Hypercalcemia in patients with cholangiocarcinoma occurs when there is abnormally high levels of calcium in the blood

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Reviewing; Hypercalcemia in Patients With Cholangiocarcinoma


Hypercalcemia IDH1 Cholangiocarcinoma intrahepatic Bisphosphonates molecular profiling Tumor Mutation Burden

The following is a review of a recent article translated into a more patient-centric style, including an obvious observation on TMB-High.

The Article

Hypercalcemia in Patients With Cholangiocarcinoma
By Matthew Stenger
Posted: 3/31/2023

But firstly what is Hypercalcemia?

Hypercalcemia is a medical condition in which there is an abnormally high level of calcium in the blood. This can be caused by several factors, including cancer, and can lead to a range of symptoms such as fatigue, nausea, and confusion. Hypercalcemia can be managed with medication and treatment of the underlying cause.

How does this occur in CCA patients?

Hypercalcemia can occur in cholangiocarcinoma patients due to the cancer cells producing substances that increase calcium levels in the blood. In addition, bone metastases (the spread of cancer to the bones) can lead to the release of calcium from the bones into the bloodstream. The prevalence of hypercalcemia in cholangiocarcinoma patients increases over time, especially in patients with IDH1-mutant intrahepatic cholangiocarcinoma.

Reviewing the article

This article reports on a study examining the prevalence and significance of hypercalcemia (high levels of calcium in the blood) in patients with cholangiocarcinoma, a type of cancer that affects the bile ducts. The study found that hypercalcemia was more common in patients with IDH1-mutant intrahepatic cholangiocarcinoma and was associated with a higher tumor burden and poor prognosis. Bisphosphonates can be used to manage hypercalcemia, and molecular profiling is crucial to assess treatment options, especially for IDH1 mutations associated with hypercalcemia. The findings highlight the importance of molecular profiling in evaluating the suitability of IDH1 inhibitors in cholangiocarcinoma patients with hypercalcemia.

  • Cholangiocarcinoma patients should be aware of hypercalcemia, which is when there are high levels of calcium in the blood, as it can impact treatment options.
  • Hypercalcemia is more common in patients with IDH1-mutant intrahepatic cholangiocarcinoma and gets worse over time.
  • Hypercalcemia is associated with poor prognosis, high tumor burden in intrahepatic disease, and poor tumor differentiation in extrahepatic disease.
  • Bisphosphonates can help manage hypercalcemia, and molecular profiling is important to assess treatment options, especially for IDH1 mutations.
  • Patients with hypercalcemia and higher tumor burden may be more likely to respond well to immune checkpoint inhibitors.

The study found that:

  1. “11% of cholangiocarcinoma patients had hypercalcemia at diagnosis, but the prevalence increased to 31% at any time during the disease course.”
  2. “IDH1-mutant intrahepatic cholangiocarcinoma patients had a higher risk of hypercalcemia than those with IDH1 wild-type or extrahepatic disease.”
  3. “Patients with hypercalcemia had a higher tumor burden in intrahepatic disease and poor tumor differentiation in extrahepatic disease.”
  4. “Hypercalcemia was linked to a poor prognosis, with a median overall survival of 4.9 months for patients with intrahepatic disease and 1.8 months for those with extrahepatic disease.”
  5. “Bisphosphonates were used less frequently when hypercalcemia was not documented.”
  6. “44% of cases with hypercalcemia based on corrected calcium levels had normal uncorrected calcium levels.”
  7. “The study highlights the importance of molecular profiling in evaluating treatment options, particularly for IDH1 mutations associated with hypercalcemia, in cholangiocarcinoma patients.” – Absolutely correct, and a crucial take-away from the study.

Bisphosphonates are a class of drugs used to treat conditions related to bone loss and can also be used to manage high levels of calcium in the blood.

An observation: Tumor Mutation Burden

In patients with hypercalcemia and higher tumor burden, immune checkpoint inhibitors may be a promising treatment option. Immune checkpoint inhibitors help the immune system attack cancer cells and may be more effective in patients with a higher tumor burden. You may also like to view theyoutube below”short-clip” which explains TMB-high very well.

Original Article

Revisit the original article 

Lipika Goyal, MD

The Patient Empowerment

Simplifying and distilling medical information in a way that we as patients can understand and act on is the beginning of patient empowerment and ‘informed choice.’ Understanding creates confidence and leads to better decision-making and confidence. Please share your thoughts and questions about the article in the comments section below so I can continue to simplify it.

