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).
1. Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J Clin
2. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol
3. Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet
4. Felix AS, Weissfeld JL, Stone RA, et al. Factors associated with Type I and Type II endometrial cancer. Cancer Causes Control
5. Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. FIGO 26th Annual Report on the results of treatment in Gynecological Cancer. Int J Gynaecol Obstet
2006; 95 (Suppl 1):S105–S143.
6. Lax SF, Pizer ES, Ronnett BM, et al. Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactivity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation. Hum Path
7▪. Voss MA, Ganesan R, Ludeman L, et al. Should grade 3 endometrioid endometrial carcinoma be considered a type 2 cancer: a clinical and pathological evaluation. Gynecol Oncol
Grade 3 endometrioid endometrial carcinomas fit imperfectly into the original classification scheme of type I and type II cancers originally developed by Bokhman. In this article, the authors examine 156 consecutive patients with grade 3 endometrioid, clear cell, uterine serous, or carcinosarcoma/sarcoma of the uterus. Grade 3 endometrioid tumors shared equivalent disease-specific and overall survival with clear cell and uterine serous histologies, as well as immunohistochemical features. The authors highlight important considerations for the classification of endometrial cancers.
8. Goff BA, Kato D, Schmidt RA, et al. Uterine papillary serous carcinoma: pattern of metastatic spread. Gynecol Oncol
9. Mutch DG. The more things change, the more they stay the same. Gynecol Oncol
10. Wilson TO, Podratz KC, Gaffey TA, et al. Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma. Am J Obstet Gynecol
11. Emons G, Fleckenstein G, Hinney B, et al. Hormonal interactions in endometrial cancer. Endocr Relat Cancer
12. Hameed K, Morgan DA. Papillary adenocarcinoma of endometrium with psammoma bodies: histology and fine structure. Cancer
13. Hamilton CA, Cheung MK, Osann K, et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer
14. Dizon DS. Treatment options for advanced endometrial carcinoma. Gynecol Oncol
15. Schwartz PE. The management of serous papillary uterine cancer. Curr Opin Oncol
16. Thomas M, Mariani A, Wright JD. Surgical management and adjuvant therapy for patients with uterine clear cell carcinoma: a multi-institutional review. Gynecol Oncol
17. Goff BA. Uterine papillary serous carcinoma: what have we learned over the past quarter century? Gynecol Oncol
18. Yoon J, Yoo S, Kim WY, et al. Para-aortic lymphadenectomy in the management of preoperative grade 1 endometrial cancer confined to the uterine corpus. Annals Surg Onc
19▪▪. Walker JL, Piedmonte MR, Spirtos NM, et al. Recurrence and survival after random assignment to laparoscopy versus laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group LAP2 Study. J Clin Oncol
In many centers, minimally invasive procedures have become the standard of care for management of early-stage endometrial cancer. Although safety has been demonstrated in retrospective studies, the authors present phase III data to support a laparoscopic staging approach. The study population includes a representative number of USCs.
20. National Comprehensive Cancer Network Practice Guidelines. Uterine Neoplasms, v 3.2012. http://http://www.nccn.org
/professionals/physician_gls/pdf/uterine.pdf. [Accessed 15 September 2012]
21. Sovak MA, Dupont J, Hensley ML, et al. Paclitaxel and carboplatin in the adjuvant treatment of patients with high-risk stage III and IV endometrial cancer: a retrospective study. Gynecol Oncol
22. Vaidya AP, Littell R, Krasner C, et al. Treatment of uterine papillary serous carcinoma with platinum-based chemotherapy and paclitaxel. Int J Gynecol Cancer
2006; 16 (suppl 1):267–272.
23. Miller D., Filiaci V., Fleming G., et al.
, Randomized phase, III, noninferiority trial of first-line chemotherapy for metastatic or recurrent endometrial carcinoma: a Gynecologic Oncology Group study [late-breaking abstract]. Annual Meeting of the Society of Gynecologic Oncologists 2012, Mar 24-7, 2012, Austin, TX.
