“So in that sense, it looks like people will be testing more and more, and doing it on liquid biopsy,” Dr. Bhargava says.
Droplet Digital PCR and next-generation sequencing are both options, he says, though every laboratory will have its own setup, and studies evaluating different technologies and platforms are limited. “And if you are an academic medical center and you have your own NGS panel, you’re not going to change based on one specific drug.” Those who order the test will have to plan accordingly. “That’s the challenge and not just with this particular testing, but many other tests that will be coming out.”
As a breast pathologist in anatomic pathology, Dr. Bean isn’t usually involved in this testing, at least not directly. But partly because this is relatively uncharted territory, he has been engaged in discussions nevertheless, and he suggests other breast pathologists might find themselves in the same scenario as well.
“There’s confusion from some clinicians,” he says. “Oncologists might just know they need to get ESR1 testing,” but don’t fully appreciate that this is a blood test, not something that’s typically done on older tissue. ESR1 mutations are dynamic and show up in subclonal percentages, he says, and are unlikely to be present at the time of a patient’s initial diagnosis and surgery.
“There have been times when we’ve gotten a request routed to us in AP,” Dr. Bean recalls, even though the oncologist actually wanted a blood test. On the other hand, he says with a laugh, “There are other times when I’ve misassumed they picked the wrong test and it turns out they did want the tumor tested.” Even though liquid biopsy is preferable, a negative result doesn’t necessarily rule out the presence of the mutation. For all its marvels, liquid biopsy works with minuscule amounts of tumor DNA versus (relatively) abundant material from tissue. “Sometimes the tissue is done as confirmation, or as a second check.”
Given all the up-in-the-air questions associated with this testing, pathologists—AP and CP/molecular—and their clinical colleagues will need to work through multiple management and logistical questions.
“We’re talking about potentially changing the paradigm of how to test, and when to test, and who to test, and how often to test,” Dr. Bean says. “This is something we haven’t done before. So everyone will have questions.”
Figuring out who to test could be a huge logistical and expensive move, he says. “Do you test everyone [who] ever had breast cancer and is on this therapy?” he asks. “Because that’s a lot of patients.” What schedule should the testing follow? The SERENA-6 trial did it every two or three months, as noted, which coincided with routine visits for tumor imaging. There’s also the question of whether laboratories will want to test just for the ESR1 gene or to use a panel.
“It’s fascinating to think about and to see how it might evolve,” Dr. Bean says.
He’s watched how other subspecialty fields, including lung and neuropathology, have embraced molecular testing, using it to shape classification systems of tumors. Breast is yet to take such a path, he says, “because we can get most of the information that’s needed for treating patients appropriately with doing a simple panel of immunohistochemical stains, at least at initial diagnosis.”
Currently NGS is, typically, reserved for patients with metastatic or advanced breast cancers. But at some point, says Dr. Bean, if other genes offer the opportunity to detect recurrences before they show up on imaging, it’s conceivable that NGS will be done earlier. “I’m curious to see if we’ll get to the point of doing NGS on all breast tumors at the time of diagnosis.” But the sheer number of breast cancer patients could make that approach cost-prohibitive, too.