Endometrial cancer (EC) accounts for 90% of cases of uterine cancer. As far back as 2013, The Cancer Genome Atlas (TCGA) started finding repeatable differences in the molecular biomarkers of endometrial cancer based on new advanced testing. Over time they described four distinct molecular subtypes of EC, which they called copy number low, copy number high, POLEmut (POLE gene mutation) and MSI (microsatellite instable).
Using the TCGA classification proved problematic as it was a complex, very expensive process and was not adopted widely into clinical practice. Various research groups devised a modified classification, which substantially reduced testing expenses, was user friendly and still had a strong adherence to the original TCGA classification.
This new molecular classification is now being incorporated more and more into clinical practice and is what I will be telling you about in this post. The new molecular subtypes are called POLEmut, P53abn, dMMR and no specific molecular profile. I am going to tell you all about these subtypes, what they mean and how they affect prognosis and treatment options. I will also be sharing specific natural supplements that help for each subtype.
Molecular subtyping is a very important tool in the assessment of endometrial cancer. It can identify patients at higher risk of recurrence, guide personalized treatment to avoid over or under treatment and even be used for early detection of endometrial cancer, but that is another topic.
If you don’t know your molecular subtype, you need to discuss this with your oncologist. Standard biopsies will give you the grade and stage of endometrial cancer, but there are other tests that should be done including immunohistochemistry, molecular biomarker tests and next generation sequencing on your tumor tissue. Please read this POST if you haven’t already, about advanced testing.
Although I will be discussing statistics, please remember, you are not a statistic! You can survive! You just need to find what works best for you. This post will give you updated information to help you make better decisions when it comes to your cancer treatment plan.
IMPORTANT TERMINOLOGY TO KNOW
MISMATCH REPAIR (MMR) STATUS
When cells divide, the DNA replicates itself so each cell has the same genetic make-up. Sometimes during this process, errors can occur in the DNA. Normal, healthy cells have a mechanism to find and fix these errors that is called mismatch repair or MMR for short.
dMMR = deficient mismatch repair. In some cancer cells, genetic changes can affect these mismatch repair proteins so they don’t work.
pMMR = proficient mismatch repair. This is when cancer cells have normal repair mechanisms that function properly.
MICROSATELLITE (MS) STATUS
A microsatellite is a repeating sequence of base pairs that make up and hold together the DNA strands. When the DNA is dividing, errors can occur in the sequence and length of these microsatellites.
MSS = microsatellite stable. These tumors have normal microsatellites. Tumors that are MSS are sometimes called “cold” tumors, meaning they are less mutated and don’t normally trigger a strong immune response. These tumors may even suppress the immune system.
MSI = microsatellite instable. Tumors that are MSI, also called MSI-H for MSI high, often produce abnormal or novel (different) proteins and these attract immune cells. These tumors are sometimes called “hot” because they have a large number of immune cells within them. MSI can be inherited and is part of Lynch Syndrome, which can predispose a woman to endometrial and colorectal cancers.
pMMR are considered to be MSS and about 70-80% of women with EC are of this type
dMMR are considered to be MSI-H and about 20-30% of women with EC are of this type
POLE
The POLE gene is responsible for encoding part of the DNA polymerase epsilon enzyme. This is a crucial enzyme involved in accurate DNA repair and replication. Mutations in the POLE gene can lead to increased cancer risk, especially endometrial, ovarian and colorectal cancers. This gene also plays a role in the regulation of cell cycle checkpoints. POLE mutations can lead to a hyper-mutated tumor phenotype, meaning the tumor cells accumulate a large number of mutations.
TP53 and p53
The TP53 gene is a tumor suppressor gene and it produces the protein p53. These two abbreviations are often used interchangeably. Mutations in this gene and protein are associated with more aggressive tumor behavior and increased risk for recurrence and metastasis. TP53 mutations are more commonly seen in high-grade EC, serous and clear cell carcinomas.
COPY NUMBER LOW
This means there is a decrease in the number of copies of a specific gene or region of DNA. This leads to gene loss or inactivation. For instance, deletions of PTEN (a tumor suppressor gene) are common in endometrial cancer. This can lead to uncontrolled cell growth and cancer development.
COPY NUMBER HIGH
This term refers to an increase in the number of copies of a gene or region of DNA. This could result from gene amplification or duplication, leading to an over expression of certain oncogenes (cancer-promoting genes), which may contribute to aggressive cancer behavior. For instance, in endometrial cancer, amplifications of the PIK3CA oncogene are common.
FOUR MOLECULAR SUBTYPES OF ENDOMETRIAL CANCER
1. POLEmut
This is EC with mutations in the polymerase epsilon gene encoding for the polymerase epsilon enzyme.
2. P53abn
This is EC with mutations in the tumor suppressor gene TP53 and subsequent abnormal expression of its protein, p53. p53abn is short for abnormal as compared to p53wt for the normal wild-type. This subtype is similar to the TCGA classification called copy number high.
3. dMMR
This is EC with a deficiency in the mismatch repair proteins and high microsatellite instability.
4. NO SPECIFIC MOLECULAR PROFILE
This is EC without any of the other mutations I listed above and is abbreviated NSMP. This falls into the original TCGA classification of copy number low.
