Endometrial Cancer – Molecular therapies

Endometrial Cancer or Uterine Cancer

1. What every clinician should know – Are you sure your patient has endometrial cancer? What should you expect to find?

Endometrial cancer is the fourth most common cancer among women in the United States and has been increasing in frequency because of an aging female population and changes in dietary and hormonal factors, with obesity as a major culprit. Interestingly, despite the discontinuation of the use of unopposed estrogen and the success of the office endometrial biopsy, the overall death rate from endometrial cancer has continued to steadily rise over the past 10 years.

Women with early-stage disease (FIGO stage I and II) and endometrioid histology (type I) have a relatively good prognosis with surgery alone or surgery plus radiation. However, 10% to 15% of patients are diagnosed with FIGO stage III disease (tumor extension outside the uterus but limited to the true pelvis) at the time of surgery, and have an estimated 5-year survival rate of 40% to 50%. Lastly, the remaining 10% to 15% of patients are diagnosed with FIGO Stage IV disease (tumor extension beyond the true pelvis) and have a very poor 5-year survival rate of 15% to 20%.

Those patients with advanced stage III or IV disease are unlikely to be cured by surgery, conventional chemotherapy, radiation, or a combination of these modalities. In addition, 20% of women will be diagnosed with an endometrial tumor of either serous or clear cell histology (type II) which behave more aggressively. Even in the setting of early-stage disease (FIGO stage I), women with type II cancers have a 5-year survival rate of 60% as compared with an 85% to 90% survival rate in those with Stage I endometrioid adenocarcinomas.

African American women suffer a much higher mortality (two-fold higher) from endometrial cancer than Caucasian women, and it is unclear whether this is the result of delayed treatment, lack of access to care, greater rates of diabetes and obesity and/or a higher likelihood of cancer with more serious prognostic characteristics such as the more lethal type II histologies. The racial distribution for type I and II endometrial cancers differs in that black women are more likely than white women to have type II disease.

A dualistic model for the development and progression of endometrial cancer exists that divides these tumors into type I and type II based on biologic, molecular, and clinical parameters. Type I or those tumors of endometrioid histology comprise 80% of cases and are thought to arise from persistent unopposed estrogen stimulation. Women who develop these tumors are typically perimenopausal and often have risk factors such as obesity, hyperlipidemia, nulliparity, diabetes mellitus and insulin resistance, polycystic ovarian syndrome (PCOS), hypertension, and late-onset menopause.

Type I tumors are preceded by an identifiable premalignant state of hyperplasia and ultimately, atypical hyperplasia, and are generally estrogen receptor (ER) and progesterone receptor (PR) positive. Genetic alterations associated with these tumors include microsatellite instability (20% to 40%), PTEN deletions or mutations (50% to 80%), PIK3CA mutations (30%) and amplification (2% to 14%), activation of K-ras (15% to 30%), and gain of function mutations in b-catenin (25% to 40%).

In contrast, type II or those tumors of atypical histologies, such as serous and clear cell carcinomas, have no association with excess endogenous or exogenous estrogen. These tumors generally occur in postmenopausal women in the setting of an atrophic endometrium. Other potential risk factors for type II endometrial cancers include obesity and diabetes. A personal history of breast cancer and being a BRCA1 mutation carrier may also be risk factors for developing serous histology endometrial tumors. Type II tumors behave much more aggressively and show a propensity for deep invasion, lymphovascular permeation, and distant spread. ER and PR are generally negative or weakly positive.

A precursor lesion is not as well defined but an in situ form of type II cancers have been described and is referred to as endometrial intraepithelial carcinoma (EIC). The molecular genetic profile for these tumors is distinctly different than type I tumors and is associated with aneuploidy, p53 mutations (80% to 90%), overexpression of HER-2/neu (40% to 80%), p16 inactivation (40%), PIK3CA mutations (20%) and amplification (46%), and E-cadherin alterations (60% to 90%).

Recent genomic characterization of endometrial cancers through The Cancer Genome Atlas (TCGA) project classified endometrial cancer into four subtypes as opposed to simply type I and type II disease: POLE ultramutated (POLE), microsatellite instability hypermutated (MSI), copy-number low (CNL) and copy-number high (CNH). The POLE, MSI and CNL clusters were composed mostly of endometrioid histology tumors, while most serous histology tumors were found in the CNH cluster. Women with POLE tumors had the best progression free survival (PFS), while women with CNH tumors had the worst PFS. This study noted significant overlap in the genetic alterations found in type I and type II endometrial cancers, suggestive of greater genetic heterogeneity in endometrial cancer than was previously appreciated.

