An Overview of ROS1 Positive Lung Cancer

Understanding ROS1 Gene Rearrangement in Non-Small Cell Lung Cancer

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A ROS1 rearrangement is an abnormality in a chromosome that can occur in cancer cells such as lung cancer cells. Chromosomes—and the genes which make up our chromosomes—carry the code for things such as the color of our eyes. They also code (act as a blueprint) for proteins that regulate the growth and division of cells. When one of these genes or chromosomes are damaged, mutated, or rearranged, they code for an abnormal protein, which may then perform abnormal functions, such as driving the growth of a cancer.

A way to think of a gene is to imagine a series of letters which spell out words. When these letters are mixed up, the words come out wrong. If genes on a chromosome are rearranged into different patterns, the words come out wrong as well. If you hear the phrase "gene translocation," this simply means that the letters of the ROS1 gene are abnormally attached to another gene, again resulting in a mix-up in what the letters "spell."

ROS1 Gene Rearrangement

Not all gene mutations and rearrangements are equal. Some code for proteins that act as drivers. The ROS1 gene codes for a protein that acts as a driver is one that can run the show when it comes to cell growth and division. When the gene is rearranged, the abnormal protein may thus drive abnormal growth and division of the cell.

This protein is one of a number of proteins (enzymes) known as tyrosine kinases. These proteins send signals to a cell’s growth center letting it know when to divide and multiply.

ROS1 rearrangements have thus far only been found in people with non-small cell lung cancer and, of this type, only people with lung adenocarcinoma. It has not been found in people who have mutations in EGFR or KRAS or ALK rearrangements.

Compared to other forms of lung cancer, a 2015 study found that:

  • The median age of people with ROS1 rearrangements was 50.5. (The median age for lung cancer, in general, is 72.)
  • It was slightly more common in women in that 64.5 percent were female. (Lung cancer in men is slightly more common than in women.)
  • A greater percentage—67.7 percent—were never-smokers. (Lung cancer certainly does occur in never-smokers, with at least 20 percent of lung cancer in women being in never-smokers.)
  • Out of people with lung adenocarcinoma, 3.1 percent had a ROS1 rearrangement.

Wondering if a tyrosine kinase inhibitor that works for another gene rearrangement—lung  cancer with an ALK rearrangement or ALK-positive lung cancer—would work to block the effects of the abnormal protein produced by a rearranged ROS1 gene? Well, researchers tried a medication that has been successfully used for people with ALK-positive lung cancer. Surprisingly, it worked for ROS1 positive lung cancer even more strongly.

Diagnostic Testing

There are a few ways in which people with lung cancer can be tested to see if they have a ROS1 rearrangement. The test is done on a tissue sample from a lung biopsy or lung cancer surgery. It’s hoped that in the future testing will be available via a liquid biopsy—a test done on blood which can be obtained with a simple blood draw.

Testing methods include immunohistochemistry and fluorescence in situ hybridization (FISH). Studies are ongoing to determine the best methods of testing.

Since people with ROS1 rearrangements do not have KRAS and EGFR mutations or ALK rearrangements (at least not in testing done to date,) testing is usually done for people who are negative for these mutations and rearrangements. You may hear this referred to as “triple negative” non-small cell lung cancer, not to be confused with triple negative breast cancer which is entirely different. In one study, it was found that, out of patients who tested negative for KRAS and EGFR, 25 percent were positive for an ALK or ROS1 fusion gene.

It's thought that anyone with non-small cell lung cancer, especially lung adenocarcinoma, should have genetic testing (molecular profiling) done on their lung tumors. Testing is especially important for young adults with lung cancer, who have a high incidence of treatable mutations and may respond well to one of the medications in the category of tyrosine kinase inhibitors. In addition, it's very important that never-smokers have testing done, as among never-smokers there is a high incidence of mutations and rearrangements.

ROS1 Positive Lung Cancer

ROS1 positive lung cancer is a lung tumor which tests positive for a ROS1 gene rearrangement, one of the known "driver mutations" found in lung cancer. ROS1 positive lung cancer accounts for only one percent to two percent of lung cancers. But, considering how common lung cancer is, it still represents many people with this disease. 

ROS1 rearrangements were first found in glioblastoma multiforme, a type of brain cancer, and have also been found in some other cancers, including ovarian cancer, colorectal carcinoma, gastric cancer, and cholangiocarcinoma.

It's important to emphasize that the type of gene rearrangement we are talking about is an acquired genetic change. Unlike some genetic mutations and rearrangements that people are born with, some of which can predispose people to cancer, the ROS1 gene rearrangement isn't present from birth. You don't have to worry that your children will inherit the rearrangement.

