预测来曲唑＋拉帕替尼新辅助治疗亚洲绝经后乳腺癌女性疗效的生物标志物：Neo-ALL-IN

　　2016年8月4日，德国施普林格旗下《癌症化疗与药理学》在线发表韩国首尔蔚山大学医学院峨山医学中心的 Neo-ALL-IN（NCT 01275859）单中心Ⅱ期临床研究报告，评估了来曲唑＋拉帕替尼新辅助治疗绝经后雌激素受体（ER）和人表皮生长因子受体2（HER2）阳性乳腺癌女性的有效性和安全性以及潜在生物标志物。

　　该研究入组了24例绝经后ER和HER2阳性II～III期乳腺癌女性，术前18～21周每天口服来曲唑2.5mg＋拉帕替尼1500mg。通过触诊、卡尺测量、乳房超声检查、乳房钼靶摄片和/或MRI评定临床效果。在三个时间点（治疗开始、第14天、术前）采集乳腺标本进行生物标记物分析。治疗开始时进行18-氟代脱氧葡萄糖（18F-FDG）和18-氟雌二醇（18-FES）正电子发射断层扫描-计算机断层扫描（PET-CT）。

　　结果，17例（70.8%）完成计划的新辅助治疗，7例因为毒性或进展而提前终止治疗并进行手术；2例出现明确进展，2例触诊发现临床再生长。所有患者最终接受乳腺癌手术。

　　毒性通常轻微，大多为1～2级，除了3例（13.6%）出现持续或反复的3级肝毒性，尽管连续减量，最终导致治疗中断。

　　临床总有效率为62.5%（15例），其中包括1例乳腺完全缓解。然而，并未获得病理学完全缓解（ypT0-is N0）。

　　治疗开始时的FES PET-CT最大标准摄取值（SUVmax）低于5.5（p=0.007）、治疗开始时的肿瘤浸润淋巴细胞（TIL）超过20%（p=0.026）、新辅助治疗后ER免疫组织化学（IHC）Allred评分降低（p=0.021）与临床效果不佳有显著相关性。

　　因此，当该无化疗药物的来曲唑联合拉帕替尼新辅助疗法用于亚洲绝经后ER和HER2阳性乳腺癌时，新辅助治疗后的TIL、ER表达变化以及治疗开始时的FES PET-CT SUVmax可被考虑作为潜在生物标志物用于这些患者。

Cancer Chemother Pharmacol. 2016 Aug 4. [Epub ahead of print]

Phase II trial of neoadjuvant letrozole and lapatinib in Asian postmenopausal women with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancer [Neo-ALL-IN]: Highlighting the TILs, ER expressional change after neoadjuvant treatment, and FES-PET as potential significant biomarkers.

Park JH, Kang MJ, Ahn JH, Kim JE, Jung KH, Gong G, Lee HJ, Son BH, Ahn SH, Kim HH, Shin HJ, Moon DH, Kim SB.

Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

PURPOSE: Neo-ALL-IN (NCT 01275859) is a single-center, phase II study aimed to evaluate the efficacy and safety profiles of neoadjuvant letrozole plus lapatinib, as well as potential biomarkers, in postmenopausal women with ER- and HER2-positive (ER+HER2+) breast cancer.

METHODS: Postmenopausal ER+HER2+ breast cancer of stages II-III was eligible. Daily 2.5 mg letrozole plus 1500 mg lapatinib were administered for 18-21 weeks before surgery. Clinical responses were assessed by palpation with caliper, breast ultrasonography, mammogram, and/or MRI. Biologic samples were collected for biomarker analyses at three time points (baseline, day 14, and before surgery). Baseline fluorine-18 fluorodeoxyglucose and fluorine-18 fluoroestradiol PET-CT scans were performed.

RESULTS: Among 24 patients enrolled, 17 (70.8 %) completed planned neoadjuvant treatment, whereas 7 prematurely terminated the treatment and proceeded to surgery because of toxicity or progression; 2 patients showed definite progression, and 2 showed clinical regrowth by palpation regardless of minimal response. All patients eventually underwent breast cancer surgery. Toxicities were generally mild mostly within grades 1-2 except prolonged or recurrent grade 3 liver toxicities in 3 patients (13.6 %) regardless of sequential dose reduction, which finally led to discontinuation of treatment. The overall clinical response rates were 62.5 % (n = 15) including 1 CR in breast. However, no pathologic CR (ypT0-is N0) was achieved. SUVmax lower than 5.5 in baseline FES PET-CT (p = 0.007), baseline TILs over 20 % (p = 0.026), and decreased IHC ER Allred score after neoadjuvant treatment (p = 0.021) were significantly associated with adverse clinical response.

CONCLUSIONS: When this chemo-free, combination neoadjuvant therapy with letrozole and lapatinib is given for Asian postmenopausal ER+HER2+ breast cancer, TILs, change of ER expression following neoadjuvant treatment, and SUVmax in baseline FES-PET are to be considered potential biomarkers in these patients.

KEYWORDS: Breast cancer; FES-PET; Lapatinib; Letrozole; Neoadjuvant; Postmenopausal; TILs

PMID: 27491481

DOI: 10.1007/s00280-016-3107-6