Association of clinicopathological and treatment variables with DFS and DRFS in ER+/HER2- ILC patients with cH/gL risk.

Transcriptomic differences between non-classic and classic ER+/HER2- ILC.

Elinzanetant, a dual neurokinin-1/-3 receptor antagonist, is approved for the treatment of moderate-to-severe vasomotor symptoms. The double-blind, randomized, placebo-controlled Phase III OASIS-1-4 studies evaluated elinzanetant's efficacy and safety in diverse populations of women, including those with vasomotor symptoms associated with natural or surgical menopause (OASIS-1, -2, and -3) and caused by endocrine therapy for breast cancer (OASIS-4). Results were similar across all trials for the respective primary and key secondary endpoints (included in the statistical testing hierarchy). Significant reductions vs. placebo in the frequency of vasomotor symptoms appeared from as early as week 1 in OASIS-1 and -2 (analyzed descriptively in OASIS-3 and -4), and at week 4 in OASIS-1, -2, and -4 (analyzed descriptively in OASIS-3). By week 12, all studies showed significant reductions vs. placebo, with benefits maintained for up to 50 weeks. In OASIS-1 and -2, the severity of vasomotor symptoms significantly decreased vs. placebo at weeks 4 and 12 (analyzed descriptively in OASIS-3 and -4). Elinzanetant treatment improved sleep disturbance, assessed by the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T-score, and menopause-related quality of life, measured as total score on the Menopause-specific Quality of Life questionnaire, across all four trials as early as week 1. Significant reductions vs. placebo were seen at week 12 in OASIS-1, -2, and -4 (key secondary endpoints; analyzed descriptively in OASIS-3 as a secondary endpoint). Elinzanetant was generally well tolerated with consistent efficacy across all OASIS trials in diverse populations of women experiencing vasomotor symptoms.

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.

Survival after metastatic breast cancer (MBC) has improved in high-income countries, yet international differences in outcomes and access to optimal care, particularly for recurrent disease remain unclear. We compared survival after recurrent MBC across four high-income countries, examining tumour subtype, treatment patterns and guideline adherence. Individual-level data were obtained from population-based cancer registries in Canada (British Columbia), Ireland, the Netherlands and the United States (Connecticut) for women who were diagnosed with stage I-III invasive breast cancer between 2005 and 2008 and developed distant metastatic recurrence between 2008 and 2010. Follow-up was from first recurrence until death, loss to follow-up or December 31, 2015. Kaplan-Meier methods were used to estimate overall survival, and age-standardised net survival (ASNS) at 1, 3 and 5 years after recurrence was estimated by registry and subtype. Among 2,735 women with recurrent MBC, treatment at initial diagnosis varied across registries. Median survival after recurrence ranged from 12 months in Ireland to 18 months in the United States (p=0.015). One-year ASNS ranged from 51.3% in Ireland to 63.6% in the United States and the Netherlands. Across countries, ASNS was highest for HR+/HER2− tumours and lowest for HR−/HER2− tumours. The Netherlands consistently showed the highest subtype-specific survival, while survival for HER2+ disease in Canada was closer to HR−/HER2− than HR+/HER2− disease. Differences narrowed over longer follow-up and in sensitivity analyses. Survival after recurrent MBC differed across these high-income countries. Improved harmonisation of recurrence data and timely implementation of evidence-based therapies may help reduce persistent international disparities.

Importance:Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective:To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review:This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings:Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug's approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance:Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens' related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.

