Breast Cancer Research

ImportanceMammographic density (MD) and pathogenic variants (PVs) in breast cancer susceptibility genes are major determinants of breast cancer risk, but their association and joint effects on breast cancer risk are unclear. ObjectiveTo investigate the association between the presence or absence of PVs in breast cancer susceptibility genes and MD measures, and their joint effects on breast cancer risk in an observational study; and to evaluate causality using Mendelian randomisation (MR) analyses. DesignCase-control analyses using data from the Breast Cancer Association Consortium (1991-2016). Sequencing and genotyping took place between 2009 and 2021. SettingMulticenter ParticipantsA total of 6,809 cases and 18,189 controls were included, from 15 studies, comprising women aged 19 to 92 years with mammograms taken at least one year before diagnosis. ExposureMD measures, including dense area (DA), non-dense area (NDA), percentage density (PD) and absolute difference in PD between left and right breasts (ADPD), and PVs in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C and RAD51D. Main outcomes and measuresBreast cancer risk overall, by oestrogen receptor expression-defined subtypes, and among BRCA1 and BRCA2 PV carriers. ResultsNo association was found between the overall burden of PVs and any MD measure. There was some evidence for a negative interaction between the burden of PVs in the eight genes and PD (OR=0.79,95%CIint=0.62,1.00, PLRT=0.047). This appears to be largely driven by a positive interaction with NDA. MR analyses indicated attenuated effects for BRCA1 (for PD, OR per standard deviation =1.02(95%CI:0.78,1.34) but not BRCA2 PV carriers (1.54,95%CI=1.08,2.24)). Conclusions and RelevanceThere was no evidence of association between PVs in breast cancer susceptibility genes and MD measures, but some suggestion that the association between MD and breast cancer risk may be weaker in PV carriers. Replication of these findings in further large datasets is required.

IMPORTANCEIn young-onset breast cancer, a diagnosis within 5-10 years of childbirth associates with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with breast cancer at younger ages, but the impact of childbirth on mortality is unknown. OBJECTIVEDetermine whether time between recent childbirth and breast cancer diagnosis impacts mortality among young-onset breast cancer patients with germline BRCA1/2 PVs. DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort study includes 903 women with germline BRCA1/2 PVs diagnosed with stage I-III breast cancer at [&le;]45 years of age, between 1950-2021 in the UK. MAIN OUTCOMES AND MEASURESThe primary outcome is all-cause mortality, censored at 20 years post-diagnosis. The primary exposure is time between most recent childbirth and breast cancer diagnosis, with recent childbirth defined as >0-<10 years post childbirth (n=419)], further delineated to >0-<5 years (n=228) and 5-<10 years (n=191). Mortality of nulliparous cases (n=224) was compared to the recent postpartum groups and the [&ge;]10 years postpartum (n=260) group. Cox proportional hazards regression analyses were adjusted for patient age, tumor stage, further stratified by tumor estrogen receptor (ER) and BRCA gene status. RESULTSFor all BRCA PV carriers, increased all-cause mortality was observed in women diagnosed >0-<10 years postpartum, compared to nulliparous and [&ge;]10 years groups, demonstrating the transient duration of postpartum risk. Risk of mortality was greater for ER-positive cases in the >0-<5 group [HR=2.35 (95% CI, 1.02-5.42)] and ER-negative cases in the 5-<10 group [HR=3.12 (95% CI, 1.22-7.97)] compared to the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5-<10 group was significantly increased, but only for BRCA1 carriers [HR=2.03 (95% CI, 1.15-3.58)]. CONCLUSIONS AND RELEVANCEYoung-onset breast cancer with germline BRCA PVs confers increased risk for all-cause mortality if diagnosed within 10 years of childbirth, with risk highest for ER+ cases at >0-<5 years postpartum, and for ER-cases at 5-<10 years postpartum. BRCA1 carriers are at highest risk for poor prognosis when diagnosed at 5-10 years postpartum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers. Key PointsO_ST_ABSQuestionC_ST_ABSIs a postpartum diagnosis an independent risk factor for mortality among young-onset breast cancer patients with germline BRCA1/2 PVs? FindingsA diagnosis <10 years postpartum associates with higher risk of mortality compared to nulliparous and [&ge;]10 years postpartum cases. Peak risk after childbirth varies for ER-positive (>0-<5 years) vs. ER-negative cases (5-<10 years). BRCA1 carriers had peak risk of mortality 5-10 years postpartum, with no associations observed for BRCA2 carriers. MeaningA breast cancer diagnosis within 10 years of childbirth independently associates with increased risk for mortality in patients with germline BRCA1/2 PVs, especially for carriers of BRCA1 PVs.

