Research ArticleClinical Studies
Open Access

Clinicopathological and Prognostic Significance of Programmed Death Ligand-1 SP142 Expression in 132 Patients With Triple-negative Breast Cancer

JINAH CHU, MIN-KYUNG YEO, SANG HWA LEE, MI YEON LEE, SEOUNG WAN CHAE, HYUN-SOO KIM and SUNG-IM DO
In Vivo November 2022, 36 (6) 2890-2898; DOI: https://doi.org/10.21873/invivo.13030

Abstract

Background/Aim: The prognostic value of programmed death ligand-1 (PD-L1) expression in triple-negative breast cancer (TNBC) has not been sufficiently investigated. In this study, we examined whether PD-L1 expression status is associated with clinicopathological features and outcomes of patients with TNBC. Patients and Methods: Immunostaining for PD-L1 SP142 was performed on tissue microarrays containing 132 TNBC samples. High PD-L1 expression was defined as ≥10% of the tumor area occupied by PD-L1-expressing cells. Results: Thirty-five (26.5%) patients showed high PD-L1 SP142 expression on immune cells (ICs). High IC PD-L1 expression was significantly correlated with smaller tumor size (p=0.030), absence of lymphovascular invasion (p=0.024), and fewer lymph node metastases (p=0.002). Multivariate survival analysis revealed that high IC PD-L1 expression independently predicted better disease-free survival (DFS) of TNBC patients. Conclusion: High PD-L1 SP142 expression on ICs was significantly associated with favorable clinicopathological parameters and better outcomes in patients with TNBC. Our observations suggest that high IC PD-L1 expression can be used as an independent prognostic marker for predicting better DFS in patients with TNBC.

Key Words:

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that lacks expression of estrogen and progesterone receptors and amplification or over-expression of human epidermal growth factor receptor 2 (HER2) (1-3). TNBC accounts for nearly one-fifth of all cases of breast cancer (4, 5), and more frequently affects young women (6). TNBC patients exhibit adverse clinicopathological features and unfavorable prognoses compared to patients with other types of breast cancer (7, 8). Particularly, early-stage TNBC is associated with a higher risk of recurrence than other types, and advanced-stage disease has a poor prognosis with a median survival of 18 months (9). The absence of hormone receptors renders endocrine and human epidermal growth factor receptor 2-targeted therapies ineffective, leaving cytotoxic chemotherapy as the standard treatment option (10). However, chemotherapy for TNBC patients results in unsatisfactory long-term results, such as suboptimal response rates and short overall survival and response durations (11-13). Therefore, novel therapeutic strategies to improve outcomes are urgently needed.

Recent advances in the immune landscape of the tumor microenvironment have shed light on novel targeted opportunities for TNBC. TNBC possesses enriched tumor-infiltrating lymphocytes (TILs) compared to other types of cancer (10, 14), suggesting that a subset of TNBCs is immunogenically active. A higher level of TILs, an important component of the local tumor microenvironment, has been reported to be significantly associated with better cancer-specific survival in patients with TNBC (15). Furthermore, TNBC has a greater number of somatic mutations due to genomic instability, leading to an abundant load of neoantigens (14). The presence of TILs and tumor neoantigens correlates with programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) expression in patients with TNBC (16, 17). Moreover, the PD-1/PD-L1 pathway plays a critical role in regulating the immune response. TNBC has a unique microenvironment with a higher level of PD-L1 expression than normal breast tissue and other breast cancer types (17). Additionally, The Cancer Genome Atlas RNA sequencing data showed significant over-expression of the PD-L1 mRNA in TNBC compared to non-TNBC (17). Thus, the emergence of immunotherapy targeting the PD-1/PD-L1 pathway will change the future treatment landscape for TNBC.

Atezolizumab, a monoclonal antibody targeting PD-L1, received accelerated approval from the US Food and Drug Administration (FDA) to be combined with nab-paclitaxel for patients with metastatic or unresectable locally advanced TNBC whose tumors express PD-L1. The IMpassion130 trial strongly confirmed that atezolizumab plus nab-paclitaxel improved both progression-free survival and overall survival in PD-L1-positive TNBC patients compared to nab-paclitaxel monotherapy (18, 19). Simultaneously, the Ventana PD-L1 SP142 assay (Ventana Medical Systems, Oro Valley, AZ, USA), was approved as a companion diagnostic device.

While the predictive value of PD-L1 expression has been documented, its prognostic role has not been sufficiently investigated in patients with TNBC. Particularly, differences in the prognostic significance have been observed depending on which clones were used, where PD-L1 expression was evaluated, or which cutoff values were used. The purpose of this study was to evaluate the prevalence of positive PD-L1 SP142 expression in patients with TNBC and to examine its association with clinicopathological features and outcomes of patients with TNBC.

