Markers, methods remake the NSCLC map

“This is a great use case for reflexive testing,” Dr. Sholl says. The trial included only patients whose tumors had L858R and ex19del mutations. “You can rationalize the use of focused assays for EGFR”—which are fairly inexpensive, she adds—“just looking at those particular alterations.”

She and her colleagues focus on all patients who get their tumors resected at Brigham and Women’s—EGFR testing is initiated when the pathology is signed out. “We choose the best block and send it right off to the lab.”

KRAS is another old-timer getting a makeover. It’s the most commonly seen lung cancer mutation, Dr. Beasley says. Although not recommended now, early on, given the relatively high frequency of occurrence, testing for KRAS alone was considered cost-effective. While KRAS itself was not amenable to targeted therapy, the presence of a KRAS mutation typically excluded the presence of EGFR mutations, indicating a patient was unlikely to respond to EGFR TKIs, the chief treatment at the time.

That has been turned on its head more recently. Now people are interested in the KRAS status because the presence of a G12C mutation enables patients to go on potentially promising targeted therapies. Labs thus need to perform tests that tell exactly what the mutation is. Black box genotyping approaches that discern a KRAS mutation but don’t specify which one are no longer appropriate, Dr. Beasley says.

KRAS mutations are complex, and the number of co-mutations could be high. Given that the tumor mutational burden is often high, it will be interesting to follow ongoing KRAS G12C trials to see if co-mutation types and mutational burden inform response rates to targeted therapies, Dr. Sholl says. Her medical oncologist colleagues tell her that toxicities associated with G12C inhibitors might make the drugs slightly less appealing than EGFR (or other) TKIs. With the availability of good immunotherapy and combined chemo-immunotherapy, “It’s a more complex thought process to figure out the right thing for patients in the frontline setting,” she says, although the answer will ultimately rest with whether G12C inhibitors are approved.

If no biomarker (or child) is special, “No single assay is perfect,” Dr. Sholl says. “Having multiple lines of evidence can be helpful, especially if you’re potentially dealing with novel alteration. You can’t close the door on any of our techniques that we’ve been working on for years.”

Nevertheless, for labs that have been using the serial dating approach to lung cancer biomarkers (but keeping them all), might the time be ripe to update their approach?

“To get comprehensive testing, you need multimodality or at least a DNA and RNA combined next-gen sequencing approach,” says Dr. Tafe.

Dr. Sholl concedes her bias is toward comprehensive sequencing, having used it for years. It does pick up mutations in other areas of genes that may be meaningless—at least for now—which invites more questions. It’s also, to some extent, a clinical discovery tool. Because it’s impossible to anticipate all the varied mechanisms that can activate different oncogenic pathways, “having an agnostic, unbiased test can show you things you didn’t know to expect. That’s important, now that we understand just how heterogeneous the mechanisms of activation are for many of the oncogenes. We may discover alterations that are actually more common than we realized—we just haven’t gone about looking for them the right way.”

NGS could also help boost biomarker testing rates, which, experts agree, need to be boosted. (See “In NSCLC, biomarker testing rates fall short,” CAP TODAY, June 2020.)

But technique isn’t everything. RET testing is critical, for example, but it doesn’t require NGS. As Dr. Sholl notes, “We’ve had the techniques to detect these fusions for many, many years.

“But that doesn’t mean we get paid to do it,” she adds.

This is a sticking point. No test can sustain a solo act. Even the best biomarker needs a posse: an FDA-approved targeted drug and an NCCN stamp of approval. Without them, labs will be reluctant to perform it clinically.

The reflexive EGFR testing at Dr. Sholl’s lab delineates the problem. Patients getting lobectomy or some kind of anatomic lung resection and mediastinal staging will be discharged within a few days, while the lab is still working up the pathology. Medicare rules are such that the lab will not get paid to do molecular testing on samples obtained in the inpatient setting when performed within the first two weeks of the patient leaving the hospital. “We essentially recognized that we were going to eat the costs of this. But because it was a low-cost endeavor, and because it looked like the right thing to do to get patients onto osimertinib, we just rolled it out.”