BackgroundAvailable data on accelerated proliferation and increased breast cancer risk due to hormone replacement therapy (HT) are inconsistent. Data on long-term effects of HT are limited. The interaction between several key factors was examined using a model-based approach. MethodsCohorts of 50 year old women, BCs were randomly generated for 30 years based on the age-specific incidence. A control group received a HT that increased the growth of occult BCs. In a 3rd cohort BCs were additionally induced by HT. This model illustrates the interrelationship of important parameters and allows the simulation and comparison of previously published clinical studies. ResultsUsing plausible parameters for BC growth factor (GF) and HT-related effects it was demonstrated that HT caused accelerated growth of occult BCs with an apparent increase in incidence and shortened time to diagnosis. The Womens Health Initiative (WHI) study was reconstructed assuming a GF of 1.43 induced by HT. The decision of millions of women to discontinue or forego HT based on the published risks of the WHI-study in 2002 could explain the marked jump of 6.7% in incidence within a few months. If additional BCs were induced by HT, then these BCs may become apparent after 10 or more years together with those appearing according to the normal incidence. At this time conclusive data on type, timing, and molecular characteristics of HT induced BCs are not yet available. ConclusionThe acceleration in growth of occult BC has been underestimated. Initially HTs can cause an apparent increase in BC incidence thereby explaining the WHI-dependent decrease in 2003. A HT associated BC risk should only be detectable with a delay of ten and more years.

BackgroundHormone replacement therapy (HRT) is currently linked to increased breast cancer (BC) diagnoses. While this appears paradox to an estimated 15-year development period of hormone receptor-positive BC, the discrepancy can be explained if HRT has two effects. MethodsWe modelled cohorts of 100,000 women using two parameters: HRT caused accelerated tumour growth and increased incidence. A reference cohort used age-specific incidence, a 15-year growth period, and life expectancy. Treatment cohorts with faster growth and higher incidence were simulated over 30 years. Study endpoints were cumulative and annual BC incidence. Using data from the Womens Health Initiative (WHI), we estimated the factors that reproduce the WHI long-term outcomes. ResultsThe data indicate that HRT accelerates the growth of previously undetected BC, causing them to appear as seemingly new cases. The timing and duration of HRT determine when this rise occurs. After roughly 15 years of tumour development, an inherent HRT-related risk becomes apparent and overlaps with the expected baseline risk of aging women. The WHI results were reproduced with a growth acceleration factor of 1.4 and an initiation risk factor of 2, consistent with an approximate 10% drop in BC incidence in the United States around 2002 following reduced HRT use. ConclusionEstimates of about one million additional HRT-associated BCs may largely reflect accelerated growth of pre-existing BCs. Risk-adapted screening strategies could diagnosis newly initiated tumours early. By communicating these short- and long-term effects of HRT on cancer risk patients and physicians could make an informed decision on the risks and benefits of HRT-use.

BackgroundIn breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. MethodsA genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC. ResultsThe discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1x10-6, 33 variants associated with one or more TP53 phenotypes with P values <1x10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1x10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8x10-5 and 9.8x10-8, respectively) and TP53 GOF mutations (P value 8.4x10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons. ConclusionsWe found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.

