Blood-based tumor mutational burden impacts clinical outcomes of immune checkpoint inhibitor treated breast and prostate cancers

Reagan M Barnett; Albert Jang; Sree Lanka; PIngfu Fu; Leslie A Bucheit; Hani Babiker; Alan Bryce; Haley M Meyer; Yujin Choi; Casey Moore; Rohan Garje; Xin Gao; Dae Won Kim; Richard Y Chang; Pat Gulhati; Ryne Ramaker; Rani Bansal; Tian Zhang; A Oliver Sartor; Andrew J Armstrong; Mehmet A Bilen; Pedro Barata

doi:10.1038/s43856-024-00687-5

Blood-based tumor mutational burden impacts clinical outcomes of immune checkpoint inhibitor treated breast and prostate cancers

Commun Med (Lond). 2024 Dec 2;4(1):256. doi: 10.1038/s43856-024-00687-5.

Authors

Reagan M Barnett¹, Albert Jang^{2

3}, Sree Lanka³, PIngfu Fu², Leslie A Bucheit¹, Hani Babiker⁴, Alan Bryce⁵, Haley M Meyer⁵, Yujin Choi⁶, Casey Moore⁷, Rohan Garje⁸, Xin Gao⁹, Dae Won Kim¹⁰, Richard Y Chang², Pat Gulhati¹¹, Ryne Ramaker¹², Rani Bansal¹², Tian Zhang⁷, A Oliver Sartor¹², Andrew J Armstrong¹³, Mehmet A Bilen⁶, Pedro Barata^{14

15}

Affiliations

¹ Guardant Health, Inc, Palo Alto, California, USA.
² University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
³ Tulane Cancer Center, New Orleans, LA, USA.
⁴ Mayo Clinic Jacksonville, Jacksonville, FL, USA.
⁵ Mayo Clinic Phoenix, Phoenix, AZ, USA.
⁶ Emory University, Atlanta, GA, USA.
⁷ UT Southwestern University, Dallas, TX, USA.
⁸ Miami Cancer Institute Baptist Health, Miami, FL, USA.
⁹ Massachuesetts General Hospital Cancer Center, Boston, MA, USA.
¹⁰ Moffitt Cancer Institute, Tampa, FL, USA.
¹¹ Rutgers University, New Brunswick, NJ, USA.
¹² Mayo Clinic, Rochester, MN, USA.
¹³ Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, USA.
¹⁴ University Hospitals Seidman Cancer Center, Cleveland, OH, USA. Pedro.Barata@UHhospitals.org.
¹⁵ Tulane Cancer Center, New Orleans, LA, USA. Pedro.Barata@UHhospitals.org.

PMID: 39623081
DOI: 10.1038/s43856-024-00687-5

Abstract

Background: Breast and prostate tumors are known to be less responsive to immune checkpoint inhibitors (ICIs). Tissue-based tumor mutation burden (tTMB) has emerged as a predictive biomarker of response to ICIs, including in these "cold tumors". In clinical practice, when tTMB is not available, blood-based TMB score (bTMB) can be used to consider treatment with ICIs.

Methods: This retrospective, real-world study included a final cohort of metastatic breast and prostate cancer patients treated with an ICI following a liquid biopsy test. Multiple bTMB-High cut-offs were assessed. Clinical, genomic, and outcomes data were collected. We hypothesized that a cut-off of bTMB ≥10 mut/Mb is not a strong predictor of response to ICIs in this setting. The Guardant Health genomic database (GHGD) was then queried (N = 13,992) for associations of bTMB with genomic alterations.

Results: In the clinical cohort (N = 48), ICI treatment is offered after a median of 3 (1-9) lines of treatment. The median bTMB is 16.4 (10-186) mut/Mb. The median time on ICI and PFS is 2.1 (0-1.7) and 3.1 months (95%CI, 1.6-4.6) respectively; no difference by MSI/MMR status (p = 0.152). Response rate among eligible patients (n = 36) is 16.7%; only N = 1/6 in bTMB <16 mut/Mb. High bMSI is associated with higher bTMB (correlation test, r = 0.66, p = 0.000). In the GHGD, patients with bTMB high have significantly more alterations than bTMB low and TP53, PIK3CA, ATM, ESR1, NF1, BRCA2, ARID1A, and APC were the most frequently altered genes.

Conclusions: In this study, the practice of offering an ICIs based on bTMB was uncommon and did not independently predict ICI benefits in patients with refractory, advanced breast and prostate cancers.

Plain language summary

The genetic changes seen in cancer tumors can be detected in blood. We aimed to investigate whether these changes detected in the blood could be used to predict the response of people with breast or prostate cancer to a type of treatment called immune checkpoint inhibitors. We found that the genetic changes detected in the blood did not predict response to the treatment. This suggests that additional or alternative information is required about patients to identify those who will benefit from immune checkpoint inhibitor treatment.