Clinical Cancer Research最新文献

{"title":"Abstract PS4-03-03: Age-driven genomic differences in breast cancer: relevance for PI3K-pathway","authors":"N. Lopetegui-Lia, A. Davenport, J. Gill, A. M. Roy, S. Myers, D. Agnese, E. Burke, T. Y. Andraos, D. M. Schimming, S. Hulett, H. LeFebvre, M. Gatti-Mays, D. Stover","doi":"10.1158/1557-3265.sabcs25-ps4-03-03","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps4-03-03","url":null,"abstract":"Background The rising incidence of Breast cancer (BC) in young women requires further genomic characterization, as only a fraction carry a germline mutation. Given the growing interest in therapies targeting the phosphoinositide 3-kinase/AKT (PI3K/AKT), mammalian target of rapamycin (mTOR), and phosphatase and tensin homolog (PTEN) pathways, central to BC pathogenesis, we evaluated whether PI3K/AKT/mTOR pathway alterations and gene expression differed by age at BC diagnosis. Methods: In this analysis of patients’ tumor/germline whole exome DNA and RNA sequencing data from the Ohio State University Total Cancer Care registry, 71 profiled patients were young adults (YA) aged < 40 years, and 675 were non-YA aged ≥40 years. Descriptive statistics characterized the frequency and co-occurrence of BC-specific alterations and mRNA expression profiles by age groups. Results The prevalence of these BC-relevant mutations are reported in Table 1 Table: Prevalence of BC-relevant mutations by age cohort Mutation Age Group % of Patients with Mutation Fisher's Exact Test p-value (<40 vs ≥ 40) PIK3CA <40 16.9% (12/71) 0.0002 ≥ 40 39% (263/675) AKT1 <40 5.6% (4/71) 0.220 ≥40 10.8% (73/675) mTOR <40 16.9% (12/71) 0.450 ≥40 21.5% (145/675) PTEN <40 12.7% (9/71) 0.550 ≥40 10.5% (71/675) . PIK3CA mutation occurred more frequently in non-YA patients (16.9% YA versus (vs) 39% non-YA; p<0.0002). The frequency of driver mutations were similar between cohorts (73% in YA vs 82% in non-YA). Most hotspot mutations were enriched in non-YA group, particularly H1047R (15.11% n=102 non-YA vs 4.23%, n=3 YA; p= 0.01). Others include: E545K (6.52%, n=44 vs 2.82%, n=2, p=0.302), E542K (4.59%, n=31 vs 1.41%, n=1; p=0.352); H1047L (1.93%, n=13 vs none, p=0.625) and N345K (1.78%, n=12 vs 1.41% n=1; p=1.00). There were no age-based differences in AKT1 mutation (5.6% YA vs 10.8% non-YA patients; p=0.220). Hotspot alterations E17K, E17G, and L52R were numerically enriched, albeit nonsignificant, in non-YA. There were no significant differences in the presence of mTOR by age (16.9% YA and 21.5% non-YA; p=0.450). Most alterations in both groups were variants of unknown significance (17/17 in YA, 157/159 in non-YA). YA and non-YA cohorts had similar frequency of PTEN mutations (12.7% YA vs 10.5% non-YA; p=0.550). The proportion of PTEN driver mutations also did not differ (82% YA and 93% non-YA). Conclusion PIK3CA mutations were more prevalent among non-YAs highlighting potential age-associated oncogenic drivers. Although AKT1, mTOR, and PTEN gene mutations did not differ between age groups, in general, oncogenic/hotspot mutations occurred more frequently in patients ≥40 years. As management of BC evolves to incorporate PI3K/AKT/mTOR inhibitors, age-specific somatic alterations may uncover therapeutic vulnerabilities and inform customized treatment. Citation Format: N. Lopetegui-Lia, A. Davenport, J. Gill, A. M. Roy, S. Myers, D. Agnese, E. Bur","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"94 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS1-09-13: Development of Staging Guidelines for Metastatic Breast Cancer: Which method is best?","authors":"J. K. Plichta, V. Rey, M. Blasingame, S. Luo, S. M. Thomas","doi":"10.1158/1557-3265.sabcs25-ps1-09-13","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps1-09-13","url":null,"abstract":"Background: Breast cancer staging is a foundational component for determining prognosis, and multiple methods have been used to create staging guidelines. However, it remains unclear which statistical approach is best. As such, we sought to compare 3 methods for developing staging guidelines, using de novo metastatic breast cancer (dnMBC) as an example. Methods: Patients with