Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

Griguolo, Gaia; Guarneri, Valentina; Dieci, Maria Vittoria

doi:10.1634/theoncologist.2019-0197

Cited by 37 publications

(25 citation statements)

References 109 publications

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“…In agreement with the literature [27], 66.9% of TNBC expressed PD-L1. PD-L1 expression on tumor cells and PD-1 expression on TILs were not different in tumor co-expressing or not AR and Cath-D, in our population.…”

Section: Discussionsupporting

confidence: 92%

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Co-Expression of Androgen Receptor and Cathepsin D Defines a Triple-Negative Breast Cancer Subgroup with Poorer Overall Survival

Mansouri

Alcaraz

Mollévi

et al. 2020

Cancers

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Background: In the triple-negative breast cancer (TNBC) group, the luminal androgen receptor subtype is characterized by expression of androgen receptor (AR) and lack of estrogen receptor and cytokeratin 5/6 expression. Cathepsin D (Cath-D) is overproduced and hypersecreted by breast cancer (BC) cells and is a poor prognostic marker. We recently showed that in TNBC, Cath-D is a potential target for antibody-based therapy. This study evaluated the frequency of AR/Cath-D co-expression and its prognostic value in a large series of patients with non-metastatic TNBC. Methods: AR and Cath-D expression was evaluated by immunohistochemistry in 147 non-metastatic TNBC. The threshold for AR positivity (AR+) was set at ≥1% of stained cells, and the threshold for Cath-D positivity (Cath-D+) was moderate/strong staining intensity. Lymphocyte density, macrophage infiltration, PD-L1 and programmed cell death (PD-1) expression were assessed. Results: Scarff-Bloom-Richardson grade 1–2 and lymph node invasion were more frequent, while macrophage infiltration was less frequent in AR+/Cath-D+ tumors (62.7%). In multivariate analyses, higher tumor size, no adjuvant chemotherapy and AR/Cath-D co-expression were independent prognostic factors of worse overall survival. Conclusions: AR/Cath-D co-expression independently predicted overall survival. Patients with TNBC in which AR and Cath-D are co-expressed could be eligible for combinatory therapy with androgen antagonists and anti-Cath-D human antibodies.

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Section: Discussionsupporting

confidence: 92%

“…Triple-negative breast cancers (TNBC) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR) and HER2 (Human Epidermal Receptor 2) expression/amplification. assays (different antibodies, scoring systems, positivity thresholds, and tumor microenvironment compartment included in the analysis) [27].…”

Section: Introductionmentioning

confidence: 99%

Co-Expression of Androgen Receptor and Cathepsin D Defines a Triple-Negative Breast Cancer Subgroup with Poorer Overall Survival

Mansouri

Alcaraz

Mollévi

et al. 2020

Cancers

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“…In contrast, among TN tumors, 42.1% (8/19) and 57.9% (11/19) of tumors were positive for PD-L1 in TCs and ICs, respectively. PD-L1 expression levels tended to be higher in ICs than in TCs, and higher in the TN type than in the HR + HER2type, concurrent with previous reports (25). Furthermore, PD-L1 expression in both TCs and ICs was significantly associated with high HG (HG 3 vs. HG1-2) (TC: P=0.0002; IC: P=0.0001), high Ki-67 index (Ki-67 >20%) (TC: P=0.0215; IC: P=0.0037), and high frequency of TILs (TC: P<0.0001; IC: P<0.0001) ( Table III).…”

Section: Pd-l1 Expression On Tcs and Ics In Primary Bcssupporting

confidence: 90%

CD204‑positive macrophages accumulate in breast cancer tumors with high levels of infiltrating lymphocytes and programmed death ligand‑1 expression

