Life support.

Top Line: In recent months we’ve learned that postoperative radiation (PORT) for unselected patients with resected non-small cell lung cancer with pathologic N2 disease is no bueno.

The Study: While the last nail may have been placed in the NSCLC-PORT coffin, the RSI folks swoop in right before it’s 6 feet under to question: but what if we’re more selective?? Here is a retrospective look at outcomes for 89 patients who received both PORT and tumor genomic sequencing at MSKCC from 2017-2019. Importantly 11% were N0, 60% N1 and only 26% N2 and 3% N3 disease. As predicted, those with mutations in radiation-resistance genes (n=16) had high rates of locoregional failure within 2 years (60%), especially compared to those with these mutations absent (11%). On the flip side, zero locoregional failures occurred among those with mutations in DNA damage response and repair (DDR) genes (n=15). Another standout predictor of improved locoregional control with PORT was higher tumor mutational burden (TMB), measured as a continuous variable. And while higher TMB is known to be associated with DDR gene mutations, which was also the case here, it remained an independent marker on multivariate analysis. In fact, ROC analysis indicated those with high TMB and absence of radioresistant mutations have a 92% chance of maintaining locoregional control after PORT. This all may have you wondering: but how would these patients fare without PORT? Fair question. While this doesn’t provide the most robust answer, neither DDR gene mutations nor TMB appeared to be related to better outcomes among a separate cohort of 19 patients who did not receive PORT. Now the million dollar question remains: can PORT actually influence distant mets or, gasp, survival, among patients with these radiosensitive indices? After all, prior trials suggest minimizing locoregional failure doesn’t necessarily translate to these more important outcomes. A more intriguing question may be if more of these patients should receive upfront radiation with some combination of systemic therapy.

TBL: Are any of the LungART and/or PORT-C trialists interested in a post-hoc analysis of outcomes stratified by radioresistance genes, DDR genes, and TMB..? Please? For your friendly rad onc colleagues? | Shaverdian, Int J Radiat Oncol Biol Phys 2022