The classic symptom of endometrial cancer is abnormal uterine bleeding, which is seen in 90% of cases. For postmenopausal women with abnormal uterine bleeding, 5% to 20% will be diagnosed with an endometrial cancer. Thus, even one drop of blood or even persistent abnormal vaginal discharge in a postmenopausal woman warrants further diagnostic testing.

Premenopausal and perimenopausal women with abnormal uterine bleeding may also need further workup if the following risk factors are present, including (1) obesity, (2) chronic anovulation, (3) unopposed estrogen therapy, (4) tamoxifen use, (5) prior history of endometrial hyperplasia, (6) diabetes mellitus, and (7) family or personal history of ovarian, breast, colon, or endometrial cancer. A minority of asymptomatic women with endometrial cancer may also be found during cervical cancer screening, via the workup of atypical glandular cells of uncertain significance (AGUS) on a pap smear or via the presence of atypical endometrial cells on pap testing.

Screening for endometrial cancer is not advocated in the general population. Women considered at higher risk for developing this disease (i.e., obese, chronic ovulation, diabetes, tamoxifen use) should be counseled about their increased risk, as well as symptoms that should be reported to their health care providers. Of special note, obese women should be encouraged to lose weight as a potential risk reducing strategy. Women who are on tamoxifen have a three- to seven-fold increased risk of endometrial cancer and possibly uterine sarcomas. Despite this, routine screening has not proven to be useful; and thus, women on tamoxifen should only undergo endometrial biopsy in the setting of abnormal vaginal bleeding.

For women with hereditary nonpolyposis colorectal cancer syndrome (HNPCC), the lifetime risk of developing endometrial cancer is 27% to 71%, which is higher than their risk of colon cancer. Endometrial cancer is often the first manifestation of malignancy in women with HNPCC, occurring at a younger age (46 to 54 years old) than sporadic endometrial cancer. Thus, the recommendation for women with HNPCC is to start annual endometrial cancer screening by the age of 30 to 35 years old and then a hysterectomy and bilateral salpingo-oophorectomy when childbearing is complete. These women also have a 3% to 14% increased risk of ovarian cancer; and thus should undergo screening via pelvic examination, CA-125, and transvaginal ultrasound every 6 to 12 months, starting at the age of 30 to 35 years old.

2. Diagnosis and differential diagnosis

The first step in diagnosing endometrial cancer is sampling of the endometrium. This is usually obtained by office endometrial biopsy using a standard Pipelle sampling device. The benefits to an office endometrial biopsy are that it is simple to perform, requires no anesthesia, and is well-tolerated by patients. In addition, this procedure has a high sensitivity for detecting disease, a low complication rate, and can be done at a low cost. Dilation and curettage (D&C) with or without hysteroscopy is another potential option, but this approach often requires anesthesia and is associated with increased complications such as uterine perforation.

However, if a patient has a negative endometrial biopsy but there remains concern for endometrial cancer, D&C and hysteroscopy is the next logical step for further workup. Findings worrisome for missing an underlying cancer in the setting of a negative endometrial biopsy would include persistent bleeding, necrosis on histology, and pyometra.

Transvaginal ultrasound (TVUS) can also be helpful in the evaluation of abnormal vaginal bleeding, especially if the office endometrial sampling is difficult due to cervical stenosis in postmenopausal women. TVUS is noninvasive and can often successfully discriminate between bleeding due to atrophy as opposed to anatomic lesions in the uterus. Studies have shown that the risk of endometrial cancer is minimal in women with an endometrial strip of less than 4 to 5 mm. Of course, women with a thickened stripe on TVUS or persistent vaginal bleeding will ultimately need endometrial sampling. TVUS is less useful in premenopausal or perimenopausal women where the endometrial stripe would be expected to be thickened.

The next step after tissue diagnosis of endometrial cancer is referral to a gynecologic oncologist for consideration of hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. For patients with grade 1 endometrial cancer, there is no need for further imaging prior to surgery, given the low risk of extrauterine disease.

For women with grade 2 and 3 lesions or suspicion for metastases on physical examination, a CT scan of the abdomen and pelvis may be performed to determine if there is any concern for disease spread prior to surgical staging. This information may be helpful in determining the surgical approach via a minimally invasive technique (i.e., laparoscopically or robotically) versus open laparotomy, which may be preferred in the case of abdominopelvic metastases or bulky lymphadenopathy.

