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Erschienen in: International Journal of Clinical Oncology 2/2022

18.10.2021 | Original Article

HER2-low breast cancer could be associated with an increased risk of brain metastasis

verfasst von: Deniz Can Guven, Mehmet Burak Kaya, Burak Fedai, Mucahit Ozden, Hasan Cagri Yildirim, Kemal Kosemehmetoglu, Neyran Kertmen, Omer Dizdar, Aysegul Uner, Sercan Aksoy

Erschienen in: International Journal of Clinical Oncology | Ausgabe 2/2022

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Abstract

Purpose

The HER2-low breast cancer is a newly recognized entity with the clinical characteristics is yet to be defined. We hypothesized that HER2-low breast cancer could lead to an increased rate of brain metastases in patients with localized breast cancer. We tested this hypothesis in a large cohort of breast cancer patients with long follow-up.

Methods

We included 2686 adult breast cancer patients followed up in Hacettepe University Cancer Center. Patients with 1 + positive HER2 expression and 2 + HER2 expression with a negative FISH were categorized as HER2-low disease. We evaluated the brain metastasis risk with binary logistic regression analyses and reported odds ratios (OR) with 95% confidence intervals (CI).

Results

During a median 95.4 (IQR 72.6–123.1) month follow-up, 184 patients developed brain metastasis (6.9%). The brain metastases were developed in 5.1% of the patients with HER2-negative disease, 8.5% of the patients with HER2-low disease, and 10.1% of the patients with HER2-positive disease. A multivariable binary logistic regression model demonstrated an increased risk of brain metastasis in patients with HER2-low disease (OR: 1.611, 95% CI 1.055–2.460, p = 0.027) and in HER2-positive patients (OR: 1.837, 95% CI 1.308–2.580, p < 0.001). Additionally, HR + -HER2-low disease was associated with a decreased DFS compared to HR + -HER2-negative disease (p = 0.008).