dnMBC in the National Cancer Database (2010-2022) were identified (N=48,832). Variables used for staging included clinical T-category, grade, ER, PR, HER2, histology, bone-only metastases, brain-only metastases, visceral metastases, and number of metastatic sites. Stage groups were assigned based on 3-year overall survival (OS) rates: stage group IVA >70%, IVB 50-70%, IVC 25-<50%, and IVD <25%. Statistical methods: (1) We conducted an analysis of all possible variable combinations (AC), yielding 643 unique characteristic profiles; OS was estimated via Kaplan-Meier, which was used to assign a subgroup (IVA-D). (2) Recursive partitioning analysis (RPA) grouped patients with similar OS based on these same disease characteristics; 3-year OS rates were estimated for each terminal node; subgroups (IVA-D) were assigned. (3) Bootstrapping was used; the RPA was repeated 1000 times (B-RPA); subgroups (IVA-D) were determined based on the subgroup each profile fell into most often. Overall, patients were categorized as stage IVA-D based on these 3 methods (AC, RPA, B-RPA), resulting in 3 stage group assignments. Differences in stage group assignments were classified as minor (1 group) or major (>1 group). Performance metrics (Akaike Information Criterion, AIC) were compared. Results: Application of the 3 methods yielded similar findings (Table), although the AC analysis had the best performance (lowest AIC), followed by the B-RPA and RPA. Patient-level Comparison (N=48,832). The same stage group (IVA-D) was assigned to 87.8% of patients by all 3 methods. Comparing B-RPA to AC, 10.6% of patients had a minor stage discrepancy and 0.4% had a major discrepancy. The RPA compared similarly to AC (10.9% minor, 0.4% major). Profile-level Comparison (N=643). Comparing B-RPA to AC, there was 60.7% agreement in stage assignments, 31.4% minor discrepancies, and 6.8% major discrepancies. Comparing RPA to AC was similar (60.8% agreement, 30.8% minor, 7.3% major). Of the 160 most common profiles, there was 85% agreement for both B-RPA and RPA. Of the 160 least common characteristic profiles, there was only 36.3% and 36.9% agreement for the B-RPA and RPA, respectively. Conclusions: Although the AC analysis had the best performance, there was a high level of agreement in stage assignment at the patient level. Potentially due to smaller patient samples in some profile subgroups, there was a moderate degree of discrepancies at the profile level, although most were minor. These findings will help inform future staging guideline development. Citation Format: J. K. Plichta, V. Rey","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS1-10-23: Real-world analysis of unmet need among patients in the US with HR+/HER2- mBC following endocrine therapy","authors":"J. O'Shaughnessy, M. Rehnquist, N. Sadetsky, W. Verret, P. Cinar, N. Sjekloca, L. Nguyen, R. Nanda, P. Sharma","doi":"10.1158/1557-3265.sabcs25-ps1-10-23","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps1-10-23","url":null,"abstract":"Background: Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (immunohistochemistry 0, 1+, or 2+/in situ hybridization-negative) metastatic breast cancer (HR+/HER2- mBC) are treated with endocrine therapy (ET) ± CDK4/6 inhibitor as the preferred option in the first-line setting followed by ET ± targeted therapy. Most HR+ disease will eventually become ET resistant, at which point treatment is primarily limited to cytotoxic therapy. This study describes characteristics, treatment patterns, and real-world outcomes among patients with HR+/HER2- mBC in the post ET-based treatment setting. Methods: This retrospective, observational cohort study utilized electronic health record-derived de-identified data from the US nationwide Flatiron Health Research Database. Women aged ≥ 18 years with HR+/HER2- mBC who received post ET-based treatment from January 1, 2015, to December 31, 2024 were included. Patient characteristics, treatment patterns, time to next treatment or death (TTNTD), and real-world overall survival (rwOS) were described; rwOS was assessed by Kaplan-Meier methods. Results: 5012 patients were included, with a median age of 63 years at mBC diagnosis. Most