After BTC progression: Are you missing new actionable targets?
No routine rebiopsy after 1L GemCis + IO: Foundational alterations (eg, FGFR2, IDH1) are unlikely to change with chemoimmunotherapy—initial molecular profile generally remains actionable for 2L decisions.
Rebiopsy at targeted therapy progression: Resistance mutations (eg, secondary FGFR2 alterations after pemigatinib) can open new options, directly altering next-line selection.
Liquid biopsy over tissue: Captures tumor heterogeneity across sites and avoids sampling bias of single lesions—more practical and often more informative for resistance mechanisms.
Molecular profiling is now standard in biliary tract cancer—but knowing when to repeat testing is less straightforward.
As targeted therapies expand, clinicians are increasingly faced with a practical question: When does rebiopsy actually change management? Douglas Rubinson, MD, PhD, shares how he approaches sequencing decisions across lines of therapy.
Rebiopsy or not? Timing repeat testing in BTC
First, he notes that, regardless of molecular subtype, first-line treatment for BTCs is gemcitabine plus cisplatin (GemCis) chemotherapy, along with immunotherapy (either durvalumab or pembrolizumab).[]
Beyond this current standard, various immunotherapy approaches are being studied in the treatment of BTCs. These strategies include immune checkpoint inhibitors (ICIs) that block immune-suppressing signals; immune-stimulating agonists; modified T cells that target tumor components (like CAR-T); and cancer vaccines.[]
The TOPAZ-1 trial yielded the first BTC-specific immunotherapy approval. Trial results supported the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic biliary tract cancers. Subsequently, the KEYNOTE-966 trial demonstrated similar positive results when administering the combination of pembrolizumab with gemcitabine and cisplatin.[]
Targeted therapy changes the rules: When repeat sequencing pays off
On failure of first-line therapy, Dr. Rubinson does not typically rebiopsy. Instead, he uses initial sequencing results to guide his choice of targeted therapies. When employing targeted therapy for second-line treatment, Dr. Rubinson often performs a solid or liquid biopsy to determine the reason for the failure. “I really wouldn't expect those targets to change on the basis of giving them first-line chemoimmunotherapy,” he says.
He explains that with targeted therapies, evolutionary pressure is placed on the cancer to develop a way to become resistant to the targeted therapy. “You do sequencing, and you see that the cancer’s picked up a mutation that's allowed it to grow despite the targeted drug the patient is on.”
Dr. Rubinson points to the example of resistant tumors arising after giving pemigatinib, an FGFR2 inhibitor. “Some FGFR2 mutations can arise in response that are still amenable to treatment with futibatinib,” he says.
Often, instead of performing a second solid biopsy, Dr. Rubinson will order a liquid biopsy. Liquid biopsy is effective without burdening the patient with the risk of repeat biopsy or a larger core biopsy.
Related: 3 BTC testing and treatment challenges you can address to improve patient outcomes“I actually think liquid biopsies may be the better option, because if you stick your needle into a lesion in the liver, all you're querying are the genetic changes in the piece of the tumor that you happen to target with the needle biopsy,” he says.
“A liquid biopsy is kind of the integral of all the genetic changes in the cancer anywhere, and so it's allowing you to query all of the progressive disease at once and see what genetic alterations are present throughout the system, as opposed to just where you happen to stick a needle.”
In BTC, initial profiling guides most decisions—but repeat biopsy becomes critical when targeted therapy fails.
Related: Why BTC is uniquely target-rich in GI oncology—and what to test at diagnosis