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
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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.
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.
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.
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.
KeywordsNeoadjuvant Lapatinib Letrozole Postmenopausal FES-PET TILs Breast cancer
The study (2007-0729) was partly granted from Novartis and GSK.
Compliance with ethical standards
Conflict of interest
- 3.Carlson RW, O’Neill A, Vidaurre T et al (2012) A randomized trial of combination anastrozole plus gefitinib and of combination fulvestrant plus gefitinib in the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer. Breast Cancer Res Treat 133:1049–1056CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Polychronis A, Sinnett HD, Hadjiminas D et al (2005) Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial. Lancet Oncol 6:383–391CrossRefPubMedGoogle Scholar
- 10.Rimawi MF, Mayer IA, Forero A et al (2013) Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol 31:1726–1731CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Gianni L, Pienkowski T, Im YH et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32CrossRefPubMedGoogle Scholar
- 18.de Azambuja E, Holmes AP, Piccart-Gebhart M et al (2014) Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol 15:1137–1146CrossRefPubMedGoogle Scholar
- 20.Loi S, Sirtaine N, Piette F et al (2013) Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860–867CrossRefPubMedGoogle Scholar
- 23.Salgado R, Denkert C, Campbell C et al (2015) Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol 1:448–454CrossRefPubMedGoogle Scholar
- 30.van Kruchten M, Glaudemans AW, de Vries EF et al (2015) Positron emission tomography of tumour [F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy. Eur J Nucl Med Mol Imaging 20:20Google Scholar
- 32.Coudert B, Pierga JY, Mouret-Reynier MA et al (2014) Use of [(18)F]-FDG PET to predict response to neoadjuvant trastuzumab and docetaxel in patients with HER2-positive breast cancer, and addition of bevacizumab to neoadjuvant trastuzumab and docetaxel in [(18)F]-FDG PET-predicted non-responders (AVATAXHER): an open-label, randomised phase 2 trial. Lancet Oncol 15:1493–1502CrossRefPubMedGoogle Scholar
- 33.Yang Z, Sun Y, Xue J et al. (2013) Can positron emission tomography/computed tomography with the dual tracers fluorine-18 fluoroestradiol and fluorodeoxyglucose predict neoadjuvant chemotherapy response of breast cancer?—A pilot study. PLoS One 8:1–7Google Scholar
- 40.Guarneri V, Generali DG, Frassoldati A et al (2014) Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol 32:1050–1057CrossRefPubMedGoogle Scholar