Ps if you would like a template of the questions that you should ask your oncologist or surgeon, then drop me an email and I will send you a copy.

Questions I have

Considering that Tumor Mutation Burden (TMB) and response to immunotherapy is of interest, here are some relevant questions:

  1. Do we, as patients with an IDH1 mutation, have a higher Tumor Mutation Burden (TMB)?
  2. If we have a higher TMB because of our IDH1 mutation, does this mean we could respond better to immunotherapy treatments?
  3. Could the IDH1 mutation or our calcium levels somehow be influencing our TMB?
  4. Can regular testing of our TMB levels help doctors better predict how we might respond to certain treatments, like immunotherapy?
  5. Are there any potential side effects or risks we should be aware of if we have a high TMB and are considering immunotherapy?
  6. If we have high calcium levels in our blood, how might this affect our response to immunotherapy?
  7. Are there specific types of immunotherapy that are more effective for us, as patients with an IDH1 mutation and potentially higher TMB?
  8. If we have both the IDH1 mutation and a high TMB, what kind of treatment plan might give us the best chances of improvement?

These are complex medical questions, and answers can vary depending on many factors, but we as patients must begin asking and simplifying where possible.

“While this article mainly discusses hypercalcemia in cholangiocarcinoma patients, it also uncovers a higher correlation between IDH1 mutations and TMB-high status. This observation leads to some interesting questions for patients:

  1. Could IDH1-mutant tumors potentially unlock more treatment options?
  2. Patients with IDH1 mutations seem to have a higher likelihood of being TMB-High, possibly making them more suitable for immune checkpoint inhibitor therapy.
  3. About 20% of cholangiocarcinoma patients have the IDH1 mutation.
  4. Does a higher TMB score offer an advantage with emerging IDH1-focused immunotherapies or targeted treatments?

Tumor Mutational Burden (TMB) refers to the total number of genetic mutations within a tumor. For cholangiocarcinoma patients, the correlation between IDH1 mutations and high TMB might suggest that these patients’ tumors carry more genetic mutations. This situation can influence the behavior of the tumor, the response to treatment, and the overall prognosis. Therefore, it’s crucial to obtain a genomic profile of the tumor to identify the driving mutation behind the cancer’s growth.”

Genomic Profiling examines a sample of tissue obtained either during surgery or a biopsy procedure.

  1. What is the difference between ‘wild type’ and ‘mutated’ IDH1?
    • ‘Wild type’ IDH1 is like the usual instruction manual in our cells, telling them what to do. ‘Mutated’ IDH1 is like a manual with a typo, causing cells to act differently, which can sometimes lead to cancer.
  2. What does IDH1 mutation mean for my treatment?
    • Knowing whether you have a ‘wild type’ or ‘mutated’ IDH1 can influence your treatment options, similar to how a car needs different fuel depending on its engine type.
  3. What’s the relationship between IDH1 mutation and TMB-high?
    • Research links IDH1 mutations to high Tumor Mutation Burden (TMB-high), but it’s complex and still being explored. Your unique situation will guide your treatment response.
  4. How does IDH1 mutation occur?
    • It’s like a typo in the DNA of cells, which can be due to various reasons, such as replication errors or exposure to certain chemicals. This ‘typo’ results in a protein behaving abnormally.
  5. How does mutated IDH1 lead to cancer?
    • The ‘typo’ in the instruction manual makes IDH1 produce an unusual product in the cell, causing it to grow uncontrollably, which may lead to cancer. But remember, not everyone with this mutation develops cancer, and many other factors play a role. Does the normal wild-type IDH1 play a role in cancer?
Does the normal wild-type IDH1 play a role in cancer?

Wild-type IDH1, when functioning normally, plays a critical role in cellular metabolism. It helps cells break down nutrients and generate energy. However, wild-type IDH1 itself, without a mutation, is not typically associated with the development of cancer.

Instead, it’s the mutation in the IDH1 gene that can contribute to cancer development. This mutation results in the IDH1 protein functioning abnormally, producing a different molecule that can cause cells to grow uncontrollably, leading to cancer. So, it’s not the normal, wild-type IDH1, but the mutated version of it that’s generally linked with cancer.

It’s important to note that while a mutation can increase the risk of cancer, not everyone with an IDH1 mutation will develop cancer. There are many other factors at play, including additional genetic changes and environmental factors.

