Recent Advances in Endometrial Cancer

Introduction

Endometrial carcinoma is the most common gynecologic malignancy in the United States, with approximately 60,050 newly diagnosed cases and 10,470 deaths expected in 2016. Additionally, the incidence of endometrial carcinoma is estimated to increase by 1–2% yearly¹. Most women are diagnosed at an early stage and have relatively good survival rates; however, women who are diagnosed with advanced-stage or recurrent disease have a poor prognosis². Thus, novel therapies are being investigated to combat the increasing disease burden of endometrial carcinoma.

Treatment modalities in endometrial cancer vary depending on the grade and the stage of the disease. Currently, the treatment and staging of endometrial carcinoma is primarily surgical, with hysterectomy and bilateral salpingo-oophorectomy being the standard of care. The issue of lymphadenectomy remains under debate, but in the U.S. it is generally performed based on criteria such as grade, depth of invasion, and tumor size. Sentinel lymph node (SLN) sampling has been advocated as an alternative to standard hysterectomy with complete lymphadenectomy. Following surgical treatment, patients may receive adjuvant radiation, chemotherapy, or both, depending on the stage and other pathologic features of their disease.

We will review the available literature regarding the current understanding of endometrial cancer, including genetic background, molecular targeting, surgical management, and adjuvant treatment.

Genetic basis of endometrial cancer

Among adenocarcinomas of the endometrium, two distinct histologic categories have been described – type 1 and type 2³. Type 1 endometrial carcinomas account for 70–80% of new cases³. These cancers are of endometrioid histology and lower grade. Type 1 cancers are estrogen mediated with high rates of K-ras and PTEN loss or mutation; there are also defects in mismatch repair (MMR) genes leading to microsatellite instability (MSI)^4–8. Women with these cancers are often obese with evidence of endogenous estrogen excess. Type 2 endometrial carcinomas, on the other hand, occur in older women who traditionally were thought to be leaner, though these patients are also of increasing BMI. These cancers show aneuploidy, p53 mutations, and overexpression of HER-2/neu^9–15. Type 2 endometrial carcinomas consist of higher-grade adenocarcinomas and the non-endometrioid histologies.

Though most endometrial cancer is sporadic, a significant proportion of endometrial cancers are due to inherited genetic mutations. Specifically, Lynch syndrome accounts for 2–5% of all endometrial carcinomas^16,17. In women with Lynch syndrome, their risk of endometrial cancer approaches 70%^18,19. Lynch syndrome is caused by germline mutation in one of many DNA MMR genes: MLH1, MSH2, MSH6, and PMS2^20,21. MMR proteins are responsible for maintaining genomic integrity by correcting base substitution mismatches and insertion-deletion mismatches resulting from DNA replication errors. MMR mutations cause alterations within microsatellite regions, resulting in MSI. The MSI may lead to downstream consequences with genetic expression, resulting in aberrant cell growth or cell death²².

Testing for Lynch syndrome generally begins with testing the tumor specimen. Initially, the tumor is tested using immunohistochemistry (IHC) to evaluate MMR protein levels. If the IHC suggests the possibility of an MMR gene defect, the tumor is tested for MSI through polymerase chain reaction^23,24. Depending on the levels of MSI detected, detection of MMR protein loss, germline mutation testing, and specific methylation status of genetic promoter regions, patients can be found to have Lynch syndrome mutations. While there is no consensus on the sequence of IHC or MSI testing and both can be concurrently examined, our practice is to order IHC testing followed by MSI testing based on both the results of IHC and clinical suspicion.

Because of the potential lifetime risk of developing a subsequent malignancy, the Society of Gynecologic Oncology advised that all women with endometrial cancer be assessed for Lynch syndrome. Additionally, women with a family history of endometrial cancer or colon cancer should pursue genetic counseling and testing¹⁶.

Data to date have been limited in associating endometrial cancer with hereditary breast and ovarian cancer syndromes. Previous literature has been conflicting on the association between BRCA mutations and serous endometrial carcinoma^25,26. Recent evidence shows a potential link between BRCA1 and the subsequent development of serous endometrial carcinoma²⁷. Further evidence is still needed to establish a firm genetic link. However, there should be a discussion of including prophylactic hysterectomy at the time of risk reduction bilateral salpingo-oophorectomy in BRCA1-affected women.

Novel surgical treatment

Surgery remains a mainstay of treatment for most women with endometrial cancer. Since 1988, the International Federation of Gynecology and Obstetrics (FIGO) requires that staging of endometrial cancer occur surgically. Surgery includes hysterectomy with possible removal of fallopian tubes and ovaries bilaterally and consideration of lymph node assessment. There are many nuances involved in the surgical and adjuvant management of patients with endometrial cancer; both the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncology (SGO) have suggested that patients would benefit most from their surgery being performed by surgeons with training in gynecologic oncology²⁸.

The requirement for surgical staging reflects the increasing data on the prognostic significance of lymph node status and the implications for treatment in node-positive cancers; however, controversy exists on the role of lymphadenectomy in endometrial carcinoma. Retrospective analyses reveal a theoretical benefit to debulking clinically enlarged lymph node metastasis and a benefit to resection of microscopic metastasis in high-risk endometrial cancers^29–35. Randomized trials show no therapeutic benefit to lymphadenectomy, though these trials comprise predominantly low-risk endometrial cancer histologies^36,37. The risk of lymphedema and increased surgical complications form the basis for the argument against lymphadenectomy³⁸. Additional evidence is necessary in order to reach consensus regarding the benefits of lymphadenectomy compared to the risks of increased surgical procedures.

