Background Guidelines recommend biopsy of first breast cancer recurrence. Our group recently showed that only half of patients in Washington diagnosed with metastatic breast cancer (MBC) between 2008 and 2017 underwent biopsy.Methods Oncologists in our group identified patients in which a lung malignancy was diagnosed in patients with a breast cancer history.Results We identified eight illustrative cases. Lung findings were typically identified on a CT obtained for staging or radiation planning. In five cases, patients were treated curatively for two early-stage malignancies. In two cases, patients with MBC were found to have early-stage lung adenocarcinomas. In one case, MBC and metastatic lung cancer were diagnosed synchronously.Conclusions While imaging can raise suspicion for breast cancer recurrence, relying on radiologic appearance to infer that a lesion (1) is malignant and (2) represents spread of the known primary risks treating both the primary tumor and the newly detected condition inappropriately.

BACKGROUND:CD47 functions as a "don't eat me" checkpoint, inhibiting macrophage-mediated phagocytosis in triple-negative breast cancer (TNBC). While anti-CD47 therapies can restore immune surveillance, their efficacy in TNBC is often limited by immune evasion and drug development challenges. METHODS:We investigated the crosstalk between the histone demethylase lysine-specific demethylase 1 (LSD1) and CD47 signaling in TNBC using in silico datasets, isogenic cell lines, conditional BRCA1 knockout models, and syngeneic mouse models. Techniques such as immunohistochemistry, multiplex immunofluorescence, immunoprecipitation, protein ubiquitination, chromatin immunoprecipitation, chemotaxis, flow cytometry, and phagocytosis assays were employed to examine the epigenetic regulation of CD47 by LSD1 and its impact on antitumor immunity. The efficacy of combining LSD1 inhibition with anti-CD47 therapy was evaluated in BALB/cJ mice bearing TNBC tumors. RESULTS:In TNBC tumors, CD47 expression is positively correlated with elevated LSD1 levels, which are associated with increased infiltration of M2 macrophages and a concomitant decrease in M1 macrophages and CD8+T cells. Inhibition of LSD1 led to downregulation of CD47 by suppressing the expression and activity of its key transcriptional regulators, NF-κB (p65) and STAT3, through distinct mechanisms. Loss of LSD1 reduced p65 transcription, which was linked to an accumulation of the repressive histone mark H3K9me2 at the p65 promoter. Conversely, LSD1 inhibition promoted polyubiquitination and subsequent destabilization of STAT3. LSD1 inhibition also enhanced phagocytosis and promoted M1 polarization of macrophages. CD47 downregulation induced the production of interferon-γ and Th1-type chemokines in TNBC cells, facilitating increased tumor infiltration of CD8+T cells. Furthermore, combining LSD1 inhibition with anti-CD47 therapy significantly improved antitumor efficacy compared with monotherapy in syngeneic tumor models, without inducing significant toxicity. This combination therapy also promoted a shift in macrophage polarization toward the M1 phenotype, further enhancing CD8+T cell infiltration within tumors. Depletion of CD8+T cells significantly diminished the antitumor efficacy of the combination therapy. CONCLUSION:Targeting LSD1 enhances the efficacy of anti-CD47 therapy by overcoming immune evasion, offering a promising strategy to improve immunotherapy outcomes in TNBC.

