PURPOSE:Within a randomized clinical trial comparing partial breast irradiation (PBI) dosing schedules, we sought to determine whether shortening the radiation course would reduce financial toxicity (FT). METHODS AND MATERIALS:In a phase 3 trial of 778 women aged ≥40 years who underwent segmental mastectomy for early breast cancer at 12 US cancer centers, patients were randomized 1:1 to external beam PBI using 15-22 fractions (control, n = 385) versus 513 fractions (experimental, n = 393) (NCT03077841). FT was assessed using comprehensive, multi-item instruments and scored using the Economic Strain and Resilience in Cancer measure at baseline, end of radiation treatment (EoT), and 6- and 18-months after radiation on a scale of 0-100 (higher score indicated worse FT). Mixed linear multivariable regression estimated adjusted difference-in-differences between EoT versus baseline FT by treatment arm. Minimal important difference (MID) in Economic Strain and Resilience in Cancer score from baseline to EoT was estimated, anchored on change in patient-reported overall financial situation during that interval. RESULTS:Treatment arms had balanced clinical and sociodemographic characteristics. Median PBI duration was 22 days (IQR, 21-25) for the control arm versus 7 days (IQR, 5-10) for the experimental arm (P < .001). FT measures were completed for 96.1% of baseline and EoT assessments (n = 1496/1556). Adjusted improvement in FT score between baseline to EoT was -2.0 (95% CI, -3.6 to -0.4; P = .02) for the experimental versus control arm. Of 52 individual FT items assessed, 9 favored the experimental arm at EoT (P < .05), whereas none favored the control arm. MID in Economic Strain and Resilience in Cancer score was 2.2 (95% CI, 1.0-3.4). CONCLUSIONS:For patients with early breast cancer eligible for PBI, shortening the radiation duration by an average of 15 days yielded a reduction in end of treatment FT that was less than the MID estimated in this study.

Abstract Background: We hypothesized that the systemic benefit of regional nodal irradiation (RNI) for breast cancer derives from immune stimulation in involved nodes. We compared involved lymph nodes (ILN) from patients treated on a prospective trial of pre-operative and post-operative conventional (2 Gy/fx) versus hypofractionated (2.67 Gy/fx) RNI regimens (SAPHIRE NCT02912312). Methods: 17 patients ILNs with ER+, pN+ BC were Digitally Spatially Profiled with immune-related proteins. 6 post-op cases had no neoadjuvant chemotherapy (NACT) (untreated controls). All others had NACT +/- RNI. 4 pre-operative RNI short-course (RNI_NACT-2.67Gy/fx); 5 pre-op standard RNI (RNI_NACT-2 Gy/fx); 3 post-op RNI after NACT. 5 Regions of Interest (ROIs) were selected and categorized as “Tumor” (PanCK+) or “Immune” (CD45+) compartments. Cell density and spatial analysis were assessed in selected cases. Pearson’s correlations, T-Test and KS tests were performed on protein expression in all ROIs, FDR < 0.1, P value < 0.05. Signals with Log2 differences between -1 and 1 were analyzed using adjusted LMM for patient-level variation, and PCA of ROIs by compartment was performed. Results: Nearest neighbor analysis shows increasing median distance between tumor and immune cells from untreated, to NACT, and NACT+RNI, and no differences between short and standard pre-operative RNI. Proximity analysis reveals the distribution of CD3+ cells from the CK+ cells changes with increasing therapy, favoring frequency of closer immune cells, although the average number of cells around each CK+ cell diminishes with increasing therapies. CK+ cell density remains stable, suggesting migration rather than cell death. Differences in expression profiles of immune ROIs suggest more immune signaling in pre-op short. Considering all RT, 27 differentially expressed proteins (DEP) were significantly upregulated in Post tumor ROIs. None were significantly downregulated. After correction by LMM, 11 markers were up in Post cases and none downregulated. We found lower expression of SMA , CD4, CD45RO, CD14, CD11c, TIM-3, and B7-H3 in the Pre nodes. No significant DEPs remain in immune ROIs after LMM correction. The first two principal components accounted for 45.8% of the total variance, with PC1 largely separating samples based on Pre RNI. Pre-short vs Pre-standard showed 9 increased and 0 decreased proteins in Pre-short including CD27, Sting, CD40, CD11c, CD25. Conclusions: Pre-operative radiation contributes to Immune microenvironment remodeling, complementing neoadjuvant chemotherapy in ILN, without altering immune cell density. Different immune signals in irradiated ILN suggest a less immunosuppressive phenotype in RNI, and potential immune activation in Pre-short RNI. Small sample size limits conclusions, immune studies will follow to optimize radiation regimens. Citation Format: Stephanie O. Dudzinski, Elizve N. Barrientos-Toro, Benjamin D. Smith, Simona F. Shaitelman, Sharia Hernandez, Alejandra Serrano, Khan Khaja, Larisa Kostousov, Wei Lu, Rensi Zacharia, Nathan Comeaux, Solis M. Luisa, Aysegul A. Sahin, Maria Gabriela Raso, Jing Wang, Karen Hoffman, Wendy A. Woodward. Spatial protein profiling of irradiated ER positive breast cancer lymph nodes suggests nodal irradiation modulates immune function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7432.

PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.

OBJECTIVES:Bone metastases are common in advanced cancers. In patients with impending pathologic fractures, prophylactic fixation can improve quality of life. Postoperative radiotherapy (RT) is the standard of care for bone metastases; however, preoperative RT may be beneficial in some patients. We evaluated outcomes in patients treated with preoperative RT for bone metastases. METHODS:We performed a retrospective review of 10 patients with bone metastases treated with preoperative RT. Descriptive statistics were used to characterise the cohort, and the Kaplan-Meier method was used to estimate time to subsequent palliative RT treatment and overall survival. RESULTS:10 patients were included in the analysis. Preoperative RT was used for various reasons, including for continuation of systemic therapy (20%), to reduce the RT field (20%) and due to medical comorbidities delaying surgery (20%). The median time from completion of RT to surgery was 13 days (IQR 7-21). The majority of patients (90%) had no postoperative complications. No patients had radiographic evidence of local disease recurrence at a median of 13 months. CONCLUSIONS:Patients treated with preoperative RT do well with minimal operative complications and improvement in reported pain. A randomised clinical trial is warranted to compare outcomes for preoperative and postoperative RT for palliation of bone metastasis requiring orthopaedic intervention.

BACKGROUND:Early-stage, hormone receptor positive (HR+) breast cancer has excellent outcomes with lumpectomy, radiotherapy, and endocrine therapy (ET), prompting interest in treatment de-escalation. Advances in stereotactic ablative radiotherapy (SABR) raise the possibility of definitive local therapy without surgery in select patients. We conducted a prospective, phase II trial (NCT02945579) evaluating SABR with ET as a non-operative strategy. MATERIALS AND METHODS:Patients aged ≥ 40 years with cT1N0M0, unicentric, HR+, HER2-negative breast cancer received 3 months of ET followed by SABR in 5 fractions. Vacuum-assisted image-guided core biopsy of the tumor bed was performed 6-12 months after SABR. Patients with pathologic complete response (pCR) omitted surgery. Co-primary endpoints were pCR and 3-year progression-free survival (PFS) rates. Patient-reported outcomes were collected as a secondary endpoint. A Bayesian framework evaluated futility using posterior probabilities to assess a clinically meaningful pCR rate. RESULTS:Twenty patients were enrolled (median age 70.5 years). Nineteen underwent biopsy after SABR. pCR was observed in 10/19 patients (53%, 95% CI 30-73%), and 7 (37%) had near complete response. Among the 12 patients managed without surgery, median follow-up was 44.9 months. Three-year PFS was 92% (95% CI 54-99%), with one non-breast cancer-related death and no breast cancer recurrences. Longitudinal patient-reported outcomes of decisional regret and breast-specific outcomes remained stable. CONCLUSION:Definitive SABR combined with ET achieved substantial pCR rates and encouraging tumor control. These findings support further evaluation of radiotherapy-based definitive treatment and potential surgery omission in carefully selected patients with favorable, HR + breast cancer.

