Invasive lobular breast cancer (ILC) is a special breast cancer (BC) subtype and is mostly hormone receptor (HR)-positive and ERBB2 non-amplified. Endocrine therapy restrains tumor proliferation and is the mainstay of lobular BC treatment. Mutation of ERBB2 has been associated with recurrent ILC. However, it is unknown whether ERBB2 mutation impacts on the otherwise exquisite responsiveness of early ILC to endocrine therapy. We have recently profiled n = 622 HR-positive early BCs from the ADAPT trial for mutations in candidate genes involved in endocrine resistance, including ERBB2. All patients were treated with short-term preoperative endocrine therapy (pET, tamoxifen or aromatase inhibitors) before tumor resection. Tumor proliferation after endocrine therapy (post-pET Ki67 index) was determined prospectively by standardized central pathology assessment supported by computer-assisted image analysis. Sustained or suppressed proliferation were defined as post-pET Ki67 ≥10% or <10%. Here, we report a subgroup analysis pertaining to ILCs in this cohort. ILCs accounted for 179/622 (28.8%) cases. ILCs were enriched in mutations in CDH1 (124/179, 69.3%, P < 0.0001) and ERBB2 (14/179, 7.8%, P < 0.0001), but showed fewer mutations in TP53 (7/179, 3.9%, P = 0.0048) and GATA3 (11/179, 6.1%, P < 0.0001). Considering all BCs irrespective of subtypes, ERBB2 mutation was not associated with proliferation. In ILCs, however, ERBB2 mutations were 3.5-fold more common in cases with sustained post-pET proliferation compared to cases with suppressed post-pET proliferation (10/75, 13.3% versus 4/104, 3.8%, P = 0.0248). Moreover, ERBB2 mutation was associated with high Oncotype DX recurrence scores (P = 0.0087). In summary, our findings support that ERBB2 mutation influences endocrine responsiveness in early lobular BC.

浸润性小叶乳腺癌 (ILC) 是一种特殊的乳腺癌 (BC) 亚型，主要为激素受体 (HR) 阳性和ERBB2非扩增型。内分泌治疗抑制肿瘤增殖，是小叶 BC 治疗的中流砥柱。ERBB2的突变与复发性 ILC 相关。然而，尚不清楚ERBB2突变是否会影响早期 ILC 对内分泌治疗的其他敏感反应。我们最近对来自 ADAPT 试验的n  = 622 HR 阳性早期 BC 进行了分析，以了解参与内分泌耐药的候选基因的突变，包括ERBB2. 所有患者在肿瘤切除前均接受短期术前内分泌治疗（pET、他莫昔芬或芳香酶抑制剂）。内分泌治疗后的肿瘤增殖（pET 后 Ki67 指数）是通过计算机辅助图像分析支持的标准化中心病理学评估前瞻性确定的。持续或抑制增殖定义为 pET 后 Ki67 ≥10% 或 <10%。在这里，我们报告了与该队列中的 ILC 相关的亚组分析。ILC 占 179/622 (28.8%) 例。ILC 富含CDH1 (124/179, 69.3%, P  < 0.0001) 和ERBB2 (14/179, 7.8%, P  < 0.0001) 突变，但在TP53 (7/179, 3.9%, P = 0.0048) 和GATA3 (11/179, 6.1%, P  < 0.0001)。考虑到所有 BC，无论亚型如何，ERBB2突变与增殖无关。然而，在 ILC 中，与 pET 后增殖受抑制的病例相比，ERBB2突变在 pET 后持续增殖的病例中常见 3.5 倍（10/75，13.3% 对 4/104，3.8%，P  = 0.0248）。此外，ERBB2突变与高 Oncotype DX 复发评分相关（P  = 0.0087）。总之，我们的研究结果支持ERBB2突变影响早期小叶 BC 的内分泌反应。