Purpose:Cyclin-dependent kinase (CDK) 4/6 inhibitors have transformed the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, yet resistance remains common. Metabolic response assessed by fluorine 18-labeled deoxyglucose might identify patients at risk of treatment failure earlier than conventional imaging. We evaluated the safety, feasibility, and efficacy of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT)-guided stereotactic body radiation therapy(SBRT) combined with CDK4/6 inhibitors. Methods and Materials:This retrospective study included 29 patients monitored with 18F-FDG-PET/CT, who received SBRT concurrently with CDK4/6 inhibitors treatment or before CDK4/6 inhibitors commencement. Median age was 61 years (IQR, 53-68). Ten patients had de novo disease. The median disease-free interval for patients with recurrent disease was 66.9 months (IQR, 34.5-108.5). The majority of patients (72%) were treated in the first-line setting; 11 received ribociclib, 15 received palbociclib, and 3 received abemaciclib. Fifty-nine radiation treatments were delivered to 70 lesions: 41 before or concomitantly with the first CDK4/6 inhibitors cycle and 18 for oligoprogressive disease. Twenty-six treatments used single-fraction SBRT, and 33 used hypofractionated SBRT. Results:Post-SBRT maximum standardized uptake value (SUVmax) reduction was observed in all but one lesion. Metabolic complete response (mCR) occurred in 33 sites (56%), more frequently after single-fraction SBRT than hypofractionated SBRT (P = .03), in smaller lesions (<14 cm3, P = .002), and in lesions with lower SUVmax (<6.3, P = .008). Each unit increase in SUVmax reduced odds of mCR by ∼18% (odds ratio, 0.824; P = .04). Median progression-free survival was 48.2 months; 2-year progression-free survival was 71.5% (95% confidence interval [CI], 50.9-84.6). Conclusions:18F-FDG-PET/CT-guided SBRT, particularly single-fraction, added to CDK 4/6 inhibitors, is a valuable treatment modality resulting in substantial rates of mCR. Whether this translates into deferring disease progression requires randomized studies with larger treatment groups. To our knowledge, this study represents the first analysis evaluating 18F-FDG-PET/CT-guided SBRT in combination with CDK4/6 inhibitor-based therapy in patients with metastatic breast cancer.

BACKGROUND:The NATALEE and monarchE trials showed significant invasive disease-free survival benefits with the addition of a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to endocrine therapy (ET) in patients with hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer (EBC). This study evaluates outcomes in real-world patients prior to widespread availability of adjuvant CDK4/6is, depending on nodal status, including N0 disease with and without high-risk features. METHODS:Anonymized data from the Flatiron Health US electronic health record database (2011 to 2023) were analyzed. Adults with American Joint Committee on Cancer anatomic stage I-III HR+/HER2- EBC who underwent surgery and adjuvant ET were included. Overall and distant recurrence and all-cause mortality risks were assessed descriptively across nodal subgroups using Cox proportional hazards models. Recurrence-free survival, distant recurrence-free survival (DRFS), and overall survival were evaluated using Kaplan-Meier methods in the NATALEE- and monarchE-eligible populations. RESULTS:Among 7481 analyzed patients, 5387 (72.0%) had N0 disease, including 604 (11.2%) with high-risk features and 4783 (88.8%) without. Additionally, 1626 (21.7%) had N1 and 468 (6.3%) had N2-N3 disease. At a potential median follow-up of 78.0 months, the N0 high-risk subgroup showed overall and distant recurrence and mortality risks similar to those in the N1 subgroup. Overall, 2534 patients (33.9%) were NATALEE-eligible, and 1157 (15.5%) were monarchE-eligible. Both populations showed relatively high 5-year distant recurrence rates (DRFS, 83.1% and 74.6%, respectively). CONCLUSIONS:This contemporary real-world analysis highlights a meaningful recurrence risk in the broader HR+/HER2- EBC population, irrespective of nodal status, and emphasizes the need for effective treatment strategies.

