ROS1-Positive Lung Cancer

For those courageously battling advanced lung cancer, their hopes and desires are deeply profound in the face of uncertainty. They carry unique hopes and dreams as compared to healthy people. Despite the harsh reality of mortality, some may wish for precious moments, wishing for more time with loved ones. The weight of unfulfilled dreams is undoubtedly difficult to bear.

Amidst this turmoil, there is hope for those with advanced NSCLC. Targeted therapies have emerged as a source of hope, offering renewed possibilities by extending the lifespan of patients.

"Today marks 11 years since I was first diagnosed with advanced lung cancer...
When I was diagnosed, my life expectancy was two years on the outside."

- Janet Freeman-Daily

Janet Freeman-Daily, a resilient soul, faced the harsh reality of stage IV lung adenocarcinoma in 2011. She tested positive for ROS1 rearrangement, but there was no FDA-approved targeted treatment for her genetic abnormality. She had never indulged in the vice of smoking or experienced secondhand smoke.

ROS1, short for c-ros avian UR2 sarcoma virus oncogene homolog 1, belongs to the family of receptor tyrosine kinases. Like EGFR, ROS1 receives external stimuli and transmits the signal into the cells. The signal transmitted by ROS1 regulates cell growth and the process of maturation, leading to the development of cells with specific functions. The protein can be found in both healthy cells and cancer cells.

In lung cancer cases, most ROS1 abnormalities involve rearrangement or translocation, resulting in the fusion of ROS1 with another gene. Numerous genes partner with abnormal ROS1,with CD74 being the most common.

The specific gene that ROS1 gene fuses with can impact the treatment approach in lung cancer. This variation can influence the treatment effectiveness, the development of drug resistance and the choice of subsequent treatment. Therefore, identifying the specific ROS1 fusion partner helps doctors to customize a strategy that maximizes effectiveness while minimizing the risk of resistance.

If you have ROS1-positive or ROS1-rearranged lung cancer, your ROS1 proteins are constantly active, driving uncontrolled cell growth, and resulting in cancer development.

ROS1 rearrangement is found in 1-2% of non-small cell lung cancer (NSCLC), mostly in lung adenocarcinoma and sometimes in squamous cell carcinoma.

Read more: Genetics Of Lung Cancer and How To Test Them

ROS1 rearrangement is often acquired throughout a person’s lifetime due to exposure to carcinogens (cancer-causing factors). Although smoking is the biggest risk factor for lung cancer overall, it is not associated with ROS1 rearrangement.

People with this gene abnormality are usually:

• Never smokers – about 67.7% of ROS1-positive cases
• Younger adults – the median age of people diagnosed with ROS1-positive is 50.5, much younger than the general median age for lung cancer
• Females – while lung cancer seems to be more common among men, ROS1 abnormality appears to have a higher prevalence in females

All patients with newly diagnosed non-small cell lung cancer (NSCLC) can now consider taking molecular or biomarker tests. These tests help to identify driver mutations, as well as the optimal targeted therapy.

There are various techniques to determine the presence of ROS1 mutations:

Broad molecular profiling. Genetic or molecular testing can be done on tissue biopsy as part of pathology assessment. Doctors may recommend a broad molecular profiling that assesses multiple driver mutations.

Examples of broad molecular profiling that identify: FoundationOne CDx; Oncomine Dx Target Test

Liquid biopsy. There may not be sufficient tumor samples for all the diagnostic tests needed for patient diagnosis. To avoid tissue re-biopsy (normally invasive), the doctor may order a minimally invasive biopsy technique called liquid biopsy. It involves drawing a few tubes of blood. liquid biopsy analyses DNA shed from lung tumors into the bloodstream. Whereas profiling using traditional biopsy analyses DNA in the tumor tissue. The US Federal Food and Drugs Administration (FDA) has approved liquid biopsy for detecting ROS1 mutation: FoundationOne Liquid CDx

Related: The Types of Lung Cancer Biomarker Tests

Local treatments are recommended for early-stage lung cancer – 1, 2, or 3A. The treatments include

• Surgery (resectable disease): to remove parts containing cancerous tissue like a wedge piece of the lung (wedge resection), a lobe of one lung (lobectomy), or an entire lung (pneumonectomy)
• Radiation: an alternative for patients who are not resectable candidates or who refuse surgery. The therapy involves high-dose of the radiation beam to destroy cancerous cells or shrink the tumor

Unfortunately, the majority of patients diagnosed with lung cancer have stage 4 (cancer spread to other body parts). The therapies include:

• Targeted therapy – Xalkori (crizotinib), Rozlytrek (entrectinib) and Augtyro (repotrectinib) are the FDA-approved targeted drugs for advanced-stage ROS1 patients
• Chemotherapy – ROS1-positive lung cancer responds well to Alimta (pemetrexed)
• Immunotherapy - immunotherapy is a treatment that boosts the immune system to fight cancer. Profiling of multiple biomarkers, including driver mutations, TMB (tumor mutation burden) and PD-L1 (programmed death-ligand 1), allows doctors and patients to decide their targeted therapies and immunotherapy simultaneously.

Treating advanced lung cancer is often a battle against time. Very rarely, doctors may start patients on chemotherapy while waiting for the molecular test results. If a driver mutation is found, targeted therapy will be ordered as soon as possible.

In Janet Freeman-Daily's case, no approved molecular test and targeted drugs were available for ROS1-positive lung cancer when she was diagnosed. In 2011, she was tested negative for EGFR and ALK, the routine driver mutations tested for advanced NSCLC at that time.

She was first treated with carboplatin, pemetrexed and bevacizumab. She then underwent radiation therapy to shrink her final lung tumor but soon found a new nodule suspicious for cancer. Because of that, she restarted her chemotherapy.

When Xalkori was in clinical for treating ROS1-positive lung cancer, Janet got screened and tested positive for ROS1 rearrangement. She enrolled in the trial. Two months into Xalkori, her PET/CT scan showed No Evidence of Disease (NED). The FDA approved Xalkori for advanced ROS1-positive NSCLC in 2016.

Janet has remained NED till today since she started taking Xalkori in 2013. She has since become a lung cancer patient activist. She is also a writer. She blogs about her cancer journey and advocates for lung cancer research and policy changes.

Janet’s journey is an inspiring testament to the power of resilience and the hope that can arise even in the face of a devastating diagnosis. Despite the initial lack of targeted treatments, she refused to give up and opted for chemotherapy and radiation therapy, taking every opportunity to fight against the disease. She also seized the opportunity when the clinical trial for Xalkori arose.

Janet’s case exemplifies that individuals can develop lung cancer even if they have never smoked. Fortunately, patients can undergo biomarker tests, which is strongly recommended for advanced-stage NSCLC. These tests can identify any genetic abnormalities, including ROS1 rearrangement. Cancer research is constantly progressing, offering newer and better tests. Such advancements enable early detection for individuals, emphasizing the tremendous advantage it brings. Stay informed and consult healthcare professionals to explore all available options. While being diagnosed with cancer is devastating, knowing various detection methods and treatments can bring comfort.