Understanding the Genetics of Cancer

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Knowing what genetic alterations drive a cancer can guide treatment.

When cancer is diagnosed - whether the condition is inherited or not - it's essential that patients and their doctors consider whether the disease is driven by any faulty genes or proteins that are treatable with targeted drugs or immunotherapies.

If tests of tumor tissue at biopsy or before surgery show this is the case, patients may be able to take drugs that specifically target these glitches, rather than chemotherapies that affect their whole bodies. For some, targeted drugs or immunotherapies can be more effective and cause fewer side effects than chemotherapy, or sometimes they are given with chemotherapy. Targeted drugs work by disabling the activity of genes, proteins or tissue environment that contributes to cancer. Immunotherapy boosts the body's natural defenses against cancer.

The Food and Drug Administration (FDA) has approved targeted drugs for the treatment of a variety of cancers, including lung, which can be driven by EGFR mutations, ALK rearrangements or the very rare ROS1 mutations; melanoma, which can arise from the BRAF mutations; breast, which can overexpress the protein HER2; and colorectal, which can feed off the overexpressed proteins EGFR or VEGF. Targeted drugs known as PARP inhibitors have been approved by the FDA in advanced or previously treated breast, ovarian, prostate and pancreatic cancers driven by mutations to the BRCA or other genes. There is a growing number of cancers for which targeted therapies have been approved, including lung, stomach, bladder, cervical, brain, head and neck, skin, kidney, liver, gastrointestinal stromal tumor, endometrial, colorectal, esophageal, thyroid and some blood diseases.

In addition, immunotherapies known as checkpoint inhibitors work against a growing number of cancers, including lung, melanoma, head and neck, bladder, liver, stomach, cervical, Hodgkin lymphoma, squamous cell carcinoma of the skin and some kidney and breast cancers, mainly by targeting the proteins PD-1 or PD-L1. Two of these drugs are approved to treat several advanced cancers that have abnormalities in their ability to repair damage to their own DNA, including certain colorectal and endometrial cancers.

Scientists are finding that cancers that originate in different parts of the body may share the same mutations. That means that, even if there is no targeted treatment approved for a particular cancer, there may be one on the market, or in clinical trials, that could work for a patient based on the mutations their disease expresses. Furthermore, new treatable mutations may emerge as a cancer progresses, or in response to therapy.

Therefore, it’s important that patients diagnosed with cancer or a recurrence ask their doctors to test them for any mutations that are known to be targetable with drugs.

TREATING GENETIC MUTATIONS, NOT CANCER TYPES

Although most treatment is based on where the disease developed in the body, such as the breast, colon, prostate or liver, a growing trend focuses on treating a cancer based on the genetic mutations that drive it.

The FDA has approved a number of drugs to treat several cancer types that develop due to the same mutations. A few examples: Herceptin (trastuzumab), which treats cancer that expresses too much of the protein HER2, can be used for both breast and stomach cancers. Avastin (bevacizumab), which slows the growth of blood vessels needed to support a tumor, is approved to treat colorectal, lung, kidney, cervical and ovarian cancers, as well as the brain cancer glioblastoma. A combination of Tafinlar (dabrafenib) and Mekinist (trametinib), which stop the proteins MEK and BRAF from stimulating out-of-control cell growth, can treat melanoma, non-small cell lung cancer and thyroid cancer.

Recently, the FDA approved some immunotherapies for even broader use. Keytruda (pembrolizumab) and Opdivo (nivolumab) can treat any cancer with microsatellite instability-high or mismatch repair-deficient status. These tumors have trouble repairing their own damaged DNA. The immunotherapies can treat any cancers that have this status, regardless of where they started in the body, marking the first FDA approvals of drugs to be given based on a cancer’s genetic mutations, rather than its type.

Another first occurred when the FDA approved a different drug for use across cancer types. Vitrakvi (larotrectinib) stops abnormal proteins that are generated by an NTRK gene alteration that stimulates cancer cells to grow. The agent is approved to treat any advanced solid tumor with the NTRK alteration. Also approved to treat that gene alteration is Rozlytrek (entrectinib).

Some clinical trials follow a similar principle when testing new cancer treatments. Basket trials enroll patients with any cancer type, as long as it is driven by a specific genetic mutation, and give them a medication that targets the problem. Alternatively, umbrella trials enroll patients with the same underlying origin of cancer, such as breast or pancreatic, but gives them different targeted therapies based on the mutations that make their cancers grow. In Lung-MAP (lung-map. org), for example, patients with lung cancer are receiving different medications based on the mutations driving their disease, and NCI-MATCH (https://tinyurl.com/ydcrxbdv) is enrolling patients with various types of solid tumors and lymphomas and treating them based on the mutations their cancers express.