24. Gallion HH, Brunetto VL, Cibull M, et al. Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol
25. Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol
26. Fleming GF, Filiaci VL, Bentley RC, et al. Phase III randomized trial of doxorubicin and cisplatin versus doxorubicin and 24-h paclitaxel with filgastrim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol
27. Thigpen JT, Brady MF, Homesley HD, et al.
Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2004; 22:3902–3908.
28. Homesley HD, Filiaci V, Gibbons SK, et al. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume-directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: a Gynecologic Oncology Group study. Gynecol Oncol
29. Viswanathan AN, Macklin EA, Berkowitz R, et al. The importance of chemotherapy and radiation in uterine papillary serous carcinoma. Gynecol Oncol
30. Sutton G, Axelrod JH, Bundy BN, et al. Adjuvant whole-abdominal irradiation in clinical stage I and II papillary serous or clear cell carcinoma of the endometrium: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol
31. Fader AN, Drake RD, O’Malley DM, et al. Platinum/taxane-based chemotherapy with or without radiotherapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma. Cancer
32. Fader AN, Nagel C, Axtell AE, et al. Stage II uterine papillary serous carcinoma: carboplatin/paclitaxel chemotherapy improves recurrence and survival outcomes. Gyneol Oncol
33. Kelly MG, O’Malley DM, Hui P, et al. Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy. Gynecol Oncol
34. Mahdavi A, Tajalli TR, Dalmar A, et al. Role of adjuvant chemotherapy in patients with early stage uterine papillary serous cancer. Int J Gynecol Cancer
35▪. Kiess AP, Damast S, Makker V, et al.
Five-year outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-II papillary serous endometrial cancer. Gynecol Oncol 2012; 127:321–325.
The authors present single-institution retrospective data across 41 patients to support a multimodal approach to treatment of early-stage USC in patients treated from 2000–2009.
36. De Leon M, Lu L, Hui P, et al. Prognostic factors and treatment-related outcomes in patients with uterine serous cancer [abstract]. J Clin Oncol
37. Kelly MG, O’Malley D, Hui P, et al. Patients with uterine papillary serous cancers may benefit from adjuvant platinum-based chemoradiation. Gynecol Oncol
38. Alektiar KM, Makker V, Abu-Rustum NR, et al. Concurrent carboplatin/paclitaxel and intravaginal radiation in surgical stage I–II serous endometrial cancer. Gynecol Oncol
39▪. Einstein MH, Frimer M, Kuo DY, et al. Phase II trial of adjuvant pelvic radiation ‘sandwiched’ between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma. Gynecol Oncol
‘Sandwich’ therapy involves radiation therapy interposed between several cycles of chemotherapy in an effort to reduce toxicities of each modality. The authors present the phase II experience with sandwich techniques across 81 patients with USC at a single institution.
40. Giuntoli RL 2nd, Gerardi MA, Yemelyanova AV, et al. Stage I noninvasive and minimally invasive uterins serous carcinoma: comprehensive staging associated with improved survival. Int J Gynecol Cancer
41. Boruta DM 2nd, Gehrig PA, Fader AN, et al. Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review. Gynecol Oncol
42. NIH Clinical Trials. Pelvic radiation therapy or vaginal implant radiation therapy, paclitaxel, and carboplatin in treating patients with high-risk stage I or stage II endometrial cancer. http://clinicaltrials.gov/show/NCT00807768. [Accessed 15 September 2012]
43. Sherman ME. Theories of endometrial carcinogenesis. Mod Pathol
44. Hecht JL, Mutter GL. Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol
45. Rosenberg P, Wingren S, Simonsen E, et al. Flow cytometric measurements of DNA index and S-phase on paraffin-embedded early stage endometrial cancer: an important prognostic indicator. Gynecol Oncol
46. Pradhan M, Abeler VM, Danielsen HE, et al. Image cytometry DNA ploidy correlates with histological subtypes in endometrial carcinomas. Mod Pathol
47. Santin AD, Bellone S, Van Stedum S, et al. Amplification of c-erbB2
oncogene: a major prognostic indicator in uterine serous papillary carcinoma. Cancer
48. Slomovitz BM, Broaddus RR, Burke TW. HER2/neu
overexpression and amplification in uterine papillary serous carcinoma. J Clin Oncol
49. Grushko TA, Filiaci VL, Mundt AJ, et al. An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol
50. Díaz-Montes TP, Ji H, Smith Sehdev AE, et al. Clinical significance of Her-2/neu overexpression in uterine serous carcinoma. Gynecol Oncol
51▪▪. Kuhn E, Wu R-C, Wu G, et al.
Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Ca Instit 2012; 104:1503–1513.
This study implicates somatic mutations in p53, cyclin E-FBXW7, and PI3K pathways in the pathogenesis of USCs using one of the first applications of whole-exome sequencing and DNA copy number analyses for this histology. Discovery of novel somatic aberrations has enormous potential to uncover new therapies for USC.
52. Konecny GE, Agarwal R, Keeney GA, et al. Claudin-3 and claudin-4 expression in serous papillary, clear-cell, and endometrioid endometrial cancer. Gynecol Oncol
53. Santin AD, Sellone S, Marizzoni M, et al. Overexpression of claudin-3 and claudin-4 receptors in uterine serous papillary carcinoma: novel targets for type-specific therapy using Clostridium perfringens
enterotoxin (CPE). Cancer
54. Llaurado M, Ruiz A, Majem B, et al.
Molecular bases of endometrial cancer: new roles for actors in the diagnosis and therapy of the disease. Mol Cell Endocrinol 2011; 358:244–255.
55. Goodsell D. The molecular perspective: p53 tumor suppressor. Oncologist
56. Attias-Geva Z, Bentov H, Kidron D, et al. p53 regulates insulin-like growth factor-1 receptor gene expression in uterine serous carcinoma and predicts responsiveness toan insulin-like growth-factor-1 receptor-directed targeted therapy. Eur J Cancer
57. Shih leM, Panuganti PK, Kuo KT, et al. Somatic mutations of PPP2R1A in ovarian and uterine carcinomas. Am J Pathol
58. Nagendra DC, Burke J, Maxwell GL, et al.
PPP2R1A mutations are common in the serous type of endometrial cancer. Mol Carcinogenesis 2011; 51:826–831.
59. Welcker M, Clurman B. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer
60. Mao J-H, Kim I-J, Wu D, et al. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science
61. Cassia R, Moreno-Bueno G, Rodriguez-Perales S, et al. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. J Pathol
62. Paradiso A, Mangia A, Tommasi S. Phosphatidylinositol 3-kinase in breast cancer: where from here? Clin Cancer Res
63. Hayes MP, Douglas W, Ellenson LH. Molecular alterations of EGFR and PIK3CA in uterine serous carcinoma. Gynecol Oncol
64. Oza AM, Elit L, Biagi J, et al.
Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer-NCICIND 160 [abstract]. J Clin Oncol 2006; 24 (18S):3003.
65. Oza AM, Elit L, Provencher D, et al.
A phase II study of temsirolimus (CCI-779) in patients with metastatic and/or locally advanced recurrent endometrial cancer previously treated with chemotherapy: NCIC GTC INC 160b [abstract]. J Clin Oncol 2008; 29:3278–3285.
66. Fleming GF, Filiaci VL, Hanjani P, et al.
Hormone therapy plus temsirolimus for endometrial carcinoma (EC): a Gyencologic Oncology Group trial (#248) [abstract]. J Clin Oncol 2011; 29S:5014.
67. Alvarez E, Brady W, Walker J, et al.
Phase II trial of combination bevacizumab ad temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study [abstract]. Gynecol Oncol 2012; 125 (S1):517.
68. Slomovitz BM, Brown J, Johnston TA, et al.
A phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma [abstract]. J Clin Oncol 2011; 29S:5012.