Conclusion

In this study, we observed an increased risk of brain metastasis in localized breast cancer patients with HER2-low disease. We think that a high level of vigilance and a low threshold for brain imaging could benefit HER2-low breast cancer patients similar to the patients with HER-positive disease.
Literatur
1.
Zurück zum Zitat Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424CrossRef Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424CrossRef
2.
Zurück zum Zitat Szymiczek A, Lone A, Akbari MR (2021) Molecular intrinsic versus clinical subtyping in breast cancer: a comprehensive review. Clin Genet 99:613–637CrossRef Szymiczek A, Lone A, Akbari MR (2021) Molecular intrinsic versus clinical subtyping in breast cancer: a comprehensive review. Clin Genet 99:613–637CrossRef
3.
Zurück zum Zitat van Maaren MC, de Munck L, Strobbe LJA et al (2019) Ten-year recurrence rates for breast cancer subtypes in the Netherlands: a large population-based study. Int J Cancer 144:263–272CrossRef van Maaren MC, de Munck L, Strobbe LJA et al (2019) Ten-year recurrence rates for breast cancer subtypes in the Netherlands: a large population-based study. Int J Cancer 144:263–272CrossRef
4.
Zurück zum Zitat Kennecke H, Yerushalmi R, Woods R et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28:3271–3277CrossRef Kennecke H, Yerushalmi R, Woods R et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28:3271–3277CrossRef
5.
Zurück zum Zitat Rouanet P, Roger P, Rousseau E et al (2014) HER2 overexpression a major risk factor for recurrence in pT1a-bN0M0 breast cancer: results from a French regional cohort. Cancer Med 3:134–142CrossRef Rouanet P, Roger P, Rousseau E et al (2014) HER2 overexpression a major risk factor for recurrence in pT1a-bN0M0 breast cancer: results from a French regional cohort. Cancer Med 3:134–142CrossRef
6.
Zurück zum Zitat Lin NU, Amiri-Kordestani L, Palmieri D et al (2013) CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res 19:6404–6418CrossRef Lin NU, Amiri-Kordestani L, Palmieri D et al (2013) CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res 19:6404–6418CrossRef
7.
Zurück zum Zitat Brufsky AM, Mayer M, Rugo HS et al (2011) Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834CrossRef Brufsky AM, Mayer M, Rugo HS et al (2011) Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res 17:4834CrossRef
8.
Zurück zum Zitat Patel A, Unni N, Peng Y (2020) The changing paradigm for the treatment of HER2-positive breast cancer. Cancers 12:2081CrossRef Patel A, Unni N, Peng Y (2020) The changing paradigm for the treatment of HER2-positive breast cancer. Cancers 12:2081CrossRef
9.
Zurück zum Zitat Slamon DJ, Clark GM, Wong SG et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182CrossRef Slamon DJ, Clark GM, Wong SG et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182CrossRef
10.
Zurück zum Zitat Hendriks BS, Klinz SG, Reynolds JG et al (2013) Impact of tumor HER2/ERBB2 expression level on HER2-targeted liposomal doxorubicin-mediated drug delivery: multiple low-affinity interactions lead to a threshold effect. Mol Cancer Ther 12:1816–1828CrossRef Hendriks BS, Klinz SG, Reynolds JG et al (2013) Impact of tumor HER2/ERBB2 expression level on HER2-targeted liposomal doxorubicin-mediated drug delivery: multiple low-affinity interactions lead to a threshold effect. Mol Cancer Ther 12:1816–1828CrossRef
11.
Zurück zum Zitat Onsum MD, Geretti E, Paragas V et al (2013) Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients. Am J Pathol 183:1446–1460CrossRef Onsum MD, Geretti E, Paragas V et al (2013) Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients. Am J Pathol 183:1446–1460CrossRef
12.
Zurück zum Zitat Fehrenbacher L, Cecchini RS, Geyer CE Jr et al (2019) NSABP B-47/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1 + or 2 +. J Clin Oncol 38:444–453CrossRef Fehrenbacher L, Cecchini RS, Geyer CE Jr et al (2019) NSABP B-47/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1 + or 2 +. J Clin Oncol 38:444–453CrossRef
13.
Zurück zum Zitat Burris HA, Rugo HS, Vukelja SJ et al (2010) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)—positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398–405CrossRef Burris HA, Rugo HS, Vukelja SJ et al (2010) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)—positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29:398–405CrossRef
14.
