BACKGROUND:The 70-gene signature (70-GS) has been shown to identify women at low-risk of distant recurrence who can safely forgo adjuvant chemotherapy. Incorporating this GS into the well-validated and widely used PREDICT breast cancer model could improve the model's ability to estimate breast cancer prognosis, and thereby further reduce overtreatment and its long-term impact on patients' quality of life. We incorporated the 70-GS into PREDICT-v2.3 and assessed the new PREDICT-GS model's ability to predict 5-year risk of breast cancer death. METHODS:Data from the MINDACT trial (N = 5920) was used to estimate the 70-GS's prognostic effect (coefficient = 0.70), which was then incorporated into PREDICT-v2.3. Netherlands Cancer Registry (NCR) data (N = 3323) was used to assess PREDICT-GS's discrimination (area under curve (AUC)), calibration and clinical utility. RESULTS:Compared to PREDICT-v2.3 (AUC: 0.71 (95 % CI: 0.63-0.79)), PREDICT-GS (AUC: 0.76 (95 % CI: 0.69-0.83)) had better discrimination. Both models tended to overestimate the 5-year risk of breast cancer death in the NCR cohort, but the absolute overestimation was smaller for PREDICT-GS. Regarding clinical utility, only at the 10 % decision threshold did we find modest improvement: four extra patients per 1000 tests were correctly classified as not needing chemotherapy by PREDICT-GS compared to PREDICT-v2.3. CONCLUSION:Extending PREDICT-v2.3 with 70-GS led to modest improvement in its ability to predict 5-year risk of breast cancer death. Future research should focus on assessing the added value of the 70-GS for longer-term prediction of recurrence and death with the incorporation of quality of life in risk prediction tools.

564 Background: Pregnancy-Associated Breast Cancer (PABC), which includes breast cancer diagnosed during pregnancy (PrBC) or postpartum (PPBC), is often more aggressive and diagnosed at more advanced stage compared to breast cancer in non-pregnant young women. The aggressive tumor growth in PABC may be influenced by the maternal shift towards immunotolerance during pregnancy, aimed at safely harboring the semi-allogenic fetus. Potentially, this shift allows cancer cells to evade immune detection. In recent years, the importance of stromal tumor-infiltrating lymphocytes (sTILs) as a marker of the anti-cancer immune response has become evident. Given the aforementioned relevance of immunotolerance in PABC development, we have evaluated the presence and prognostic importance of sTILs in PrBC and PPBC patients in this most extensive study to date. Methods: We assessed tumor tissues from the Dutch Pregnancy-Associated Breast Cancer Cohort, which includes PrBC and PPBC (≤1 year postpartum) patients diagnosed between 1988 and 2022. Whole slide images (H&E) of tumors from 200 patients were uniformly reviewed, and sTILs were scored according to international guidelines. Given the lack of previous sTIL cutoffs for PABC, a data-driven approach was chosen. Results: Our initial analysis revealed a clear survival benefit for a sTIL score of at least 20%. Therefore, our PrBC/PPBC patient group was divided into a “Low sTILs” ( < 20%, n = 153) and a “High sTILs” (≥20%, n = 47) group. High sTIL scores were associated with a higher histologic grade (89% grade III versus 73% in the low sTIL group, p = 0.043) and more frequent triple negativity (68% versus 43%, p = 0.021) Despite this more aggressive histopathology, higher sTILs were associated with a significantly better 5-year overall survival (OS) probability (94% versus 69%, p < 0.001). In a multivariable analysis, correcting for disease stage, intrinsic subtype and tumor grade, high sTIL scores remained a strong prognostic indicator in PABC (HR 7.3, 95% CI 2.24 – 23.9). In a subgroup analysis for triple negative disease only (n = 93), patients with a high sTIL score (n = 30) showed a better 5-year OS probability (93% versus 60%, p = 0.002), which also persisted in a multivariable analysis (HR 4.7, 95% CI 1.4 – 15.7). Conclusions: Despite the immunotolerance in pregnancy, this study demonstrates the presence and prognostic importance of sTILs in PABC. Importantly, patients with high sTILs (≥20%) had a markedly better prognosis despite having more aggressive disease characteristics, regardless of subtype. Therefore, sTILs may be an important prognostic indicator and may aid in selecting patients to forgo adjuvant systemic therapy, especially during pregnancy.

