Roque, Dana M.; Santin, Alessandro D.
Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer with distinct molecular pathogenesis. This review summarizes the rationale behind current clinical approaches, as well as recent advances made towards the elucidation of underlying pathway aberrations and development of targeted therapies that exploit these unique characteristics.
BURDEN OF DISEASE
Endometrial cancer is the most common gynecologic malignancy in developed countries, with 47 130 new cases and 8010 deaths projected in the United States alone for 2012 . Endometrial carcinomas may be broadly dichotomized into two classes with distinct underlying molecular pathogenesis, clinical behavior, and histopathology . Type I endometrial cancers comprise 80% of cases and are associated with endometrioid histology (grade 1 or 2) [3,4], relatively young age at onset (mean: 63 years), and indolent course . These cancers are preceded by hyperplasia and often a history of exposure to unopposed estrogen with retention of estrogen/progestin receptor status . Type II endometrial cancers constitute a minority of cases and are characterized by serous, clear cell or grade 3 endometrioid histology [7▪,8,9] with presentation at later stage and age and higher frequency in black patients . Loss of estrogen/progestin receptors  is common and endometrial intraepithelial carcinoma (EIC) serves as a precursor lesion. USC was first reported in 1972  and is the most biologically aggressive type II variant. This histology constitutes only 10% of all endometrial cancers but is characterized by a potentially fulminant clinical course with relatively poor prognosis. Type II disease accounts for 74% of all endometrial cancer deaths; the 5-year disease-specific survival rate for USC is only 55% , which compares unfavorably to the rate of 89% for grade 1/2 endometrioid cancers .
CURRENT STANDARD OF CARE: SURGICAL MANAGEMENT
Treatment for USC begins with complete surgical staging with intent for cytoreduction to no residual disease . Staging should consist of total hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic/para-aortic lymphadenectomy, omentectomy, and peritoneal washings with biopsies [15,16] given that 52–70% of patients with type II disease will exhibit extrauterine spread at time of initial surgery [16,17] and have a higher likelihood of positive para-aortic lymph node involvement compared with the rate of 4.6% observed in low-grade tumors .
Thus far, no data exist to suggest that a laparoscopic approach is contraindicated for management of early-stage USC. Survival and recurrence data from GOG-LAP2 [19▪▪] became available in 2012. This study randomized 2 181 patients with clinical stage I–IIA disease to laparoscopy versus laparotomy (2 : 1), including 289 (13%) with USC. Among all patients, the 3-year recurrence rates differed by only 1.14% [11.4 versus 10.2%, 90% confidence interval (CI) 1.28–4.0%] with identical estimated 5-year overall survival rates (89.8%). In patients with USC, there were 82 recurrences (30.8%), but the relative hazard ratio among those randomized to laparoscopy versus laparotomy was 1.087. Overall, port site metastases were observed in only 0.24% of cases, the strongest risk factor for which appeared to be extrauterine disease at time of staging but not necessarily serous histology.
CURRENT STANDARD OF CARE: CHEMOTHERAPY AND RADIATION
Following surgical staging, most clinicians consider adjuvant carboplatin and paclitaxel as standard of care in conjunction with or without tumor-directed radiation therapy for advanced endometrial cancers, including USC [20–22]. As presented at the 2012 Annual Meeting of the Society of Gynecologic Oncologists, preliminary analyses of GOG 209 now support the noninferiority and favorable side effect profile of six cycles of carboplatin (AUC 6)/paclitaxel (175 mg/m2) over cisplatin (50 mg/m2)/doxorubicin (45 mg/m2)/paclitaxel (160 mg/m2) , adding to the cumulative experience from five large phase III studies previously conducted by the GOG [24–28]. In accordance with previous experience in USC, a review of 135 patients with stage I-IV USC treated at Brigham and Women's Hospital demonstrated longer overall and relapse-free survival with a paclitaxel/platinum-based regimen relative to radiation therapy (hazard ratio 0.34, 95% CI 0.15–0.74, P = 0.007; hazard ratio 0.45, 95% CI 0.25–0.77, P = 0.004, respectively) .
