Abstract P1-09-09: Efficacy and gene expression results from SOLTI1007 NEOERIBULIN phase II clinical trial in HER2-negative early breast cancer

Abstract

Background: Eribulin is the only cancer agent that has demonstrated a significant prolongation in overall survival on previously treated breast cancer patients. To date, no biomarker exists to prospectively select patients who will derive the maximum benefit from this chemotherapeutic. In the SOLTI1007-NeoEribulin study, we explored, in a prospective clinical trial, the efficacy and the association of pre-treatment expression of RNA in patients with HER2-negative breast cancer treated with neoadjuvant eribulin. Methods: SOLTI1007 is a phase II, open-label, single-arm, exploratory pharmacogenomic study of single agent eribulin as neoadjuvant treatment for stage I-II HER2-negative breast cancer (planned n=100 hormonal receptor-positive [HR+] and n=100 HR-negative). Patients received 1.4 mg/m2 of eribulin intravenously on Days 1 and 8 every 21-day cycle, for 4 cycles. Baseline and post-treatment (surgical) formalin-fixed, paraffin-embedded tissue samples were collected and gene expression profiled. PAM50 intrinsic subtype and the Risk of Relapse based on subtype and proliferation (ROR-P) were evaluated in each time-point. The association of each PAM50 signature and pathological complete response in the breast (pCRB) was evaluated using univariate logistic regression models. Results: Between September 2012 and October 2015, one hundred and seventy-four patients (TNBC n=73 and HR+ n=101) were recruited. Mean age (55.5), stage II (90%), negative axilla (78% and 67%), grade 3 (62% and 26%), mean tumor size (3 cm and 3.6 cm) and mean Ki-67 (61% and 31%). Completion of 4 cycles of eribulin was achieved by 85% of the patients. Grade 3-4 toxicities were observed in 19.54%, mostly due to neutropenia (5.1%) and alopecia (4.02%). The overall pCRB was 5.4%. No significant differences were observed between HR+ and TNBC disease. Distribution of the PAM50 intrinsic subtypes was as follows: Luminal A (n=43, 27.7%), Luminal B (n=42, 27.1%), Basal-like (n=63, 40.6%) and HER2-enriched (n=7, 4.5%). pCRB rates by subtype were the following: HER2-enriched (28.6%, 2/7), Luminal B (7.1%, 3/42), Basal-like (4.8%, 3/63), Luminal A (2.3%, 1/43). pCRB rates significantly (p=0.047) differed when HER2-enriched was compared to the other subtypes (odds ratio = 8.06, 95% CI 1.32-49.1). pCRB rate differed significantly by ROR-P (p=0.006): ROR-P high (17.1%, 6/35), ROR-P med (2.7%, 2/75), ROR-P low (2.2%, 1/45). Ki67 % by IHC did not predict pCRB (p=0.918). Subtype change at surgery occurred in 60% (3/5) HER2-enriched, 44.1% (15/34) of Luminal Bs, 10.3% (4/39) of Luminal A and 5.4% (2/37) of Basal-like tumors. 100% of subtype changes in Luminal B disease were to Luminal A. Conclusions: From a response and biological perspective, patients with HER2-enriched and Luminal B disease may benefit the most from eribulin therapy. Mechanistically, our gene expression data further supports previous preclinical evidence suggesting that eribulin triggers a phenotypic conversion. Citation Format: Prat A, Ortega V, Villagrasa P, Paré L, Galván P, Oliveira M, Nucíforo P, Lluch A, Morales S, Amillano K, Lopez R, Gonzalez R, Manso L, Martinez J, Llombart A, De la Peña L, Di Cosimo S, Rubio IT, Harbeck N, Baselga J, Cortés J. Efficacy and gene expression results from SOLTI1007 NEOERIBULIN phase II clinical trial in HER2-negative early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-09.

A Pathology-Based Combined Model to Identify PAM50 Non-luminal Intrinsic Disease in Hormone Receptor-Positive HER2-Negative Breast Cancer

“…PAM50 gene expression and pathology-based data from 1,416 HR+/HER2-negative early breast tumors were obtained from 8 independent studies that are summarized in Table 1 (20, 25–30). The GEICAM/9906 is a phase III adjuvant trial in women with lymph node-positive disease that compared treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P) (25).…”

“…A total of 531 HR+/HER2-negative tumor samples were analyzed (26). SOLTI-1007 NeoEribulin trial is a neoadjuvant trial within HER2-negative breast cancer, where patients were treated with eribulin monotherapy for 4 cycles (20). A total of 93 HR+/HER2-negative baseline tumor samples were analyzed.…”

“…At the same time, cumulative evidence from recent studies suggests that 5–30% of HR+/HER2-negative tumors are not Luminal A or B by gene expression and fall into the HER2-enriched (HER2-E) and Basal-like categories (14). From a clinical perspective, these non-luminal tumors have been associated with low estrogen dependency (15–17), high chemo-sensitivity (18–20), potential lower activity of CDK4/6 inhibitors (21, 22) and poor outcome in both early and the advanced/metastatic breast cancer (22–24). Thus, clinical utility of the identification of the two non-luminal subtypes within HR+/HER2-negative disease is now being pursued.…”

Clinical implications of the non-luminal intrinsic subtypes in hormone receptor-positive breast cancer

“…Non-luminal disease, especially Basal-like, has shown higher chemosensitivity than luminal disease [36][37][38]. However, whether this premise held true in patients with HR+/HER2-negative disease was unknown until recently.…”

“…In the SOLTI-NEOERIBULIN phase II clinical trial, neoadjuvant eribulin monotherapy was evaluated for 4 cycles in 101 patients with HR+/HER2-negative BC and PAM50 was performed before starting treatment [37]. As expected, the overall pCR in the breast rate was low (6.17%) [37]. However, pCR rates differed by subtype: 33.3% in HER2-E, 12.5% in Luminal B, 0% in Basal-like and 0% in Luminal A [37].…”