BACKGROUND:Leptomeningeal metastases (LM) in patients with breast cancer (BC) are associated with a dismal prognosis. We explored clinical characteristics and prognostic factors in patients with BC and LM in the German Brain Metastases in Breast Cancer Registry. METHODS:All patients with histologically confirmed BC and diagnosis of LM (defined as the presence of tumor cells in the cerebrospinal fluid, or presence of typical clinical symptoms in combination with typical magnetic resonance imaging findings) were included. RESULTS:A total of 3857 patients were included in the analysis (n = 859 (22.3 %) with LM). Among patients with LM a median progression-free survival was 4.2 months (95 % CI 3.6-4.8), and median overall survival was 5.7 months (95 % CI 4.9-6.7). In the multivariate analysis older age ( ≥ 60 vs. <60 years, Hazard ratio (HR): 1.65, 95 %CI: 1.25-2.18), worse performance status (ECOG 2-4 vs. 0-1 HR: 2.15, 95 %CI: 1.63-2.82), hormone receptor positive/HER2-negative (HR+/HER2-) or triple-negative subtype (HR: 1.54 95CI%: 1.07-2.23 and HR: 1.87, 95 %CI: 1.25-2.81), and higher number of BM (2-3 vs. 1, HR: 1.49, 95 %CI: 1.05-2.11 4) were significantly associated with a higher risk of death. Stereotactic radiotherapy (HR 0.49 95 %CI 0.30-0.79) and whole brain irradiation (HR: 0.58, 95 %CI: 0.42-0.80), endocrine therapy in patients with HR + BC (HR: 0.31, 95 %CI: 0.21-0.45) as well as HER2-targeted therapy for patients with HER2+ BC (HR 0.41, 95 %CI: 0.25-0.68) were associated with a significantly longer survival. CONCLUSIONS:Clinicopathological factors associated with survival can help clinicians identify patients who are candidates for treatment (de)escalation in clinical trials.

AIMS:In breast cancer (BC) pathology reports, small differences around cut-off values can impact staging and consequently, clinical decision-making. Several pathology variables are not very exact, leaving room for interpretation by the pathologist. Therefore, the aim of this study was to investigate pathologists' decision-making around clinically relevant cut-off values. METHODS:We performed a retrospective, population-based analysis of primary invasive BC specimens using real-world data from the Dutch National Pathology Registry. Data collection included tumour diameter and oestrogen receptor (ER)/progesterone receptor (PgR) status from patients diagnosed between 2014 and 2022. RESULTS:Overall, 64,099 BCs were analysed for tumour diameter. For larger tumours (>2 cm), rounding was observed to the nearest half or whole centimetre. For smaller tumours, rounding occurred only to half centimetres, while there was an avoidance of the 1.0 and 2.0 cm thresholds. For ER/PgR assessment, 74,502 BCs were analysed. In cases with low ER expression, rounding was observed at multiples of 5%. However, around the clinically relevant cut-off value of 10% in the Netherlands, pathologists tend to semiquantify the percentage of ER and/or PgR expression by also using 9% and 11%, with a trend to classify a case as just positive (10% or 11%). CONCLUSION:Pathologists take clinical cut-off values into account in their decision-making process. For tumour size, they tend to avoid the 1.0 and 2.0 cm thresholds. For ER/PgR, they tend to categorize the tumour as positive around the threshold. Further research is needed to determine the implication of this for treatment decisions.

