Clinical application of molecular classification of carcinoma endometrium in India

INTRODUCTION

The molecular classification of endometrial cancer (EC) was introduced by The Cancer Genome Atlas in 2013, classifying into four categories: Polymerase ε (POLE) (ultramutated), microsatellite instability (MSI) (hypermutated), copy number low, and copy number high.^[1] It was incorporated into the treatment guidelines in 2020, according to the European Society of Gynaecological Oncology (ESGO) the European Society for Radiotherapy and Oncology, and the European Society of Pathology (ESTRO ESP) GUIDELINES- risk stratification (low, intermediate, high-intermediate, high, advanced metastatic).^[2] The Federation of Gynecology and Obstetrics (FIGO) 2023 (International FIGO) has incorporated molecular classification of EC into the staging system, making it more complex for both the pathologist and clinician.^[3] There are various retrospective trials suggesting that it provides a risk stratification system and guides further adjuvant treatment.^[4]

However, even after 2 years of changing treatment guidelines, there is huge heterogeneity in the management of these patients worldwide (as compared to prior uniformity in treatment guidelines before the introduction of molecular markers). Hence, this causes confusion among clinicians and over- or undertreatment of patients in a few cases due to incomplete molecular testing and the non-availability of these tests in most centers in India, especially POLE mutation analysis.

MATERIAL AND METHODS

We conducted a nationwide online survey among healthcare professionals directly managing EC patients. The multiple-choice questionnaire contained 14 questions to understand their knowledge and clinical application of molecular classification of EC in their clinical practice. This was designed using Google Docs (http://docs.google.com). The questionnaire was developed after an extensive literature review and discussion among the authors. It was reviewed by experienced gynecologic oncologists for content adequacy and clarity. A preliminary dry run was conducted with a small group of clinicians to identify ambiguous questions, and revisions were made accordingly. Although formal psychometric validation was not performed, efforts were made to ensure face and content validity before distribution. The survey link was shared in WhatsApp groups, Telegram, and the emails of various national oncology groups. The responses were collected between July 17, 2023, and July 25, 2023, and 820 clinicians were reached out. The study excluded all incomplete and duplicate replies. Our survey aimed to study the clinical application of molecular classification among Indian clinicians treating endometrial carcinoma and to analyze the limitations hampering the acceptability of these guidelines.

RESULTS

A total of 129 healthcare professionals responded out of 820 (15.7%), with complete responses to 14 questions in the survey. All clinicians were treating EC and, hence, were eligible for further analysis. This included 55 gyneoncologists (42.6%), 43 general gynecologists (33.3%), 6 surgical oncologists (4.7%), 7 medical oncologists (5.4%), and 18 radiation oncologists (13.9%) [Figure 1]. About 114 out of 129 clinicians (88.4%) were aware of the new molecular classification.

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Figure 1:

The distribution of study population.

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The majority of clinicians, 53 (41.1%) get only immunohistochemistry (IHC) markers done, i.e., p53 and mainly mismatch repair (MMR), while only 14 (10.9%) get the complete profile with genetic markers and next-generation sequencing (NGS), including POLE mutation. About 28 (21.7%) clinicians get these done only in specific cases, and 27 (20.9%) clinicians want to get these done but, due to a lack of facilities in their setups, are not able to get them done currently. Rest 7 (5.4%) clinicians were not in favor of getting these markers done even if facilities were available.

About 43 (33.3%) of clinicians got it done on the final histopathology specimen, while 78 (60.5%) of clinicians felt that this test should be done on pre-operative endometrial biopsy, and the rest 8 (6.2%) clinicians got it done at the time of relapse/recurrence/residual disease [Figure 2].

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Figure 2:

When do you think the molecular testing should be done?

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Only 100 (77.5%) of clinicians would change adjuvant treatment based on molecular markers. However, the rest, 29 (22.5 %), were unsure about it [Figure 3].

