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Intratumor spatial heterogeneity in programmed death-ligand 1 (PD-L1) protein expression in early-stage breast cancer

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Abstract

Purpose

Programmed death-ligand 1 (PD-L1) expression is required for benefit from immune checkpoint inhibitors in metastatic triple negative breast cancer (TNBC). In contrast, in the neoadjuvant setting patients benefited regardless of PD-L1 expression. We hypothesized that, in stages II-III breast cancers, low levels of PD-L1 expression may be sufficient to confer sensitivity to therapy and focal expression could be missed by a biopsy.

Methods

In this study, we examined intratumor spatial heterogeneity of PD-L1 protein expression in multiple biopsies from different regions of breast cancers in 57 primary breast tumors (n = 33 TNBC, n = 19 estrogen receptor-positive [ER-positive], n = 5 human epidermal receptor 2-positive [HER2 +]). E1L3N antibody was used to assess PD-L1 status and staining was scored using the combined positivity score (CPS) with PD-L1 positive defined as CPS ≥ 10.

Results

Overall, 19% (11/57) of tumors were PD-L1 positive based on positivity in at least 1 biopsy. Among TNBC, PD-L1 positivity was 27% (9/33). The discordance rate, defined as the same tumor yielding PD-L1 positive and negative samples in different regions, was 16% (n = 9) in the whole study population and 23% (n = 7) in TNBC. Cohen’s kappa coefficient of agreement was 0.214 for the whole study and 0.239 for TNBC, both of which falling into a non-statistically significant fair agreement range. Among all PD-L1 positive cases, 82% (n = 9/11) had positivity in only one of the tissue assessments.

Conclusion

These results indicate that the overall 84% concordance is driven by concordant negative results. In PD-L1 positive cancers, within-tumor heterogeneity in PD-L1 expression exists.

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Data availability

The data generated in this study are available as supplement material.

References

  1. Schmid P et al (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379(22):2108–2121

    Article  CAS  PubMed  Google Scholar 

  2. Schmid P et al (2020) 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

    Article  CAS  PubMed  Google Scholar 

  3. Cortes J et al (2020) Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396(10265):1817–1828

    Article  PubMed  Google Scholar 

  4. Cortés J, Cescon DW, Rugo HS, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Perez-Garcia J, Iwata H, Masuda N (2021) LBA16 - KEYNOTE-355: final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Ann Oncol 32:S1289–S1290

    Article  Google Scholar 

  5. Winer EP et al (2021) Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol 22(4):499–511

    Article  CAS  PubMed  Google Scholar 

  6. Administration, U.S.F.a.D. FDA grants accelerated approval to pembrolizumab for locally recurrent unresectable or metastatic triple negative breast cancer. 2020 1/31/2022]; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-locally-recurrent-unresectable-or-metastatic-triple.

  7. Rozenblit M et al (2020) Comparison of PD-L1 protein expression between primary tumors and metastatic lesions in triple negative breast cancers. J Immunother Cancer. https://doi.org/10.1136/jitc-2020-001558

    Article  PubMed  PubMed Central  Google Scholar 

  8. Schmid P et al (2020) Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382(9):810–821

    Article  CAS  PubMed  Google Scholar 

  9. Schmid P, C.J., Dent R, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Ding Y, Tryfonidis K, Aktan G, Karantza V, O’Shaughnessy J., VP7-2021: KEYNOTE-522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC, in ESMO Virtual Plenary Abstracts. 2021. p. 1198-1200

  10. Mittendorf EA et al (2020) Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396(10257):1090–1100

    Article  CAS  PubMed  Google Scholar 

  11. Pusztai L et al (2021) Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: results from the adaptively randomized I-SPY2 trial. Cancer Cell. https://doi.org/10.1016/j.ccell.2021.05.009

    Article  PubMed  Google Scholar 

  12. Loibl S et al (2019) A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 30(8):1279–1288

    Article  CAS  PubMed  Google Scholar 

  13. Loibl S, Schneeweiss A, Huober JB, Braun M, Rey J, Blohmer JU, Furlanetto J, Zahm DM, Hanusch C, Thomalla J, Jackisch C (2021) Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC). J Clin Oncol. https://doi.org/10.1200/JCO.2021.39.15_suppl.506

    Article  PubMed  PubMed Central  Google Scholar 

  14. Administration, U.S.F.a.D. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. 2021 10/3/2021]; Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer.

