Multicenter Study

. 2024 Aug 15;130(16):2746-2762.

doi: 10.1002/cncr.35323. Epub 2024 May 16.

Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study

Francesco Schettini^{1

2

3}, Eva Blondeaux⁴, Chiara Molinelli^{5

6}, Raphaëlle Bas⁷, Hee Jeong Kim⁸, Antonio Di Meglio⁹, Rinat Bernstein Molho¹⁰, Sabine C Linn^{11

12}, Katarzyna Pogoda¹³, Estela Carrasco¹⁴, Kevin Punie¹⁵, Elisa Agostinetto¹⁶, Nerea Lopetegui-Lia¹⁷, Kelly-Anne Phillips^{18

19

20}, Angela Toss^{21

22}, Christine Rousset-Jablonski^{23

24

25}, Marion Acheritogaray²⁶, Alberta Ferrari^{27

28}, Shani Paluch-Shimon²⁹, Robert Fruscio³⁰, Wanda Cui^{18

19}, Stephanie M Wong³¹, Claudio Vernieri^{32

33}, Maria Vittoria Dieci^{34

35}, Alexios Matikas³⁶, Mariya Rozenblit³⁷, Cynthia Villarreal-Garza³⁸, Laura De Marchis^{39

40}, Fabio Puglisi^{41

42}, Leonor Vasconcelos de Matos⁴³, Monica Mariño⁴⁴, Luis Teixeira⁴⁵, Rossella Graffeo⁴⁶, Alessia Rognone⁴⁷, Alessandra Chirco⁴⁸, Nicoleta Antone⁴⁹, Yara Abdou⁵⁰, Maximilian Marhold⁵¹, Ivana Božović-Spasojević⁵², Alfonso Cortés Salgado⁵³, Luca Carmisciano⁵⁴, Marco Bruzzone⁴, Giuseppe Curigliano^{55

56}, Aleix Prat^{1

3

57

58

59}, Matteo Lambertini^{5

6}

Affiliations

¹ Translational Genomics and Targeted Therapies in Solid Tumors group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
² Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.
³ Department of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
⁴ U.O. Epidemiologia Clinica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
⁵ Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy.
⁶ Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
⁷ Department of Medical Oncology, Universite Paris Cité, Institut Curie, Paris, France.
⁸ Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁹ Cancer Survivorship Group, INSERM U981, Gustave Roussy, Villejuif, France.
¹⁰ Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center affiliated to Tel Aviv University, Tel Hashomer, Israel.
¹¹ Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
¹² Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
¹³ Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
¹⁴ Hereditary Cancer Genetics Unit, Medical oncology Department, Vall d´Hebron University Hospital, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁵ Department of General Medical Oncology and Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹⁶ Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B.), Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium.
¹⁷ Department of Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
¹⁸ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
¹⁹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
²⁰ Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²¹ Department of Oncology and Haematology, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
²² Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
²³ Department of Surgery, Leon Berard Cancer Center, Lyon, France.
²⁴ Unité INSERM U1290, Université Claude Bernard Lyon 1, Lyon, France.
