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Unveiling the HER2-low phenomenon: exploring immunohistochemistry and gene expression to characterise HR-positive HER2-negative early breast cancer

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Abstract

Purpose

HER2-low breast cancer (BC) is a novel entity with relevant therapeutic implications, especially in hormone receptor (HR) positive BC. This study examines whether HER2 mRNA through the 21-gene assay, Oncotype DX (ODX), can refine the diagnosis of HER2-low and HER2-zero, obtained by immunohistochemistry (IHC).

Methods

Between Jan 2021 and Jan 2023, 229 consecutive HR-positive HER2-negative early BC (T1-3 N0-1) have been characterised by IHC and ODX. HER2 status by IHC was either zero (IHC-0) or low (IHC-1 + and IHC-2 + /ISH-negative) while HER2-zero was further divided into HER2-null (IHC-0) and HER2-ultralow (IHC-1–10%). HER2 gene expression by ODX was negative if lower 10.7.

Results

The distribution of HER2 IHC was as follows: 53.3% HER2-0, 29.25% HER2-1 + , and 17.5% HER2-2 + . The clinicopathological characteristics were similar in the three groups, with higher PgR-negative rate in HER2-zero (13.9% vs 3% vs 5%). The distribution of RS was homogeneous in the three groups with the median HER2 gene expression of 9.20 [IQR: 8.70–9.60]. HER2 gene expression gradually increased as the IHC score, with substantial overlap. After adjusting for confounders, HER2-1 + and HER2 2 + had a significant positive correlation between HER2 gene expression and IHC [OR 1.42, 95% CI 1.21 to 1.68, p < 0.001; OR 1.96, 95% CI 1.61 to 2.37, p < 0.001] compared to the HER2-zero group. HER2 gene expression did not differ between HER2-null and HER2-ultralow subgroups.

Conclusion

Due to the substantial overlap, the HER2 gene expression is unable to properly distinguish HER2-low and HER2-zero IHC whose accurate identification is critical in the context of HER2-negative BC.

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Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Abbreviations

ADC:

Antibody–drug conjugate

ASCO-CAP:

American Society of clinical oncology and the College of American pathologists

BC:

Breast cancer

CI:

Confidence interval

DDFS:

Disease-free survival

DFS:

Disease-free survival

ER:

Oestrogen receptor

FISH:

Fluorescent in situ hybridization

HER2:

Human epidermal growth factor receptor 2

HR:

Hormone receptor

iDFS:

Invasive disease-free survival

IHC:

Immunohistochemistry

IQR:

Interquartile range

ODX:

Oncotype DX

OS:

Overall survival

PgR:

Progesterone receptor

pCR:

Pathological complete response

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

RS:

Recurrence score

SD:

Standard deviation

T-DXd:

Trastuzumab deruxtecan

References

  1. Hayes DF (2019) HER2 and breast cancer—A phenomenal success story. N Engl J Med 381:1284–1286. https://doi.org/10.1056/NEJMCIBR1909386

    Article  PubMed  Google Scholar 

  2. Wolff AC, Hammond MEH, Schwartz JN et al (2007) American Society of clinical oncology/College of American pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145. https://doi.org/10.1200/JCO.2006.09.2775

    Article  CAS  PubMed  Google Scholar 

  3. Tozbikian GH, Zynger DL (2018) HER2 equivocal breast cancer that is positive by alternative probe HER2 FISH are classified as HER2 negative by oncotype DX. Breast J 24:535–540. https://doi.org/10.1111/TBJ.13004

    Article  CAS  PubMed  Google Scholar 

  4. Schlam I, Church SE, Hether TD et al (2021) The tumor immune microenvironment of primary and metastatic HER2- positive breast cancers utilizing gene expression and spatial proteomic profiling. J Transl Med 19:480. https://doi.org/10.1186/s12967-021-03113-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang H, Katerji H, Turner BM et al (2022) HER2-low breast cancersnew opportunities and challenges. Am J Clin Pathol 157:328–336. https://doi.org/10.1093/AJCP/AQAB117

    Article  CAS  PubMed  Google Scholar 

  6. Poh A (2022) T-DXd: new standard for HER2-low breast cancer. Cancer Discov 12:1828. https://doi.org/10.1158/2159-8290.CD-NB2022-0043

    Article  Google Scholar 

  7. Modi S, Jacot W, Yamashita T et al (2022) Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. https://doi.org/10.1056/NEJMOA2203690/SUPPL_FILE/NEJMOA2203690_DATA-SHARING.PDF

    Article  PubMed  PubMed Central  Google Scholar 

  8. Geukens T, De Schepper M, Richard F et al (2023) Intra-patient and inter-metastasis heterogeneity of HER2-low status in metastatic breast cancer. Eur J Cancer 188:152–160. https://doi.org/10.1016/j.ejca.2023.04.026

