Historically, FLC has been diagnosed as a primary tumor arising from the liver, with highly distinctive features that are apparent when the cancer cells are examined under the microscope. Most notable are the fibrous bands that gave it the name “fibrolamellar”. The Guideline adds a strong consensus recommendation to supplement microscopic examination of tissue with diagnostic molecular testing for a genetic abnormality specific to FLC cancer cells. This follows from compelling evidence, accumulated over the past dozen years, that a unique “gene fusion” mutation found in ~99% of FLC tumors is necessary, and possibly sufficient, to cause and maintain the cancer.
The genetic mutations that cause and sustain FLC affect protein kinase A (PKA), an important regulator that contributes to the control of cells’ energy use, gene activity, growth, and division. In ~99% of FLC tumors, the cancer cells contain a deletion (loss of DNA) that fuses PRKACA, the gene for the active enzymatic chain of PKA, with DNAJB1, an unrelated nearby gene. The structure of the resulting protein “chimera” (abbreviated DNAJ-PKAc, or simply DP) is identical in every case. The fusion alters the quantity and/or regulation of PKA such that its activity runs amok, changing gene expression, causing persistent uncontrolled cell growth, and driving resistance to cell death pathways – important hallmarks of cancer cells.
Molecular Testing
Testing for the DP fusion can be carried out from samples shaved from blocks of wax-embedded tumor tissue that are routinely used to prepare microscope slides for hospital pathologists. Deep characterization of the RNAs made by a patient’s tumor cells is now offered by several commercial labs, and it can routinely detect the critical RNA species found only in FLC and other cancers driven by the DP fusion protein. In addition, a specialized diagnostic assay for the chromosomal deletion associated with the gene fusion is offered by Mayo Clinic Laboratories [PRKAF (Fibrolamellar Carcinoma, 19p13.1, FISH, Ts)].
The Guideline also recommends the use of DNA sequencing to identify any additional gene mutations, identified in various cancers, that might predict sensitivity to specific “precision” cancer therapies. However, other than the nearly universal DP gene fusion, it acknowledges that actionable mutations are seen only rarely in FLC, which is genetically more stable than most other cancers.
Targets for Therapy
Some emerging precision approaches are seen as potentially more widely applicable in FLC than hunting for gene mutations other than the DP fusion. One is the identification of certain “target” proteins present at high levels on the outer surface of some types of cancer cells, but at much lower levels or not at all on most normal cells throughout the body. Such targets can be exploited for treatment using a growing class of drugs called “antibody-drug conjugates” (ADCs). These are “molecular smart bombs”, designed to deliver a “payload” of an extremely toxic chemotherapy drug directly to cancer cells, thereby increasing efficacy while substantially decreasing the risk of side effects compared to the chemo drug alone.
One ADC already being tried in FLC patients uses as its “guided missile” an antibody to a protein called HER2. Recent studies show that this drug, commercial name Enhertu, is beneficial not only to treat high-HER2 expressing tumors of the breast, for which it was first developed, but also for certain cancers of other organs that make HER2 at somewhat lower levels. Such “tumor-type agnostic” use of Enhertu recently was approved by the US Food and Drug Administration (FDA), and it is potentially applicable to FLC patients whose cancers make enough HER2. Preliminary studies indicate that other ADCs, currently in clinical development, also could be useful for many FLC patients. Matching an ADC to an individual patient’s cancer is most readily done by “immunohistochemistry”, to stain cancer cells that express the target with a labeled form of the relevant target-seeking antibody.
Assessing Cancer Cell Burden
Yet another emerging arena of cancer diagnostics focuses on determining the overall cancer burden, that is, the number of live cancer cells present in a patient, especially one in whom treatment already may have eliminated all tumors visible by radiological imaging (e.g., CT, PET/CT, MRI, or Bone Scans). The method addresses the problem that a tumor just below the threshold for detection by such imaging may still contain in the range of 100 million to 1 billion cancer cells, more than enough to cause fatal recurrence of disease.
Tests to determine the extent of “minimal (or measurable) residual disease” (MRD) in patients with clean scans have gained traction because of evidence that the eradication of all detectable cancer cells strongly favors extended survival. Some assays for MRD measure “circulating tumor DNA (ctDNA),” by detecting in a patient’s blood DNA sequences that come from their cancer cells. The Guideline notes that a report has appeared on the use of one such an assay, called Signatera, to track MRD in FLC patients, with promising results. However, there is concern that the test apparently failed to detect ctDNA in some of the patients who subsequently experienced tumor recurrence. Other tests for the extent of MRD rely on the detection in a patients’ blood of chemicals or proteins secreted by living cancer cells. The are often referred to as “biomarkers.” One biomarker for FLC is ammonia, which, unusually among malignancies, is produced by the cancer cells due to a quirk in their metabolism. In addition, a very recent paper indicates that FLC cells secrete substantial quantities of procalcitonin (PCT), a precursor of a hormone normally made in the thyroid gland. Small amounts of PCT can be measured accurately in serum, and the paper provided encouraging evidence that this test will serve as an important new “biomarker” for FLC diagnosis and disease monitoring.