Background: Cancer is the leading cause of death in the US Hispanic/Latinx population and Latina women are 20% more likely to die from breast cancer (BC) compared to non-Latina women. An estimated 80% of US Latina women have overweight or obesity, which is a major contributor to BC incidence and recurrence. Culturally tailored, effective, and accessible weight loss interventions for Latina BC survivors are needed. Aims: The ¡Vida! Study primary aim is to compare the effectiveness of adaptive weight loss interventions in decreasing total body weight by ≥7% at 12 months in Latinas with early-stage BC and obesity not on current chemoradiotherapy. The secondary aim will investigate baseline characteristics as moderators of the intervention effects to inform personalized strategies for weight management. Exploratory aims will examine other moderators and mediators of intervention effects, effects of the intervention on cardiometabolic biomarkers, and contextual factors that contribute to study outcomes. Design: Participants will be recruited from NCI SEER registries in California and Washington. This study is a 4-group, 2-stage, sequential multiple assignment randomized trial (SMART) of: 1) the ¡Vida! Program, 2) ¡Vida! + Experiential Learning (EL), 3) ¡Vida! + EL + health coaching (HC), or 4) ¡Vida! + EL + HC + delivered groceries (DG). In Stage One, participants will be randomized to ¡Vida! or ¡Vida! + EL. In Stage Two, at week 8 participants who do not respond to the intervention (i.e., loss of <2% of their body weight) will be re-randomized to receive additional components. A community advisory board of project stakeholders, community-based organizations in Washington and California representing medical services, social services, and patient-advocates will provide input throughout the study process. Intervention: The ¡Vida! Program adapts the National Diabetes Prevention Program to Latina BC survivors using the Framework for Reporting Adaptations and Modifications. Live, remotely delivered, nutritional and physical activity (PA) educational sessions through the Fred Hutch Cancer Center Cook for Your Life website will be delivered over 12 months. The EL component will include live, virtual, hands-on sessions delivered by lifestyle health educators (promotoras) and will focus on increasing knowledge, skills, and self-efficacy to achieve and maintain weight, diet and PA goals. The HC component will include individualized remote sessions. Health coaches will identify patient diet and PA goals, and support weight loss self-efficacy, motivation for adopting a hypocaloric high-quality diet, and increasing moderate-to-vigorous PA. The DG component will include a bag of supplemental fresh vegetables, whole grains, and healthy oils. DG will include ingredients used in recommended recipes and recipes prepared in the EL sessions. Data Collected: Baseline data will be collected on participant demographics, clinical characteristics, acculturation, and taste preferences. Body weight, daily PA, and accelerometry; patient-reported food intake and diet quality, global quality of life, social support, perceived stress, and self-efficacy for healthy eating and PA; and dried blood spot biomarkers will be monitored for change between baseline and 12 months. Conclusion: The ¡Vida! trial is on track to open in Fall 2024. The results of this adaptive, remotely delivered, and culturally tailored weight loss trial in Latina early-stage BC survivors will identify scalable, effective, personalized strategies to support weight loss and improve BC related outcomes due to obesity in this population with high cancer health disparities. Citation Format: Blake Langley, Eileen Rillamas-Sun, Jennifer Whitten, Yarizel Herrera, Sheryl Rothmuller, Sara Buzali, Jennifer Dearden, Ashkan Ertefaie, Chongzhi Di, Nancy Davidson, Rachel Yung, India Ornelas, Heather Greenlee. Using a SMART Approach to Culturally-Adapt and Remotely Deliver a Weight Loss Intervention for Latina Breast Cancer Survivors: The ¡Vida! Study Methods [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-23.

Background18F-Fluorodeoxyglucose (FDG) and 18F-Fluorestradiol (FES) have been FDA approved for measuring tumor glycolytic activity and estrogen receptor (ER) uptake, respectively, in clinical positron emission tomography (PET) imaging for patients with hormone-receptor (HR) positive metastatic breast cancer (MBC), but little is known about its utility in patients with breast tumors that overexpress human epidermal growth factor 2 (HER2). We hypothesize that comparing patterns of FDG and FES uptake in patients with HER2-positive versus HER2-negative MBC can guide further biologic and clinical studies into the HR/HER2-positive phenotype.MethodsWe conducted a retrospective study examining uptake in matched lesions for FES and FDG-PET scans, assessing these parameters in 213 patients with ER-positive/HER2-positive (n = 33) versus ER-positive/HER2-negative MBC (n = 180). We employed log-rank and t-tests to assess the association of HER2 status with outcome variables and the hypotheses that patients expressing HER2-positive disease lived longer than patient with HER2-negative disease.ResultsNo difference in FES or FDG avidity was observed between patients with HER2-negative or HER2-positive tumor status. Limited data also suggests that patients with HER2-positive disease had better overall survival (p = 0.024), than those with HER2-negative disease, but not time-to-progression between the same patient cohorts.ConclusionThis retrospective analysis suggests that there is a possible role for future trials using FES-PET in helping to select patients with ER+/HER2-positive primary tumors who retain ER expression at all sites of disease and may benefit from endocrine therapy.

Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening results from conventional 2D cancer cell lines with 3D tumor tissues and find that, on average, three times more drugs are effective in 3D microtumors. We confirm the effectiveness of doramapimod, a compound that reduces microtumor viability and suppresses tumor growth in mouse models but has no effect on cancer cell growth in monolayers. Mechanistically, doramapimod targets DDR1/2 and MAPK12 kinases in cancer-associated fibroblasts (CAFs), decreasing extracellular matrix (ECM) production and enhancing interferon signaling. These kinases regulate ECM through GLI1 activity in CAFs, independently of canonical hedgehog signaling. Inhibiting the DDR1/2-MAPK12-GLI axis enhances the effectiveness of chemotherapy and immunotherapy in patient tumor slices and preclinical models. These findings highlight the importance of DDR1/2-MAPK12-GLI axis in CAF function and demonstrate the utility of 3D tissue models in identifying microenvironment-specific therapeutic targets.

BACKGROUND:Depression has been identified as an adverse mental health outcome in women with breast cancer (BC). Depression was investigated as a risk factor for poor survival in premenopausal women with hormone-responsive early BC treated in the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials. METHODS:The data used were from a subset of patients who participated in TEXT or SOFT and completed the Center of Epidemiologic Studies-Depression scale. Associations between baseline depression-score categories and baseline characteristics were assessed using the Cochran-Mantel-Haenszel test controlling for antidepressant use. Multivariable proportional hazards regression models were used to test the association between baseline depression and disease-free survival (DFS) and overall survival (OS). Regression models were adjusted for factors known to be associated with outcomes, baseline antidepressant use, and early treatment cessation. RESULTS:Forty percent (2287 of 5738) of the women enrolled in the SOFT and TEXT trials were included in this analysis (SOFT, n = 1259; TEXT, n = 1028). Twenty-seven percent of women reported mild-to-moderate or severe depression at baseline. Race (p = .001), body mass index (p = .02), family history (p = .02), and performance status (p =.007) were significantly associated with the severity of depression. Relative to the no-symptomatology group, the hazard ratios (overall p = .04) for DFS were 1.34 (95% confidence interval [CI], 1.03-1.76) for women with mild-to-moderate depression and 1.34 (95% CI, 0.96-1.87) for those with severe depression. Relative to the no-symptomatology group, the hazard ratios (overall p = .008) for OS were 1.68 for mild-to-moderate depression (95% CI, 1.15-2.44) and 1.67 for those with severe depression (95% CI, 1.05-2.66). CONCLUSIONS:In premenopausal women with hormone-responsive early BC, depression at baseline is a risk factor for poorer DFS and OFS. Further investigation of the underlying interactive processes is needed. TRIAL REGISTRATION:Clinicaltrials.gov NCT00066703 (SOFT) and NCT00066690 (TEXT).