The PREDICT breast prognostic and treatment benefit model has undergone several revisions since its first release. The most recent version (v3.1) was developed using a data set of 35,474 cases diagnosed between 2000 and 2017 in a single region of England. PREDICT breast provides predicted outcomes at 5, 10 and 15 years, but most clinicians use the 10-year outcomes for decision making. The purpose of this study was to reparameterize the model using a larger data set from across the UK and to compare the performance of v4.0 with that of v3.1. There were 172,208 eligible cases randomly split 50:50 into model development and validation data sets. Cox proportional hazards models were derived for estrogen receptor negative and estrogen receptor positive cancer for breast cancer specific mortality with a third model for non-breast cancer mortality. In cases with at least five years follow-up and censored at ten years, the model was well-calibrated with a less than 5% difference between observed and predicted breast cancer deaths. Model discrimination was also good with AUCs in the validation data of 0.735 and 0.794 for ER negative and ER positive cases respectively. Calibration and discrimination were slightly improved compared to PREDICT breast v3.1.

Circulating lipids have been associated with breast cancer (BCa). This association may, in part, be due to an effect of lipids on insulin-like growth factors (IGFs), which have been reliably associated with BCa. In two-sample Mendelian randomization (MR) analyses, we found that low density lipoprotein (LDL-C) was associated with IGFBP-3 (beta:0.08 SD; 95%CI:0.02,0.15; p = 0.01, per SD increase in LDL-C) and IGFBP-3 was associated with postmenopausal BCa (OR:1.09; 95%CI:1.00,1.19; p = 0.05, per SD increase in IGFBP-3). We also found that triglycerides were associated with IGF-I (beta:-0.13SD; 95%CI:-0.22,-0.03, per SD increase in triglycerides) and that IGF-I was associated with overall BCa (OR:1.10;95%CI:1.02,1.18, per SD increase in IGF-I). Taken together, these results suggest that IGFBP-3 may be a potential causal step between LDL-C and postmenopausal BCa and IGF-I a potential causal for triglycerides. Our two-step MR results build on evidence linking circulating lipids and IGFs with BCa, however, multivariable MR analyses are currently unable to support this relationship due to weak instruments.

Structured AbstractO_ST_ABSPurpose/ObjectivesC_ST_ABSThe role of postmastectomy radiotherapy (PMRT) in patients with pathologic N1 (pN1) breast cancer, including triple-negative breast cancer (TNBC), remains controversial in the era of modern systemic therapy. We evaluated the association between PMRT and recurrence-free survival (RFS) and overall survival (OS) and identified prognostic factors in a contemporary single-institution pN1 cohort. Materials/MethodsWe retrospectively reviewed female patients with pT1-2N1M0 breast cancer treated with mastectomy between 2016 and 2022. RFS and OS were estimated using Kaplan-Meier methods and compared by PMRT status with log-rank testing. Univariable Cox proportional hazards models assessed associations between clinical factors--including tumor laterality, receptor subtype (TNBC vs non-TNBC), nodal burden, and adjuvant therapies--and survival outcomes, with subgroup analyses by PMRT status and receptor subtype. ResultsFifty-seven patients were included; 22 (38.6%) received PMRT. With a median follow-up of 85 months, PMRT was not associated with improved RFS (median 133 vs 120 months; p=0.256) or OS (not reached vs 195 months; p=0.154). Hormone therapy was significantly associated with improved RFS (HR 0.43; p=0.026) and OS (HR 0.13; p=0.003), while having 2-3 positive lymph nodes predicted worse RFS (HR 2.86; p=0.007). No significant differential benefit from PMRT was observed in patients with TNBC or non-TNBC disease. ConclusionsPMRT was not associated with a survival benefit in this pN1 cohort, including patients with TNBC. Interpretation is limited by modest sample size and statistical power. Outcomes appeared driven by tumor biology, nodal burden, and systemic therapy, supporting individualized PMRT decision-making.