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Figure 3:

Do you thick adjuvant treatment should be changed based on molecular markers?

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For the management of P53+ve with low-risk EC, 41 (31.8%) would give both combined chemotherapy and radiation therapy while 24 (18.6%) would only observe. The majority, 46 (35.7%) would give them either external beam radiotherapy (EBRT) or vaginal brachytherapy (VBT), while 14 (10.9%) clinicians would give them chemotherapy only. Rest 4 (3.1%) had varied opinions for the management of these patients, such as getting a complete genetic profile, including POLE, before deciding on further management of these patients [Figure 4].

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Figure 4:

Management of p53-positive low-risk tumours.

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For stage II EC with POLE mutation, 38 (29.5%) of clinicians would downstage them and observe only, 60 (46.5%); hence, the majority of clinicians would give them EBRT/VBT while 30 (23.3%) would give them both chemotherapy and EBRT. One (0.8%) clinician would give chemotherapy alone.

For mismatch repair-deficient (MMRd) tumors, 29 (22.5%) would not change adjuvant management, while 22 (17.1%) would upscale the treatment. Further, 80 (62%) of clinicians get further genetic testing before advising on preventive strategies for colon cancer in these patients.

If the molecular markers are available preoperatively, the majority, i.e., 55 (42.6%) of clinicians agreed to limit surgery of POLE m like avoiding complete lymphadenectomy, aggressive surgery for P53 positive-like doing complete lymphadenectomy and omentectomy, and avoiding a minimally invasive route. While 43 (33.3%) want to wait for further studies before modifying their surgical management.

Only 87 (67.4%) are aware of multiple classifiers. Only 25 (19.4%) would undertreat them, and 16 (12.4%) would over treat them.

Overall, 92 (71.3%) of clinicians want to wait for further prospective studies, and only 5 (3.9%) feel that current data are sufficient to change the management; rest, 32 (24.8%) clinicians were unsure about it. The summary of the results is depicted in Figure 5.

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Figure 5:

Key practice trends among the study population.

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DISCUSSION

Uterine cancer is the most common gynecological malignancy in developed nations, while it is the third most common in India after carcinoma cervix and ovary.^[5] Etiopathogenesis of EC is sporadic in most cases, related to high-risk factors including obesity, hypertension and diabetes, but some are caused by germline mutations, MMR genes contributing to hereditary cases.^[6] Hence, testing for molecular alterations provides an opportunity to enhance diagnostic testing modalities and personalize treatments through targeted therapy.

Recently, FIGO 2023 has incorporated molecular classification of EC into the staging system, lympho-vascular space invasion, and synchronous tumors of the ovary.^[3] This is a prognostic system as compared to the previous anatomical system, hence helping us to guide treatment. However, this system overcame the shortcomings of the Bokhman classification^[7] and the World Health Organization classification.^[8] This was probably due to the pathologist’s observer bias in reporting the type of tumor.^[9] Based on this classification, patients with histologically similar EC had very different outcomes, notably in patients with high-grade endometrial carcinomas.^[10] This suggested the dire need for a standard classification to appropriately prognosticate the patients and guide the need for adjuvant therapy. However, it is more complex for both the pathologist and clinician due to limited knowledge of molecular markers and their heterogeneity (multiple classifiers).

The response rate in our study was just 15.7%, which is relatively low and may introduce response bias, as those clinicians more familiar with or interested in molecular classification might have been more likely to respond. This could potentially overestimate awareness and readiness to adopt molecular testing in routine practice. However, given the wide geographical distribution of respondents, representation of multiple oncology subspecialties, and consistency of our findings with international reports, we believe the results still provide valuable insight into the current challenges and perceptions among Indian clinicians.

