Mesothelioma Diagnosis, Staging, and Personalized Treatment Strategies

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• Histology for Prognosis and Treatment
• Sarcomatoid Mesothelioma and Immunotherapy
• Molecular Diagnostics and Targeted Therapy
• Agnostic Treatment Approach in Mesothelioma
• Future Treatment Strategies
• Full Transcript

Histology for Prognosis and Treatment

Dr. Dean Fennell, MD, emphasizes that diagnostic histology provides vital information for mesothelioma treatment selection. Mesothelioma presents in one of three primary morphologies under the microscope. The most common form is epithelial mesothelioma. Patients with this histology tend to have a better prognosis and live longer.

This critical distinction directly informs the initial treatment strategy. Accurate histological classification is a cornerstone of modern mesothelioma care.

Sarcomatoid Mesothelioma and Immunotherapy

Sarcomatoid mesothelioma represents the other extreme of the disease spectrum. Dr. Dean Fennell, MD, notes these are highly aggressive, drug-resistant, and symptomatic cancers. Patients with sarcomatoid histology derive minimal benefit from traditional surgery or chemotherapy.

Immunotherapy emerges as the primary effective modality for this patient group. Dr. Fennell advocates for combination immunotherapy as a first-line treatment for sarcomatoid mesothelioma without hesitation.

Molecular Diagnostics and Targeted Therapy

Molecular diagnostics show promising early evidence for personalized mesothelioma treatment. Dr. Dean Fennell, MD, discusses emerging research on targeting specific proteins like CDK4 or CDK6. This approach benefits patients with common genetic alterations affecting CDKN2A.

Recent studies published in The Lancet Oncology demonstrate disease control and tumor shrinkage in the majority of these patients. This represents a significant shift toward molecularly-enriched treatment selection in mesothelioma care.

Agnostic Treatment Approach in Mesothelioma

The agnostic treatment approach has historically failed in mesothelioma management. Dr. Dean Fennell, MD, explains that empirical clinical trials with drugs like sorafenib and bortezomib showed limited success. These trials typically followed a pattern of few exceptional responses, some short-term stable disease, and many immediate treatment failures.

Dr. Dean Fennell, MD, emphasizes that 21st-century technology now enables deeper biological understanding of these tumors. This advancement allows clinicians to identify what drives exceptional treatment responses in specific patient subgroups.

Future Treatment Strategies

Future mesothelioma treatment will focus on biological targeting of cancer vulnerabilities. Dr. Dean Fennell, MD, describes an approach centered on understanding cancer biology in relation to specific drugs. This methodology involves testing targeted hypotheses in clinical trials to achieve better disease control.

The ultimate goal is to effectively reduce tumor burden and help patients live longer. This represents a paradigm shift from traditional empirical treatment to biologically-informed personalized therapy.

Full Transcript

Dr. Anton Titov, MD: What diagnostic tests after mesothelioma diagnosis can help to select the best available treatment for particular patients? I understand that chest CT with intravenous contrast is usually the first test that people get.

Dr. Dean Fennell, MD: But once the mesothelioma diagnosis is suspected, what imaging or perhaps molecular genetic markers might help in the treatment of mesothelioma and from a prognostic standpoint?

Yeah, so I think that certainly histology helps. Having the diagnostic histology gives us very, very important information in mesothelioma. We know that mesothelioma can be, in very simple terms, in one of three morphologies or forms under the microscope.

The most common by far is the epithelial mesothelioma. And we know that those patients with epithelial mesothelioma do better. They live longer. Patients with the other extreme of this disease, or sarcomatoid mesothelioma, will tend to do very badly.

Indeed, actually, they have very drug-resistant, invasive cancers, which are highly symptomatic. Patients with sarcomatoid mesothelioma don't benefit very much from any of the treatment modalities, whether it's surgery or chemotherapy.

The one modality of treatment they may benefit from is immunotherapy. And therefore I'm sure we'll come on to this.

Dr. Dean Fennell, MD: But if considering any treatment as a first-line therapy based on new options, which have become available for patients with sarcomatoid mesothelioma, you wouldn't hesitate to offer immunotherapy. You would want to go straight for combination immunotherapy in sarcomatous mesothelioma.

In terms of molecular diagnostics, we don't have licensed treatments yet that are going to be selected on the basis of the genetics of cancer or the molecular basis of cancer.

Dr. Dean Fennell, MD: But we are seeing early evidence that drugs may have activities that are important in certain groups of mesothelioma. So one example is just going to be published in The Lancet Oncology.

It is a drug which targets a particular protein CDK4 or CDK6 in mesothelioma patients with a very common genetic alteration, affecting CDKN2A. And those patients actually, the majority of them had some form of disease control or shrinkage of their mesothelioma cancer.

It suggests that we might be able to enrich for treatment-sensitive patients in the future on the basis of molecular tests. So this is a very, very early area.

I think of the development that we're seeing with multiple drugs at the moment. And we've been very interested in trying to see whether or not we can target an Achilles heel within this cancer, mesothelioma.

So I think it's only a matter of time before something arises. That's very promising.

Dr. Anton Titov, MD: CDK4 and CDK6 inhibitors are also used in another cancer, in breast cancer, certainly. So people speak now of the agnostic nature of treatments in oncology that are based on the molecular signature of the tumor rather than the traditional tissue origin of the cancer.

Is that something that can also be applied to mesothelioma? Or is mesothelioma perhaps unique among the spectrum of tumors where it's hard to apply the agnostic approach to oncology treatments?

Dr. Dean Fennell, MD: I think the agnostic approach has actually failed in mesothelioma. Over the last three decades, we've had empirical clinical trials, where drugs that have shown a reasonable activity may be licensed in other tumors.

Sorafenib and Bortezomib and other drugs like this. They have been trialed in well-designed, well-executed, single-arm phase two clinical trials.

The problem has always been, as we see in these traditional trials, and we are used to that. Maybe a few patients will have an exceptional response. A fair number of patients will have stable disease lasting for perhaps a short period of time.

And then, of course, there'll be a subgroup of cancer patients who simply fail to get any benefit whatsoever. And they progress immediately.

I think this is where we are today in the 21st century. We now have technology that allows us to really dig deep into the biology of these tumors in the clinical context.

We can try to understand what is driving exceptional response of cancer to therapy.

Dr. Dean Fennell, MD: But it's only on the basis of that, that we may be finding ourselves in the position where we can use this knowledge to then select patients with a very much higher likelihood of benefiting.

So I think, certainly, the approach I would take is to look at the biology to try and get a model of cancer as it relates to drugs. This cancer therapy approach can target vulnerabilities, and then test those hypotheses in clinical trials.

We hope that we will be able to get good disease control and trim these cancers down to help patients live longer.