The SLN technique attempts to strike a balance between the risks and benefits of surgical lymph node evaluation. The SLN represents the first node to drain a tumor site and often is the first site of occult malignancy. If an SLN can be accurately identified and there is a high amount of certainty in detecting metastatic disease within the SLN, this technique obviates the need for a complete lymphadenectomy. Thus, the viability of this technique depends on the ability of dye or tracer to map from the tumor to the SLN. The complicating factor of the SLN technique is that the lymphatic drainage of the endometrium is complex, unlike in breast or vulvar cancer.

Because of the location of the disease, endometrial tumors are less readily accessible for peritumoral injection. Several techniques have been described for injecting dye either through the cervix, via hysteroscopy, or through fundal injections. Cervical injections have been the easiest to perform and have been found to have SLN detection rates that are comparable to other described methods^39,40.

Various dyes and tracers have been used in endometrial cancer in an attempt to improve SLN detection, each with their own unique risks and benefits. Isosulfan blue is a dye that works by staining the lymph nodes and lymph vessels, and it is one of the most frequently used methods for SLN detection – the colorimetric method. Cervical injection of this dye requires no specialized equipment; however, visualization of dye in obese patients is inferior to visualization of dye in non-obese patients. Technetium sulfur colloid (Tc⁹⁹) is a radioactive tracer able to be detected by gamma probes. When using technetium, preoperative lymphoscintigraphy and a handheld gamma probe can be used to map lymphatic drainage. This technique also has its own limitations, including additional operative time, coordination of procedures, and evidence of poor correlation between lymphoscintigraphy and surgical SLN mapping⁴¹. Lastly, indocyanine green (ICG) has been reported to have excellent signal uptake while allowing for real-time visualization of lymphatic drainage using near-infrared fluorescence imaging. Bilateral detection rates with ICG are comparable or better than either Tc⁹⁹ or blue dye⁴².

The crux of the SLN technique lies within its diagnostic accuracy. In a prospective multicenter study, patients with early stage disease underwent SLN assessment with a combination of dyes followed by pelvic-node dissection. The overall predictive value of the SLN technique was found to be 97%. The patients who did not have positive lymph nodes detected had type 2 endometrial cancer⁴³. The false negative results of this trial underscore a potential limitation surrounding SLN techniques.

In high-risk (type 2) endometrial cancers, the application of the SLN technique remains controversial. Patients with high-risk endometrial cancer are at a higher risk for unsuccessful mapping and isolated positive para-aortic lymph nodes. Retrospective series have suggested similar outcomes in women with high-grade cancers undergoing the SLN technique or a complete lymphadenectomy; however, data from prospective trials remain lacking^44,45.

If the SLN technique is to be used, it is important to adhere to the National Comprehensive Cancer Network (NCCN) guidelines. According to the guidelines, lymph nodes that are mapped or look suspicious should be removed. If there is no mapping on a hemi-pelvis, the NCCN guidelines suggest performing a side-specific lymphadenectomy. The necessity for a para-aortic dissection is left to the discretion of the surgeon.

Molecular targeted therapies

Our understanding of endometrial cancer has shifted dramatically. Historically, endometrial cancer has been designated as type 1 and type 2, each type being associated with its own genetic aberrations. As we discussed previously, type 1 endometrial cancers have deletions in K-ras, PTEN, or MMR^{4–8,46–48}. Conversely, type 2 endometrial cancers show aneuploidy, p53 mutations, and overexpression of Her-2/neu^9–15. Using integrated genomics and epigenomic, transcriptomic, and proteomic techniques, The Cancer Genome Atlas (TCGA) has recently provided compelling evidence that endometrial cancers can be classified into four categories: polymerase epsilon (POLƐ) ultramutated, MSI hypermutated, copy-number low, and copy-number high, serous-like⁴⁹.

Our understanding of the genetic aberrations of endometrial cancers may represent a better tool to classify and guide future therapies towards more biologically aggressive diseases. Common targets for therapeutics involve drugs that affect apoptosis, signal transduction, epigenetic modification, cell cycle progression, protein folding and degradation, hormone receptor activation, and angiogenesis. We will be focusing on the uses of anti-angiogenic agents, epidermal growth factor receptor (EGFR) inhibitors, HER2/neu antibodies, and phosphoinositide 3-kinase (PI3K)-PTEN-AKT-mammalian target of rapamycin (mTOR) pathway inhibitors in endometrial cancer (see Table 1). Further targets, novel therapies, and genome-guided clinical trials may arise as we gain a deeper understanding of the molecular pathways and genetic aberrations in endometrial cancer.

Current trials

The landscape of our understanding of endometrial cancer continues to change. As such, the NRG Oncology has ongoing trials and there are continued trials from the Gynecology Oncology Group (GOG) (see Table 2).

Conclusion

Endometrial cancer remains the most common gynecologic malignancy in the United States. Improving our knowledge of the genetic aberrations and molecular derangements of this heterogeneous disease will allow for novel therapeutic options to be identified. Furthermore, improved surgical techniques allow for reducing morbidity associated with surgical intervention. The goal of treatment for this disease remains to maximize survival outcomes while minimizing all treatment-related morbidities; the rapid advancements in our knowledge gap will continue to allow us to achieve this goal. Moreover, focusing on the preventative measures available for endometrial cancer – like attempting to decrease the epidemic of obesity – may have larger implications on combating this disease.