Patients and Methods

Patient selection. The Institutional Review Board of Kangbuk Samsung Hospital reviewed and approved this study (approval number: 2022-05-030). We collected 132 consecutive cases of primary TNBC. The final diagnoses were established based on the fifth edition of the World Health Organization Classification of Breast Tumours (20). Pathologists inspected the resected specimens prior to fixation in 10% neutral-buffered formalin. The tissues were macroscopically examined and sectioned after fixation for 12-24 h. The sections were embedded in paraffin blocks after being processed with an automatic tissue processor. Using a rotary microtome, each formalin-fixed, paraffin-embedded (FFPE) tissue block was cut into 4 μm-thick slices, which were subsequently stained with hematoxylin and eosin in an automatic staining instrument. All available hematoxylin and eosin-stained slides were examined by two board-certified pathologists. The following clinicopathological information was obtained from electronic medical records and pathology reports: patients’ age, histological grade (21), pathological tumor (pT) and nodal (pN) stage, lymphovascular invasion (LVI), tumor multiplicity, extensive intraductal component, first post-operative recurrence or metastasis, and follow-up period. The modified Bloom-Richardson grading system was applied to assign histological grades. The eighth edition of the American Joint Committee on Cancer Staging Manual was used for pathological staging (22). To estimate disease-free survival (DFS), patients were followed-up from the date of surgery to the date of death or other events, such as locoregional recurrence or distant metastasis. The development of recurrence or metastasis was confirmed by computed tomography or magnetic resonance imaging.

Tissue microarray. Tissue microarray blocks were constructed as previously described (1, 23). In brief, the two most representative tumor areas were marked on all hematoxylin and eosin-stained slides, and the corresponding FFPE tissue blocks. Two 2-mm diameter tissue cores were taken from marked tumor areas in each block and manually assembled into recipient tissue microarray blocks. Each core had more than 70% of tumor volume. For recipient blocks, holes for array cores at 1-mm intervals were created using an X-Y position guide and the appropriate instruments. The obtained tissue core was transferred into holes in the recipient block. Finally, for each case, a pair of tissue microarray blocks was constructed.

Immunostaining. The 4-μm slices from FFPE blocks were subjected to a series of processes including deparaffinization, dehydration with xylene, and rehydration in a graded series of alcohol solutions. Immunostaining was performed using an automatic immunostainer and a compact polymer method (Bond Intense Detection Kit, Leica Biosystems, Newcastle upon Tyne, UK) (1, 21, 23-27). We used a rabbit recombinant monoclonal PD-L1 antibody (clone SP142, prediluted, Ventana Medical Systems) as the primary antibody. After chromogenic visualization (EnVision+ Detection Systems, Dako, Glostrup, Denmark), the slices were counterstained with hematoxylin and coverslipped. PD-L1 expression was evaluated in both immune cells (ICs) and tumor cells (TCs) (28, 29). The scoring of PD-L1 expression on ICs was evaluated as the percentage of the tumor area covered with any detectable PD-L1 staining of any intensity. The tumor area was defined as the region occupied by TCs with intratumoral and peritumoral stroma. The ICs included macrophages, dendritic cells, and granulocytes as well as lymphocytes. For TCs, PD-L1 expression was scored as the proportion of tumor area with any intensity. The ICs and TCs were scored using continuous scores (0-100%) and categorical scores (<1%, 1-9%, 10-49%, and ≥50%). High PD-L1 expression was defined as ≥10% of the tumor area occupied by PD-L1-expressing cells at any staining intensity.

Statistical analysis. All statistical analyses were performed using STATA version 17.0 software (StataCorp, College Station, TX, USA). Independent two-sample t-tests, Pearson’s Chi-squared test, Fisher’s exact test, or linear-by-linear association test was used to determine the association between PD-L1 SP142 expression status and clinicopathological features of TNBC patients. Univariate and multivariate survival analyses were used to examine the prognostic significance of PD-L1 SP142 expression. Curves for DFS were drawn using the Kaplan-Meier method, and differences were analyzed by applying the log-rank test for univariate survival analysis. Multivariate survival analysis was performed using the Cox proportional hazards model (95% confidence interval) with the backward stepwise elimination method. Statistical significance was defined as a p-value <0.05.

Results

Baseline clinicopathological characteristics of TNBC. Table I summarizes the baseline clinicopathological characteristics of the 132 TNBC patients enrolled in this study. The mean age of patients at the time of surgery was 53 years (range=25-85 years). Approximately 63.6% of the TNBC cases (84/132) were classified as histological grade 3 tumors, while 3.8% (5/132) and 32.6% (43/132) of cases were diagnosed as histological grades 1 and 2, respectively. Additionally, more than half of the tumors (77/132; 58.3%) were staged as pT2 or higher, and 43 patients (32.6%) had lymph node metastases. Moreover, the pN stage distribution was as follows: pN0: 67.4% (89/132), pN1: 18.9% (25/132), pN2: 6.8% (9/132), and pN3: 6.8% (9/132). LVI was detected in 34 (25.8%) cases. Finally, only 8 patients (6.1%) had multiple tumors.

View this table:
Table I.

Baseline characteristics of 132 patients with triple-negative breast cancer.

PD-L1 SP142 expression in ICs and TCs of TNBC. We conducted PD-L1 SP142 immunostaining on tissue microarray blocks containing 132 FFPE TNBC tissue samples. The PD-L1 expression status in ICs and TCs of TNBC is shown in Table II. Regarding ICs, 35 cases (26.5%) were classified as IC PD-L1-high TNBC. Among these, eight cases (6.1%) exhibited IC PD-L1 expression ≥50%. In contrast, 51 tumors (38.6%) showed IC PD-L1 expression <1%. Regarding TCs, only six cases (4.6%) expressed high TC PD-L1 levels. In most cases (95.5%), TCs showed low PD-L1 immunoreactivity. In particular, 68.2% (90/132) of TC samples exhibited <1% of PD-L1 expression. Representative photomicrographs depicting PD-L1 SP142 immunoreactivities in ICs and TCs of TNBC are demonstrated in Figure 1.