were Caucasian (62%), treated in the community setting (82%), had ECOG PS 0-1 (78%) at start of first post ET-based treatment, were diagnosed with recurrent mBC (68%), and had ≥ 2 prior lines of ET-based treatment in the mBC setting (65%) The median time from mBC diagnosis to first post ET-based treatment was 19 months. The median follow-up after the first post ET-based treatment in the mBC setting was 12 months. Ninety-six percent of patients received chemotherapy-based regimens as their first post ET-based treatment; capecitabine monotherapy was the most prescribed chemotherapy (34%) followed by taxane monotherapy (18%). Thirty percent of patients who initiated a post ET-based treatment did not survive to the next line of treatment. The median (95% CI) rwOS from start of first post ET-based treatment was 13.4 (12.9-13.9) months. There was a decrease in median (95% CI) rwOS with each subsequent line of treatment, ranging from 10.7 (10.2-11.1) months (second post ET-based treatment) to 7.4 (6.4-8.6) months (fifth post ET-based treatment) (Table). Similar trends were observed for TTNTD. Conclusions: These findings establish the high unmet need in patients with HR+/HER2- mBC treated with the standard of care regimens following ET-based treatment. For these patients, options are limited primarily to chemotherapy, with almost one-third not surviving to receive the second line of post ET-based treatment. This highlights the importance of making the most robust agents available for this patient population and demonstrates a clear and urgent need for new effective treatments in this setting. Citation Format: J. O'Shaughnessy, M. Rehnquist, N. Sadetsky, W. Verret, P. Cinar, N. Sjekloca, L. Nguyen, R. Nanda, P. Sharma. Real-world analysis of unmet need among pa","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"52 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS1-13-23: Survival Results of Phase II Bria-IMT Allogenic Whole Cell-Based Cancer Vaccine","authors":"C. Nangia, S. Chumsri, K. Rowland, L. Negret, J. Knecth, B. Bayer, T. Aghajanian, W. Williams, G. Del Priore, C. Calfa","doi":"10.1158/1557-3265.sabcs25-ps1-13-23","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps1-13-23","url":null,"abstract":"Background Management of metastatic breast cancer (MBC) continues to present obstacles, as many pts develop resistance to or cannot tolerate standard of care treatments. Bria-IMT combines two modalities to both overcome immune exhaustion and minimize the toxic safety profiles commonly observed in contemporary late stage therapies: an allogeneic whole-cell vaccine (SV-BR-1-GM) and checkpoint inhibition (CPI). The SV-BR-1-GM cell line originates from breast cancer cells and are engineered to secrete GM-CSF and irradiated before administration. These cells upregulate surface presentation of tumor associated antigens on both HLA class I and II, enhancing tumor recognition by T cells. Coadministration w/ an anti-PD-1 CPI, the vaccine response is reinforced, counteracting the immuno-suppressive tumor microenvironment. Methods This phase I/II study evaluated the Bria-IMT regimen: low-dose cyclophosphamide (Day –2) followed by SV-BR-1-GM and CPI (pembrolizumab or retifanlimab), then low-dose local peg- interferon α. Cycles q3w. In the phase II study, pts were randomized 1:1 to start CPI immediately at cycle 1 (C1) or delayed start at cycle 2 (C2). There were 2 formulations of SV-BR-1-GM w/ IFNγ stimulation (IFNγ) or unstimulated (PH3). Cancer-associated macrophage-like cells (CAMLs), circulating tumor cells (CTCs), and PD-L1 expression scores on these cells were monitored as biomarkers. Candida skin test assessed anergy status before cycle 1, and a delayed type hypersensitivity (DTH) skin test to SV-BR-1-GM was assessed at each cycle w/ a small SV-BR-1-GM dose before the full dose. Results Results of the randomized phase II study cohort are reported (n = 32). Retifanlimab was co-administered w/ SV-BR-1-GM at C1 or C2. Median age 61 (41-80) years; median number of prior regimens was 6 (2-13). 