Greater debate surrounds treatment of early-stage USC. Whole-abdominal radiation alone has proven to be of minimal benefit (GOG-94) . Adjuvant carboplatin/paclitaxel has been shown to improve recurrence rates, overall survival, and progression-free survival [31–34]. There is growing evidence to support the use of vaginal cuff brachytherapy in conjunction with platinum-based chemotherapy. Kiess et al.[35▪] published the Memorial Sloan Kettering Cancer Center experience across 41 patients with stage I/II USC who received intravaginal radiation therapy (21 Gy in three fractions) in conjunction with carboplatin (AUC 5–6) and paclitaxel (175 mg/m2). With a median follow-up of 58 months, 5-year disease-free and overall survival rates were 90 and 85%, respectively; pelvic, para-aortic, and distant recurrences occurred at a rate of 9, 5, and 10%, respectively over 5 years. De Leon et al. similarly found that platinum-based chemotherapy with vaginal brachytherapy in USC patients treated at Yale University from 1987–2009 had the best overall and disease-free survival compared with any other treatment (i.e., observation, platinum-based chemotherapy alone, whole-pelvic radiation alone, vaginal brachytherapy alone) regardless of stage. These findings corroborate multiple previous retrospective reviews [37,38] to support this treatment approach for early-stage disease.
Recently, there has been growing interest in exploring sandwich techniques with the intention of reducing the individual toxicities of each modality. In one such scheme [39▪], carboplatin/paclitaxel is administered for three cycles, followed by external beam radiation therapy with extended fields in the event of positive nodes and in most instances vaginal brachytherapy, prior to completion of the last three cycles of chemotherapy. Although the number of patients treated in this report was small, 3-year survival probabilities for patients with early and advanced USC were 84 and 50%, respectively.
Interestingly, for patients with stage I noninvasive or minimally invasive (<3 mm) USC, Giuntoli et al. found in contrast to conventional guidelines  little role of adjuvant therapy outside comprehensive staging. In this retrospective review of 41 patients, those who underwent comprehensive staging (29%) experienced no disease-specific deaths despite absence of adjuvant therapy, although median follow-up was only 2.62 years.
Despite abundant retrospective reports, the paucity of prospective data remains pervasive. The results of GOG-249 (NCT 00807768) , a phase III trial comparing pelvic radiotherapy or vaginal cuff brachytherapy in conjunction with carboplatin/paclitaxel in high-risk stage I or II endometrial carcinoma, are eagerly awaited.
MOLECULAR PATHOGENESIS AND NEW TARGETS
The molecular landscape of type II cancers differs greatly from that of type I disease, which often harbors mutations in k-Ras, PTEN, or mismatch repair mechanisms [43,44]. USCs tend to exhibit aneuploidy [45,46], overexpress HER2/neu [47–50], cyclin E [51▪▪] and the tight junction proteins claudin-3 and claudin-4 [52,53], as well as harbor mutations in TP53, among other aberrations .
Genome-wide analyses have recently clarified the molecular aberrations underlying this entity. Using the first application of whole-exome sequencing in USC, Kuhn et al.[51▪▪] described not only high rates of somatic mutation in the tumor suppressor TP53 (tumor protein 53; 81.6%), but mutations in PIK3CA (phosphatidyl inositol 3-kinase catalytic subunit; 23.7%), FBXW7 (F-box/WD repeat-containing protein 7; 19.7%), and PPP2R1A (protein phosphatase 2 regulatory subunit alpha; 18.4%) in both carcinomas and matched precursor EIC. Somatic copy number analyses identified frequent deletion of FBXW7 or amplification of CCNE1 (cyclin E), a known substrate for FBXW7. Thus, molecular genetic aberrations involving TP53, PIK3CA, PPP2R1A, cyclin E and FBXW7 pathways represent major mechanisms in the development of USC, and such mutations may take place very early (i.e., at the preinvasive stage) in USC.
