Approximately 23% of non-small cell lung cancer (NSCLC) have an EGFR-positive mutation. Advanced-stage NSCLC patients whose tumors have an EGFR mutation are often treated with one of several drugs known as TKIs (tyrosine kinase inhibitors) that have been developed to target tumors with EGFR mutations. Over the past decade, five TKI inhibitors have been introduced to treat patients with EGFR-positive NSCLC.
Oncologists have observed that in up to 15% of patients treated with these TKIs, the NSCLC cells learn to evade TKI treatment by transforming into small cell lung cancer (SCLC) cells that then begin to grow again. This is called histological transformation.
Researchers have studied histological transformation by sequencing the tumor DNA. This sequencing data has revealed a biomarker consisting of three genetic mutations (in EGFR, p53 and Rb1 genes) that indicates a patient’s tumor is at increased risk of transforming to SCLC histology.
However, when tested in the laboratory, these mutations are not sufficient to cause the transformation. This suggests that there are other biological pathways that are involved in histologically transforming NSCLC cells into SCLC cells.
“My collaborators and I wanted to find better ways to treat our patients,” says Helena Yu, MD, medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), who specializes in treating patients with EGFR-positive NSCLC.
“We realized that we first need to understand the steps the tumors take to change histology. Then, once we have identified the key steps, we can find therapeutics to target those steps and stop tumors from transforming.”
To conduct this important work, Dr. Yu was awarded an EGFR Resisters/LUNGevity Lung Cancer Research Award in 2021. This award program, a partnership between LUNGevity Foundation and EGFR Resisters—a grassroots patient-led group that has 2,500+ patients and caregivers from 75+ countries—supports critical research to substantially improve outcomes for NSCLC patients with EGFR mutations.
“The EGFR Resisters are an amazing group of people who advocate hard for what they need,” says Dr. Yu. “Our goal is to use our expertise to help them get treatments as quickly as possible.”
“In my clinic, we do routine DNA sequencing on all patients on targeted therapies, so I know who has the biomarker and who is at increased risk for histological transformation,” says Dr. Yu. “I follow their progress over time. If their tumors grow again, we re-biopsy the tumors and collect tissue samples.”
In addition to helping guide patient care, these samples become part of a growing collection that is used by Dr. Yu and her colleagues to study multiple types of molecular changes that occur in the tumor cells before and after treatment with TKIs. These tissues samples are a critical asset in helping the research team identify the key changes that cause histological transformation.
Knowing that patients are waiting for these research results, Dr. Yu and her team have worked to speed up their results as much as possible. “We are pleased to leverage some of the policies at MSKCC, such as the commitment to re-biopsies, to improve our studies and speed our results. Also, we have already developed patient-derived cell lines that will improve preclinical testing as we recreate histological transformations in the laboratory.”
“It is so powerful to be selected by the patients themselves as the recipient of this award,” says Dr. Yu. “We are proud to be working toward effective treatment options for patients as quickly as we can.”
Related Reading:
- Understanding Histological Transformation in EGFR-positive NSCLC
- Living with Two Types of Cancer
- EGFR Resisters and LUNGevity Foundation Partner on Lung Cancer Research Award
Juhi Kunde, MA, is a science writer for LUNGevity.