So basically a mutated IDH1 is the cause of a cancer not the wild-type version

Yes, the mutated IDH1 is typically the one associated with certain types of cancers, not the wild-type (normal) version. Mutations in the IDH1 gene cause the IDH1 enzyme to behave abnormally, leading to an accumulation of a molecule that can promote uncontrolled cell growth, a hallmark of cancer. However, it’s important to remember that cancer usually arises from a combination of genetic mutations and other factors, not just one mutation alone.

What does IDH1 mean and what is its normal function

IDH1 stands for Isocitrate Dehydrogenase 1. It’s a gene that gives instructions to make an enzyme (a kind of protein) that plays a role in how our body’s cells produce energy.

In normal circumstances, the IDH1 enzyme helps convert a molecule called isocitrate into another molecule called alpha-ketoglutarate. This process is a step in a larger pathway that cells use to transform nutrients into energy. This regular process is essential for our cells to function properly.

In simple terms, you can think of IDH1 like a worker in a factory line: it helps change one thing into another so that our cells can use it for energy. When IDH1 is mutated, this worker starts doing its job differently, leading to the production of unusual molecules that can contribute to cancer development.

An IHC Immunohistochemical Test Saved My Life:

You need to look no matter how slim the statistics, I am alive because my Oncologist looked – it is that simple and that’s all it took to set my success in motion against all odds, I know others who are the same as me.

The biggest problem I encounter with patients who reach out to me for help, is too many do not look, their oncologists have not educated them on this choice, or further, still, they have actively discouraged them into the belief that it is only a rare chance – so it’s not worth looking or asking the question!

I personally believe that biopsies are the second most important option we as patients have after surgery and must be a subject fully pursued and ruled in or out, that is why a second opinion is essential, and it must come from an Oncologist in concert with a surgeon who both have the current expertise and experience with your exact cholangiocarcinoma diagnosis

IHC: is a type of pathology test that takes 1-2 weeks for results.

For cholangiocarcinoma patients, certain biomarkers can play a significant role in determining treatment options. These biomarkers can be identified through immunohistochemistry (IHC) testing.

Some important biomarkers include IDH1/IDH2 mutations, FGFR2 fusions, BRAF V600E mutations, PD-L1 expression, microsatellite instability (MSI), and HER2 overexpression/amplification. Each of these biomarkers has specific targeted therapies or immunotherapy options associated with them. It is important that patients know this.

Genomic Profiling: a more in-depth look which takes 4 – 6 weeks for results

Additionally, it is highly recommended that cholangiocarcinoma patients consider genetic profiling of their tumor. Genomic profiling provides a more in-depth understanding of the genetic alterations driving tumor growth. This information can help identify additional biomarkers and potential targeted therapies, offering a more precise and personalized treatment approach. By undergoing genetic profiling, patients can unlock valuable insights into their cancer and potentially access more effective treatment options.

What you should know or ask for in an IHC Test:

The IHC test is fast and efficient here is a summary of the most important biomarkers to ask your oncologist about in order of priority:

  1. dMMR (deficient mismatch repair) status: This test assesses the DNA repair system of your tumor cells and determines if there is a deficiency. It can indicate high levels of microsatellite instability (MSI-H) and potential responsiveness to immunotherapy with immune checkpoint inhibitors.
  2. MSI-high (microsatellite instability-high): This is a result of the dMMR status and indicates high levels of genetic instability in the tumor cells. MSI-high tumors have shown positive responses to immunotherapy.
  3. PD-L1 expression: PD-L1 is a protein that regulates immune responses. Testing for PD-L1 expression can help determine if immunotherapy with immune checkpoint inhibitors like pembrolizumab may be an option.

Additional biomarkers to consider:

  • IDH1/IDH2 mutations: Testing for mutations in the IDH1 or IDH2 genes can guide treatment decisions, as certain targeted therapies may be effective against these mutations.
  • FGFR2 gene fusions: Testing for FGFR2 fusions can inform the use of targeted drugs specifically designed to inhibit these fusions.
  • BRAF V600E mutation: Testing for the BRAF V600E mutation can help identify patients who may benefit from combination therapies targeting this mutation.
  • HER2 overexpression or amplification: Testing for HER2 overexpression or gene amplification can guide treatment decisions and the use of targeted therapies.

Remember ask your oncologist for a Genomic Profiling to obtain a more in-depth view.

Useful Video references

I hope this article has helped empower your knowledge and understanding, let me know your thoughts in the comments below. 

Regards Steve
Ps Have you visited the CCA Patient Toolkit?
Eat light – Move light, be Open, Be Willing, be consistent.