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Lung cancer: More options for treatment

A better understanding of lung cancer has led to more diagnostic and treatment options for patients.

Thanks to an improved understanding and a much wider range of diagnostic and treatment options, lung cancer patients have a much better chance of survival and recovery today.

At the CME webinar session on lung cancer, Dr Brendan Pang, Consultant Pathologist at ParkwayHealth Laboratory Services, and Dr Chin Tan Min, Senior Consultant Medical Oncologist at Parkway Cancer Centre, gave more than 600 attending doctors an overview of the available and upcoming diagnostic tools and new medications.

In his presentation, Dr Pang gave an overview of how DNA and RNA mutations and rearrangements can lead to lung cancer. As lung cancer is a complex disease, gene sequencing and molecular testing can help doctors identify the type of cancer that the patient is suffering from, so that they can target it with the appropriate medication, he said.

The five biomarkers that can be tested routinely are EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF mutations, and PD-L1 expressions. These biomarkers can be found in non-small cell lung cancer (NSCLC), which accounts for the majority of mutations in lung cancers.

These mutations can be detected through several methods including real-time polymerase chain reaction (real-time PCR), reverse transcriptase PCR (RT-PCR), immunohistochemistry (IHC), fluorescence in situ hybridisation (FISH) or in situ hybridisation (ISH), and next-generation sequencing (NGS) or Sanger sequencing by RNA and DNA.

New kits that have come onto the market for some of these tests can produce results within two to three hours, allowing doctors to come up with a faster diagnosis, said Dr Pang. Different tests are effective for different types of molecular alteration:

• Base substitutions: IHC is limited, RT-PCR is fast but limited, while NGS is the “gold standard” but tedious.
• Insertion or deletion: RT-PCR is fast but limited, while NGS is the “gold standard”.
• Copy number changes: IHC can be used as a screening method. FISH or ISH is the “gold standard”, while NGS is limited.
• Gene fusion: IHC, RT-PCR and FISH or ISH is fast but limited, while NGS is the “gold standard”.

Doctors can use a combination of tests, using the faster ones to obtain a speedier diagnosis before confirming with a slower but more accurate method like NGS. Among the factors that doctors consider are speed and costs, said Dr Pang. Gene sequencing tests typically cost a few hundred dollars, and can go up to thousands.

“We have to work out the best interests for the patient,” he said. “There are many tests and tools, the aim is to cobble together the most expedient tests and do it quickly so we have a good turnaround time.”

Dr Pang also explained the role of the PD-1 pathway in cancer. This immune checkpoint pathway is expressed on the surface of activated T-cells, and one of its ligands, PD-L1 is expressed on the surface of tumour cells. Binding PD-1 with PD-L1 inhibits the activation of T-cells, allowing immunosuppression and neoplastic growth.

He gave some examples of what tests doctors can use, in which sequence, and how long they normally take. “Next-generation testing can shorten diagnostic cycles,” he noted. “It’s all a matter of finding the right test.”

Better treatment options

Finding the right test, however, is the first half of the battle: the second comes from finding the right treatment. In this, too, there have been many significant developments in targeted treatments that have vastly improved the outlook for lung cancer patients.

In the 1990s, noted Dr Chin, a patient with lung cancer had limited treatment options and typically faced a “dismal” prognosis of just eight months’ survival. By the 2000s, however, an improved understanding of genetic factors meant that a patient could be given inhibitors that had a quick effect on the tumour, extending the survival period by many months. The latest generation inhibitors can raise this to two to three years or even more.

Tyrosine kinase inhibitors (TKIs) are now increasingly seen as a frontline treatment for lung cancer caused by genetic mutations such as EGFR. They act like a switch, stopping further growth of the cancer. Dr Chin cited cases of good clinical response, with the tumour mass in the lungs shrinking within two months. Patients do well with improvement of their symptoms of cough, shortness of breath, and pain.

TKIs have several advantages: they can be taken orally and do not compromise patients’ immunity, unlike chemotherapy.

To match the increasing number of cell mutation types discovered, more TKIs have been produced by pharmaceutical companies to combat cancer cells. For example, there are three generations of TKIs for EGFR and ALK mutations respectively.

Dr Chin recalled the case of a young lung cancer patient who was unable to get through a sentence without having to catch his breath when he first came to the clinic. Tests revealed his disease to be ALK-positive, and he was put on an appropriate TKI. “Within six weeks, the tumour had reduced significantly, and he could hold a good and long conversation,” said Dr Chin. “It’s been six years now, and he is disease-free – even though he had Stage 4 cancer.”

But while TKIs might appear to be a “magic bullet” for cancer treatment, Dr Chin stressed that the reality is more complex. “Unfortunately, just as humans are made differently, every cancer is also different,” she said. “They can morph and transform. Some are more resistant and resilient.”

Citing EGFR cases in which patients responded very differently to TKIs, she said: “No two cancers are alike. Although they may have the same molecular signature, they can behave differently clinically.”

Also, TKIs may affect similar-looking targets within the body, and this can cause side effects. Fortunately, most of these side effects are mild and can be well managed.

“What is important is that this treatment can improve patients’ quality of life, and the chances of survival,” concluded Dr Chin.

Immunotherapy

Another development that has improved significantly the survival outlook of patients, is immunotherapy. It boosts the body’s own immune system to help control cancer. It does this by unmasking the “shield” of cancer cells that had enabled them to elude the immune system in the first place.

Dr Chin gave the example of a patient who had been treated with multiple lines of chemotherapy and targeted treatment, and despite of this, the cancer had metastasised and spread. He had a limited prognosis and chance of survival. The patient, who had a high PD-L1 marker, was started on immunotherapy. Two months after treatment, he showed good progress with significant shrinkage of the tumour, and the patient remains well after four years of completion of treatment with no evidence of recurrence.

Immunotherapy has been shown to work for both NSCLC as well as small cell lung cancer. There are some biomarkers that may predict a better response, and this includes a PD-L1 expression of more than 50 per cent. Most patients tolerate immunotherapy relatively well, but some may have more serious side effects, as immunotherapy makes the body’s immunity system more active.

When asked if doctors were likely to see a cure for Stage 4 metastatic NSCLC in this lifetime, she said that she was hopeful. “Ten years ago, the answer was a ‘no’. But now, immunotherapy is the game changer and we’re beginning to see patients still alive and well after two to three years,” she observed. “I am hopeful that in our lifetime, we will be able to treat it like a chronic illness, if not cure Stage 4 lung cancer.”