BackgroundTall women are more likely to develop breast cancer (BC). High Mobility Group AT-Hook 1(HMGA1), an oncofetal protein, plays a role in the progression of breast cancer. Non-coding sequences proximal to HMGA1 contain variants associated with 4.83 cm taller height. In the current study, we used UK Biobank data to examine the relationship of HMGA1 to height, risk, and prognosis of women with breast cancer. MethodsOur analysis included all subjects with invasive BC that occurred either before or after participant enrollment and were recorded in the UK Biobank database using self-reported data and the International Classification of Diseases (ICD10, ICD9). We divided the subjects into three previously described three height groups: Short (< 155 cm), Medium (155 cm to 175 cm), Tall (> 175 cm). We analyzed the HMGA1 SNP rs41269028, a single nucleotide intron variant, C > T, minor allele frequency 0.044. SNP rs41269028 was previously evaluated in subjects with diabetes. ResultsHeight of 9583 women with BC homozygous for the HMGA1 SNP rs41269028 major allele was 162.29 cm {+/-} 6.18. Height of 944 women with BC who were carriers or homozygotes (CT + TT) of the minor allele T was 162.88 cm {+/-} 6.001. This difference was significant (p = 0.005). The effect of height group on survival was significant (p = 0.032, log rank test). Tall women had the poorest survival. The effect of HMGA1 SNP rs41269028 genotype on BC risk (p = 0.602) and survival (p = 0.439, log rank test) was insignificant. ConclusionWe conclude that HMGA1 influences height, but we were unable to demonstrate that HMGA1 is related to increased incidence or poor prognosis of tall women with breast cancer. We did find that tall women with breast cancer have poorer survival than short women. Our finding that tall women have a worse prognosis is important because it could help the oncologist decide, along with other prognostic factors, whether adjuvant therapy is warranted.

BackgroundBreast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals. MethodsWe assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women. Discriminatory ability was evaluated using the area under the receiver operating characteristic curve (AUC). High-risk criteria included: 5-year absolute risk [&ge;]1{middle dot}66% by the Gail model [GAILbinary]; first-degree family history of breast cancer [FHbinary]; 5-year absolute risk [&ge;]1{middle dot}66% by a 313-variants polygenic risk score [PRSbinary]; and carriers of pathogenic variants in breast cancer predisposition genes [PTVbinary]. FindingsThe 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeansvs controls: AUCPRS=0{middle dot}635 [0{middle dot}632-0{middle dot}638] vs AUCGail=0{middle dot}492 [0{middle dot}489-0{middle dot}495]; Asiansvs controls: AUCPRS=0{middle dot}564 [0{middle dot}556-0{middle dot}573] vs AUCGail=0{middle dot}506 [0{middle dot}497-0{middle dot}514]). PRSbinary and GAILbinary identified more high-risk European than Asia individuals. High-risk proportions were higher among BrCa (16-26%) and DCIS (20-33%) compared to controls (9-15%) among young Europeans and all Asians. Fewer than 7% of BrCa, 10% of DCIS, and 3% of controls were classified as high-risk by multiple risk classifiers. Overlap between PRSbinary and PTVbinary was minimal (<0{middle dot}65% Europeans, <0{middle dot}15% Asians) compared to the proportion at high risk using PTVbinary alone (Europeans: 4{middle dot}6%, Asians: 4{middle dot}4%) and PRSbinary alone (Europeans: 13{middle dot}9%, Asians: 8{middle dot}5%). PRSbinary and FHbinary uniquely identified 5-6% and 9-11% of young BrCa, respectively. InterpretationThe incomplete overlap between high-risk individuals identified by PRSbinary, GAILbinary, FHbinary, and PTVbinary highlights the need for a comprehensive approach to breast cancer risk prediction. SIGNIFICANCEThis study shows that different ways of predicting breast cancer risk do not always flag the same people, suggesting that combining multiple risk factors could improve early detection and screening.