All of these mutations also have important implications in cancer progression. The tumor suppressor TP53 is a transcriptional regulator that triggers apoptosis or cell cycle arrest in the setting of DNA damage; when defective, it is thought to contribute to approximately half of all cases of human cancer . TP53 has recently been implicated in regulation of insulin-like growth factor receptor-1 (IGFR-1) in USC cell lines . PP2R1A is a regulatory unit of the serine/threonine protein phosphatase 2 (PP2), which has been implicated in regulation of growth; mutations have previously been reported in as many as 19–32% of USC [57,58]. FBXW7, a member of the F-box family of proteins, is critical in ubiquitination and subsequent targeting of several tumor-promoting proteins including cyclin E (CCNE1) for proteosomal degradation [59,60]; CCNE1 controls the G1 to S transition of the cell cycle  (Fig. 1a). Importantly, in the study by Kuhn et al.[51▪▪], 57% of USC demonstrated cyclin E activation, either by inhibition of its degradation due to FBXW7 mutations or by increased expression as a result of gene amplification, suggesting for the first time a major role of this pathway in driving the tumorigenesis of a large number of USCs. PIK3CA, a 34-kb gene encoding the catalytic p110-α subunit of phosphatidylinositol 3-kinase (PI3K) located on chromosome 3q26.3, plays a role in activation of the PTEN/AKT pathway downstream of epidermal growth factor receptor (EGFR) and FGFR (fibroblast growth factor receptor) through phosphorylation of phosphatidyl inositol-3,4-diphosphate (PIP2) to generate phosphatidyl inositol-3,4,5-triphosphate (PIP3) [62,63] [Fig. 1b]. Nearly half (i.e., 48%) of the sequenced USCs harbored PIK3CA mutations and/or PIK3CA amplifications suggesting that inhibitors of PI3K/AKT/mTOR pathway should be particularly powerful against USC. mTOR [64–70] and FGFR inhibition (e.g., TKI258, NCT01379534)  in the treatment of endometrial cancers is an area of active investigation.
The epithelial–mesenchymal transition
The ‘epithelial to mesenchymal transition’ describes a process by which cells lose polarity and adhesion proteins such as e-cadherin or cytokeratin intermediate filaments, acquire spindle morphology and mesenchymal markers such as vimentin or fibronectin, and thereby gain capacity for increased migration and invasion (reviewed by Colas et al.[72▪]). In accordance with an unpredictable pattern of extrauterine spread [8,17], which may be as high as 60% even with noninvasive disease , USC often exhibits loss of e-cadherin . Other important triggers for e-cadherin downregulation include transforming growth factor β, EGFR, IGF-1, vascular endothelial growth factor (VEGF), platelet-derived growth factor, integrin/integrin-linked kinase, FGF, and Wnt/β-catenin (reviewed in [72▪]). Van der Horst et al. illustrated using endometrial cancer cell lines the role of PR signaling loss, a common feature of USC and other high-grade histologies, in induction of the epithelial-mesenchymal transition (EMT). There is also preliminary evidence to suggest a role in type II endometrial cancer progression for micro-RNAs (miR) 194 and 200, highly conserved noncoding RNAs ranging from 19 to 23 base pairs that moderate posttranslational silencing [76,77]. HMGA2 (high mobility group AT-hook 2), another participant in EMT , has recently been shown to be present in EIC and to differentiate USC from endometrioid tumors by immunoreactivity .
The association of USC with hereditary cancer syndromes is unclear. BRCA mutation status has been implicated in some [80–82] but not other [83,84] reports. Using massively parallel sequencing techniques, Pennington et al.[85▪] demonstrated a 2% frequency of BRCA1 germline mutations in association with USC, which exceeds the rate of 0.06% within the general population . BRCA1 has been shown to be highly expressed in USC cell lines and linked to decreased expression of insulin growth factor I receptor (IGFR-1) . In this study, germline mutations of the CHEK2 (checkpoint kinase), an upstream regulator of BRCA and putative driver of non-BRCA hereditary breast cancer syndrome , also occurred at a frequency of 1.3%.
