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Lung cancer has the dubious distinction of being the most common solid tumor to metastasize to the central nervous systems (CNS), with about one-fourth of patients with stage IV non-small-cell lung cancer (NSCLC) having brain metastases at diagnosis.

"Historically, whole-brain radiotherapy (WBRT) had been the cornerstone of treatment for brain metastases in patients with advanced NSCLC, especially when stereotactic radiosurgery (SRS) and surgery were not feasible or indicated," explained Ernest Nadal, MD, PhD, of the Institut Català d'Oncologia /L'Hospitalet de Llobregat in Barcelona, Spain, and colleagues.

But the underwhelming survival benefit, not to mention high impact on quality of life (QOL), has made WBRT less appealing in these patients, the researchers stated in the . On the other hand, "immunotherapy has shown encouraging intracranial efficacy in patients with oncogene driver–negative PD-L1-positive NSCLC who have brain metastases that are untreated or progressing after previous radiotherapy."

Nadal's group conducted the open-label, single-arm, phase II Atezo-Brain/GECP17/05 trial at 15 hospitals in Spain. The 40 patients received atezolizumab plus carboplatin and pemetrexed for 4-6 cycles, followed by atezolizumab plus pemetrexed until progression for a maximum of 2 years.

The team reported an overall 12-week progression-free survival (PFS) rate of 62.2%, and an intracranial median PFS of 6.9 months at a median follow-up of 31 months. The median overall survival (OS) was 11.8 months and the 2-year OS rate was 27.5%.

Nadal and colleagues also explained that most patients who had disease progression in the brain were considered candidates for salvage brain radiotherapy -- primarily WBRT and SRS. "In our study, we observed that systemic therapy allowed for the deferral of WBRT without a decline in QOL," the researchers said.

Yet they cautioned that "when considering the initiation of ... systemic therapy and the deferral of brain-directed local therapy in patients with lung cancer, it is important to discuss within a multidisciplinary tumor board that includes radiation oncologists and neurosurgeons."

Might there be a way to determine how suitable patients with advanced lung cancer are for radiation therapy? Aadel Chaudhuri, MD, PhD, of Washington University in St. Louis, and colleagues looked for an answer to that question with their study presented at the 2023 (ASTRO) annual meeting.

"We hypothesized that pre-RT liquid biopsy circulating tumor DNA (ctDNA) analysis could risk-stratify oligometastatic [NSCLC] patients and enable earlier personalized selection for consolidative RT," the researchers explained in their ASTRO abstract.

They evaluated a "real-world" multi-institutional cohort of 309 patients who were diagnosed with oligometastatic NSCLC. Each patient underwent liquid biopsy ctDNA analysis at least once with the Tempus xF assay (version 2). The group reported that overall PFS and OS were significantly worse in oligometastatic NSCLC patients with detectable ctDNA pre-RT versus those without detectable ctDNA pre-RT. Chaudhuri shared the results at ASTRO.

What was the impetus for the study, "?"

Chaudhuri: Oligometastatic lung cancer is an "in-between" localized and widely metastatic lung cancer and, as a result, it represents a bit of a conundrum. Oligometastatic lung cancer can be treated quite effectively, and in some cases quite definitively, with SBRT [stereotactic body RT], but it's challenging to know which patients would benefit from this.

The issue is that for some patients, what you see on imaging more or less represents the disease that they have, but in other patients, imaging may not represent a patient's true burden of disease, because there may be micrometastatic disease beyond what is visible on imaging. In those cases, when we try to consolidate what we see on imaging, the patient may come back in 3 months with more widely metastatic disease, and we haven't really then done them a service. If anything, you could argue that the time spent delivering RT was time taken away from what could have been stronger systemic therapy.

The question we asked is, can we use liquid biopsy to improve clarity and precision in this space, and really enhance RT decision-making?

What were some of the main findings?

Chaudhuri: The results of our study suggest that ctDNA detection prior to RT could predict survival. What we saw was that patients who had nondetectable ctDNA had improved PFS outcomes after RT compared with those who had detectable ctDNA.

Now I use these terms detectable versus nondetectable. I will say that the Tempus xF assay is not an MRD [minimal residual disease] assay -- it doesn't have an ultra-low limit of detection. So what I really think is that these nondetectable patients represent a lower level of ctDNA, falling below the limit of detection of this assay. But as a result, they likely have less micrometastatic disease, and are more likely to benefit from RT compared with the patients with higher, or detectable, ctDNA levels.

There were similar data with OS ... I think ctDNA is a more granular measure and could help us decide which patients would benefit from RT versus systemic therapy when we divide our ctDNA groups into three strata -- undetectable, low [max variant allele frequency <0.1], and high [max variant allele frequency ≥0.1]. You do appear to see a dose-dependent relationship with the patients with elevated levels of ctDNA having a worse PFS; undetectable [ctDNA patients] have much better PFS.

Circulating tumor DNA results did not correlate well with the number of organ metastatic sites on the available imaging.

What's the take-home message?

Chaudhuri: These real-world data suggest that pre-treatment ctDNA cold be a predictive biomarker for oligometastatic NSCLC treated with RT. This was a retrospective study, however, and it will be important for us to perform solid prospective follow-up.

Oligometastatic patients with low or undetectable ctDNA had improved survival outcomes with RT. I think that's exciting and it suggests that ctDNA could be a biomarker, especially when you look at some of the studies in the oligometastatic space. If you think about breast cancer and , a negative study, could you potentially take a biomarker like ctDNA, and in the subset of patients, determine who would benefit from SBRT consolidation?

Anecdotally, all of us radiation oncologists have these patients that have benefited [from RT]. Could a biomarker essentially select those [patients] so that it's less anecdotal?

While ctDNA correlated with survival outcomes, the number of metastatic sites did not -- again suggesting that perhaps our selection criteria could at least incorporate ctDNA, and not be purely reliant on the number of metastatic sites on imaging.

Read the study here.