WHAT THESE SUBTYPES MEAN
POLEmut
This is a rare mutation occurring in approximately 7-15% of EC patients. Women with POLEmut tend to be younger and have a lower body mass index (BMI). These tumors are often classified as high grade because they are ultra-mutated. Studies show that the POLEmut is more common in patients with FIGO grade 3 endometrial carcinoma, stages 1-2 and with myometrial invasion <50%. They tend to have fewer lymph node metastases, but a very high tumor mutational burden (>100 mut/Mb).
Without diving too deep into the weeds, it is important to know that there are two different categories of POLEmut. It’s crucial to know which one you have because it makes a big difference in regard to treatment.
First there is the pathogenic POLEmut with mutations inside the exonuclease domains (EDM). The second is the non-pathogenic POLE, with mutations outside the exonuclease domains. The non-pathogenic POLE is similar to the POLEwt (wild type). You want to have the pathogenic POLEmut EDM.
There is also a scoring system that has been established to further differentiate the POLEmut tumors. This is something you would need to discuss with your oncologist and may require more testing. Ideally, you will have a score of >/= 4.
POLE score
>/= 4 is consistent with the pathogenic POLEmut EDM
=3 is a variant of unknown significance
<3 is the non-pathogenic POLE, which is similar to the POLEwt
Although POLEmut tumors often have poor clinicopathologic features and appear aggressive, the prognosis is excellent and no adjuvant treatments after surgery are necessary. Women with the pathogenic POLEmut have very favorable clinical outcomes in comparison to POLEwt EC, including improved overall survival and progression-free survival. It is thought that this can be attributed to the high tumor mutational burden and the significant number of tumor-infiltrating lymphocytes found in tumors with the POLEmut. These tumors tend to have an enhanced immune response.
Although POLEmut cancer rarely recurs or metastasizes, if it did, these patients would be very good candidates for immunotherapy with immune checkpoint inhibitors like Keytruda.
dMMR
This happens to be the subtype I fall into and accounts for approximately 30% of endometrial cancer cases. Lynch syndrome falls into this category (about 10% of patients).
Endometrial cancers with this subtype tend to be higher grade, have a higher tumor mutational burden (>10, but <100 mut/Mb) and lymphovascular space invasion is commonly observed. These tumors are not usually related to excess estrogen. This subtype carries an intermediate prognosis that mainly depends on the grade and stage. Local recurrences and metastases are more common.
For women with early stage disease, adjuvant treatments beyond surgery may not be necessary, but oncologists often recommend prophylactic vaginal brachytherapy or external beam radiation therapy to prevent recurrence.
For higher grades and later stages, adjuvant treatments including chemotherapy and radiation therapy will be recommended. However, studies, including this one, are showing that this subtype may not respond as well to chemotherapy, although radiation can be effective for disease control. Read More
The good news is that with the dMMR subtype, immunotherapy has been found to be very effective. These tumors are highly immunogenic with a large infiltrate of white blood cells. Although the standard of care is to use chemotherapy first, followed by immunotherapy, some oncologists and researchers are now using immunotherapy as a first line monotherapy for this subtype.
There is an ongoing study that is looking at whether immunotherapy (Keytruda) alone vs. chemotherapy with carboplatin and paclitaxel is more effective at treating women with this subtype. They hypothesize that Keytruda alone as a first line treatment will be more effective and better tolerated than chemotherapy. This study is set to finish in 2027. Read More
I personally declined chemo and radiation and opted for immunotherapy as a sole treatment. Within three months, the tumor that was growing near my bladder disappeared and I have been in remission ever since. I have heard stories like this from other women with this subtype and they are maintaining remission long-term after stopping Keytruda. You may want to ask your oncologist about using immunotherapy as a first line treatment if you have this subtype.
Natural supplements and off-label drugs to help with this subtype include: metformin, ivermectin, fenbendazole, low-dose naltrexone, vitamin D, melatonin, fish oil, ECGC from green tea, curcumin, quercetin, medicinal mushroom extracts (turkey tail, reishi and maitake), beta-glucans, probiotics (especially akkermansia) and fermented foods like kefir and sauerkraut. High dose intravenous vitamin C is an excellent treatment for this subtype.
P53abn
Unfortunately, this is considered the most aggressive subtype and has a poor prognosis. Fortunately, only about 15% of EC patients fall into this category, but it is responsible for 50-70% of EC mortality. This subtype is often made up of women with more malignant forms of endometrial cancer including, serous carcinoma (93%), carcinosarcoma, clear cell carcinoma and grade 3 endometrial carcinoma. Studies have shown that women with grade 1 and 2 endometrial cancer with a p53abn subtype have similar prognosis to grade 3 EC.
Women in this group tend to have a lower body mass index and are older. Recurrences and distant metastases are common.
These tumors often have a low tumor mutational burden, substantial lymphovascular space invasion and 20-25% have HER2 amplification. HER2 is an oncogene that can contribute to cancer development and spread. It is often a target for therapy so ask to have the HER2 status of the tumor tested.