69. Mackay H, Welch S, Tsao MS, et al.
Phase II study of oral ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192 [abstract]. J Clin Oncol 2011; 29S:5013.
70. Oza AM, Poveda A, Clamp AR, et al.
A randomized phase II trial of ridaforolimus compared with progestin or chemotherapy in female adult patients with advanced endometrial carcinoma [abstract]. J Clin Oncol 2011; 29S:5009.
71. NIH Clinical Trials. A Phase II study to evaluate the efficacy of TKI258 for the treatment of patients with FGFR2 mutated or wild-type advanced and/or metastatic endometrial cancer. http://clinicaltrials.gov/ct2/show/NCT01379534. [Accessed 15 September 2012]
72▪. Colas E, Pedrola N, Devis L, et al.
The EMT signaling pathways in endometrial carcinoma. Clin Transl Oncol 2012; 14:715–720.
The authors provide a concise review of progress towards understanding the mechanisms underlying epithelial-to-mesenchymal transition specific to endometrial cancer.
73. Gehrig PA, Groben PA, Fowler W, et al. Noninvasive papillary serous carcinoma of the endometrium. Obstet Gynecol
74. Holcomb K, Delatorre R, Bader Pedemonte B, et al. E-Cadherin expression in endometrioid, papillary serous, and clear cell carcinoma of the endometrium. Obstet Gynecol
75. van der Horst PH, Wang Y, Vandenput I, et al. Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer. PLoS One
76. Dong P, Kaneuchi M, Watari H, et al. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer
77. Castilla MA, Moreno-Bueno G, Romero-Pérez L, et al. Micro-RNA signatures in the epithelial-to-mesenchymal transition in endometrial carcinoma. J Pathol
78. Thault S, Valcourt U, Petersen M, et al. Transforming growth factor-β employs HMGA2 to elicit epithelial–mesenchymal transition. J Cell Biol
79. McCluggage WG, Connolly LE, McBride HA, et al. HMGA2 is commonly expressed in uterine serous carcinomas and is a useful adjunct to diagnosis. Histopathol
80. Lavie O, Ben-Arie A, Segev Y, et al. BRCA germline mutations in women with uterine serous carcinoma-still a debate. Int J Gynecol Cancer
81. Hornreich G, Beller U, Lavie O, et al. Is uterine serous papillary carcinoma a BRCA1-related disease? Case report and review of the literature. Gynecol Oncol
82. Biron-Shental T, Drucker L, Altaras M, et al. High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma. Eur J Surg Oncol
83. Goshen R, Chu W, Elit W, et al. Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast–ovarian cancer syndrome? Gynecol Oncol
84. Levine D, Lin O, Barakat R, et al. Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol
85▪. Pennington KT, Walsh T, Lee M, et al.
BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer 2012. doi://10.1002/cncr.27720. [Epub ahead of print]
USCs have not been clearly linked to any hereditary syndromes. Using targeted capture and massively parallel genomic sequencing to examine uterine serous cancer from 151 participants, the authors find that the germline rate of BRCA1 mutation exceeds that of a nonfounder population and propose that patients diagnosed with this histology and breast cancer undergo BRCA testing.
86. Ford D, Easton DF, Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet
87. Amichay K, Kidron D, Attias-Geva Z, et al. BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor I receptor (IGF-IR) gene expression in USC cell lines. Int J Gynecol Ca
88. Desrichard A, Bidet Yannick, Uhrhammer N, et al. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Ca Res
89. Growden WB, Rauh-Hain J, Cordon A, et al. Prognostic determinants in patients with stage I uterine papillary serous carcinoma. Int J Gynecol Ca
90. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst
91. Hampbel H, Frankel W, Panescu J, et al. Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among endometrial cancer patients. Cancer Res
92. Meyer LA, Broaddus RR, Lu KH. Endometrial cancer and Lynch syndrome: clinical and pathologic considerations. Cancer Control
93. Goodfellow PJ, Buttin BM, Herzog TJ, et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in unselected series of endometrial cancers. Proc Natl Acad Sci U S A
94▪. Dewdney SB, Kizer NT, Andaya AA, et al. Uterine serous carcinoma: increased familial risk for Lynch-associated malignancies. Cancer Prev Res
In this study, the authors provide a thorough investigation of familial risk for Lynch-associated cancers among patients with USC using an institutional cohort with validation across a multiinstitutional database.
