University of Rochester Department of Medicine, Rochester, New York.
Biotheranostics, A Hologic Company, San Diego, California.
JAMA Oncol. 2024 Oct 1;10(10):1379-1389. doi: 10.1001/jamaoncol.2024.3044.
Adjuvant 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.
To 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 PARTICIPANTS: This 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.
Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses.
Tumor 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.
In 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.
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结局，但会增加不良反应。缺乏用于选择最有可能从 OFS 治疗中获益的患者的基因组生物标志物。
评估乳腺癌指数（BCI）在 HR+乳腺癌绝经前女性中预测 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 Suppression of Ovarian Function Trial（SOFT）中所有可用的女性患者的肿瘤组织样本。这些患者被随机分配接受 5 年的辅助他莫昔芬单独治疗、他莫昔芬加 OFS 或依西美坦加 OFS 治疗。BCI 检测在不了解临床数据和结局的情况下进行。假设是 BCI HOXB13/IL17BR 比值（BCI[H/I]）高的肿瘤将从 OFS 中获益更多，并且在该人群中高 BCI 预示着预后较差。研究地点跨越了多个国际中心。参与者包括 HR+早期乳腺癌的绝经前女性，有可用于提取 RNA 的国际乳腺癌研究组肿瘤库标本。数据收集于 2003 年 12 月至 2021 年 4 月，分析于 2022 年 5 月至 2022 年 10 月进行。
预测分析的主要终点是乳腺癌无复发生存期（BCFI），预后分析的主要终点是远处无复发生存期（DRFI）。
SOFT 意向治疗人群中 3047 名女性患者中有 1718 名患者的肿瘤标本可供使用。1687 名（98.2%）标本有足够的 RNA 进行 BCI 检测的患者代表了原试验人群。中位（IQR）随访时间为 12（10.5-13.4）年，512 名（30.3%）患者年龄小于 40 岁。972 名患者（57.6%）的肿瘤为 BCI[H/I]-低，715 名患者（42.4%）的肿瘤为 BCI[H/I]-高。BCI[H/I]-低的患者，与他莫昔芬单药治疗相比，接受依西美坦加 OFS 治疗的 12 年 BCFI 绝对获益为 11.6%（HR，0.48 [95%CI，0.33-0.71]），接受他莫昔芬加 OFS 治疗的绝对获益为 7.3%（HR，0.69 [95%CI，0.48-0.97]）。相比之下，BCI[H/I]-高的患者接受依西美坦加 OFS 治疗（绝对获益，-0.4%；HR，1.03 [95%CI，0.70-1.53]；P 交互 = .006）或他莫昔芬加 OFS 治疗（绝对获益，-1.2%；HR，1.05 [95%CI，0.72-1.54]；P 交互 = .11）均未获益于他莫昔芬单药治疗。BCI 连续指数在 N0 亚组的 DRFI 中具有显著的预后意义（n = 1110；P = .004），低风险、中风险和高风险 N0 癌症的 12 年 DRFI 分别为 95.9%、90.8%和 86.3%。
在这项对 SOFT 入组患者的前瞻性回顾性转化研究中，BCI 被证实对 HR+乳腺癌的绝经前女性具有预后价值。BCI[H/I]-低肿瘤患者从含 OFS 的辅助内分泌治疗中获益更大，而 BCI[H/I]-高肿瘤患者则不然。BCI[H/I]-低状态可能有助于识别可能从这种更强化的内分泌治疗中获益的绝经前患者。