View this table:
Table II.

Programmed death ligand 1 (PD-L1) SP142 expression on immune cells (ICs) and tumor cells (TCs).

Figure 1.
Figure 1.

Programmed death ligand-1 (PD-L1) SP142 immunoreactivity in immune cells (ICs) and tumor cells (TCs) of triple-negative breast cancer (TNBC). Original magnification, 100×.

Association between PD-L1 expression status and clinicopathological characteristics of patients with TNBC. A total of 132 TNBC patients were divided into two groups according to their IC PD-L1 expression status, with a cutoff value of 10%. Table III summarizes the results of the statistical analysis of the clinicopathological significance of IC PD-L1 expression in TNBC. High IC PD-L1 expression was significantly associated with lower pT (smaller tumor size; p=0.030), fewer lymph node metastases (p=0.002), and the absence of LVI (p=0.024). Most cases (62/77; 80.5%) of pT2-3 TNBC (>2 cm) showed low IC PD-L1 expression, while more than half (20/35; 57.1%) of the patients with high IC PD-L1 expression had pT1 (≤2 cm) tumors. The mean number of metastatic lymph nodes was significantly lower in IC PD-L1-high patients (0.43) than in IC PD-L1-low patients (2.78). The majority of IC PD-L1-high patients (31/35; 88.6%) did not have LVI. Additionally, although the presence of lymph node metastasis was not significantly associated with IC PD-L1 expression, the frequency of LVI was significantly different according to IC PD-L1 expression status. The differences in age, tumor multiplicity, and the presence of an extensive intraductal component between IC PD-L1-high and -low patients were not statistically significant. Finally, no significant difference was observed in clinicopathological characteristics of TNBC patients according to TC PD-L1 expression status (data not shown).

View this table:
Table III.

Relationship between programmed death ligand-1 (PD-L1) SP142 expression on immune cells (ICs) and clinicopathologic parameters of 132 patients with triple-negative breast cancer.

Association between PD-L1 expression status and patient outcome. Univariate and multivariate survival analyses were performed to investigate the prognostic significance of IC PD-L1 expression in TNBC patients (Table IV). The median post-operative follow-up time was 32 months. Moreover, 26 (20.0%) patients developed post-operative locoregional or metastatic recurrences. Univariate analysis revealed that pN1 (p=0.018) and pN2-3 (p=0.005) significantly predicted worse DFS. Moreover, high IC PD-L1 expression was significantly associated with favorable DFS with a hazard ratio of 0.12 (p=0.020). Kaplan-Meier plots showing the difference in DFS according to the expression status of IC PD-L1 in patients with TNBC demonstrated that patients whose tumor exhibited high IC PD-L1 expression showed better DFS than those with low PD-L1 expression (Figure 2). In addition to these three significant clinicopathological parameters, tumor multiplicity, which showed a marginal significance in univariate analysis (p=0.092), was entered into the multivariate analysis with a backward stepwise elimination method. As a result, pN1, pN2-3, and high IC PD-L1 expression maintained their statistical significance at the multivariate level (p=0.015, p=0.014, and p=0.038, respectively), indicating that these parameters were independent prognostic factors for predicting worse DFS in patients with TNBC. The hazard ratio for IC PD-L1-high patients compared to IC PD-L1-low patients was 0.10 in multivariate analysis. Tumor multiplicity of TNBC was not an independent predictor of DFS (p=0.908) in this study. Finally, no significant differences were observed in DFS according to TC PD-L1 expression status (data not shown).

View this table:
Table IV.

Univariate and multivariate survival analyses for prognostic significance of programmed death ligand-1 (PD-L1) SP142 expression on immune cells (ICs) and clinicopathologic parameters of 132 patients with triple-negative breast cancer.

Figure 2.
Figure 2.

Kaplan-Meier plots showing the difference in disease-free survival (DFS) according to the expression status of programmed death ligand-1 (PD-L1) SP142 in triple-negative breast cancer (TNBC). Patients whose tumor exhibits high PD-L1 expression (≥10%) show better DFS than those with low PD-L1 expression (<10%) TNBC (p=0.020).

Discussion

PD-L1 is expressed in TCs, as well as ICs. The binding of PD-L1 to its receptor, PD-1 prevents autoimmunity by the suppression of T cell effector functions (30, 31). In tumors, where PD-L1 expression is upregulated, the immunosuppressive effect of PD-1/PD-L1 signaling helps the tumor escape from the anti-tumor immune response (32). Immune checkpoint inhibition by blocking the PD-1/PD-L1 axis has emerged as an effective treatment for various solid tumors (33). PD-L1 expression has been evaluated as a biomarker for predicting the therapeutic response to anti-PD-1/PD-L1 drugs. Since TNBC was found to exhibit a higher tumor mutational burden, TILs, and PD-L1 expression than other types of breast cancer, immune checkpoint inhibitors have been considered an effective strategy for the treatment of TNBC (34). Previous studies of TNBC have shown that the expression of PD-L1 occurs mainly on tumor-infiltrating ICs, rather than TCs (17, 35). The IMpassion130 trial confirmed the overall survival benefit of atezolizumab plus nab-paclitaxel in IC PD-L1-positive TNBC patients (25.0 months; hazard ratio=0.62; 95% confidence interval=0.45-0.86), versus the placebo plus nab-paclitaxel (15.5 months) (18, 19). The US FDA approved atezolizumab combined with chemotherapy for PD-L1-positive metastatic TNBC and the PD-L1 SP142 assay as a companion diagnostic test to determine PD-L1 expression on ICs.

