Background Metastatic breast cancer (MBC) remains a treatable, but incurable disease. Anti-cancer treatments and supportive therapies aim to control disease, prolong survival, ameliorate physical symptoms and improve quality of life (QoL). Currently, no validated MBC-specific patient-reported outcome measures exist, and existing tools may lack specific content and sensitivity to measure the impact of MBC. This study aims to develop a European Organisation for Research and Treatment of Cancer (EORTC) module for MBC. Methods Development followed EORTC module guidelines. In phase 1, QoL issues were identified via systematic literature reviews and assessed by semi-structured interviews with healthcare professionals (HCPs) and patients. In phase 2, the most relevant and important issues were converted into questionnaire items using the EORTC Item Library to form the provisional module. Results The review included 103 papers (phase III clinical trials n=70 and observational or qualitative studies n=33), from which 185 issues were extracted, spanning physical, psychological, emotional and social domains. Interviews with 41 HCPs and 187 patients from eight countries refined this list to 44. After expert panel review, the provisional module consisted of 40 issues, assessed by 44 items (EORTC QLQ-MBR44). A sub-analysis of the EORTC QLQ-C30 revealed its content to be considered relevant to MBC by HCP and patients. Conclusion The provisional EORTC MBC-specific module aims to enhance understanding and measurement of QoL in clinical research and care and be the first QoL tool dedicated to MBC. The standardised tool contains relevant QoL issues and is currently undergoing qualitative and psychometric testing.
Background Extremely dense breast tissue is associated with increased breast cancer risk and reduced sensitivity of digital mammography (DM). This study evaluated the cost-effectiveness of abbreviated breast MRI (AB-MRI) and contrast-enhanced mammography (CEM) versus DM for screening women with extremely dense breasts. Methods This micro-simulation study applied the validated SimRisc Breast model. Screening strategies included biennial supplemental full-protocol MRI (FP-MRI), supplemental AB-MRI, supplemental CEM, AB-MRI alone and CEM alone, with biennial DM (ages 50-74) as reference. Costs and life-years gained (LYG) were discounted at 3%. Average cost-effectiveness ratios (ACERs) were calculated versus the reference, and incremental cost-effectiveness ratios (ICERs) for pairwise comparisons. A willingness-to-pay threshold of €20,000 per LYG was applied. Results Compared with the reference, all alternative screening strategies increased cancer detection and LYG, while reducing interval cancers and breast cancer deaths. CEM alone and supplemental CEM slightly increased in radiation-induced tumors. In cost-effectiveness analysis, supplemental AB-MRI and supplemental FP-MRI were not favorable (ACERs of €24,700–€34,400 per LYG), whereas CEM alone, AB-MRI alone, and supplemental CEM were cost-effective (ACERs €13,400–€19,600 per LYG). Incremental comparisons indicated that all supplemental strategies were dominated, with CEM alone optimal (ICER €13,400 per LYG vs. reference) and AB-MRI alone at €49,400 per LYG relative to CEM alone. Conclusion Both AB-MRI and CEM could reduce breast cancer mortality through earlier detection, with low additional risks and reasonable incremental costs. Among the modeled strategies, CEM was estimated to be the most cost-effective, although further prospective clinical studies are needed to confirm these findings.
Purpose Ductal carcinoma in situ (DCIS) is a non-invasive precursor to breast cancer, frequently oestrogen receptor (ER)-positive and detected through screening. Neoadjuvant endocrine therapy (NET), established in ER-positive invasive breast cancer, is being investigated in DCIS both as a short-term biological response model and as a potential component of emerging non-surgical or active-surveillance strategies. This review synthesises current clinical and biological evidence on NET in ER-positive DCIS and identifies knowledge gaps and future directions. Methods A systematic search (PubMed/MEDLINE, the Cochrane CENTRAL, Embase) was performed to identify prospective and retrospective studies evaluating NET in DCIS. Eligible studies included those assessing biological (Ki-67, PR expression) or radiological (lesion volume reduction) outcomes. Data were narratively synthesised due to study heterogeneity. Results Four early-phase trials demonstrated consistent biological responsiveness of ER-positive DCIS to NET, with suppression of Ki-67 and PR expression, and occasional histologic regression. Aromatase inhibitors produced measurable radiologic downsizing in selected cohorts, although the clinical significance of these changes in DCIS remains uncertain. Pathologic complete response was uncommon, and a small proportion of cases were found to have occult invasive disease at surgery, underscoring the need for careful patient selection and cautious interpretation of early NET studies. Furthermore, the validity of short-term surrogate endpoints, such as Ki-67 suppression and radiological volume reduction, remains unproven regarding long-term prevention of invasive transformation. Conclusion NET demonstrates consistent biological activity in ER-positive DCIS, supporting its use as a tool for tumour biology assessment rather than as a therapeutic alternative to surgery. Further prospective studies (COMET, LORETTA, RECAST, HORNEO01) are required to determine the safety, efficacy, appropriate patient population, and long-term outcomes of endocrine-inclusive personalised strategies. Given the exploratory nature and limitations of current data, these findings offer a conceptual framework that mandates robust, long-term prospective validation before any non-operative endocrine approach can be integrated into routine clinical practice.
