Abstract ES07-1: Inflammatory breast cancer: Diagnosis, treatment and biology

Inflammatory breast cancer (IBC) is an extremely aggressive disease that progresses rapidly and carries a very grim prognosis. It is characterized by erythema, rapid enlargement of the breast, skin ridging, and a characteristic peau d’orange appearance of the skin secondary to dermal lymphatic tumor involvement. IBC incidence is 2.5-3.% but is frequently misdiagnosed and it is responsible for a disproportionate number of breast cancer-related deaths. The expression of hormonal receptors (ER and PR) and HER-2 and other prognostic and predictive markers in IBC have been documented in numerous studies. Although all molecular subtypes described in non-IBC are present in IBC they appear with different frequencies with luminal A subtype having a lower frequency (19% vs. 42%, p<0.001) and HER2 enriched subtype having a higher frequency (22% vs. 9%, P <0.001) among patients with IBC and non-IBC respectively. Moreover, a supervised analysis of gene expression profiling within the same study identified and validated an IBC-specific, molecular subtype-independent -gene signature, which held independent prognostic value. Functional analysis revealed attenuated TGF-b signaling in IBC. Other characteristics of IBC tumors include high level of mutations of the tumor suppressor TP53 and over-expression of the epidermal growth factor receptor (EGFR), which are both associated with a poor prognosis The management of IBC is multidisciplinary and the combination of systemic therapy and locoregional treatments contributed to the improvement of prognosis for this disease compared to historical studies involving only local therapies. Further improvement in the dismal outcome of these patients is much related to the further advancing in our understanding on the biology of the disease and the availability of novel therapies. More recently, the introduction of HER-2 targeted therapies dramatically contributed to modify the natural history of Her2 over expressing IBC tumors. The efficacy of trastuzumab has been investigated in the neoadjuvant setting in a phase III study that investigated 235 women with Her2 positive LABC 63 of whom had IBC. The investigators reported a higher pCR rate (38% vs 19%) and higher 3 –year event free survival (71% vs 56%) amongst women who received trastuzumab compared to those who did not. Furthermore, the efficacy of lapatinib, a receptor-tirosine kinase inhibitor targeting the intracelleular domain of the Her-receptor, has been investigated in a phase II study of 42 women with Her 2 positive IBC treated with neoadjuvant lapatinib and paclitaxel. An overall clinical response rate 78.6% and a pCR rate of 18.2% was reported. The BEVERLY-2 studies investigated the role of bevacizumab in combination to trastuzumab achieved a 63% pCR suggesting a potential role in the neoadjuvant management of these patients. The recent availability of novel preclinical models recapitulating the peculiar features of the disease and allowing for the discovery of molecular drivers of IBC including overexpression of the anaplastic lymphoma kinase (ALK) gene. Moreover, the therapeutic role of inhibitors of the chaperone protein, heat shock protein 90 (HSP-90) are explored in combination regimens for the molecular activity involving a number of IBC-related proteins, including EGFR, ALK, HER2. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES07-1.