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STK11 alterations in the pan-cancer setting: prognostic and therapeutic implications
Nithya Krishnamurthy1, Aaron M Goodman2, Donald A Barkauskas3
1Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, La Jolla, CA, 92093, USA; Yale University, New Haven, CT, 06520, USA.
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 median 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 immunotherapy, 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.
Insights
STK11 alterations indicate a poor prognosis across cancers, but do not alone impact immunotherapy outcomes in NSCLC. Co-alterations with KRAS worsen prognosis regardless of treatment type.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- STK11 is a tumor suppressor gene implicated in immunotherapy resistance in non-small-cell lung cancers (NSCLC), particularly with KRAS co-alterations.
- Understanding the prognostic and predictive implications of STK11 alterations is crucial for optimizing cancer treatment strategies.
Purpose of the Study:
- To investigate the impact of STK11 alterations on patient outcomes across various cancer types.
- To evaluate the association between STK11 alterations, KRAS co-alterations, and response to immunotherapy.
- To determine the prognostic significance of STK11 alterations in the context of different cancer treatments.
Main Methods:
- Analysis of next-generation sequencing data from 4446 patients, including tissue and circulating tumor DNA (ctDNA).
- Assessment of STK11 alterations in 1.35% of the analyzed tumors.
- Statistical evaluation of progression-free survival (PFS) and overall survival (OS) in relation to STK11 and KRAS alterations, and immunotherapy response.
Main Results:
- STK11 alterations were associated with significantly shorter median time to progression and overall survival across cancers (p=0.001 and p=0.03, respectively).
- Pan-cancer patients with co-altered STK11 and KRAS exhibited significantly shorter median PFS (p<0.0005) and OS (p=0.02) compared to those with STK11 alterations alone.
- In patients treated with checkpoint blockade, co-altered STK11/KRAS showed shorter PFS (p=0.04) and a trend towards shorter OS (p=0.06).
Conclusions:
- STK11 alterations correlate with a poor prognosis irrespective of therapy, but do not independently predict inferior immunotherapy outcomes in NSCLC or pan-cancer settings.
- Co-alteration of STK11 and KRAS significantly worsens outcomes for pan-cancer patients, regardless of treatment modality.
- The findings highlight the complex interplay between STK11, KRAS, and treatment response, emphasizing the need for personalized therapeutic approaches.
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