    Article  CAS  PubMed  Google Scholar 

  9. van’t Veer LJ, Paik S, Hayes DF (2005) Gene expression profiling of breast cancer: a new tumor marker. J Clin Oncol 23:1631–1635. https://doi.org/10.1200/JCO.2005.12.005

    Article  CAS  Google Scholar 

  10. Paik S, Shak S, Tang G et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826. https://doi.org/10.1056/NEJMOA041588

    Article  CAS  PubMed  Google Scholar 

  11. Jacobs F, Gaudio M, Benvenuti C et al (2022) Controversies and opportunities in the clinical daily use of the 21-gene assay for prognostication and prediction of chemotherapy benefit in HR+/HER2- early breast cancer. Cancers (Basel). https://doi.org/10.3390/cancers15010148

    Article  PubMed  Google Scholar 

  12. Sparano JA, Gray RJ, Makower DF et al (2018) Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111–121. https://doi.org/10.1056/NEJMOA1804710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kalinsky K, Barlow WE, Gralow JR et al (2021) 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 385:2336–2347. https://doi.org/10.1056/NEJMoa2108873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Syed YY, Oncotype DX (2020) Breast recurrence score®: a review of its use in early-stage breast cancer. Mol Diagn Ther 24:621–632. https://doi.org/10.1007/S40291-020-00482-7

    Article  PubMed  Google Scholar 

  15. Mutai R, Barkan T, Moore A et al (2021) Prognostic impact of HER2-low expression in hormone receptor positive early breast cancer. Breast 60:62–69. https://doi.org/10.1016/j.breast.2021.08.016

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wolff AC, Hammond MEH, Allison KH et al (2018) Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/College of American pathologists clinical practice guideline focused update. J Clin Oncol 36:2105–2122. https://doi.org/10.1200/JCO.2018.77.8738

    Article  CAS  PubMed  Google Scholar 

  17. Munoz-Arcos LS, Nicolo’ E, Newman LA et al (2023) Impact of HER2 low expression in the oncotype DX RS in patients with operable hormone receptor positive early stage breast cancer. J Clin Oncol 41:575. https://doi.org/10.1200/JCO.2023.41.16_suppl.575

    Article  Google Scholar 

  18. Noske A, Loibl S, Darb-Esfahani S et al (2011) Comparison of different approaches for assessment of HER2 expression on protein and mRNA level: prediction of chemotherapy response in the neoadjuvant GeparTrio trial (NCT00544765). Breast Cancer Res Treat 126:109–117. https://doi.org/10.1007/s10549-010-1316-y

    Article  CAS  PubMed  Google Scholar 

  19. Furrer D, Paquet C, Jacob S et al (2018) The Human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive biomarker: molecular insights into HER2 activation and diagnostic implications. In: Lemamy GJ (ed) Cancer prognosis. IntechOpen, London. https://doi.org/10.5772/intechopen.78271

    Chapter  Google Scholar 

  20. Gheni N, Westenberg D (2020) Quantitative real-time PCR assay with immunohistochemical evaluation of HER2/neu oncogene in breast cancer patients and its correlation with clinicopathological findings. Indian J Pathol Microbiol 63:123–128. https://doi.org/10.4103/IJPM.IJPM_136_19

    Article  Google Scholar 

  21. Zoppoli G, Garuti A, Cirmena G et al (2017) Her2 assessment using quantitative reverse transcriptase polymerase chain reaction reliably identifies Her2 overexpression without amplification in breast cancer cases. J Transl Med 15:91. https://doi.org/10.1186/s12967-017-1195-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tvrdík D, Staněk L, Skálová H et al (2012) Comparison of the IHC, FISH, SISH and qPCR methods for the molecular diagnosis of breast cancer. Mol Med Rep 6:439–443. https://doi.org/10.3892/mmr.2012.919

    Article  CAS  PubMed  Google Scholar 

  23. Koudelakova V, Berkovcova J, Trojanec R et al (2015) Evaluation of HER2 gene status in breast cancer samples with indeterminate fluorescence in situ hybridization by quantitative real-time PCR. J Mol Diagn 17:446–455. https://doi.org/10.1016/j.jmoldx.2015.03.007

    Article  CAS  PubMed  Google Scholar 

  24. Cronin M, Pho M, Dutta D et al (2004) Measurement of gene expression in archival paraffin-embedded tissues: development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay. Am J Pathol 164:35–42. https://doi.org/10.1016/S0002-9440(10)63093-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Esteva FJ, Sahin AA, Cristofanilli M et al (2005) Prognostic role of a multigene reverse transcriptase-PCR assay in patients with node-negative breast cancer not receiving adjuvant systemic therapy. Clin Cancer Res Off J Am Assoc Cancer Res 11:3315–3319. https://doi.org/10.1158/1078-0432.CCR-04-1707

    Article  CAS  Google Scholar 

  26. Chang JC, Makris A, Gutierrez MC et al (2005) Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue. Clin Cancer Res Off J Am Assoc Cancer Res 11:3315–3319. https://doi.org/10.1007/s10549-006-9366-x