Considering PD-L1 expression as a prognostic marker for breast cancer patients, several studies have demonstrated that positive PD-L1 expression is associated with adverse clinicopathological features, such as more advanced stage and lymph node metastasis, as well as worse survival (36-38). However, in the case of TNBC, conflicting results have been documented. PD-L1 immunostaining has been a complex issue for the pathology laboratory as it requires an understanding of multiple clones and testing platforms, each with variable scoring criteria. The lack of standardization and reproducibility provide conflicting data regarding the clinicopathological significance of PD-L1 expression in TNBC. The utilization of various PD-L1 antibody clones has led to these controversies. In published data using E1L3N antibody in TNBC, the relationship between positive PD-L1 expression and patient outcome varied from better (39-41) to worse (42, 43) or insignificant (44, 45). Similarly, some previous studies regarding the SP142 antibody on TNBC revealed an association between positive PD-L1 expression and better outcomes (21, 26, 46), whereas a recent study on 223 patients with TNBC showed that PD-L1 SP142 expression in ICs was independently prognostic of worse overall survival (47). Similarly, the cutoff scores for positive or high PD-L1 expression vary among studies. According to the results of previous studies evaluating PD-L1 SP142 expression in TNBC, the frequency of IC PD-L1 expression ≥1% ranged from 28% to 53% (21, 26, 46-48). In this study, the positive rate of PD-L1 expression ≥1% on ICs was relatively higher (61.4%; 81/132) than that of previous studies. However, unlike other studies using SP142 antibody (21, 26, 46-48), we could not find a statistically significant difference in survival between IC PD-L1 ≥1% and <1% tumors. Instead, when we applied a cutoff value of 10% for high IC PD-L1 expression, we observed that 26.6% (35/132) of the cases were classified as IC PD-L1-high tumors. Additionally, high IC PD-L1 expression was significantly associated with favorable clinicopathologic parameters, including smaller tumor size, fewer lymph node metastases, and the absence of LVI. Survival analyses also revealed that high IC PD-L1 expression was an independent prognostic factor of better DFS for patients with TNBC. Although the treatment-related cutoff value of PD-L1 SP142 (≥1% of ICs) is well established in TNBC, further investigations are warranted to determine its prognosis-related cutoff value.

This study had several limitations. First, we enrolled patients with TNBC who underwent surgery at a single institution. As this study did not include patients who received radiation therapy only or concurrent chemoradiation therapy, the cohort size was relatively small. Second, we did not analyze the statistical differences in locoregional recurrence-free survival or distant metastasis-free survival according to PD-L1 expression status. Further investigations using more detailed prognostic information obtained from larger cohorts are necessary. Third, we did not use morphometric or computer-assisted analyses for the quantification of PD-L1 expression. Finally, we did not measure PD-L1 expression in patients treated with anti-PD-1/PD-L1 therapies. Comparing the matched pre- and post-treatment expression levels of PD-L1 may better address its clinicopathological significance.

In conclusion, we demonstrated that when the cutoff value of 10% was applied, high IC PD-L1 expression was significantly associated with smaller tumor size, fewer lymph node metastases, the absence of LVI, and better DFS in patients with TNBC. In the multivariate analysis, IC PD-L1 expression status was an independent predictor of DFS. Although the impact of PD-L1 expression on TNBC outcomes had not been clearly established, our results indicate that IC PD-L1 SP142 expression is a significant marker of a better prognosis for patients with TNBC.

Acknowledgements

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (HR20C0025).

