Preclinical evidence suggests cetuximab should work in TNBC, but trials to date have yielded dismal response rates, both for cetuximab alone and in combination with other therapies. Specifically, in 2012, the randomized phase 2 TNBCRC 001 trial reported a response rate of 6% for the cetuximab alone arm and 16% for the cetuximab plus carboplatin arm.2 Also, a phase 2 trial of 173 patients with metastatic TNBC, published in 2013, failed to meet its primary end point, yielding a response rate of 20% for the cetuximab plus chemotherapy arm and 10% for the chemotherapy-alone arm.3
During an interview with Cancer Therapy Advisor, Charles Shapiro, MD, director of translational breast cancer research at The Tisch Cancer Research at Mount Sinai, New York, New York, explained that the trials were done at a time when the efficacy of EGFR inhibitors was studied in relation to protein expression, not gene copy number, because gene copy number was not realized as a way to obtain alterations. At the time, the general assumption was that if EGFR were overexpressed as a protein — which is the case in 20% to 50% of TNBC cases — it was the result of an EGFR gene amplification. Now it is known that EGFR overexpression is not always an indicator of the presence of an EGFR amplification.
While the case report findings are “interesting” and “novel” according to Dr Shapiro, who was not involved in the study, he said that comparative genomic hybridization requires specialized techniques that are not available in the average oncology pathology lab.
“CGH [comparative genomic hybridization] is not used diagnostically, as it requires large amount of DNA,” explained Rohit Bhargava, MD, director of anatomic pathology, UPMC Magee-Womens Hospital, during an interview with Cancer Therapy Advisor. Dr Bhargava, who was not involved in the case report, noted, “[CGH] can better distinguish between copy number increase via true amplification versus chromosomal ploidy.”
Dr Bhargava added that fluorescence in situ hybridization (FISH), a technique routinely used and widely available, can be “equally good” if one keeps a high threshold for determining amplification and also uses information on the chromosomal marker on which the gene resides.
Given the lack of availability of comparative genomic hybridization, Dr Shapiro cautioned that the case report currently has “limited clinical impact.” That said, he was optimistic about the future. “This is technology that’s not readily available now, but could be readily available in 5 years.”
- Sabatier R, Lopez M, Guille A, et al. High response to cetuximab in a patient with EGFR-Amplified heavily pretreated metastatic triple-negative breast cancer [published online April 3, 2019]. JCO Precis Oncol. doi: 10.1200/PO.18.00310
- Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol. 2012;30(21):2615-2623.
- Baselga J, Gómez P, Greil R, et al. 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. J Clin Oncol. 2013;31(20):2586-2592.