Other pretreatment testing would include a complete pelvic and physical examination to assess uterine size and mobility, evidence of ascites or extrauterine masses, or nodal disease (i.e., groin and supraclavicular nodes). A CA-125 may also be measured and has been shown to be a predictor of extrauterine spread of endometrial cancer, although the optimal threshold of detection is unclear. If a woman has an elevated CA-125 prior to treatment, the CA-125 may then be a marker for her disease and be useful in follow-up for recurrence after treatment. Given that most women with endometrial cancer will undergo surgical staging, other pretreatment testing would be focused on comorbidities for surgery, requiring some women to undergo medical or cardiac clearance.

3. Management

A. What therapies should you initiate immediately (i.e., emergently)?

After the diagnosis of endometrial cancer, no particular therapies need to be initiated within hours to days of the diagnosis. In the rare case of excessive uterine bleeding, a patient may need to undergo emergent hysterectomy/BSO and staging.

B. What should the initial definitive therapy for the cancer be?

The standard surgical staging for endometrial cancer includes total extrafascial hysterectomy, BSO, washings, and pelvic and paraaortic lymph node dissection. Exceptions to this would include young women with type I, grade I endometrial cancer who desire fertility or women at increased risk of mortality from surgery related to their medical comorbidities.

Controversy surrounds the necessity of lymph node evaluation for all endometrial cancer patients as well as the extent of lymph node dissection. The reasoning behind the recommendation of comprehensive surgical staging is based on maximizing information needed for the optimal management of this disease. However, many gynecologic oncologists advocate selective lymph node dissection based on intra-operative assessment of the uterus. Although many algorithms are available, the most widely used is the “Mayo Criteria” that recommends omitting lymph node dissection in low-risk patients defined as those with myometrial invasion less than 50%, no cervical invasion, G1 and G2 endometrioid histology, and a tumor < 2 cm on intra-operative frozen section. One concern of this approach is that depth of invasion and tumor grade may differ between frozen section and final pathology, with discrepancies noted in about 20% of cases. Sentinel lymph node dissection is emerging as another potential option for assessing lymph node status and avoiding the morbidity of complete lymphadenectomy. For patients with metastatic disease in the abdomen and pelvis, optimal cytoreductive surgery should be attempted and is associated with improved outcomes.

Hysterectomy/BSO +/- surgical staging for early-stage endometrial cancer is generally curative, and close follow-up is all these patients will need postoperatively. For patients with high, intermediate-risk, early-stage disease, vaginal cuff brachytherapy has been shown to decrease the rate of vaginal and pelvic recurrences but has not impacted overall survival. High, intermediate-risk patients were characterized by GOG 99 as one of the following:

• Over 70 years old, grade 2-3 OR invasion of outer one third of the myometrium OR lymphovascular space involvement

• 50 to 69 years old, two of the above risk factors

• Younger than 50 years old, all 3 risk factors

Vaginal cuff brachytherapy is considered the equivalent of pelvic radiation in this patient population, with fewer side effects and a shorter duration of treatment, and thus has emerged as the current standard of care. Given that vaginal cuff brachytherapy does not increase the overall survival rate, observation may also be a reasonable alternative for early-stage endometrial cancer patients. Vaginal cuff brachytherapy does prevent local recurrences; however, local recurrences are likely to be salvageable by radiation, accounting for the lack of a survival benefit. The risks and benefits of both options should be discussed with the patient.

Approximately 15% of women with early-stage endometrial cancer will recur and often have high risk factors such as increased grade, deep myometrial invasion, lymphovascular space involvement, or atypical histologies (i.e., serous and clear cell). For these patients, it is not known whether more intensive treatment such as chemotherapy would improve outcomes. The Gynecologic Oncology Group (GOG) explored this question via GOG 249, which was a phase II trial of pelvic radiation therapy versus vaginal cuff brachytherapy, followed by three cycles paclitaxel/carboplatin chemotherapy in patients with high-risk, early-stage endometrial cancer. Relapse free interval was found to be no different between the two arms. The lack of benefit of chemotherapy on GOG 249 is unclear, and some hypothesize that maybe 3 cycles of chemotherapy was not enough.

Although early-stage disease has a high survival and cure rate, women with advanced-stage disease have a much poorer prognosis. In addition, the prognosis for recurrent disease is even more dismal, with expected overall survival of only 14 to 15 months. Much needs to be learned about how to best manage patients with advanced-stage or recurrent endometrial cancer.

In general, advanced endometrial cancer patients are treated with chemotherapy, possibly in combination with pelvic, paraaortic, or vaginal cuff radiation for local control. Adjuvant pelvic and whole abdominal external beam radiation have been effective in decreasing the rate of pelvic recurrences, but have not significantly impacted overall survival time. Approximately 30% to 50% of patients with stage III and IV disease develop distant metastases, demonstrating the need for effective systemic therapies.

