TBCRC 001: Randomized Phase II Study of Cetuximab in Combination With Carboplatin in Stage IV Triple-Negative Breast Cancer

Abstract

A B S T R A C T PurposeEpidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy. Patients and MethodsIn this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m 2 load then 250 mg/m 2 per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition. ResultsIn 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five. ConclusionDespite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.

Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer*

“…Indeed, knockdown of some of these components, including laminins, THBS1 and PXDN, hindered the proliferation of PIK3CA mutant MCF10A and BLBC cell lines. PI3K activation was associated with increased exosome secretion, which could be because of the promotion of actin cytoskeletal rearrangements, such as invadopodia formation by PI3K lipid products (30,40). A phosphoproteomic and signaling network analysis of PIK3CA mutant MCF10A cells revealed novel substrates of Akt1, including cortactin, which was an important substrate for the enhanced migration induced by PIK3CA mutation (41).…”

Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

“…Several inhibitors of the Raf/MEK/ERK pathway are currently under clinical evaluation alone and in combination with PIK3CA/mTOR inhibitors (Table 3) [9,58,94,95]. Furthermore, PI3K inhibition has been shown to boost the ERK pathway through the enhancement of the epidermal growth factor receptor (EGFR)/HER2/human epidermal growth factor receptor 3 (HER3) signaling, and HER3 may in turn promote the reactivation of the PI3K/AKT and MAPK pathways [96,97].The modest activity of EGFR inhibitors in TNBC may also be due to crosstalk between signaling pathways and compensatory feedback loops [98][99][100][101]. Thus, combination trials with other drugs, including NOTCH and AXL inhibitors, warrant further clinical investigation [99][100][101].…”

The recent progress of neoadjuvant chemotherapy in triple negative breast cancer: A short review

“…These data prompted two phase II ramdomized studies that tested the role of cetuximab in patients with metastatic TNBC. Cetuximab used as monotherapy provided poor response rates [60] , despite the EGFR pathway is active in these patients indicating that alternative pathway activation mechanisms exist in these patients. The addition of cetuximab though to cisplatin improved responses in the metastatic setting in comparison to cisplatin monotherapy despite the study did not met predefined criteria for OS and PFS [61] indicating that EGFR inhibition could have therapeutic benefit in these patients.…”