Background In KEYNOTE-522 (NCT03036488), addition of perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved pathological complete response (pCR), event-free survival (EFS), and overall survival (OS) in early-stage triple-negative breast cancer (TNBC). pCR and EFS results in participants enrolled in Asia were consistent with those in the overall population. We report OS, updated EFS, and safety outcomes in participants enrolled in Asia. Methods Participants with newly diagnosed, high-risk, early-stage TNBC (T1c [N1‒N2] or T2‒T4 [N0‒N2] per AJCC 7th edition) were randomized 2:1 to 8 cycles of neoadjuvant pembrolizumab 200 mg Q3W or placebo plus chemotherapy. After definitive surgery, participants received adjuvant pembrolizumab 200 mg Q3W or placebo for ≤9 cycles. Primary endpoints were pCR (ypT0/Tis ypN0) and EFS. OS was a secondary endpoint. Results Of 1174 randomized participants, 216 were enrolled in Asia. At data cutoff (March 22, 2024), EFS events occurred in 18/136 participants (13.2%) in the pembrolizumab+chemotherapy group versus 22/80 (27.5%) in the placebo+chemotherapy group (HR, 0.43 [95% CI, 0.23‒0.81]); 60-month EFS rates (95% CIs) were 87.4% (80.6%‒92.0%) and 72.1% (60.7%‒80.6%), respectively. In the respective groups, 12/136 (8.8%) and 16/80 participants (20.0%) died (HR, 0.41 [95% CI, 0.19‒0.86]); 60-month OS rates (95% CIs) were 91.9% (85.8%‒95.4%) and 81.1% (70.5%‒88.1%). Treatment-related AEs led to treatment discontinuation in 19/136 participants (14.0%) with pembrolizumab+chemotherapy and 7/79 (8.9%) with placebo+chemotherapy. Conclusions OS and updated EFS outcomes in KEYNOTE-522 participants enrolled in Asia were consistent with those in the overall population and support use of perioperative pembrolizumab+neoadjuvant chemotherapy as a standard-of-care treatment in this setting.
Background HER2-low and HER2-ultralow expressions have recently emerged as actionable targets in breast cancer (BC). However, data remain limited regarding the consistency of immunohistochemistry (IHC) scoring when both categories are considered. This study aimed to evaluate interobserver variability in assessing HER2-negative BC, with particular focus on the reproducibility of HER2-low and -ultralow classifications. Methods A total of 389 consecutive HER2-negative BC cases were re-evaluated by six pathologists with varying experience (1-20 years). The panel included dedicated breast pathologists, general pathologists routinely covering breast services, and a surgical pathology fellow in training. HER2 expression was categorized as HER2-null (no staining), -ultralow, 1+, or 2+. Interobserver agreement was analyzed using Fleiss’ kappa statistics and intraclass correlation coefficients (ICCs). Results Three scoring schemes were compared: a 4-tier scheme (null, ultralow, 1+, 2+), a 3-tier scheme (combining 1+ and 2+), and a 2-tier scheme (combining ultralow and low). The overall Fleiss’ kappa values were 0.67, 0.68, and 0.77 for the 4-, 3-, and 2-tier schemes, respectively, indicating substantial agreement. Ten rater pairs demonstrated substantial agreement (0.61–0.80), and five showed moderate agreement (0.41–0.60), all involving one rater who consistently assigned lower scores. ICCs ranged from 0.75 to 0.90, reflecting good reliability. Unanimous agreement among all raters was achieved in 53.0%, 61.2%, and 85.7% of cases with the 3 tier schemes, respectively. Conclusion Despite the nuanced distinction between HER2-low and HER2-ultralow categories, IHC remains a reliable and reproducible method for evaluating HER2 expression in BC, even in the era of expanded HER2-targeted therapies, although reproducibility is lower for borderline HER2-ultralow cases.