BackgroundBreast cancer prognosis changes over time in complex ways depending on individual risk factors. This study aimed to analyze how breast cancer outcomes in New Zealand women change over time and identify features associated with breast cancer specific survival and locoregional recurrence across different receptor subtypes. MethodsA retrospective cohort study was conducted using data from Te R[e]hita Mate [U]taetae (Breast Cancer Foundation National Register) on 21,574 women diagnosed with invasive breast cancer between 2000-2019. We applied k-medians survival clustering, landmark analysis, and piecewise Cox regression to identify time-specific risk patterns and prognostic features. ResultsSurvival improved significantly for women diagnosed more recently. Triple-negative breast cancer had the poorest 5-year breast cancer specific survival but demonstrated better outcomes for women surviving beyond this period. In contrast, ER+/HER2-tumors, associated with favorable short-term outcomes, showed the highest risk of late recurrence and breast cancer mortality beyond 10 years. Younger age at diagnosis ([&le;]44 years) was associated with increased recurrence risks, especially for ER-/HER2+ tumors. Radiation therapy reduced early LRR across subtypes. Tumor grade was inversely associated with late recurrence, while stage 2 disease in ER+ tumors markedly elevated late recurrence odds compared to stage 1. ConclusionsThis study demonstrates the dynamic nature of breast cancer prognosis, with key findings emphasizing the time-dependent shifts in risk across receptor subtypes. These findings underscore the importance of personalized, receptor-specific follow-up strategies, including extended monitoring for subgroups at heightened long-term risk.

BackgroundThe reduced risk of breast cancer (BC) following increasing parity has been known for decades. Most prospective studies have presented the relative risk as the percentage decrease for each child during follow-up. Since the risk reduction is up to ten percent for each child, the overall lifelong BC risk reduction could be under communicated. In this study we use cumulative incidence rates (CIR) to calculate and describe the lifelong risk of BC in relation to parity. MethodsNOWAC is a prospective cohort study with 172,000 women recruited between 1991 and 2007 with follow-up through questionnaires and national registers of cancer and death. For the present analyses, we included 165 238 women with follow-up from 01.01.2000 until 31.12. 2018. We calculated CIR of BC by parity, stratified by other established BC risk factors (maternal age at first birth, breastfeeding, body mass index (BMI), smoking and alcohol consumption). ResultsAfter 17.3 years of average follow-up, 8120 women aged 35-84 years developed breast cancer. Age-specific incidence rates increased for each age group up to 60-64 years, decreased for the age group 75-79 years, and increased again among the oldest women aged 80-84. CIR for all participants up to 84 years was 11 700 per 100 000 person years (PY). In analyses stratified by parity, the CIR of BC for nullipara was 12 600 per 100 000 PY, for 1-2 children: 12 100, 3-4 children: 10 200, and 5-6 children: 8 700 per 100 000 PY. The parity-specific CIR of BC had the same pattern of decrease in analyses stratified for other BC risk factors. ConclusionCumulative incidence rates showed a consistent decrease in BC risk for each additional child. The decrease was consistent in strata of other established BC risk factors.

BackgroundObservational studies regarding the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) reported inconsistent findings. We performed a two-sample Mendelian randomization using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. MethodsWe assessed the association between single-nucleotide polymorphisms (SNPs) and drug targetable gene expression with expression quantitative trait loci in blood. Further, we investigated association between the SNPs and BC risk with genome-wide association study summary statistics. We then confirmed the hits from Mendelian randomization with tissue-specific analyses along with additional sensitivity assessments (horizontal pleiotropy, colocalization, multiple tissue enrichment etc.). ResultsThe overall BC risk was decreased 16% with one standard deviation (SD) increase of SLC12A2 gene expression in blood (odds ratio, 0.86, 95% confidential interval, 0.78-0.94). This signal was further confirmed in estrogen receptor positive (ER+) BC (0.85, 0.78-0.94). In addition, one SD increase in expression of PDE1B in blood was associated with 7% increased risk of ER+ BC (1.07, 1.03-1.11). We detected no evidence of horizontal pleiotropy for these associations and the probability of the causal variants being shared between the gene expression and BC risk was 81.5%, 40.5% and 66.8%, respectively. We failed to observe any significant association between other targeted genes and BC risk. ConclusionsUse of antihypertensive medications that target SLC12A2 and PDE1B is associated with increased and decreased BC risk, respectively. FundingThis work was supported by the Swedish Research Council [2018-02400 to K.S., 2020-01175 to J.S., 2021-01187 to J.J.], Cancerfonden [2017 CAN2017/340 to J.J.], Crafoordska Stiftelsen [to J.J.], MAS Cancer [to J.J.], ALF funding from Region Sk[a]ne [to J.J. and K.S.]. The funding body was not involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