541 Background: Systemic treatment decisions for young BRCA carriers with small node-negative breast cancers present unique challenges due to limited evidence on the benefits of chemotherapy in this setting. This study evaluated chemotherapy use and survival outcomes among these patients. Methods: The BRCA BCY collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included carriers of germline pathogenic variants in BRCA1/2 diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. Among patients diagnosed with T1N0 disease, survival outcomes - disease-free survival (DFS) and overall survival (OS) defined from breast cancer diagnosis - were compared between patients who received chemotherapy and those who did not, using multivariate Cox models adjusted for propensity score (including age at diagnosis, histology, grade, country and year of diagnosis) and risk-reducing surgeries (bilateral risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO)), and accounting for the delayed entry at the time of BRCA testing (i.e. left truncation). Subgroup analyses were performed according to tumor subtype (HR+/HER2- vs triple negative breast cancer (TNBC)). Results: Out of 5660 from 109 centers, 1280 patients had T1N0 breast cancer: T1mic (n = 14, 1.1%), T1a (n = 92, 7.2%), T1b (n = 303, 23.7%), T1c (n = 778, 60.8%), and T1 size unknown (n = 93, 7.3%). Most patients received chemotherapy (80%), although use was less frequent over time. Among patients who received chemotherapy, the majority were treated with an anthracycline-containing regimen (83.6%) and in the adjuvant setting (85.7%). Patients who received chemotherapy were younger and more likely to have high grade, TNBC or larger tumors compared to those who did not. The median follow-up was 8.7 years (IQR 5.0-13.4 years), during which 428 had DFS events including second primary breast cancer (n = 174), locoregional (n = 130), distant relapse (n = 65), second primary non breast cancer (n = 53), and 88 had died. Overall, 8-year DFS was 69.4%. In multivariate analysis, no significant differences in DFS or OS were observed between patients who received chemotherapy and those who did not (DFS HR = 0.92, 95% CI 0.65-1.31; OS HR = 0.68, 95% CI 0.37-1.24). No significant difference in 8-year DFS was observed between patients with HR+/HER2- breast cancer (n = 474) treated with or without chemotherapy (HR 0.91: 95% CI 0.59-1.43), or between patients with TNBC (n = 637) treated with or without chemotherapy (HR 0.84: 95% CI 0.46-1.53). Conclusions: In this global study of young BRCA carriers with T1N0 breast cancer, chemotherapy was not associated with better DFS or OS overall. However, these patients remain at high risk of events and warrant investigation of additional risk-reduction strategies.

BACKGROUND:Routine brain imaging screening (BIS) in patients with metastatic breast cancer (BC) without neurological symptoms is currently not recommended, as no survival/quality-of-life improvements have been demonstrated. We aimed to examine physicians and patients' attitudes and perceptions toward BIS. METHODS:International cross-sectional online survey for patients and physicians, distributed from May 2023 to February 2024. Patients with BC diagnosis were deemed eligible for patients' survey completion and BC-treating physicians were invited to fill the physicians' questionnaire. RESULTS:A total of 529 physicians from 50 countries (80 % European) responded, mostly medical oncologists (70 %) working in academic hospitals (53 %). Most physicians request BIS (65 %), mainly when extracranial progression occurs, especially for HER2+ and triple negative BC (TNBC). Among physicians never performing BIS (35 %), 91 % would in case of proved clinical benefit. A total of 545 patients from 14 European countries completed the questionnaire. Median age was 50 years, 86 % had metastatic BC, 51 % hormone receptor-positive (HR+)/HER2-negative, 30 % HER2-positive (HER2+) and 19 % TNBC. BM were diagnosed in 11.5 % patients with metastatic BC. 85 % patients would like to undergo BIS, especially younger ones (p = 0.02) and with HR-disease (p = 0.03), despite the uncertain clinical benefit. Notably, 91 % of patients would like to receive information regarding BM, while only 13 % of physicians routinely address the issue. CONCLUSIONS:These results underline the willingness of patients to know more about the prospects of BM development, in contrast to the lack of routine discussion of this topic by physicians. Further investigation is warranted to demonstrate the clinical utility of routine BIS.

