Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul 10;11(1):70.
doi: 10.1038/s41523-025-00781-4.

Genomic landscape of breast cancer in elderly patients

Pier Selenica #  1 , Higinio Dopeso #  1 , Matteo Repetto #  1   2 , Thais Basili  1 , Andrea M Gazzo, Christopher J Schwartz  1 , Fatemeh Derakhshan  1   3 , Antonio Marra  1   4 , Lorenzo Ferrando  1   5 , Regina G H Beets-Tan  6 , Y H Wen  1 , Dara S Ross  1 , Edi Brogi  1 , Hong Zhang  1 , Larry Norton  7 , Sarat Chandarlapaty  7 , Pedram Razavi  7 , Diana Mandelker  1 , Jorge S Reis-Fiho  1   8 , Britta Weigelt  9 , Fresia Pareja  10
Affiliations

Genomic landscape of breast cancer in elderly patients

Pier Selenica et al. NPJ Breast Cancer. .

Abstract

Breast cancer (BC) displays age-related histopathologic and transcriptomic heterogeneity. Whether BC in elderly patients differs genetically from that of younger individuals remains unclear. We re-analyzed sequencing data from 1918 BCs previously subjected to an FDA-cleared paired tumor-normal targeted sequencing assay across elderly (≥65 years), middle-aged (>45 and <65 years) and young (≥45 years) patients. BCs in elderly individuals exhibited fewer germline but were numerically enriched in somatic homologous recombination deficiency (HRD)/DNA damage response (DDR) genetic alterations. Primary ER+/HER2- BC in elderly patients showed shifts in the spectrum of actionable PI3K/AKT alterations, whereas metastatic cases were enriched in FAT1 and RB1 mutations and fewer ESR1 mutations, suggesting age-dependent therapeutic resistance mechanisms. Metastatic ER+/HER2- lobular BCs were enriched in actionable ERBB2 mutations. Resistance-associated alterations were more prevalent in metastatic vs primary BC in elderly patients. Our findings reveal distinct actionable genetic features in elderly patients, highlighting the importance of genomic profiling and treatment personalization in this population.

PubMed Disclaimer

Conflict of interest statement

Competing interests: A.M. reported consulting or advisory role for Menarini/Stemline and AstraZeneca, honoraria as speaker’s bureau from Roche and Eli Lilly, received travel accommodation from Menarini/Stemline and Daiichi Sankyo, outside the submitted work. S.C. has received institutional grant/funding from Daiichi-Sankyo, AstraZeneca, and Lilly, Share options Totus Medicines, and consultation/Ad board/Honoraria from AstraZeneca, Lilly, Casdin Capital, Nuvalent, Blueprint, and SAGA Diagnostics. J.S.R.-F. is an employee of AstraZeneca and owns AstraZeneca stocks. Prior Conflicts of Interest in the last 2 yeas include the receipt of personal fees for the following activities: Board Membership at Grupo Oncoclinicas, consultant for Goldman Sachs Merchant Banking, consultant for Bain Capital, consultant for and SAB member of Paige.ai, consultant for and SAB member of Repare Therapeutics, Consultant of SAGA Diagnostics, Consultant of Personalis, and consultant at MultiplexDx. B.W. reports research grants from REPARE Therapeutics and SAGA Diagnostics paid to the institution, and employment of an immediate family member at AstraZeneca. F.P. reports membership on advisory boards for AstraZeneca and MultiplexDx, as well as receipt of consultancy fees from AstraZeneca. All other authors have nothing to disclose.

