Tumor Mutational Burden and PTEN Alterations as Molecular Correlates of Response to PD-1/L1 Blockade in Metastatic Triple-Negative Breast Cancer.

Abstract

PURPOSE:

Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC.

EXPERIMENTAL DESIGN:

We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features.

RESULTS:

Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169).

CONCLUSIONS:

Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.

• Authors: Romualdo Barroso-Sousa, Tanya E Keenan, Sonia Pernas, Pedro Exman, Esha Jain, Ana C Garrido-Castro, Melissa Hughes, Brittany Bychkovsky, Renato Umeton, Janet L Files, Neal I Lindeman, Laura E MacConaill, F Stephen Hodi, Ian E Krop, Deborah Dillon, Eric P Winer, Nikhil Wagle, Nancy U Lin, Elizabeth A Mittendorf, Eliezer M Van Allen, Sara M Tolaney
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 11 Pg. 2565-2572 (06 01 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32019858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adult
• Aged
• B7-H1 Antigen (antagonists & inhibitors)
• Biomarkers, Tumor (genetics)
• Cohort Studies
• Female
• Follow-Up Studies
• Humans
• Immune Checkpoint Inhibitors (therapeutic use)
• Immunotherapy (methods)
• Middle Aged
• Mutation
• PTEN Phosphohydrolase (genetics)
• Prognosis
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Survival Rate
• Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)