Treatment

  • Surgery—For people with stage I to stage IIIA, lung cancer surgery may be an option. Not all tumors of these stages are operable, but when they are, surgery may offer the chance for a cure.
  • Chemotherapy—Besides targeted therapy, some chemotherapy agents are also effective in ROS1 positive tumors. ROS1 positive lung cancer appears to be particularly sensitive to the chemotherapy drug Alimta (pemetrexed) with over 50 percent of people responding to the drug in one study.
  • Targeted therapies—Xalkori (crizotinib) is a tyrosine kinase inhibitor that was originally approved for ALK-positive lung cancer. It is recommended first line—that is, before any other treatments (though other treatments may be used at the same time) as well as for anyone who has had prior treatments for the disease. This medication was approved for ALK-positive lung cancer in 2013 and created excitement later when phase I clinical trials with people with ROS1 lung cancer responded even better to the drug. In these clinical trials, the number of people who responded to the drug was between 70 and 80 percent. The drug was given breakthrough therapy designation for treating ROS1 positive lung cancer in April of 2015.
  • Clinical trials—Other medications, particularly targeted therapies, are being studied in clinical trials for people with ROS1 positive lung cancer. Some of these include Zykadia (ceritinib), another drug similar to crizotinib that is approved for ALK-positive lung cancer. Other medications that are being studied for lung cancers positive for a ROS1 rearrangement include Cometriq (cabozantinib) and foretinib. To learn more about clinical trials for lung cancer, consider contacting the free clinical trial matching service available for all lung cancer patients.

Brain Metastases

ROS1 positive lung cancers too commonly spread to the brain. It’s estimated that 25 percent to 40 percent of people diagnosed with non-small cell lung cancer will develop brain metastases within the first two years of treatment. 

Unfortunately, Xalkori (crizotinib) doesn’t work very well for brain metastases in people with ROS1 positive lung cancer. This medication, as many, does not cross the blood-brain barrier very well. The blood-brain barrier is a control system of specialized membranes that work to prevent toxins (as well as chemotherapy drugs) from entering the sensitive environment of the brain.

Radiation therapy for metastases to the brain in people with lung cancer can work fairly well. And it has been found that people with ROS1 rearrangements have tumors that may be particularly sensitive to these treatments. Radiation may be given in a couple different ways:

  • Stereotactic radiotherapy—In this approach, which you may hear called “cyberknife” or gamma knife, radiation is delivered to localized spots in the brain.
  • Whole brain radiotherapy—With whole brain radiation therapy, the entire brain is treated with radiation.

The choice between these two treatments is an area of debate. Stereotactic radiotherapy—since it only treats a small portion of the brain—has fewer side effects. Yet, whole brain radiotherapy may lessen the chance of recurrent brain metastases—something that is very common in people who have had brain metastases already.

The number of “spots” also plays a role in this decision. People who have a few—up to three or four metastases—are more easily treated with the stereotactic method than those who have multiple metastases.

Drug Resistance

Most people eventually become resistant to Xalkori (crizotinib) due to new acquired mutations. A new medication in this category, Cometriq (cabozantinib), appears very promising in initial studies. It seems to be able to overcome resistance from these secondary mutations in early studies.

Prognosis

ROS1 positive lung cancers tend to be aggressive and grow and spread fairly rapidly, but also respond in an almost unprecedented way to targeted therapy. Since treatment was just recently approved, it's hard to know what a person's life expectancy will be on average. But, the responses seen thus far are encouraging.

In one study the median amount of time that Xalkori worked (the time after which it had stopped working for half of the people but was continuing to work for the other half) was 17 months; the majority of people treated responded to the drug.

It's hoped that when people become resistant to this medication that others will be available, approved, or in clinical trials that can then replace the medication that has stopped working. As noted, there are signs that this may be the case.

In the near future, hopefully, lung cancer with these mutations and rearrangements will be treated more like a chronic disease, such as how we treat diabetes. Even if the cancer is not yet curable, it will hopefully be controllable.

A Word From Verywell

Nobody should go through lung cancer alone. If your loved one has been diagnosed with lung cancer, check out these thoughts about when your loved one has lung cancer.

Becoming involved in a lung cancer community may be very helpful, even for those who ordinarily shun groups. Since ROS1 positive lung cancer is fairly uncommon, it’s unlikely that you’ll find many people in your community who are experiencing the same physical and emotional challenges that you are.

In 2015, at the LUNGevity HOPE Summit, a group formed which consists exclusively of people facing ROS1 positive lung cancer. This is an exciting era for people with lung cancer, as patients are working side-by-side with doctors not only to understand their disease, but to give input on research that still needs to be done.

Sources:

Davare, M., Saborowski, A., Eide, C. et al Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins. Proceedings of the National Academy of Sciences of the United States of America. 2013. 110(48):19519-24.

Drilon, A., Somwar, R., Wagner, J. et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clinical Cancer Research. 2015 Dec 16.

Katayama, R., Kobayashi, Y., Friboulet, L. et a. Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer. Clinical Cancer Research. 2015. 21(1):166-74.

Lukas, R., Hasan, Y., Nicholas, M., and R. Salgia. ROS1 rearranged non-small cell lung cancer brain metastases respond to low dose radiotherapy. Journal of Clinical Neuroscience. 2015. 22(12):1978-9.

Mazieres, J., Zalcman, G., Crino, L. et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. Journal of Clinical Oncology. 2015. 33(9):992-9.

Sequist, L, and J. Neal. Personalized, genotype-directed therapy for advanced non-small cell lung cancer. UpToDate. 01/12/16.

Shaw, A., Ou, S., Bang, Y. et al. Crizotinib in ROS-1 rearranged non-small-cell lung cancer. The New England Journal of Medicine. 2014. 371(21):1963-71.

Solomon, B. Validating ROS1 Rearrangements as a Therapeutic Target in Non-Small-Cell Lung Cancer. Journal of Clinical Oncology. February 9, 2015.

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