Background. Clinical prediction models provide tailored risk estimates that can help guide decisions in breast cancer care. Despite their potential, few models are widely used in clinical practice. We aimed to identify the factors influencing breast cancer clinicians’ decisions to adopt prediction models and assess their relative importance. Methods. We conducted a mixed-methods study, beginning with semi-structured interviews, followed by a nationwide online survey. Thematic analysis was used to qualitatively summarize the interviews and identify key factors. For the survey, we used descriptive analysis to characterize the sample and Mann–Whitney U and Kruskal–Wallis tests to explore differences in score (0 = not important to 10 = very important ) distributions. Results. Interviews ( N = 16) identified eight key factors influencing model use. Practical/methodological factors included accessibility, cost, understandability, objective accuracy, actionability, and clinical relevance. Perceptual factors included acceptability, subjective accuracy, and risk communication. In the survey ( N = 146; 137 model users), clinicians ranked online accessibility (median score = 9 [interquartile range = 8–10]) as most important. Cost was also highly rated, with preferences for freely available models (9 [8–10]) and those with reimbursable tests (8 [8–10]). Formal regulatory approval (7 [5–8]) and direct integration with electronic health records (6 [3–8]) were considered less critical. Subgroup analysis revealed differences in score distributions; for example, clinicians from general hospitals prioritized inclusion of new biomarkers more than those in academic settings. Conclusions. Breast cancer clinicians’ decisions to initiate use of prediction models are influenced by practical and perceptual factors, extending beyond technical metrics such as discrimination and calibration. Addressing these factors more holistically through collaborative efforts between model developers, clinicians, and communication and implementation experts, for instance, by developing clinician-friendly online tools that prioritize usability and local adaptability, could increase model uptake. Highlights Accessibility, cost, and practical considerations, such as ease of use and clinical utility, were prioritized slightly more than technical validation metrics, such as discrimination and calibration, when deciding to start using a clinical prediction model. Most breast cancer clinicians valued models with clear inputs (e.g., variable definitions, cutoffs) and outputs; few were interested in the exact model specifications. Perceptual or subjective factors, including perceived accuracy and peer acceptability, also influenced model adoption but were secondary to practical considerations. Sociodemographic variables, such as clinical specialization and hospital setting, influenced the importance of factors for model use.

507 Background: In young women with hormone receptor-positive (HR+) breast cancer (BC), ovarian function suppression (OFS) has been shown to improve outcomes when combined with adjuvant endocrine therapy (ET). However, limited evidence exists on its efficacy in germline BRCA (gBRCA) carriers. Here we investigated the association between OFS plus ET and outcomes in the largest global cohort of young g BRCA carriers with BC. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study of women harboring germline BRCA1/2 pathogenic/likely pathogenic variants, diagnosed between 2000 and 2020 with stage I-III invasive BC at age of ≤ 40 years. The analysis included patients with HR+ BC and available data on ET and OFS. The OFS group included patients treated with luteinizing hormone-releasing hormone agonists (LHRHa) and/or bilateral risk-reducing salpingo-oophorectomy (RRSO) within 1 year of BC diagnosis. Outcome analyses included disease-free survival (DFS), BC-free interval (BCFI) and overall survival (OS). Cox proportional hazard models, stratified for country, year of diagnosis, nodal status, and surgery type and adjusted for RRSO and bilateral risk-reducing mastectomy (time-dependent), were used to explore the association between OFS use (vs non-use) and outcomes. Sensitivity analysis explored OFS as time-dependent covariate. To address immortal time bias, an additional Cox model accounted for left truncation, considering differences in time to BRCA testing. Results: Among 5,660 patients from 109 centers, 1,865 patients with HR+ BC were included, of whom 1,071 (57%) received OFS plus ET ( 35% with an aromatase inhibitor [AI], 65% with tamoxifen [tam])and 794 (43%) received tam alone. Patients receiving OFS were more likely to have node-positive disease (56% vs 47%), receive treatment in recent years (36% vs 17%), undergo mastectomy (70% vs 57%) and be tested for g BRCA at diagnosis (46% vs 30%). With a median follow-up of 7.8 years (IQR 4.6-12.1), OFS combined with ET was associated with significantly improved DFS (adjusted HR [aHR] 0.79, 95% CI 0.66-0.94), BCFI (aHR 0.74, 95% CI 0.61-0.89) and OS (aHR 0.66, 95% CI 0.50-0.88) over tam alone. Sensitivity analysis using OFS as a time-dependent factor yielded consistent results. No significant interactions were observed between OFS use and specific g BRCA mutations or HER2 status. Sub-analyses by type of ET (OFS + AI vs. OFS + tam vs. tam alone) will be presented at the conference. Conclusions: In this global cohort of young BRCA mutation carriers, OFS combined with ET was associated with improved DFS, BCFI and OS versus tam without OFS. These findings support the consideration of OFS as a key component of adjuvant therapy in this population.

