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
Review
. 2025 Jul 22:83:104544.
doi: 10.1016/j.breast.2025.104544. Online ahead of print.

Impact of germline BRCA1/2 status on outcomes for patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors: a systematic review and meta-analysis

Michele Bottosso  1 , Christian Zurlo  1 , Federica Miglietta  1 , Anna Chiara Cattelan  1 , Daniela Iannaccone  1 , Maria Vittoria Dieci  1 , Gaia Griguolo  2 , Fabio Girardi  3 , Valentina Guarneri  1
Affiliations
Review

Impact of germline BRCA1/2 status on outcomes for patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors: a systematic review and meta-analysis

Michele Bottosso et al. Breast. .

Abstract

Background: Almost 60 % of breast cancers (BCs) diagnosed in germline BRCA1/2 mutation (gBRCAm) carriers are HR+/HER2-. Sparse data suggest limited CDK4/6 inhibitors benefit among gBRCAm carriers. However, prespecified subgroup analyses from pivotal trials are lacking, and current data quality is poor given the small patient populations.

Methods: We conducted a systematic review and meta-analysis of studies evaluating CDK4/6 inhibitors outcomes in patients with HR+/HER2-metastatic BC according to gBRCA status. Progression free survival (PFS) and overall survival (OS) were compared between gBRCAm patients and those with wild type (wt) or unknown (wt/unk) gBRCA status.

Results: Of 1339 potentially eligible records, 14 studies were included, covering a population of 618 gBRCAm patients. Studies were mostly retrospective, with moderate-to-high risk of bias according to ROBINS-E algorithm. Three studies included only gBRCA tested patients; all others also allowed gBRCA untested patients. Meta-analysis of studies with available data for gBRCAm vs. gBRCAwt patients resulted in an HR for PFS of 1.68 (95 %CI 1.37-2.05) and an HR for OS of 1.73 (95 %CI 1.12-2.67). Inclusion of patients with unknown gBRCA status led to similar results (gBRCAm vs. gBRCAwt/unk), with an HR for PFS of 2.02 (95 %CI 1.59-2.57) and for OS of 1.46 (95 %CI 1.08-2.00).

Conclusions: Emerging data suggest that gBRCAm patients with advanced HR+/HER2- BC may experience shorter PFS and OS with CDK4/6 inhibitor compared to gBRCAwt. Given the low level of evidence and the high risk of bias in available studies, further research is needed to understand molecular mechanisms and identify the optimal treatment sequence.

Keywords: BRCA1/2; Breast cancer; CDK4/6 inhibitors; Meta-analysis; Systematic review.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest MB reports travel support from Eli Lilly. CZ reports travel support from Eli Lilly, Sanofi, Gilead. FM reports personal fees from Roche, Novartis, Pfizer, Seagen, Menarini, MSD, Gilead, Astrazeneca MVD reports personal fees for consultancy/advisory role from: Eli Lilly, Pfizer, Novartis, Seagen, Gilead, MSD, Exact Sciences, AstraZeneca, Roche, Daiichi Sankyo, Roche. The other authors declare no conflicts of interest. GG reports fees for advisory role from Gilead, Seagen, Menarini, personal fees as an invited speaker from Eli Lilly, Novartis, MSD, travel support Gilead, Eli Lilly, Pfizer, Novartis, Daiichi Sankyo, AMGEN, AstraZeneca. FG reports travel support from Eli Lilly, Gilead, Novartis; honoraria for lectures from AstraZeneca, Eli Lilly, Gilead. VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre, Roche, Menarini Stemline, personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Novartis, Roche, Zentiva, Menarini Stemline, personal fees for expert testimony for Eli Lilly.

Figures

Fig. 1
Fig. 1
PRISMA flowchart.
Fig. 2
Fig. 2
Hazard ratios for progression free survival (A) and overall survival (B) according to gBRCA status.
Fig. 3
Fig. 3
Hazard ratios for progression free survival (A) and overall survival (B) for patients with gBRCAm vs gBRCAwt + unk.
Fig. 4
Fig. 4
Subgroup analysis of hazard ratios for progression free survival for patients with gBRCAm vs gBRCAwt + unk according to type of publication (full article vs. abstract/poster).
Fig. 5
Fig. 5
Meta-regression analysis assessing the association between publication type and progression-free survival (logarithmic scale for hazard ratios).
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Malvezzi M., Santucci C., Boffetta P., Collatuzzo G., Levi F., La Vecchia C., et al. European cancer mortality predictions for the year 2023 with focus on lung cancer. Ann Oncol. 2023 doi: 10.1016/j.annonc.2023.01.010. - DOI - PubMed
    1. GLOBOCAN 2020, International Agency for Research on Cancer n.d. https://doi.org/10.8..
    1. Lobbezoo D.J.A., van Kampen R.J.W., Voogd A.C., Dercksen M.W., van den Berkmortel F., Smilde T.J., et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res Treat. 2013;141:507–514. doi: 10.1007/s10549-013-2711-y. - DOI - PubMed
    1. Gennari A., André F., Barrios C.H., Cortés J., de Azambuja E., DeMichele A., et al. ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32:1475–1495. doi: 10.1016/j.annonc.2021.09.019. - DOI - PubMed
    1. Tung N., Lin N.U., Kidd J., Allen B.A., Singh N., Wenstrup R.J., et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol. 2016;34:1460–1468. doi: 10.1200/JCO.2015.65.0747. - DOI - PMC - PubMed