²⁵ Hopital Femme Mère Enfant, Hospice civils de Lyon, Bron, France.
²⁶ Department of Gynecology, Cote Basque Hospital Center, Bayonne, France.
²⁷ Hereditary Breast and Ovarian Cancer (HBOC) Unit and General Surgery 3 - Senology, Breast Cancer Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
²⁸ University of Pavia, Pavia, Italy.
²⁹ Sharett institute of oncology, Hadassah University Hospital & Faculty of Medicine, Hebrew University, Jerusalem, Israel.
³⁰ UO Gynecology, Department of Medicine and Surgery, University of Milan-Bicocca, IRCCS San Gerardo dei Tintori, Monza, Italy.
³¹ Stroll Cancer Prevention Centre, Jewish General Hospital, and McGill University Medical School, Montreal, Quebec, Canada.
³² Medical Oncology Department, Breast Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
³³ Oncology and Hematology-Oncology Department, University of Milan, Milano, Italy.
³⁴ Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università di Padova, Padova, Italy.
³⁵ Oncologia 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.
³⁶ Department of Oncology/Pathology, Karolinska Institute and Breast Center, Karolinska University Hospital, Stockholm, Sweden.
³⁷ Medical Oncology, Yale University, New Haven, Connecticut, USA.
³⁸ Breast Cancer Center, Hospital Zambrano Hellion - TecSalud, Tecnologico de Monterrey, Monterrey, Mexico.
³⁹ Division of Medical Oncology, Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
⁴⁰ Medical Oncology Department of Hematology, Oncology, Dermatology, Umberto 1 University Hospital, Rome, Italy.
⁴¹ Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
⁴² Department of Medicine, University of Udine, Udine, Italy.
⁴³ Breast Cancer Unit, Champalimaud Clinical Center, Champalimaud Foundation, Lisbon, Portugal.
⁴⁴ Hospital Universitari Son Espases Palma, Palma, Spain.
⁴⁵ Department of Senology, Université Paris Cité, Assistance Publique-Hôpitaux de Paris, Saint Louis University Hospital, Paris, France.
⁴⁶ Oncology Institute of Southern Switzerland, EOC-IOSI, Bellinzona, Switzerland.
⁴⁷ Department of Oncology, IRCCS Ospedale San Raffaele, Milano, Italy.
⁴⁸ Medical Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.
⁴⁹ Institute of Oncology "Ion Chiricuta", Cluj-Napoca, Romania.
⁵⁰ University of North Carolina - Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
⁵¹ Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
⁵² Institute for Oncology and Radiology of Serbia, University of Belgrade, Faculty of Medicine, Belgrade, Serbia.
⁵³ Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
⁵⁴ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁵⁵ Early Drug Development for Innovative Therapies Division, IRCCS European Institute of Oncology (IEO), Milan, Italy.
⁵⁶ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
⁵⁷ Institute of Cancer and Blood Disorders, Hospital Clinic of Barcelona, Barcelona, Spain.
⁵⁸ Reveal Genomics, Barcelona, Spain.
⁵⁹ Institute of Oncology (IOB)-Hospital Quirón Salud, Barcelona, Spain.