Objective(s): To define pathologic response rates to endocrine therapy and ablative radiotherapy, with omission of breast surgery, for early-stage, hormone receptor (HR)+ breast cancer in a prospective, phase II trial (NCT02945579). Methods: Twenty eligible patients with HR+, HER2-, clinical stage I, unicentric, non-lobular breast cancers with no lymphovascular space invasion, Oncotype ≤25 and age ≥50 were accrued to an IRB approved-protocol. Enrolled patients received three months of endocrine therapy followed by restaging ultrasound and ablative radiotherapy, 37.5Gy/5 fractions every other day. MR LINAC was used when feasible. After radiotherapy, patients continued on endocrine therapy and underwent percutaneous vacuum-assisted, image-guided core biopsy (VAIGCB) of the tumor 6-12 months following radiation, with a minimum of 12 9G cores. Near complete response (nCR) was defined as Miller-Payne 4 and pCR as 5. Patients with a pathologic complete response (pCR) were followed every 6 months with imaging; those without a pCR were recommended for standard-of-care surgery. Miller-Payne score was evaluated on core biopsy and surgical specimens. Co-primary endpoints are pCR on VAIGCB and tumor control at 3 years. We report here the former co-primary endpoint of pCR along with the 95% credible interval (CI). Results: 19 of 20 (95%) of patients underwent VAIGCB; 1 declined and elected continued observation. Of the 19 biopsies, 10 (52.6%) demonstrated pCR (Miller-Payne 5), 7 (36.8%) nCR (Miller-Payne 4) and 2 (10.5%) Miller-Payne 3. Of patients who had a VAIGCB 6 months after radiotherapy, 5/11 (45.4%, 95% CI 18.9%-71.5%) had pCR; of those with VAIGCB 12 months after RT, 5/8 (62.5%, 95% CI 27.4%-86.6%) had pCR. 7/9 patients with residual disease (Miller-Payne <5) underwent surgery, one of whom had pCR in the surgical specimen, consistent with complete removal at VAIGCB. There were no postoperative complications. Two patients with nCR declined surgery: one underwent cryoablation and one continued endocrine therapy and underwent repeat biopsy 4 months later with pCR. In total, 17/19 pts who underwent VAIGCB (89.5%) had pCR or nCR. The 1 patient who declined VAIGCB has no residual disease on imaging 2 years after RT. Median follow-up time for all patients who did not have surgery is 26 (range 18 to 38 mo months), with none (0/12) experiencing progression or recurrence. Conclusion: This is the first study to demonstrate a high rate of VAIGCB pCR and nCR following endocrine therapy and ablative radiotherapy for early stage, HR+, HER2- breast cancers. This may be an appealing approach for patients with breast cancer interested in non-surgical approaches to definitively treat their tumors and highlights the efficacy for non-surgical candidates. Citation Format: Simona Shaitelman, Savitri Krishnamurthy, Gaiane M. Rauch, Yu Shen, PhD, Yan H. Lin, Benjamin D. Smith, Melissa P. Mitchell, Karen E. Hoffman, Chelain R. Goodman, Vicente Valero, Helen M. Johnson, Wendy A. Woodward, Henry Kuerer. Eliminating breast surgery for invasive, hormone-positive breast cancers with an exceptional response to endocrine therapy and ablative radiotherapy: a single-arm, phase 2 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 PS6-04.

Background: Cardiovascular disease (CVD) and cancer are the leading causes of mortality in the United States. Large-scale population-based and mechanistic studies support a direct effect of CVD on accelerated tumor growth and spread, including in breast cancer. Our objective was to test the hypothesis that individuals with prevalent CVD will present with more advanced breast cancers at the time of diagnosis compared to those without CVD. Methods: We conducted a retrospective cohort study in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases from 2009-2020. Participants were female patients aged 66 years or older at diagnosis of invasive breast cancer. We utilized a case-control design, based on breast cancer stage at diagnosis, propensity score matched on factors know to be related to delayed cancer diagnosis. Our full analytic cohort included 19,292 matched individuals, with median age 73 years (interquartile range 70-79), of which 86% were white and 49% had prevalent CVD. The exposure was prevalent CVD prior to breast cancer diagnosis. Our a priori hypothesis tested the odds of locally advanced (T3-4 or N+) or metastatic (M+) breast cancer at diagnosis based on prevalent CVD status. Results: In propensity score matched, multivariable adjusted models we found that individuals with prevalent CVD had a statistically significantly increased odds of locally advanced or metastatic breast cancer at diagnosis (OR, 1.10; 95% CI, 1.03-1.17; p=0.007). This association was observed among hormone receptor positive (OR, 1.11; 95% CI, 1.03-1.19; p=0.006), but not hormone receptor negative (OR, 1.02; 95% CI, 0.86-1.21; p=0.834) breast cancer. Our results were directionally consistent when separately examining locally advanced (OR, 1.09; 95% CI, 1.02-1.17; p=0.017) and metastatic (OR, 1.20; 95% CI, 0.94-1.54; p=0.152) disease, among all receptor subtypes. Conclusions: Our study provides evidence that prevalent cardiovascular disease is associated with more advanced breast cancer at diagnosis. This finding may be specific to hormone receptor positive disease. Future studies are needed to confirm our findings and investigate interventions to improve patient outcomes, including personalized screening. Citation Format: Kevin Nead, Ivan Angelov, Allen M. Haas, Elizabeth Brock, Lingfeng Luo, Jing Zhao, Benjamin D. Smith, Sharon H. Giordano, Nicholas J. Leeper. The impact of cardiovascular disease on breast cancer stage at diagnosis [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 P4-06-29.

Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2-positive (formerly HER2-positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. The primary outcome was ipsilateral breast tumor recurrence. Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2-positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. ClinicalTrials.gov Identifier: NCT02945579

Background: Regional nodal irradiation (RNI) improves breast cancer survival but is associated with treatment-related toxicity. Volumetric Modulated Arc Therapy (VMAT)/Intensity Modulated Radiation Therapy (IMRT) treatment technique has been shown in other disease sites to improve dose homogeneity while reducing side effects compared to 3-Dimensional Conformal Radiation Therapy (3D-CRT). To evaluate the association of radiotherapy (RT) treatment technique with acute toxicity for patients receiving RNI, we performed a secondary analysis of the Shortening Adjuvant Photon Irradiation to Reduce Edema (SAPHIRe) trial, a Phase III trial evaluating conventional (CFx) vs. hypofractionation (HFx). We hypothesized that VMAT technique would be associated with reduced acute toxicity compared to 3D-CRT. Methods: Patients with clinical or pathologic T0-3 N0-2a/3a invasive breast cancer dispositioned to receive comprehensive RNI were randomized to CFx vs. HFx (50Gy/25Fx or 40.05Gy/15Fx). Nodal target volumes included the axilla, infraclavicular and supraclavicular nodal basins, and internal mammary chain. Acute RT-related toxicity was graded utilizing the NCI CTCAE v4.0 scale at the end of RT. Associations between treatment technique with clinicopathologic and treatment variables, dosimetric data, and toxicity endpoints were determined using the Fisher’s Exact, Mann-Whitney U, and Kruskal-Wallis tests. Univariate analysis and multivariable binomial logistic regression were performed to calculate adjusted odds ratios (OR) for factors associated with Grade 2+ toxicity at the end of RT. Results: A total of 645 patients with available RT variables and end of RT toxicity assessments were enrolled from 2017-2024 (median follow-up, 20 months [IQR, 7-35]). Patients treated with VMAT technique were balanced across randomization arm (CFx vs HFx) as well as clinicopathologic and treatment variables but had significantly higher body mass index (BMI) (30 [25-34] vs. 28 [24-33], p=0.004) and were more likely to undergo plastic surgery reconstruction (40% vs. 21%, p<0.001). Patients treated with VMAT technique experienced significantly reduced Grade 2+ toxicity at the end of RT treatment compared to 3D-CRT (38% vs. 51%, p=0.002), including Grade 2+ dermatitis (32% vs. 47%, p<0.001), Grade 1+ fatigue (50% vs. 60%, P=0.03), Grade 1+ pruritus (40% vs. 49%, p=0.02), and Grade 1+ breast edema (0.4% vs. 3.9%, p=0.02). VMAT technique was associated with significantly reduced volume of the body receiving ≥105% (V105%) of the prescription dose (72cc vs. 351cc), V107% (2cc vs. 186cc), and V110% (0cc vs. 77cc; all p<0.001), as well as the maximum percentage dose (Dmax) to the nodes (106% vs 120%, p<0.001). 3D-CRT technique was associated with significantly increased dose to the ipsilateral lung (V20Gy [CFx]/V16Gy [HFx]>35% = 12% vs. 1%, p<0.001) as well as mean heart dose (MHD>4Gy [CFx]/3.2Gy [HFx] = 6% vs. 1%, p=0.007). V105% to the body and Dmax to the nodes were significantly associated with increased rates of acute dermatitis (p=0.004 and p=0.01, respectively) and breast edema (p=0.02 and p=0.005, respectively) while V107% was associated with significantly increased fatigue (p=0.02). On multivariable analysis, increased BMI (OR [95% CI]=1.04 [1.00-1.07], p=0.03) was significantly associated with increased rates of Grade 2+ toxicity at the end of RT while hypofractionation (OR=0.28 [0.19-0.42], p<0.001), VMAT treatment technique (OR=0.38 [0.21-0.68], p=0.001), and absence of boost (OR=0.38 [0.15-0.87], p=0.03) were associated with significantly decreased rates of Grade 2+ toxicity at the End of RT. Conclusion: In this secondary analysis of a prospective randomized clinical trial, patients treated with RNI utilizing VMAT technique compared with 3D-CRT experienced significantly decreased rates of acute treatment-related toxicity, including any Grade 2+ toxicity, in the setting of improved dose homogeneity. Citation Format: Chelain Goodman, Melissa P. Mitchell, Saleh Ramezani, Simona F. Shaitelman, Rensi F. Zacharia, Isidora Y. Arzu, Elizabeth Bloom, Clifton D. Fuller, Melissa M. Joyner, Lauren L. Mayo, George H. Perkins, Jay Reddy, Puneet Singh, Michael C. Stauder, Eric A. Strom, Valerie K. Reed, Pamela J. Schlembach, Wendy A. Woodward, Benjamin D. Smith, Karen E. Hoffman. Association of VMAT versus 3D-CRT Radiotherapy Treatment Technique with Acute Toxicity of Regional Nodal Irradiation: A Secondary Analysis of the SAPHIRe Phase III Randomized Clinical 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 PS6-02.

