Advanced or recurrent endometrial cancer: Molecular classification and treatment decisions

Podcast Transcript

Advanced or recurrent endometrial cancer: Molecular classification and treatment decisions

Brought to you by:

Prof. Xavier Matias-Guiu, Pathologist, University of Barcelona and Lleida, Barcelona, Spain Dr Jurjees Hasan, Medical Oncologist, The Christie NHS Foundation Trust, Manchester, UK

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Dr Jurjees Hasan

The treatment for advanced endometrial cancer has evolved towards a more targeted approach. But how can we optimise treatment selection to improve patient outcomes? Welcome to this podcast. My name is Jurjees Hasan. I'm a Medical Oncologist at the Christie Hospital in Manchester, UK, and I'm joined by my esteemed colleague.

Prof. Xavier Matias-Guiu

My name is Xavier Matias-Guiu, I’m a Pathologist in Barcelona, Spain. And it's a pleasure for me to be together with Doctor Hasan here.

Dr Jurjees Hasan

Thank you very much, Xavier. So given the significant changes in molecular profiling for endometrial cancer, what do you think is the most effective approach to guide therapy selection in patients with advanced or recurrent endometrial cancer?

Prof. Xavier Matias-Guiu

Yes, of course, pathology remains very important because pathological features are important in staging. But of course, the molecular classification has emerged as a very important tool for clinicians to take decisions on patients. And the molecular classification is based on the TCGA (The Cancer Genome Atlas Program) study that was published ten years ago. This was a very thorough molecular analysis. We are using a surrogate and the standard protocol for the surrogate is just three immunohistochemical markers and a mutational analysis of one gene that is POLE.

So with that we have four subtypes. One is POLE mutant tumours associated with very good prognosis. Then we have the group of tumours with mismatch repair deficiency. Then we have the tumours that are p53 abnormal. And we have finally the tumours that are non- specific molecular profiles because they don't have any of the previously stated molecular alterations. So this is very important and this is helping clinicians to take decisions.

Dr Jurjees Hasan

Great. So we've got mismatch repair or MR testing. And we can also test for microsatellite instability. What do these two tests actually mean and is one preferred over the other?

Prof. Xavier Matias-Guiu

As I said, what we are doing is a surrogate of the TCGA and the surrogate is based on the easiest techniques. And for mismatch repair testing, immunohistochemistry is the best technique. This is important to remember that this is a surrogate. Surrogate means that nothing is perfect. And of course immunohistochemistry for mismatch repair deficiency is not perfect. So you can use PCR techniques. But PCR techniques are also not perfect. So these have 90% correlation in both directions.

So in clinical practice what we do, is that we perform immunohistochemistry, it’s fast, it’s cheaper. But whenever we have doubts we are performing PCR testing. And with the two of them, I think that we get the whole picture of each case.

Doctor Hasan, with the pMMR status observed in the vast majority of patients, what 1st line therapeutic options exist? Does prior chemotherapy exposure impact your approach?

Dr Jurjees Hasan

Very much so and we take into account the MMR status of all patients’ tumours to decide what would be the optimal treatment for these patients. So, broadly speaking, the patients may be classed into proficient MMR or deficient MMR subgroups. 70 to 80% of patients may have the proficient MMR phenotype and 20% with deficient MMR status.

For tumours that are deficient in MMR or mismatch repair protein expression, the standard treatment is chemotherapy plus immunotherapy. Chemotherapy being platinum-based, and the two common immunotherapy drugs that are used are dostarlimab and pembrolizumab. This pathway is not very well established.

For patients that are of proficient MMR, platinum-based chemotherapy is the standard of care for these patients. The addition of immunotherapy adds some benefit, although it is not to the same magnitude as it is in patients with a deficient MMR status.

There's of course some new data coming out of combinations of immunotherapy agents with other drugs such as PARP inhibitors, and this may well become a new standard of care in the very near future.