The level of tumour-infiltrating lymphocytes (TILs) is a prognostic factor for patients with (triple-negative) breast cancer (BC). Computational TIL assessment (CTA) has the potential to assist pathologists in this labour-intensive task, but current CTA models rely heavily on many detailed annotations. We propose and validate a fundamentally simpler deep learning based CTA that can be trained in only ten minutes on hundredfold fewer pathologist annotations. We collected whole slide images (WSIs) with TILs scores and clinical data of 2,340 patients with BC from six cohorts including three randomised clinical trials. Morphological features were extracted from whole slide images (WSIs) using a pathology foundation model. Our label-efficient Computational stromal TIL assessment model (ECTIL) directly regresses the TILs score from these features. ECTIL trained on only a few hundred samples (ECTIL-TCGA) showed concordance with the pathologist over five heterogeneous external cohorts (r=0.54-0.74, AUROC=0.80-0.94). Training on all slides of five cohorts (ECTIL-combined) improved results on a held-out test set (r=0.69, AUROC=0.85). Multivariable Cox regression analyses indicated that every 10 survival independent of clinicopathological variables (HR 0.86, p<0.01), similar to the pathologist score (HR 0.87, p<0.001). We demonstrate that ECTIL is highly concordant with an expert pathologist and obtains a similar hazard ratio. ECTIL has a fundamentally simpler design than existing methods and can be trained on orders of magnitude fewer annotations. Such a CTA may be used to pre-screen patients for, e.g., immunotherapy clinical trial inclusion, or as a tool to assist clinicians in the diagnostic work-up of patients with BC. Our model is available under an open source licence (https://github.com/nki-ai/ectil).

Background: This study determines the prognostic value of the luminal-like subtype in patients with hormone receptor- positive breast cancer and explores whether the efficacy of extended anastrozole therapy differs between patients with luminal A-like versus luminal B-like tumours. Materials and methods: The phase III DATA study (NCT00301457) examined the efficacy of 6 versus 3 years of anastrozole in postmenopausal women with early-stage hormone receptor-positive breast cancer who had received 2-3 years of tamoxifen. Patients with available formalin-fixed paraffin-embedded tissue blocks were identified and classified by immunohistochemical luminal-like subtype. Distant recurrence (DR) and breast cancer-specific mortality (BCSM) were compared by luminal-like subtype and treatment arm using competing risk methods. Results: This study included 788 patients: 491 had a luminal A-like tumour and 297 had a luminal B-like tumour. The median follow-up time was 13.1 years. Patients with luminal B-like tumours experienced a higher risk of DR [subdistribution hazard ratio (sHR) 1.44, 95% confidence interval (CI) 1.03-2.01, P = 0.03] and BCSM (sHR 1.68, 95% CI 1.15-2.45, P = 0.008) than patients with luminal A-like tumours. The efficacy of extended anastrozole therapy differed between patients with luminal A-like tumours (DR: sHR 0.51, 95% CI 0.30-0.88, P = 0.02; BCSM: sHR 0.39, 95% CI 0.19-0.82, P = 0.01) and patients with luminal B-like tumours (DR: sHR 2.09, 95% CI 0.96-4.53, P = 0.06; BCSM: sHR 2.36, 95% CI 0.80-7.00, P = 0.12) (P-interaction = 0.03 and P-interaction = 0.06, respectively). Conclusion: In patients with hormone receptor-positive breast cancer, the luminal B-like subtype was associated with a significantly worse prognosis when compared with the luminal A-like subtype. Extended anastrozole therapy halved the risk of DR and BCSM in patients with luminal A-like tumours, whereas no effect was seen in patients with luminal B-like tumours.

