndrome and acute leukemia, was not more frequent in the olaparib arm versus placebo.
2020 RECOMMENDATION
Before the publication of the OlympiA data, the management of hereditary breast cancer joint Panel published this practice recommendation in 2020: For germline BRCA mutation carriers, there are insufficient data at this time to recommend a PARP inhibitor for patients with nonmetastatic breast cancer.
2021 UPDATED RECOMMENDATION
The updated recommendation for June 2021 is that for patients with early-stage, HER2-negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, one year of adjuvant olaparib should be offered after completion of (neo)adjuvant chemotherapy and local treatment, including radiation. For those who had surgery first, 1 year of adjuvant olaparib should be offered for patients with triple-negative breast cancer and tumor size > 2 cm or any involved axillary nodes. For those with hormone receptor-positive disease, 1 year of adjuvant olaparib should be offered to those with at least four involved axillary lymph nodes. For patients who had neoadjuvant chemotherapy, 1 year of adjuvant olaparib should be offered to patients with triple-negative breast cancer and any residual cancer; for patients with hormone receptor-positive disease, 1 year of adjuvant olaparib should be offered to patients with residual disease and a clinical stage, pathologic stage, estrogen receptor, and tumor grade score ≥ 3.
DISCUSSION
Although the 3-year estimated overall survival was greater with olaparib, the difference was not statistically significant at the time of this interim analysis at a 2.5-year median follow-up. Of note, postneoadjuvant capecitabine was not permitted in the OlympiA trial because this therapy was not the standard of care when the trial was designed. Thus, the trial cannot inform the relative efficacy of olaparib as compared with capecitabine in this context. Safety and tolerability in OlympiA were manageable, and no significant problems with quality of life (global measurement) were noted at the interim analysis. Further follow-up is needed for myelodysplastic syndrome and acute myelogenous leukemia given that PARP inhibitors are DNA-interacting drugs and have the potential to induce hematologic malignancies. Finally, OlympiA did not assess the effect of olaparib as adjuvant therapy in any hereditary forms of breast cancer other than that associated with germline BRCA1 or BRCA2 mutations or assess benefit in patients who lack the high-risk clinical features required for eligibility in this trial.
PMID: 34343058
DOI: 10.1200/JCO.21.01532