Zurück zum Zitat Modi S, Park H, Murthy RK et al (2020) Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low–expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol 38:1887–1896CrossRef Modi S, Park H, Murthy RK et al (2020) Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low–expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol 38:1887–1896CrossRef
15.
Zurück zum Zitat Banerji U, van Herpen CML, Saura C et al (2019) Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol 20:1124–1135CrossRef Banerji U, van Herpen CML, Saura C et al (2019) Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol 20:1124–1135CrossRef
16.
Zurück zum Zitat Tarantino P, Hamilton E, Tolaney SM et al (2020) HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol 38:1951–1962CrossRef Tarantino P, Hamilton E, Tolaney SM et al (2020) HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol 38:1951–1962CrossRef
17.
Zurück zum Zitat Eiger D, Agostinetto E, Saúde-Conde R et al (2021) The exciting new field of HER2-low breast cancer treatment. Cancers 13 (5):1015CrossRef Eiger D, Agostinetto E, Saúde-Conde R et al (2021) The exciting new field of HER2-low breast cancer treatment. Cancers 13 (5):1015CrossRef
18.
Zurück zum Zitat Marchiò C, Annaratone L, Marques A et al (2021) Evolving concepts in HER2 evaluation in breast cancer: heterogeneity, HER2-low carcinomas and beyond. Semin Cancer Biol 72:123–135CrossRef Marchiò C, Annaratone L, Marques A et al (2021) Evolving concepts in HER2 evaluation in breast cancer: heterogeneity, HER2-low carcinomas and beyond. Semin Cancer Biol 72:123–135CrossRef
19.
Zurück zum Zitat Koscielny S, Terrier P, Daver A et al (1998) Quantitative determination of c-erbB-2 in human breast tumours: potential prognostic significance of low values. Eur J Cancer 34:476–481CrossRef Koscielny S, Terrier P, Daver A et al (1998) Quantitative determination of c-erbB-2 in human breast tumours: potential prognostic significance of low values. Eur J Cancer 34:476–481CrossRef
20.
Zurück zum Zitat Dittadi R, Brazzale A, Pappagallo G et al (1997) ErbB2 assay in breast cancer: possibly improved clinical information using a quantitative method. Anticancer Res 17:1245–1247PubMed Dittadi R, Brazzale A, Pappagallo G et al (1997) ErbB2 assay in breast cancer: possibly improved clinical information using a quantitative method. Anticancer Res 17:1245–1247PubMed
21.
Zurück zum Zitat Gilcrease MZ, Woodward WA, Nicolas MM et al (2009) Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Am J Surg Pathol 33:759–767CrossRef Gilcrease MZ, Woodward WA, Nicolas MM et al (2009) Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Am J Surg Pathol 33:759–767CrossRef
22.
Zurück zum Zitat Wolff AC, Hammond MEH, Allison KH et al (2018) HER2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update Summary. J Oncol Pract 14:437–441CrossRef Wolff AC, Hammond MEH, Allison KH et al (2018) HER2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update Summary. J Oncol Pract 14:437–441CrossRef
23.
Zurück zum Zitat Gradishar WJ, Moran MS, Abraham J et al (2021) NCCN Guidelines® Insights: breast cancer, version 4.2021: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw 19:484–493CrossRef Gradishar WJ, Moran MS, Abraham J et al (2021) NCCN Guidelines® Insights: breast cancer, version 4.2021: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw 19:484–493CrossRef
24.
Zurück zum Zitat Cardoso F, Paluch-Shimon S, Senkus E et al (2020) 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 31:1623–1649CrossRef Cardoso F, Paluch-Shimon S, Senkus E et al (2020) 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol 31:1623–1649CrossRef
25.
Zurück zum Zitat Charlson ME, Pompei P, Ales KL et al (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383CrossRef Charlson ME, Pompei P, Ales KL et al (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383CrossRef
26.
Zurück zum Zitat Achrol AS, Rennert RC, Anders C et al (2019) Brain metastases. Nat Rev Dis Prim 5:5CrossRef Achrol AS, Rennert RC, Anders C et al (2019) Brain metastases. Nat Rev Dis Prim 5:5CrossRef
27.
Zurück zum Zitat Steindl A, Kreminger J, Moor E et al (2020) 363O Clinical characterization of a real-life cohort of 6001 patients with brain metastases from solid cancers treated between 1986–2020. Ann Oncol 31:S397CrossRef Steindl A, Kreminger J, Moor E et al (2020) 363O Clinical characterization of a real-life cohort of 6001 patients with brain metastases from solid cancers treated between 1986–2020. Ann Oncol 31:S397CrossRef
