Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study

Roberta Scafetta; Raffaella Troiano; Carla Gullotta; Alessandra Guarino; Cristina Fiore; Luisana Sisca; Elena Speziale; Marco Donato; Simone Foderaro; Fabio Venuti; Francesco Antonio Vilardi; Valentina Ricozzi; Michele Iuliani; Sonia Simonetti; Silvia Cavaliere; Alessio Cortellini; Annalisa La Cesa; Andrea Botticelli; Simone Scagnoli; Simona Pisegna; Carmen Criscitiello; Rebecca Pedersini; Caterina Sposetti; Elisa Tiberi; Giuliana D'Auria; Matteo Vergati; Marco Mazzotta; Roberta Caputo; Annarita Verrazzo; Ornella Garrone; Federica Domati; Claudia Piombino; Francesca Sofia Di Lisa; Lorena Filomeno; Teresa Arcuri; Federica Puce; Federica Riva; Michela Palleschi; Marianna Sirico; Marta Piras; Luigia Stefania Stucci; Delia De Lisi; Paolo Orsaria; Antonella Grasso; Edy Ippolito; Sara Ramella; Luca Visani; Lorenzo Livi; Stefania Gori; Icro Meattini; Et al.

doi:10.1016/j.ejca.2026.116703

Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study

Roberta Scafetta
, Raffaella Troiano
, Carla Gullotta
, Alessandra Guarino
, Cristina Fiore
, Luisana Sisca
, Elena Speziale
, Marco Donato
, Simone Foderaro
, Fabio Venuti
, Francesco Antonio Vilardi
, Valentina Ricozzi
, Michele Iuliani^*
, Sonia Simonetti
, Silvia Cavaliere
, Alessio Cortellini
, Annalisa La Cesa
, Andrea Botticelli
, Simone Scagnoli
, Simona Pisegna

Carmen Criscitiello, Rebecca Pedersini, Caterina Sposetti, Elisa Tiberi, Giuliana D'Auria, Matteo Vergati, Marco Mazzotta, Roberta Caputo, Annarita Verrazzo, Ornella Garrone, Federica Domati, Claudia Piombino, Francesca Sofia Di Lisa, Lorena Filomeno, Teresa Arcuri, Federica Puce, Federica Riva, Michela Palleschi, Marianna Sirico, Marta Piras, Luigia Stefania Stucci, Delia De Lisi, Paolo Orsaria, Antonella Grasso, Edy Ippolito, Sara Ramella, Luca Visani, Lorenzo Livi, Stefania Gori, Icro Meattini, Et al.

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation. RANKL inhibition with denosumab could disrupt tumor–bone microenvironment crosstalk and potentially limit metastatic progression. We evaluated the association between denosumab and real-world progression-free survival (rwPFS) in germline BRCA1/2-mutated hormone receptor–positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) with bone metastases. Methods We performed a retrospective, multicenter study across 24 Italian hospitals including HR+/HER2- bone mBC patients treated in first- or second-line with a CDK4/6 inhibitor plus endocrine therapy. rwPFS was estimated by Kaplan–Meier and compared with log-rank tests. Center-stratified multivariable Cox models adjusted for clinically relevant covariates were used to assess the association between denosumab exposure and rwPFS. Effect modification by BRCA status was evaluated using a denosumab×BRCA1/2 mutation status. Results Among 1399 patients, 46 harbored germline BRCA1/2 mutations (13 BRCA1, 33 BRCA2), and 21 of these patients received denosumab. Among patients not receiving denosumab, BRCA1/2-wild-type/unknown patients had better rwPFS than BRCA1/2-mutated patients (median 28 vs 13 months; hazard ratio (HR) 0.48, 95% CI 0.32–0.73; p = 0.001). Among BRCA1/2-wild-type/unknown patients, denosumab use did not affect rwPFS (HR 0.98, 95% CI 0.85–1.12). Conversely, denosumab use was associated with longer rwPFS among patients with BRCA1/2 mutations (median 35 months, 95% CI 24–NR vs 13 months, 95% CI 9–27; HR 0.34, 95% CI 0.16–0.74; p = 0.006), with no significant difference between BRCA1 and BRCA2-mutated subgroups. Multivariable analysis confirmed the rwPFS benefit of denosumab in BRCA1/2-mutated patients (adjusted HR 0.45, 95% CI 0.21–0.99; p = 0.048). Conclusion In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2- mBC with bone metastases.