Dr. Sholl asked her oncologist colleagues how long they could wait for EGFR mutation status. It appeared two months might be acceptable. That might allow labs to rationalize not doing the test reflexively and instead wait for the clinician to order the test when they see the patient in clinic postsurgically. But dancing past Medicare’s 14-day rule has its own downsides: The clinician may neglect to order the test, and labs will need to go back and pull tissues a second time.

Reflexive testing is less cumbersome, “but you have to have a hospital that’s willing to accept the risk of not getting paid,” Dr. Sholl says. At her institution, that meant “a detailed conversation with our finance people and our compliance office to make sure it was all aboveboard and appropriate.” It helped that the ADAURA results were so compelling that when oncologists knew they had a patient with an EGFR mutation and a IB–IIIA tumor, “It was very clear what they were going to do.” If the drug hadn’t received such quick approval, they would likely have considered osimertinib use off-label. “So we felt justified in the approach we took.”

Dr. Beasley and her colleagues at Mount Sinai “have worked very hard to find a solution” to the ordering piece, to avoid duplicate testing and related billing issues, as well as delays in testing. “What we finally ended up doing was having a standing blanket order for all the tumors that might need testing.”

At Dartmouth-Hitchcock, pathologists will automatically order the molecular and PD-L1 testing upfront in NSCLC cases. “That gets the ball rolling as soon as we have a diagnosis,” Dr. Tafe says.

Labs could more easily provide needed comprehensive testing, says Dr. Sholl, “if we didn’t get nickeled and dimed at every turn.” Following up initial EGFR and ALK tests using NGS is cheaper and easier than running six or seven single-gene assays to fill in the rest of the targets. But payers won’t reimburse for a second EGFR or ALK test that’s part of the panel, nor will they consistently pay for a panel code. “What are we supposed to do?” Dr. Sholl asks.

Comprehensive testing is better for patient care and saves money in the long run. “I don’t want to throw insurers under the bus, although sometimes I do,” Dr. Sholl laughs. While there’s been a broad push to give targeted therapies, “appropriate testing has not been incentivized.” Biomarker testing, she says, is “the forgotten stepchild of oncology.”

The nudge toward NGS is likely to persist. “As we add on more and more biomarkers, a sequential strategy is simply not viable,” Dr. Sholl says. “Just tagging on yet another variant to a long list of complex variants that we need to pick up is not, operationally, a good way to go. You’ve got to flip the switch over to more of a panel-based approach to get all these things.”

“You need to be doing a multigene panel,” Dr. Beasley agrees, “and NGS in particular, because the number of potentially targetable mutations is just going to keep changing and growing.” When a new marker emerges, “I just verify it’s part of our panel—it usually is.”

“People need to realize that these more infrequent mutations, like RET and MET, are evolving to the point where they have targeted therapies,” she continues. “So they need to be doing a bigger panel. And NGS is the best way to do that.”

NGS is useful in another regard, Dr. Beasley says. “We see more and more lung cancer patients with multiple tumors.” NGS can help sort out whether they belong to the same tumor, or if they’re multiple synchronous primaries, which is important to know for treatment strategy and prognosis.

And because lung cancer has been the poster child for doing more tests with small biopsies, NGS helps with efficiency, Dr. Tafe says. “Doing more and more targets used a lot of tissue when we were doing single-gene assays.”

But it’s not as if once a drug is approved, “you snap your fingers and you get the right platform in your lab the next day,” Dr. Sholl says. “We end up playing catch-up.”

There’s the negotiation for capital equipment upgrade, for starters. And even if the hospital green-lights the expense, there’s the validation of an entirely new panel. It also requires personnel with the experience to run it. “That’s not always available in every practice,” says Dr. Beasley.