For patients with a proficient MMR status that make up the vast majority of the advanced endometrial cancer population, chemotherapy with platinum, and a non-platinum agents such as paclitaxel, is the standard of care. However, at the time of relapse there is strong data from the KEYNOTE-775 trial to confirm that the combination of pembrolizumab with a multi tyrosine kinase inhibitor, lenvatinib, is highly effective in terms of keeping the disease under control and for making patients live longer. And this is now the established standard of care for these patients.

It is also worth noting that there was a 1st line trial of chemotherapy versus pembrolizumab and lenvatinib, the LEAP-001 trial. While this study showed, broadly speaking, similar outcomes with these two, types of treatment, it is worth noting that for a subset of patients within this trial who’d had previous chemotherapy, the benefit or the outcomes of these patients with pembrolizumab and lenvatinib were far superior to chemotherapy. And for that reason, pembrolizumab and lenvatinib should be considered the standard of care for any patient with advanced or recurrent endometrial cancer who may have received platinum-based chemotherapy at some point in the past.

Prof. Xavier Matias-Guiu

Yes, so it seems that mismatch repair testing is really crucial in your scheme. So I think that both of us agree that nowadays mismatch repair deficiency should be established, when the patient is diagnosed either at the biopsy or at the specimen, because this is really important, but also, since there is a subset of patients in which there is change in the status upon progression I think it's very important whenever this is possible, whenever this is possible, testing at progression and also testing also for the estrogen receptor, because this is another marker that is sometimes changing, during progression of the disease.

Do you agree with that?

Dr Jurjees Hasan

Absolutely. And I think the implication of MMR testing is different in earlier stages of disease as compared to advanced stages. In stage I to stage III endometrial cancer we use MMR testing alongside p53 status to help us determine which patients may benefit from adjuvant treatment, whereas in patients with advanced disease, we use that, of course, to test their suitability for an immunotherapy agent alongside chemotherapy or a combination of immunotherapy, pembrolizumab in combination with lenvatinib.

Prof. Xavier Matias-Guiu

Very good. So pMMR is really a heterogeneous group of those?

Dr Jurjees Hasan

Indeed it is. And I think we obviously need to look into that in more detail in the future, to help us identify further subsets of patients that will respond better to treatment.

Prof. Xavier Matias-Guiu

Doctor Hasan, do you think it is important to explain the results of the molecular classification to patients? And how do you do that in your clinical practice?

Dr Jurjees Hasan

Absolutely. It's very important that we involve patients in our decision-making process right at the outset, and explain to them fully what the molecular genetics of the particular tumour are so we can tailor treatments specifically to individual patients. We do that by undertaking reflex testing at the time of diagnosis. And a full discussion is had with the patients when they first come to see us in the medical oncology clinic. And during the course of their discussion, they're supported by their specialist nurse or key worker, with some written information as well, to explain the implications of the results of these tests, both for their treatment and also if there's an underlying genetic predisposition to certain cancers associated with Lynch syndrome for some of these patients.

Prof. Xavier Matias-Guiu

So maybe we can take some takeaway messages from our discussion, Doctor Hasan. Some of the conclusions that we can take is that mismatch repair status should be tested in all patients at diagnosis. And upon disease progression to guide personalised treatment decisions. Immunotherapy and chemotherapy combinations including maintenance olaparib demonstrate benefits in patients with non-dMMR advanced/recurrent endometrial cancer with greater efficacy observed in dMMR population. And lenvatinib plus pembrolizumab is a viable option not only as 2nd line therapy but also as 1st line therapy for patients with non- dMMR advanced/recurrent endometrial cancer who have progressed after prior systemic therapy in any settings. And of course, shared decision-making supported by patient education is essential for optimising the treatment outcomes.

Dr Jurjees Hasan

I completely agree with your assessment. I think, molecular profiling and personalised therapy is the future for all cancer treatments. We've made substantial progress in endometrial cancer and I completely agree that there's more to come on this.

Thank you all very much for listening.

Tonke de Jong (COR2ED)

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