Antibody-drug conjugates (ADCs) represent an effective class of agents for the treatment of several tumor types, including breast cancer (BC), featuring approved molecules such as trastuzumab-emtansine, trastuzumab-deruxtecan, and sacituzumab-govitecan. Immune-checkpoint inhibitors (ICIs) also showed activity in selected BC subtypes, and two agents, pembrolizumab and atezolizumab, are currently approved for the treatment of triple-negative BC patients. The potential synergy between ADCs and immunotherapy in BC remains an area of active investigation. Preclinical studies suggest that ADCs promote immune surveillance, modulating tumor microenvironment, inducing immunogenic cell death, and enhancing antitumor immunity. Translational evidence has shown potential predictive biomarkers for ADCs alone or in combination with immunotherapy, including expression of target antigen, oncogenic pathways, tumor-infiltrating lymphocytes, and neutrophil-to-lymphocyte ratio. Given this background, several clinical trials evaluated ADC-ICI combinations in BC patients, demonstrating promising outcomes with an overall manageable toxicity profile, and many studies are currently ongoing to confirm the efficacy and feasibility of this therapeutic approach. In the present review, we summarized the available evidence about the integration of ADCs and immunotherapy for the management of BC, emphasizing the need for further translational and clinical investigations to optimize this treatment strategy and elucidate predictive biomarkers, eventually improving patient outcomes.

Triple-negative breast cancer (TNBC) represents about 15% of all breast cancers and is usually characterized by aggressive clinical behavior and a poor prognosis. Four TNBC subgroups have been previously defined with different molecular profiles: (i) luminal androgen receptor (LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS) and (iv) basal-like immune-activated (BLIA). Among these, LAR is characterized by the expression of the androgen receptor (AR), and exhibits genomic characteristics that resemble luminal breast cancers, with a still undefined prognosis and clinical behavior. Here, we report a case of a woman affected by recurring LAR TNBC, which underwent phenotypic changes throughout its natural history. After the initial diagnosis of LAR breast cancer, the patient experienced local recurrence with strong expression of the estrogen receptor. Due to this finding, she started treatment with a CDK4/6-inhibitor and an aromatase inhibitor, followed by oral vinorelbine, both with dismal outcomes. Then, she received everolimus and exemestane, which determined temporary disease stabilization. An extensive NGS analysis of tumor tissue showed PIK3CA and HER2 mutations. Our case is consistent with previous reports of LAR breast cancer and underlines the potential utility of re-biopsy and molecular testing in breast cancer (BC), especially in rare subtypes.

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard-of-care for hormone receptor-positive (HR+)/HER2-negative (HER2−) metastatic breast cancer (MBC). Palbociclib, the first approved CDK4/6i, significantly improved progression-free survival (PFS) in randomized controlled trials (RCTs). However, real-world (RW) outcomes may differ due to broader patient populations. This meta-analysis evaluates the applicability of pivotal RCT findings to RW settings. Methods: We conducted a systematic review and meta-analysis of RW studies on HR+/HER2− MBC treated with palbociclib+aromatase inhibitors (AI) or fulvestrant, reporting median PFS (mPFS) and/or overall survival (mOS). Pooled mPFS/OS was estimated using the median of medians (MM) and weighted MM (WM). RW estimates were deemed comparable to RCTs if MMPFS/OS or WMPFS/OS fell within RCTs’ 95% confidence intervals (CI). Similar criteria applied to pooled hazard ratios (HR) of PFS/OS for palbociclib+AI vs AI in visceral/non-visceral subgroups. Results: Twelve RW studies were analyzed. First-line palbociclib+AI MMPFS (22.5 months, 95%CI: 19.5–31.8) aligned with PALOMA-1/2 pooled mPFS (23.9, 95% CI: 20.2–27.6). First-line palbociclib+fulvestrant MMPFS (13.5, 95%CI: 11.6–28.5) exceeded PALOMA-3 (11.2, 95%CI: 9.5–12.9). Second-line palbociclib+fulvestrant MMPFS (11.5 months, 95%CI: 6.3–15.3) was consistent with PALOMA-3. RW first-line mOS (51.2 months, 95%CI: 49.1–53.3) surpassed PALOMA-1/2 pooled mOS (45.7, 95%CI: 37.5–53.8). WMOS (49.1 months, 95%CI: 49.1–53.3) was slightly lower than RCTs (53.7, 95%CI: 37.5–53.8). Palbociclib+AI outperformed AI in RW visceral disease, aligning with RCTs, and showed heterogeneous but favorable benefit in non-visceral disease. Conclusions: RW data confirm palbociclib+endocrine therapy effectiveness, reinforcing its applicability to broader patient populations.