Breast cancer diagnosed during pregnancy (PrBC) or postpartum (PPBC) is associated with a poorer prognosis, and earlier research indicated that outcomes differ based on timing of diagnosis. We updated and expanded our Dutch nationwide pregnancy-associated breast cancer (PABC) cohort, now also including patients diagnosed within one year after an interrupted pregnancy (AABC), to compare disease characteristics and prognosis across PrBC-, PPBC- and AABC subgroups and to non-PABC patients. All breast cancer pathology reports of women < 45 years in the Netherlands (1988–2022) were screened to identify patients diagnosed with PrBC, PPBC (< 12 months postpartum) or AABC (< 12 months after pregnancy interruption). PABC patients were 1:3 matched on age and year of diagnosis to non-PABC breast cancer patients. In our PABC cohort (N = 787), the majority was diagnosed during pregnancy (n = 471, 60

PURPOSE:In hormone receptor-positive, HER2-negative, early-stage breast cancer, cyclin-dependent kinase 4 and 6 inhibition combined with endocrine therapy could represent a less toxic alternative to neoadjuvant chemotherapy (CT). The NEOLBC trial studied whether neoadjuvant ribociclib plus letrozole (RL) results in a doubling of complete cell-cycle arrest (CCCA; Ki67 <1% on IHC) compared with CT in the surgical specimen in luminal breast cancer. PATIENTS AND METHODS:This randomized phase II trial tailored neoadjuvant therapy in postmenopausal patients with early, luminal, HER2-negative, stage II/III breast cancer based on the percentage of Ki67-positive cancer cells after 2 weeks of letrozole. Patients with a Ki67 ≥1% were randomized between RL and standard CT. Secondary endpoints included pathologic response and toxicity. RESULTS:Of 161 registered patients, 70 were randomized, and 66 started the allocated treatment. The CCCA in the surgical specimen was similar for both groups: 35.3% in the RL group and 31.3% in the CT group (P = 0.73). The response according to Miller and Payne was not significantly different between the two groups, nor was the pathologic complete response rate. Overall toxicity was observed more often in the CT group. In the RL group, eight patients discontinued treatment due to toxicity, and in the CT group, 10 patients discontinued treatment. CONCLUSIONS:Although the primary endpoint was not met, the NEOLBC trial (NCT03283384) showed a similar CCCA and pathologic response for RL and CT with less toxicity. Therefore, RL as an alternative to neoadjuvant CT merits further investigation.

AIMS:Breast cancer (BC) during pregnancy (PrBC) and the postpartum period (PPBC) often exhibits more aggressive tumour characteristics and is associated with a poorer prognosis compared with age-matched nonpregnant patients with BC. The underlying mechanisms for this increased aggressiveness remain unresolved. Intratumoral hypoxia, a known adverse prognostic marker in nonpregnant BC, has not yet been studied in PrBC/PPBC. This is particularly intriguing due to the potential exposure to angiogenesis-stimulating factors during pregnancy, which may influence tumour behaviour. METHODS:Tumour tissues from 148 patients with PrBC and 45 patients with PPBC were used to create a tissue microarray (TMA), and clinical and outcome data were obtained. The TMAs were stained for hypoxia-associated protein markers: glucose transporter-1, carbonic anhydrase IX and hypoxia-inducible factor-1α. RESULTS:Of all 193 tumours, 152 (79%) expressed at least one of these proteins indicative of intratumoral hypoxia. The presence of intratumoral hypoxia was associated with a higher histological grade (83% grade III vs 63%) and frequent hormone receptor negativity (68% vs 39%). In a multivariable analysis, the presence of intratumoral hypoxia indicated a significantly worse prognosis (HR 2.532, 95% CI 1.1 to 5.7) for patients with PrBC and PPBC. CONCLUSION:This unique study, the first in patients with PrBC and PPBC, showed that, despite their likely exposure to angiogenesis-stimulating factors, intratumoral hypoxia is frequent and affects 79% of patients. Importantly, patients with tumours overexpressing hypoxia markers have significantly worse survival. This suggests that hypoxia may be an important mechanism in carcinogenesis and clinical behaviour of PrBC and PPBC.