Original language	English
Article number	116703
Number of pages	7
Journal	European Journal of Cancer
Volume	239
DOIs	https://doi.org/10.1016/j.ejca.2026.116703
Publication status	Published - 15 May 2026

Keywords

Bone metastases
BRCA1
BRCA2
Denosumab
HR+ /HER2 - breast cancer
RANKL
Real-world progression-free survival

Access to Document

10.1016/j.ejca.2026.116703Licence: CC BY

Fingerprint

Dive into the research topics of 'Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study'. Together they form a unique fingerprint.

Cite this

Scafetta, R., Troiano, R., Gullotta, C., Guarino, A., Fiore, C., Sisca, L., Speziale, E., Donato, M., Foderaro, S., Venuti, F., Vilardi, F. A., Ricozzi, V., Iuliani, M., Simonetti, S., Cavaliere, S., Cortellini, A., Cesa, A. L., Botticelli, A., Scagnoli, S., ... Et al. (2026). Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study. European Journal of Cancer, 239, Article 116703. https://doi.org/10.1016/j.ejca.2026.116703

@article{891867471b484af49b62e802d19e50bf,

title = "Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study",

abstract = "Background Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation. RANKL inhibition with denosumab could disrupt tumor–bone microenvironment crosstalk and potentially limit metastatic progression. We evaluated the association between denosumab and real-world progression-free survival (rwPFS) in germline BRCA1/2-mutated hormone receptor–positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) with bone metastases. Methods We performed a retrospective, multicenter study across 24 Italian hospitals including HR+/HER2- bone mBC patients treated in first- or second-line with a CDK4/6 inhibitor plus endocrine therapy. rwPFS was estimated by Kaplan–Meier and compared with log-rank tests. Center-stratified multivariable Cox models adjusted for clinically relevant covariates were used to assess the association between denosumab exposure and rwPFS. Effect modification by BRCA status was evaluated using a denosumab×BRCA1/2 mutation status. Results Among 1399 patients, 46 harbored germline BRCA1/2 mutations (13 BRCA1, 33 BRCA2), and 21 of these patients received denosumab. Among patients not receiving denosumab, BRCA1/2-wild-type/unknown patients had better rwPFS than BRCA1/2-mutated patients (median 28 vs 13 months; hazard ratio (HR) 0.48, 95\% CI 0.32–0.73; p = 0.001). Among BRCA1/2-wild-type/unknown patients, denosumab use did not affect rwPFS (HR 0.98, 95\% CI 0.85–1.12). Conversely, denosumab use was associated with longer rwPFS among patients with BRCA1/2 mutations (median 35 months, 95\% CI 24–NR vs 13 months, 95\% CI 9–27; HR 0.34, 95\% CI 0.16–0.74; p = 0.006), with no significant difference between BRCA1 and BRCA2-mutated subgroups. Multivariable analysis confirmed the rwPFS benefit of denosumab in BRCA1/2-mutated patients (adjusted HR 0.45, 95\% CI 0.21–0.99; p = 0.048). Conclusion In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2- mBC with bone metastases.",

keywords = "Bone metastases, BRCA1, BRCA2, Denosumab, HR+ /HER2 - breast cancer, RANKL, Real-world progression-free survival",