PurposeThis study evaluated the prognostic performance of RlapsRisk BC, a multimodal deep learning tool designed to predict distant recurrence-free interval (dRFI) in early-stage, ER-positive, HER2-negative breast cancer using routine H&E-stained whole-slide images (WSIs) and standard clinicopathologic features. MethodsRlapsRisk BC was developed and internally validated on seven retrospective cohorts totaling 6,039 patients. Its ability to stratify patients into high- and low-risk groups for dRFI was then assessed in a blinded, retrospective validation across three independent international cohorts (UK, France, USA), including 591 patients with non-metastatic ER+/HER2- breast cancer treated with adjuvant endocrine therapy alone. ResultsAcross all validation cohorts, RlapsRisk BC showed strong prognostic performance, stratifying patients into distinct low- and high-risk groups with hazard ratios from 3.93 to 9.05. At 5 years, distant recurrence ranged from 0.85%-4.7% in low-risk vs. 6.39%-34.8% in high-risk groups. This separation remained robust across subgroups, including grade 2 tumors, menopausal status, and nodal involvement. RlapsRisk BC was also an independent prognostic factor and improved performance when combined with clinical variables (age, tumor size, nodal status). It increased the c-index by 0.08, 0.19, and 0.20 across the three cohorts, with significant improvement in two. Compared to genomic assays, RlapsRisk BC showed complementary--and sometimes superior--performance, particularly for identifying low-risk patients. At matched specificity, it achieved higher sensitivity: 0.85 vs. 0.33 (Oncotype DX) and 0.74 vs. 0.49 (EndoPredict). ConclusionRlapsRisk BC demonstrates strong, independent prognostic value and may offer a scalable, accessible alternative to genomic assays. Further studies are needed to confirm clinical utility and support integration into treatment decisions. ContextO_ST_ABSKey ObjectiveC_ST_ABSThis study aimed to assess whether RlapsRisk BC, a digital pathology-based AI model, can provide clinically meaningful prognostic stratification in ER-positive, HER2-negative early breast cancer. The AI model combines standard histology exhibited in whole slide images of hematoxylin and eosin stained tissue sections and clinical data. The prognostic performance of RlapsRisk BC was evaluated across multiple independent patient cohorts. Knowledge GeneratedThe study demonstrates that RlapsRisk BC offers independent prognostic value beyond established clinical variables and genomic assays. It consistently stratifies patients into high- and low-risk groups for distant recurrence, with reproducible performance across diverse and independent cohorts, supporting its potential integration into routine clinical decision-making. RelevanceRlapsRisk BC may serve as a scalable alternative or adjunct to molecular assays, supporting more personalized and accessible treatment decisions in breast cancer, particularly in settings where genomic testing is unavailable, limited, or yields intermediate-risk results.

BackgroundThe management of residual axillary disease after neoadjuvant therapy (NAT) remains controversial, as current recommendations often treat ypN1 breast cancer as a homogeneous entity despite potential prognostic heterogeneity. Evidence supporting uniform axillary surgical strategies across different levels of residual nodal burden is limited. We investigated whether survival associations related to axillary surgical evaluation differ according to residual nodal burden in ypN1 disease, using an adjuvant cohort to validate a SEER-based proxy for surgical extent. MethodsPatients with 1-3 positive lymph nodes were identified in the SEER database (2000-2022) and stratified into neoadjuvant (NAT; n=30,560) and adjuvant (AT; n=197,586) cohorts. Axillary surgical evaluation was categorized as limited (2-3 examined nodes) or extensive ([&ge;]10 examined nodes). Survival was analyzed using Kaplan-Meier methods and log-logistic accelerated failure-time models, adjusted with inverse probability of treatment weighting. ResultsIn the ypN1 cohort, limited axillary evaluation was not associated with inferior overall survival among patients with a single residual positive node (IPTW-adjusted HR: 1.15, p=0.134; time ratio [TR]: 0.86, p=0.184). In contrast, limited evaluation was associated with worse survival in patients with two positive nodes (HR: 1.70, 95%CI 1.54-1.87; TR: 0.58, 95%CI 0.53-0.64). The findings were similar when using breast cancer-specific survival as the endpoint. ConclusionsSurvival associations related to axillary surgical evaluation after NAT vary according to residual nodal burden. Axillary de-escalation appears feasible in patients with a single residual positive node but cannot be extrapolated to those with multiple residual nodes, underscoring heterogeneity within ypN1 disease.

