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Original Research| Volume 148, P215-229, May 2021

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

  • Nithya Krishnamurthy
    Correspondence
    Corresponding author: UC San Diego - Moores Cancer Center, 3855 Health Sciences Drive, MC #0658, La Jolla, CA, 92093-0658, USA. Fax: (858) 822 2300
    Affiliations
    Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, La Jolla, CA, 92093, USA

    Yale University, New Haven, CT, 06520, USA
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  • Aaron M. Goodman
    Affiliations
    Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, La Jolla, CA, 92093, USA

    Department of Medicine, Division of Blood and Marrow Transplantation, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
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  • Donald A. Barkauskas
    Affiliations
    Biostatistics Division, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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  • Razelle Kurzrock
    Affiliations
    Center for Personalized Cancer Therapy, University of California, Moores Cancer Center, La Jolla, CA, 92093, USA
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Published:March 19, 2021DOI:https://doi.org/10.1016/j.ejca.2021.01.050

      Highlights

      • STK11 alterations had shorter median time to progression and overall survival (OS).
      • Pan-cancer co-altered STK11/KRAS did worse, regardless of treatment type.
      • STK11 alterations alone did not associate with inferior immunotherapy outcome.
      • STK11 and KRAS and TP53 mutations had a significantly shorter PFS and OS.

      Abstract

      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.

      Keywords

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