20(63%) pts were ER+/PR+/HER2-; 3(9%) HER2+, and 9 (28%) triple-negative (TNBC). The Bria-IMT regimen was well tolerated, w/ no drop-outs attributable to Bria-IMT. The majority of adverse events (93.8%) grade 1-2, w/ (40.6%) grades 3 and 4. Common AEs included injection site reactions (53%), nausea (43.8%), and fatigue (34%). The median progression free survival (PFS) was 3.5 (range: 1.8-24.5) and overall survival (OS) 9.5 (2.4-31.6) months. One patient remains on therapy, approaching 25 months of PFS. PFS and OS among pts who received immediate vs. delayed start of CPI (PFS 3.7 vs. 3.3 mo, HR: 0.59; 95% CI 0.3-1.2, p=0.16 | OS 13.3 vs. 7.4 months, HR: 0.78; 95% CI 0.34-1.8, p = 0.56). Pts who received the SV-BR-1-GM Ph3 formulation (n=21) had an increase in both PFS (4.1 vs 2.6 months, p = 0.005) and OS (16.6 vs. 9.1 months, HR: 0.6; 95% CI 0.2 - 1.4, p = 0.24); best objective response rate was 12% and the clinical benefit rate was 53%. In ER+/PR+/HER2-, overall OS was 11.7 (3.5-31.6) mo, 17.3 mo (3.5-27.9) in Ph3; HER2+ 7.2 (4.7-24.5) mo, all received Ph3; TNBC 9.9 (2.4-23.0) mo, 16.6 mo (2.4-23.0) in Ph3. In pts w/ available data, pts w/ post-dose CTC count &l","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS2-12-08: Obi-201: a bispecific trop2 × her2 antibody-drug conjugate to expand therapeutic reach beyond her2-low limitations","authors":"C. Lu, S. Wang, Y. Chen, Y. Wu, T. Huang, W. Chan, L. Chen, H. Wu, C. Wei","doi":"10.1158/1557-3265.sabcs25-ps2-12-08","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-12-08","url":null,"abstract":"Background: While Enhertu® has delivered meaningful clinical benefits in HER2-positive and HER2-low cancers, many patients still experience suboptimal outcomes, particularly in HER2-low tumors that account for over 50% of the HER2-positive pan cancer population. Resistance to HER2-targeted therapies remains a critical challenge, including HER2 downregulation or loss, which diminishes antibody binding and payload delivery. OBI Pharma is the first to discover that TROP2 and HER2 form heterodimers (Data not published) in cancer cells. This TROP2 and HER2 crosstalk provides a strong rationale for dual targeting. In response, we developed OBI-201—a bispecific antibody-drug conjugate (ADC) engineered to simultaneously engage both TROP2 and HER2, aiming to enhance tumor specificity and overcome resistance associated with single-target therapies. Method: OBI-201 is a next-generation bispecific ADC that co-targets HER2 and TROP2, using site-specific GlycOBI® glycan-based conjugation technology to attach an exatecan payload at a DAR of 4 for precise delivery. To assess the efficiency of internalization, pHAb-labeled OBI-201 was applied to HER2/TROP2 co-expressing cells by quantifying fluorescence signals. To evaluate its antitumor activity, OBI-201 was tested in both cell line-derived xenograft (CDX) models and patient-derived xenograft (PDX) models. Results: The bispecific ADC format of OBI-201 was designed to enhance tumor targeting and promote efficient internalization, which was confirmed by strong internalization signals observed in cells co-expressing HER2 and TROP2. OBI-201 demonstrated superior antitumor activity compared to Enhertu®, Datroway®, and Trodelvy® in HER2-low colorectal, pancreatic, and NSCLC models, as well as in Enhertu-resistant NSCLC CDX models. Remarkably, in a HER2-low TNBC PDX model with established multi-drug resistance, including resistance to Trodelvy®, OBI-201 achieved complete tumor regression in 3 out of 6 mice, highlighting its potential to overcome treatment resistance and address unmet needs in difficult-to-treat tumors. Conclusion: OBI-201 is a next-generation bispecific ADC targeting HER2 and TROP2, designed to overcome the limitations of single-target therapies. Its dual-targeting approach, enabled by GlycOBI®, proprietary ADC enabling technologies for precise payload delivery, offers strong potential to overcome HER2-low expression and resistance, addressing significant unmet needs across a broad spectrum of solid tumors. Citation Format: C. Lu, S. Wang, Y. Chen, Y. Wu, T. Huang, W. Chan, L. Chen, H. Wu, C. Wei. Obi-201: a bispecific trop2 × her2 antibody-drug conjugate to expand therapeutic reach beyond her2-low limitations [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS2-12-08.