This subtype is greatly benefited by the use of chemotherapy and radiation therapy. In the study I linked above under dMMR, it showed that chemoradiotherapy resulted in 5 year recurrence free survival of 61% vs 37% for radiation therapy alone. A current study (RAINBO-p53abn-Red) is examining the effects of combing chemoradiation with olaparib, a PARP inhibitor.
Some specific natural supplements and off-label drugs that can boost the production and activation of p53 include: curcumin, ECGC in green tea, quercetin, fisetin, sulphorophane, vitamin D, fish oil, ginger, selenium, alpha-lipoic acid, medicinal mushroom extracts (turkey tail, reishi and maitake), CBD oil, metformin and fenbendazole. High dose intravenous vitamin C is an excellent treatment for this type.
NSMP
This is the most common subtype and 50-60% of women diagnosed with EC fall into this group. There are no mismatch repair defects, p53 abnormalities or POLE mutations. These tumors fall into the category of pMMR/MSS and often have high estrogen and progesterone receptor expression. Women in this group tend to have a higher BMI and these tumors are commonly low grade. There are often mutations in the PTEN, PIK3CA and CTNNB1 genes.
The five year recurrence free survival for NSMP is very good, 74.4% and 5 year overall survival 88.5%. With chemo and radiation, the recurrence free survival is 79.7% and with radiation alone it is 67.7%.
I have come across some new information on the NSMP subtype. They are now classifying NSMP into low-risk and high risk groups.
Low Risk – These patients have low grade (1 or 2) endometrioid carcinoma with a positive estrogen receptor test. 84% of women with NSMP fall into this category and have an excellent prognosis regardless of stage according to a recent study! In fact, along with POLEmut, these patients can benefit from a reduction in adjuvant treatments like chemotherapy and radiation therapy. See link below.
High Risk – anything that is not the above. i.e. grade 3 carcinoma or serous cell or clear cell carcinomas, ER negative. These patients have a more guarded prognosis and further treatments may be necessary.
Grade and Estrogen Receptor Expression identify a Subset of No Specific Molecular Profile Endometrial Carcinomas at Very-Low Risk of Disease Specific Death Read More
Low-Risk and High-Risk NSMPs: A Prognostic Subclassification of No Specific Molecular Profile Subtype of Endometrial Carcinomas Read More
The problem with the NSMP subtype is that these cancers do not show significant genetic alterations, making it more difficult to identify specific molecular targets for treatment. They are also not immunogenic, meaning they don’t have a large infiltrate of white blood cells in the tumors, making them less responsive to immunotherapy.
For low-grades and stages and for low-risk NSMP, no further treatment after surgery may be necessary. Approximately 20% may recur. For higher grades or stages, the standard treatments for this subtype are chemotherapy and radiation therapy with mixed results. Studies are also looking into hormone blocking agents combined with targeted therapies, such as PARP inhibitors and CDK inhibitors, but again, with mixed results.
Make sure to discuss your biomarker test results with your oncologist. If you fall into the low-risk category, you may not need further treatments. This will be an important question to ask. This is brand new information so please do more research on your own.
Natural supplements and off-label drugs that may help with this subtype include: metformin, ivermectin, fenbendazole, low-dose naltrexone, CBD oil, DIM (diindolylmethane), indole-3 carbinol (I3C), mistletoe, melatonin, ECGC from green tea, berberine, quercetin, alpha-lipoic acid, vitamin D and fish oil. High dose intravenous vitamin C is also an excellent treatment for this type.
MULTIPLE CLASSIFIERS
Although this isn’t a specific subtype, it’s important to know that about 3-6% of ECs fall into more than one genetic condition and are called multiple classifiers. For instance, someone with dMMR, may also have POLEmut. Some problems arise because of the very good prognosis of the POLEmut and the poor prognosis of the p53abn subtype. So, how do you know what to do if you fall into more than one subtype?
- First, you need to know if you have the pathogenic POLEmut vs. the non-pathogenic POLEwt. Any subtype (dMMR, p53abn, NSMP) combined with the pathogenic POLEmut should be treated as having the POLEmut with little to no adjuvant therapy and careful monitoring.
- Next, you need to know your MMR status. For those with POLEwt and dMMR it should be treated as a dMMR subtype.
- Lastly, you need to know your p53 status. For those with POLEwt, NSMP and p53abn, it should be treated as a p53abn. For those with POLEwt, NSMP and p53wt, it should be treated as NSMP.
I hope this information has helped you learn what subtype you fall into and what specific natural supplements and standard of care treatments are helpful. I’ll link some references below for more information. Make sure to ask lots of questions when you talk to your oncologist and do your own research into your specific subtype.
REFERENCES
Molecular Classification of Endometrial Cancer and Its Impact on Therapy Selection Read More
Molecular subtypes of endometrial cancer: Implications for adjuvant treatment strategies Read More
Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy Read More
The Clinical and Pathological Characteristics of POLE-Mutated Endometrial Cancer: A Comprehensive Review Read More
Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta-analysis Read More
Genomic Landscape of Endometrial Carcinomas of No Specific Molecular Profile Read More
A heart at peace gives life to the body. ~Proverbs 14:30