PURPOSE:Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer after invasive breast cancer of no special type (IBC-NST). This retrospective analysis of the MINDACT trial investigated transcriptomic differences between estrogen receptor (ER)-positive/HER2-negative ILC and ER+/HER2- IBC-NST; classic and nonclassic ER+/HER2- ILC; and recurring and nonrecurring ER+/HER2- ILC in patients with a low genomic risk and either a low clinical/low genomic (cL/gL) or high clinical/low genomic (cH/gL) risk. EXPERIMENTAL DESIGN:We analyzed 4,262 ER+/HER2- tumors (63.7%; 464 ILC and 3,798 IBC-NST) with central pathology review. Differential gene expression analysis was adjusted for age and grade, followed by gene set enrichment analysis. Adjusted regression models evaluated associations of transcriptomic profiles with disease-free survival and distant recurrence-free survival. RESULTS:An increased expression of CDH1 (E-cadherin) in IBC-NST compared with ILC was observed. ILC showed more uptake of extracellular lipid sources (LPL, CD36, LEP, and LEPR), whereas IBC-NST favored lipid synthesis (FASN). Decreased ER signaling, increased PI3K/Akt signaling, and differences related to the extracellular matrix were also observed in ILC. Classic and nonclassic ILC differed subtly, notably in cell-cycle regulation. In patients with ER+/HER2- ILC with a cL/gL risk, enrichment of apoptosis, inflammatory response, hypoxia, and oncogenic signaling (PI3K/Akt, Ras, and c-Myc) were associated with worse survival. In contrast, in the cH/gL group, associations between ILC transcriptomic features and survival were more subtle. CONCLUSIONS:This represents the largest transcriptomic dataset for ILC from a clinical trial with central histology review. These findings may provide insights to refine treatment strategies and relapse risk assessment for patients with ILC.

Association of enrichment of molecular hallmarks with DRFS in ER+/HER2- ILC and IBC-NST patients with cH/gL risk.

512 Background: In the Phase III OASIS-4 trial, elinzanetant (EZN), a dual neurokinin (NK)-targeted therapy (NK-1 and NK-3 receptor antagonist), significantly improved vasomotor symptoms (VMS), sleep disturbance and menopause-related quality of life (QoL) in women taking endocrine therapy (ET) for breast cancer. This post hoc analysis evaluated the effect of EZN on sleep disturbance and menopause-related QoL by ET type. Methods: Women aged 18–70 years with ≥35 moderate-to-severe ET-associated VMS/week were randomized 2:1 to EZN 120 mg daily for 52 weeks or placebo (PBO) for 12 weeks then EZN 120 mg for 40 weeks. Mean change from baseline (BL) to week 12 in Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) 8b total T-score (range 28.9–76.5; < 55 normal, 55– < 60 mild, 60– < 70 moderate, ≥70 severe) and Menopause-specific QoL questionnaire (MENQOL) total/domain scores (range 1–8; higher score indicates greater bother) were analyzed descriptively by ET type (tamoxifen [TAM], aromatase inhibitor [AI], ovarian function suppression [OFS], no OFS). Results: Mean BL PROMIS SD SF 8b total T-scores and MENQOL total scores were numerically similar across ET subgroups (Table), with some variability in MENQOL domain scores (ranges: vasomotor 6.6–6.9; psychosocial 3.3–4.2; physical 4.1–4.6; sexual 3.7–5.5). Greater numerical reductions with EZN vs PBO from BL to week 12 were observed across all subgroups for PROMIS SD SF 8b total T-score and MENQOL total score (Table), as well as MENQOL domain scores (ranges: vasomotor -2.6 to -2.9 vs -1.2 to -1.5; psychosocial -0.8 to -1.0 vs -0.4 to -0.6; physical -0.7 to -0.9 vs -0.3; sexual -0.5 to -0.9 vs -0.3 to 0.0). Conclusions: In this post hoc analysis, EZN consistently improved sleep disturbance and menopause-related QoL, including vasomotor, psychosocial, physical and sexual aspects, across all ET subgroups. Taken with previous data, findings suggest to support the efficacy of EZN in reducing VMS, sleep disturbance and improving menopause-related QoL independently of ET type. TAM AI OFS No OFS EZN (n=175) PBO (n=90) EZN (n=141) PBO (n=68) EZN (n=88) PBO (n=48) EZN (n=228) PBO (n=110) PROMIS SD SF 8b total T-score, mean (95% CI) BL 61.0 (60.1, 61.9) 60.5 (59.0, 62.0) 60.1 (59.0, 61.2) 61.1 (59.5, 62.7) 60.4 (59.0, 61.7) 61.6 (59.5, 63.7) 60.7 (59.9, 61.5) 60.4 (59.1, 61.7) Change from BL to Week 12 -11.0 (-12.3, -9.7) -4.3 (-5.9, -2.6) -10.0 (-11.4, -8.7) -3.8 (-5.5, -2.0) -10.4 (-12.1, -8.7) -6.5 (-8.7, -4.2) -10.6 (-11.8, -9.5) -3.1 (-4.5, -1.7) MENQOL total score, mean (95% CI) BL 4.7 (4.5, 4.9) 4.5 (4.2, 4.7) 5.0 (4.8, 5.2) 5.2 (4.9, 5.5) 4.9 (4.6, 5.1) 4.9 (4.5, 5.3) 4.8 (4.7, 5.0) 4.7 (4.5, 5.0) Change from BL to Week 12 -1.4 (-1.6, -1,2) -0.5 (-0.7, -0.3) -1.2 (-1.4, -1.0) -0.6 (-1.0, -0.3) -1.2 (-1.5, -1.0) -0.6 (-1.0, -0.3) -1.3 (-1.5, -1.2) -0.5 (-0.7, -0.3)