Figures

Fig. 1
Fig. 1. Clinicopathologic characteristics and repertoire of somatic genetic alterations in ER-positive/HER2-negative primary breast cancer in elderly patients.
a Histologic subtype and histologic grade of primary ER+/HER2- breast cancer (BC) in elderly (n = 179), middle-aged (n = 390) and young (n = 170) patients. b Recurrent somatic genetic alterations in primary ER+/HER2- BC in elderly, middle-age, and young patients. Cases are shown in columns and genes in rows. Histological subtype, grade are shown in phenobars (top). Genetic alterations are color-coded according to the legend. Forest plots showing odds ratio (OR) of cancer genes altered at statistically significantly different rates in elderly individuals compared to young patients (c), and compared to middle-aged patients (d). Tumor mutational burden (TMB; e) and fraction of genome altered (FGA; f) of primary ER+/HER2- BC in elderly, middle-age, and young patients. g Dominant mutational signatures in primary ER+/HER2- BC in elderly, middle-age, and young patients. n.s., non-significant; *P < 0 .05, **P < 0.01, ***P < 0.001; Mann-Whitney U test and Fisher’s exact test. IDC-NST invasive ductal carcinoma of no special type, HRD homologous recombination deficiency, ILC invasive lobular carcinoma, mixed D-L mixed ductal-lobular.
Fig. 2
Fig. 2. Clinicopathologic characteristics and repertoire of somatic genetic alterations in ER-positive/HER2-negative metastatic breast cancer in elderly patients.
a Histologic subtype and histologic differentiation of metastatic ER+/HER2- breast cancer (BC) in elderly (n = 81), middle-aged (n = 408) and young (n = 273) patients. b Recurrent somatic genetic alterations in metastatic ER+/HER2- BC in elderly, middle-age, and young patients. Cases are shown in columns and genes in rows. Histological subtype and histologic differentiation are shown in phenobars (top). Genetic alterations are color-coded according to the legend. Forest plots showing odds ratio (OR) of cancer genes altered at statistically significantly different rates in elderly individuals compared to young patients (c), and compared to middle-aged patients (d). Tumor mutational burden (TMB; e) and fraction of genome altered (FGA; f) of metastatic ER+/HER2- BC in elderly, middle-age, and young patients. g Dominant mutational signatures in metastatic ER+/HER2- BC in elderly, middle-age, and young patients. n.s. non-significant; *P < 0 .05, **P < 0.01, ***P < 0.001; Mann-Whitney U test and Fisher’s exact test. IDC-NST invasive ductal carcinoma of no special type, HRD homologous recombination deficiency, ILC invasive lobular carcinoma, mixed D-L mixed ductal-lobular.
Fig. 3
Fig. 3. Repertoire of somatic genetic alterations in ER-positive/HER2-negative primary ductal and metastatic lobular breast cancer in elderly patients.
Recurrent somatic genetic alterations in primary ER+/HER2- invasive ductal carcinoma of no special type (IDC-NST; a) and in metastatic lobular breast cancer (ILC; e) in elderly (primary IDC-NST, n = 133; metastatic ILC, n = 25), middle-aged (primary IDC-NST, n = 287; metastatic ILC, n = 90), and young (primary IDC-NST, n = 139; metastatic ILC, n = 32) patients. Cases are shown in columns and genes in rows. Genetic alterations are color coded according to legend. Forest plots depicting odds ratio (OR) of cancer genes altered at statistically significantly different rates between young and elderly (b, f) and middle-aged and elderly patients (c, g). Dominant mutational signatures in primary IDC-NST (d) and metastatic ILC (h) ER+/HER2- BC in elderly, middle-age, and young patients. (i) Lollipop plot of ERBB2 mutations in metastatic ER+/HER2- ILC in elderly, middle-aged, and young patients. ERBB2 domains and mutations are color coded according to the legend. n.s., non-significant; *P < 0 .05, **P < 0.01, ***P < 0.001; Mann-Whitney U test and Fisher’s exact test. IDC-NST invasive ductal carcinoma of no special type, HRD homologous recombination deficiency, ILC invasive lobular carcinoma, mixed D-L mixed ductal-lobular.
Fig. 4
Fig. 4. Comparison of primary and metastatic ER-positive/HER2-negative breast cancer in elderly patients and spectrum of germline and somatic alterations in HRD/DDR genes in the whole cohort.
a Forest plots showing odds ratio (OR) of cancer genes altered at statistically significantly different rates between metastatic (n = 81) and primary (n = 179) ER+/HER2- breast cancer (BC) samples in elderly individuals. b Dominant mutational signatures in primary and metastatic ER+/HER2- BC in elderly patients. Boxplots depicting mutational signature exposures of aging (c) and APOBEC (d) signatures in primary and metastatic ER+/HER2- BC in elderly patients. Tumor mutation burden (TMB; e) and fraction of genome altered (FGA; f) or primary and metastatic ER+/HER2- BC. n.s., non-significant; *P < 0 .05, **P < 0.01, ***P < 0.001; Mann-Whitney U test and Fisher’s exact test.
Fig. 5
Fig. 5. Genetic alterations in homologous recombination deficiency/DNA damage repair genes in breast cancer according to age.
Frequency of germline and somatic genetic alterations in homologous recombination deficiency (HRD)/DNA damage response (DDR) genes in elderly, middle-aged and young patients (a), and proportion of mono- and bi-allelic inactivation in HRD/DDR-altered cases according to age (b). Analysis includes all breast cancer samples regardless of sample type or ER/HER2 status. n.s. non-significant; Fisher’s exact test.
See this image and copyright information in PMC

References

    1. Martelotto, L. G., Ng, C. K., Piscuoglio, S., Weigelt, B. & Reis-Filho, J. S. Breast cancer intra-tumor heterogeneity. Breast Cancer Res.16, 210 (2014). - PMC - PubMed
    1. Weigelt, B., Geyer, F. C. & Reis-Filho, J. S. Histological types of breast cancer: how special are they?. Mol. Oncol.4, 192–208 (2010). - PMC - PubMed
    1. Pareja, F. & Reis-Filho, J. S. Triple-negative breast cancers—a panoply of cancer types. Nat. Rev. Clin. Oncol.15, 347–348 (2018). - PubMed
    1. Feng, Y. et al. Breast cancer development and progression: risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis. Genes Dis.5, 77–106 (2018). - PMC - PubMed
    1. Wang, M. X., Ren, J. T., Tang, L. Y. & Ren, Z. F. Molecular features in young vs elderly breast cancer patients and the impacts on survival disparities by age at diagnosis. Cancer Med. 10.1002/cam4.1544 (2018). - PMC - PubMed

LinkOut - more resources