Randomized Phase II Study of the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab With Cisplatin Versus Cisplatin Alone in Patients With Metastatic Triple-Negative Breast Cancer

Baselga, José; Gómez, Patricia; Greil, Richard; Braga, Sofía; Climent, Miguel Ángel; Wardley, Andrew M; Kaufman, Bella; Stemmer, Salomon M.; Pêgo, António; Chan, Arlene; Goeminne, Jean Charles.; Graas, Marie-Pascale; Kennedy, M. John; Gil, Eva; Schneeweiß, Andreas; Zubel, Angela; Groos, Jutta; Melezínková, Helena; Awada, Ahmad

doi:10.1200/jco.2012.46.2408

Cited by 310 publications

(254 citation statements)

References 29 publications

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“…Recently, however, EGFR-targeting monoclonal antibody, cetuximab, has improved outcomes in triple-negative breast cancers. 24 EGFR gene amplification, one of the mechanisms of EGFR overexpression, is highly variable and found in up to 24% of triple-negative breast cancer. 10,11,13,14,19,25 EGFR gene mutation, another mechanism of EGFR overexpression, has been reported to be rare, 11,17,19,25,26 although a recent study reported that it was present in 11% of triplenegative breast cancers.…”

Section: Introductionmentioning

confidence: 99%

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

Park¹,

et al. 2014

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Epidermal growth factor receptor (EGFR) is frequently overexpressed in triple-negative breast cancer and is emerging as a therapeutic target. EGFR gene copy number alteration and mutation are highly variable and scientists have been challenged to define their prognostic significance in triple-negative breast cancer. We examined EGFR protein expression, EGFR gene copy number alteration and mutation of exon 18 to 21 in 151 cases of triple-negative breast cancer and correlated these findings with clinical outcomes. In addition, intratumoral agreement of EGFR protein overexpression and gene copy number alteration was evaluated. EGFR overexpression was found in 97 of 151 cases (64%) and high EGFR gene copy number was detected in 50 cases (33%), including 3 gene amplification (2%) and 47 high polysomy (31%). Five EGFR mutations were detected in 4 of 151 cases (3%) and included G719A in exon 18 (n ¼ 1), V786M in exon 20 (n ¼ 1), and L858R in exon 21 (n ¼ 3). One case had two mutations (G719A and L858R). High EGFR copy number, but not EGFR mutation, correlated with EGFR protein overexpression. Intratumoral heterogeneity of EGFR protein overexpression and EGFR copy number alteration was not significant. In survival analyses, high EGFR copy number was found to be an independent prognostic factor for poor disease-free survival in patients with triple-negative breast cancer. Our findings showed that EGFR mutation was a rare event, but high EGFR copy number was relatively frequent and correlated with EGFR overexpression in triple-negative breast cancer. Moreover, high EGFR copy number was associated with poor clinical outcome in triple-negative breast cancer, suggesting that evaluation of EGFR copy number may be useful for predicting outcomes in patients with triple-negative breast cancer and for selecting patients for anti-EGFR-targeted therapy.

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Section: Introductionmentioning

confidence: 99%

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

Park¹,

et al. 2014

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“…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. Another EGFR inhibitor, erlotinib, has also shown encouraging pCR rates when combined with Carboplatin-Docetaxel chemotherapy in a small phase II trial [62] .…”

Section: Novel Agents In the Neoadjuvant Treatment Of Tnbcmentioning

confidence: 95%

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

Liontos

Karageorgopoulou²,

Michalaki³

et al. 2015

JST

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Triple negative breast cancer (TNBC) encompasses tumors that do not express either the estrogen receptor (ER) or the progesterone receptor (PR) and also do not overexpress the Human Epidermal growth factor Receptor 2 (HER2). This is a heterogenous group of tumors that significantly overlaps with both basal-like tumors and BRCA1/BRCA2 mutationassociated tumors. TNBC is highly aggressive in nature and exhibits worse prognosis than the other subtypes of breast cancer, despite its increased chemosensitivity. Neoadjuvant chemotherapy (NACT) is a treatment option regularly incorporated in clinical practice to improve subsequent surgical management. In parallel, allows rating of the pathological compete response (pCR) which is associated with the prognosis of these patients and evaluates the efficacy of the applied treatment as well. Platinum-based regimens and novel targeted therapies have shown some benefit in TNBC, though an unmet need for improved therapeutic strategies in this patient population still remains. In this review, the latest progresses in NACT in TNBC are discussed, along with the improved understanding of molecular targets and useful biomarkers in this group of patients.

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“…Development of new HER2-targeted therapies, including antibody-delivered cytotoxins and chimeric antigenbased immune cell repertoires, has shown promise in both research and clinical settings (14,15,(30)(31)(32). However, while clinical targeting of EGFR function through small molecule inhibitors or antibody inhibition of EGFR signaling has shown some promise, successful long-term outcomes are rare because of compensatory kinase domain mutations or alternate receptor signaling and problems with toxicity to normal tissue (33)(34)(35)(36). As ITs target protein synthesis rather than receptor signaling pathways, mutations in the receptor active site or alternate signaling pathways should not affect the activity of this therapeutic.…”

Section: Discussionmentioning

confidence: 99%

Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer

Simon

Antignani

Sarnovsky

et al. 2016

JNCI J Natl Cancer Inst

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Background: Triple-negative breast cancers (TNBCs) are typically more aggressive and result in poorer outcomes than other breast cancers because treatment options are limited due to lack of hormone receptors or amplified human epidermal growth factor receptor 2 (HER2). Many TNBCs overexpress the epidermal growth factor receptor (EGFR) or manifest amplification of the EGFR gene, supporting EGFR as a therapeutic target. While EGFR-directed small molecule inhibitors have shown limited effectiveness in clinical settings, use of EGFR as a mechanism of delivering enzymatic cytotoxins to TNBC has not been demonstrated. Methods: Using the single-chain variable fragment (scFv) of the 806 antibody that binds only cells with overexpressed, misfolded, or mutant variants of the EGFR, a recombinant immunotoxin was engineered through gene fusion with Pseudomonas aeruginosa Exotoxin A (806-PE38). The potency of 806-PE38 on reducing TNBC cell growth in vitro and in xenograft models (n 6) was examined for six TNBC cell lines. All statistical tests were two-sided. Results: 806-PE38 statistically significantly reduced the viability of all tested TNBC lines, with IC 50 values below 10 ng/mL for three of six cell lines, while not affecting cells with wild-type EGFR (IC 50 >300 ng/mL). Systemic treatments with 806-PE38 vs vehicle resulted in statistically significantly reduced tumor burdens (806-PE38 mean ¼ 128 mm 3 [SD ¼ 46 mm 3 ] vs vehicle mean ¼ 749 mm 3 [SD ¼ 395 mm 3 ], P ¼ .001) and increased median survival (806-PE38 median ¼ 82 days vs vehicle median ¼ 50 days, P ¼ .01) in a MDA-MB-468 TNBC mouse xenograft. Deletion of the catalytic residue eliminated both cytotoxic activity in vitro and the reduction in tumor burden and survival (P ¼ .52). Conclusions: These data support the further development of the 806-PE38 immunotoxin as a therapeutic agent for the treatment of patients with EGFR-positive TNBC. Follow-up experiments with combination therapies will be attempted to achieve full remissions.

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Randomized Phase II Study of the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab With Cisplatin Versus Cisplatin Alone in Patients With Metastatic Triple-Negative Breast Cancer

Cited by 310 publications

References 29 publications

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

High EGFR gene copy number predicts poor outcome in triple-negative breast cancer

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

Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer

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