Growden et al. recently reported the institutional experience with 84 stage I USC patients treated from 1992 to 2007 and found that 44% harbored a second malignancy (22 breast, nine synchronous müllerian tumors). These patients had an increased hazard ratio of 2.75 (95% CI 1.09–6.93, P = 0.031) for death in multivariate analyses. Tamoxifen use was not assessed, although the link between tamoxifen and USC seems uncertain given that among 6681 women treated with the drug for 5 years in National Surgical Adjuvant Breast and Bowel Project, none of the resultant endometrial cancers were serous in nature .
Approximately, 2% of all endometrial cancers occur in association with Lynch syndrome, but frequency in USC has been understudied [91–93]. Dewdney et al.[94▪] recently reported high rates of pancreatic cancer (odds ratio 2.39, 95% CI 1.0–5.38, P = 0.03) in the relatives of 348 patients with pure/mixed serous histology enrolled in GOG-210. Although defects in mismatch repair mechanisms that define Lynch syndrome could not be implicated in this study, it did raise the possibility of an otherwise undescribed familial syndrome underlying USC.
Targeted immunotherapy represents a promising strategy for type II endometrial cancers. Monoclonal antibodies (mAb) result in tumor lysis through antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Both pathways begin with recognition and binding of the mAb to tumor antigen. The Fc region may then be recognized by Fc receptors located on natural killer cells, monocytes, macrophages, or granulocytes to initiate ADCC or by C1 (the first component of the complement cascade) to activate the classic pathway of CDC ending in osmotic lysis through the membrane-attack complex. Preclinical data suggest that epithelial cell adhesion molecule , trophoblast cell surface marker (Trop-2) [96▪], and αV integrins  may represent target antigens for immunotherapeutic strategies, and that modulation of membrane complement regulatory proteins may augment cytotoxicity [98▪].
The human epidermal growth factor receptor family consists of four members: EGFR (ErbB1), HER2/Neu (ErbB2), HER-3 (ErbB3), and HER-4 (ErbB4). Ligand binding induces heterodimerization or homodimerization and subsequent activation of pathways integral to proliferation pathways . Amplification of HER2/Neu has been documented in 26–62% of USC cases [47–50] and has been linked to poor prognosis [47,100].
Trastuzumab (Herceptin, Genentech, San Francisco, California, USA) is a humanized monoclonal IgG1 antibody that works through recruitment of natural killer cells and initiation of ADCC as well as abrogation of downstream effectors . It is FDA-approved as an adjunct to cyclophosphamide, paclitaxel, and doxorubicin in the treatment of early-stage HER2/neu-positive, node-positive breast cancer and as a single agent for adjuvant treatment of early-stage HER2/neu-positive high-risk estrogen/progestin-negative breast cancers following multimodality anthracycline-based therapy [102,103]. Despite encouraging case reports [104–106] and sound biologic plausibility, when evaluated as a single agent, trastuzumab 4 mg/kg in week 1 then 2 mg/kg weekly until disease progression in stage III/IV or recurrent endometrial cancers at the phase II level failed to demonstrate significant activity (GOG-181B ). Notably, 45.5% of treated patients did not have definitive HER2/Neu amplification . It has also been proposed that interindividual variation in trastuzumab efficacy for USC might be influenced by variable amounts of HER2/Neu extracellular domain shedding leading to antibody neutralization [109▪]. A phase II study of carboplatin/paclitaxel with or without trastuzumab in patients with advanced or recurrent uterine papillary serous carcinoma confirmed to be HER2/Neu-positive by immunohistochemistry or fluorescence in-situ hybridization is currently underway (NCT01367002) .
