Dataset Information

Biomarker predictors for immunotherapy benefit in breast: beyond PD-L1.

ABSTRACT:

Purpose of review

Immune checkpoint blockade (ICB) has changed the clinical course of multiple cancer types and durable responses have now been observed in breast cancer (BC) patients. Most data suggest that, compared to other subtypes, triple-negative BC (TNBC) patients are more responsive to ICB, and anti-PD-L1 therapy is now approved in PD-L1+ metastatic TNBC, in combination with chemotherapy.

Recent findings

Nearly 40% of PD-L1+ TNBC patients did not respond to this combination. Thus, additional biomarkers appear to be necessary to more precisely identify potential responders. A comprehensive analysis of the breast tumor microenvironment (TME) and peripheral blood may identify potential biomarkers for a more accurate selection of patients likely to respond to ICB.

Summary

Herein, we summarize key features of the breast TME, and beyond, that may hold predictive power in determining immunotherapy benefit. Incorporation of these features in controlled clinical trials may help further guide personalized care for BC immunotherapy.

SUBMITTER: James JL

PROVIDER: S-EPMC7731906 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Biomarker predictors for immunotherapy benefit in breast: beyond PD-L1.

James Jamaal L JL Balko Justin M JM

Current breast cancer reports 20191111 4

<h4>Purpose of review</h4>Immune checkpoint blockade (ICB) has changed the clinical course of multiple cancer types and durable responses have now been observed in breast cancer (BC) patients. Most data suggest that, compared to other subtypes, triple-negative BC (TNBC) patients are more responsive to ICB, and anti-PD-L1 therapy is now approved in PD-L1+ metastatic TNBC, in combination with chemotherapy.<h4>Recent findings</h4>Nearly 40% of PD-L1+ TNBC patients did not respond to this combinatio ...[more]

PMID: 33312343

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Project description:Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment.SignificanceThis study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown.

Project description:Anti-PD-1/PD-L1 immunotherapy could offer an alternative to traditional chemo- and/or radiotherapy to treat pediatric cancer patients. To unveil the potential benefit of this new therapeutic approach, the prevalence of PD-L1 and other relevant immune markers using quantitative digital image analysis (DIA) could help to clarify this point. A bridging study was first conducted using commercially available normal formalin-fixed paraffin-embedded (FFPE) tonsils to compare immunostaining patterns and intensities from PD-L1, tumor infiltrating lymphocyte (TIL) markers CD3, CD8, FoxP3, CD45RO, and macrophage marker CD68 in adult (n = 5) and pediatric (n = 10) samples. Then, commercially available pediatric FFPE tumor samples from five prevalent pediatric solid tumor indications: ganglioneuroblastoma (n = 7); neuroblastoma (n = 23); nephroblastoma (n = 30); osteosarcoma (n = 24); and rhabdomyosarcoma (n = 25) were immunostained and their images (n = 654) digitally analyzed using predefined algorithms. The qualitative analysis of staining patterns and intensities in all 15 tonsils for all 6 biomarkers was similar regardless of age category. Quantitative DIA showed that PD-L1 values varied across cancer-types, nephroblastoma having the lowest counts. PD-L1 counts in ganglioneuroblastoma, our pediatric indication with the highest average value, was approximately 12-times lower than in a similar nonsmall cell lung cancer study, an indication approved for anti-PD-1/PD-L1 immunotherapies. Variable values were measured for the TIL markers CD3, CD8, and CD45RO. FoxP3 was scant across all indications. The macrophage marker CD68 showed highest values in ganglioneuroblastoma, with lowest levels in nephroblastoma. In conclusion, the low PD-L1 levels uncorrelated with TIL values from the present biomarker morphological study suggest that a PD-L1 immunohistochemistry patient selection strategy used for anti-PD-1/PD-L1 monotherapy in adult tumors may not succeed in these pediatric indications.

Dataset Information

Biomarker predictors for immunotherapy benefit in breast: beyond PD-L1.

Purpose of review

Recent findings

Summary

Publications

Biomarker predictors for immunotherapy benefit in breast: beyond PD-L1.

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