Background

The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [¹⁸Fluorine]fluorodeoxyglucose-positron emission tomography ([¹⁸F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [¹⁸F]FDG-PET disease detection were evaluated.

Methods

A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [¹⁸F]FDG-PET status. The association between baseline SUVmax and [¹⁸F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [¹⁸F]FDG-PET eligibility criteria.

Results

Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [¹⁸F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [¹⁸F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [¹⁸F]FDG-PET [−]/[+] criteria patients (p = 0.73), [¹⁸F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [¹⁸F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [¹⁸F]FDG-PET [−] and [¹⁸F]FDG-PET[+] criteria patients.

Conclusions

These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [¹⁸F]FDG-PET imaging as a tool to guide therapy.

Trial registration

Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017.

中文翻译：

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HER2 阳性早期乳腺癌 [18F]FDG-PET 疾病检测的临床病理学和分子预测因子：RESPONSE，随机 PHERGain 试验的子研究

背景

PHERGain 研究 (NCT03161353) 正在使用 [ ¹⁸氟]氟脱氧葡萄糖-正电子发射断层扫描 ([ ¹⁸ F]FDG-PET) 和病理学完全缓解适应评估对曲妥珠单抗-帕妥珠单抗新辅助治疗和化疗降阶梯的早期代谢反应HER2 阳性 (HER2+) 早期乳腺癌 (EBC) 的治疗策略。在此，我们提出了 RESPONSE，这是一项 PHERGain 子研究，其中评估了[ ¹⁸ F]FDG-PET 疾病检测的临床病理学和分子预测因子。

方法

RESPONSE 子研究纳入了 PHERGain 试验中筛查出的 500 名 HER2 + EBC 患者，其中磁共振成像 (MRI) 肿瘤大小 > 1.5 cm。 PET[−] 标准要求不存在 ≥ 1 个乳腺病变，且最大标准化摄取值 (SUVmax) ≥ 1.5 × SUVmean 肝脏 + 2 标准差。在筛选的 75 名 PET[−] 患者中，根据与 [ ¹⁸ F]FDG-PET 状态相关的患者特征，随机选择 21 名 SUVmax 水平 < 2.5 的患者，并与 21 名 SUVmax 水平≥ 2.5 的 PET[+] 患者进行匹配。评估基线SUVmax和[ ¹⁸ F]FDG-PET状态（[−]或[+]）与临床病理学特征之间的关联。此外，根据 [ ¹⁸ F]FDG-PET 资格标准，在排除和入组患者的匹配队列中，使用 PAM50 和 Vantage 3D™ 癌症代谢面板对间质肿瘤浸润淋巴细胞 (sTIL) 进行评估和基因表达分析进行专门比较。

结果

基线时 SUVmax 中位数为 7.2（范围：1-39.3）。在所有分析的患者中，较高的 SUVmax 与较高的肿瘤分期、较大的肿瘤大小、淋巴结受累、激素受体阴性状态、较高的 HER2 蛋白表达、较高的 Ki67 增殖指数和较高的组织学分级相关 ( p  < 0.05)。与[ ¹⁸ F]FDG-PET [−] 标准患者相比，[ ¹⁸ F]FDG-PET [−]标准患者的肿瘤尺寸较小 ( p  = 0.014)，并且没有淋巴结受累，且组织学分级较低( p  < 0.01) 。尽管 42 名匹配的 [ ¹⁸ F]FDG-PET [−]/[+] 标准患者的 sTIL 水平没有差异( p  = 0.73)，但 [ ¹⁸ F]FDG-PET [−] 标准患者的 sTIL 水平下降与 [ ¹⁸ F]FDG-PET[+] 患者相比，复发风险 (ROR) 和 PAM50 HER2 富集亚型比例较低( p  < 0.05)。在[ ¹⁸ F]FDG-PET [−]和[ ¹⁸ F]FDG-PET[+]标准患者之间观察到参与癌症代谢的基因表达的差异。

结论

这些结果强调了 HER2+ 乳腺癌的临床、生物学和代谢异质性，这可能有助于选择可能受益于 [ ¹⁸ F]FDG-PET 成像作为指导治疗工具的 HER2+ EBC 患者。

试用注册

临床试验.gov； NCT03161353；报名日期：2017年5月15日。