Genetic Testing of Breast Cancer Patients with Very Early-Onset Breast Cancer (≤30 Years) Yields a High Rate of Germline Pathogenic Variants, Mainly in the BRCA1, TP53, and BRCA2 Genes

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Jul 13

PMID 39001430

Authors

Paraskevi Apostolou

Vasiliki Dellatola

Athanasios Papathanasiou

Despoina Kalfakakou

Elena Fountzilas

Dimitrios Tryfonopoulos

Sofia Karageorgopoulou

Drakoulis Yannoukakos

Irene Konstantopoulou

Florentia Fostira

Affiliations

Soon will be listed here.

Abstract

Early-onset breast cancer constitutes a major criterion for genetic testing referral. Nevertheless, studies focusing on breast cancer patients (≤30 years) are limited. We investigated the contribution and spectrum of known breast-cancer-associated genes in 267 Greek women with breast cancer ≤30 years while monitoring their clinicopathological characteristics and outcomes. In this cohort, a significant proportion (39.7%) carried germline pathogenic variants (PVs) distributed in 8 genes. The majority, namely 36.7%, involved , and . PVs in were the most prevalent (28.1%), followed by (4.5%) and BRCA2 (4.1%) PVs. The contribution of PVs in , , , , and was limited to 3%. In the patient group ≤26 years, PVs were significantly higher compared to the group 26-30 years ( = 0.0023). A total of 74.8% of carriers did not report a family history of cancer. Carriers of PVs receiving neoadjuvant chemotherapy showed an improved event-free survival ( < 0.0001) compared to non-carriers. Overall, many women with early-onset breast cancer carry clinically actionable variants, mainly in the and genes. The inclusion of timely testing of in these patients provides essential information for appropriate clinical management. This is important for countries where reimbursement involves the cost of genetic analysis of only.

References

Tavtigian S, Oefner P, Babikyan D, Hartmann A, Healey S, Le Calvez-Kelm F . Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009; 85(4):427-46. PMC: 2756555. DOI: 10.1016/j.ajhg.2009.08.018. View

Evans D, van Veen E, Byers H, Evans S, Burghel G, Woodward E . High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer. J Med Genet. 2021; 59(2):115-121. PMC: 8788257. DOI: 10.1136/jmedgenet-2020-107347. View

Myers S, Sevilimedu V, Barrio A, Tadros A, Mamtani A, Robson M . Mutational Status is Associated with a Higher Rate of Pathologic Complete Response After Neoadjuvant Chemotherapy in Hormone Receptor-Positive Breast Cancer. Ann Surg Oncol. 2023; 30(13):8412-8418. PMC: 10752194. DOI: 10.1245/s10434-023-14319-0. View

Slavin T, Maxwell K, Lilyquist J, Vijai J, Neuhausen S, Hart S . The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 2017; 3:22. PMC: 5466608. DOI: 10.1038/s41523-017-0024-8. View

Mai P, Best A, Peters J, DeCastro R, Khincha P, Loud J . Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016; 122(23):3673-3681. PMC: 5115949. DOI: 10.1002/cncr.30248. View

Evans D, Moran A, Hartley R, Dawson J, Bulman B, Knox F . Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status. Br J Cancer. 2010; 102(7):1091-8. PMC: 2853095. DOI: 10.1038/sj.bjc.6605606. View

Jmor S, Al-Sayer H, Heys S, Payne S, Miller I, Hutcheon A . Breast cancer in women aged 35 and under: prognosis and survival. J R Coll Surg Edinb. 2002; 47(5):693-9. View

Han W, Kang S . Relationship between age at diagnosis and outcome of premenopausal breast cancer: age less than 35 years is a reasonable cut-off for defining young age-onset breast cancer. Breast Cancer Res Treat. 2009; 119(1):193-200. DOI: 10.1007/s10549-009-0388-z. View

Shin S, Dodd-Eaton E, Peng G, Bojadzieva J, Chen J, Amos C . Penetrance of Different Cancer Types in Families with Li-Fraumeni Syndrome: A Validation Study Using Multicenter Cohorts. Cancer Res. 2019; 80(2):354-360. PMC: 6980689. DOI: 10.1158/0008-5472.CAN-19-0728. View

10.

Bignon L, Fricker J, Nogues C, Mouret-Fourme E, Stoppa-Lyonnet D, Caron O . Efficacy of anthracycline/taxane-based neo-adjuvant chemotherapy on triple-negative breast cancer in BRCA1/BRCA2 mutation carriers. Breast J. 2017; 24(3):269-277. DOI: 10.1111/tbj.12887. View

11.

Konstantopoulou I, Tsitlaidou M, Fostira F, Pertesi M, Stavropoulou A, Triantafyllidou O . High prevalence of BRCA1 founder mutations in Greek breast/ovarian families. Clin Genet. 2013; 85(1):36-42. DOI: 10.1111/cge.12274. View

12.

Buys S, Sandbach J, Gammon A, Patel G, Kidd J, Brown K . A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer. 2017; 123(10):1721-1730. DOI: 10.1002/cncr.30498. View

13.

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M . ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006; 38(8):873-5. DOI: 10.1038/ng1837. View

14.

Maxwell K, Wubbenhorst B, DAndrea K, Garman B, Long J, Powers J . Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2014; 17(8):630-8. PMC: 4465412. DOI: 10.1038/gim.2014.176. View

15.

Da Silva L, Lakhani S . Pathology of hereditary breast cancer. Mod Pathol. 2010; 23 Suppl 2:S46-51. DOI: 10.1038/modpathol.2010.37. View

16.

Kurian A, Hare E, Mills M, Kingham K, McPherson L, Whittemore A . Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014; 32(19):2001-9. PMC: 4067941. DOI: 10.1200/JCO.2013.53.6607. View

17.

Sandoval R, Bottosso M, Tianyu L, Polidorio N, Bychkovsky B, Verret B . TP53-associated early breast cancer: new observations from a large cohort. J Natl Cancer Inst. 2024; 116(8):1246-1254. PMC: 11308175. DOI: 10.1093/jnci/djae074. View

18.

Kuchenbaecker K, Hopper J, Barnes D, Phillips K, Mooij T, Roos-Blom M . Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017; 317(23):2402-2416. DOI: 10.1001/jama.2017.7112. View

19.

Fostira F, Konstantopoulou I, Mavroudis D, Tryfonopoulos D, Yannoukakos D, Voutsinas G . Genetic evaluation based on family history and Her2 status correctly identifies TP53 mutations in very early onset breast cancer cases. Clin Genet. 2014; 87(4):383-7. DOI: 10.1111/cge.12397. View

20.

Dorling L, Carvalho S, Allen J, Gonzalez-Neira A, Luccarini C, Wahlstrom C . Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med. 2021; 384(5):428-439. PMC: 7611105. DOI: 10.1056/NEJMoa1913948. View