Footnotes

  • Authors’ Contributions

    All Authors made substantial contributions to the conceptualization and design of the study, the acquisition, analysis, interpretation, and validation of the data, drafting of the article, critical revision of the article for important intellectual content, and the final approval of the version to be published.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received September 7, 2022.
  • Revision received September 19, 2022.
  • Accepted September 21, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Chung Y,
    2. Kim S,
    3. Kim HS and
    4. DO SI
    : High receptor-interacting serine/threonine-protein kinase 3 (RIP3) expression serves as an independent poor prognostic factor for triple-negative breast carcinoma. Anticancer Res 42(5): 2753-2761, 2022. PMID: 35489766. DOI: 10.21873/anticanres.15754
    OpenUrlAbstract/FREE Full Text
    1. Lim HI,
    2. Sun YU,
    3. Han Q,
    4. Yamamoto J and
    5. Hoffman RM
    : Efficacy of oral recombinant methioninase and eribulin on a PDOX model of triple-negative breast cancer (TNBC) liver metastasis. In Vivo 35(5): 2531-2534, 2021. PMID: 34410939. DOI: 10.21873/invivo.12534
    OpenUrlAbstract/FREE Full Text
  3. ↵
    1. Hasegawa Y,
    2. Matsubara N,
    3. Kogawa T,
    4. Naito Y,
    5. Harano K,
    6. Hosono A,
    7. Onishi T,
    8. Hojo T,
    9. Shimokawa M and
    10. Mukohara T
    : Neo-bioscore in guiding post-surgical therapy in patients with triple-negative breast cancer who received neoadjuvant chemotherapy. In Vivo 35(2): 1041-1049, 2021. PMID: 33622900. DOI: 10.21873/invivo.12348
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Liao PA,
    2. Chu PY,
    3. Tan ZL,
    4. Hsu FT,
    5. Lee YC and
    6. Wu HJ
    : STAT3 inactivation and induction of apoptosis associate with fluoxetine-inhibited epithelial-mesenchymal transition and growth of triple-negative breast cancer in vivo. Anticancer Res 42(8): 3807-3814, 2022. PMID: 35896246. DOI: 10.21873/anticanres.15871
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Wang YC,
    2. Wang ZH,
    3. Yen JH,
    4. Shen YC,
    5. Shen TC,
    6. Chang WS,
    7. Su CH,
    8. Chen KY,
    9. Yen CM,
    10. Lee HT,
    11. Yang JS,
    12. Bau DT and
    13. Tsai CW
    : The contribution of interleukin-8 Rs4073 genotypes to triple negative breast cancer risk in Taiwan. Anticancer Res 42(8): 3799-3806, 2022. PMID: 35896229. DOI: 10.21873/anticanres.15870
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Howard FM and
    2. Olopade OI
    : Epidemiology of triple-negative breast cancer: a review. Cancer J 27(1): 8-16, 2021. PMID: 33475288. DOI: 10.1097/PPO.0000000000000500
    OpenUrlCrossRefPubMed
  7. ↵
    1. Dent R,
    2. Trudeau M,
    3. Pritchard KI,
    4. Hanna WM,
    5. Kahn HK,
    6. Sawka CA,
    7. Lickley LA,
    8. Rawlinson E,
    9. Sun P and
    10. Narod SA
    : Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1): 4429-4434, 2007. PMID: 17671126. DOI: 10.1158/1078-0432.CCR-06-3045
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Carey L,
    2. Winer E,
    3. Viale G,
    4. Cameron D and
    5. Gianni L
    : Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol 7(12): 683-692, 2010. PMID: 20877296. DOI: 10.1038/nrclinonc.2010.154
    OpenUrlCrossRefPubMed
  9. ↵
    1. DeSantis CE,
    2. Ma J,
    3. Gaudet MM,
    4. Newman LA,
    5. Miller KD,
    6. Goding Sauer A,
    7. Jemal A and
    8. Siegel RL
    : Breast cancer statistics, 2019. CA Cancer J Clin 69(6): 438-451, 2019. PMID: 31577379. DOI: 10.3322/caac.21583
    OpenUrlCrossRefPubMed
  10. ↵
    1. Kwapisz D
    : Pembrolizumab and atezolizumab in triple-negative breast cancer. Cancer Immunol Immunother 70(3): 607-617, 2021. PMID: 33015734. DOI: 10.1007/s00262-020-02736-z
    OpenUrlCrossRefPubMed
  11. ↵
    1. Cardoso F,
    2. Costa A,
    3. Senkus E,
    4. Aapro M,
    5. André F,
    6. Barrios CH,
    7. Bergh J,
    8. Bhattacharyya G,
    9. Biganzoli L,
    10. Cardoso MJ,
    11. Carey L,
    12. Corneliussen-James D,
    13. Curigliano G,
    14. Dieras V,
    15. El Saghir N,
    16. Eniu A,
    17. Fallowfield L,
    18. Fenech D,
    19. Francis P,
    20. Gelmon K,
    21. Gennari A,
    22. Harbeck N,
    23. Hudis C,
    24. Kaufman B,
    25. Krop I,
    26. Mayer M,
    27. Meijer H,
    28. Mertz S,
    29. Ohno S,
    30. Pagani O,
    31. Papadopoulos E,
    32. Peccatori F,
    33. Penault-Llorca F,
    34. Piccart MJ,
    35. Pierga JY,
    36. Rugo H,
    37. Shockney L,
    38. Sledge G,
    39. Swain S,
    40. Thomssen C,
    41. Tutt A,
    42. Vorobiof D,
    43. Xu B,
    44. Norton L and
    45. Winer E