BACKGROUND:This study compared complication rates and outcomes between patients who underwent premastectomy radiation therapy (Pre-MRT) followed by mastectomy with microsurgical immediate breast reconstruction (IMBR) and patients who underwent mastectomy followed by postmastectomy RT (PMRT) then microsurgical delayed breast reconstruction (DBR). STUDY DESIGN:This is a secondary analysis of a randomized clinical trial (NCT02912312) that randomized patients with breast cancer to receive hypofractionated (40.05 Gy in 15 fractions) or conventionally fractionated (50 Gy in 25 fractions) regional nodal irradiation between August 2018 and August 2022. Demographic, treatment, and outcomes data were collected. The primary outcome was the rate of autologous flap loss. Secondary outcomes included rates of other recipient-site complications. RESULTS:A total of 144 patients were included: 41 underwent Pre-MRT with IMBR and 103 underwent PMRT with DBR, including 66 patients who had tissue expander (TE) placement at the time of mastectomy and 37 who underwent total mastectomy. The median time from mastectomy to DBR was 12.8 months (interquartile range 9.7 to 16.3 months). There were no complete autologous flap losses in either group, and rates of other recipient-site complications were similar between the groups. Infection at the recipient site occurred in 20% (13 of 66) of patients in the PMRT group who underwent TE placement, and 9 (14%) required TE explantation because of complications. CONCLUSIONS:Pre-MRT with microvascular IMBR is associated with a similar complication rate to PMRT with microvascular DBR while avoiding complications relating to TE placement and a reduced time to achieve definitive breast reconstruction. A larger randomized clinical trial of Pre-MRT followed by mastectomy and IMBR is currently underway (NCT05774678).

The aim of this study was to evaluate trends in the total mastectomy (TM) rates in patients with early stage breast cancer (BC) undergoing surgery first at a single institution and compare overall (OS), distant metastasis-free (DMFS), local-regional recurrence (LRR), and BC-specific (BCSS) survival between lumpectomy followed by radiation (breast-conserving therapy (BCT)) and TM. A total of 8967 women with clinical stage T1–2, N0–1, M0 BC who underwent upfront surgery from 1 January 2000 to 31 December 2014 were included. TM rates were evaluated. Inverse probability weighting (IPW) based on propensity scores was used to remove confounding in the survival models in the whole cohort and subset analyses (different stage combined with different hormone receptor status). TM rates increased from 39.7 to 59.9

Importance:Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. Objective:To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). Design, Setting, and Participants:This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2-positive (formerly HER2-positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Intervention:Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. Main Outcome Measures:The primary outcome was ipsilateral breast tumor recurrence. Results:Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2-positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. Conclusions and Relevance:The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. Trial Registration:ClinicalTrials.gov Identifier: NCT02945579.