95. El-Sawhi K, Bellone S, Cocco E, et al. Overexpression of EpCAM in uterine serous papillary carcinoma: implications for EpCAM-specific immunotherapy with human monoclonal antibody adecatumumab (MT201). Mol Cancer Ther
96▪. Varughese J, Cocco E, Bellone S, et al. Uterine serous papillary carcinomas overexpress human trophoblast cell surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. Cancer
Trop-2 overexpression has been found to correlate with invasive behavior and poor prognosis in various types of human carcinomas. hRS7 is a humanized IgG1 monoclonal antibody developed against Trop-2. The authors demonstrate overexpression of Trop-2 in primary USC cell lines and show that these cell lines are highly sensitivity to hRS7-mediated cytotoxicity in vitro. The authors subsequently suggest that hRS7 may represent a novel therapeutic agent for USPC refractory to standard treatment modalities.
97. Bellone M, Cocco E, Varughese JV, et al. Expression of α-V integrins in uterine serous papillary carcinomas: implications for immunotherapy with intetumumab (CTNO-95), a fully human antagonist anti α-V integrin antibody. Int J Gynecol Cancer
98▪. Bellone S, Roque D, Cocco E, et al. Down-regulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitizes uterine serous carcinoma overexpressing HER2/neu to complement and antibody-dependent-cell-cytotoxicity in vitro
: implications for trastuzumab-based immunotherapy. Br J Cancer
Despite strong preclinical data, immunotherapies such a trastuzumab often fail in the clinical realm. In this study, the authors examine the role of membrane complement regulatory proteins (mCRPs) in reducing cellular and complement-mediated cellular cytotoxicity in response to cancer immunotherapies. USC cell lines were found to overexpress high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitized USC to both complement-mediated and antibody-dependent cellular cytotoxicity, and therefore the authors suggest mCRP modulation as an approach to enhancing immunotherapy with trastuzumab and other antibodies.
99. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nature Rev Mol Cell Biol
100. Berchuck A, Rodriguez G, Kinney RB, et al. Overexpression of HER2/Neu in endometrial cancer is associated with advanced stage disease. Am J Obstet Gynecol
101. Arnould L, Gelly M, Penault-Llorca F, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer
102. Piccart-Gebhart M, Proctor M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med
103. Genentech, Inc. Herceptin development timeline. http://http://www.gene.com
/gene/products/information/oncology/herceptin/timeline.html. [Accessed 15 September 2012]
104. Santin AD, Bellone S, Roman JJ, et al. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/Neu. Int J Gynaecol Obstet
105. Jewell E, Secord AA, Brotherton T, et al. Use of trastuzumab in the treatment of metastatic endometrial cancer. Int J Gynecol Cancer
106. Villella JA, Cohen S, Smith DH, et al. HER2/Neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. Int J Gynecol Cancer
107. Fleming GF, Sill MW, Darcy KM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: A Gynecologic Oncology Group study. J Clin Oncol
108. Santin AD. Letter to the Editor RE: Phase II trial of trastuzumab in women with advanced or recurrent HER2-positive endometrial carcinoma: A Gynecologic Oncology Group Study. Gynecol Oncol
109▪. Todeschini P, Cocco E, Bellone S, et al. HER2/Neu extracellular domain shedding in uterine serous carcinomas: implications for immunotherapy with trastuzumab. Br J Cancer
Clinical trials of trastuzumab in endometrial cancer have been surprisingly disappointing. The authors examine the extent of Her2/Neu extracellular domain shedding in USC cell lines and its effect on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity. They conclude that high levels of Her2/neu extracellular domain shedding in patients with USC may potentially neutralize its therapeutic effect in vivo.
