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Recurrence rates and patterns of recurrence in stage IA p53abn endometrial cancer with and without myometrial invasion
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  1. Amy Jamieson1,
  2. Marcel Grube2,
  3. Samuel Leung3,
  4. Derek Chiu3,
  5. Amy Lum3,
  6. Janice S Kwon1,
  7. Aline Talhouk1,
  8. Blake Gilks4,
  9. Stefan Kommoss2 and
  10. Jessica N McAlpine1
    1. 1 Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, The University of British Columbia and BC Cancer, Vancouver, British Columbia, Canada
    2. 2 Department of Women’s Health, Tübingen University Hospital, Tübingen, Germany
    3. 3 Department of Molecular Oncology, University of British Columbia, Vancouver, British Columbia, Canada
    4. 4 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
    1. Correspondence to Dr Amy Jamieson, Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, The University of British Columbia, Vancouver, Canada; amy.jamieson{at}vch.ca

    Abstract

    Objectives Optimal management of patients with stage IA p53abn endometrial cancer without myoinvasion, classified as intermediate risk in the 2020 European Society of Gynaecological Oncology, European Society for Radiotherapy and Oncology, and European Society of Pathology (ESGO-ESTRO-ESP) guidelines, and the 2022 European Society of Medical Oncology (ESMO) guidelines, is currently unclear. Practice varies from surgery alone to adjuvant radiation±chemotherapy. Our aim was to assess the risk of disease recurrence in patients with stage IA p53abn endometrial cancer without myoinvasion compared with stage IA with myoinvasion (<50%).

    Methods Stage IA p53abn endometrial cancers were identified from retrospective cohorts. Cases were segregated into stage IA with no myoinvasion, including (1) tumor restricted to a polyp, (2) residual endometrial tumor, and (3) no residual tumor in hysterectomy specimen, versus stage IA p53abn with myoinvasion (<50%), with treatment and outcomes assessed.

    Results There were 65 stage IA p53abn endometrial cancers with no myoinvasion (22 polyp confined, 38 residual endometrial tumor, 2 no residual in hysterectomy specimen, 3 not specified) and 97 with myoinvasion. There was no difference in survival outcomes in patients with stage IA without myoinvasion (16% of patients recurred, 19% if there was residual endometrial disease) compared with stage IA with myoinvasion (17%). The risk of recurrence was lowest in patients with stage IA p53abn endometrial cancer without myoinvasion treated with chemotherapy±radiation (8%). Most recurrences in patients with stage IA without myoinvasion were distant (89%), with no isolated vaginal vault recurrences, and all except one distant recurrence occurred in patients who had not received adjuvant chemotherapy.

    Conclusion The recurrence rate in patients with stage IA p53abn endometrial cancer without myoinvasion was 16%, highest in the setting of residual endometrial disease (19%), and exceeding the threshold where adjuvant therapy is often considered. The high frequency of distant recurrences observed may support chemotherapy as part of the treatment regimen.

    • endometrium
    • uterine cancer

    Data availability statement

    Data are available upon reasonable request.

    https://doi.org/10.1136/ijgc-2023-005149

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      WHAT IS ALREADY KNOWN ON THIS TOPIC

      • p53abn endometrial cancers are responsible for the majority of recurrences and death from this disease. The 2020 ESGO-ESTRO-ESP and 2022 ESMO endometrial cancer guidelines categorize p53abn endometrial cancers with myoinvsion as high risk and recommend treatment with chemotherapy±radiation, regardless of stage, grade or histotype. The optimal management of patients with stage IA p53abn endometrial cancer without myoinvasion is highly debated.

      WHAT THIS STUDY ADDS

      • The recurrence rates in p53abn endometrial cancer stage IA without myoinvasion were 16%; highest in patients with residual endometrial tumor (19%). Recurrence rates in p53abn stage IA without myoinvasion did not differ compared with p53abn stage IA with myoinvasion, where adjuvant treatment is routinely recommended. Most recurrences in patients with p53abn endometrial cancer stage IA without myoinvasion were distant (89%) and fatal.

      HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

      • This study highlights the importance of molecular classification and identifying patients with p53abn endometrial cancer in order to recognize an aggressive endometrial cancer cohort where adjuvant treatment is needed. High rates of distant and unsalvageable recurrences in stage IA p53abn endometrial cancer with residual endometrial tumor (even without myoinvasion) may justify discussion about adjuvant chemotherapy.

      INTRODUCTION

      The molecular classification of endometrial cancer provides a reproducible framework for categorization of tumors with important diagnostic, prognostic, and therapeutic implications.1–11 The copy number high group identified by The Cancer Genome Atlas was characterized by tumors with a very high number of somatic copy number alterations, low mutation rate, and frequent TP53 mutations.12 These tumors are now identified in clinical practice by a more pragmatic method of mutant-pattern p53 immunohistochemistry (IHC) staining, which has been shown to be an excellent surrogate maker for TP53 mutational status.7 9–11 13 14 The p53 abnormal (p53abn) endometrial cancer subtype has since been shown to have poor clinical outcomes,7–11 15 even in stage I disease,16 regardless of histotype8 17 and tumor grade.18

      Although p53abn endometrial cancers comprise only ~15% of all endometrial cancer cases, this subtype is responsible for 50–70% of all endometrial cancer mortality.15 Recent data have shown improved survival outcomes in patients with p53abn endometrial cancer when adjuvant chemotherapy is used in addition to radiation.8 19 Furthermore, the 2020 European Society of Gynaecological Oncology, the European Society for Radiotherapy and Oncology, and the European Society of Pathology (ESGO-ESTRO-ESP)20 and 2022 European Society of Medical Oncology (ESMO)21 endometrial cancer guidelines both recommend that all patients with p53abn endometrial cancer with any myometrial invasion (myoinvasion) be considered high risk and treated with chemotherapy±radiation, regardless of stage, grade or histotype. However, for stage IA p53abn endometrial cancers without myoinvasion, both guidelines state there is currently insufficient evidence to guide management in these patients and the potential benefit of adjuvant therapy is unclear. Therefore, the recommendation for adjuvant treatment versus observation has been based on clinician or institutional preference and/or patient factors. Our aim was to assess the risk and pattern of disease recurrence in patients with stage IA p53abn endometrial cancer without myoinvasion compared with stage IA with myoinvasion (<50%).

      METHODS

      Case Selection

      This study was approved by the University of British Columbia ethics board. We searched for International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IA p53abn endometrial cancers from historical institutional (42%)7 10 11 and population-based (58%) cohorts of endometrial cancer17 22 that had undergone molecular classification and where clinicopathologic and outcomes data were available. This included patients from 29 centers across Canada and a single center in Germany. We included patients with no myoinvasion and with myoinvasion <50%. The pathology reports of patients with no myoinvasion were reviewed to document whether tumor was (1) restricted to a polyp, (2) there was residual endometrial tumor, or (3) no residual tumor in the hysterectomy specimen (all tumor having presumably been removed by endometrial biopsy or curettage). Molecular classification was performed as previously described.7 10 11 17 22

      In brief, representative formalin fixed paraffin embedded tumor sections were assembled, with DNA extraction from tumor cells for focused next generation sequencing to assess for pathogenic POLE mutations. POLEmut assignment was limited to a list of 11 well characterized pathogenic mutations.23 IHC for mismatch repair (MMR) proteins and p53 was also performed. Molecular classification was achieved by first assigning patients identified to have pathogenic POLE mutations (POLEmut), then categorizing the remaining endometrial cancers by MMR status identifying patients whose tumor demonstrated loss of one or more MMR proteins (MMRd), and finally by p53 status (abnormal; overexpression or null (p53abn), vs wildtype staining patterns (NSMP)).

      Statistical Analyses

      Kaplan-Meier survival analysis and the log-rank test were used to test for associations between outcomes (progression-free survival, disease-specific survival, and overall survival) based on the presence or absence of myoinvasion. Within the cohort of stage IA with no myoinvasion, outcomes were also compared between patients who received adjuvant chemotherapy versus no chemotherapy and polyp confined disease versus residual endometrial tumor. All statistical analyses were done using R project for statistical computing with significance set at α=0.05.