Doxorubicin and cisplatin have been shown to be effective as single agents and in combination. Overall objective response rates have been reported as 24% to 28% for doxorubicin, 21% to 25% for cisplatin, and 31% to 60% for the combination of these drugs. The addition of paclitaxel to this regimen has also been associated with increased response rates but at the expense of higher toxicities in those patients receiving the three-drug regimen.

The combination of paclitaxel and carboplatin has emerged as front-line treatment for advanced and recurrent endometrial cancer. The efficacy of this drug combination has been assessed in several retrospective studies and phase II trials, with overall response rates between 43% to 78%. The majority of these studies included both type I and type II endometrial cancers. The Gynecologic Oncology Group (GOG) completed a randomized phase II trial (GOG 209), comparing doxorubicin/cisplatin/paclitaxel versus the less toxic combination of paclitaxel/carboplatin, and no difference was noted in PFS or overall survival (OS) between the treatment arms.

Other chemotherapeutic agents with a response rate of approximately 20% are topotecan, ifosfamide, cyclophosphamide, and docetaxel. Given that type I endometrial cancers are associated with a state of estrogen excess, hormonal therapy using a variety of antiestrogens, including progestins, tamoxifen, and letrozole, have been assessed in endometrial cancer management.

In the normal endometrium, progesterone antagonizes the actions of estrogen and inhibits estrogen-induced cell proliferation. Progestins, such as medroxyprogesterone acetate, have been used in the treatment of endometrial cancer in two diverse settings: (1) palliative treatment for advanced or recurrent disease or (2) primary treatment in premenopausal women with grade 1 tumors who are interested in preserving their fertility or in those women considered poor operative candidates.

The response rate for progestin therapy in the primary setting is estimated at approximately 60% and only 10% to 25% in the palliative setting. In general, women with well-differentiated tumors and high progesterone receptor content have better response rates to progestin therapy. The obvious appeal of progestin therapy has been the ease of administration and excellent tolerability. Megestrol acetate alternating in sequence with tamoxifen has been assessed in a phase II GOG study in women with advanced and metastatic endometrial cancer (GOG 248). Tamoxifen was added to megestrol acetate therapy as a means to increase progesterone receptor (PR) expression, potentially increasing efficacy of the progestin agent. This treatment regimen resulted in an overall response rate of 27% with a median progression free (PFS) and overall survival (OS) of 2.7 and 14 months, respectively. Baseline estrogen receptor-alpha (ER-α) but not PR expression was found to predict clinical response to daily tamoxifen and intermittent megestrol acetate.

Despite efficacy in breast cancer, many other hormonal therapies have shown minimal activity in advanced and recurrent endometrial cancer, such as aromatase inhibitors (i.e. letrozole and anastrozole), fulvestrant, mifepristone and gnonadotropin-releasing hormone analogues. Tamoxifen alone has a reported modest response rate of 10-46%. Everolimus in combination with letrozole appears to have increased activity over letrozole alone in recurrent endometrial cancer patients, with an objective response rate of 32%. Lastly, carboplatin has also been combined with sequential hormonal therapy with megestrol acetate and tamoxifen in a phase II clinical trial in advanced and recurrent endometrial cancer, and this study found a complete response rate of 31%, a partial response rate of 46% and a median survival of 11 months.

Unfortunately, many endometrial cancers have low levels or gradual loss of PR such that durable responses are rarely achieved, limiting the clinical application of progestins and other hormonal therapies. Combining hormonal therapy with targeted therapies for overcoming progestin resistance and maintaining PR expression is a critical area of future work. Although it was postulated that mTOR inhibitors may overcome progestin resistance, temsirolimus in combination with alternating megestrol acetate with daily tamoxifen did not have increased activity, and a high rate of venous thromboembolism was noted with this combination.

Despite some success with cytotoxic and hormonal therapies, advanced or recurrent endometrial cancer is notoriously difficult to treat with poor response rates and dismal overall survival time. Women with high-risk histology (i.e., serous and clear cell) also have a much poorer prognosis, even in the setting of early-stage disease, and require adjuvant chemotherapy. Thus the search has been for novel agents that target specific cellular signaling pathways thought to be essential in endometrial cancer progression and metastasis. The GOG has conducted a series of phase II trials to evaluate some of these targeted therapies in advanced and recurrent endometrial cancer patients.