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"47 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS4-03-16: Characterization of the cytokine profile of metastatic Breast Cancer, from mediators of chronic inflammation to potential biomarkers","authors":"M. M. Caffarel, U. Alvarez, P. Azcoaga, A. Romo, S. Manzano, P. Petit, I. Garmendia, M. Garzón, Z. Telletxea, M. Otaño, A. Urruticoechea, I. Alvarez-Lopez","doi":"10.1158/1557-3265.sabcs25-ps4-03-16","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps4-03-16","url":null,"abstract":"Inflammation is a natural immune response that can protect against cancer in early stages but, when becomes chronic, creates an immunosuppressive tumour microenvironment (TME) that promotes tumour progression. Recognized as a hallmark of cancer, chronic inflammation offers potential for new therapeutic strategies, particularly immunotherapy. However, some solid tumours, such as breast cancer, show partial resistance to these treatments. Cytokines are key regulators of inflammation, influencing cell communication and immune responses within the TME (1,2). Importantly, current clinical classification of BC often neglects the immune landscape, limiting the ability to predict responses to immunotherapy. Our hypothesis is that the cytokine profile of metastatic breast cancer possesses prognostic and predictive value and that cytokines can be potential biomarkers in breast cancer. Understanding how cytokine loops are coordinated within the breast TME could also lead to novel cytokine-based therapeutic strategies. Cytokine levels in serum and fresh tissue samples from metastatic BC patients (n=150) and in serum samples from metastatic cancer patients from other solid tumour types (n=186) were measured by Olink cytokine panel, which quantitatively assess 40 cytokines. Cytokine levels were correlated with clinical data, including overall and relapse free survival. The statistical analysis was done using different mathematical modelling methods. Our unpublished results show that the serum and tumour cytokine profiles do not correlate significantly, supporting the idea that some cytokines act locally in the TME. In addition, comparison with other metastatic tumour samples, led to the identification of some cytokines that are differentially expressed in BC. Integration of these data will shed light on the characterization of cytokine interactions in metastatic BC, helping to define its immune landscape. 1. Soler MF, Abaurrea A, Azcoaga P, Araujo AM, Caffarel MM. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family. J Immunother Cancer. 2023;11(11):e007530; 2. Manzano S, Caffarel MM. Cytokine-centered strategies to boost cancer immunotherapy. Mol Oncol. 2025;19(3):579-583 Citation Format: M. M. CaffarelU. AlvarezP. AzcoagaA. RomoS. ManzanoP. PetitI. GarmendiaM. GarzónZ. TelletxeaM. OtañoA. UrruticoecheaI. Alvarez-Lopez. Characterization of the cytokine profile of metastatic Breast Cancer, from mediators of chronic inflammation to potential biomarkers [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS4-03-16.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"278 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS4-10-20: Exploring Potential Predictive Factors for Immunotherapy Response in Early-Stage TNBC: Insights from a Retrospective Analysis","authors":"A. Sweidan, J. Sherwood, M. Ahmed, S. Bai, H. Ali","doi":"10.1158/1557-3265.sabcs25-ps4-10-20","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps4-10-20","url":null,"abstract":"Background: Neoadjuvant chemoimmunotherapy (NACT-IO) has been the standard of care for high-risk early-stage triple-negative breast cancer (eTNBC) for over five years. However, data on predictive biomarkers and clinical factors associated with treatment response remain limited. This study evaluates the association of several factors with pathological complete response (pCR) following NACT-IO. BRCA1/2 mutations, present in ∼15-20% of TNBC cases, are linked to higher tumor mutational burden (TMB), potentially enhancing immunotherapy response. Angiotensin-converting enzyme (ACE) is intrinsically expressed