Although pre-operative endometrial biopsy may not be the representative sample, molecular markers have high accuracy, so can be done on either preoperative or postoperative biopsy. The majority, 60% of clinicians, prefer to do it on a pre-operative endometrial biopsy. Most of the centers in India have the facility of only IHC markers. Moreover, NGS is an expensive test that most Indians are not able to afford. This could justify the response in our survey as only 10% of clinicians are getting NGS for molecular classification routinely, while the majority 41% are getting only IHC markers done. 43% of clinicians agreed to tailor the surgery based on POLE and P53, while 33% await future prospective trials. Currently, there are no standard guidelines that guide us to modify our surgery based on molecular markers. Hence, most clinicians did not agree with this.

We also analyzed the clinicians’ knowledge of molecular classification and its clinical application regarding adjuvant treatment. About one-third of clinicians will escalate treatment for stage I p53+ve, and one-third would de-escalate for stage II POLEm following ESMO clinical practice guidelines.^[11] POLE mutation is associated with a good prognosis, and p53 is associated with a bad prognosis, as seen in various retrospective studies.^[12] Hence, treatment for these mutations can be personalized as per recent treatment guidelines for EC. 23% of clinicians would not change their treatment even if molecular markers are available, and a further 64% want to wait for more prospective data.

MMR deficiency/MSI on IHC has to be confirmed with genetic testing/NGS before advising preventive strategies for associated colonic cancer, and no change in adjuvant treatment.^[11] As per our survey, 22.5% would not change adjuvant management, while 17.1% would upscale the treatment in MMRd tumors. Further, only 62% of clinicians get further genetic testing before advising on preventive strategies for colon cancer in these patients. This suggests a lack of knowledge among clinicians about molecular markers and management regarding the adjuvant treatment of its basis. This could be because this newer concept is far away from Indian clinics currently, and it can be bridged by some solid clinical evidence, which makes the clinicians feel its importance, leading them to modify their adjuvant management based on molecular markers.

Multiple classifiers are a term used when POLE mutation co-exists with MSI/MMR deficiency or p53.^[13] About 33.6% of clinicians were not aware of multiple classifiers, and of those who knew about them, only 20% correctly knew to undertreat them as per the better prognostic marker. 48 (38.4%) clinicians felt further studies are needed before we decide to change our management because of them.

Overall, 71.3% of clinicians want to wait for further prospective studies, and only 3.9% feel that current data is sufficient to change management. This strongly suggests the need for future prospective trials, as most clinicians are not comfortable relying on retrospective trials for guiding the treatment of patients. **According to the author’s opinion, we should wait for the results of current prospective trials-PORTEC 4a^[14] and RAINBO^[15] before relying on these guidelines.

Our findings of heterogeneity in the use of molecular classification mirror results from other regions. A ESGO survey reported that although more than 80% of clinicians were aware of molecular subgroups, <20% routinely incorporated them into management decisions, largely due to lack of access to testing and uncertainty regarding treatment implications.^[16] Similar barriers have been described in North America, where surveys among gynecologic oncologists revealed high awareness but limited application outside of academic centers with access to next-generation sequencing.^[17] In contrast, some high-resource settings, such as parts of Western Europe, have reported greater adoption of molecular profiling into risk stratification, supported by institutional funding and national guidelines.^[18] Taken together, our results highlight that India’s challenges – limited infrastructure, cost constraints, and variability in clinician confidence – are not unique but are accentuated in low- and middle-income settings. This underscores the importance of developing region-specific implementation strategies and resource-adapted guidelines for equitable adoption of molecular classification in clinical practice.^[19]

In Europe, longitudinal surveys have shown that IHC-based testing – particularly for MMR – is now routine in most EC pathology laboratories.^[19] For instance, nearly all laboratories in the UK and Switzerland perform MMR IHC on all EC cases, compared to 80% in Spain and about 47.5% in Italy. In contrast, adoption of POLE testing remains limited in several European countries, often owing to reimbursement constraints, though access in the UK has increased following inclusion in the national genomic test directory in 2022.