Mammography is used as secondary prevention for breast cancer. Computer-aided detection and image-based short-term risk estimation were developed to improve the accuracy of mammography. However, most approaches inherently lack the ability to connect observations at the mammography level to observations of cancer onset and progression seen at a smaller scale, which can occur years before imageable cancer and lead to primary prevention. The Hurst exponent (H) can quantify mammographic tissue into regions of dense tissue undergoing active restructuring and regions that remain passive, with amounts of active and passive dense tissue that differ between cancer and controls at diagnosis. A longitudinal retrospective case-control study was conducted to test the hypothesis that differences can be detected before diagnosis and changes could signal developing cancer. Mammograms and reports were collected from 50 patients from Maine Medical Center in 2015 with at least a 5-year screening history. Age-matching patients within 2 years created a primary dataset, and within 5 years, a secondary dataset was created to test for sensitivity. The amount of passive (H [&ge;] 0.55) and active dense tissue (0.45 < H < 0.55) was calculated for each breast and was predicted by creating a linear mixed-effects model. Cancer status was a predictor for passive (p = 0.036) and active (p = 0.025) dense tissue using the primary dataset. However, when increasing the power, cancer status was a predictor for active dense tissue (p = 0.013), while breast status (p = 0.004), time (p = 0.009), and interaction (p = 0.038) were predictors for passive dense tissue. This suggests active dense tissue is a risk for cancer and passive dense tissue is an indication of developing cancer. Required Key MessagesO_LIMammographic dense breast tissue can be separated into regions of active and passive. C_LIO_LIThere is more active dense breast tissue in pathology-confirmed cancer cases than controls. C_LIO_LIIncreases in passive dense tissue in a breast could indicate a developing tumor. C_LI

BackgroundGenitourinary syndrome of menopause (GSM) frequently occurs after breast cancer (BC), leading to symptoms that can severely affect quality of life. Vaginal estrogen therapies (VETs), including compounds like promestriene and estriol, are recommended for GSMs. However, there is concern that VETs might affect the risk of BC relapse in women with a history of BC. Material and MethodsUtilizing data from the French National Health Data System, we emulated target trials to investigate the effect of VET initiation (promestriene or estriol) on disease-free survival (DFS) in women with a history of non-metastatic BC. Trials were emulated sequentially at 12, 24, 36, and 48 months after BC diagnosis. We estimated survival probabilities at three and five years and used inverse probability weights to adjust for confounders. ResultsOf the 136,408 unique patients meeting the inclusion criteria for at least one the emulated trials, 1,737 (1{middle dot}3%) initiated VET. In patients with hormone receptor (HR)-positive tumors treated with tamoxifen, the estimated difference in DFS for VET initiation versus no initiation was 0{middle dot}2 percentage-point at five years (95% CI -4{middle dot}1; 3{middle dot}6), while it was -2{middle dot}9 (95% CI -6{middle dot}5; 0{middle dot}0) in patients with HR-positive tumors treated with aromatase inhibitors. In this subgroup, the estimated difference in DFS for promestriene initiation versus no VET initiation was -2{middle dot}5 percentage-points at five years (95% CI -6{middle dot}7; 1{middle dot}1) while it was -3{middle dot}7 (95% CI -10{middle dot}1; 1{middle dot}8) for estriol initiation versus no VET initiation; and the differences between the two molecules were even more pronounced at three years. DiscussionOur results do not find evidence that VET decreases DFS in patients with HR-positive tumor treated with tamoxifen. However, VET initiation might decrease DFS in patients treated with aromatase inhibitors, with estriol leading to a more pronounced decrease in DFS than promestriene.

