Solid Tumors
We’ve seen how molecular testing uncovers the specific genetic mistakes driving leukemias. Now, let’s move into the complex and incredibly diverse world of solid tumors. These are cancers that form a mass, like lung, colon, breast, or skin cancer. If leukemias are often caused by one big “smoking gun” event like a translocation, you can think of solid tumors as being caused by a conspiracy of smaller genetic mistakes that accumulate over time
Molecular diagnostics for solid tumors has completely transformed oncology. We are no longer just identifying a cancer by its location (e.g., “lung cancer”). We are identifying it by its unique genetic driver mutations. Our job in the lab is to read the tumor’s “genetic owner’s manual” to find the specific broken parts. This provides a molecular roadmap that tells the oncologist which targeted drugs will work and which will fail. It’s the ultimate in personalized medicine
The Goal: Finding an “Actionable” Target
The entire point of most solid tumor molecular testing is to find an actionable mutation. This is a specific genetic alteration for which a targeted therapy exists. We’re looking for the tumor’s “Achilles’ heel.” This usually falls into one of two categories:
- A Stuck Gas Pedal (Activating Mutations in Oncogenes): Oncogenes are genes that normally tell the cell to grow. In cancer, they can get a mutation that makes them permanently “on,” like a gas pedal stuck to the floor. Targeted drugs can act as a “boot” that pulls the pedal back up
- Cut Brake Lines (Inactivating Mutations in Tumor Suppressor Genes): Tumor suppressor genes are the cell’s braking system, telling it to stop growing or to die if it’s damaged. If these genes are mutated and inactivated, the cell loses its brakes. While it’s harder to fix a broken brake line, some newer drugs are finding clever ways to do it
The “Case Files”: Key Examples by Tumor Type
The best way to understand this is to look at some of the most common scenarios we see in the molecular oncology lab
Lung Cancer (Non-Small Cell)
Lung cancer is the poster child for molecularly-guided therapy. Before molecular testing, all patients received generalized chemotherapy. Today, treatment is dictated by the tumor’s genetics
- EGFR: Mutations The Epidermal Growth Factor Receptor (EGFR) gene is a classic oncogene. Certain mutations, particularly deletions in Exon 19 and a point mutation called L858R, make the EGFR protein hyperactive. This is a direct target for EGFR inhibitor drugs like osimertinib. Testing for these mutations is standard practice for all patients with lung adenocarcinoma
- ALK: Rearrangements Similar to the translocations in leukemia, the ALK gene can fuse with another gene (like EML4), creating a fusion protein that drives cancer growth. Patients with ALK-positive lung cancer see incredible responses to ALK inhibitor drugs
- KRAS: Mutations For a long time, finding a KRAS mutation was considered “undruggable” and was bad news. It predicted a patient would not respond to EGFR inhibitors. Recently, however, new drugs have been developed that can specifically target one of the most common KRAS mutations (G12C), turning this from a prognostic marker into an actionable target
Colorectal Cancer
- “RAS Pathway” Mutations: Mutations in the KRAS and NRAS genes are critical to test for. If a colorectal tumor has a mutation in either of these genes, it means the growth signaling pathway is already activated downstream of EGFR. Therefore, giving that patient an EGFR inhibitor drug would be like blocking a dam upstream when the flood is already happening downstream—it’s completely ineffective. This is a classic example of using a molecular test to predict a lack of response
- BRAF: V600E Mutation This specific mutation identifies a particularly aggressive subset of colon cancers but also provides a specific target for BRAF inhibitor drugs
Breast Cancer
- HER2 (ERBB2): Amplification This is a classic example of a “gene amplification”—where the tumor makes dozens or even hundreds of extra copies of the HER2 gene. This leads to a massive overproduction of the HER2 protein on the cell surface, driving aggressive growth. This is tested by FISH or CISH (looking for extra gene copies) or immunohistochemistry (IHC, looking for excess protein). Finding HER2 amplification is crucial because it means the patient is eligible for the highly effective targeted drug trastuzumab (Herceptin)
- PIK3CA: Mutations These are common mutations in hormone receptor-positive breast cancer and are another example of a target for a specific class of inhibitor drugs
Beyond Single Genes: Immunotherapy and the Liquid Biopsy
The field is constantly evolving. Two major advances are changing the game
Predicting Response to Immunotherapy
Immunotherapy drugs called checkpoint inhibitors work by “releasing the brakes” on the patient’s own immune system, allowing it to recognize and attack the cancer. But they don’t work for everyone. Molecular testing can help predict who will benefit
- Microsatellite Instability (MSI): Some tumors have a broken DNA mismatch repair system. This causes them to accumulate thousands of mutations, especially in repetitive DNA sequences called microsatellites. These “hypermutated” tumors look very strange to the immune system and are highly susceptible to immunotherapy. MSI testing is now standard for colorectal, endometrial, and other cancers
- Tumor Mutational Burden (TMB): This is a measurement of the total number of mutations per megabase of DNA in a tumor. A high TMB, like MSI, means the tumor has many novel proteins that the immune system can recognize, making it a good candidate for immunotherapy
The Rise of the Liquid Biopsy
Getting a tissue biopsy can be difficult and invasive. The liquid biopsy is a revolutionary alternative. It involves drawing a simple blood sample and analyzing the tiny fragments of circulating tumor DNA (ctDNA) that are shed from the tumor into the bloodstream. This can be used to: 1. Find initial actionable mutations when a tissue biopsy is not possible 2. Monitor treatment response (a dropping ctDNA level is a good sign) 3. Detect the emergence of new resistance mutations (like the EGFR T790M mutation) without needing a new invasive biopsy
Key Terms
- Targeted Therapy: A type of cancer treatment that uses drugs designed to “target” specific genetic mutations, proteins, or other changes in cancer cells, leaving normal cells largely unharmed
- Oncogene: A gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell by promoting uncontrolled cell growth. Often called the “gas pedal” of the cell
- Tumor Suppressor Gene: A gene that protects a cell from becoming cancerous by controlling cell growth, repairing DNA, or initiating cell death. Its inactivation can lead to cancer; often called the “brakes” of the cell
- Companion Diagnostic: A molecular test used as a prerequisite to determine if a patient is eligible for a specific targeted therapy. The test and the drug are developed and approved together
- Microsatellite Instability (MSI): A condition of genetic hypermutability that results from a defective DNA mismatch repair system. Tumors with high MSI (MSI-H) are highly responsive to immunotherapy
- Liquid Biopsy: A test done on a sample of blood to look for cancer cells or for pieces of DNA from a tumor (ctDNA). It is a non-invasive alternative to a tissue biopsy
- ctDNA (Circulating Tumor DNA): Fragments of DNA originating from tumor cells that are found circulating in the bloodstream. They carry the same mutations as the tumor itself