Dieci Maria Vittoria, Bisagni Giancarlo, Bartolini Stefania, Schirone Alessio, Cavanna Luigi, Musolino Antonino, Giotta Francesco, Rimanti Anita, Garrone Ornella, Bertone Elena, Cagossi Katia, Sarti Samanta, Ferro Antonella, Piacentini Federico, Orvieto Enrico, Sanders Melinda, Miglietta Federica, Massa Davide, Balduzzi Sara, Conte Pierfranco, D'Amico Roberto, Guarneri Valentina
Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy.
Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.
JAMA Oncol. 2025 Apr 1;11(4):386-393. doi: 10.1001/jamaoncol.2024.6872.
For patients with early ERBB2 (formerly HER2)-positive breast cancer, there is a need to identify biomarkers to guide treatment de-escalation.
To evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free (DDFS) and overall survival (OS) for patients with ERBB2-positive early breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: The ShortHER randomized clinical trial was a multicentric trial in Italy that enrolled patients with ERBB2-positive breast cancer from December 2007 to October 2013. Patients received 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Tumor samples were evaluated for TILs. Herein, patients were evaluated at a median follow-up of 9 years, and data were analyzed from February 2023 to August 2024.
Four cycles of anthracycline-based chemotherapy followed by 4 courses of taxanes combined with trastuzumab for 1 year (long arm) or 3 courses of taxanes combined with trastuzumab for 9 weeks followed by reduced-dose anthracycline-based chemotherapy for 3 courses (short arm).
The association of TILs with DDFS and OS was assessed with Cox models.
Of 1253 patients enrolled in the ShortHER trial, 866 women (median [IQR] age, 56 [48-64] years) had evaluable TILs. In Cox models with relevant factors, each 5% TIL increment was associated with improved DDFS (hazard ratio [HR], 0.87; 95% CI, 0.80-0.95; P = .001) and OS (HR, 0.89; 95% CI, 0.81-0.98; P = .01). The 10-year OS rate was 91.3% for patients with TILs 20% or higher, 93.3% for patients with TILs 30% or higher, and 98.1% for patients with TILs 50% or higher, resulting higher vs lower TIL counterparts. Patients with TILs lower than 20% showed a better outcome with the long vs short treatment (10-year DDFS, 88.7% vs 81.0%), whereas patients with TILs 20% or higher showed the opposite (10-year DDFS, 87.1% vs 92.2%; P for interaction = .01). Similarly, patients with TILs 20% or higher had a 10-year OS rate of 89.3% in the long arm vs 93.1% in the short arm (HR, 0.36; 95% CI, 0.10-1.36); patients with TILs lower than 20% had a 10-year OS rate of 91.3% in the long arm vs 86.9% in the short arm (HR, 1.36; 95% CI, 0.82-2.23; P for interaction = .06).
This follow-up analysis of the ShortHER randomized clinical trial is, to our knowledge, the first demonstration of an independent effect of TILs in terms of OS for patients with ERBB2-positive early breast cancer treated with adjuvant chemotherapy and anti-ERBB2 therapy. Patients with TILs 20% or higher who de-escalated trastuzumab duration and chemotherapy dose were not exposed to an excess risk of distant relapse or death.
EudraCT: 2007-004326-25.
对于早期ERBB2（原HER2）阳性乳腺癌患者，需要识别生物标志物以指导治疗降级。
评估肿瘤浸润淋巴细胞（TILs）与ERBB2阳性早期乳腺癌患者远处无病生存（DDFS）和总生存（OS）的相关性。
设计、设置和参与者：ShortHER随机临床试验是意大利的一项多中心试验，于2007年12月至2013年10月招募ERBB2阳性乳腺癌患者。患者接受9周或1年的辅助曲妥珠单抗联合化疗。对肿瘤样本进行TILs评估。在此，对患者进行了9年的中位随访，并于2023年2月至2024年8月进行数据分析。
四个周期的蒽环类化疗，随后4个疗程的紫杉烷联合曲妥珠单抗治疗1年（长臂组），或3个疗程的紫杉烷联合曲妥珠单抗治疗9周，随后进行3个疗程的低剂量蒽环类化疗（短臂组）。
采用Cox模型评估TILs与DDFS和OS的相关性。
在ShortHER试验纳入的1253例患者中，866例女性（中位[四分位间距]年龄，56[48 - 64]岁）有可评估的TILs。在包含相关因素的Cox模型中，TILs每增加5%与DDFS改善相关（风险比[HR]，0.87；95%置信区间，0.80 - 0.95；P = 0.001）和OS改善相关（HR，0.89；95%置信区间，0.81 - 0.98；P = 0.01）。TILs为20%或更高的患者10年总生存率为91.3%，TILs为30%或更高的患者为93.3%，TILs为50%或更高的患者为98.1%，TILs较高者与较低者相比生存率更高。TILs低于20%的患者接受长疗程与短疗程治疗的结局更好（10年DDFS，88.7%对81.0%），而TILs为20%或更高的患者情况相反（10年DDFS，87.1%对92.2%；交互作用P = 0.01）。同样，TILs为20%或更高的患者在长臂组的10年总生存率为89.3%，在短臂组为93.1%（HR，0.36；95%置信区间，0.10 - 1.36）；TILs低于20%的患者在长臂组的10年总生存率为91.3%，在短臂组为86.9%（HR，1.36；95%置信区间，0.82 - 2.23；交互作用P = 0.06）。
据我们所知，ShortHER随机临床试验的这项随访分析首次证明了TILs在接受辅助化疗和抗ERBB2治疗的ERBB2阳性早期乳腺癌患者的总生存方面具有独立作用。TILs为20%或更高且降低曲妥珠单抗疗程和化疗剂量的患者未面临远处复发或死亡的额外风险。
EudraCT：2007 - 004326 - 25。