Multi-cancer early detection assays are being increasingly studied as a way to efficiently and effectively screen for low-stage and treatable cancers from various tissue origins with a single blood test. However, many of these tests suffer from a low positive predictive value and, in positive cases, may suggest tumor origin from a tissue site that is ultimately found to be inaccurate. This can lead to an expensive and often unnecessary diagnostic work-up. Seminomas of the testicle are poorly represented in the studies that have been done, as most of the studies enroll patients over the age of 50, a demographic with a very low incidence of germ cell tumors.Here, we report a case of a 67-year-old male who was found to have a “positive” cancer signal on the multi-cancer early detection assay used in the PATHFINDER-2 trial. An ensuing work-up showed an enlarged external iliac lymph node that was hypermetabolic on whole-body PET CT scan. A core biopsy was diagnostic of seminoma. Further evaluation and surgery revealed an ipsilateral regressed germ cell tumor of the testicle and evidence of additional non-regional lymph node metastases.

Mastectomy, as treatment or preventative measure for breast cancer, is a critical procedure to reduce breast cancer risk and manage disease. Postmastectomy breast reconstruction (PMBR) aims to restore physical appearance and quality of life but carries significant risks (e.g. 20% chance of implant failure) particularly following postmastectomy radiation therapy. While radiation exposure, obesity, and diabetes are known contributors, currently there are no predictors of implant failure, underscoring a crucial gap in clinical decision-making. This study investigates the role of nanomechanical properties of skin and scar tissues in patients undergoing PMBR. This research is part of the EMPOWER study (NCT06584396), a single-center, prospective, observational trial at MD Anderson Cancer Center (MDACC), including female patients undergoing preventive or curative mastectomy who opted for tissue expander-based reconstruction. Since the study start in 2023, 95 eligible patients have been enrolled, with 61 patients (131 samples) successfully measured. During expander-to-implant replacement surgeries, plastic surgeons collect skin and fibrous capsule samples containing scar tissue, then resized by MDACC pathologists and analyzed using the ARTIDIS ART-1 Nanomechanical Phenotype System. This system provides nanoscale-resolution spatial analysis of tissue mechanical parameters, generating over 10,000 data points per sample. Nanomechanical profiling is combined with histopathological annotations, and primary endpoints are clinical outcomes (e.g. implant loss) and patient-reported outcomes assessed using the BREAST-Q survey at multiple time points. Initial analysis of stiffness, adhesion, and dissipation data revealed clear nanomechanical signature differences between skin and scar tissue, with scarred areas characterized by incomplete extracellular matrix (ECM) remodeling and disorganization, and non-scarred areas being driven by ECM maturity and deeper skin characteristics. These findings underscore the precision of tissue collection methods and ARTIDIS' ability to differentiate closely located, but functionally different tissue types. This study provides the clinical first evidence of physical tissue characterization as a potential predictor of clinical outcomes in the context of post-mastectomy implant-based reconstruction. These findings lay the groundwork for developing nanomechanical signatures as clinical biomarkers to predict implant failure, improve preoperative risk stratification, and enhance clinical decision-making. Papa Diogop Ndiaye, Mark V. Schaverien, Victor J. Hassid, Paul L. Shay, John W. Shuck, Mark W. Clemens, Jessie Z. Yu, Austin Y. Ha, Gregory Reece, Margaret J. Roubaud, Alexander F. Mericli, Mark T. Villa, Ashleigh M. Francis, David M. Adelman, Donald Baumann, Joani M. Christensen, Ryan M. Dickey, Philip Hanwright, Sahil K. Kapur, Johnathan B. Olenczak, Aysegul A. Sahin, Edna Paredes, Ahmed Jizawi, Gitika Srivastava, Tobias Appenzeller, Sara Nizzero, Marko Loparic, Marija Plodinec, Benjamin D. Smith. Characterizing nanomechanical properties of skin tissue in postmastectomy implant reconstruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB403.

