STK11 alterations in the pan-cancer setting: prognostic and therapeutic implications

Background: STK11 is an important tumour suppressor gene reported to confer immunotherapy resistance in non-small-cell lung cancers (NSCLC) especially in the presence of KRAS co-alterations Methods: This study analysed 4446 patients for whom next-generation sequencing of tissue and/or circulating tumour DNA (ctDNA) had been performed. Results: Overall, 60 of 4446 tumours (1.35%) harboured STK11 alterations. STK11 alterations were associated with shorter median time to progression and overall survival (OS) across cancers from diagnosis: 6.4 months (5.1-7.9) versus 12 months (11.7-12.3; p = 0.001); and 20.5 (17.4-23.5) versus 29.1 (26.9-31.3; p = 0.03), respectively (pan-cancer). Pan-cancers, the me-dian progression-free survival (PFS; 95% CI) for first-line therapy (regardless of treatment type) for those with co-altered STK11 and KRAS (N = 27; versus STK11-altered and KRAS wild type [N = 33]), was significantly shorter (3 [1.3-4.7] versus 10 [4.9-15.7] months, p < 0.0005, p multivariate, 0.06); the median OS also was also shorter (p multivariate = 0.02). In pan-cancer patients treated with checkpoint blockade, STK11 and KRAS co-altered versus STK11-altered/KRAS wild type had a shorter median PFS and trend toward shorter OS (p = 0.04 and p = 0.06, respectively). In contrast, in examining STK11- altered versus wild-type pan-cancer patients treated with checkpoint blockade immuno-therapy, the two groups showed no difference in outcome (PFS [p = 0.4]; OS [p = 0.7]); STK11-altered versus wild-type lung cancer patients also did not fare worse on immunotherapy. Conclusions: Across cancers, STK11 alterations correlated with a poor prognosis regardless of therapy. However, STK11 alterations alone did not associate with inferior immunotherapy outcome in the pan-cancer setting or in NSCLC. Pan-cancer patients with co-altered STK11/KRAS did worse, regardless of treatment type. (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

The study revealed that mutations in the STK11 gene are closely associated with the malignancy and survival rates of tumors, especially when co-altered with KRAS. Patients with co-alterations of STK11 and KRAS in the pan-cancer setting had worse outcomes regardless of treatment type.