Biomarkers in Breast Cancer: An Integrated Analysis of Comprehensive Genomic Profiling and PD-L1 Immunohistochemistry Biomarkers in 312 Patients with Breast Cancer

Abstract

Background We examined the current biomarker landscape in breast cancer when programmed death‐ligand 1 (PD‐L1) testing is integrated with comprehensive genomic profiling (CGP). Material and Methods We analyzed data from samples of 312 consecutive patients with breast carcinoma tested with both CGP and PD‐L1 (SP142) immunohistochemistry (IHC) during routine clinical care. These samples were stratified into hormone receptor positive (HR+)/human epidermal growth factor receptor negative (HER2−; n = 159), HER2‐positive (n = 32), and triple‐negative breast cancer (TNBC) cohorts (n = 121). Results We found that in the TNBC cohort, 43% (52/121) were immunocyte PD‐L1–positive, and in the HR+/HER2− cohort, 30% (48/159) had PIK3CA companion diagnostics mutations, and hence were potentially eligible for atezolizumab plus nab‐paclitaxel or alpelisib plus fulvestrant, respectively. Of the remaining 212 patients, 10.4% (22/212) had a BRCA1/2 mutation, which, if confirmed by germline testing, would allow olaparib plus talazoparib therapy. Of the remaining 190 patients, 169 (88.9%) were positive for another therapy‐associated marker or a marker that would potentially qualify the patient for a clinical trial. In addition, we examined the relationship between immunocyte PD‐L1 positivity and different tumor mutation burden (TMB) cutoffs and found that when a TMB cutoff of ≥9 mutations per Mb was applied (cutoff determined based on prior publication), 11.6% (14/121) patients were TMB ≥9 mutations/Mb and of these, TMB ≥9 mutations per Mb, 71.4% (10/14) were also positive for PD‐L1 IHC. Conclusion Our integrated PD‐L1 and CGP methodology identified 32% of the tested patients as potentially eligible for at least one of the two new Food and Drug Administration approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker‐guided potential therapeutic options. Implications for Practice This integrated programmed death‐ligand 1 immunohistochemistry and comprehensive genomic profiling methodology identified 32% of the tested patients as eligible for at least one of the two new Food and Drug Administration‐approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker‐guided potential therapeutic options. These findings suggest new research opportunities to evaluate the predictive utility of other commonly seen PIK3CA mutations in hormone receptor‐positive breast cancers and to standardize tumor mutation burden cutoffs to evaluate its potentially predictive role in triple‐negative breast cancer.

Clinicopathologic, genomic and protein expression characterization of 356ROS1fusion driven solid tumors cases

“…As TMB and MSI are also CPI biomarkers, the higher expression of PD‐L1 in ROS1 fusion pos tumors contrasts with the lower median and mean TMB and no MSI‐H cases in the ROS1 fusion pos cohort. While patients with TMB‐High and/or MSI‐H are eligible for CPIs, PD‐L1 expression identifies a subset of low TMB/ Microsatellite Stable patients that are still eligible for CPIs as previously described 30,31 . While the exact mechanism for higher PD‐L1 and lower TMB‐H/MSI‐H remains elusive, these data suggest that CPIs could be further explored in tumors with ROS1 fusion.…”

“…As TMB and MSI are also CPI biomarkers, the higher expression of PD-L1 in ROS1 fusion pos tumors contrasts with the lower median and mean TMB and no MSI-H cases in the ROS1 fusion pos cohort. While patients with TMB-High and/or MSI-H are eligible for CPIs, PD-L1 expression identifies a subset of low TMB/ Microsatellite Stable patients that are still eligible for CPIs as previously described 30,31. While the exact mechanism for higher PD-L1 and lower TMB-H/MSI-H remains elusive, these data suggest that CPIs could be further explored in tumors with ROS1 fusion.Overall, the amount of driver mutations in the ROS1 fusion positive cohorts is low when compared to the ROS1 fusion negative patient cohorts and suggests that, when identified, ROS1 fusion is an important driver genomic alteration in both the NSCLC and non-NSCLC ROS1 fusion pos patients.…”

“…While patients with TMB-High and/or MSI-H are eligible for CPIs, PD-L1 expression identifies a subset of low TMB/ Microsatellite Stable patients that are still eligible for CPIs as previously described. 30,31 While the exact mechanism for higher PD-L1 and lower TMB-H/MSI-H remains elusive, these data suggest that CPIs could be further explored in tumors with ROS1 fusion.…”

Clinicopathologic and Genomic Characterization of PD-L1 Positive Urothelial Carcinomas

“…While the relationship of PD-L1 IHC, TMB, MSI, and CD274 amplification has been recently studied by Huang et al in >48,000 samples tested with both PD-L1 IHC and CGP, the investigation of clinicopathologic and genomic features of PD-L1 positive tumors in most tumor types is lacking in the literature. [20,21] To the best of our knowledge, this is the first study that examined the clinicopathologic and genomic features of PD-L1 pos and PD-L1 neg (as defined by the DAKO 22C3 CDx assay) UC patients in a large cohort of clinical samples. In our PD-L1 pos disease subset, we saw an increased association with GA in RB1 and TP53.…”

Pan-cancer landscape ofCD274(PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression

“…1 These include microsatellite instability (MSI) testing, where MSI-High (MSI-H) patients with solid tumors are eligible for pembrolizumab; tumor mutational burden (TMB) testing by comprehensive genomic profiling (CGP), where solid tumor patients with TMB ≥10 mutations/ megabase (mut/Mb) (TMB-High, TMB-H) are also eligible for pembrolizumab; and PD-L1 expression measured by immunohistochemistry (IHC), where PD-L1 positive tumor cells or immunocytes in certain tumor types enable the selection of ICPI such as pembrolizumab, atezolizumab or nivolumab. [2][3][4][5][6] One promising but not as well studied biomarker for ICPI is CD274 (PD-L1) gene copy number (CN) changes.…”