Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study

Nanda, Rita; Chow, Laura Q.M.; Dees, Claire; Berger, Raanan; Gupta, Shilpa; Geva, Ravit; Pusztai, Lajos; Pathiraja, Kumudu; Aktan, Gursel; Cheng, Jonathan D.; Karantza, Vassiliki; Buisseret, Laurence

doi:10.1200/jco.2015.64.8931

Cited by 1,197 publications

(887 citation statements)

References 42 publications

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“…35 The objective response rate in a recently reported phase Ib clinical trial of programmed-cell death protein 1 (PD-1) immune checkpoint inhibition in heavily pre-treated TNBC patients with PD-L1 expressing tumors was only 18.5%. 36 In our study, 36% of Basal-like tumors were classified as TMB-Hi, and 24% of these tumors (9% overall) belonged to the FID subclass, suggesting by extrapolation that only a relatively small fraction of these tumors may be particularly immunogenic. In TNBC tumors, we observed a protective effect for TMB-Hi in tumors of the FID immune subclass, but not in those of the WID and PID immune subclasses, though this sub-analysis was potentially limited by small sample size and sparsity of survival events.…”

Section: Discussionmentioning

confidence: 49%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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Section: Discussionmentioning

confidence: 49%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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“…Although ER- breast cancer, in particular basal and triple negative breast cancer, is considered the most immunogenic subtype, reports from immune checkpoint inhibitor clinical trials are not as encouraging. Early reports suggest metastatic breast cancer patients may benefit most from PD-1/PD-L1 blockade monotherapy in the first-line setting, or in combination with chemotherapy agents for second or third-line therapy with an objective response rate ranging from 10%-40% 9-11 (for review, see ref. 12 ).…”

Section: Discussionmentioning

confidence: 99%

“…Immune checkpoint inhibitors targeting cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) or its ligand (PDL-1) perform best in immunogenic cancers such as melanoma and non-small cell lung cancer 7,8 , but responses have recently been reported in triple negative/basal-like breast cancers 9–11 (for reviews see refs. 12,13 ).…”

Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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“…Nanda and colleagues reported initial results from the KEYNOTE 0-12 Phase Ib study of pembrolizumab in patients with metastatic triple-negative breast cancer with PD-L1-positive tumor status (expression in stroma or in ≥ 1% tumor cells). Among 27 evaluable patients with a median of 2 prior therapies for metastatic disease, the objective response rate was 18.5% [58]. The subsequent KEYNOTE-086 Phase II trial evaluated pembrolizumab in metastatic TNBC patients that were previously treated with any level of PD-L1 expression (Cohort A) and as 1st line treatment in patients with PD-L1+ status (Cohort B) [59].…”

Section: Targeting the Pd-1/pd-l1 Checkpoint In Tnbcmentioning

confidence: 99%

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Telli

Stover

Loi

et al. 2018

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. Methods We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Results Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. Conclusions HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

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Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study

Cited by 1,197 publications

References 42 publications

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

TIM-3 expression in breast cancer

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

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