TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer

Abstract

Purpose: Epidermal 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 methods: In 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.

Results: In 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.

Conclusion: Despite 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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram.

Fig 2.

(A) Time to progression (TTP) with cetuximab alone and combination cetuximab plus carboplatin. (B) Overall survival (OS) in patients treated initially with cetuximab alone followed by cetuximab plus carboplatin on progression (blue line) and in patients treated with cetuximab plus carboplatin from the beginning (yellow line). 95% confidence limits shaded; crosses indicate censored data.

Fig 3.

Example of a target lesion biopsied and examined by microarray for epidermal growth factor receptor (EGFR) pathway expression and activation (A) before and (B) after therapy. Each bubble represents the relative gene expression of a different gene/mRNA in the EGFR pathway (blue, above average expression; dark gold, average; gold, below average). Across the bottom are three previously defined EGFR activation signatures demonstrating activation in the pretherapy specimen and inactivation after 1 week of combination cetuximab plus chemotherapy. This patient experienced clinical response.

Fig 4.

Effect of cetuximab-based therapy on epidermal growth factor receptor (EGFR) pathway expression. (A) Mean expression of the a priori–defined EGFR activation cluster 2 in 18 patients, including 16 serial biopsy specimens before and after beginning anti-EGFR therapy, demonstrating that most, but not all, triple-negative breast cancers were basal like, and most had activation of the EGFR pathway (above dashed line). EGFR pathway inhibition was apparent in only a minority of tumors 7 to 14 days after beginning anti-EGFR therapy. Subtype is designated by shape, whereas colors designate clinical response. Dashed line represents the cut point for high or “on” EGFR activation signature. (B) Relationship of EGFR expression signature to response before treatment, demonstrating that high EGFR expression was significantly associated with poor responsiveness to therapy, particularly if EGFR expression remained high after 7 to 14 days of therapy. HER2, human epidermal growth factor receptor 2; ND, not known; PD, progressive disease; PR, partial response; SD, stable disease.

Fig 5.

Relationship of signatures (measured pretreatment and after 7 to 14 days) known to affect epidermal growth factor receptor signaling on response to cetuximab-based therapy. Low expression of several signatures measured in pretreatment samples was not associated with response; however, low expression of the same signatures after 7 to 14 days of treatment was significantly associated with clinical benefit: (A, B) 11-gene proliferation signature, (C, D) distance to claudin-low centroid (smaller distance indicates more claudin-low like), and (E, F) KRAS amplicon (amp) signature. PD, progressive disease; PR, partial response; SD, stable disease.