      RESULTS

      Cohort

      There were 65 patients with stage IA p53abn endometrial cancer with no myometrial invasion (22 polyp confined, 38 residual endometrial disease, two with no residual tumor after hysterectomy; in three cases it was not possible to determine whether tumor was confined to a polyp or not) and 97 with myoinvasion <50%. Table 1 demonstrates the clinicopathologic characteristics, adjuvant treatment given, and outcomes of the total cohort comparing patients with stage IA p53abn endometrial cancer with and without myoinvasion. There were statistically significant differences between age at diagnosis, body mass index, presence and extent of lymphovascular invasion, and use of adjuvant treatment between these stage 1A subsets; 73% of patients in the stage IA with no myoinvasion group did not receive adjuvant therapy compared with 29% in patients with myoinvasion.

      View this table:
      Table 1

      Clinicopathologic features of the cohort of stage IA p53abn endometrial cancer with and without myoinvasion

      A total of 86% of patients in the stage IA with no myoinvasion group underwent lymph node assessment compared with 81% in the stage IA with myoinvasion group. Eighty-five per cent of patients in the stage IA with no myoinvasion group had an omental biopsy performed compared with 69% in the stage IA with myoinvasion group. Peritoneal washings for cytology were only performed in 51% of the stage IA without myoinvasion group (all negative) and 60% in the stage IA with myoinvasion group (3% were positive for malignant cells). Nineteen per cent of tumors in this p53abn endometrial cancer study were low grade (grade 1–2) endometrioid.

      Outcomes

      There was no difference in rates of disease recurrence in patients with stage IA p53abn endometrial cancer with no myoinvasion (16%) compared with stage IA patients with myoinvasion (17%), acknowledging that a higher proportion of patients with stage IA with myoinvasion received adjuvant therapy (71% vs 27%). There were also no differences in disease-specific survival and overall survival for stage IA patients with no myoinvasion compared with patients with myoinvasion (Figure 1). The risk of recurrence was lower in patients with stage IA no myoinvasion and disease confined to a polyp (10%) compared with stage IA no myoinvasion and residual endometrial disease in the hysterectomy specimen (19%), but this difference was not statistically significant (p=0.43) (Online Supplemental Figure 1). Likewise, we observed a trend in improved disease-specific survival in patients with no myoinvasion and tumor confined to a polyp compared with no myoinvasion and residual endometrial tumor, but this was not statistically significant (Online Supplemental Figure 1). There were only two patients with no residual tumor in the hysterectomy specimen, and one of these patients recurred. Table 2 details the adjuvant therapy given to patients with stage IA p53abn endometrial cancer with no myoinvasion according to disease location (polyp, residual endometrial tumor, no residual tumor). The risk of recurrence was lowest in patients with stage IA p53abn endometrial cancer with no myoinvasion treated with chemotherapy±radiation (8%). We observed a trend in improved progression-free survival and disease-specific survival in stage IA p53abn endometrial cancer with no myoinvasion in patients treated with adjuvant chemotherapy compared with those who did not receive chemotherapy, but this was not statistically significant (Figure 2). There was no difference in outcomes (progression-free survival, disease-specific survival, and overall survival) by L1CAM status (Online Supplemental Figure 2).

      Supplemental material

      Figure 1
      Figure 1

      Kaplan-Meier survival analyses demonstrating no significant difference in progression-free survival (PFS) (A) and disease-specific survival (DSS) (B) in p53abn stage IA patients with myometrial invasion (1–<50%) compared with no myometrial invasion (none).

      Figure 2
      Figure 2

      Kaplan-Meier survival analyses demonstrating progression-free survival (PFS) (A) and disease-specific survival (DSS) (B) in patients with stage IA no myometrial invasion who received adjuvant chemotherapy compared with those who did not have chemotherapy.

      View this table:
      Table 2

      Details of adjuvant treatment given for patients with stage IA p53abn endometrial cancer with and without myoinvasion

      Site of Disease Recurrence

      There were 10/65 (16%) patients with stage IA p53abn endometrial cancer with no myoinvasion who had a disease recurrence. The site of disease recurrence was available in nine of the 10 cases; eight were distant recurrences without any local component and one was pelvic only. There were no isolated vaginal vault recurrences in this cohort. In the eight patients with a distant recurrence, seven had died of disease at the time of data collection (with an average time to death from recurrence of 1.9 years and average follow-up 2.9 years). In these 10 patients that recurred, seven had received no adjuvant therapy, two had vault brachytherapy only, and one patient had chemoradiation.