28.
Zurück zum Zitat Cheng X, Hung MC (2007) Breast cancer brain metastases. Cancer Metastasis Rev 26:635–643CrossRef Cheng X, Hung MC (2007) Breast cancer brain metastases. Cancer Metastasis Rev 26:635–643CrossRef
29.
Zurück zum Zitat Berghoff A, Bago-Horvath Z, De Vries C et al (2012) Brain metastases free survival differs between breast cancer subtypes. Br J Cancer 106:440–446CrossRef Berghoff A, Bago-Horvath Z, De Vries C et al (2012) Brain metastases free survival differs between breast cancer subtypes. Br J Cancer 106:440–446CrossRef
30.
Zurück zum Zitat Sun MS, Liu YH, Ye JM et al (2021) A nomogram for predicting brain metastasis in patients with de novo stage IV breast cancer. Ann Transl Med 9:853CrossRef Sun MS, Liu YH, Ye JM et al (2021) A nomogram for predicting brain metastasis in patients with de novo stage IV breast cancer. Ann Transl Med 9:853CrossRef
31.
Zurück zum Zitat Zimmer AS, Van Swearingen AED, Anders CK. HER2-positive breast cancer brain metastasis: a new and exciting landscape. Cancer Rep (Hoboken) 2020; e1274. Zimmer AS, Van Swearingen AED, Anders CK. HER2-positive breast cancer brain metastasis: a new and exciting landscape. Cancer Rep (Hoboken) 2020; e1274.
32.
Zurück zum Zitat Gupta P, Srivastava SK (2014) HER2 mediated de novo production of TGFβ leads to SNAIL driven epithelial-to-mesenchymal transition and metastasis of breast cancer. Mol Oncol 8:1532–1547CrossRef Gupta P, Srivastava SK (2014) HER2 mediated de novo production of TGFβ leads to SNAIL driven epithelial-to-mesenchymal transition and metastasis of breast cancer. Mol Oncol 8:1532–1547CrossRef
33.
Zurück zum Zitat Agostinetto E, Rediti M, Fimereli D et al (2021) HER2-low breast cancer: molecular characteristics and prognosis. Cancers 13:2824CrossRef Agostinetto E, Rediti M, Fimereli D et al (2021) HER2-low breast cancer: molecular characteristics and prognosis. Cancers 13:2824CrossRef
34.
Zurück zum Zitat Rossi V, Sarotto I, Maggiorotto F et al (2012) Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist 17:1418–1425CrossRef Rossi V, Sarotto I, Maggiorotto F et al (2012) Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist 17:1418–1425CrossRef
35.
Zurück zum Zitat Camp RL, Dolled-Filhart M, King BL et al (2003) Quantitative analysis of breast cancer tissue microarrays shows that both high and normal levels of HER2 expression are associated with poor outcome. Can Res 63:1445 Camp RL, Dolled-Filhart M, King BL et al (2003) Quantitative analysis of breast cancer tissue microarrays shows that both high and normal levels of HER2 expression are associated with poor outcome. Can Res 63:1445
36.
Zurück zum Zitat Eggemann H, Ignatov T, Burger E et al (2015) Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer. Endocr Relat Cancer 22:725–733CrossRef Eggemann H, Ignatov T, Burger E et al (2015) Moderate HER2 expression as a prognostic factor in hormone receptor positive breast cancer. Endocr Relat Cancer 22:725–733CrossRef
37.
Zurück zum Zitat Howlader N, Cronin KA, Kurian AW et al (2018) Differences in breast cancer survival by molecular subtypes in the United States. Cancer Epidemiol Biomark Prev 27:619CrossRef Howlader N, Cronin KA, Kurian AW et al (2018) Differences in breast cancer survival by molecular subtypes in the United States. Cancer Epidemiol Biomark Prev 27:619CrossRef
38.
Zurück zum Zitat Fallahpour S, Navaneelan T, De P et al (2017) Breast cancer survival by molecular subtype: a population-based analysis of cancer registry data. CMAJ Open 5:E734–E739CrossRef Fallahpour S, Navaneelan T, De P et al (2017) Breast cancer survival by molecular subtype: a population-based analysis of cancer registry data. CMAJ Open 5:E734–E739CrossRef
39.
Zurück zum Zitat 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 7:1CrossRef 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 7:1CrossRef
Metadaten
Titel
HER2-low breast cancer could be associated with an increased risk of brain metastasis
verfasst von
Deniz Can Guven
Mehmet Burak Kaya
Burak Fedai
Mucahit Ozden
Hasan Cagri Yildirim
Kemal Kosemehmetoglu
Neyran Kertmen
Omer Dizdar
Aysegul Uner
Sercan Aksoy
Publikationsdatum
18.10.2021
Verlag
Springer Singapore
Erschienen in
International Journal of Clinical Oncology / Ausgabe 2/2022
Print ISSN: 1341-9625
Elektronische ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-021-02049-w

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