    : 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3). Breast 31: 244-259, 2017. PMID: 27927580. DOI: 10.1016/j.breast.2016.10.001
    OpenUrlCrossRefPubMed
    1. Garrido-Castro AC,
    2. Lin NU and
    3. Polyak K
    : Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment. Cancer Discov 9(2): 176-198, 2019. PMID: 30679171. DOI: 10.1158/2159-8290.CD-18-1177
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Mazzio E,
    2. Almalki A,
    3. Darling-Reed SF and
    4. Soliman KFA
    : Effects of wild yam root (Dioscorea villosa) extract on the gene expression profile of triple-negative breast cancer cells. Cancer Genomics Proteomics 18(6): 735-755, 2021. PMID: 34697066. DOI: 10.21873/cgp.20294
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Sasaki R,
    2. Horimoto Y,
    3. Yanai Y,
    4. Kurisaki-Arakawa A,
    5. Arakawa A,
    6. Nakai K,
    7. Saito M and
    8. Saito T
    : Molecular Characteristics of Lymphocyte-predominant Triple-negative Breast Cancer. Anticancer Res 41(4): 2133-2140, 2021. PMID: 33813424. DOI: 10.21873/anticanres.14985
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Liu S,
    2. Lachapelle J,
    3. Leung S,
    4. Gao D,
    5. Foulkes WD and
    6. Nielsen TO
    : CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res 14(2): R48, 2012. PMID: 22420471. DOI: 10.1186/bcr3148
    OpenUrlCrossRefPubMed
  16. ↵
    1. Wimberly H,
    2. Brown JR,
    3. Schalper K,
    4. Haack H,
    5. Silver MR,
    6. Nixon C,
    7. Bossuyt V,
    8. Pusztai L,
    9. Lannin DR and
    10. Rimm DL
    : PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res 3(4): 326-332, 2015. PMID: 25527356. DOI: 10.1158/2326-6066.CIR-14-0133
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Mittendorf EA,
    2. Philips AV,
    3. Meric-Bernstam F,
    4. Qiao N,
    5. Wu Y,
    6. Harrington S,
    7. Su X,
    8. Wang Y,
    9. Gonzalez-Angulo AM,
    10. Akcakanat A,
    11. Chawla A,
    12. Curran M,
    13. Hwu P,
    14. Sharma P,
    15. Litton JK,
    16. Molldrem JJ and
    17. Alatrash G
    : PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4): 361-370, 2014. PMID: 24764583. DOI: 10.1158/2326-6066.CIR-13-0127
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Schmid P,
    2. Adams S,
    3. Rugo HS,
    4. Schneeweiss A,
    5. Barrios CH,
    6. Iwata H,
    7. Diéras V,
    8. Hegg R,
    9. Im SA,
    10. Shaw Wright G,
    11. Henschel V,
    12. Molinero L,
    13. Chui SY,
    14. Funke R,
    15. Husain A,
    16. Winer EP,
    17. Loi S,
    18. Emens LA and IMpassion130 Trial Investigators
    : Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379(22): 2108-2121, 2018. PMID: 30345906. DOI: 10.1056/NEJMoa1809615
    OpenUrlCrossRefPubMed
  19. ↵
    1. Schmid P,
    2. Rugo HS,
    3. Adams S,
    4. Schneeweiss A,
    5. Barrios CH,
    6. Iwata H,
    7. Diéras V,
    8. Henschel V,
    9. Molinero L,
    10. Chui SY,
    11. Maiya V,
    12. Husain A,
    13. Winer EP,
    14. Loi S,
    15. Emens LA and IMpassion130 Investigators
    : Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21(1): 44-59, 2020. PMID: 31786121. DOI: 10.1016/S1470-2045(19)30689-8
    OpenUrlCrossRefPubMed
  20. ↵
    1. Lee M,
    2. Chun SM,
    3. Sung CO,
    4. Kim SY,
    5. Kim TW,
    6. Jang SJ and
    7. Kim J
    : Clinical utility of a fully automated microsatellite instability test with minimal hands-on time. J Pathol Transl Med 53(6): 386-392, 2019. PMID: 31606978. DOI: 10.4132/jptm.2019.09.25
    OpenUrlCrossRefPubMed
  21. ↵
    1. Kim HS,
    2. DO SI,
    3. Kim DH and
    4. Apple S
    : Clinicopathological and prognostic significance of programmed death ligand 1 expression in korean patients with triple-negative breast carcinoma. Anticancer Res 40(3): 1487-1494, 2020. PMID: 32132048. DOI: 10.21873/anticanres.14093
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Son T,
    2. Sun J,
    3. Choi S,
    4. Cho M,
    5. Kwon IG,
    6. Kim HI,
    7. Cheong JH,
    8. Choi SH,
    9. Noh SH,
    10. Woo Y,
    11. Fong Y,
    12. Park S and
    13. Hyung WJ
    : Multi-institutional validation of the 8th AJCC TNM staging system for gastric cancer: Analysis of survival data from high-volume Eastern centers and the SEER database. J Surg Oncol 120(4): 676-684, 2019. PMID: 31338834. DOI: 10.1002/jso.25639
    OpenUrlCrossRefPubMed
  23. ↵
    1. Do SI,
    2. Yoon G,
    3. Kim HS,
    4. Kim K,
    5. Lee H,
    6. Do IG,
    7. Kim DH,
    8. Chae SW and
    9. Sohn JH
    : Increased Brahma-related gene 1 expression predicts distant metastasis and shorter survival in patients with invasive ductal carcinoma of the breast. Anticancer Res 36(9): 4873-4882, 2016. PMID: 27630343. DOI: 10.21873/anticanres.11051
    OpenUrlAbstract/FREE Full Text