Background The NRG/RTOG 9804 and ECOG-ACRIN E5194 studies sub-classified duct carcinoma in situ (DCIS) into different risk groups after breast conservation surgery (BCS) based on size, DCIS grade, and margin width. NRG/RTOG 9804 randomized patients with “good risk” DCIS (size ≤2.5 cm, grade 1-2, margin ≥3mm) to whole breast radiation (RT) or none, and ECOG-ACRIN E5194 had 2 cohorts, one observing patients with the same “good risk” characteristics after BCS without RT. In both trials, the use of tamoxifen) was optional but tracked. This ancillary analysis of both trials was undertaken to assess the role of tamoxifen alone on ipsilateral breast recurrence (IBR) in this “good risk” group not receiving RT. Methods A combined database from the non-RT arm of NRG/RTOG 9804 and the “good risk” cohort from ECOG-ACRIN E5194 was created and distributions of patient and DCIS characteristics by tamoxifen use (yes vs. no) were compared using the Chi-square test. IBR, invasive IBR, DCIS IBR and contralateral breast event (CBE) were estimated by the cumulative incidence method and distributions between tamoxifen use were compared using Gray’s test. A 2-sided significance level of 0.05 was used. Univariate and multivariable Fine-Gray regression was used to analyze the effects of factors, in addition to tamoxifen use, that may be associated with endpoints. Results 878 patients were analyzed, 317 patients from NRG/RTOG 9804, and 561 from ECOG-ACRIN E5194. Median age was 59, margin width was ≥3mm or negative by re-excision in 97.8%, size was ≤5mm in 48.1%, and grade was 1-2 in 87.5%. The use of tamoxifen in the combined no-RT group was 43.1% (65.6% in NRG/RTOG 9804 and 30.3% in ECOG-ACRIN E5194). Median follow up of all patients was 14.85 years. There were 117 IBR, 65 invasive and 52 DCIS. There was a statistically significant association for reduced IBR with tamoxifen use (p=0.001); estimated 15-year IBR (95% CI) with tamoxifen is 11.4% (7.9%, 15.5%) and without is 19.0% (15.3%, 22.9%). Further analysis showed the reduction to be significantly associated with tamoxifen use for invasive IBR (p=0.0048) but not for DCIS IBR (p=0.089). No associations were seen for CBE. On univariable analysis, pathologic size (≤ 5 mm vs. > 10 mm) was significantly associated with IBR (p=0.0001) as was DCIS grade (1 vs 2, p=0.042). On multivariable analysis for IBR, DCIS grade fell out of the model and after adjusting for pathologic size, tamoxifen use remained statistically significantly associated with reduced IBR. On multivariable analysis for invasive IBR, size fell out of the model and adjusting for grade, tamoxifen use remained statistically significantly associated with reduced invasive IBR. Patients who received tamoxifen were 44% less likely to have any IBR (HR = 0.56, 95% CI: 0.38, 0.84; p=0.0044), and 51% less likely to have invasive IBR (HR=0.49, 95% CI: 0.28, 0.84; p=0.0092), as compared to patients with no tamoxifen. Conclusions For women with “good risk” DCIS who opt for BCS without RT, the use of tamoxifen is significantly associated with a reduction in IBR overall and specifically invasive IBR, not DCIS IBR. Citation Format: Jean Wright, Jennifer Moughan, Habib Rahbar, Amit B Shah, Christopher Comstock, Lesly A Jarvis, Judy A Tjoe, Isabelle Germain, Sunil S Badve, Eric Strom, Abram Recht, Diane C Ling, Laura A Vallow, Joseph J Stephenson, Adam Currey, Eleanor M Walker, Harold Reiter, Michael L. Steinberg, Lori J Pierce, Kathryn Winter, Joseph Sparano, Nancy E Davidson, Antonio C. Wolff, Robert J Gray, and Beryl McCormick. Impact of Tamoxifen Only after Breast Conservation Surgery for "Good Risk" Duct Carcinoma in Situ: Results from the NRG Oncology/RTOG 9804 and ECOG-ACRIN E5194 Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-02.

Latina women experience a 20% higher breast cancer (BC) mortality rate than non-Latina women, with over 80% classified as overweight or obese—risk factors for recurrence. Few culturally tailored interventions support sustainable weight loss in this population. The ¡Vida! trial is a Sequential Multiple Assignment Randomized Trial (SMART) evaluating the feasibility and effectiveness of adaptive, remotely delivered weight loss strategies among Latina BC survivors with obesity. Participants in Washington and California are recruited via SEER registries and community outreach. Women who self-identify as Latina, have a prior diagnosis of stage I–III breast cancer, have completed treatment (endocrine therapy allowed), and have a body mass index (BMI) ≥27 kg/m2 are eligible. In Stage 1, participants are randomized to: (1) ¡Vida!, a virtually delivered, culturally adapted lifestyle weight loss program with 24 one-hour group sessions over 12 months; or (2) ¡Vida! plus Experiential Learning, which adds monthly Zoom sessions focused on cooking and physical activity. In Stage 2 (week 8), participants who lose <2% of baseline weight (measured via Fitbit Aria scale) are re-randomized to either continue the initial intervention or receive individualized health coaching using motivational interviewing or a Mailed Toolkit with culturally tailored shelf-stable foods, kitchen tools, and physical activity equipment. All participants receive a Fitbit Charge 6 and Aria scale for self-monitoring and have access to Cook for Your Life, a bilingual nutrition website for cancer survivors. Data are collected at baseline, 2, 6, and 12 months. A subset of participants provide ActiGraph data at each time point to assess physical activity patterns, and in-depth qualitative interviews will be conducted post-intervention. All components are offered in Spanish and English. As of June 24, 2025, 22 English-speaking participants have completed baseline assessments, and 14 Spanish-speaking participants have consented. The first intervention cohort will begin once 60–70 English-speaking participants are enrolled. Recruitment to date has been limited to the Washington State SEER registry, with expansion to California anticipated in summer 2025. However, the most common reason for ineligibility is BMI <30, and many SEER-provided phone numbers are unresponsive or inactive. In response, the BMI threshold was lowered to ≥27, and recruitment strategies are being broadened beyond SEER. Additionally, logistical issues with planned grocery delivery prompted a shift to Mailed Toolkits with shelf-stable foods and health-related equipment. The ¡Vida! trial has begun enrolling participants to test culturally tailored adaptive interventions to promote weight loss in Latina BC survivors. In response to recruitment and implementation challenges, the study team has adapted core components of the intervention and infrastructure to support broader reach and engagement. These early adaptations position the trial for future intervention effectiveness testing. Juan Gudino, Blake Langley, Jennifer Whitten, Yarizel Herrera, Kelley Nay, Sheryl Rothmuller, Sara Buzali, Jennifer Dearden, Sayan Dasgupta, Ashkan Ertefaie, Chongzhi Di, Nancy Davidson, Rachel Yung, India Ornelas, Heather Greenlee. ¡Vida! SMART Trial: Implementation readiness and early adaptation insights from a culturally tailored weight loss trial for Latina breast cancer survivors [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr B099.

