Objectives

We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), determine whether these gPVs were biallelic alterations, and define associations with clinicopathologic features.

Methods

Germline assessment of ≥76 genes was performed in patients with EC undergoing clinical tumor-normal MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) sequencing from 1/2015-6/2021. Molecular subtypes were assigned using immunohistochemistry and somatic sequencing. In ECs with gPVs, biallelic alterations were identified through analysis of loss-of-heterozygosity and somatic PVs. Clinicopathologic variables were compared.

Results

Of 1625 patients, 216 (13%) had gPVs. Compared to patients without gPVs, gPV patients were younger, more likely to self-identify as White, less obese, and had more endometrioid/clear cell vs. serous/carcinosarcoma histologies (p<0.05). 231 gPVs were identified in 35 genes—75 (32%) in high-penetrance, 39 (17%) in moderate-penetrance, and 117 (51%) in low/recessive/uncertain-penetrance genes. Seventy-four (32%) of 231 were biallelic. For ECs with high-penetrance gPVs, 63% (47/75) were biallelic, primarily affecting mismatch repair (MMR) and homologous repair (HR) genes, including novel HR genes RAD51D (2/2) and PALB2 (2/3) in addition to BRCA1 (10/10) and BRCA2 (6/11).Among all ECs, 552 (34%) were copy number (CN)-low, 514 (32%) CN-high, 413 (25%) microsatellite instability (MSI)-high, 106 (7%) POLE, and 40 (2%) unclassifiable. MSI-high and CN-high ECs were more likely to have biallelic gPVs (p<0.001; Figure).

Conclusions

Thirteen percent of patients had gPVs; 63% of high-penetrance gPVs potentially drove cancer development, supporting the utility of germline assessment given implications for treatment, cancer prevention, and at-risk relatives.

Objectives

In patients with advanced endometrial cancer (aEC), lenvatinib + pembrolizumab (L+P) demonstrated statistically significant and clinically meaningful improvements in PFS, OS, and ORR versus treatment of physician’s choice (TPC) at first efficacy interim analysis. Efficacy was maintained with extended follow-up at the final prespecified data cutoff (1March2022). Here we report additional safety/tolerability analyses from the same final prespecified data cutoff.

Methods

Detailed methods have been published [Makker 2022]. Briefly, patients with aEC and 1 prior platinum-based chemotherapy regimen (up to 2 if 1 given in the neoadjuvant/adjuvant setting) were randomized (1:1) to receive lenvatinib 20mg orally QD + pembrolizumab 200mg IV Q3W or TPC (doxorubicin 60mg/m² IV Q3W or paclitaxel 80mg/m² IV QW [3-weeks-on/1-week-off]). We report safety data of patients who received treatment with 16 months of additional follow-up since the primary analysis.

Results

794 Patients treated with L+P (n=406) or TPC (n=388) were included. Data for these patients regarding adverse events are shown in the Table.

Dose interruptions due to treatment-emergent adverse events were experienced by 71.9% of patients treated with L+P (lenvatinib: 61.6%; pembrolizumab: 52.5%; L+P: 32.5%) and by 28.4% of patients treated with TPC. Dose reductions were needed for 67.2% of patients who received lenvatinib and 12.6% of patients who received TPC. Treatment was discontinued by 39.2% of patients who received L+P (lenvatinib: 35.7%; pembrolizumab: 22.2%; L+P: 16.0%) and by 8.0% of patients who received TPC.

Conclusions

In patients with aEC, updated safety/tolerability results with L+P over extended time were generally consistent with the primary analysis from Study 309/KEYNOTE-775.

Objectives

Adjuvant vaginal cuff brachytherapy (VCB) improves vaginal control rates in early stage endometrial cancer. We propose a shorter course of VCB would be non-inferior in safety, efficacy and quality of life metrics compared to standard course VCB.