North American surveys echo the pattern of high awareness but variable adoption. A recent U.S.-based survey revealed that while 93% of gynecologic oncologists adhere to universal Lynch syndrome (MMR) screening guidelines, fewer consistently implement comprehensive molecular profiling outside academic centres, despite increasing uptake over the past 3 years.^[17]

These comparisons underscore that India’s challenges – constrained infrastructure, cost barriers, and clinician hesitation – mirror global experiences, though they are often more pronounced in low- and middle-income settings. High-resource environments in Western Europe benefit from structured funding mechanisms, integrated laboratory networks, and supportive guidelines that promote molecular testing uptake. Our findings therefore reinforce the need for India-specific pathways and policies – including scalable testing models, clinician training programs, and funding strategies – to enable sustainable integration of molecular classification into routine care.

This study has certain limitations that must be acknowledged. First, the response rate was relatively low (15.7%), which may introduce selection bias, as clinicians with a greater interest in molecular classification were more likely to participate. Second, the use of an online survey distribution through professional networks may have restricted participation to digitally active clinicians, potentially under-representing those in peripheral or resource-limited settings. Third, our survey relied exclusively on quantitative multiple-choice responses, without incorporating qualitative data such as in-depth interviews or open-ended feedback, which might have provided richer insights into the reasons behind clinical decision-making. Finally, as with any self-reported data, there is a possibility of reporting bias, where stated practices may differ from actual clinical behavior. These limitations should be considered when interpreting the findings, and future studies should explore mixed-methods approaches with broader sampling to capture a more comprehensive understanding of practice patterns in India.” This study has certain limitations that must be acknowledged. First, the response rate was relatively low (15.7%), which may introduce selection bias, as clinicians with a greater interest in molecular classification were more likely to participate. Second, the use of an online survey distribution through professional networks may have restricted participation to digitally active clinicians, potentially under-representing those in peripheral or resource-limited settings. Third, our survey relied exclusively on quantitative multiple-choice responses, without incorporating qualitative data such as in-depth interviews or open-ended feedback, which might have provided richer insights into the reasons behind clinical decision-making. Finally, as with any self-reported data, there is a possibility of reporting bias, where stated practices may differ from actual clinical behaviour. These limitations should be considered when interpreting the findings, and future studies should explore mixed-methods approaches with broader sampling to capture a more comprehensive understanding of practice patterns in India.

Notably, the recently published 2025 ESGO–ESTRO–ESP guidelines for endometrial carcinoma incorporate molecular subtyping as a central component of risk stratification, reflecting a shift toward biologically informed staging and management based on robust evidence and expert consensus.^[20] These guidelines were developed through a systematic literature review and global peer review, and they affirm the pivotal role of molecular classification in tailoring surgical and adjuvant therapies. Our study reveals that, while awareness of molecular subgroups among Indian clinicians is high, implementation remains inconsistent due to infrastructure limitations and cost constraints. Alignment with the ESGO–ESTRO–ESP recommendations underscores the urgency for India-specific strategies – such as capacity building, adoption of validated surrogate assays, and prospective validation – to facilitate integration of molecular classification into standard practice and develop locally adapted guidelines.

CONCLUSION

Molecular classification has transformed the prognostication and treatment paradigm of EC, yet its routine application in India remains limited by cost, infrastructure, and clinician readiness. Our survey highlights significant heterogeneity in practice, underscoring the urgent need for strategies that enable equitable adoption. Moving forward, concrete steps include capacity-building initiatives such as training programs for pathologists and oncologists, the establishment of quality-assured molecular diagnostic laboratories, and integration of these tests into national cancer care networks. Adoption of cost-effective surrogate assays (e.g., IHC-based panels for p53, MMR, and surrogate markers for POLE status) should be prioritized to allow broader access in resource-constrained settings. Finally, India-specific prospective validation trials are critical to generate local evidence, build clinician confidence, and inform context-adapted guidelines. Such efforts will not only reduce variability in treatment but also move India closer to delivering globally benchmarked, personalized cancer care for women with endometrial carcinoma.