We tested the feasibility and preliminary efficacy of an online diet and physical activity program for women with early-stage breast cancer who had completed surgery, chemotherapy, and radiation therapy (ongoing endocrine therapy allowed). Participants with low fruit and vegetable (F/V) consumption and/or low moderate-to-vigorous physical activity (MVPA) levels were randomized to one of two doses - low (one Zoom group session) or high (12 Zoom group sessions) - of an online lifestyle program with the goal of improving F/V intake and MVPA. All participants received eHealth communications (text messages, study website access), a Fitbit, and a WiFi-enabled scale. Primary objectives evaluated feasibility. Secondary objectives compared the 6-month change in F/V intake and MVPA between the two dose groups. Seventy-four women (mean age = 58.4 years; 87% non-Hispanic White; mean time since diagnosis = 4.6 years) were accrued. Among women in the low dose group, 94% attended the single session; among women in the high dose group, 84% attended at least 8 of the 12 sessions. Retention at 6 months was 93%. High relative to low dose participants consumed 1.5 more servings/day of F/V at 6 months (P = 0.007) but MVPA levels did not differ between groups. We successfully implemented an online lifestyle program for early-stage breast cancer survivors. The high dose intervention demonstrated preliminary efficacy in improving F/V consumption in early-stage breast cancer survivors. Future trials can test the intervention in a larger and more diverse population of breast cancer survivors.