author = "Roberta Scafetta and Raffaella Troiano and Carla Gullotta and Alessandra Guarino and Cristina Fiore and Luisana Sisca and Elena Speziale and Marco Donato and Simone Foderaro and Fabio Venuti and Vilardi, \{Francesco Antonio\} and Valentina Ricozzi and Michele Iuliani and Sonia Simonetti and Silvia Cavaliere and Alessio Cortellini and Cesa, \{Annalisa La\} and Andrea Botticelli and Simone Scagnoli and Simona Pisegna and Carmen Criscitiello and Rebecca Pedersini and Caterina Sposetti and Elisa Tiberi and Giuliana D'Auria and Matteo Vergati and Marco Mazzotta and Roberta Caputo and Annarita Verrazzo and Ornella Garrone and Federica Domati and Claudia Piombino and Lisa, \{Francesca Sofia Di\} and Lorena Filomeno and Teresa Arcuri and Federica Puce and Federica Riva and Michela Palleschi and Marianna Sirico and Marta Piras and Stucci, \{Luigia Stefania\} and Lisi, \{Delia De\} and Paolo Orsaria and Antonella Grasso and Edy Ippolito and Sara Ramella and Luca Visani and Lorenzo Livi and Stefania Gori and Icro Meattini and \{Et al.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2026. Published by Elsevier Ltd.",

year = "2026",

month = may,

day = "15",

doi = "10.1016/j.ejca.2026.116703",

language = "English",

volume = "239",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd",

}

Scafetta, R, Troiano, R, Gullotta, C, Guarino, A, Fiore, C, Sisca, L, Speziale, E, Donato, M, Foderaro, S, Venuti, F, Vilardi, FA, Ricozzi, V, Iuliani, M, Simonetti, S, Cavaliere, S, Cortellini, A, Cesa, AL, Botticelli, A, Scagnoli, S, Pisegna, S, Criscitiello, C, Pedersini, R, Sposetti, C, Tiberi, E, D'Auria, G, Vergati, M, Mazzotta, M, Caputo, R, Verrazzo, A, Garrone, O, Domati, F, Piombino, C, Lisa, FSD, Filomeno, L, Arcuri, T, Puce, F, Riva, F, Palleschi, M, Sirico, M, Piras, M, Stucci, LS, Lisi, DD, Orsaria, P, Grasso, A, Ippolito, E, Ramella, S, Visani, L, Livi, L, Gori, S, Meattini, I & Et al. 2026, 'Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study', European Journal of Cancer, vol. 239, 116703. https://doi.org/10.1016/j.ejca.2026.116703

Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study. / Scafetta, Roberta; Troiano, Raffaella; Gullotta, Carla et al.
In: European Journal of Cancer, Vol. 239, 116703, 15.05.2026.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors

T2 - A multicenter Italian study

AU - Scafetta, Roberta

AU - Troiano, Raffaella

AU - Gullotta, Carla

AU - Guarino, Alessandra

AU - Fiore, Cristina

AU - Sisca, Luisana

AU - Speziale, Elena

AU - Donato, Marco

AU - Foderaro, Simone

AU - Venuti, Fabio

AU - Vilardi, Francesco Antonio

AU - Ricozzi, Valentina

AU - Iuliani, Michele

AU - Simonetti, Sonia

AU - Cavaliere, Silvia

AU - Cortellini, Alessio

AU - Cesa, Annalisa La

AU - Botticelli, Andrea

AU - Scagnoli, Simone

AU - Pisegna, Simona

AU - Criscitiello, Carmen

AU - Pedersini, Rebecca

AU - Sposetti, Caterina

AU - Tiberi, Elisa

AU - D'Auria, Giuliana

AU - Vergati, Matteo

AU - Mazzotta, Marco

AU - Caputo, Roberta

AU - Verrazzo, Annarita

AU - Garrone, Ornella

AU - Domati, Federica

AU - Piombino, Claudia

AU - Lisa, Francesca Sofia Di

AU - Filomeno, Lorena

AU - Arcuri, Teresa

AU - Puce, Federica

AU - Riva, Federica

AU - Palleschi, Michela

AU - Sirico, Marianna

AU - Piras, Marta

AU - Stucci, Luigia Stefania

AU - Lisi, Delia De

AU - Orsaria, Paolo

AU - Grasso, Antonella

AU - Ippolito, Edy

AU - Ramella, Sara

AU - Visani, Luca

AU - Livi, Lorenzo

AU - Gori, Stefania

AU - Meattini, Icro

AU - Et al.