INTRODUCTION:Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2-) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2- tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2- BC. METHODS:We accessed data from metastatic HER2- BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/-, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER-/-, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/-, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR-/-, n = 41). RESULTS:In line with previous reports, ER+/- BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/- BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/- or PR+/- status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/- BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. CONCLUSIONS:Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2- metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.
Background HER2 expression is described along a biological continuum from null to positive and serves as a critical biomarker for therapeutic guidance in breast cancer (BC). While HER2-low and ultra-low categories have emerged as actionable targets for antibody-drug conjugates (ADCs) in female BC, their molecular and immune characteristics remain largely unexplored in male breast cancer. Methods We profiled 214 male breast tumors using next-generation sequencing and whole-transcriptome sequencing to assess mutational, transcriptomic, and immune landscapes. Tumor mutational burden (TMB) was defined as high if > 10 mutations/Mb. Immune cell fractions were inferred using Quantiseq deconvolution. Results Among 214 samples, 66 (30.8%) were HER2-null, 53 (24.8%) HER2 ultra-low, 80 (37.4%) HER2-low, and 15 (7.0%) HER2-positive. HER2 ultra-low tumors exhibited a higher prevalence of PIK3CA mutations (39.2% vs 22.6%, p ≤ 0.05) compared to HER2-null. No significant differences were observed in TMB-high frequency or PD-L1 expression across subgroups. Immune composition differed primarily between HER2-null and HER2-expressing subgroups: HER2-ultra-low tumors showed higher B-cell infiltration, whereas HER2-null tumors were enriched in neutrophils. Transcriptomic analysis revealed upregulation of selected stemness-associated genes (NANOG, KLF4, POU5F1) and CEACAM1 in HER2-null tumors, while HER2-low and HER2-ultra-low tumors were largely similar across most molecular and immune readouts in this cohort. Conclusions HER2-null male breast cancer appears to represent the most biologically divergent subgroup within the HER2-negative spectrum, whereas HER2-low and HER2-ultra-low tumors were largely similar in this cohort. These findings support further investigation of HER2-null disease as a distinct biological state and provide hypothesis-generating data for biomarker development in this rare population.
Despite the initial clinical success of CDK4/6 inhibitors in combination with endocrine therapy, the development of resistance (intrinsic and acquired) remains a significant challenge in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2–) metastatic breast cancer (mBC). Emerging evidence highlights cell cycle reprogramming as a central mechanism of resistance, driven by alterations such as RB1 loss, cyclin E1 overexpression with CDK2 activation, and CDK4/6 upregulation, enabling bypass of CDK4/6 dependency. While additional pathways, including PI3K/AKT/mTOR and FGFR signaling, also contribute, their relative importance varies across tumor contexts. These findings have highlighted the need for next-generation therapeutic approaches aimed at overcoming resistance. Selective targeting of CDK2 and CDK4 represents a promising approach, particularly by inhibiting CDK2-mediated escape mechanisms and improving therapeutic index. Early-phase clinical trials have shown encouraging activity, although evidence remains limited. Beyond cell cycle kinases, epigenetic regulators such as lysine acetyltransferases (KATs) have emerged as novel therapeutic targets, with the potential to restore endocrine sensitivity and modulate oncogenic transcriptional programs. In parallel, AURKA inhibitors are being explored to target cell cycle reprogramming associated with resistance. This review focuses on cell cycle–centric mechanisms of resistance to CDK4/6 inhibitors, with particular emphasis on CDK2/CDK4-directed strategies and emerging epigenetic approaches such as KAT inhibition.