Genomic assays (GA) guide chemotherapy (CT) use in stage I-II endocrine receptor-positive (ER+)/HER2-negative (HER2-) breast cancer (BC). In tumors N0/intermediate-risk or N1/low-to-intermediate-risk, randomized trials with OncotypeDX® showed a CT benefit only for women aged≤ 50 years/premenopausal. Comparable data for the Prosigna® GA are lacking. We retrospectively included 567 women aged≤ 50 years with stage I-II ER+ /HER2 - BC tested with Prosigna® across 10 hospitals in Spain/Italy (2014-2023). Patients received endocrine therapy (ET) with/without (neo)adjuvant CT. Event-free survival (EFS) was analyzed using Kaplan-Meier curves, log-rank tests, and Cox regression. Propensity score matching (PSM) was applied. 5-year EFS rates were numerically compared with those of OncotypeDX® trials. Of 567 patients, 73.7% were N0 and 26.3% N1, 39.7% were Prosigna risk-of-relapse (ROR)-low (RL), 33.0% ROR-intermediate (RI), 27.3% ROR-high (RH) and 48.3% received CT. CT independently improved EFS in N0/RI and N1/RL-RI (5-year EFS 97.9% vs. 86.6%; adjusted hazard ratio=0.07, p = 0.018). In premenopausal women, CT benefit persisted only when adjuvant gonadotropin-releasing hormone analogue was not administered (p = 0.008), especially in N0/RI (p = 0.023). Results were confirmed after PSM. CT-treated N0/RH showed similar EFS to CT-treated N0/RI+N1/RL-RI, while N1/RH showed poor prognosis despite CT use. 5-year EFS rates were generally consistent with OncotypeDX® trials. Prosigna can help identify young women with stage I-II ER+ /HER2- BC who gain benefit from (neo)adjuvant CT and those in need of further escalated treatments. In premenopausal N0/RI and N1/RL-RI disease, the effect of CT seems to be driven by ovarian function suppression. Prospective validation is required.

Aim: Clinico-pathological features have traditionally guided prognosis and adjuvant therapy for breast cancer (BC) patients. In the past decade, genomic tests such as Oncotype DX entered clinical practice to refine risk stratification and predict chemotherapy benefit for hormone-receptor positive (HR+)/human epidermal growth factor-receptor 2 negative (HER2–) BC patients after surgery. This is a retrospective analysis to investigate the correlation between histopathological parameters and recurrence score (RS), accounting for menopausal status. Methods: Data on HR+/HER2– early BC patients who underwent Oncotype DX were collected using an institutional database. Clinico-pathological characteristics were retrieved. Linear regression was used with RS as a continuous outcome, while logistic regression was performed for pre- and post-menopausal patients, dichotomizing RS at thresholds of 16 and 25, respectively. Results: A total of 180 women were included (35% pre-menopausal, 65% post-menopausal). Median age was 57.5 years. Most patients had pT1, pN0, G2 BC, with median estrogen receptor (ER) expression of 95% and a median Ki67 of 25%. Median RS was 16 [interquartile range (IQR) 12–22] in the overall cohort, 15 in pre-menopausal, and 17 in post-menopausal women. In the entire cohort, RS significantly correlated with G3 (P = 0.01), Ki67% (P < 0.0001), ER% (P = 0.03), and progesterone receptor (PgR)% (P < 0.0001). In pre-menopausal patients, only Ki67% (P = 0.02), ER% (P = 0.01), and PgR% (P < 0.0001) showed significant correlations, while in post-menopausal patients, G3 (P = 0.03), Ki67% (P = 0.001), and PgR% (P < 0.0001) achieved statistical significance. Logistic regression analysis showed that in pre-menopausal patients, PgR% predicted RS > 16 [odds ratio (OR) 0.95, P = 0.001]. In post-menopausal women, Ki67% (OR 1.08, P = 0.031) and PgR% (OR 0.95, P < 0.0001) predicted RS > 25. Conclusions: In this patient cohort, classical clinico-pathological features showed varying correlations with RS, depending on menopausal status. These findings highlight the complexity of risk stratification, suggesting that further research is needed to better understand the factors influencing RS and its clinical utility.