Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study

Breast Cancer Research and Treatment Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study Genomic Health 0 2 3 Penobscot Dr 0 2 3 Redwood City 0 2 3 0 Abbreviations BCS Breast-conserving surgery CI Confidence interval CR Complete response ER Estrogen receptor protein 1 Hiroji Iwata 2 Okayama University Hospital , 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558 , Japan 3 Hirosaki Municipal Hospital , 3-8-1 Oaza Omachi, Hirosaki, Aomori 036-8004 , Japan Purpose The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated whether Recurrence Score results can predict clinical response to neoadjuvant letrozole. Methods NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS < 18 versus RS ≥ 31. Secondary endpoints included evaluation of clinical response and rate of breast-conserving surgery (BCS) by continuous Recurrence Score result, ESR1 and PGR single-gene scores, and ER genegroup score. Results Of 295 TransNEOS patients (median age 63 years; median tumor size 25 mm; 66% grade 1), 53.2% had RS < 18, 28.5% had RS18-30, and 18.3% had RS ≥ 31. Clinical response rates were 54% (RS < 18), 42% (RS18-30), and 22% (RS ≥ 31). A higher proportion of patients with RS < 18 had clinical responses (p < 0.001 vs. RS ≥ 31). In multivariable analyses, continuous Recurrence Score result (p < 0.001), ESR1 score (p = 0.049), PGR score (p < 0.001), and ER gene-group score (p < 0.001) were associated with clinical response. Recurrence Score group was significantly associated with rate of BCS after neoadjuvant treatment (RS < 18 vs. RS ≥ 31, p = 0.010). Conclusion The Recurrence Score test is validated to predict clinical response to neoadjuvant letrozole in postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer. Breast cancer; Hormonal therapy; Neoadjuvant; Oncotype DX; Recurrence score - Extended author information available on the last page of the article ESR1 HER2 IHC MRI NEOS NSABP PD PGR PgR PR RS RT-PCR Neoadjuvant therapy for locally advanced breast cancer has the potential to improve rates of breast-conserving surgery (BCS), permit the assessment of patients’ primary tumor response to systemic therapy, and reduce rates of distant metastases by as much as that observed with adjuvant approaches [ 1–6 ]. Clinical and pathological complete responses (CR) to neoadjuvant therapy are associated with improved clinical outcomes, and both are considered to be valid surrogates of clinical outcomes for some types of breast cancer [ 1, 6, 7 ]. Previous studies have demonstrated higher rates of clinical and pathological CR to neoadjuvant chemotherapy in high-grade tumors and tumors with higher levels of Ki-67 protein expression, but lower rates of response in tumors positive for estrogen receptor (ER) protein expression [ 7–9 ]. Historically, neoadjuvant hormonal therapy was reserved only for patients who were not candidates for neoadjuvant chemotherapy or surgery. Studies conducted since 2001, however, have demonstrated that neoadjuvant hormonal therapy can yield clinically meaningful response rates in more general populations of patients with ER + breast cancer [ 10–16 ]. Therefore, many patients with locally advanced ER + breast cancer may be considered for neoadjuvant hormonal therapy, as a viable means to achieve clinical response and improve rates of BCS [ 12–19 ]. As in the adjuvant setting, however, response to neoadjuvant hormonal therapy can vary across patients with ER + breast cancer [ 20 ]. Thus, the capacity to select patients who are more likely to benefit from neoadjuvant hormonal therapy would represent an advance in the clinical management of breast cancer. The Oncotype DX Breast Recurrence Score® test is a validated clinical tool that predicts benefit of adjuvant chemotherapy in patients with ER+, HER2-negative, node-negative [ 21–25 ], and node-positive [ 24, 26 ] early breast cancer who receive five years of hormonal therapy. In addition, the Recurrence Score test is validated to predict distant recurrence in patients treated with adjuvant hormonal therapy. The clinical validation study used samples from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial to show that the Recurrence Score® (RS) results quantified the likelihood of distant recurrence in patients with node-negative, E (...truncated)