No time to wait: How rapid NGS changed cancer care

The microscopic exam helps them better interpret their NGS results too. “So we’re finding that the two tools are very complementary.”

With training and validation completed, he said, “we could offer next-generation sequencing in this community setting and deliver it in an analogous fashion to IHC.”

Of the first 578 cases they looked at, from the October 2020–October 2021 period, 57 percent were NSCLC (Sheffield BS, et al. Curr Oncol. 2022;29[3]:1326–1334). As further validation, they monitored the prevalence of key driver mutations in lung cancer. Their EGFR rate was 16 percent, “which is exactly where we expect it to fall.” The same was true for the others: ALK, three percent; BRAF, ERBB2, and MET, four percent each; and other drivers, 14 percent. “It’s a further validation that the assay as well as the people using the assay are performing as expected.”

Colon cancers made up 11 percent of the first 578 cases. Here, they expect about 50 percent to be KRAS mutated, and their KRAS mutation frequency was 50.9 percent. “An interesting fact about colon cancer is that compared to single-gene testing,” which is what they used in the past, “switching to next-generation sequencing allowed us to detect actionable driver mutations in colon cancer more than 10 percent of the time,” mutations that would not have been identified by single-gene testing methods, he said (Raskin W, et al. J Clin Oncol. 2022;40[suppl 4]:172).

Turnaround time was where they saw the biggest impact of having the NGS onsite and in point-of-care fashion. Median turnaround time for the first 578 cases was three days, with 50 percent or more of the cases completed within two to four days—this in a system where it took more than two months previously to obtain biomarker results. A number of cases were turned around within zero-day turnaround time (diagnosis and biomarkers issued at same time), and an additional small number of cases had a one-day TAT. The one-day TAT is most difficult; it reflects an urgent phone call, text, or email from an oncologist for which the lab stops what it’s doing, runs the NGS, and reports the next day.

They’re now able to report lung cancer cases in the same way they report breast cancer cases. In Fig. 1 are the results of a patient who was diagnosed “not with a lung cancer,” Dr. Sheffield said, “but with an EGFR-driven lung cancer. The biomarker results are from the exact same document as the diagnosis. So anytime a clinician pulls this diagnosis, they will be stuck permanently together with those biomarker results. And this would be an example of a zero-day turnaround time report. The pathologist would have received the slides with their regular signout and they’d order an NGS test with their diagnostic IHC.”

Dr. Sheffield presented a cytopathology colleague’s case of a young patient admitted to the intensive care unit with metastatic disease to the bone, liver, and lung. The diagnosis was made on a bronchoalveolar lavage. The material was limited to cytology slides; there was no additional material to work with. When his colleague saw what it was, she went straight to the molecular laboratory and asked if the material could be subjected to DNA and RNA extraction.

Rather than attempt to confirm the diagnosis with immunohistochemistry or traditional diagnostic markers, she confirmed the diagnosis with NGS and documented a ROS1 fusion. Because of her quick action, the patient was able to get on a ROS1 inhibitor and leave the ICU, “which we don’t believe the patient would have been able to do otherwise,” Dr. Sheffield said.

He shared an email from one of the oncologists to provide a sense of what this way of practicing is like for them. “It speaks volumes to what we’ve been able to achieve.” It is addressed directly to the histotechnologists who perform biomarker testing and it reads: “Hi, Team: Most recent biopsy can be tested. The patient has sarcomatoid NSCLC. Needs urgent NGS and high chance of MET exon 14 skipping.”

“There’s no form, there’s no fax, they’re not going through any of the middlemen who would otherwise slow down this process,” Dr. Sheffield said. “And I think it’s great that she refers to our technologists as her team.” With interactions like this between technologists and oncologists, he said, the oncologist is able to do “light teaching” by indicating there’s a special histologic subtype of this lung cancer and that this subtype is highly associated with certain driver mutations.

The oncologist’s request just missed the 9 AM NGS run, Dr. Sheffield said, but two minutes later the lab was able to let her know that it’ll be on the next-morning’s run. Within five minutes, a technologist was able to pull the tissue and have it ready for review. “This would have had to take about a week using the old system to get this into another hospital,” he said.

Just over two days later, they are able to confirm the patient has a MET-skipping mutation, as the oncologist had predicted, making the patient eligible for targeted therapy.

In another email he shared, an oncologist inquired about the result of a liquid biopsy performed in spring of this year on a patient with a suspected cancer of unknown primary who was doing poorly and is a nonsmoker. “I was hoping the patient might have a mutation,” the oncologist wrote.

It was now a few days later and the oncologist didn’t have a result yet. “She’s emailing to see what’s up,” Dr. Sheffield explained. “We had a situation in the lab where we ran out of a certain reagent we needed to extract the DNA and RNA from blood, so we decided to hold all of the specimens and wait until we got emails exactly like this so that we could triage out the most urgent cases using our last remaining reagents. So this plan worked perfectly.” They explained this to the oncologist, who asked them to proceed, and less than 90 minutes later the lab was able to authorize the extraction.

Twenty-two hours after the oncologist’s request, the oncologist receives an email that says the patient was found to have an EGFR exon 19 deletion on liquid biopsy. “That allows us to make a diagnosis of metastatic pulmonary adenocarcinoma, as that particular mutation is not typically seen in any other tumor types,” Dr. Sheffield said. “And it simultaneously allows us to tell the oncologist that the patient’s treatment should be an EGFR tyrosine kinase inhibitor. So with one test in less than one day, we’re able to make the diagnosis as well as a treatment recommendation, and spare this very sick patient the need for any tissue biopsy at all.”

All of which is to show, he said, that “when we have NGS available at our fingertips, this improves the working relationship between a pathology lab and oncology clinic, and it means we can interact with our colleagues in real time. And play a more meaningful role on this team.”

The pathologists maintain a close relationship with the oncologists to stay on top of new drugs and new markers. “We’re one ASCO or ESMO meeting away from having to go back to the drawing board on the panel,” he said.

Dr. Sheffield and colleagues at Osler launched on the sequencer their tissue assay first and a liquid biopsy a few months later. But with NGS results made available so quickly using tissue, “the demand for liquid biopsy evaporated,” Dr. Sheffield said.

“A lot of oncologists were using liquid biopsy because of the difficulty accessing tissue-based NGS,” he explained, “and simply by offering the rapid turnaround, we saw a massive drop in our requests for liquid biopsy.”

Economics are often a barrier, he acknowledges, when trying to implement NGS or comprehensive biomarker profiling. He too faced this barrier, and said it’s important to “de-silo the different costs.”

“A lot of focus is on the material cost of NGS testing, things like the chemicals, the plastics, the other consumables. However, what we need to focus on is how much money we’re saving on things like shipping, transcription, oncology visits that are purposeless because they’re attended with no biomarker data, as well as the cost overall to our health care system of providing supportive care to sick lung cancer patients while they wait for those biomarker test results” (Sheffield B, et al. J Thorac Oncol. 2022;17[9][suppl]:S86–S87). When the full costs of such are known, he insists, “this style of NGS is not just fast but very much cost saving for the health system as a whole.”

Sherrie Rice is editor of CAP TODAY.