Even the larger academic labs have their personnel problems. Dartmouth-Hitchcock uses a third-party vendor for the bioinformatics piece. “You don’t have to have a team of 20 bioinformaticians in order to do this type of testing,” Dr. Tafe says. “It’s not our dream to always be that way, but it has filled in some gaps, where we haven’t had the manpower to cover those areas of expertise to build out our own pipelines.”

If a lab recognizes its internal assays are no longer sufficient to perform comprehensive workups, send-outs are an option. But that can be expensive.

They can also take longer, says Dr. Sholl. “The reality is, these big, hybrid-capture assays that a lot of us have adopted over the last seven or eight years just take a long time. It’s complex chemistry. It can take a day just to go through the bioinformatics pipeline.” A 500-gene assay, from start to finish, takes a minimum of one week, “and often it’s closer to two weeks. And it can be longer than that, depending on logistical hurdles of getting the specimen into the lab.”

That’s why Dr. Sholl expects to see labs continue using quick, very focused assays to ensure basic testing. EGFR assays are robust, and ALK and ROS1 can be tested quickly with IHC.

Sometimes the need for speed is paramount. At Dartmouth-Hitchcock, “We keep a few single-gene assays live and available for some circumstances—where there’s high clinical suspicion in advanced stage disease, and that one-week difference would make a difference in the patient’s care,” says Dr. Tafe.

But complications can arise quickly as well. Dr. Sholl describes this typical scenario: A patient pre-sents with an aggressive sarcomatoid lung cancer with widely disseminated metastases. The tumor is negative for EGFR mutation, and ALK and ROS1 IHC are negative as well; PD-L1 is 90 percent. “If you read the letter of the law for immunotherapy approvals, this person is ideal” for such treatment, Dr. Sholl says. If full-panel sequencing results will take two weeks, “What are you going to do?” Often patients will be started on chemo or chemo-immunotherapy before full genotyping results are available.

On the other hand, some results come almost too quickly, often through the back door. Cell-free DNA tests are now pervasive, Dr. Sholl says. Their value is real; so are the headaches they cause. Results typically are sent directly to the clinicians. These private transactions mean the data isn’t flowing to the lab. Dr. Sholl has had cases where a sample is sent out for cell-free testing “literally before we get a diagnostic biopsy. We spend five days trying to figure out what a poorly differentiated tumor is,” while the clinician already knows there’s an ALK rearrangement, for example.

Even when the information makes it into the medical record—and there’s no guarantee it will—it’s an odyssey trying to find the information. Says Dr. Beasley, “We usually don’t know the results.” That can, furthermore, create issues if patients change oncologists or seek a second opinion. “Having all of these different, outside tests is being recognized as a problem.” It’s a pending point of discussion with clinicians at Mount Sinai—even they are struggling to keep up with so many free-floating results. “But we haven’t found a solution yet.”

As the list of biomarkers swells, pathologists might also be feeling overwhelmed. “In all fairness, this is hard to keep up with if you’re not solely dedicated to lung,” Dr. Beasley says. Mount Sinai is very subspecialized—her own practice is almost exclusively focused on thoracic.

Also worth remembering, says Dr. Beasley, is that lung cancer doesn’t account for a substantial percentage of most pathology practices. CME won’t necessarily help. “You’re going to be focusing on things you do the most,” such as prostate, GI, breast. A similar story unfolds on the clinician side. “As you get away from subspecialized practices, you get people who are treating all comers for cancer, as opposed to just focusing on one cancer. It’s just so difficult to keep up with this literature, because everything’s coming at you so quickly.”

Dr. Sholl is the first to admit, “I live and breathe this stuff, but not everybody does.”

Even Dr. Beasley says she relies on oncologists to keep her updated with news from ASCO and ESMO; she in turn will tell them about updates in the pathology literature that haven’t yet trickled over to the oncology side, and she will ask whether they want to consider new testing. “It’s a give and take.” But oncologist-pathologist communication is critical to “make sure everything’s covered for your lung cancer patients.”

Karen Titus is CAP TODAY contributing editor and co-managing editor.