Abstract Background: Up to 30% of patients (pts) with ER-positive early breast cancers develop metastatic relapse. The molecular differences between endocrine therapy (ET)-sensitive and ET-resistant relapses, as well as the impact of specific adjuvant ET-based therapies, remain unclear. Methods: The AURORA program (NCT02102165) analyzed multi-omics data of paired primary (prim) and metastatic (meta) tumor tissue, along with plasma samples, from 1,156 patients with metastatic breast cancer (MBC). Targeted genome sequencing (TGS), RNA sequencing, and circulating tumor DNA analysis were performed. ET-resistance at MBC diagnosis was defined following the 5th ESO-ESMO ABC Guidelines. Results: We studied 628 pts with metastatic ER+/HER2- disease. Patient´s median age was 56 years, 133 (21%) were premenopausal, 314 (50%) had ET-resistance at recurrence (9% primary, 41% secondary), 132 (21%) had ET-sensitive recurrence, and the rest were ET-naive recurrences or de novo MBC. Adjuvant treatment was aromatase inhibitor (AI) +/- ovarian function suppression (OFS) in 288 (46%) pts, while 159 (25%) had tamoxifen only (+/- OFS). Gene expression correlation significantly differed (p < 0.005) based on ET-resistance in 92 paired samples. ET-sensitive (n=11) and de-novo tumors (n=41) showed higher correlation than primary (n=7) and secondary ET-resistance (n=32), regardless of adjuvant ET type. Prim and meta showed concordance in 91% of IHC subtypes and 62% of intrinsic subtypes. Intrinsic subtype showed 9% of prim luminal tumors switching to meta non-luminal, with 66% of Luminal A switching to Luminal B. Neither IHC nor intrinsic subtype switching was associated with the type of adjuvant ET or ET resistance. Pts with meta non-luminal intrinsic subtype (18%) had worse PFS on CDK4/6i (HR 4.0, 95% CI 1.9-8.7) and OS (HR 3.6, 95% CI 2.0-5.7) than luminal subtypes. TGS was performed in 534 meta (365 before 1L, 305 pairs). In meta before 1L, the dN/dS algorithm revealed selection in 17 genes, including TP53, PIK3CA, and ESR1. Mutations (mut) in ESR1, ERBB2, ERBB3, and RB1 among others, were specifically identified in meta. The incidence of ESR1mut was 3% in prim, 12.6% before 1L, 23.4% after 1L, and 4.7% in meta from ET-naive tumors (Table). Before 1L, ESR1mut was higher after adjuvant AI vs tamoxifen (21% vs. 4%, p< 0.001). ESR1mut incidence varied with ET-resistance (16% primary, 19% secondary, 9% sensitive, 4% ET-naïve/de novo, p< 0.01). Paired samples showed that ESR1mut were mainly acquired events and associated with higher ER mRNA signaling (hallmark estrogen response) compared to ESR1wt (p < 0.05). The agreement between ESR1mut detected in ctDNA and tissue was high before 1L (90%), and slightly lower after 1L (84%). In a multivariate model with relevant clinical factors, ESR1mut were associated with worse OS (HR 1.76, 95% CI 1.2-2.5, p=0.003), independently of TP53 and PIK3CA mutational status. Conclusion: AURORA study sheds light on metastatic tumor alterations acquired under anti-cancer therapy, in ER+/HER2- MBC. We observed a high prevalence of acquired ESR1mut prior to the initiation of first-line therapy, particularly in tumors exposed to adjuvant AI or with primary or secondary ET_resistance. The association of ESR1muts with poorer OS underscores the importance of implementing effective adjuvant ET strategies to prevent the emergence of these mutations. Frequency of driver gene mutations in primary and metastastic tumors before 1st-line treatment according to adjuvant ET and type of ET resistance Table. Citation Format: Angel Guerrero-Zotano, Matteo Benelli, Alexandre Irrthum, David Cameron, Lorenzo Ferrando, Dario Romagnoli, Marta Paoli, Arnau Llinas, Maya Dadiani, Danai Fimereli, Mafalda Oliveira, Carmela Caballero, Thayane Crestani, Elisa Agostinetto, Diogo Martins-Branco, Florentine Hilbers, Einav Gal-Yam, Marija Balic, Fatima Cardoso, Jorge Reis-Filho, Christos Sotiriou, Giuseppe Curigliano, Barbro Linderholm, Evandro de Azambuja, Susan Knox, Cristina Rotaru, Eva Ciruelos, Nancy E Davidson, Giuseppe Viale, Donatienne Taylor, Jean-Luc Canon, Lourdes Calvo, Joan Albanell, Marco Colleoni, Caroline Duhem, Nadia Harbeck, Catherine Herremans, Sibylle Loibl, Sandrine Marreaud, Elsemieke Scheepers, Alice Raimbault, Theodora Goulioti, Andrea Vingiani, Chiara Biagioni, Sebastian Vosberg, Gabriele Zoppoli, Jose Seoane, David Venet, Philippe Aftimos, Martine Piccart. Clinical and Genomic Features of ER-Positive/HER2-negative Metastatic Breast Cancer in AURORA Molecular Screening Initiative (BIG 14-01): Mechanisms of Endocrine Therapy Resistance and Implications for Adjuvant Approaches [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-04.

Importance Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. Objective To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. Design, Setting, and Participants This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Main Outcomes and Measures Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Results Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. Conclusions and Relevance In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