in immune cells and may influence anti-tumor immunity. Additionally, immune-related adverse events (irAEs) occur in ∼30% of eTNBC patients receiving NACT-IO; while higher-grade irAEs have been linked to improved pCR, data on low-grade irAEs remain limited. Thus, we assessed how BRCA1/2 status, ACE inhibitor use, and irAE severity may impact response to NACT-IO. Methods: A retrospective analysis was conducted on eTNBC patients treated with NACT-IO at Henry Ford Hospital (Detroit, MI) between July 2021 and October 2024. Categorical variables were analyzed using Chi-square or Fisher exact tests; P < 0.05 was considered significant. Results: Among 173 eligible patients, 14 (8%) had pathogenic BRCA1/2 mutations, 18 (10%) were on ACE inhibitors, 7 (4%) had grade 1 irAEs, and 51 (29%) had grade ≥2 irAEs. pCR rates were significantly higher among those with grade ≥2 irAEs versus those with grade 1 or no irAEs. No significant differences in pCR rates were seen by BRCA status or ACE inhibitor use, though BRCA-mutated patients showed a numerical trend toward higher pCR rates. Conclusion: pCR rates were significantly higher in patients with grade ≥2 irAEs. The low number of grade 1 irAEs may reflect underreporting. While BRCA1/2 mutation carriers had numerically higher pCR rates, this was not statistically significant, suggesting a potential improvement in response that warrants further study. Notably, ∼22% of patients lacked documented BRCA status, underscoring the need for universal genetic testing in TNBC. No significant association was found between ACE inhibitor use and surgical outcomes; however, larger studies are needed to clarify their potential impact on response to immunotherapy. Citation Format: A. Sweidan, J. Sherwood, M. Ahmed, S. Bai, H. Ali. Exploring Potential Predictive Factors for Immunotherapy Response in Early-Stage TNBC: Insights from a Retrospective Analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl): nr PS4-10-20.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"70 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PD9-07: The Genomic, Transcriptomic, and Immune Hallmarks of Metastatic Lobular Breast Cancer","authors":"G. Nader-Marta, S. Kumar Deshmukh, K. Fanucci, P. Tarantino, S. Schnitt, A. Lee, S. Oesterreich, S. Wu, J. Xiu, P. Advani, M. Lustberg, N. Lin, S. Tolaney, E. Mayer, O. Metzger, G. Sledge, R. Jeselsohn","doi":"10.1158/1557-3265.sabcs25-pd9-07","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-pd9-07","url":null,"abstract":"Background: Invasive lobular carcinoma (ILC) is the second most common breast cancer (BC) subtype, accounting for up to 15% of cases. Although several biologic differences between ILC and invasive carcinoma of no special type (NST) have been described, most data are derived from primary tumors. In contrast, the biology of metastatic ILC remains poorly defined. This study aimed to investigate the unique genomic, transcriptomic, and immune landscapes of metastatic ILC using a multi-omic approach. Methods: This real-world study included patients with confirmed NST or pure ILC who had a biopsy of a metastatic lesion or a breast lesion in the setting of known metastatic disease. Tumors underwent whole exome sequencing (NGS 592, NextSeq; WES, NovaSeq), whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Demographic and baseline molecular features were compared across histologic subtypes. Tumor mutational burden (TMB; high ≥10 mut/MB) was assessed by NGS. Immune cell populations were estimated by RNAseq deconvolution (quanTIseq). Pathway enrichment analysis was determined by GSEA. Overall survival (OS) was defined from the date of biopsy to death from any cause using Kaplan-Meier estimates. Statistical tests included chi-square and Mann-Whitney U with multiple testing correction (q<0.05). Results: Among 2,651 metastatic BC samples (ILC n = 608; NST n = 2,043), patients with ILC were older (median 67 vs 63 yrs) and more likely white (81.5% ILC vs 73.1% NST), all p<0.05. By IHC, ILC were more frequently HR+/HER2- (83.6% vs 55.9%), less commonly triple-negative (11.9% vs 29.8%) or HER2+ (4.6% vs 14.3%), all p<0.05. PAM50 subtypes differed between ILC and