Angiogenesis inhibitors

Angiogenesis is the formation of new blood vessels and is thought to be critical in the growth and metastasis of many malignancies, including endometrial cancer. Vascular endothelial growth factor (VEGF) induces this new blood vessel formation and thus is the target of many angiogenesis inhibitors. Not surprisingly, VEGF expression is seen in the majority of endometrial cancer specimens (56% to 100%), but it is unclear whether there is an association between VEGF expression and clinical outcomes.

A number of anti-angiogenic agents have been explored in the treatment of endometrial cancer, including bevacizumab, thalidomide, sorafenib, aflibercept, lenvatinib, sunitinib, brivanib, nintedanib, cediranib, trebananib, and cabozantanib. All have demonstrated a modest effect as single agents in endometrial cancer with response rates ranging from 3-18%.

Bevacizumab is a humanized mAb to VEGF-A and has been the anti-angiogenic agent most studied in endometrial cancer. This drug was first evaluated as a single agent in women with recurrent endometrial cancer (GOG 229-E). In this trial, bevacizumab showed promising activity with a response rate (RR) of 13.5% and with 40.4% of women remaining progression free at 6 months. Translational studies found a correlation between plasma VEGF-A levels and tumor response and survival. The combination of bevacizumab with the mTOR inhibitor, temsirolimus, was also explored in a similar patient population (GOG 229-G). The response rate was 24.5%; however, significant related toxicity was found, including gastrointestinal-vaginal fistulas, bowel perforations, venous thromboses and even treatment-related death. Bevacizumab has also been evaluated in a phase II trial of carboplatin and paclitaxel versus bevacizumab in combination with carboplatin and paclitaxel. The addition of bevacizumab increased PFS by 4.3 months but was associated with substantially increased G3 cardiotoxicity.

Epidermal growth factor receptor inhibitors

The epidermal growth factor receptor (EGFR) has been found to be overexpressed in 50% to 80% of women with endometrial cancer and has been correlated with increasing grade, deep myometrial invasion, and a poor survival rate. Thus, this seemed to be a logical therapeutic target for endometrial cancer treatment.

Antibodies (i.e., cetuximab, matuzumab, pertuzumab, trastuzumab) and small molecule tyrosine kinase inhibitors (i.e., lapatinib, gefitinib, erlotinib) against EGFR have been explored in women with endometrial cancer. Unfortunately, the activity of anti-EGFR therapy has been very limited in this disease. Among these clinical trials, EGFR overexpression has not been a strong predictive marker of response to anti-EGFR therapy.

HER2 amplification is rare in type I endometrial cancer but is seen in a larger majority of type II disease. Given this, the GOG explored trastuzumab as a single agent in a phase II trial (GOG-181-B) that enrolled chemotherapy-exposed endometrial cancers. The results from this trial were disappointing in that no objective responses were found among the patients with HER2 amplification. This is dramatically different from response rates seen among HER2-amplified metastatic breast cancers, and the reason behind this discrepancy is unclear.

Phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (mTOR) inhibitors

Loss of PTEN expression is one of the most prevalent molecular abnormalities associated with endometrial cancers and occurs in an estimated 50% to 80% of type I endometrial cancers. Unlike most other tumor types, loss of PTEN expression is observed in premalignant lesions of the endometrium, suggesting that PTEN loss may be a potential initiator of endometrial cancer development. Wild-type PTEN downregulates the PI3K/Akt/mTOR signaling pathway, which transduces extracellular growth regulatory signals to intracellular mediators of growth and cell survival.

Loss of PTEN results in constitutive activation of Akt and subsequently leads to promotion of cellular proliferation and resistance to apoptosis. In addition to PTEN mutations, mutations and amplifications of the catalytic subunit of PI3K (i.e., PIK3CA) are commonly seen in both type I and II endometrial cancer. Therefore, the PI3K/Akt/mTOR pathway seems like an especially logical target for endometrial cancer therapy. Many types of drugs are being developed to target this pathway with the rapamycin analog mTOR inhibitors (i.e., everolimus, temsirolimus and ridaforolimus) being the most well-studied. As single agents, a modest effect in endometrial cancer has been found with up to a 25% response rate.

mTOR inhibitors have been combined with hormonal and anti-angiogenic therapy as well as chemotherapy. A phase 2 trial of temsiroliums versus the combination of temsirolimus with megestrol acetate and tamoxifen (GOG 248) closed early due to unacceptably high rates of venous thromboses in the combination arm and no indication of improved clinical benefit. In contrast, the combination of everolimus and letrozole exhibited more promising efficacy, with an overall response rate of 32%. The doublet of everolimus and letrozole has been expanded to include metformin in an ongoing phase 2 trial.

