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Clin Cancer Res. 2020 Feb 4. pii: clincanres.3507.2019. doi: 10.1158/1078-0432.CCR-19-3507. [Epub ahead of print]

Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer.

Author information

1
Oncology Center, HOSPITAL SIRIO-LIBANES.
2
Medical Oncology, Dana-Farber Cancer Institute.
3
Medical oncology, Catalan Institute of Oncology, IDIBELL.
4
Breast Oncology, Dana-Farber Cancer Institute.
5
Centre of Regenerative Medicine, Massachusetts General Hospital.
6
Population Science, Dana-Farber Cancer Institute.
7
Dana-Farber Cancer Center.
8
Informatics and Analytics, Dana-Farber Cancer Institute.
9
Midical Oncology, Dana-Farber Cancer Institute.
10
Brigham and Women's Hospital.
11
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute.
12
Department of Pathology, Brigham & Women's Hospital.
13
Division of Breast Oncology, Dana-Farber Cancer Institute.
14
Department of Surgery, Brigham and Women's Hospital.
15
Department of Medical Oncology, Dana-Farber Cancer Institute.
16
Department of Medical Oncology, Dana-Farber Cancer Institute Sara_Tolaney@dfci.harvard.edu.

Abstract

PURPOSE:

Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICIs). Based on 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.

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