  15. Mani NL et al (2016) Quantitative assessment of the spatial heterogeneity of tumor-infiltrating lymphocytes in breast cancer. Breast Cancer Res 18(1):78

    Article  PubMed  PubMed Central  Google Scholar 

  16. von Wahlde MK et al (2017) Intratumor heterogeneity of homologous recombination deficiency in primary breast cancer. Clin Cancer Res 23(5):1193–1199

    Article  Google Scholar 

  17. Shi W et al (2018) Reliability of whole-exome sequencing for assessing intratumor genetic heterogeneity. Cell Rep 25(6):1446–1457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rimm DL et al (2017) A Prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol 3(8):1051–1058

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pelekanou V et al (2017) Effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance. Breast Cancer Res 19(1):91

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wimberly H et al (2015) PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunol Res 3(4):326–332

    Article  CAS  PubMed  Google Scholar 

  21. Gaule P et al (2017) A quantitative comparison of antibodies to programmed cell death 1 ligand 1. JAMA Oncol 3(2):256–259

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sun WY, Lee YK, Koo JS (2016) Expression of PD-L1 in triple-negative breast cancer based on different immunohistochemical antibodies. J Transl Med 14(1):173

    Article  PubMed  PubMed Central  Google Scholar 

  23. Denkert C et al (2010) Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol 28(1):105–113

    Article  CAS  PubMed  Google Scholar 

  24. Ranganathan P, Pramesh CS, Aggarwal R (2017) Common pitfalls in statistical analysis: measures of agreement. Perspect Clin Res 8(4):187–191

    Article  PubMed  PubMed Central  Google Scholar 

  25. Viera AJ, Garrett JM (2005) Understanding interobserver agreement: the kappa statistic. Fam Med 37(5):360–363

    PubMed  Google Scholar 

  26. Reisenbichler ES et al (2020) Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer. Mod Pathol 33(9):1746–1752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pelekanou V et al (2018) Tumor-Infiltrating lymphocytes and PD-L1 expression in pre- and posttreatment breast cancers in the SWOG S0800 phase II neoadjuvant chemotherapy trial. Mol Cancer Ther 17(6):1324–1331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yoshikawa K et al (2021) Immunohistochemical comparison of three programmed death-ligand 1 (PD-L1) assays in triple-negative breast cancer. PLoS ONE 16(9):e0257860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yu H et al (2016) PD-L1 expression in lung cancer. J Thorac Oncol 11(7):964–975

    Article  PubMed  PubMed Central  Google Scholar 

  30. Karpathiou G et al (2022) PD-L1 expression in head and neck cancer tissue specimens decreases with time. Pathol Res Pract 237:154042

    Article  CAS  PubMed  Google Scholar 

  31. Emens LA, Middleton G (2015) The interplay of immunotherapy and chemotherapy: harnessing potential synergies. Cancer Immunol Res 3(5):436–443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Voorwerk L et al (2019) Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med 25(6):920–928

    Article  CAS  PubMed  Google Scholar 

  33. Szekely B et al (2018) Immunological differences between primary and metastatic breast cancer. Ann Oncol 29(11):2232–2239

    Article  CAS  PubMed  Google Scholar 

  34. El Bairi K et al (2021) The tale of TILs in breast cancer: a report from the international immuno-oncology biomarker working group. NPJ Breast Cancer 7(1):150

    Article  PubMed  PubMed Central  Google Scholar 

  35. Telli ML et al (2018) Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer. Breast Cancer Res Treat 168(3):625–630

    Article  CAS  PubMed  Google Scholar 

  36. Tutt A et al (2018) Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 24(5):628–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mills AM et al (2018) The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol 42(2):183–191

    Article  PubMed  Google Scholar 

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Acknowledgements

We appreciate the funding provided by Susan Komen Foundation Leadership Award (SAC160076) and Breast Cancer Research Foundation Investigator Award (BCRF-21-133) to L.P allowing us to perform this study.

Funding

We appreciate the funding provided by Susan Komen Foundation Leadership Award (SAC160076) and Breast Cancer Research Foundation Investigator Award (BCRF-21-133) to LP allowing us to perform this study.

Author information

Authors and Affiliations

  1. Section of Medical Oncology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    Adriana Matutino Kahn & Lajos Pusztai

  2. Department of Pathology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    Reza Golestani & Malini Harigopal

  3. Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, 300 George St, Suite 120, Rm 133, New Haven, CT, 06520, USA

    Lajos Pusztai

Authors
  1. Adriana Matutino Kahn
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  2. Reza Golestani
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  4. Lajos Pusztai
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Contributions

AMK. and LP contributed with the study design. RG and MH contributed with pathology analyses and results. AMK performed the statistical analyses. All authors contributed, reviewed and agreed with final manuscript version.

Corresponding author

Correspondence to Lajos Pusztai.

Ethics declarations

Competing interests

AMK, RG and MH report no conflict of interest; LP reports consulting fees and honoraria from Pfizer, Astra Zeneca, Merck, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Personalis, Daiichi, Natera, Exact Sciences and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer and Bristol Myers Squibb.

Ethical approval

Tissues were collected under the Yale Human Investigational Committee protocol number 1207010483].

Informed consent

Informed consent to participate and publish was obtained from all individual participants included in the study.

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Kahn, A.M., Golestani, R., Harigopal, M. et al. Intratumor spatial heterogeneity in programmed death-ligand 1 (PD-L1) protein expression in early-stage breast cancer. Breast Cancer Res Treat 201, 289–298 (2023). https://doi.org/10.1007/s10549-023-06977-1

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