BACKGROUND:Adjuvant chemotherapy for hormone receptor-positive (HR+) breast cancer relies on taxanes, but existing tests do not identify which patients benefit from them. The SETER/PR index, a measure of endocrine-related transcriptional activity in HR + tumors, recently predicted benefit from paclitaxel when low (<0.75), but not for anthracycline-based therapy. We tested whether SETER/PR could predict benefit from docetaxel in node-positive, HR + patients enrolled in the PACS-01 trial (docetaxel after fluorouracil-epirubicin-cyclophosphamide (3FEC+3D) versus 6FEC). PATIENTS AND METHODS:SETER/PR index and Recurrence Score (RS) were obtained for 490 patients. SETER/PR was quantified using the QuantiGene Plex assay from RNA remaining after RS testing. Pre-specified analyses assessed SETER/PR as a continuous variable and using the predefined <0.75 cut point, as well as continuous RS and the >25 cut point. The primary endpoint was distant recurrence-free interval (DRFI). Predictive value was assessed using Cox models including biomarker, treatment arm, and interaction term. RESULTS:Continuous SETER/PR demonstrated significant interaction with treatment on DRFI (Pinteraction = 0.028), whereas predefined <0.75 cut point was not predictive (Pinteraction = 0.668). Exploratory analyses identified a cut point at 1.50 (Pinteraction = 0.013): patients with SETER/PR ≥ 1.50 had worse outcomes with 3FEC+3D versus 6FEC (HR 3.16, 95%CI 1.28-7.85), while outcomes were similar between arms when SETER/PR < 1.50 (HR 0.83, 95%CI 0.51-1.35). RS did not predict differential benefit, either continuously (Pinteraction = 0.670) or at the >25 threshold (Pinteraction = 0.534). CONCLUSION:Including sequential docetaxel (3FEC+3D) was less effective than continued anthracycline chemotherapy (6FEC) when breast cancer had high endocrine-related transcriptional activity (i.e., SETER/PR index ≥1.50). TRIAL REGISTRATION:PACS-01.
Objectives To evaluate nationwide trends in administration of (partial) breast radiation therapy (RT) following breast-conserving surgery (BCS) in women with early-stage, ER + breast cancer (BC). Methods Women aged ≥50 years with ER+, HER2-, non-metastatic BC, treated between 2014 and 2024 with BCS were included. Eligible tumours were ≤1 cm grade 1 or 2, or ≤2 cm grade 1. Descriptive statistics and multivariable logistic regression were performed. Results In total 21,418 patients were included. Endocrine therapy was administered in 3.5%.Age related differences in RT administration were observed. In younger patients (50-69 years), RT omission increased from 1.8% (2014-2016) to 8.7% (2023-2024, p < 0.001). Among older patients (≥70 years), omission increased from 4.6% (2014-2016) to 55.3% (2020-2022) and 33.8% (2023-2024, p < 0.001).RT type was comparable across age groups. Whole breast RT (WBRT) without boost was most common (>65%), followed by partial breast irradiation (PBI) (>21%). Over time, application of WBRT without boost decreased from 81.2% (2014-2016) to 46.5% (2023-2024, p < 0.001), while PBI increased from 4.3% (2014-2016) to 51.9% (2023-2024, p < 0.001). Age (OR 10.1) and year of diagnosis were strongly associated with RT omission. Conclusion Younger patients received RT more often than older patients. Over time, WBRT remained the most common RT type, although its use decreased over time, while PBI increased. Omission of RT became more frequent, most markedly in older patients, partially driven by participation in a national trial on RT omission (TOP-1 study). Ultimately, RT was omitted in about one third of older patients, indicating an ongoing shift towards treatment de-escalation, individualized medicine or premature trial implementation.
BACKGROUND:The Clinical Treatment Score post-5 years (CTS5), a prognostic tool for late distant recurrence, was validated in postmenopausal patients, but its value in premenopausal women remains unclear. Using 8-year ASTRRA data, we evaluated the prognostic performance of CTS5 in premenopausal breast cancer patients. METHODS:Patients without any event within the first 5 years were included in this analysis and were categorized into three risk groups based on CTS5 cutoff values. Late distant metastasis-free survival (DMFS) and overall survival were analyzed. Subgroup analyses were conducted to compare outcomes between the tamoxifen (TAM)-only and TAM + ovarian function suppression (OFS) groups. RESULTS:Of the 1028 included premenopausal patients, late distant metastasis rates were 3.43% (low-risk, n = 466), 2.56% (intermediate-risk, n = 312), and 9.63% (high-risk, n = 270). The high-risk group showed a significantly higher risk of late DMFS compared to the low-risk group (HR = 3.32; 95% CI: 1.73-6.37; p < 0.001). The intermediate-risk group showed no significant difference (HR = 1.06; p = 0.876). When combining the low/intermediate-risk groups, the high-risk group maintained a significantly elevated risk (HR = 3.16; p = 0.015). OS results were consistent. Subgroup analysis confirmed that CTS5's prognostic ability was maintained in both the TAM-only (HR = 3.23; 0 = 0.004) and TAM + OFS groups (HR = 3.49; p = 0.029), consistently identifying high-risk patients. CONCLUSION:In this randomized trial, unmodified CTS5 identifies high-risk patients but exhibits threshold inversions, making it unreliable for premenopausal extended therapy.