GOG 3007 is another ongoing randomized phase II trial which will compare everolimus/letrozole to medroxy-progesterone acetate/tamoxifen. The combination of bevacizumab with the mTOR inhibitor, temsirolimus, has also been explored in pre-treated endometrial cancer patients (GOG 229-G). The response rate was promising at 24.5% but most patients experienced significant toxicity and had to discontinue treatment. GOG-86P was a randomized phase II study of carboplatin/paclitaxel/temsirolimus versus carboplatin/paclitaxel/bevacizumab versus carboplatin/paclitaxel/ixabepilone as first line treatment in advanced endometrial cancer patients. There was no significant difference in PFS between these treatment groups or when compared to historical controls (GOG 209 control arm).

Despite the high prevalence of PTEN and PIK3CA alterations in endometrial cancers, no biomarker has yet emerged to predict response to mTOR inhibitor treatment. PTEN status and Akt/mTOR overexpression have both been examined but have failed to emerge as biomarkers of sensitivity, although these studies have been limited by small sample size. The possibility of PIKCA mutations being predictive of sensitivity may be a possibility but has yet to be fully explored. This search to identify appropriate biomarkers of response will continue to remain an important objective of future clinical trials.

Temsirolimus, everolimus, and deforolimus are considered first generation mTOR inhibitors in that these drugs only inhibit mTOR complex 1 (mTORC1) and not mTOR complex 2 (mTORC2). It is hypothesized that the effectiveness of mTOR inhibitors may be increased by the simultaneous inhibition of both mTORC1 and mTORC2. Thus, second generation, dual mTORC1/mTORC2 inhibitors are being developed and evaluated in clinical trials. Other targeted therapies within this pathway include pan-PI3K and Akt inhibitors, and dual PI3k/mTOR catalytic inhibitors, among others. The mTOR pathway is clearly implicated in endometrial cancer pathogenesis and should continue to be an active area of investigation for targeted therapies related to this seemingly critical pathway.

Other emerging agents

Fortunately, many other targeted agents are on the horizon as potential therapies for endometrial cancer, and this list is rapidly growing as we have come to better understand the underlying molecular basis of type I and II endometrial cancer as well the four subtypes of endometrial cancer identified by TCGA. PARP inhibitors are one example. In addition to its effects on mTOR signaling, PTEN loss of function leads to impaired homologous recombination repair of DNA double-strand breaks and thus enhanced sensitivity to PARP (poly[ADP]-ribose polymerase) inhibition. Given this relationship between PTEN loss and PARP inhibition, PARP inihibitors are being explored as single agents in endometrial cancer and in combination with mTORC1/2 inhibitors and Akt inhibitors.

Another example would be immunotherapies such as anti-PD-1 inhibitors and immune checkpoint regulators. The vast majority of endometrial cancers express PD-1 and/or its ligand PD-L1. In addition, the TCGA designated POLE and MSI subtypes of endometrial cancer possess high mutation load which aligns with high PD-1 expression.

Obesity, diabetes and insulin resistance are associated with increased risk of and worse outcomes for endometrial cancer. Metformin is a biguanide that is often used as first line treatment for type 2 diabetes. Epidemiological evidence suggests that metformin use lowers cancer risk and reduces cancer deaths among diabetic patients, including that of endometrial cancer. Metformin is thought to exert anti-tumorigenic activity through indirect effects on decreasing circulating insulin and glucose levels and direct effects on the tumor through inhibition of mitochondrial complex 1 and subsequent AMPK activation and mTOR pathway inhibition.

There have been five phase 0 studies of metformin for the treatment of endometrial cancer reported in the literature. Four out of five of these studies reported a statistically significant decrease in Ki-67 staining, a marker of cell proliferation as well as downstream markers of both the MAPK and mTOR pathway. In addition, metformin treatment resulted in decreases in circulating metabolic factors such as insulin, glucose, insulin-like growth factor-1 (IGF-1), leptin and insulin-like growth factor binding protein-7 (IGFBP-7).

There are currently 6 open studies of metformin for the treatment of endometrial hyperplasia/cancer. Studies that are being conducted for endometrial hyperplasia/cancer include a clinical trial of metformin in combination with the levonorgestrel-releasing intrauterine device (IUD) in non-surgical patients with endometrial cancer/complex atypical hyperplasia, a phase II trial of metformin in combination with letrozole/RAD001 in advanced and recurrent endometrial cancer patients, a randomized phase II trial of the mirena IUD alone or in combination with metformin versus a weight loss intervention in endometrial hyperplasia/cancer patients, a randomized phase II trial of megestrol acetate +/- metformin in endometrial hyperplasia/cancer patients, and a phase I/II study of cyclophosphamide, metformin and olaparib in advanced or recurrent endometrial cancer patients.

