Author(s): Carlton L Schwab aff1 , Alessandro D Santin aff1
HER2; PIK3CA; mTOR; targeted therapy; uterine serous carcinoma
Endometrial cancer is the most common of gynecologic malignancies in the US with nearly 52,630 diagnoses and 8590 deaths in 2014 [1 ]. Endometrial cancers are thought of in two broad categories; type I and type II. Type I tumors make up the majority of all new diagnoses and are estrogen and progesterone receptor positive. These hormonally driven tumors are typically diagnosed at an early stage, are endometrioid in histology and are highly curable. Type II endometrial cancers are characterized by more aggressive histotypes including serous, clear cell, mucinous, squamous, transitional cell, mesonephric and undifferentiated. Type II endometrial cancers are responsible for the majority of deaths from endometrial cancer [ 2 ]. Unlike type I endometrial cancers, these carcinomas are generally not hormonally driven or responsive to hormonal treatments making potentially available treatments more limited. Out of these aggressive histologic types, uterine serous cancers (USC) are the most common and most aggressive variant. If these cancers recur, they are less responsive to chemotherapy and usually fatal. Initial treatment for USC comprises surgical staging usually followed by cytotoxic chemotherapy with or without radiation therapy. Despite aggressive treatment, uterine serous carcinomas carry a far worse prognosis (5-year survival of 30% ± 9) and recurrence rate with 50-80% of patients developing recurrence after initial treatment [2-4 ].
The aggressive nature of uterine serous carcinoma has led to extensive study of molecular characteristics to better understand the tumor biology and what drives their proliferation. Data suggest a number of molecular alterations are found in USC with mutations affecting genomic stability and cell cycle regulation including the deletion or mutation of TP53 tumor suppressor gene among a number of other mediators, chromatin remodeling genes involved in the NuRD pathway and proliferation signaling mediated through both amplification and/or mutations in HER2/neu and PIK3CA [5 ]. While a number of different molecular targets have been identified in USC, the HER2/neu regulated PIK3CA/AKT/mTOR pathway remains the most promising target for therapy at this time.
Uterine serous carcinoma harboring HER2/neu gene amplification has been identified in up to 35% of newly diagnosed USC patients [6 ]. While amplification has been associated with overall worse prognosis, it may provide an ideal target for therapy. The Gynecologic Oncology Group assessed the use of single-agent trastuzumab in patients with endometrial cancer and found that trastuzumab did not improve outcome [7 ]. Ongoing clinical trials have been designed to assess the use of trastuzumab in a more homogenous group of patients with HER2/neu amplified uterine serous carcinoma and in combination with chemotherapy (NCT01367002). While trials are ongoing, new data have emerged regarding the targeting of the HER2/neu pathway in USC. Including use of antibody cytotoxic drug conjugates, small tyrosine kinase inhibitors, and dual HER2/neu pathway targeted therapy.
Drug-antibody conjugates are attractive for use in HER2/neu targeted therapy. The drug-antibody conjugate, trastuzumab ematansine (T-DM1), has shown promise in preclinical studies with improved responses seen in HER2/neu amplified USC...