Targeting the EGFR pathway in chemotherapy-resistant triple-negative breast cancer - a phase II study.

PURPOSE: Epidermal growth factor receptor (EGFR) pathway activation causes chemotherapy resistance and inhibition of the EGFR pathway sensitizes TNBC to chemotherapy in preclinical models. Given the high prevalence of EGFR overexpression in TNBC, we conducted a single-arm phase II study of panitumumab (anti-EGFR monoclonal antibody), carboplatin, and paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02593175). PATIENTS AND METHODS: Patients with early-stage, AC-resistant TNBC, defined as disease progression or ≤80% reduction in tumor volume after 4 cycles of AC. were eligible for this study and received panitumumab (2.5 mg/kg IV, Q1 week x 13), paclitaxel (80mg/m2 IV Q1 week x 12), and carboplatin (AUC=4 IV, Q3 weeks x 4) as the second phase of NAT. A two-stage Gehan-type design was employed to detect an improvement in the pCR/residual cancer burden class I (RCB-I) rate from 5% to 20%. Whole exome sequencing was performed on diagnostic tumor biospecimens, where available. RESULTS: From 11/3/2016 through 8/3/2021, 43 patients with AC-resistant TNBC were enrolled. The combined pCR/RCB-I rate was 30.2%. The most common treatment-related adverse events were neutropenia (72%) and anemia (61%), with 7 (16%), 16 (37%), and 8 (19%) patients experiencing grade 4 neutropenia, grade 3 neutropenia, and grade 3 anemia, respectively. No new safety signals were observed. CONCLUSIONS: This study met its primary endpoint (pCR/RCB-I=30.2% vs. 5% in historical controls), suggesting that panitumumab should be evaluated as a component of neoadjuvant therapy in patients with chemotherapy-resistant TNBC in a larger, randomized clinical trial.

Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer.

PURPOSE: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies. EXPERIMENTAL DESIGN: To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide-based neoadjuvant therapy. RESULTS: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P = 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P = 0.15), metastasis-free survival (30.3 vs. 32.4 months, P = 0.22); and overall survival (32.6 vs. 34.3 months, P = 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P = 0.07) and its pathway (41% vs. 18%, P = 0.02) were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable and characterized by distinctive gene signatures. Among nonmetaplastic (non-Mp) TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC. CONCLUSIONS: Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.