Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.
BRCA
HER2‐low
breast cancer
subtypes
young women
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
16 May 2024
16 May 2024
Historique:
revised:
17
02
2024
received:
09
01
2024
accepted:
18
03
2024
medline:
16
5
2024
pubmed:
16
5
2024
entrez:
16
5
2024
Statut:
aheadofprint
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : MFAG 2020 ID 24698
Informations de copyright
© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.
Références
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
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
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
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
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
Tarantino P, Hamilton E, Tolaney SM, et al. HER2‐low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951‐1962. doi:10.1200/jco.19.02488
Wolff AC, Hammond MEH, Allison KH, et al. 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. 2018;36(20):2105‐2122. doi:10.1200/jco.2018.77.8738
Molinelli C, Jacobs F, Marchiò C, et al. HER2‐low breast cancer: where are we? Breast Care. 2022;17(6):533‐545. doi:10.1159/000527391
Iwata H, Tamura K, Doi T, et al. Trastuzumab deruxtecan (DS‐8201a) in subjects with HER2‐expressing solid tumors: long‐term results of a large phase 1 study with multiple expansion cohorts. J Clin Orthod. 2018;36(15_suppl):2501. doi:10.1200/jco.2018.36.15_suppl.2501
Modi S, Park H, Murthy RK, et al. 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. 2020;38(17):1887‐1896.
Schettini F, Chic N, Brasó‐Maristany F, et al. Clinical, pathological, and PAM50 gene expression features of HER2‐low breast cancer. NPJ Breast Cancer. 2021;7:1. doi:10.1038/s41523‐020‐00208‐2
Agostinetto E, Rediti M, Fimereli D, et al. HER2‐low breast cancer: molecular characteristics and prognosis. Cancers. 2021;13(11):2824. doi:10.3390/cancers13112824
Tarantino P, Gupta H, Hughes ME, et al. Comprehensive genomic characterization of HER2‐low and HER2‐0 breast cancer. Nat Commun. 2023;14(1):7496. doi:10.1038/s41467‐023‐43324‐w
Molinelli C, Jacobs F, Agostinetto E, et al. Prognostic value of HER2‐low status in breast cancer: a systematic review and meta‐analysis. ESMO Open. 2023;8(4):101592. doi:10.1016/j.esmoop.2023.101592
Tarantino P, Jin Q, Tayob N, et al. Prognostic and biologic significance of ERBB2‐low expression in early‐stage breast cancer. JAMA Oncol. 2022;8:1177‐1183. doi:10.1001/jamaoncol.2022.2286
Lambertini M, Blondeaux E, Agostinetto E, et al. Pregnancy after breast cancer in young BRCA carriers: an international hospital‐based cohort study. JAMA. 2024;331(1):49‐59. doi:10.1001/jama.2023.25463
Allison KH, Hammond MEH, Dowsett M, et al. Estrogen and progesterone receptor testing in breast cancer: ASCO/CAP Guideline Update. J Clin Orthod. 2020;38(12):1346‐1366. doi:10.1200/jco.19.02309
Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2‐low‐positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021;22(8):1151‐1161. S1470‐2045(21)00301‐6. doi:10.1016/s1470‐2045(21)00301‐6
Tan RSYC, Ong WS, Lee K‐H, et al. HER2 expression, copy number variation and survival outcomes in HER2‐low non‐metastatic breast cancer: an international multicentre cohort study and TCGA‐METABRIC analysis. BMC Med. 2022;20(1):105. doi:10.1186/s12916‐022‐02284‐6
Schettini F, Brasó‐Maristany F, Kuderer NM, Prat A. A perspective on the development and lack of interchangeability of the breast cancer intrinsic subtypes. NPJ Breast Cancer. 2022;8(1):85. doi:10.1038/s41523‐022‐00451‐9
Hartman A‐R, Kaldate RR, Sailer LM, et al. Prevalence of BRCA mutations in an unselected population of triple‐negative breast cancer. Cancer. 2012;118(11):2787‐2795. doi:10.1002/cncr.26576
Nielsen K, Sode M, Jensen M‐B, et al. High inter‐laboratory variability in the assessment of HER2‐low breast cancer: a national registry study on 50,714 Danish patients. Breast Cancer Res. 2023;25(1):139. doi:10.1186/s13058‐023‐01739‐9
Zaakouk M, Quinn C, Provenzano E, et al. Concordance of HER2‐low scoring in breast carcinoma among expert pathologists in the United Kingdom and the Republic of Ireland ‐ on behalf of the UK national coordinating committee for breast pathology. Breast. 2023;70:82‐91. doi:10.1016/j.breast.2023.06.005
Whitaker K, Obeid E, Goldstein L, Daly M. Abstract P6‐08‐21: prevalence of HER2 positivity in germline BRCA 1/2‐associated breast cancers (gBRCA1/2‐BC). Cancer Res. 2020;80(4_Supplement):P6‐08–21. doi:10.1158/1538‐7445.sabcs19‐p6‐08‐21
Rosenberg S, Devir M, Kaduri L, et al. Distinct breast cancer phenotypes in BRCA 1/2 carriers based on ER status. Breast Cancer Res Treat. 2023;198(2):197‐205. doi:10.1007/s10549‐022‐06851‐6
Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2‐low advanced breast cancer. N Engl J Med. 2022;387(1):9‐20. doi:10.1056/nejmoa2203690
Schettini F, Pascual T, Ghiglione L, et al. 55P Clinicopathological and molecular changes induced by neoadjuvant therapy (NAT) in hormone receptor‐positive (HR+)/HER2‐low vs HER2 0 breast cancer (BC) [Internet]. ESMO Open. 2023;8(1):101279. [cited 2023 Aug 18]. doi:10.1016/j.esmoop.2023.101279
Miglietta F, Griguolo G, Bottosso M, et al. HER2‐low‐positive breast cancer: evolution from primary tumor to residual disease after neoadjuvant treatment. NPJ Breast Cancer. 2022;8(1):66. doi:10.1038/s41523‐022‐00434‐w
Tarantino P, Gandini S, Nicolò E, et al. Evolution of low HER2 expression between early and advanced‐stage breast cancer. Eur J Cancer. 2022;163:35‐43. doi:10.1016/j.ejca.2021.12.022
Brasó‐Maristany F, Paré L, Chic N, et al. Gene expression profiles of breast cancer metastasis according to organ site. Mol Oncol. 2021;16(1):69‐87. doi:10.1002/1878‐0261.13021
Geukens T, De Schepper M, Richard F, et al. Intra‐patient and inter‐metastasis heterogeneity of HER2‐low status in metastatic breast cancer. Eur J Cancer. 2023;188:152‐160. doi:10.1016/j.ejca.2023.04.026
Prat A, Modi S, Tsurutani J, et al. Abstract HER2‐18: HER2‐18 determination of HER2‐low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY‐Breast04. Cancer Res. 2023;83(5_Supplement):HER2‐18. doi:10.1158/1538‐7445.sabcs22‐her2‐18
Tarantino P, Viale G, Press MF, et al. ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2‐low breast cancer. Ann Oncol. 2023;34(8):645‐659. doi:10.1016/j.annonc.2023.05.008
Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747‐752. doi:10.1038/35021093
Prat A, Pineda E, Adamo B, et al. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast. 2015;24(Suppl 2):S26‐S35. doi:10.1016/j.breast.2015.07.008
Schettini F, Martínez‐Sáez O, Falato C, et al. Prognostic value of intrinsic subtypes in hormone‐receptor‐positive metastatic breast cancer: systematic review and meta‐analysis. ESMO Open. 2023;8(3):101214. doi:10.1016/j.esmoop.2023.101214
Luen SJ, Viale G, Nik‐Zainal S, et al. Genomic characterisation of hormone receptor‐positive breast cancer arising in very young women. Ann Oncol. 2023;34(4):397‐409. doi:10.1016/j.annonc.2023.01.009
Lambertini M, Ceppi M, Hamy A‐S, et al. Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants. NPJ Breast Cancer. 2021;7(1):16. doi:10.1038/s41523‐021‐00224‐w
Jonasson JG, Stefansson OA, Johannsson OT, et al. Oestrogen receptor status, treatment and breast cancer prognosis in Icelandic BRCA2 mutation carriers. Br J Cancer. 2016;115(7):776‐783. doi:10.1038/bjc.2016.249
Schmidt MK, van den Broek AJ, Tollenaar RAEM, et al. Breast cancer survival of BRCA1/BRCA2 mutation carriers in a hospital‐based cohort of young women. J Natl Cancer Inst. 2017;109(8). doi:10.1093/jnci/djw329
Metcalfe K, Lynch HT, Foulkes WD, et al. Oestrogen receptor status and survival in women with BRCA2‐associated breast cancer. Br J Cancer. 2019;120(4):398‐403. doi:10.1038/s41416‐019‐0376‐y
Goodwin PJ, Phillips K‐A, West DW, et al. Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population‐based cohort study. J Clin Oncol. 2012;30(1):19‐26. doi:10.1200/jco.2010.33.0068
Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow‐up. Ann Oncol. 2019;30(10):1674. doi:10.1093/annonc/mdz189
Pagani O, Walley BA, Fleming GF, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer: long‐term follow‐up of the combined TEXT and SOFT trials. J Clin Oncol. 2023;41(7):1376‐1382. doi:10.1200/jco.22.01064
Chic N, Schettini F, Brasó‐Maristany F, et al. Oestrogen receptor activity in hormone‐dependent breast cancer during chemotherapy. EBioMedicine. 2021;69:103451. doi:10.1016/j.ebiom.2021.103451
Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21‐gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111‐121. doi:10.1056/nejmoa1804710
Kalinsky K, Barlow WE, Gralow JR, et al. 21‐gene assay to inform chemotherapy benefit in node‐positive breast cancer. N Engl J Med. 2021;385(25):2336‐2347. doi:10.1056/nejmoa2108873
Piccart M, van’t Veer LJ, Poncet C, et al. 70‐gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021;22(4):476‐488. doi:10.1016/s1470‐2045(21)00007‐3
Prat A, Ellis MJ, Perou CM. Practical implications of gene‐expression‐based assays for breast oncologists. Nat Rev Clin Oncol. 2011;9(1):48‐57. doi:10.1038/nrclinonc.2011.178
Cejalvo JM, Martínez de Dueñas E, Galván P, et al. Intrinsic subtypes and gene expression profiles in primary and metastatic breast cancer. Cancer Res. 2017;77(9):2213‐2221. doi:10.1158/0008‐5472.can‐16‐2717