      DISCUSSION

      Summary of Main Results

      This study demonstrated high rates of recurrence in patients with stage IA p53abn endometrial cancer (16–17%), with or without myoinvasion, with most recurrences being distant. When looking across all stage IA patients who had not received any adjuvant therapy, rates of disease recurrence were similar in patients with stage IA and no myoinvasion (16%) compared with patients with myoinvasion (19%). Assessing both treated and untreated patients together, the risk of recurrence was higher in patients with stage IA no myoinvasion but with residual disease identified in the endometrium (19%) compared with stage IA no myoinvasion and disease confined to a polyp (10%), with numbers insufficient to comment on cases where there was no remaining tumor in the hysterectomy specimen (although one out of these two individuals did experience a recurrence).

      Results in Context of Published Literature

      Current endometrial cancer guidelines, from ESMO21 and ESGO-ESTRO-ESP,20 state the benefit of chemotherapy or indeed any adjuvant therapy is unclear in stage IA p53abn endometrial cancers without myoinvasion as these patients have not been included in historic randomized clinical trials. Both guidelines, however, recommend that all patients with p53abn endometrial cancer with myoinvasion be considered high risk and treated with chemotherapy±radiation, regardless of stage, grade, or histotype. The National Comprehensive Cancer Network (NCCN) guidelines24 differ from ESMO and ESGO-ESTRO-ESP as they recommend treatment based on histotype rather than molecular subtype. For example, for patients with stage IA grade 3 endometrioid endometrial cancer with no myoinvasion, observation is recommended. For patients with stage IA serous or clear cell carcinomas with no myoinvasion if the washings are negative then vault brachytherapy is recommended, whereas chemotherapy plus vault brachytherapy is recommended for positive washings. Finally in NCCN, for patients with stage IA carcinosarcoma, chemotherapy plus vault brachytherapy±external beam radiation is recommended for all with no segregation based on myoinvasion. Treatment based on molecular subtype rather than histotype is supported by the evidence that shows there is no difference in clinical outcomes between histotypes within p53abn endometrial cancers8 25 26 as well as the poor reproducibility of histotype assignment in endometrial cancer, especially within high grade tumors.27–29

      Given the lack of high level evidence for this subgroup of stage IA p53abn endometrial cancer without myoinvasion, the decision for adjuvant treatment or observation has been left to the individual clinician or institutional guidelines and certainly can be influenced by patient factors. The majority of the previously published data addressing treatment in stage IA (FIGO 2009) endometrial cancers without myoinvasion have consisted of small series (range 5–49 patients), limited to serous carcinomas, with recurrence rates ranging from 5–18%.30 One large cohort, published by Nasioudis et al in 2020,31 came from the US National Cancer Data Base and included 1709 patients with stage I serous carcinoma confined to the endometrium. Patients were included in the analysis only if they had undergone hysterectomy and bilateral salpingo-oophorectomy with at least 10 pelvic lymph nodes removed. Seventy-five per cent of this cohort also had undergone para-aortic lymph node dissection. The authors reported the use of adjuvant chemotherapy (with or without radiation) was associated with significantly improved survival compared with no adjuvant therapy or use of radiation alone.

      A more recent study by Kurnit et al also assessed outcomes in early stage serous endometrial cancers including 238 patients with stage IA disease confined to the endometrium. They also found adjuvant chemotherapy with or without vault brachytherapy was associated with improved recurrence-free survival and overall survival compared with no adjuvant therapy.32 In our study cohort we found all but one patient with stage IA disease without myoinvasion who recurred had a distant recurrence without any local component. There was one pelvic recurrence and no isolated vaginal vault recurrences. This is important when considering choice of adjuvant therapy, as many centers recommend vault brachytherapy only for these patients (and vault brachytherapy among the list of potential treatments recommended by the ESGO-ESTRO-ESP guidelines) which would not be anticipated to help prevent distant metastases. Our results, in addition to publications from Nasioudis and Kurnit, suggest adjuvant chemotherapy plays a more important role in this patient population.

