Tyrosine kinase inhibitors (TKIs) are a class of drugs used to treat patients with certain types of advanced-stage non-small cell lung cancer (NSCLC). Each TKI targets cancer cells with a specific mutation, including EGFR mutations. Five TKIs have been FDA-approved to treat patients with EGFR mutations: afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib. While these treatments have had success in treating EGFR-positive NSCLC, many cancers begin to grow at point during treatment. In up to 15% of patients, cancer cells learn to evade treatment by transforming to small cell lung cancer (SCLC) cells and then continuing to grow. This is called histological transformation.
LUNGevity Foundation spoke with Helena Yu, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, who is a specialist in treating patients with EGFR-positive NSCLC as well as the recipient of an EGFR Resisters/LUNGevity Lung Cancer Research Award in 2021. She explains how histological transformations are diagnosed and treated in EGFR-positive NSCLC patients.
LUNGEVITY Foundation: How are histological transformations diagnosed?
Dr. Helena Yu: We and other researchers have found a biomarker consisting of three genetic mutations (in EGFR, p53 and Rb1 genes) present in the lung cancer. This biomarker is a strong indicator that a patient’s tumor is at increased risk of transforming to SCLC histology. In my clinic, tumors from all patients go through DNA sequencing. Patients whose tumors have all three mutations are put on a watch list, and we monitor them for histological transformations.
We monitor these high-risk patients using CT scans. If we start to see growth at a tumor site, we do a tissue biopsy—not a blood biopsy. A change in histology is a change in the way that the cancer cells look. Therefore, a tissue biopsy must be done to look at the cancer cells and diagnose histological transformations.
LF: What should a patient do after being diagnosed with histological transformation?
HY: These histological transformations are rare, and many oncologists may not have experience in treating them. With telemedicine now being so common, I highly recommend having an EGFR expert weigh in on the treatment plan.
LF: How can patients partner with their oncologists to have the best possible outcome from their treatment?
HY: I think that nowadays patients are very educated and aware of their options, so it’s great to bring that knowledge to your appointments. Keep an eye out for any clinical trials that appear on clinicaltrials.gov. Ask about things you read about on LUNGevity blogs or the EGFR Resisters discussion pages. Don’t be afraid to be your own advocate.
LF: What are some of the current treatment options for a patient with EGFR-positive NSCLC that has transformed into SCLC?
HY: Because this is a very new area of research, there aren’t clinical trial results to help guide treatment protocols. There is a lot of gray here. So, the experience and intuition of the oncologist is important.
One of the ways I decide the treatment plan is by looking at how the tumor sites are growing. For example, if multiple tumor sites have grown and one site is biopsied and comes back positive for SCLC histology, I would likely assume that all sites had transformed to SCLC. I would then consider putting the patient on a first-line chemotherapy treatment for SCLC, such as etoposide-cisplatin doublet chemotherapy.
However, if only one site is growing and has come back positive for SCLC histology, while the other tumor sites are stable, I would consider leaving the patient on the TKI because those other sites are still responding well to treatment. In this case, I might add in chemotherapy treatment for SCLC along with the TKI treatment or do radiation or local therapy only to the growing lesion.
LF: What cutting-edge research is underway to help treat and prevent histological transformation of EGFR-positive NSCLC?
HY: The first goal of my collaborative EGFR Resisters/LUNGevity research project is to understand the steps tumors take to evade treatment and change histologically. Then, once we have identified the key steps, we can find therapeutics to target those steps to stop tumors from transforming. We will validate our findings in the laboratory and get the results into clinical trials as soon as possible.
This an exciting time in this research space. A lot of smart people are coming together to find answers and to work on assembling clinical trials for EGFR-positive NSCLC patients.
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Juhi Kunde, MA, is a science writer for LUNGevity.