Background The benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear. Methods We evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, <= 2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant metastasis) who had ypN0 status after neoadjuvant chemotherapy were randomly assigned to receive regional nodal irradiation or no regional nodal irradiation. The primary end point was the interval of freedom from invasive breast cancer recurrence or death from breast cancer (invasive breast cancer recurrence-free interval). Secondary end points included the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, and overall survival. Safety was also assessed. Results A total of 1641 patients were enrolled in the trial; 1556 were included in the primary-event analysis: 772 in the irradiation group and 784 in the no-irradiation group. After a median follow-up of 59.5 months, 109 primary end-point events (50 in the irradiation group and 59 in the no-irradiation group) had occurred. Regional nodal irradiation did not significantly increase the invasive breast cancer recurrence-free interval (hazard ratio, 0.88; 95% confidence interval, 0.60 to 1.28; P=0.51). Point estimates of survival free from the primary end-point events were 92.7% in the irradiation group and 91.8% in the no-irradiation group. Regional nodal irradiation did not increase the locoregional recurrence-free interval, the distant recurrence-free interval, disease-free survival, or overall survival. No deaths related to the protocol-specified therapy were reported, and no unexpected adverse events were observed. Grade 4 adverse events occurred in 0.5% of patients in the irradiation group and 0.1% of those in the no-irradiation group. Conclusions The addition of adjuvant regional nodal irradiation did not decrease the risk of invasive breast cancer recurrence or death from breast cancer in patients who had negative axillary nodes after neoadjuvant chemotherapy.

Radiotherapy is a pillar of breast cancer treatment; however, it remains unclear how radiotherapy modulates the tumor microenvironment. We investigated this question in a cohort of 20 patients with estrogen-receptor positive (ER+) breast tumors who received neoadjuvant radiotherapy. Tumor biopsies were collected before and 7 days postradiation. Single-cell DNA sequencing (scDNA-seq) and scRNA-seq were conducted on 8 and 11 patients, respectively, at these two time points. The scRNA data showed increased infiltration of naive-like CD4 T cells and an early, activated CD8 T cell population following radiotherapy. Radiotherapy also eliminated existing cytotoxic T cells and resulted in myeloid cell increases. In tumor cells, the scDNA-seq data showed a high genomic selection of subclones in half of the patients with high ER expression, while the remaining number had low genomic selection and an interferon response. Collectively, these data provide insight into the impact of radiotherapy in ER+ breast cancer patients.

ImportanceCardiovascular disease (CVD) and cancer are the leading causes of mortality in the US. Large-scale population-based and mechanistic studies support a direct effect of CVD on accelerated tumor growth and spread, specifically in breast cancer.ObjectiveTo assess whether individuals presenting with advanced breast cancers are more likely to have prevalent CVD compared with those with early-stage breast cancers at the time of diagnosis.Design, Setting, and ParticipantsThis population-based case-control study used data from the Surveillance, Epidemiology, and End Results–Medicare linked databases from 2009 to 2020. The analysis was completed from May 2023 to August 2024. Participants were female patients aged at least 66 years diagnosed with invasive breast cancer. Cases were matched with controls by breast cancer stage at diagnosis and propensity scores using factors known to be associated with delayed cancer diagnosis.ExposurePrevalent CVD prior to breast cancer diagnosis.Main Outcomes and MeasuresThe outcome of interest was the odds of locally advanced (T3-4 or N+) or metastatic (M+) breast cancer status at diagnosis.ResultsThe full analytic cohort included 19 292 matched individuals, with median (IQR) age 73 (70-79) years, of whom 1676 (8.7%) were Black and 16 681 (86.5%) were White; 9478 individuals (49.1%) had prevalent CVD. Propensity score–matched, multivariable-adjusted models found that individuals with locally advanced or metastatic breast cancer at diagnosis had statistically significantly increased odds of prevalent CVD (odds ratio [OR], 1.10; 95% CI, 1.03-1.17; P = .007). This association was observed among hormone receptor–positive (OR, 1.11; 95% CI, 1.03-1.19; P = .006) but not hormone receptor–negative (OR, 1.02; 95% CI, 0.86-1.21; P = .83) breast cancer. ORs were directionally consistent when separately examining locally advanced (OR, 1.09; 95% CI, 1.02-1.17; P = .02) and metastatic (OR, 1.20; 95% CI, 0.94-1.54; P = .15) disease, among all receptor subtypes.Conclusions and RelevanceThis case-control study found that individuals with more advanced breast cancer at diagnosis were more likely to have prevalent CVD. This finding may be specific to hormone receptor–positive and ERBB2-negative (formerly HER2) disease. Future studies are needed to confirm these findings and investigate interventions to improve patient outcomes, including personalized cancer screening.