Background Trastuzumab deruxtecan (T-DXd) is a key treatment for HER2-positive metastatic breast cancer (mBC); however, data on T-DXd rechallenge remain limited. Patients and methods This post-hoc subgroup analysis evaluated T-DXd rechallenge in patients with HER2-positive mBC using data from EN-SEMBLE, a nationwide cohort study in Japan (N = 664). Results Twenty-six patients were included. Median real-world progression-free survival, real-world time to treatment failure, and overall survival were 6.5, 4.9, and 14.2 months, respectively. The objective response rate was 27%. Patients who discontinued initial T-DXd without progressive disease had numerically longer real-world progression-free survival. No interstitial lung disease occurred during rechallenge. Conclusion T-DXd rechallenge may have clinical activity in selected patients with HER2-positive mBC. Clinical trial registration number jRCT1030220506.
PURPOSE:Second breast conserving treatment (2ndBCT) has emerged as an option for patients with low-risk second ipsilateral breast cancer event (2ndiBCE) after prior breast BCT combining lumpectomy and irradiation. However, HER2-positive (HER2+) and triple-negative (TN) subtypes are considered poor candidates for 2ndBCT. We evaluated oncologic outcomes after 2ndBCT versus mastectomy in high-risk 2ndiBCE. METHODS AND MATERIALS:We performed a propensity score-matched cohort study of patients diagnosed with 2ndiBCE between 1995 and 2017. Data were collected from 15 centers across seven European countries. Patients underwent mastectomy or lumpectomy plus Multicatheter-interstitial brachytherapy (MIB). One-to-one matching used ten clinicopathologic variables. The primary endpoint was 5-year overall survival (OS). Secondary endpoints included 5-year cumulative incidence of third breast events, regional relapse, distant metastasis, disease-free survival (DFS) and cause-specific survival (CSS). RESULTS:Among 1327 patients (Mastectomy 945; 2ndBCT 382), 241 were matched (Mastectomy versus 2ndBCT): HER2+ 70/62 and TN 55/54. Median tumour size (mm) for mastectomy versus 2ndBCT was 17/13 in HER2+ and 13/12 in TN. Median follow-up was 79.9 and 80.5 months for HER2+ and TN, respectively, without group differences. No statistical differences in 5-year OS were observed between mastectomy and 2ndBCT (HER2+: 85% vs 79%, p = 0.85; TN: 89% vs 81%, p = 0.4). Similarly, the secondary endpoints were also comparable between groups. CONCLUSION:This first matched comparison of mastectomy and 2ndBCT with MIB in patients with HER2+ and TN tumours did not identify clear differences in efficacy. Given the limited sample size, 2ndBCT may warrant consideration in selected patients seeking breast preservation.
BACKGROUND:Prediction models can guide breast cancer treatment decisions by estimating individualized prognosis and treatment benefit. Since older women with breast cancer are more heterogeneous and face more competing non-breast cancer mortality, model performance may differ from that observed in the general breast cancer population. We externally validated PREDICT version 3.1 in a population-based cohort of Dutch older women with breast cancer. METHODS:Women aged ≥70 years with breast cancer were included from the Dutch Cancer Registry. Observed 5- and 10-year overall survival (OS) were estimated using Kaplan-Meier methods and compared with predicted outcomes. Calibration was assessed using smooth calibration curves and observed/expected (O/E) ratios. Discrimination was evaluated with area under the curve (AUC). Performance was examined across age groups and comorbidity strata. RESULTS:We included 11.041 women (median age 75.8 years, IQR 72.8-81.6). PREDICT v3.1 overestimated 5-year OS by 7.2% (95% CI = 6.3-8.0) and 10-year OS by 12.1% (95% CI = 11.1-13.1). Calibration plots showed deviation from the ideal line and the O/E ratio was 1.39 (95% CI = 1.34-1.44) for 5-year and 1.30 (95% CI = 1.27-1.34) for 10-year. The AUC for 5- and 10-year OS was 0.75 (95% CI = 0.74-0.76) and 0.76 (95% CI = 0.75-0.77), respectively. Overestimation of survival increased with age and number of comorbidities. CONCLUSION:PREDICT v3.1 overestimates survival in older women, particularly those with comorbidities and increased age. Despite moderate discrimination, poor calibration limits clinical applicability in this population.