    Article  CAS  Google Scholar 

  27. Cobleigh MA, Tabesh B, Bitterman P et al (2005) Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res 11:8623–8631. https://doi.org/10.1158/1078-0432.CCR-05-0735

    Article  CAS  PubMed  Google Scholar 

  28. Baehner FL, Achacoso N, Maddala T et al (2010) Human epidermal growth factor receptor 2 assessment in a case-control study: comparison of fluorescence in situ hybridization and quantitative reverse transcription polymerase chain reaction performed by central laboratories. J Clin Oncol 28:4300–4306. https://doi.org/10.1200/JCO.2009.24.8211

    Article  PubMed  Google Scholar 

  29. Zattarin E, Presti D, Mariani L et al (2023) Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors. npj Breast Cancer 9:27. https://doi.org/10.1038/s41523-023-00534-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tarantino P, Jin Q, Tayob N et al (2022) Prognostic and biologic significance of ERBB2-low expression in early-stage breast cancer. JAMA Oncol 8:1177–1183. https://doi.org/10.1001/JAMAONCOL.2022.2286

    Article  PubMed  PubMed Central  Google Scholar 

  31. Molinelli C, Jacobs F, Agostinetto E et al (2023) Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis. ESMO open 8:101592. https://doi.org/10.1016/j.esmoop.2023.101592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dvorak L, Dolan M, Fink J et al (2013) Correlation between HER2 determined by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction of the oncotype DX test. Appl Immunohistochem Mol Morphol AIMM 21:196–199. https://doi.org/10.1097/PAI.0B013E3182632FF5

    Article  CAS  PubMed  Google Scholar 

  33. Metzger Filho O, Viale G, Trippa L et al (2019) HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: results from a prospective clinical trial. J Clin Oncol 37:502. https://doi.org/10.1200/JCO.2019.37.15_suppl.502

    Article  Google Scholar 

  34. Schettini F, Chic N, Brasó-Maristany F et al (2021) Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. npj Breast Cancer 7:1. https://doi.org/10.1038/s41523-020-00208-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Filho OM, Viale G, Stein S et al (2021) Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab. Cancer Discov 11:2474–2487. https://doi.org/10.1158/2159-8290.CD-20-1557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mosele MF, Lusque A, Dieras V et al (2022) LBA1 Unraveling the mechanism of action and resistance to trastuzumab deruxtecan (T-DXd): Biomarker analyses from patients from DAISY trial. Ann Oncol 33:S123. https://doi.org/10.1016/j.annonc.2022.03.277

    Article  Google Scholar 

  37. Diéras V, Deluche E, Lusque A et al (2022) Abstract PD8–02: trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: a phase II study with biomarkers analysis (DAISY). Cancer Res. https://doi.org/10.1158/1538-7445.sabcs21-pd8-02

    Article  Google Scholar 

  38. Abelman RO, Medford A, Spring L et al (2022) Antibody drug conjugates in breast cancer: spotlight on HER2. Cancer J 28:423. https://doi.org/10.1097/PPO.0000000000000634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study received no funding.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Humanitas University, 20072, Pieve Emanuele, MI, Italy

    M. Gaudio, F. Jacobs, C. Benvenuti, G. Saltalamacchia, R. Gerosa, R. De Sanctis, A. Santoro & A. Zambelli

  2. Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, 20089, Rozzano, MI, Italy

    M. Gaudio, F. Jacobs, C. Benvenuti, R. Gerosa, R. De Sanctis, A. Santoro & A. Zambelli

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  1. M. Gaudio
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Contributions

AZ: has conceived the idea of the study. MG: collected and analysed the data. MG, FJ, CB, GS, RG, RDS, AS, and AZ: interpreted the data, wrote the manuscript, and revised the final version. MG, RDS, AS, and AZ: had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to R. De Sanctis.

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Conflict of interests

R.D.S.: Lilly, Novartis, Istituto Clinico Gentili, Amgen, EISAI, and Ipsen; all disclosures are outside the submitted work. A.S.: Bristol Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, Incyte. Speakers' Bureau: Takeda, Roche, AbbVie, Amgen, Celgene, AstraZeneca, Lilly, Sandoz, Novartis, BMS, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, ArQule; all disclosures are outside the submitted work. A.Z.: Novartis, AstraZeneca, Lilly, Pfizer, Daiichi Sankyo, MDS (Merck Sharp&Dome), Roche, Seagen, Exact Sciences, Gilaed, Istituto Gentili; all disclosures are outside the submitted work. M.G., F.J., C.B., G.S., and R.G. have no conflict of interest to declare.

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Gaudio, M., Jacobs, F., Benvenuti, C. et al. Unveiling the HER2-low phenomenon: exploring immunohistochemistry and gene expression to characterise HR-positive HER2-negative early breast cancer. Breast Cancer Res Treat 203, 487–495 (2024). https://doi.org/10.1007/s10549-023-07151-3

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