      There is currently no absolute value or threshold at which adjuvant therapy in endometrial cancer is dictated; however, risk of recurrence of greater than 15% may prompt consideration of therapy at multidisciplinary tumor boards. We found stage IA patients who did not receive adjuvant therapy had a 17% recurrence rate, both in the setting of having myoinvasion (19%) and without myoinvasion (16%). This is especially important in a cohort of patients where the risk of recurrence is distant which is almost always fatal/non-salvageable, a notable concern in this study where 88% of those who recurred had died from disease by 3 years.

      This study also provides further evidence that there is a subset of patients with low grade (grade 1 and 2) endometrioid endometrial cancer that are p53abn molecular subtype, which has been another subject of debate. Recent assessment of low-grade p53abn endometrial cancers within the PORTEC-1/-2 trials and Canadian retrospective cohorts demonstrated that a proportion of p53abn endometrial cancers are morphological low grade endometrioid and these patients had a much higher rate of disease recurrence, even in stage I disease, compared with low grade NSMP tumors.18 This supports application of the ESGO-ESTRO-ESP and ESMO endometrial cancer guidelines to include these patients with other p53abn endometrial cancers and offer adjuvant chemotherapy±radiation.

      Of note, FIGO 2009 endometrial cancer staging was used in this study. The recently published 2023 FIGO staging separates patients with stage IA and no myoinvasion into non-aggressive histological types limited to an endometrial polyp or confined to the endometrium (stage IAI) and aggressive histological types limited to a polyp or confined to the endometrium (stage IC).1 Patients with p53abn endometrial cancer with disease confined to the uterine corpus with any myoinvasion would now be stage IICmp53abn. However, the treatment of these stage IAI versus IC versus IICmp53abn patients is not discussed in the new FIGO document.

      Strengths and Weaknesses

      A strength of this study is the relatively large sample size for a rare endometrial cancer subset, inclusion of all p53abn endometrial cancer histotypes (not just serous carcinoma), and the ability to stratify within stage IA no myoinvasion: (1) tumor restricted to a polyp, (2) residual endometrial tumor, and (3) no residual tumor after hysterectomy. A weakness of this study is not all patients had full surgical staging (86% did have pelvic nodal assessment and 85% had an omental biopsy in the stage IA no myoinvasion group), thus there could be some occult stage III cases included, with a higher rate of node positive disease appreciated in p53abn endometrial cancers.33 Another weakness is that it is a retrospective cohort, and we are unable to determine how or why adjuvant treatment decisions were made or what variables might have influenced those treatment decisions.

      Implications for Practice and Future Research

      This study reinforces the importance of identifying p53abn molecular subtype of endometrial cancer in order to recognize an aggressive subset where adjuvant treatment is needed, and recurrence is relatively frequent and may not be salvageable, even in early stage disease without myoinvasion.

      CONCLUSION

      The recurrence rate in patients with stage IA p53abn endometrial cancer without myoinvasion was 16%, exceeding the threshold where adjuvant therapy is often considered, and equal to the recurrence rate of patients with stage IA p53abn endometrial cancer with myoinvasion who are recommended adjuvant therapy. The high frequency of distant recurrences observed may support chemotherapy as part of the treatment regimen.

      Data availability statement

      Data are available upon reasonable request.

      Ethics statements

      Patient consent for publication

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      Supplementary materials

      • Supplementary Data

        This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

      Footnotes

      • Twitter @DrAmyJamieson

      • Contributors AJ, JNM and JSK conceptualized the study and provided cases. AT, SK and MG also contributed cases. AL and CBG performed the molecular classification. SL and DC analyzed the data. AJ drafted the manuscript, and all authors were involved with editing the final manuscript. AJ and JNM accept responsibility for the overall content/data.

      • Funding This work was supported by the Canadian Cancer Society Aggressive Uterine Cancer Grant, the Canadian Institute for Health Research, the Terry Fox Research Institute, the BC Cancer Foundation (a grateful patient from Victoria and the Clinician Scientist Award (JMc)), the Vancouver General Hospital Foundation, the Vancouver Coastal Health Research Institute (AJ), the Canada Research Chair Program and Chew Wei Memorial Chair in Gynecologic Oncology (JMc), and the Miller-Mindell Fellowship (AJ).

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.