NST: luminal A (Lum A) (31.1% vs 13.7%) and luminal B (Lum B) (44.9% vs 43.8%) intrinsic subtypes were enriched in ILC, while NST was more frequently basal (1.2% vs 22.4%) and HER2-enriched (19.8% vs 22.2%), all p<0.05. Within luminal BC, Lum B was more common than Lum A in both histologies, but Lum A was proportionally more frequent in ILC (ILC: 40.3% Lum A vs 59.7% Lum B; NST: 23.4% Lum A vs 76.6% Lum B), p<0.0001. Comparative multi-omic analysis focused on the 922 HR+/HER2- tumors (ILC n = 275; NST n = 647). Compared to NST, ILC had higher frequency of CDH1 (87.3% vs 6.1%), PIK3CA (52.7% vs 38.5%), FOXA1 (9.0% vs 3.4%), ERBB2 (7.1% vs 2.0%), ARID1A, and NF1 (both q < 0.05) mutations and TMB high (17.7% vs 9.9%), but lower frequency of TP53 (15.7% vs 33.3%), ESR1 (10.9% vs 18.1%) and GATA3 (2.3% vs 14.9%) mutations along with FGFR1 amplifications (15.3% vs 6.7%), all q<0.05. ILC had higher expression of androgen receptor (91.2% vs 83.5%, q<0.05) and higher MAPK activation score (-0.81 vs -1.19, q<0.05), consistent with a luminal, hormone-driven phenotype. NST tumors demonstrated enrichment of pathways involved in the cell cycle and metabolic activity, including E2F targets, G2M checkpoint, MYC targets, mTORC1 sig","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"7 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS5-02-12: Intracranial Activity and Systemic Efficacy of Trastuzumab Deruxtecan in Breast Cancer Patients with Brain Metastases","authors":"Z. Sarfraz, V. Podder, K. Vazquez, F. Akkoc Mustafayev, M. Jaramillo, K. A. Qidwai, M. Ganiyani, V. Andion Camargo, R. Mahtani, M. Ahluwalia","doi":"10.1158/1557-3265.sabcs25-ps5-02-12","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-02-12","url":null,"abstract":"Background: Trastuzumab deruxtecan (T-DXd), a novel antibody-drug conjugate (ADC), has shown promising intracranial efficacy in breast cancer (BC) patients with brain metastases (BM). This meta-analysis evaluates the intracranial activity and systemic efficacy of T-DXd in patients with metastatic BC and BM. Methods: A systematic search was conducted from inception until May 6, 2025, across PubMed, Cochrane Library, and oncology conference abstracts (ASCO, ESMO, SABCS, and EANO). Eligible studies included clinical trials and cohort studies reporting outcomes for BC patients with BM receiving T-DXd. Random-effects meta-analysis models with Freeman-Tukey transformations were used for pooling proportions (intracranial clinical benefit rate [IC-CBR], intracranial objective response rate [IC-ORR], and 12-month systemic overall survival [OS]). Systemic progression-free survival (PFS) was pooled using a random-effects inverse-variance model. For PFS, means and standard deviations (SDs) were extracted when available or estimated from medians and IQRs using the Wan et al. (2014) method: mean = (Q1 + median + Q3)/3 and SD = (Q3 − Q1)/1.35, adjusted for sample size. Heterogeneity was assessed using the I2 statistic, with values ≤25% considered low, 26-75% moderate, and >75% high. Registration: osf.io/swghm. Results: Of the 489 screened records, 14 studies were included; 1 was a randomized controlled trial, 6 were prospective single-arm trials, and 7 were retrospective cohort studies, including real-world data from early access programs. Median patient age was 56.3 years; 97.3% had HER2-positive BC, and 2.7% HER2-low. Prior cranial radiotherapy was administered in 61%, with concurrent radiotherapy at T-DXd initiation in 1.4%. Median follow-up duration was 12.9 months (IQR: 11-15). T-DXd was administered uniformly at 5.4 mg/kg IV every three weeks, with protocol-specified dose reductions allowed. Pooled IC-CBR was 81% (95% CI: 69-91%, p<0.001), indicating strong intracranial clinical efficacy, with low heterogeneity (I2=18.6%). IC-ORR was 62% (95% CI: 51-74%, p<0.001), suggestive of substantial intracranial tumor responses. Moderate heterogeneity was noted (I2=71.8%). The pooled mean systemic PFS was 12.6 months (95% CI: 7.1-18.1, I2=99.8%, p<0.001). Pooled 12-month OS was 81% (95% CI: 66-93%, p<0.001), highlighting favorable survival outcomes despite high heterogeneity (I2=86.5%). Conclusion: T-DXd