Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors

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Sarah Abou Alaiwi1, Amin H Nassar1,2, Wanling Xie3

  • 1Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cancer Immunology Research
|April 24, 2020
PubMed

Insights

Loss-of-function variants in the mammalian SWI/SNF complex do not consistently predict improved outcomes with immune checkpoint inhibitors (ICI). However, renal cell carcinoma patients with these variants showed better survival, primarily linked to PBRM1 mutations.

Area of Science:

  • Oncology
  • Genetics
  • Immunotherapy

Background:

  • Prior studies suggested a link between mammalian SWI/SNF (mSWI/SNF) complex inactivation and enhanced tumor sensitivity to immune checkpoint inhibitors (ICI).
  • The role of mSWI/SNF variants in predicting clinical outcomes to ICI therapy remains variably understood.

Purpose of the Study:

  • To investigate the association between somatic loss-of-function (LOF) variants in key mSWI/SNF genes and clinical outcomes in cancer patients treated with systemic ICIs.
  • To determine if mSWI/SNF variants can serve as predictive biomarkers for ICI response.

Main Methods:

  • Correlated LOF variants in mSWI/SNF genes (ARID1A, ARID1B, SMARCA4, SMARCB1, PBRM1, ARID2) with clinical outcomes in two patient cohorts (DFCI and MSKCC).
  • Utilized multivariable analyses adjusted for baseline factors and tumor mutational burden.
  • Examined seven solid tumor subtypes.

Main Results:

  • In the DFCI cohort, mSWI/SNF LOF variants did not predict improved overall survival (OS), time-to-treatment failure (TTF), or disease control rate.
  • A significant improvement in OS and TTF was observed in renal cell carcinoma patients with mSWI/SNF LOF, largely driven by PBRM1 mutations.
  • In the MSKCC cohort, mSWI/SNF LOF did not correlate with improved OS across any tumor subtype.

Conclusions:

  • There is no consistent association between mSWI/SNF LOF variants and improved clinical outcomes with ICIs.
  • mSWI/SNF variants are unlikely to be reliable biomarkers for predicting ICI response across all cancer types.
  • Further research may be warranted for specific subtypes like renal cell carcinoma.

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