    1. Koh HH,
    2. Jung YY and
    3. Kim HS
    : Clinicopathological characteristics of gastric-type endocervical adenocarcinoma misdiagnosed as an endometrial, ovarian or extragenital malignancy, or mistyped as usual-type endocervical adenocarcinoma. In Vivo 35(4): 2261-2273, 2021. PMID: 34182505. DOI: 10.21873/invivo.12499
    OpenUrlAbstract/FREE Full Text
    1. Choi S,
    2. Kim SW and
    3. Kim HS
    : Invasive stratified mucin-producing carcinoma (ISMC) of the uterine cervix: clinicopathological and molecular characteristics with special emphasis on the first description of consistent programmed death-ligand 1 (PD-L1) over-expression. Cancer Genomics Proteomics 18(5): 685-698, 2021. PMID: 34479920. DOI: 10.21873/cgp.20290
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Ahn SG,
    2. Kim SK,
    3. Shepherd JH,
    4. Cha YJ,
    5. Bae SJ,
    6. Kim C,
    7. Jeong J and
    8. Perou CM
    : Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer. Breast Cancer Res Treat 188(1): 165-178, 2021. PMID: 33770313. DOI: 10.1007/s10549-021-06193-9
    OpenUrlCrossRefPubMed
  27. ↵
    1. Kim HG,
    2. Kim H,
    3. Yeo MK,
    4. Won KY,
    5. Kim YS,
    6. Han GH,
    7. Kim HS and
    8. Na K
    : Mesonephric-like adenocarcinoma of the uterine corpus: comprehensive analyses of clinicopathological, molecular, and prognostic characteristics with retrospective review of 237 endometrial carcinoma cases. Cancer Genomics Proteomics 19(4): 526-539, 2022. PMID: 35732320. DOI: 10.21873/cgp.20338
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Ahn S,
    2. Woo JW,
    3. Kim H,
    4. Cho EY,
    5. Kim A,
    6. Kim JY,
    7. Kim C,
    8. Lee HJ,
    9. Lee JS,
    10. Bae YK,
    11. Kwon Y,
    12. Kim WS and
    13. Park SY
    : Programmed death ligand 1 immunohistochemistry in triple-negative breast cancer: evaluation of inter-pathologist concordance and inter-assay variability. J Breast Cancer 24(3): 266-279, 2021. PMID: 34128367. DOI: 10.4048/jbc.2021.24.e29
    OpenUrlCrossRefPubMed
  29. ↵
    1. Phillips T,
    2. Simmons P,
    3. Inzunza HD,
    4. Cogswell J,
    5. Novotny J Jr.,
    6. Taylor C and
    7. Zhang X
    : Development of an automated PD-L1 immunohistochemistry (IHC) assay for non-small cell lung cancer. Appl Immunohistochem Mol Morphol 23(8): 541-549, 2015. PMID: 26317305. DOI: 10.1097/PAI.0000000000000256
    OpenUrlCrossRefPubMed
  30. ↵
    1. Pardoll DM
    : The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4): 252-264, 2012. PMID: 22437870. DOI: 10.1038/nrc3239
    OpenUrlCrossRefPubMed
  31. ↵
    1. Swaika A,
    2. Hammond WA and
    3. Joseph RW
    : Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol Immunol 67(2 Pt A): 4-17, 2015. PMID: 25749122. DOI: 10.1016/j.molimm.2015.02.009
    OpenUrlCrossRefPubMed
  32. ↵
    1. Vranic S,
    2. Cyprian FS,
    3. Gatalica Z and
    4. Palazzo J
    : PD-L1 status in breast cancer: Current view and perspectives. Semin Cancer Biol 72: 146-154, 2021. PMID: 31883913. DOI: 10.1016/j.semcancer.2019.12.003
    OpenUrlCrossRefPubMed
  33. ↵
    1. Sharma P and
    2. Allison JP
    : The future of immune checkpoint therapy. Science 348(6230): 56-61, 2015. PMID: 25838373. DOI: 10.1126/science.aaa8172
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Swoboda A and
    2. Nanda R
    : Immune checkpoint blockade for breast cancer. Cancer Treat Res 173: 155-165, 2018. PMID: 29349763. DOI: 10.1007/978-3-319-70197-4_10
    OpenUrlCrossRefPubMed
  35. ↵
    1. Sabatier R,
    2. Finetti P,
    3. Mamessier E,
    4. Adelaide J,
    5. Chaffanet M,
    6. Ali HR,
    7. Viens P,
    8. Caldas C,
    9. Birnbaum D and
    10. Bertucci F
    : Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6(7): 5449-5464, 2015. PMID: 25669979. DOI: 10.18632/oncotarget.3216
    OpenUrlCrossRefPubMed
  36. ↵
    1. Wang C,
    2. Zhu H,
    3. Zhou Y,
    4. Mao F,
    5. Lin Y,
    6. Pan B,
    7. Zhang X,
    8. Xu Q,
    9. Huang X and
    10. Sun Q
    : Prognostic value of PD-L1 in breast cancer: a meta-analysis. Breast J 23(4): 436-443, 2017. PMID: 28079291. DOI: 10.1111/tbj.12753
    OpenUrlCrossRefPubMed
    1. Qin T,
    2. Zeng YD,
    3. Qin G,
    4. Xu F,
    5. Lu JB,
    6. Fang WF,
    7. Xue C,
    8. Zhan JH,
    9. Zhang XK,
    10. Zheng QF,
    11. Peng RJ,
    12. Yuan ZY,
    13. Zhang L and
    14. Wang SS
    : High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget 6(32): 33972-33981, 2015. PMID: 26378017. DOI: 10.18632/oncotarget.5583
    OpenUrlCrossRefPubMed
  38. ↵
    1. Muenst S,
    2. Schaerli AR,
    3. Gao F,
    4. Däster S,
    5. Trella E,
    6. Droeser RA,
    7. Muraro MG,
    8. Zajac P,
    9. Zanetti R,
    10. Gillanders WE,
