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).

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.

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.