There is growing awareness of the unique etiology, biology, and clinical presentation of invasive lobular breast cancer (ILC), but additional research is needed to ensure translation of findings into management and treatment guidelines. We conducted a survey with input from breast cancer physicians, laboratory-based researchers, and patients to analyze the current understanding of ILC, and identify consensus research questions. 1774 participants from 66 countries respondents self-identified as clinicians (N = 413), researchers (N = 376), and breast cancer patients and advocates (N = 1120), with some belonging to more than one category. The majority of physicians reported being very/extremely (41%) to moderately (42%) confident in describing the differences between ILC and invasive breast cancer of no special type (NST). Knowledge of histology was seen as important (73%) and as affecting treatment decisions (51%), and most agreed that refining treatment guidelines would be valuable (76%). 85% of clinicians have never powered a clinical trial to allow subset analysis for histological subtypes, but the majority would consider it, and would participate in an ILC clinical trials consortium. The majority of laboratory researchers, reported being and very/extremely (48%) to moderately (29%) confident in describing differences between ILC and NST. They reported that ILCs are inadequately presented in large genomic data sets, and that ILC models are insufficient. The majority have adequate access to tissue or blood from patients with ILC. The majority of patients and advocates (52%) thought that their health care providers did not sufficiently explain the unique features of ILC. They identified improvement of ILC screening/early detection, and identification of better imaging tools as top research priorities. In contrast, both researchers and clinicians identified understanding of endocrine resistance and identifying novel drugs that can be tested in clinical trials as top research priority. In summary, we have gathered information from an international community of physicians, researchers, and patients/advocates that we expect will lay the foundation for a community-informed collaborative research agenda, with the goal of improving management and personalizing treatment for patients with ILC.

We report the 20-year rate of ipsilateral breast event (IBE) for patients with ductal carcinoma in situ (DCIS) treated with lumpectomy without radiation on a non-randomized prospective clinical trial. Patients were enrolled in cohort 1: low- or intermediate-grade DCIS, size ≤ 2.5 cm ( n = 561); or cohort 2: high-grade DCIS, size ≤ 1 cm ( n = 104). The Kaplan–Meier method was used to estimate time-to-event distributions. Cox proportional hazard methods were used to estimate hazard ratios (HRs) and tests for significance for event times. 561 patients were enrolled in cohort 1 and 104 in cohort 2. After central pathology review, 26% in cohort 1 were recategorized as high-grade and 26% in cohort 2 as low- or intermediate-grade. Mean DCIS size was similar at 7.5 mm in cohort 1 and 7.8 mm in cohort 2. Surgical margin was ≥3 mm in 96% of patients, and about 30% received tamoxifen. Median follow-up was 19.2 years. There were 104 IBEs, of which 54 (52%) were invasive. The IBE and invasive IBE rates increased in both cohorts up to 15 years, then plateaued. The 20-year IBE rates were 17.8% for cohort 1 and 28.7% for cohort 2 ( p = 0.005), respectively. Invasive IBE occurred in 9.8% and 15.1% ( p = 0.09), respectively. On multivariable analysis, IBE risk increased with size and was higher in cohort 2, but grade and margin width were not significantly associated with IBE. For patients with DCIS treated with excision without radiation, the rate of IBE increased with size and assigned cohort mostly in the first 15 years.

Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8+ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.

Breast cancer (BC) is the most common non-skin cancer and the second leading cause of cancer death in American women. The initiation and progression of BC can proceed through the accumulation of genetic and epigenetic changes that allow transformed cells to escape the normal cell cycle checkpoint control. Unlike nucleotide mutations, epigenetic changes such as DNA methylation, histone posttranslational modifications (PTMs), nucleosome remodeling and non-coding RNAs are generally reversible and therefore potentially responsive to pharmacological intervention. Epigenetic dysregulations are critical mechanisms for impaired antitumor immunity, evasion of immune surveillance, and resistance to immunotherapy. Compared to highly immunogenic tumor types, such as melanoma or lung cancer, breast cancer has been viewed as an immunologically quiescent tumor which displays a relatively low population of tumor-infiltrating lymphocytes (TIL), low tumor mutational burden (TMB) and modest response rates to immune checkpoint inhibitors (ICI). Emerging evidence suggests that agents targeting aberrant epigenetic modifiers may augment host antitumor immunity in BC via several interrelated mechanisms such as enhancing tumor antigen presentation, activation of cytotoxic T cells, inhibition of immunosuppressive cells, boosting response to ICI, and induction of immunogenic cell death (ICD). These discoveries have established a highly promising basis for using combinatorial approaches of epigenetic drugs with immunotherapy as an innovative paradigm to improve outcomes of BC patients. In this review, we summarize the current understanding of how epigenetic processes regulate immune cell function and antitumor immunogenicity in the context of the breast tumor microenvironment. Moreover, we discuss the therapeutic potential and latest clinical trials of the combination of immune checkpoint blockers with epigenetic agents in breast cancer.

Genome wide genotyping of E5103 samples. Quality controls for GWAS.

XLSX file - 20K, Description and specifics regarding the ILC E2 geneset.