GOG has an ongoing two arm, randomized, placebo-controlled phase II/III trial designed to assess efficacy and safety of metformin in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in women with advanced and recurrent endometrial cancer (GOG 286B) (NCT02065687). The phase 2 portion of this study has completed, and the phase 3 study has recently opened to accrual.

4. Complications

A. What complications could arise as a consequence of condition? Are there strategies to lower risk of complications?

The main complication that can occur as a consequence of endometrial cancer is vaginal bleeding, leading to anemia. To prevent this, patients diagnosed with endometrial cancer should be referred to a gynecologic oncologist in a timely fashion for treatment management. Women should also be educated to seek medical attention for postmenopausal vaginal spotting/bleeding or for premenopausal or perimenopausal bleeding if at high risk for this disease (i.e., obese, diabetic, polycystic ovarian syndrome).

B. What complications could arise as a consequence of the management – chemotherapy, radiation, and/or surgery?

Surgery

Complications of surgery for endometrial cancer are those that are related to all surgeries such as intraoperative/postoperative hemorrhage, genitourinary or gastrointestinal injury, ileus/small bowel obstruction, deep venous thrombosis/pulmonary embolus, and infection. Lymphedema (13% to 15%) and lymphocysts (2%) can also occur related to pelvic and paraaorotic lymphadenectomy as part of surgical staging. Many endometrial cancer patients are obese and thus at a higher risk of surgical and postoperative complications, especially given their often related co-morbidities (i.e., diabetes, hypertension, coronary artery disease, sleep apnea, obesity hypoventilation syndrome).

Chemotherapy

Complications of chemotherapy depend on the drug being used but common toxicities include hematologic toxicity (i.e., neutropenia, anemia, and thrombocytopenia), gastrointestinal toxicity (i.e., nausea, vomiting, and constipation), hypersensitivity reactions (taxanes and platinum compounds are the most likely culprits), and renal toxicity with cisplatin and neurologic toxicity (i.e., peripheral neuropathy for paclitaxel and cisplatin).

Radiation

Complications of radiation therapy depend on the extent of radiation (i.e., vaginal cuff brachytherapy versus pelvic and extended field radiation). Acute complications of radiation include radiation proctitis and enteritis with associated diarrhea, radiation cystitis, and bone marrow effects (i.e., anemia, neutropenia, thrombocytopenia). Late complications of radiation therapy for endometrial cancer can also occur and include chronic radiation cystitis, small bowel obstruction, and fistulas, but these are rare.

C. What other therapies are helpful for reducing complications?

Surgery

To reduce complications of surgery, two measures can be undertaken. Perioperative antibiotic prophylaxis are typically used for the prevention of infections. Thromboembolic prophylaxis also is the standard of care through mechanical methods (i.e., graduated compression stockings and external pneumatic compression) and pharmacologic intervention (i.e., low-dose heparin and low molecular weight heparin). Dual prophylaxis should be considered in high-risk patients, such as those older than 60 years undergoing endometrial cancer surgery OR obese patients younger than 60 years undergoing endometrial cancer surgery).

Chemotherapy

As far as complications of chemotherapy related to endometrial cancer treatment, growth factor support (i.e., filgrastim and long-acting pegfilgrastim) can be useful to accelerate neutrophil recovery, maintain treatment doses, and prevent febrile neutropenia in regimens significantly associated with this life-threatening side toxicity. Emesis prevention is related to the emetic risk of each agent and combination of agents.

Those regimens considered to be at high or moderate emetic risk should include premedication with aprepitant or fosaprepitant plus dexamethasone plus a 5-HT3 agonist +/- lorazepam and +/- an H2 blocker or proton pump inhibitor. Many drugs used for endometrial cancer treatment are considered high or moderate emetic risk, including cisplatin, carboplatin and doxorubicin. Hypersensitivity reactions to paclitaxel can be decreased from 30% to 10% with the use of premedication via dexamethasone, diphenhydramine, and a H2 agonist.

Radiation

The two most common complications from radiation therapy are radiation proctitis/enteritis with associated diarrhea and radiation cystitis. Diarrhea can be effectively managed with dietary modifications and antidiarrheal medications (i.e., Lomotil and Imodium). Management of urinary symptoms include increased oral liquid intake and urinary analgesics.