Importance Subgroup definitions for possible deescalation of neoadjuvant cancer treatment are urgently needed in clinical practice. Objective To investigate the effect of BRCA1 and/or BRCA2 tumor pathogenic variants (tPVs) by comparing 2 deescalated neoadjuvant regimens (nab-paclitaxel plus either carboplatin or gemcitabine) on pathologic complete response (pCR), invasive disease-free survival (IDFS), and overall survival (OS) of patients with early-stage triple-negative breast cancer (TNBC). Design, Setting, and Participants This was a preplanned secondary analysis of a phase 2 prospective randomized clinical trial (ADAPT-TN) conducted by the West German Study Group (WSG) at 45 sites in Germany between June 2013 and February 2015. The trial enrolled patients with noninflammatory early-stage TNBC (clinical tumor size >= 1 cm; estrogen receptor and progesterone receptor expression <1%; and ERBB2 negative). DNA samples from pretreatment biopsies were obtained. Genetic analysis was performed between January 2018 and March 2020. Final data analyses took place in September 2023. Exposure Patients were randomized to 12 weeks of treatment with nab-paclitaxel plus either carboplatin or gemcitabine; omission of otherwise mandatory anthracycline-containing chemotherapy was allowed in the case of pCR. tPVs in 20 cancer-associated genes, including BRCA1 and BRCA2, were analyzed using a customized gene panel. Main Outcomes and Measures The prevalence of BRCA1 and/or BRCA2 tPVs and their effect on pCR rate, IDFS, and OS were evaluated using logistic and Cox proportional hazards regression. Results Of the 307 patients with DNA samples from pretreatment biopsies available, tumor next-generation sequencing analyses were successful for 266 patients. The 266 patients included in this analysis were female, with a median age of 51 years (range, 26-76 years). A total of 162 patients (60.9%) had a clinical tumor size of 2 cm or greater, and 70 (26.3%) had clinical node-positive disease. BRCA1 and/or BRCA2 tPVs were detected in 42 patients (15.8%). The highest pCR rate among patients with BRCA1 and/or BRCA2 tPVs was seen in the nab-paclitaxel plus carboplatin group (9 of 14 patients [64.3%]) compared with the nab-paclitaxel plus gemcitabine group (10 of 28 [35.7%]) (odds ratio, 3.24 [95% CI, 0.85-12.36]; P = .08); the highest numeric 5-year IDFS and OS rates (84.4% and 92.9%, respectively) were seen in the nab-paclitaxel plus carboplatin group. Conclusions and Relevance In this secondary analysis of the WSG-ADAPT-TN randomized clinical trial on tPVs, deescalated nab-paclitaxel plus carboplatin was superior to nab-paclitaxel plus gemcitabine, particularly in patients with BRCA1 and/or BRCA2 tPVs. These findings suggest that BRCA1 and/or BRCA2 tPV status could be a candidate marker for a deescalation strategy in early-stage TNBC; however, prospective validation of survival outcomes in larger cohorts with differentiation between germline and somatic pathogenic variants is necessary.