We prospectively evaluated surgical outcomes following neoadjuvant pembrolizumab or placebo added to neoadjuvant chemotherapy among participants with early-stage triple-negative breast cancer (TNBC) in the phase 3 KEYNOTE-522 study (NCT03036488). Participants with previously untreated, early-stage TNBC (AJCC stage T1c N1–2 or T2–4 N0–2) were randomized 2:1 to neoadjuvant pembrolizumab/placebo plus paclitaxel-carboplatin for 4 cycles, followed by pembrolizumab/placebo plus doxorubicin/epirubicin and cyclophosphamide for 4 cycles. After definitive surgery, participants received adjuvant pembrolizumab/placebo Q3W for 9 cycles. Surgery type and timing, nodal status postsurgery, and adverse events within 30 days following surgery were recorded. Among 1,174 randomized participants (pembrolizumab plus chemotherapy, n = 784; placebo plus chemotherapy, n = 390), similar proportions underwent breast-conserving surgery (45.2 https://www.clinicaltrials.gov/study/NCT03036488

BACKGROUND:In patients with hormone receptor (HR)-positive early breast cancer (BC), the POSITIVE trial demonstrated that temporary interruption of adjuvant endocrine therapy (ET) for pregnancy is feasible and safe in early follow-up (median 41 months). In this article, we report updated results from a preplanned analysis with 2.5 years of additional follow-up. PATIENTS AND METHODS:POSITIVE, a single-arm prospective trial evaluating temporary interruption of adjuvant ET (after 18-30 months and for up to 2 years) to attempt pregnancy in young patients with BC, enrolled 518 eligible women (≤42 years of age, stage I-III BC, desiring pregnancy) from December 2014 to December 2019. Using the bootstrap-matching method, 5-year breast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) event rates were compared with those of the SOFT/TEXT trials as external controls. RESULTS:At a median follow-up of 71 months in the POSITIVE cohort and 80 months in the SOFT/TEXT cohort, the 5-year cumulative incidence of BCFI events was 12.3% in POSITIVE and 13.2% in SOFT/TEXT [-0.9% difference, 95% confidence interval (CI) -4.2% to 2.6%]. The 5-year cumulative incidence of DRFI events was 6.2% and 8.3%, respectively (-2.1% difference, 95% CI -4.5% to 0.4%). Among 497 women followed for nondisease outcomes, 377 (76%) had ≥1 documented pregnancy on trial, and 343 of 497 (69%) had ≥1 live birth, totaling 440 offspring. In an unadjusted analysis comparing the 180 women (36%) who had pre-enrollment embryo/oocyte cryopreservation with those who did not, the 5-year cumulative incidence of BCFI events was 14.0% (95% CI 9.6% to 20.2%) and 11.5% (95% CI 8.4% to 15.7%), respectively. CONCLUSION:Longer-term follow-up of the POSITIVE trial demonstrates that temporary interruption of ET for pregnancy, including use of fertility preservation, does not increase the risk of BC events. Continued follow-up is warranted given the known risk of late recurrence in this population.

