Treatment & Doctors

Mesothelioma Patients Can Avoid Chemotherapy Resistance

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Written By: Dr. Peter J. Wild, Last modified: March 10, 2021
chemotherapy Infusion equipment

Standard chemotherapy has been shown to be effective in only about one-third of patients with malignant pleural mesothelioma, unnecessarily exposing the other two-thirds to side effects, most of which are undesirable.

It doesn’t have to be that way anymore. We believe our latest study, recently published in Clinical Cancer Research, could lead us in a new direction.

The growing use of novel immunotherapy drugs today could turn the treatment of mesothelioma into a dynamic field, opening the door to more innovative treatment regimens.

That will start with being better able to predict which patients with mesothelioma will respond to chemotherapy and which will not, which prompted this latest project.

A lack of alternative options in the past has led most all mesothelioma patients to receive the same kind of chemotherapy treatment.

The question we asked ourselves was: Is there a way to distinguish between patients who respond to chemotherapy and those who don’t, before treatment starts?

Signals of Non-Response to Chemotherapy 

What we found was that in our cohort, alterations in a gene called BAP1 were associated with a non-response to chemotherapy. BAP1 is a protein that plays an important role, for example in the repair of DNA damage and in the controlled cell death that is called apoptosis.

We clearly found that alternations in BAP1 were a negative predictor of chemotherapy response. Our hypothesis is that alterations in BAP1 lead to a reduction in apoptosis, which is induced by chemotherapy, and needed for therapy efficacy. Therefore, patients showing a BAP1 mutation are very likely not going to benefit from chemotherapy. So why put them through the side effects?

In detail, in our retrospective biomarker study, we screened 67 patients. All underwent first-line treatment of cisplatin and pemetrexed followed by surgery at the University Hospital Zurich.

Formalin-fixed tumor and normal tissue was obtained to look for a genetic marker predictive of response to chemotherapy. We found that alterations in BAP1, mutations or deletions, were a negative predictor of outcome for patients.

Improving Mesothelioma Treatment for All

While this negative predictive impact of BAP1 must be verified in a larger international study, in the future we may be able to use this as a pre-treatment patient stratification before chemotherapeutic treatment is delivered. It could spare many from the serious side effects of unnecessary chemotherapy.

Maybe those who test positive for the BAP1 mutation might be treated first with the recently approved immunotherapy, or in combination with a not-so-high dose of chemotherapy.

These findings could lead to a molecular stratification of mesothelioma patients, which should lead to treatment improvement for all.

As in all types of tumor, mesothelioma in one patient is not the same as mesothelioma in another patient.

Among other features, the genetic makeup, which is different in every single tumor, has to be taken into account for an improved treatment of the disease.

A well-known example of a successful molecular stratification is the detection of BRCA1/2 alterations in breast cancer, which are a response marker for a drug called Olaparib.

Rationale for Testing Biomarkers

We hope that our study and other following studies will lead in a similar direction, offering new treatment options due to molecular stratification for mesothelioma patients.

Since mesothelioma is, unlike breast cancer, a very rare tumor, it is in our eyes absolutely essential to synchronize and combine efforts internationally, including as many working groups as possible, to ensure high quality and reliability of the studies.

In regard to molecular stratification using BAP1 alterations, the fastest and easiest way of verifying our results would be to include the molecular analysis of BAP1 in future studies and clinical trials. The analysis can be done in a standard sequencing laboratory in very short time, similar to the analysis of BRCA1/2.

Unlike the detection of BRCA1/2 mutations in breast cancer, our finding is a negative predictive finding. We did not find a better target for treatment, but an explanation why some of the tumors are resistant to a given treatment. We provided the rationale for testing biomarkers in mesothelioma patients.

Peter J. Wild, M.D., is corresponding author of the latest study exploring chemotherapy resistance in pleural mesothelioma. Research was conducted by Dr. Kathrin Oehl, who received her Ph.D. from the Wild Lab. The manuscript was recently published by Clinical Cancer Research. Wild and Oehl wrote jointly about the findings for The Mesothelioma Center at Asbestos.com.

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