BackgroundTo determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on ovarian reserve by serum anti-Mullerian hormone (AMH) levels in women with breast cancer. MethodsOne-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate+5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. ResultsBoth chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p<0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p=0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. ConclusionsBoth AC-based and CMF regimens significantly compromise ovarian reserve, which does not recover during the 12-24-month post-chemotherapy follow up. In contrast, tamoxifen treatment does not seem to alter ovarian reserve. This novel information should be valuable for fertility preservation counselling and in assessing future reproductive potential of breast cancer survivors.

ImportanceData on fertility after breast cancer (BC) relative to the general population are lacking. ObjectiveTo compare the time-to-pregnancy between women with and without prior BC seeking to become pregnant. DesignProspective exposed-unexposed cohort study. Women were included from March 13, 2018 to June 27, 2019. Data were collected every six months via online questionnaires for up to three years. SettingParticipants were recruited through the French collaborative network for cancer research Seintinelles*. ParticipantsExposed women (cases) were women aged 18-43 years with a history of localized BC who had completed treatment, without relapse. Unexposed women (controls) were women of the same age group with no history of BC. Exposure(s)The exposure of interest was a prior history of BC. Main Outcome(s) and Measure(s)The primary endpoint was time-to-pregnancy. The hypothesis tested was formulated before data collection. Secondary endpoints included the use of ART, including the use of cryopreserved material, factors associated with time-to-pregnancy, and pregnancy and neonatal outcomes. Statistical analysis was based on Kaplan-Meier survival analysis and multivariate Cox proportional-hazards models with adjustment for confounding factors by inverse probability of treatment weighting (IPTW). ResultsWe enrolled 4351 women in this study. Follow-up data were available for 642 women (76 cases, 566 controls) who sought to become pregnant during the study period. Median time-to-pregnancy was 5 months (95% CI: 3 months to 7 months) for cases and 3 months (95% CI: 2 months to 5 months) for adjusted controls, with no significant difference between the groups (p=0.34). Cases were more likely to resort to the use of ART than controls (RR=13.9, 95% CI [2.2- 154.6]), but time-to-pregnancy was similar in cases and controls, with and without ART use. Time-to-pregnancy was influenced by factors such as age, parity, menstrual cycle regularity, BMI, and ART, but not by prior BC. Pregnancy and neonatal outcomes did not differ significantly between cases and controls. Conclusions and RelevanceTime-to-pregnancy, in women seeking to become pregnant, was similar for women with and without a history of BC, raising hopes for women with BC wishing to have children.

Homologous recombination deficiency (HRD) originating from inactivation of genes like BRCA1/BRCA2 is a targetable abnormality common in triple-negative breast cancer (TNBC). In estrogen-receptor (ER)-positive HER2-negative (ERpHER2n) breast cancer (BC), HRD prevalence and clinical impact are unclear. We analyzed 502 ERpHER2n tumors from patients recruited via the population-representative Swedish SCAN-B study, by whole genome sequencing (WGS) defining mutational signatures-based HRD, as well as matched transcriptional, DNA methylation, clinicopathological, treatment and outcome data. HRD is much less frequent in ERpHER2n BC (8.4%) compared to TNBC (58.6%), though induced by similar genetic/epigenetic mechanisms acting on mainly BRCA1/BRCA2/RAD51C/PALB2. Our modelled estimate of HRD in Western European BC is [~]10-13%. HRD tumors were observed across all gene expression subtypes and did not exhibit a unique, defining transcriptional or DNA methylation profile. Though numbers are limiting, we present early evidence that HRD stratification by WGS could impact therapeutic strategies, as HRD BCs trended to poorer outcomes, especially when not treated with chemotherapy.