Vascular endothelial growth factor-A
VEGF induces pathologic neoangiogenesis in a variety of human cancers (reviewed by Sitohy et al.). VEGF is a homodimeric glycoprotein that exists in at least four isoforms due to alternative splicing of the primary messenger RNA transcript, the most common of which is VEGF-A. In endometrial cancers, VEGF-A expression has been associated with high grade, lymphovascular space invasion, lymphatogenous spread, poor prognosis [112–114], and p53 upregulation . Bevacizumab (Avastin, Genentech) is a recombinant human monoclonal IgG1 antibody that neutralizes all isoforms of VEGF . In a phase II study of recurrent endometrial cancer (GOG 229E) , bevacizumab 15 mg/kg every 3 weeks produced clinical response rate of 13.5%, including one complete and six partial responses. Median progression-free and overall survival rates were 4.2 and 10.5 months, respectively. Notably, despite representing only 27% of the study population, serous histology was observed in 100% of complete responses and 50% of partial responses. Presently, bevacizumab in combination with paclitaxel and carboplatin is under study for advanced endometrial cancer (NCT00513786) . Another three-arm phase II trial is investigating carboplatin/paclitaxel/bevacizumab, carboboplatin/paclitaxel/temsirolimus, and carboplatin/ixabepilone/bevacizumab (NCT00977574, GOG-86P) . VEGF Trap (Afibercept, Sanofi-Aventis, Paris, France), a fusion protein containing receptor components and fully human immunoglobulin constant region, is also under evaluation (NCT00462826) .
NOVEL CYTOTOXIC AGENTS
Over the past quarter century, the GOG has evaluated over 25 novel cytotoxic agents at the phase II level for use in endometrial cancers, and exceedingly few of these have proceeded to phase III testing . Resistance to paclitaxel has been tied to overexpression of the class III β isotype of tubulin  given the preferential binding of paclitaxel to class I β isotype . Class III tubulin differs from class I tubulin at paclitaxel binding sites involving amino acid positions 175 (Ser→Ala) and 364–365 (Ala-Val→Ser-Ser) . Class III β-tubulin overexpression correlates with poor clinical outcome in a variety of human cancers, including ovarian , lung , and breast .
Epothilones (EPOxide THIazoLe ketONEs) are novel microtubule-stabilizing macrolides isolated from Sorangium cellulosum with activity in paclitaxel-resistant malignancies, and the unique ability to bind class III and I isoforms with at least equal affinity . Patupilone (Novartis, Basel, Switzerland) and ixabepilone (Ixempra/BMS-247550; Bristol-Meyers-Squibb, Princeton, New Jersey, USA) are notable members of this group that vary from each other in structure by only a single moiety.
In vitro, patupilone is highly effective relative to paclitaxel against USC cell lines that express high levels of both class III β-tubulin and HER2/Neu , a known poor prognostic factor [47–49]. Overexpression of class III β-tubulin predicts poorer overall survival in USC as well as sensitivity to patupilone (Roque et al. unpublished data). In vivo, ixabepilone has been FDA-approved for treatment of locally advanced/metastatic breast cancer with capecitabine after failure of anthracycline/taxane therapy or as monotherapy after failure of anthracyclines, taxanes, and capecitabine ; applications for gynecologic malignancies are expanding. GOG-129P evaluated 50 patients with recurrent or persistent endometrial cancer who received one prior line of taxane-based chemotherapy including 40% with serous histology. An overall response rate of 12% was achieved using 40 mg/m2 every 21 days; disease stabilization for at least 8 weeks occurred in 60%. Median progression-free and overall survival was 2.9 months and 8.7 months, respectively . Ixabepilone is currently under evaluation investigation as first-line therapy with carboplatin and bevacizumab in stage III/IV primary or recurrent endometrial cancers, including USC (GOG-86P; NCT977574 ).
USCs constitute a minority of cases but a disproportionate number of deaths from endometrial cancer. Given an unpredictable pattern of spread, complete surgical staging is essential. Adjuvant platinum-based combination chemotherapy with or without radiation is indicated in patients with advanced-stage disease; many patients with early-stage disease should also receive platinum-based chemotherapy with consideration for vaginal cuff brachytherapy though conflicting evidence exists and results of prospective trials are eagerly awaited. Uncovering a hereditary basis for this disease may provide means for strategies towards early detection. Further elucidation of the molecular pathogenesis underlying this entity remains key to the development of novel therapeutic approaches.
Conflicts of interest
The authors have no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 84–85).
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