et al. 2020

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Although immunotherapy has been demonstrated to be promising in triple-negative (TN) breast cancer (BC), most BC cases are classified as non-TN. To enrich the responders for immunotherapy regardless of their subtypes, classification based on tumor-infiltrating lymphocyte (TIL) levels and programmed death ligand-1 (PD-L1) status may be useful. However, this classification has not been fully applied to BC. Furthermore, suppressive subsets in the local tumor microenvironment, such as tumor-associated macrophages (TAMs), which promote tumor progression, cannot be ignored to overcome immunotherapy resistance. The aims of the present study were to classify primary BC cases based on the TIL levels and PD-L1 status, and to identify suppressive immune subsets in each categorized group. A retrospective analysis of 73 patients with invasive BC was performed. The frequency of TILs was evaluated in HE-stained slides (10% cutoff), and PD-L1 levels (SP142; 1% cutoff), as well as immune subsets (CD3 + , CD8 + , FOXP3 + , CD20 + , CD68 + and CD204 + cells) were assessed using immunohistochemistry. It was revealed that 22% (16/73) of the tumors were categorized as TIL + PD-L1 + , of which 69% (11/16) were TN type. By contrast, 66% (48/73) of the tumors were categorized as TIL − PD-L1 − , of which 77% (37/48) were HR + and HER2 − types. The number of CD204 + M2-type macrophages was significantly associated with high histological grade (P=0.0246) and high Ki-67 (P=0.0152), whereas CD68 + macrophages were not associated with these factors. Furthermore, CD204 + macrophages and FOXP3 + Tregs accumulated in 88% (14/16) and 63% (10/16) of TIL + PD-L1 + tumors, respectively, compared with 20.8% (10/48) and 27.1% (13/48) of TIL − PD-L1 − tumors. In conclusion, 22% of BC tumors were classified as TIL + PD-L1 + (69% were TN), which were enriched with suppressive immune subsets. These cell types may serve as potential novel immunotherapeutic targets.

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“…This might be caused by the so called "abscopal effect, " which describes a "response at a distance from the irradiated volume" (37). However, breast cancer is so far not considered a typical immunogenic cancer (38). Nonetheless, especially triple negative or Her2/neu rich breast cancer seems to show a high proportion of tumor infiltrating immune cells (39,40).…”

Section: Discussionmentioning

confidence: 99%

Extracranial Stereotactic Body Radiotherapy in Oligometastatic or Oligoprogressive Breast Cancer

et al. 2020

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Purpose/Objective: Oligometastatic disease (OMD) and oligoprogressive disease (OPD) describe tumor states with a limited metastasization. In contrast to other disease states, treatment of OMD or OPD has not yet become common for breast cancer. We sought to understand the outcomes and toxicities of this treatment paradigm. Material/Methods: We retrospectively analyzed female breast cancer patients with OMD (≤3 metastases) or OPD (1 progressive lesion) who received stereotactic body radiotherapy (SBRT) for their respective extracranial metastatic lesions between 01/2002 and 07/2019. Survival analysis was performed using the Kaplan-Meier method with log-rank test being used for evaluation of significance. Cox regression was used to detect prognostic outcome factors. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). Results: Forty-six patients (70% OMD; 30% OPD) with 58 lesions met criteria for inclusion. The majority of treatments (34 out of 58; 58.6%) were delivered from 2017 to 2018. Treatment sites were bone, liver, lung [n = 19 (33%) for each site], and adrenal gland [n = 1 (1%)]. Median biologically effective dose (BED at α/β = 10) was 81.6 Gy (range: 45-112.5 Gy) and median planning target volume was 36.60 mL (range: 3.76-311.00 mL). At 2 years, local control (LC) was 89%, distant control (DC) was 44%, progression free survival (PFS) was 17% and overall survival (OS) was 62%. Multivariate analysis identified the diagnosis of a solitary metastasis as an independent prognostic factor for superior DC (HR = 0.186, CI [0.055; 0.626], p = 0.007) and PFS (HR = 0.363, CI [0.152; 0.863], p = 0.022). OS was independently inferior for patients treated at a higher age (HR = 5.788, CI [1.077; 31.119] p = 0.041). Nine (15.5%) grade I • and one (1.7%) grade II • toxicities were recorded, with no grade III • or higher toxicities. Weykamp et al. SBRT in Oligometastatic Breast Cancer Conclusion: Extracranial SBRT in breast cancer patients with OMD or OPD was well-tolerated with excellent LC. SBRT should especially be offered to younger OMD and OPD breast cancer patients with only one metastasis. The increase in utilization since 2017 points toward a growing acceptance of SBRT for OMD and OPD in breast cancer.

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Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

Cited by 37 publications

References 109 publications

Co-Expression of Androgen Receptor and Cathepsin D Defines a Triple-Negative Breast Cancer Subgroup with Poorer Overall Survival

Co-Expression of Androgen Receptor and Cathepsin D Defines a Triple-Negative Breast Cancer Subgroup with Poorer Overall Survival

CD204‑positive macrophages accumulate in breast cancer tumors with high levels of infiltrating lymphocytes and programmed death ligand‑1 expression

Extracranial Stereotactic Body Radiotherapy in Oligometastatic or Oligoprogressive Breast Cancer

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