demonstrates robust intracranial activity and 12-month survival in breast cancer patients with brain metastases. The pooled IC-CBR of 81% notably exceeds historical benchmarks reported with T-DM1 or chemotherapy, which typically range from 30-50% in this population. Prospective studies are needed to refine patient selection and optimize therapeutic sequencing. Citation Format: Z. Sarfraz, V. Podder, K. Vazquez, F. Akkoc Mustafayev, M. Jaramillo, K. A. Qidwai, M. Ganiyani, V. Andion Camargo, R. Mahtani, M. Ahluwalia. Intracranial A","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PS5-08-07: Open-label Single-arm Phase 2 Trial of Trastuzumab Deruxtecan in Previously Treated HER2-Immunohistochemistry (IHC) 0 Advanced Breast Cancer - HER2 PARADIGM trial","authors":"A. Kahn, J. Du, N. Casasanta, S. Schellhorn, M. Digiovanna, T. Sanft, M. Rozenblit, A. Silber, L. Pusztai, Z. Rahman, D. O'Neil, R. Legare, W. Kidwai, J. Kanowitz, A. Bulgaru, N. Fischbach, S. Hall, K. Fenn, K. Blenman, O. Blaha, E. Winer, I. Krop, D. Rimm, M. Lustberg","doi":"10.1158/1557-3265.sabcs25-ps5-08-07","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-08-07","url":null,"abstract":"Background: Trastuzumab-deruxtecan (T-DXd) showed impressive efficacy in patients whose breast cancers are either human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) positive or HER2-low/ultralow. In a phase 2 trial, patients with HER2-IHC 0 who received T-DXd had an objective response rate of approximately 30%, revealing activity regardless of HER2-IHC status. In this study, we will treat patients with advanced HER2 IHC 0 breast cancers with T-DXd and assess biomarkers of response and resistance to therapy. We will investigate patients’ tumor biopsies for more precise quantitative HER2 tests, including the High-Sensitivity (HS)-HER2 Troplex testing, that could help determine if T-DXd is active in patients with HER2-IHC 0 tumors regardless of HER2 quantitative expression or if there is a potentially optimal cutoff value of HER2 expression with respect to clinical outcomes for response, improving patient selection and prevention of unnecessary toxicity. Methods: This is a non-randomized, single-arm, open-label, phase 2 study to assess the efficacy and safety of T-DXd in patients whose breast cancer is HER2-IHC 0 (including 0-null and 0-ultralow) in all prior biopsies, with unresectable and/or metastatic disease regardless of hormone receptor (HR) status (NCT06750484). Key eligibility criteria include ECOG-PS 0-2; up to 2 prior lines of systemic cytotoxic therapy for treatment in the metastatic setting; no upper limit of prior endocrine, immunologic or targeted therapy lines. Fifty subjects will be included to achieve 82% power to detect a difference in ORR of 0.15 from historical control (ORR in experimental arm of 0.3 vs. ORR in historical control of 0.15) using a two-sided exact test with a target significance level of 0.1. The study treatment with T-DXd administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight will be continued in the absence of withdrawal of subject consent, progressive disease (PD), death, or unacceptable toxicity. Patients will be followed and evaluated by RECIST v1.1 criteria. Objective response to T-DXd will be evaluated in the entire study population and separately in the High-Sensitivity (HS)-HER2 Troplex detectable and non-detectable cohorts (defined by the limit of detection [LOD] of the analytic HS-HER2 Troplex assay). In addition, HER2 tissue concentrations (measured by the HS-HER2 Troplex assay in attomole/mm2) will be plotted and analyzed as a function of response to determine levels of tumor expression and potential cut-points associated with benefit from T-DXd. Since the Troplex assay simultaneously provides TROP2 levels in attomole/mm2, the influence of TROP2 levels on response to T-DXd will also be exploratorily investigated. Additional objectives are to assess efficacy in terms of progression-free survival and overall survival, safety, and explore potential biomarkers of response and resistance to therapy with T-DXd. The trial is currently open and enrollin","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}