    11. Weber WP and
    12. Soysal SD
    : Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 146(1): 15-24, 2014. PMID: 24842267. DOI: 10.1007/s10549-014-2988-5
    OpenUrlCrossRefPubMed
  39. ↵
    1. Sobral-Leite M,
    2. Van de Vijver K,
    3. Michaut M,
    4. van der Linden R,
    5. Hooijer GKJ,
    6. Horlings HM,
    7. Severson TM,
    8. Mulligan AM,
    9. Weerasooriya N,
    10. Sanders J,
    11. Glas AM,
    12. Wehkamp D,
    13. Mittempergher L,
    14. Kersten K,
    15. Cimino-Mathews A,
    16. Peters D,
    17. Hooijberg E,
    18. Broeks A,
    19. van de Vijver MJ,
    20. Bernards R,
    21. Andrulis IL,
    22. Kok M,
    23. de Visser KE and
    24. Schmidt MK
    : Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival. Oncoimmunology 7(12): e1509820, 2018. PMID: 30524905. DOI: 10.1080/2162402X.2018.1509820
    OpenUrlCrossRefPubMed
    1. Li X,
    2. Wetherilt CS,
    3. Krishnamurti U,
    4. Yang J,
    5. Ma Y,
    6. Styblo TM,
    7. Meisel JL,
    8. Peng L,
    9. Siddiqui MT,
    10. Cohen C and
    11. Aneja R
    : Stromal PD-L1 expression is associated with better disease-free survival in triple-negative breast cancer. Am J Clin Pathol 146(4): 496-502, 2016. PMID: 27686176. DOI: 10.1093/ajcp/aqw134
    OpenUrlCrossRefPubMed
  41. ↵
    1. Beckers RK,
    2. Selinger CI,
    3. Vilain R,
    4. Madore J,
    5. Wilmott JS,
    6. Harvey K,
    7. Holliday A,
    8. Cooper CL,
    9. Robbins E,
    10. Gillett D,
    11. Kennedy CW,
    12. Gluch L,
    13. Carmalt H,
    14. Mak C,
    15. Warrier S,
    16. Gee HE,
    17. Chan C,
    18. McLean A,
    19. Walker E,
    20. McNeil CM,
    21. Beith JM,
    22. Swarbrick A,
    23. Scolyer RA and
    24. O’Toole SA
    : Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology 69(1): 25-34, 2016. PMID: 26588661. DOI: 10.1111/his.12904
    OpenUrlCrossRefPubMed
  42. ↵
    1. Zhu X,
    2. Zhang Q,
    3. Wang D,
    4. Liu C,
    5. Han B and
    6. Yang JM
    : Expression of PD-L1 attenuates the positive impacts of high-level tumor-infiltrating lymphocytes on prognosis of triple-negative breast cancer. Cancer Biol Ther 20(8): 1105-1112, 2019. PMID: 30929569. DOI: 10.1080/15384047.2019.1595282
    OpenUrlCrossRefPubMed
  43. ↵
    1. Adams TA,
    2. Vail PJ,
    3. Ruiz A,
    4. Mollaee M,
    5. McCue PA,
    6. Knudsen ES and
    7. Witkiewicz AK
    : Composite analysis of immunological and metabolic markers defines novel subtypes of triple negative breast cancer. Mod Pathol 31(2): 288-298, 2018. PMID: 28984302. DOI: 10.1038/modpathol.2017.126
    OpenUrlCrossRefPubMed
  44. ↵
    1. Doğukan R,
    2. Uçak R,
    3. Doğukan FM,
    4. Tanık C,
    5. Çitgez B and
    6. Kabukcuoğlu F
    : Correlation between the expression of PD-L1 and clinicopathological parameters in triple negative breast cancer patients. Eur J Breast Health 15(4): 235-241, 2019. PMID: 31620682. DOI: 10.5152/ejbh.2019.4912
    OpenUrlCrossRefPubMed
  45. ↵
    1. Li M,
    2. Li A,
    3. Zhou S,
    4. Xu Y,
    5. Xiao Y,
    6. Bi R and
    7. Yang W
    : Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of triple negative breast cancer. BMC Cancer 18(1): 4, 2018. PMID: 29291717. DOI: 10.1186/s12885-017-3916-y
    OpenUrlCrossRefPubMed
  46. ↵
    1. Ghosh J,
    2. Chatterjee M,
    3. Ganguly S,
    4. Datta A,
    5. Biswas B,
    6. Mukherjee G,
    7. Agarwal S,
    8. Ahmed R,
    9. Chatterjee S and
    10. Dabkara D
    : PDL1 expression and its correlation with outcomes in non-metastatic triple-negative breast cancer (TNBC). Ecancermedicalscience 15: 1217, 2021. PMID: 34158821. DOI: 10.3332/ecancer.2021.1217
    OpenUrlCrossRefPubMed
  47. ↵
    1. Wang X and
    2. Liu Y
    : PD-L1 expression in tumor infiltrated lymphocytes predicts survival in triple-negative breast cancer. Pathol Res Pract 216(3): 152802, 2020. PMID: 32005408. DOI: 10.1016/j.prp.2019.152802
    OpenUrlCrossRefPubMed
  48. ↵
    1. Al-Jussani GN,
    2. Dabbagh TZ,
    3. Al-Rimawi D and
    4. Sughayer MA
    : Expression of PD-L1 using SP142 CDx in triple negative breast cancer. Ann Diagn Pathol 51: 151703, 2021. PMID: 33454500. DOI: 10.1016/j.anndiagpath.2021.151703
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Clinicopathological and Prognostic Significance of Programmed Death Ligand-1 SP142 Expression in 132 Patients With Triple-negative Breast Cancer
JINAH CHU, MIN-KYUNG YEO, SANG HWA LEE, MI YEON LEE, SEOUNG WAN CHAE, HYUN-SOO KIM, SUNG-IM DO
In Vivo Nov 2022, 36 (6) 2890-2898; DOI: 10.21873/invivo.13030
Twitter logo Facebook logo Mendeley logo

Jump to section

Related Articles

  • No related articles found.

Cited By...

More in this TOC Section

Similar Articles

Keywords