The role of germline genetics in adjuvant aromatase inhibitor (AI) treatment efficacy in ER-positive breast cancer is poorly understood. We employed a two-stage candidate gene approach to examine associations between survival endpoints and common germline variants in 753 endocrine resistance-related genes. For a discovery cohort, we screened the Breast Cancer Association Consortium database (n ≥ 90,000 cases) and retrieved 2789 AI-treated patients. Cox model-based analysis revealed 125 variants associated with overall, distant relapse-free, and relapse-free survival (p-value ≤ 1E-04). In validation analysis using five independent cohorts (n = 8857), none of the six selected candidates representing major linkage blocks at CELA2B/CASP9, NR1I2/GSK3B, LRP1B, and MIR143HG (CARMN) were validated. We discuss potential reasons for the failed validation and replication of published findings, including study/treatment heterogeneity and other limitations inherent to genomic treatment outcome studies. For the future, we envision prospective longitudinal studies with sufficiently long follow-up and endpoints that reflect the dynamic nature of endocrine resistance.

BACKGROUND:The non-inferiority randomized controlled trial BOOG 2013-08 investigates the oncological safety and impact on health-related quality of life (HRQoL) of sentinel lymph node biopsy (SNLB) omission in cT1-2 N0 breast cancer. The primary aim of the present study was to compare patient-reported arm function and HRQoL up to 3 years after study inclusion in cT1-2 N0 patients with breast cancer undergoing breast-conserving surgery (BCS) with or without SLNB. The secondary aim was to explore the association between personality traits 'trait anxiety' and 'neuroticism', and perceived arm function and HRQoL. METHODS:A total of 1733 women with unilateral cT1-2 N0 invasive breast cancer treated with BCS with or without SLNB were included. The primary outcomes of arm function (assessed using the Lymphoedema Functioning, Disability, and Health Questionnaire) and HRQoL (assessed using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR-23 questionnaires) were analysed. RESULTS:Analyses included 821 patients (383 with SLNB and 438 without SLNB). Those in the SLNB group experienced a slight, temporary decline in arm function (P < 0.025) and reported more HRQoL arm and breast symptoms (P < 0.049). High trait anxiety or neuroticism was associated with significant poorer arm function and lower HRQoL. CONCLUSION:SLNB slightly reduced arm function, temporarily affecting HRQoL arm and breast symptoms. Neuroticism significantly negatively impacted arm function and HRQoL. Measuring and stratifying for personality traits is crucial for interpreting patient-reported outcomes and to identify patients needing additional support after surgery. REGISTRATION NUMBER:NCT02271828 (http://www.clinicaltrials.gov).

BACKGROUND:"Breast implant illness" (BII) is a constellation of non-specific constitutional, rheumatologic, mental, and cognitive symptoms reported increasingly by women carrying silicone breast implants (SBIs). The impact of BII on the well-being of breast cancer patients with SBI-based breast reconstructions is a subject of debate. METHODS:In a multicenter cohort of breast cancer survivors (n = 9590) treated between 2000 and 2015 in 6 major regional hospitals in the Netherlands, we performed a health survey (response rate 64.7%). The presence of 18 BII-associated symptoms was compared between patients with and without SBIs in multivariable logistic regression models. In a latent class analysis (LCA), distinct symptom patterns were identified in the study population. RESULTS:Median follow-up time was 13.7 (IQR, 6.8) years. Of all SBI-exposed patients (n = 1821), 20.7% reported ≥4 BII-associated symptoms vs 21.2% of non-exposed patients (risk ratio 0.98; 95% CI = 0.88 to 1.09). Joint pain, sicca, sleep impairment, morning stiffness, and shoulder pain were reported most frequently. Patients with SBIs did not have a significantly increased risk of any of the individual BII-associated symptoms. The LCA identified 5 distinct symptom clusters. Patients with SBI-exposure had a lower risk of falling in the most severe symptom cluster (odds ratio 0.64; 95% CI = 0.43 to 0.96). The other symptom clusters were not significantly associated with SBI-exposure. CONCLUSIONS:Our results indicate that breast cancer survivors with SBI-based reconstructions do not experience more BII-associated symptoms than breast cancer survivors without SBIs, challenging the notion of BII as a distinct clinical entity based on a generic silicone-induced biomechanical pathophysiological mechanism. TRIAL REGISTRATION:This study was preregistered at ClinicalTrials.gov on June 2, 2022 (NCT05400954).