Sunday, October 24, 2021

It is a truism that genes and genetic changes play a fundamental role in the manifestation of the cancer phenotype, the traits that a malignant cell manifests, as we concluded in our last article. All of the genes that are active in cancer are present in all of our cells, even under normal circumstances. This is important to appreciate—there is no gene in a cancer cell that is not present in the human genome during our normal lifetimes. It is just that in a malignant cancer cell these genes become expressed in the wrong way—overexpressed or underexpressed at the wrong time.

Thus, there are genes whose overexpression leads to a higher likelihood of the cell becoming malignant. These genes are known as oncogenes. Likewise, there are genes whose normal role is to suppress or inhibit the manifestation of malignancy—for these tumor suppressor genes, something occurs, usually a mutation in a critical location, which inactivates them so that they no longer are able to suppress malignancy.

Under normal circumstances, in all of our cells for most of our lives, these tumor expressor genes and tumor suppressor genes coexist in balance so that the cell is and appears to be normal, i.e., nonmalignant. But as I indicated, the genes get out of balance and so the cell behaves increasingly abnormal until it becomes fully malignant. What causes this? A topic for another day.

An example of an oncogene is HER2-neu (human epidermal growth factor receptor 2), which is over-expressed in 20% of breast cancer. In those cases of breast cancer, it has an unusually dominant effect on the malignant expression of the tumor. Extra copies of this gene are made. The breast tumors which have this marker are theoretically at higher risk with worse survival.

But this oncogene also gives us an unusual opportunity: Because it is this oncogene that is driving the cancer cell to express itself and create the problem, then a drug that obstructs or inhibits the oncogene (or the protein it produces) would have the opposite effect.

Dennis Slamon, formerly at Genentech and now at UCLA, working with others, persisted over more than a decade to develop an antibody that could inhibit the HER2 receptor protein. This antibody, known as Herceptin or trastuzumab, was initially utilized in women with HER2-positive metastatic breast cancer and dramatically increased their response rate to multi-drug chemotherapy regimens and their survival rates, as presented in 1998. This success led to its being extended to use in the adjuvant setting (women with resected localized HER2-positive breast cancer). A study, published with Slamon as first author in the New England Journal of Medicine in 2011, randomized over 3000 women with HER2-positive early stage resected breast cancer to the usual chemotherapy with or without one year of Herceptin. At five years of follow-up, the overall survival was 92% for the Herceptin group versus 87% for the chemotherapy-alone group.

Gastrointestinal stromal tumors (GISTs) are uncommon sarcomas (about 5,000 each year in the U.S.) which occur in the small bowel primarily or elsewhere in the GI tract. Depending on their size and other characteristics at diagnosis, they can be difficult to treat and quite deadly. About 80% of them are associated with a mutation in the KIT gene which turns on a cascade of proteins that control various cellular growth and proliferation pathways. Certain types of these mutations can turn on these pathways permanently so that the cellular proliferation and growth becomes uncontrolled and the cell becomes malignant; thus, the KIT gene acts as an oncogene. Again, its overexpression is the control switch that causes the GIST to be expressed and potentially deadly. Importantly, a similar genetic mutation is found in Philadelphia-positive chronic myelogenous leukemia (CML), and the bcr-abl protein is produced as a result, causing the expression of the CML.

The scientists who sought to inhibit these oncogenes and the proteins they produced did so by rational drug design and sheer brute force. They basically screened every drug library for a drug that would inhibit this protein using high-throughput screening. When they finally found one drug that had some efficacy, they then modified it chemically in various ways until it became more and more efficacious. The end result was imatinib (Gleevec). This drug completely revolutionized the treatment of both CML and GIST. The survival of people with CML has now almost approached those of healthy patients.

These two drugs are prime early examples of the success of precision medicine. In precision medicine, a genetic understanding of the tumor is utilized to customize our approach to its care, also known as personalized medicine. Thus, rather than giving Herceptin to all women with breast cancer when only 20% have any potential of benefiting from it, by identifying the marker in advance, we can subject only 20% to taking the drug for a year, to its costs and side effects and benefits, and spare the other 80% the futility of receiving a useless drug.

Next week, we will resume with a discussion of tumor suppressor genes in Thoughts on Cancer.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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