110. NIH Clinical Trials. Evaluation of carboplatin/paclitaxel with and without trastuzumab (Herceptin) in uterine serous cancer. http://clinicaltrials.gov/ct2/show/NCT01367002. [Accessed 15 September 2012]
111. Sitohy B, Nagy JA, Dvorak HF. Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res
112. Morotti M, Menada MV, Venturini PL, et al. Bevacizumab in endometrial cancer treatment. Expert Opin Biol Ther
113. Kamat AA, Merritt WM, Coffey D, et al. Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res
114. Hirai M, Nakagawara A, Oosaki T, et al. Expression of vascular endothelial growth factors (VEGF-A/VEGF-1and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma. Gyneol Oncol
115. Mazurek A, Pierzyński P, Kuć P, et al. Evaluation of angiogenesis, p-53 tissue protein expression, and serum VEGF in patients with endometrial cancer. Neoplasma
116. Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res 2005; 65:671–680.
117. Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group Study. J Clin Oncol
118. NIH Clinical Trials. Evaluation of carboplatin /paclitaxel /bevacizumab in the treatment of advanced stage endometrial carcinoma. http://clinicaltrials.gov/ct2/show/NCT00513786. [Accessed 15 September 2012]
119. NIH Clinical Trials. Paclitaxel, carboplatin, and bevacizumab or paclitaxel, carboplatin, and temsirolimus or ixabepilone, carboplatin, bevacizumab in treating patients with stage III, stage IV, or recurrent endometrial cancer. http://clinicaltrials.gov/ct2/show/NCT00977574. [Accessed 15 September 2012]
120. NIH Clinical Trials. VEGF Trap in treating patients with recurrent or persistent endometrial cancer. http://clinicaltrials.gov/ct2/show/NCT00462826. [Accessed 15 September 2012]
121. McMeekin SD, Filiaci VL, Thigpen JT, et al. The relationship between histology and outcome in advanced and recurrent endometrial cancer patients participating in first-line chemotherapy trials: a Gynecologic Oncology Group study. Gynecol Oncol
122. Kavallaris M, Kuo D, Burkhart CA, et al. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific β-tubulin isotypes. J Clin Invest
123. Magnani M, Ortuso F, Soro S, et al. The βI/βIII-tubulin isoforms and their complexes with antimitotic agents: docking and molecular dynamics studies. FEBS J
124. Ferlini C, Raspaglio G, Cicchillitti L, et al. Looking at drug resistance mechanisms for microtubule interacting drugs: does TUBB3 work? Cur Cancer Drug Targets
125. Ferrandina G, Zannoni GF, Martinelli E, et al. Class III β-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients. Clin Cancer Res
126. Seve P, Isaac S, Trédan O, et al. Expression of class III β-Tubulin is predictive of patient outcome in patients with nonsmall cell lung cancer receiving vinorelbine-based chemotherapy. Clin Cancer Res
127. Paradiso A, Mangia A, Chiriatti A, et al. Biomarkers predictive for clinical efficacy of taxol-based chemotherapy in advanced breast cancer. Ann Oncol
2005; 16 (Suppl 4):14–19.
128. Bollag DM, McQueney PA, Zhu J, et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res
129. Paik D, Cocco E, Bellone S, et al. Higher sensitivity to patupilone versus paclitaxel chemotherapy in primary uterine serous papillary carcinoma cell lines with high versus low HER-2/neu expression in vitro
. Gynecol Oncol
130. Bristol-Meyers Squibb. Ixempra prescribing information. http://http://www.accessdata.fda.gov
/drugsatfda_docs/label/2009/022065s001lbl.pdf. [Accessed 15 September 2012]
131. Dizon DS, Blessing JA, McMeekin DS, et al. Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: Gynecologic Oncology Group Trial 129-P. J Clin Oncol