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.

Figure 1.. Kaplan-Meier Curves for Progression-Free and Overall Survival by Biomarker Status in Anti-PD-1/L1-Treated Cohort.

(A) Progression-free survival and (C) overall survival by tumor mutational burden status (<10 vs ≥10 mutations/megabase); (B) progression-free survival and (D) overall survival by PTEN alteration (absent vs present). Abbreviations: TMB: tumor mutational burden; WT: wild type.

Figure 2.. Adjusted Hazard Ratios (HR) for Progression-Free Survival (PFS) and Overall Survival (OS) by Biomarker Status in Anti-PD-1/L1-Treated Cohort.

PFS and OS HRs by TMB ≥10 vs. <10 mutations/megabase and PTEN alterations (present vs. absent), adjusted for ECOG PS (≥ 1 vs. 0), previous lines of therapy (≥ 1 vs. 0), regimen (monotherapy vs. combination therapy), and visceral metastases (present vs. absent). Abbreviations: ECOG-PS: Eastern Cooperative Oncology Group performance status; CI: confidence interval; HR: hazard ratio; TMB: tumor mutational burden.