BACKGROUND:Brain metastases (BM) cause substantial morbidity and reduced survival in metastatic breast cancer (MBC). Therapeutic advances may have altered BM incidence and outcomes across subtypes. Real-world data are crucial to assess these trends and guide BM-specific clinical trials. Here, we report BM data from the Austrian Study Group for Medical Tumor Therapy MBC registry. METHODS:Patients with known hormone receptor (HR) and HER2 status and sufficient outcome data were included. Logistic regression was used to assess the risk of BM. Overall survival (OS) was estimated using Kaplan-Meier methods and compared by log-rank tests. Multivariable Cox models with BM as a time-dependent variable and competing-risk analyses were applied. RESULTS:Among 2775 patients, 477 (17.2%) developed BM during the metastatic course; 56 patients (2.0%) had brain-only disease at first metastatic diagnosis. Compared with luminal MBC, BM risk was higher in HR-/HER2+ (OR 3.57), HR+/HER2+ (OR 4.43), and triple-negative breast cancer (TNBC; OR 2.91). At a median follow-up of 77 months, BM were associated with significantly shorter OS (HR 4.23; p < 0.001). TNBC showed the shortest BM-free survival (7.1 months) and poorest OS after BM diagnosis (4.7 months). Brain-only disease was associated with improved OS compared to concurrent extracranial disease (HR 0.58; p = 0.001). Use of whole brain radiotherapy declined over time, while neurosurgery or focal radiotherapy were associated with longer OS. Receptor discordance included HR loss (14.5%) and HER2 gain (9.8%). CONCLUSION:BM remain frequent and prognostically relevant in MBC, underscoring the need for improved risk stratification and subtype-specific therapies.
Visani et al. [1]. Provide the largest real-world evidence that concomitant trastuzumab deruxtecan (T-DXd) and radiotherapy (RT) does not significantly increase acute severe adverse events (AEs) in metastatic breast cancer. Yet “concomitant” is not a biological concept: radiosensitisation depends on RT intent, anatomical site, fractionation and tumour biology, not merely a temporal window. This Viewpoint argues that the field must move beyond binary safety questions to stratified decision-making, distinguishes the distinct radionecrosis risk profiles of T-DM1 and T-DXd payloads, expand the decision framework to conventional and moderately hypofractionated radiotherapy beyond stereotactic techniques, and identify three high-priority research gaps: thoracic irradiation, HER2-low metastatic breast cancer, and cardiac vulnerability during combined therapy.
PURPOSE:Treatment of breast cancer in female patients has evolved over the past 20 years to improve outcomes, however it is unclear to what extent treatment has evolved in male patients. This bi-national registry observational study examined the disease burden and treatment landscape for new diagnoses of male breast cancer undergoing surgical management in Australia and New Zealand in comparison to females. METHODS:A twenty-year study of male breast cancer patients compared to females was conducted for the period of 2003-2022 using the Breast Surgeons of Australia and New Zealand Quality Audit (BQA) database. Demographic, histological and treatment data was analysed according to biological sex and decade of breast cancer diagnosis (2003-2012 versus 2013-2022). RESULTS:Data from 258,246 patients (1542 males, 256,704 females) were analysed. Treatment of male breast cancer was largely unchanged in the later decade compared to the earlier decade apart from sentinel lymph node biopsy uptake which was significantly higher in the later decade (66% vs 47%, p < 0.001). In contrast, significant differences in both surgical and adjuvant therapies were noted in the female group for every domain except post-mastectomy radiotherapy. Females treated early in the study period were associated with higher rates of adjuvant chemotherapy use than those treated in the later decade (OR 1.10, 95%CI 1.10; 1.11, p < 0.001), while adjuvant chemotherapy use was stable over time in the male group. CONCLUSIONS:In Australia and New Zealand there has been a de-escalation in axillary surgery for male breast cancer during the multimodality era. This evolution has been modest compared to the extensive changes in therapy for female breast cancer in line with formalised treatment guidelines.
