ImportanceAdjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor–positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking.ObjectiveTo assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer.Design, Setting, and ParticipantsThis prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])–high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022.Main Outcomes and MeasuresPrimary end points were breast cancer–free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses.ResultsTumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, −0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, −1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively.Conclusions and RelevanceIn this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

中文翻译：

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早期激素受体阳性乳腺癌绝经前妇女的乳腺癌指数


重要性口服内分泌治疗辅助卵巢功能抑制 （OFS） 可改善激素受体阳性 （HR+） 乳腺癌绝经前患者的预后，但会增加不良反应。缺乏用于选择最有可能从基于 OFS 的治疗中受益的患者的基因组生物标志物。目的评估乳腺癌指数 （BCI） 对 HR+ 乳腺癌绝经前妇女 OFS 获益的预测和预后性能。设计、设置和参与者这项前瞻性回顾性转化研究使用了来自卵巢功能抑制试验 （SOFT） 的女性患者的所有可用肿瘤组织样本。这些个体被随机分配接受 5 年单独辅助他莫昔芬、他莫昔芬加 OFS 或依西美坦加 OFS。BCI 测试对临床数据和结果不知情。先验假设是 BCI HOXB13/IL17BR 比值 （BCI[H/I]）——高肿瘤将从 OFS 中获益更多，而高 BCI 预示着该人群的预后较差。设置跨越了国际上的多个中心。参与者包括患有 HR+ 早期乳腺癌的绝经前女性患者，其标本位于国际乳腺癌研究组肿瘤存储库中，可用于 RNA 提取。数据收集时间为 2003 年 12 月至 2021 年 4 月，并于 2022 年 5 月至 2022 年 10 月进行分析。主要结局和测量主要终点是用于预测分析的无乳腺癌间期 （BCFI） 和用于预后分析的无远处复发间期 （DRFI）。结果SOFT 意向治疗人群中 3047 例女性患者中有 1718 例可获得肿瘤标本。1687 名患者 （98.2%） 的标本产生了足够的 RNA 用于 BCI 检测，代表了亲本试验人群。 中位 （IQR） 随访时间为 12 （10.5-13.4） 年，512 例患者 （30.3%） 年龄小于 40 岁。972 例患者 （57.6%） 的肿瘤为 BCI （H/I） -低，715 例患者 （42.4%） 的肿瘤为 BCI （H/I） -高。归类为 BCI（H/I）-low 的肿瘤患者在依西美坦加 OFS 的 BCFI 中 12 年绝对获益为 11.6%（风险比 [HR]，0.48 [95% CI，0.33-0.71]），他莫昔芬加 OFS 的绝对获益为 7.3%（HR，0.69 [95% CI，0.48-0.97]）相对于单独使用他莫昔芬。相比之下，BCI（H/I） 高肿瘤患者未从依西美坦加 OFS 中获益（绝对获益，-0.4%;HR，1.03 [95% CI，0.70-1.53];相互作用的 P = .006）或他莫昔芬加 OFS（绝对益处，-1.2%;HR，1.05 [95% CI，0.72-1.54];相互作用的 P = .11） 与单独使用他莫昔芬相比。BCI 连续指数在 DRFI 的 N0 亚组中具有显著的预后 （n = 1110;P = .004），BCI 低风险、中风险和高危 N0 癌症的 12 年 DRFI 分别为 95.9%、90.8% 和 86.3%。结论和相关性在这项针对 SOFT 入组患者的前瞻性回顾性转化研究中，BCI 被证实为患有 HR+ 乳腺癌的绝经前妇女的预后。含 OFS 的辅助内分泌治疗对 BCI（H/I）-low 肿瘤患者的益处大于 BCI（H/I）-high 肿瘤患者。BCI（H/I） 低状态可以识别可能从这种更强化的内分泌治疗中受益的绝经前患者。