A 63 years old woman with lung cancer who never smoked.
She was our first patient we met in 2003. She had lung cancer (non-small cell lung cancer, adenocarcinoma) although she had never smoked. The (primary) lung tumor was previously surgically removed, but now she had multiple lung and brain metastasis. Despite radio- and chemotherapy her condition was worsening and was treated at the intensive care unit due to high intracranial pressure.
The patient’s daughter found us through the internet, and asked our help. In 2003, the first targeted drug in lung cancer, gefitinib, was tried in clinical trials. The results of the trial were very disappointing in general, but there were few cases who mysteriously responded to the therapy very well.
We knew that gefitinib targets a molecule, called EGFR (Epidermal Growth Factor Receptor). Therefore, we not only checked if the molecule is present in the tumor sample of the patient, but we also used molecular diagnostics to see of the number of the genes is normal or not. Normally we have two copies of genes (one from our mother and another from our father), but in cancer cells, genes encoding molecules, which can stimulate growth can be multiplied, called „high copy number” or „amplification”. Cancer cells can contain dozens and hundreds of these genes. The many genes produce abnormal quantity of molecules, which over stimulate the cell similarly to the doping of athletes. In this patient, we found that her tumor cells contained a lot of this gene, therefore we hypothesized that gefitinb, which targets the product of this gene can stop tumor cells. Since gefitinib was not effective for most of lung cancer patients it was not available in Europe. We had to initiate a single patient clinical trial to treat this patient.
Luckily, together with partner physicians we could organize the target based treatment of the patient. It was only a pill she had to take once a day. After two months therapy her metastasis in her brain disappeared. She went home and started a normal life again. She traveled to Rome for pilgrimage. She remained tumor free for more than five years. She died of pancreatitis after a heavy dinner, not due to her cancer.
While this patient received gefitinib treatment, scientists at Harvard and other centers found in retrospective studies that good responders to gefitinib also have specific mutations in EGFR gene. We found the same mutation in this tumor besides the gene amplification. Our hypothesis is that the amplification of the mutant gene allele caused an extreme sensitivity to gefitinib.
Scientifically, the interesting thing in this case was that we used molecular diagnostics based evidence to initiate a prospective treatment of a lung cancer patient with a targeted drug. This is why the scientific journal of the American Association Clinical Oncology accepted the case for publication (1)
EGFR gene mutations occur in 5-10% of lung cancer patients, and now there are three targeted drugs in clinical use which can block this gene. EGFR mutations were found in few percent of small cell lung cancer, ovarian cancer, breast cancer, gall cancer.
We have found dozens of patients with EGFR mutations and almost all of them responded to targeted therapy (2).
Luckily, now days, the are several known molecules whose genes can be mutated in lung cancer. These can be targeted with novel targeted drugs. Analysis of all cancer genes can also predict the ineffectivity of routinely used EGFR inhibitor drugs used not only in EGFR mutant tumors.
(1) Amplification and mutation of the epidermal growth factor receptor in metastatic lung cancer with remission from gefitinib. Schwab R, Pinter F, Moldvay J, Papay J, Strausz J, Kopper L, Keri G, Pap A, Oreskovich K, Mangel L. Petak I, J Clin Oncol. 2005 Oct 20;23(30):7736-8)
(2). Epidermal growth factor receptor (EGFR) high gene copy number and activating mutations in lung adenocarcinomas are not consistently accompanied by positivity for EGFR protein by standard immunohistochemistry. Pinter F, Papay J, Almasi A, Sapi Z, Szabo E, Kanya M, Tamasi A, Jori B, Varkondi E, Moldvay J, Szondy K, Keri G, Dominici M, Conte P, Eckhardt S, Kopper L, Schwab R, Petak I. J Mol Diagn. 2008 Mar;10(2):160-8.