PMID: 38752572
DOI: 10.1002/cncr.35323

Free article

Multicenter Study

Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study

Francesco Schettini et al. Cancer. 2024.

Free article

. 2024 Aug 15;130(16):2746-2762.

doi: 10.1002/cncr.35323. Epub 2024 May 16.

Authors

Affiliations

¹ Translational Genomics and Targeted Therapies in Solid Tumors group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
² Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain.
³ Department of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
⁴ U.O. Epidemiologia Clinica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
⁵ Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy.
⁶ Department of Medical Oncology, U.O. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
⁷ Department of Medical Oncology, Universite Paris Cité, Institut Curie, Paris, France.
⁸ Division of Breast Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁹ Cancer Survivorship Group, INSERM U981, Gustave Roussy, Villejuif, France.
¹⁰ Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center affiliated to Tel Aviv University, Tel Hashomer, Israel.
¹¹ Department of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
¹² Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
¹³ Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
¹⁴ Hereditary Cancer Genetics Unit, Medical oncology Department, Vall d´Hebron University Hospital, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁵ Department of General Medical Oncology and Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
¹⁶ Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B.), Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium.
¹⁷ Department of Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, USA.
¹⁸ Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
¹⁹ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
²⁰ Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
²¹ Department of Oncology and Haematology, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy.
²² Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
²³ Department of Surgery, Leon Berard Cancer Center, Lyon, France.
²⁴ Unité INSERM U1290, Université Claude Bernard Lyon 1, Lyon, France.
²⁵ Hopital Femme Mère Enfant, Hospice civils de Lyon, Bron, France.
²⁶ Department of Gynecology, Cote Basque Hospital Center, Bayonne, France.
²⁷ Hereditary Breast and Ovarian Cancer (HBOC) Unit and General Surgery 3 - Senology, Breast Cancer Center, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
²⁸ University of Pavia, Pavia, Italy.
²⁹ Sharett institute of oncology, Hadassah University Hospital & Faculty of Medicine, Hebrew University, Jerusalem, Israel.
³⁰ UO Gynecology, Department of Medicine and Surgery, University of Milan-Bicocca, IRCCS San Gerardo dei Tintori, Monza, Italy.
³¹ Stroll Cancer Prevention Centre, Jewish General Hospital, and McGill University Medical School, Montreal, Quebec, Canada.
³² Medical Oncology Department, Breast Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
³³ Oncology and Hematology-Oncology Department, University of Milan, Milano, Italy.
³⁴ Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Università di Padova, Padova, Italy.
³⁵ Oncologia 2, Istituto Oncologico Veneto IRCCS, Padova, Italy.
³⁶ Department of Oncology/Pathology, Karolinska Institute and Breast Center, Karolinska University Hospital, Stockholm, Sweden.
³⁷ Medical Oncology, Yale University, New Haven, Connecticut, USA.
³⁸ Breast Cancer Center, Hospital Zambrano Hellion - TecSalud, Tecnologico de Monterrey, Monterrey, Mexico.
³⁹ Division of Medical Oncology, Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
⁴⁰ Medical Oncology Department of Hematology, Oncology, Dermatology, Umberto 1 University Hospital, Rome, Italy.
⁴¹ Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.
⁴² Department of Medicine, University of Udine, Udine, Italy.
⁴³ Breast Cancer Unit, Champalimaud Clinical Center, Champalimaud Foundation, Lisbon, Portugal.
⁴⁴ Hospital Universitari Son Espases Palma, Palma, Spain.
⁴⁵ Department of Senology, Université Paris Cité, Assistance Publique-Hôpitaux de Paris, Saint Louis University Hospital, Paris, France.
⁴⁶ Oncology Institute of Southern Switzerland, EOC-IOSI, Bellinzona, Switzerland.
⁴⁷ Department of Oncology, IRCCS Ospedale San Raffaele, Milano, Italy.
⁴⁸ Medical Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.
⁴⁹ Institute of Oncology "Ion Chiricuta", Cluj-Napoca, Romania.
⁵⁰ University of North Carolina - Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
⁵¹ Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
⁵² Institute for Oncology and Radiology of Serbia, University of Belgrade, Faculty of Medicine, Belgrade, Serbia.
⁵³ Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
⁵⁴ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁵⁵ Early Drug Development for Innovative Therapies Division, IRCCS European Institute of Oncology (IEO), Milan, Italy.
⁵⁶ Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
⁵⁷ Institute of Cancer and Blood Disorders, Hospital Clinic of Barcelona, Barcelona, Spain.
⁵⁸ Reveal Genomics, Barcelona, Spain.
⁵⁹ Institute of Oncology (IOB)-Hospital Quirón Salud, Barcelona, Spain.

PMID: 38752572
DOI: 10.1002/cncr.35323

Abstract

Background: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset.

Methods: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05.

Results: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS.

Conclusions: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Keywords: BRCA; HER2‐low; breast cancer; subtypes; young women.

PubMed Disclaimer

References

REFERENCES

1. Azim HA, Partridge AH. Biology of breast cancer in young women. Breast Cancer Res. 2014;16(4):427. doi:10.1186/s13058‐014‐0427‐5
1. Partridge AH, Hughes ME, Warner ET, et al. Subtype‐dependent relationship between young age at diagnosis and breast cancer survival. J Clin Oncol. 2016;34(27):3308‐3314. doi:10.1200/jco.2015.65.8013
1. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young‐onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169‐180. doi:10.1016/s1470‐2045(17)30891‐4
1. Tomasello G, Gambini D, Petrelli F, et al. Characterization of the HER2 status in BRCA‐mutated breast cancer: a single institutional series and systematic review with pooled analysis. ESMO Open. 2022;7(4):100531. doi:10.1016/j.esmoop.2022.100531
1. Breast Cancer Association Consortium, Dorling L, Carvalho S, et al. Breast cancer risk genes ‐ association analysis in more than 113,000 women. N Engl J Med. 2021;384(5):428‐439. doi:10.1056/nejmoa1913948

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

MFAG 2020 ID 24698/Associazione Italiana per la Ricerca sul Cancro

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study

Affiliations

Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous