In this post, I will discuss some targeted therapies that are recommended to women who have advanced or recurrent endometrial cancer. Unfortunately, endometrial cancer can become resistant to chemotherapy and there is a limit to the amount of radiation treatments you can receive. The cancer often becomes more aggressive and oncologists are left with few options.
I will specifically review mTOR inhibitors and explain the latest studies so you know what these are and if they may be right for you. It’s hard to think clearly when you are scared and the cancer is back so you might be tempted to jump in to any type of treatment the doctors recommend, but I want you to have all the details first. I hope this will help you as you navigate through your journey.
mTOR SIGNALING PATHWAY
The mammalian target of rapamycin (mTOR) is a very important signaling pathway in endometrial cancer. The mTOR pathway is a central regulator of cell growth, proliferation, survival, metabolism and angiogenesis (formation of new blood vessels). mTOR decides if a cell should grow, divide or “eat itself” called autophagy. This pathway is important for tissue repair and regeneration and embryological development. Cells are constantly being replaced in your body. mTOR ensures a healthy turnover of these dead or damaged cells.
When conditions are good and nutrients are plentiful, the mTOR pathway is activated, ensuring cells are thriving, growing and performing their functions efficiently. This keeps the body in a state of balance and renewal.
In cancer, this system goes haywire and the mTOR pathway becomes overactive and stuck on “go”. This means the cancer cells are constantly getting signals to grow and divide uncontrollably. This overactivity is often due to mutations or deletions in specific genes, especially the PTEN gene. PTEN is a tumor suppressor gene and normally sends a “stop” signal in the cell’s growth pathway. When PTEN is faulty or missing, this stop signal isn’t there and activation of the mTOR signaling pathway keeps running unchecked. PTEN mutations are very common in endometrial cancer. Another commonly mutated gene that leads to this overactivity is the PIK3CA gene.
mTOR INHIBITORS
mTOR inhibitors that have been studied for use in endometrial cancer include everolimus, temsirolimus and ridaforolimus. These drugs are rapamycin analogs. This means they are structurally similar to rapamycin, the original mTOR inhibitor. By inhibiting mTOR, these drugs turn off the “go” signal for many of these cancer promoting processes. They may be given alone or in combination with chemotherapy or hormonal therapy. They are not FDA (Food and Drug Administration) approved specifically for endometrial cancer, but are used in an off-label fashion. So how effective are they?
EVEROLIMUS (Afinitor)
Everolimus is an oral medication that targets the mTOR signaling pathway.
1. Phase II Study of Everolimus and Letrozole in Patients with Recurrent Endometrial Carcinoma 2015
In this study, they combined everolimus with letrozole. Letrozole is an aromatase inhibitor used to reduce the amount of estrogen in the body. 35 patients were evaluated for a response. All patients were considered incurable and had at least two prior chemotherapy regimens. Both drugs were given orally on a daily basis for 4 weeks at a time until there was progression, toxicity or a complete response.
- 14 of 35 patients (40%) had a clinical benefit; 9 a complete response, 2 partial responses and 3 with stable disease (> or = 4 months).
- 4 patients who had a complete response were still disease free at 22-36 months after completion of the study. 3 went off treatment and 1 continued with letrozole and metformin only. All of these patient’s tumors were estrogen and progesterone receptor positive.
- 5 complete responders eventually had progression, but it was a prolonged period of 10-29 months before recurrence.
- No patients had to discontinue the treatment protocol due to toxicity.
- Patients who had serous cell carcinoma did not respond.
- Patients with endometrial carcinoma and CTNNB1 gene mutations responded well.
- 21 of the 35 patients (60%) did not gain any benefit from this regimen.
- Common adverse events were hyperglycemia (69%), hypercholesterolemia (49%) and hypertriglyceridemia (60%), not great when it comes to cancer and heart disease. They used statins and metformin to control these side effects. Grade 3 adverse events were managed with a dose reduction of everolimus, but if they were grade 4, they discontinued it.
- Interestingly, 9 patients took metformin during this study (500mg twice a day). 5 of these 9 patients (56%) had an objective response rate (ORR), which is a measurable reduction in their tumor or disease burden, vs. only 23% ORR for those who didn’t take metformin.
- Pneumonitis (non-infectious inflammation of the lungs) occurred in 3 patients. Treatment was withheld and symptoms resolved in all 3. Everolimus was resumed at a lower dose with no problems.
- Read More
2. Everolimus, Letrozole and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study 2020
In this clinical trial they also combined everolimus with letrozole, but they added metformin. Metformin is an oral drug that reduces glucose and is commonly used by diabetics, but it has excellent anti-cancer benefits as well (see my post on metformin here). 54 patients were evaluated. These patients had < or = 2 prior chemotherapy regimens and many had had radiation treatments as well. Patients were excluded if they had carcinosarcoma, clear cell carcinoma or any component of serous cell carcinoma.
- 27 of the 54 patients (50%) had a clinical benefit, however there were no complete responses.
- 15 had a partial response and 12 had stable disease.
- The median progression free survival was 5.7 months.
- The median overall survival was 19.6 months.
- If a tumor had a positive progesterone expression, there was a higher clinical benefit.
- Only 1 patient was taken off the study due to toxicity.
- Common adverse events in this study were anemia, hypertriglyceridemia, hyperglycemia, fatigue and oral mucositis (painful inflammation and ulceration of the mucus lining in the mouth).
- Read More
3. A Randomized Phase II Trial of Everolimus and Letrozole or Hormonal Therapy in Women with Advanced, Persistent or Recurrent Endometrial Carcinoma 2022
This clinical trial was started between February 2015 and April 2016. I will focus on the everolimus and letrozole treatment, not the hormonal treatment for this report, which was separate. These were 37 women with advanced, persistent or recurrent endometrial cancer whether they had prior chemotherapy or not. They received everolimus and letrozole daily. They followed them for a median of 37 months. Unfortunately, I am unable to access the complete study so I can only give the abstract highlights here.
- Only 8 of the 37 patients (22%) responded to the treatment, 1 had a complete response.
- The median progression free survival was 6 months, but patients that had not received chemotherapy prior had a 28 month median progression free survival.
- The main side effects were anemia and mucositis.
- Read More
TEMSEROLIMUS (Torisel)
Temsirolimus is an intravenous mTOR inhibitor.
1. Phase II Study of Temsirolimus in Women with Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group 2011
In this clinical trial, temsirolimus was given intravenously as a single agent once a week in 4 week cycles. There were two groups of patients.
In the first group, 29 women who had never had chemotherapy were evaluated.
- 4 women (14%) had a partial response for a median duration of 5.1 months.
- 20 women (68%) had stable disease for a median duration of 9.7 months.
- There were no complete responses and 5 patients had progressive disease.
- The median overall survival was 7.33 months.
The second group included 25 women who had one prior course of chemotherapy.
- Only 1 patient had a partial response.
- 12 patients (48%) had stable disease with a median duration of 3.8 months.
- 12 had progressive disease.
- The median progression-free survival was only 3.25 months.
When the study was published in 2022, all the patients were off the study. 32 had documented progression, 16 had to stop because of toxicity, only 4 completed the treatment, 1 had refused further treatment and 2 for other reasons not mentioned. Temsirolimus as a single agent treatment was not very effective.
2. Temsirolimus with or without Megestrol Acetate and Tamoxifen for Endometrial Cancer: A Gynecologic Oncology Group Study 2014
In this trial, patients were stage 3 or 4 and had persistent or recurrent endometrial cancer after treatment. There were very strict eligibility requirements. Patients could not have received any prior hormonal therapy and only up to one chemotherapy +/- radiation regimen. There were two different groups (arms). The first group received temsirolimus only once a week. The second group received temsirolimus and alternating oral megestrol acetate for 3 weeks, then oral tamoxifen for 3 weeks.
- This study was conducted between 2008 and 2010. In October 2009, the combination arm was completely closed because of excessive venous thromboses. After closing this arm, the temsirolimus only arm continued. 3 patients in this arm eventually developed a deep vein thrombosis as well.
- Of the 22 women who received the combination treatment, 5 developed deep vein thromboses, 2 had pulmonary embolisms, 1 had a heart attack and 1 sudden death.
- On the temsirolimus only arm, 11 patients (22%) came off the study treatment for toxicity. 5 (10%) patients decided to stop therapy.
- 5 patients were removed from temsirolimus due to pneumonitis and 1 of these women died.
- Of 50 eligible patients receiving temserolimus, there were 11 responses, 3 complete responses and 8 partial responses.
- The median progression free survival (PFS) for both arms combined in women with prior chemotherapy was 4.9 months and overall survival (OS) 10.8 months. For women who did not receive chemotherapy, the median PFS was 8.2 months and OS 20.7 months.
- Read More
3. A Phase II Study of Frontline Paclitaxel/Carboplatin/Bevacizumab, Paclitaxel/Carboplatin/Temsirolimus or Ixabepilone/Carboplatin/Bevacizumab in Advanced/Recurrent Endometrial Cancer 2018
This clinical trial compared three different treatment regimens to a historical control group of women who had received standard paclitaxel/carboplatin chemotherapy used very commonly to treat endometrial cancer. These patients had stage 3 or 4a cancer with measurable disease present. If they were stage 4b with or without measurable disease or had recurrent endometrial cancer, they were also included.
There were very strict eligibility requirements, so they wanted relatively healthy, well-functioning patients who were completely recovered from surgery or radiation therapy.
- Arm 2 were the patients who received chemotherapy every 3 weeks, along with temsirolimus intravenously on days 1 and 8 of the cycle, then on days 1, 8 and 15 during maintenance. There were 113 patients in this group.
- All the women in this group had adverse events and 111 of 113 patients (98.2%) experienced > or = to grade 3 adverse events! They had higher rates of pneumonitis, rash, oral mucositis and hypertriglyceridemia compared to the other groups. In fact, 26 of the women (23%) had to drop out of the study due to drug toxicity.
- The toxicity of all the groups was very high including 9 treatment related deaths.
- They did not find any increase in overall response rate, progression-free survival or overall survival when compared to the control group when adding temsirolimus to chemotherapy.
- One genetic mutation in TSC2 (very uncommon in endometrial cancer), was shown to be predictive of an improved progression-free survival in the temsirolimus group.
- Read More
4. Temsirolimus in Combination with Metformin in Patients with Advanced or Refractory Endometrial Cancers 2020
40 patients were treated in this study. They received temsirolimus intravenously once a week and a very high dose of metformin (2000mg per day) in 28 day cycles. Only 33 patients were able to be evaluated for a response.
- 2 patients (5%) had a partial response.
- 13 patients (32%) had stable disease > or = to 4 months.
- They found that 3 patients who had alterations in both the PI3K and RAS pathways achieved stable disease.
- 3 of 4 patients with resistant KRAS mutation had progressive disease.
- 34 of 40 (85%) women had drug-related adverse events. 11 grade 3 drug related adverse events were reported.
- The most common side effects included, mucositis, anorexia, diarrhea and anemia.
- Read More
RIDAFOROLIMUS
Ridaforolimus was studied in endometrial cancer patients, but it faced regulatory challenges and was rejected by the FDA due to insufficient data. Currently, it is not FDA approved for use in endometrial cancer or any other indication and is no longer being developed by Merck pharmaceutical company.
RETROSPECTIVE STUDY
In this retrospective study they reviewed clinical trials using mTOR inhibitors alone or in combination with other drugs and compared them to standard treatments using chemotherapy alone or in combination with hormonal therapy.
Their conclusions were that an mTOR inhibitor containing regimen as a first-line therapy, made little to no difference in overall survival compared to chemotherapy and in fact, may have worsened progression-free survival. For recurrent disease or as second or third line treatment, mTOR inhibitors may have improved progression-free survival, but made no difference in overall survival or tumor response rate compared to chemotherapy or hormonal therapy.
KEY TAKEAWAYS
- mTOR inhibitors may not be effective for women with serous cell carcinoma.
- Tumors that had CTNNB1 or PIK3CA mutations and were estrogen and progesterone receptor positive had better responses to everolimus.
- Women who had not had prior chemotherapy responded better.
- Common side effects of mTOR inhibitors include oral mucositis, anorexia, diarrhea, pneumonitis, hyperglycemia, anemia, hypercholesterolemia and hypertriglyceridemia.
- Patients with the KRAS gene mutation had progressive disease. KRAS mutations have been associated with resistance to everolimus. Read More
- Temsirolimus does not appear to be as effective as everolimus.
- Temsirolimus combined with megestrol acetate and tamoxifen is not an acceptable treatment due to the high likelihood of developing blood clots and thrombotic events.
- Temsirolimus combined with paclitaxel and carboplatin chemotherapy did not result in any increase in overall response rate, progression-free survival or overall survival when compared to chemotherapy alone.
- Temsirolimus with chemotherapy has a high incidence of grade 3 or higher adverse events
- Mutation in the TSC2 gene is a predictive biomarker of better response to mTOR inhibitors.
- In general, a higher number of adverse events are reported with temsirolimus compared to everolimus.
- mTOR inhibitors as a first-line therapy made little to no difference in overall survival compared to traditional chemotherapy and hormonal therapy and may have actually worsened progression free survival.
- mTOR inhibitors as second and third line therapy improved progression free survival, but made no difference in overall survival or tumor response rate compared to chemotherapy or hormonal therapy.
This was an in-depth review of mTOR inhibitors. If your doctors are recommending any of these therapies, I suggest you re-read this or bring it with you to review the results of these studies with your oncologist. It is so important to be aware of the actual study results, the gene mutations your particular cancer has and the different side effects to know whether this might be a valid option for you. It can’t be overstated that changing your lifestyle and improving your overall health may make you a better candidate for these treatments.
I will leave you with a list of supplements that are natural mTOR inhibitors with none of the horrible side effects. Curcumin, Green Tea, Melatonin, Berberine, Quercetin, Fish Oil and Resveratrol. Metformin is a repurposed drug that is also very effective against the mTOR signaling pathway.
I wait for the Lord, my soul doth wait, and in His word do I hope. Psalm 130:5