LETTER TO THE EDITOR Is HER2 overexpression sufficient for optimal response to Pertuzumab? Mehmet Ali Nahit S ¸ endur • Sercan Aksoy • S ¸ ebnem Yaman • Nuriye YıldırımO ¨ zdemir • Nurullah Zengin Received: 16 January 2012 / Accepted: 1 February 2012 / Published online: 16 February 2012 Ó Springer Science+Business Media, LLC 2012 To the editor, Human epidermal growth factor receptor (HER) 2 overexpression is observed approximately 20 percent of the breast cancer patient’s tumors. HER2 overexpression is associated with more aggressive phenotype and poor prognosis [1]. Overexpression of HER family members, HER1 and HER3, is associated with poor prognosis in patients with early breast cancer [2]. On the other hand, HER4 overexpression appears to be a good prognostic factor for these patients [3]. Anti-HER2 humanized monoclonal antibody (Trastuzumab) plus chemotherapy is a standard approach for metastatic breast cancer patients with visceral crisis. However, a proportion of patients with HER2-positive breast cancer are not responding to these combinations. Furthermore, the majority of the patients progress within 1 year under these combinations [4]. Thus, new therapies are needed that target to HER2 or new targets. A new class of agents targeting HER2 inhibits dimer- ization with other receptors in its family and is known as HER dimerization inhibitors. Pertuzumab is the first drug in this class that was successfully and effectively used in neoadjuvant and metastatic setting. Pertuzumab, a recom- binant humanized monoclonal antibody binding to the HER2 dimerization domain, prevents dimerization of HER2 with other HER receptors (HER3, HER1, and HER4) especially with HER3 [5]. This novel mechanism of action gives pertuzumab an effective role in the treatment of breast cancer. In neoadjuvant pertuzumab and trast- uzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere) study, Gianni L. reported that adding pertuzumab to docetaxel plus trastuzumab had a significantly improved pathological complete response rate compared with those given trast- uzumab plus docetaxel (45.8 vs 29.0%; p = 0.0141) [6]. In another recently published study, the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study, Baselga J. and colleagues reported that in patients with HER2-positive metastatic breast cancer receiving first-line therapy, adding pertuzumab to docetaxel-trastuzumab combination significantly improved progression-free sur- vival compared with docetaxel plus trastuzumab (18.5 vs 12.4 months; p \ 0.001) [7]. In both studies, there was no information about the HER family overexpression status, except HER2. We state that other HER family expression (HER1 and HER4, especially HER3) status may affect the response to pertuzumab. Chiu et al [8] reported that HER3 overexpression was identified in 10.0% of breast cancer patient’s tumors and a significant marker of reduced patient breast cancer-specific survival. In another randomized phase II study, Makhija et al. [9] showed that low HER3 levels corresponded with response to pertuzumab in platinum-resistant ovarian can- cer patients. It seems that HER3 overexpressing patients have more aggressive phenotype and a poor prognosis. We believe that HER3 expression besides the HER2 is important, and it can modulate the response to pertuzumab. We should define new subgroups in HER2-positive group like HER3-positive and HER3-negative subgroups to pre- dict the prognosis in patients treated with pertuzumab. Conflict of interest The authors declare that they have no conflict of interest. M. A. N. S ¸ endur (&) Á S. Aksoy Á S ¸ . Yaman Á N. Y. O ¨ zdemir Á N. Zengin Department of Medical Oncology, Ankara Numune Education and Research Hospital, 06100 Sihhiye, Ankara, Turkey e-mail: masendur@yahoo.com.tr 123 Med Oncol (2012) 29:2565–2566 DOI 10.1007/s12032-012-0183-2