Methods

This multi-institutional trial randomized early stage endometrial patients to adjuvant short course VCB (11 Gy x 2 fractions to the surface delivered a week apart) or the standard of care VCB (either 6 Gy x 5 fractions to the surface, 7 Gy x 3 fractions or 5-5.5 Gy x 4 fractions at 0.5 cm depth). All patients underwent hysterectomy with pathologically confirmed endometrioid adenocarcinoma, serous, clear cell or carcinosaroma histology. Eligible patients included all FIGO IB or II, FIGO 1A gr 2 -3 or FIGO 1A gr 1 with LVSI. Primary endpoint was health related quality of life (HRQOL) using the Global Health Score from the QLQ-C30 at 1 month.

Results

There were 108 patients enrolled from 5 institutions. At a median follow-up of 12.85 months, there have been no isolated vaginal recurrences. Table 1 shows the distribution of recurrences. Adverse events are shown in Table 2. At the 1 month and 6 month time point, the QLQ-C30 scores in the experimental arm were non-inferior (P= p=0.00002).

Conclusions

This prospective randomized trial showed short course VCB is non-inferior to standard course VCB. While longer follow up data is necessary, short course VCB supports a growing literature in providing more options for women with early stage endometrial cancer.

Objectives

Fragmentation of cancer care (FC) occurs when patients receive treatment across several different hospitals. Patients with high-grade endometrial cancer often require adjuvant treatment after surgery, and it is unknown if change of location during treatment impacts patient outcomes.

Methods

This population-based retrospective cohort study included patients diagnosed between 2003-2017 with high-grade endometrial cancer who received adjuvant treatment post-operatively. Non-fragmented care (NFC) was defined as receiving surgery and adjuvant treatment at the same institution. The primary outcome was overall survival (OS).

Results

We identified 1,795 patients, of whom 583 (32.5%) had FC. Patients with NFC were more likely to have had surgery by a Gynecologic Oncologist (92.4 vs 58.8%, p<0.001), surgical staging (66.6 vs 44.8%, p<0.001), and less travel for surgery (mean 30.8 km vs 93.7 km, p<0.001). They were less likely to receive chemotherapy (26.3 vs 30%, p<0.001) and chemoradiation (38.4 vs 41.3%, p<0.001). Median survival was 9 years. There was no significant difference in OS between patients who received FC and NFC. 92.4 and 93.5% of the patients in the FC and NFC groups were treated at a specialized gynecologic oncology centre for at least part of their treatment (surgery, adjuvant treatment or both).

Conclusions

We have previously shown that regionalization of surgery in high-grade endometrial cancer is associated with improved survival. Fragmentation of surgery and adjuvant treatment in this population does not have an adverse effect on survival. After receiving surgical treatment with a Gynecologic Oncologist, these patients may receive adjuvant treatment closer to home to decrease financial and travel burden.

Objectives

Several studies have investigated whether patients with prior breast cancer (BC) are at increased risk for endometrial cancer/uterine serous cancer (USC). We aimed to study this relationship and analyze the effect of prior BC on the incidence and prognosis of USC patients.

Methods

With permission of the Surveillance, Epidemiology and End Results (SEER) program of the United States National Cancer Institute, clinicopathological information of women diagnosed with BC and following USC were analyzed. The recorded data included age at diagnosis, stage of disease, cause of death, interval time between BC and USC diagnosis and overall survival.

Results

The SEER database included 10021 patients with USC during the years 1975-2015. 698 (6.96%) of these patients had been previously diagnosed with breast cancer (BC).

The incidence of USC in patients with BC history was 57 times higher than in women without BC history (p value < 0.001). The incidence of USC did not differ between ER positive and ER negative BC patients (p. value 0.94). The mean survival of USC patients with previous BC history was 8 years (96 months, 95% CI 85.7-106.2), shorter than in USC patients with no BC history presenting a mean survival of 10.6 years (127 months, 95% CI 124.0-130.8) (p. value =0.002).

Conclusions

Our results highlight the relationship between BC and USC, suggesting an increased risk for USC among BC patients. This clinical association should be introduced to BC patients, and physicians should be alert to any EC presenting symptom in BC survivors.