What is this review about? During the menopausal transition , women may experience disruptive symptoms like hot flashes during the day or night (night sweats) and have trouble sleeping. Many current treatments for hot flashes do not work for everyone because of potential side effects, health concerns, or individual needs and preferences. Elinzanetant is a hormone-free treatment for hot flashes linked to menopause . It works by targeting the source of hot flashes in the brain. This summary covers the results from four randomized clinical trials that tested elinzanetant in women: OASIS-1, OASIS-2, OASIS-3, and OASIS-4. The OASIS trials looked at how well elinzanetant works for women with menopause symptoms. OASIS-1, OASIS-2, and OASIS-3 included women with hot flashes from natural or surgical menopause. OASIS-4 focused on women who had hot flashes because they were taking endocrine therapy after initial treatment for breast cancer. What were the results? The OASIS trials showed that elinzanetant rapidly reduces the number and severity of hot flashes experienced by women from natural or surgical menopause or due to endocrine therapy for breast cancer. Elinzanetant also improved their sleep and overall well-being. The side effects seen with elinzanetant were mainly mild and tolerable, the most common being headache, fatigue, and sleepiness. We use the term ‘women’ throughout for simplicity, but we recognize that menopause and its treatments may also be relevant to people who do not identify as women.

BACKGROUND:Scientific advancements have increased the use of biomarker testing for metastatic breast cancer (mBC) treatment decisions, adding complexity which may impact patient understanding. This study assesses patient recall and understanding of biomarker information and barriers to understanding diagnosis. MATERIALS AND METHODS:An online, multi-language, 15-question multiple choice survey was distributed to people with a self-reported diagnosis of mBC through the Advanced Breast Cancer (ABC) Global Alliance. Data collected included patient demographics, disease history, information seeking behaviour, and barriers to learning about their breast cancer subtype. RESULTS:Across 36 countries, 1064 respondents completed the survey. 81% recognised that their breast cancer subtype influences treatment decisions, though there was wide variation in patient recall of terminology used by their healthcare professionals (HCPs). Recall of the term 'biomarker' was low (8%). Geographical differences existed in patient recall of specific biomarkers used to describe mBC diagnosis; 'hormone receptor-positive (HR+)' recall was significantly higher for patients from North America (73%), compared with other regions (14%-56%). One-third (33%) of patients did not understand their breast cancer subtype and what it means. Only 44% of patients felt HCPs had given them sufficient information about their breast cancer subtype. A subset of patients (7%) reported not wanting to learn more, with the highest proportion from Latin America (17%). CONCLUSIONS:Findings demonstrate limited patient recall and understanding of breast cancer biomarkers and subtype, with significant variation based on geography. Results may be used to improve two-way communication and patient understanding regarding biomarker status, to facilitate shared decision-making.

Association of clinicopathological and treatment variables with DFS and DRFS in ER+/HER2- IBC-NST patients with cL/gL risk.