5. Prognosis and outcome

The majority (approximately 84%) of type I endometrial cancers are diagnosed at an early stage and have a good prognosis. Five-year survival for Stage I disease is 85% to 90% and 70% for Stage II. Survival time is much worse for stage III and IV disease at 40% to 50% and 15% to 20%, respectively. In contrast for type II endometrial cancers, more women present with advanced-stage disease (approximately 38%), and stage for stage, the 5-year survival rates are much poorer. Women with type II endometrial cancer and stage I and II disease have a survival rate of 50% to 60%; this drops to 5% to 20% for advanced-stage patients.

First-line chemotherapy for advanced endometrial cancer is usually combination therapy with paclitaxel/carboplatin. Response rates to this these treatment regimens ranges from 30% to 78%. For advanced endometrial cancer patients with lymph node only disease, chemotherapy is usually combined with pelvic radiation +/- extended field radiation that is given in either a sandwich (three cycles of chemotherapy followed by radiation followed by three more cycles of chemotherapy) versus a sequential fashion. Women with the more aggressive type II cancers and early-stage disease are also usually treated with a combination of chemotherapy and radiation, although many times vaginal brachytherapy is substituted for the pelvic radiation.

If patients fail these treatment regimens, second-line chemotherapy options for endometrial cancer fair worse. Most patients who progress through first-line chemotherapy have little hope for disease remission. The GOG has conducted multiple phase II trials of single-agent chemotherapy in the second-line treatment setting, with response rates ranging from 7% to 27%. Unfortunately, even for patients who do respond to treatment, most responses only last for several months.

Response rates to single-agent paclitaxel on a weekly and every 3 week schedule have been the best in the second-line setting and are reported to be 26% to 27%. Clinical trials of therapies that target specific molecular abnormalities for endometrial cancer, such as mTOR inhibitors and vascular epidermal growth factor inhibitors (VEGF), have shown some promise in the second-line setting. However, based on clinical trials in other malignancies, these targeted therapies may have the greatest clinical impact when combined with cytotoxic chemotherapy and when given to patients with tumors bearing alterations in the specific molecular pathway being “targeted” by these various agents. Thus more research is needed to assess the therapeutic potential of these novel treatments.

"What if" scenarios

The most common pitfall in the management of patients with advanced stage endometrial cancer is progression through first-line chemotherapy. Paclitaxel/carboplatin is what is commonly used as first-line treatment in advanced or recurrent endometrial cancer patients. If patients progress through this regimen, other options include a clinical trial versus other cytotoxics, including doxorubicin, weekly taxol, liposomal doxorubicin monthly taxotere, doxil, gemzar, topotecan or the mTOR inhibitor, and temsirolimus. Hormonal therapy is another option using either megestrol acetate or megestrol acetate in combination with tamoxifen. Given the overall poor prognosis, no treatment is also a reasonable option after failing paclitaxel/carboplatin. Of course, patient preferences, functional status, preexisting toxicities, availability of appropriate clinical trials, and scheduling concerns all play a role in treatment decision making.

6. Follow-up surveillance and therapy management of recurrences

Current endometrial cancer surveillance recommendations differ according to stage and histology. Women with low risk disease (stage 1A1 or 1A2) undergo symptom review and physical examination every 6 months for the first year and then yearly. For women with intermediate-risk disease (Stage 1B-2), these visits should be every 3 months for the first year and then every 6 months until year 5. Lastly, for women with high-risk disease (stage 3-4, type II histologies), clinic visits should occur every 3 months for follow-up years 1 and 2 and then every 6 months for follow-up years 3 to 5.

Pap smear testing at these visits is no longer recommended given the low yield of detecting early recurrences. If CA-125 is a marker for the disease (i.e., elevated prior to treatment), this may be useful in selected patients but is not recommended for routine care. Periodic radiographic imaging is also not indicated for routine use, and should be only performed in the setting of suspicion for recurrent disease.

If recurrence is suspected based on physical examination findings or symptoms, CT scan or PET imaging should be performed +/- CA-125. FNA can also be helpful for a palpable inguinal or supraclavicular node.

Recurrences can be local or distant, with the most common site of local recurrence being the vagina or pelvis. Isolated vaginal recurrences are usually treated with surgical resection (even including pelvic exenteration in some instances) versus radiation therapy. Localized pelvic recurrences can also be surgically managed if complete surgical resection is possible. Surgery in these instances is often followed by multimodality treatment, including radiation and chemotherapy. For patients with disseminated recurrences, chemotherapy is usually the only option for treatment and management is similar to what has already been described for advanced endometrial cancer.

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