PY - 2026/5/15

Y1 - 2026/5/15

N2 - Background Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation. RANKL inhibition with denosumab could disrupt tumor–bone microenvironment crosstalk and potentially limit metastatic progression. We evaluated the association between denosumab and real-world progression-free survival (rwPFS) in germline BRCA1/2-mutated hormone receptor–positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) with bone metastases. Methods We performed a retrospective, multicenter study across 24 Italian hospitals including HR+/HER2- bone mBC patients treated in first- or second-line with a CDK4/6 inhibitor plus endocrine therapy. rwPFS was estimated by Kaplan–Meier and compared with log-rank tests. Center-stratified multivariable Cox models adjusted for clinically relevant covariates were used to assess the association between denosumab exposure and rwPFS. Effect modification by BRCA status was evaluated using a denosumab×BRCA1/2 mutation status. Results Among 1399 patients, 46 harbored germline BRCA1/2 mutations (13 BRCA1, 33 BRCA2), and 21 of these patients received denosumab. Among patients not receiving denosumab, BRCA1/2-wild-type/unknown patients had better rwPFS than BRCA1/2-mutated patients (median 28 vs 13 months; hazard ratio (HR) 0.48, 95% CI 0.32–0.73; p = 0.001). Among BRCA1/2-wild-type/unknown patients, denosumab use did not affect rwPFS (HR 0.98, 95% CI 0.85–1.12). Conversely, denosumab use was associated with longer rwPFS among patients with BRCA1/2 mutations (median 35 months, 95% CI 24–NR vs 13 months, 95% CI 9–27; HR 0.34, 95% CI 0.16–0.74; p = 0.006), with no significant difference between BRCA1 and BRCA2-mutated subgroups. Multivariable analysis confirmed the rwPFS benefit of denosumab in BRCA1/2-mutated patients (adjusted HR 0.45, 95% CI 0.21–0.99; p = 0.048). Conclusion In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2- mBC with bone metastases.

AB - Background Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation. RANKL inhibition with denosumab could disrupt tumor–bone microenvironment crosstalk and potentially limit metastatic progression. We evaluated the association between denosumab and real-world progression-free survival (rwPFS) in germline BRCA1/2-mutated hormone receptor–positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) with bone metastases. Methods We performed a retrospective, multicenter study across 24 Italian hospitals including HR+/HER2- bone mBC patients treated in first- or second-line with a CDK4/6 inhibitor plus endocrine therapy. rwPFS was estimated by Kaplan–Meier and compared with log-rank tests. Center-stratified multivariable Cox models adjusted for clinically relevant covariates were used to assess the association between denosumab exposure and rwPFS. Effect modification by BRCA status was evaluated using a denosumab×BRCA1/2 mutation status. Results Among 1399 patients, 46 harbored germline BRCA1/2 mutations (13 BRCA1, 33 BRCA2), and 21 of these patients received denosumab. Among patients not receiving denosumab, BRCA1/2-wild-type/unknown patients had better rwPFS than BRCA1/2-mutated patients (median 28 vs 13 months; hazard ratio (HR) 0.48, 95% CI 0.32–0.73; p = 0.001). Among BRCA1/2-wild-type/unknown patients, denosumab use did not affect rwPFS (HR 0.98, 95% CI 0.85–1.12). Conversely, denosumab use was associated with longer rwPFS among patients with BRCA1/2 mutations (median 35 months, 95% CI 24–NR vs 13 months, 95% CI 9–27; HR 0.34, 95% CI 0.16–0.74; p = 0.006), with no significant difference between BRCA1 and BRCA2-mutated subgroups. Multivariable analysis confirmed the rwPFS benefit of denosumab in BRCA1/2-mutated patients (adjusted HR 0.45, 95% CI 0.21–0.99; p = 0.048). Conclusion In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2- mBC with bone metastases.

KW - Bone metastases

KW - BRCA1

KW - BRCA2

KW - Denosumab

KW - HR+ /HER2 - breast cancer

KW - RANKL

KW - Real-world progression-free survival

U2 - 10.1016/j.ejca.2026.116703

DO - 10.1016/j.ejca.2026.116703

M3 - Article

SN - 0959-8049

VL - 239

JO - European Journal of Cancer

JF - European Journal of Cancer

M1 - 116703

ER -