Hannover Medical School, Institute of Pathology, Hannover, Germany.
West German Study Group, Moenchengladbach, Germany.
Cancer Med. 2021 Dec;10(23):8581-8594. doi: 10.1002/cam4.4376. Epub 2021 Nov 14.
Whereas the genomic landscape of endocrine-resistant breast cancer has been intensely characterized in previously treated cases with local or distant recurrence, comparably little is known about genomic alterations conveying primary non-responsiveness to endocrine treatment in luminal early breast cancer.
In this study, 622 estrogen receptor-expressing breast cancer cases treated with short-term preoperative endocrine therapy (pET) from the WSG-ADAPT trial (NCT01779206) were analyzed for genetic alterations associated with impaired endocrine proliferative response (EPR) to 3-week pET with tamoxifen or aromatase inhibitors. EPR was categorized as optimal (post-pET Ki67 <10%) versus slightly, moderately, and severely impaired (post-pET Ki67 10%-19%, 20%-34%, and ≥35%, respectively). Recently described gene mutations frequently found in previously treated advanced breast cancer were analyzed (ARID1A, BRAF, ERBB2, ESR1, GATA3, HRAS, KRAS, NRAS, PIK3CA, and TP53) by next-generation sequencing. Amplifications of CCND1, FGFR1, ERBB2, and PAK1 were determined by digital PCR or fluorescence in situ hybridization.
ERBB2 amplification (p = 0.0015) and mutations of TP53 (p < 0.0001) were significantly associated with impaired EPR. Impaired EPR in TP53-mutated breast cancer cases was independent from the Oncotype DX Recurrence Score group and was seen both with tamoxifen- and aromatase inhibitor-based pET (p = 0.0005 each).
We conclude that impaired EPR to pET is suitable to identify cases with primary endocrine resistance in early luminal breast cancer and that TP53-mutated luminal cancers might not be sufficiently treated by endocrine therapy alone.
尽管内分泌耐药乳腺癌的基因组图谱在局部或远处复发的既往治疗病例中已得到深入描述，但在激素受体阳性早期乳腺癌中，导致内分泌治疗原发性无反应的基因组改变相对知之甚少。
本研究分析了来自 WSG-ADAPT 试验（NCT01779206）的 622 例接受短期术前内分泌治疗（pET）的雌激素受体阳性乳腺癌病例，这些病例的遗传改变与接受他莫昔芬或芳香化酶抑制剂 3 周 pET 的内分泌增殖反应（EPR）受损相关。EPR 分为最佳（pET 后 Ki67<10%）、轻度、中度和重度受损（pET 后 Ki67 分别为 10%-19%、20%-34%和≥35%）。通过下一代测序分析了最近在既往治疗的晚期乳腺癌中经常发现的基因突变为 ARID1A、BRAF、ERBB2、ESR1、GATA3、HRAS、KRAS、NRAS、PIK3CA 和 TP53）。通过数字 PCR 或荧光原位杂交确定 CCND1、FGFR1、ERBB2 和 PAK1 的扩增。
ERBB2 扩增（p=0.0015）和 TP53 突变（p<0.0001）与 EPR 受损显著相关。在 TP53 突变的乳腺癌病例中，EPR 受损独立于 Oncotype DX 复发评分组，且在他莫昔芬和芳香化酶抑制剂 pET 中均可见（p=0.0005 各）。
我们得出结论，pET 时 EPR 受损适合于鉴定早期激素受体阳性乳腺癌中存在原发性内分泌耐药的病例，而内分泌治疗单独治疗 TP53 突变的激素受体阳性乳腺癌可能不够。