Introduction Cyclin-dependent kinase (CDK) 4/6 inhibitors have transformed treatment of hormone receptor–positive (HR+)/HER2-negative metastatic breast cancer, yet resistance remains common. Metabolic response assessed by fluorine-18-labeled deoxyglucose might identify patients at risk of treatment failure earlier than conventional imaging. We evaluated the safety, feasibility, and efficacy of 18F-FDG-PET/CT-guided stereotactic body radiotherapy (SBRT) combined with CDK4/6 inhibitors. Materials and Methods This retrospective study included twenty-nine patients monitored with 18F-FDG PET/CT, who received SBRT concurrently with CDK4/6 inhibitors treatment or before CDK4/6 inhibitors commencement. Median age was 61 years (IQR 53–68). Ten patients had de novo disease. The median disease-free interval for patients with recurrent disease was 66.9 months (IQR 34.5–108.5). The majority of patients (72%) were treated in the first-line setting; 11 received ribociclib, 15 palbociclib, and three abemaciclib. Fifty-nine radiation treatments were delivered to 70 lesions: 41 before or concomitantly with the 1st CDK4/6 inhibitors cycle and 18 for oligoprogressive disease. Twenty-six treatments used single-fraction SBRT (SF-SBRT) and 33 hypofractionated SBRT (HF-SBRT). Results Post-SBRT SUVmax reduction was observed in all but one lesion. Metabolic complete response (mCR) occurred in 33 sites (56%), more frequently after SF-SBRT than HF-SBRT (p=0.03), in smaller lesions (<14 cm3, p=0.002), and in lesions with lower SUVmax (<6.3, p=0.008). Each unit increase in SUVmax reduced odds of mCR by ∼18% (OR 0.824, p=0.04). Median progression-free survival (PFS) was 48.2 months; 2-year PFS was 71.5% (95% CI 50.9–84.6). Conclusions 18F-FDG-PET/CT-guided SBRT, particularly single-fraction, added to CDK 4/6 inhibitors, is a valuable treatment modality resulting in substantial rates of metabolic complete response. Whether this translates into deferring disease progression requires randomized studies with larger treatment groups. To our knowledge, this study represents the first analysis evaluating 18F-FDG-PET/CT-guided SBRT in combination with CDK4/6-inhibitor-based therapy in patients with metastatic breast cancer.

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.

507 Background: KEYNOTE-522 (NCT03036488) showed statistically significant and clinically meaningful improvements in pCR, EFS, and OS with the addition of pembrolizumab (pembro) to chemotherapy (chemo) in participants (pts) with high-risk early-stage TNBC. Here, we present updated results from the final analysis. Methods: Eligible pts with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to neoadjuvant pembro 200 mg Q3W or placebo (pbo), both given with 4 cycles of paclitaxel + carboplatin, then 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received adjuvant pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS (time from randomization to disease progression that precluded definitive surgery, local/distant recurrence, second primary cancer, or death from any cause); OS is the key secondary endpoint. Results: 1174 pts were randomized to pembro (n = 784) or pbo (n = 390). At the data cutoff date (October 14, 2025), median follow-up (range) was 93.8 mo (84.7-102.8). The 7-yr EFS rate (95% CI) was 78.3% (75.3-81.1) in the pembro group vs 69.8% (65.0-74.2) in the pbo group; the HR was 0.68 (95% CI, 0.54-0.86). The 7-yr OS rate (95% CI) was 85.1% (82.5-87.5) in the pembro group vs 77.2% (72.7-81.1) in the pbo group; the HR was 0.64 (95% CI, 0.49-0.85). The benefit of pembro on EFS and OS was generally consistent across most prespecified subgroups, including those defined by PD-L1 expression, nodal status, and disease stage. Rates of grade ≥3 treatment-related AEs were 77.1% in the pembro group and 73.3% in the pbo group (death incidence, 0.5% vs 0.3%, respectively); rates of any grade immune-mediated AEs were 35.0% vs 13.1%, respectively. Conclusions: After a median follow-up of 7.8 years, neoadjuvant pembro + chemo followed by adjuvant pembro continues to show a clinically meaningful survival benefit compared with neoadjuvant chemo alone in pts with high-risk early-stage TNBC. Clinical trial information: NCT03036488 .