Clinical Cancer Research最新文献

{"title":"Abstract PS2-02-07: Impact of BRCA homozygous copy loss on clinical outcomes of patients (pts) with metastatic breast cancer (MBC) treated with PARP inhibitors (PARPi)","authors":"A. Rodríguez-Hernández, J. Quintanilla, R. Graf, A. Schrock, A. Gasco, B. Bychkovsky, R. Kitadai, S. Morganti, D. Abravanel, S. Tolaney, J. Garber, R. Jeselsohn, N. Lin, F. Lynce","doi":"10.1158/1557-3265.sabcs25-ps2-02-07","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-02-07","url":null,"abstract":"Background: PARPi are used to treat MBC, particularly in pts with genomic alterations (GA) in BRCA1/2 by targeting homologous recombination deficiency (HRD). This study explored clinical and genomic factors associated with PARPi sensitivity in a real-world MBC cohort. Methods: This retrospective study included 290 pts with MBC who had genomic testing via FoundationOne/FoundationOne CDx tissue comprehensive genomic profiling (CGP) and prior to treatment with a PARPi. Clinical data were sourced from the US-wide de-identified Flatiron Health-Foundation Medicine clinic genomic database, including ∼800 sites across ∼280 US cancer clinics (Jan 2011-Dec 2024). HRD alterations (alts) were defined as mutations, homozygous copy loss, or structural rearrangements in any of the following genes: BRCA1/2, ATM, ATR, ATRX, BAP1, BARD1, BRIP1, CHEK1/2, CDK12, FANCA, FANCL, MRE11, RAD51B/C/D, RAD54L or PALB2. HRD signature (HRDsig) status, which is offered as a laboratory professional service, was calculated using genome-wide copy number features, with scores from 0 to 1 and a predefined cutoff of 0.7 to call HRDsig (+). BRCA1/2 germline status was inferred using a validated somatic-germline-zygosity algorithm. Time to next treatment or death (TTNT) on PARPi was analyzed using Cox models adjusted for clinical variables. Results: Among 290 pts, most were female (96.6%, n=280), with a median age of 57 years at PARPi initiation. Of these, 186 (64.1%) had hormone receptor-positive (HR+) disease and 104 (35.9%) had HR- disease. In total, 21 had HER2+ tumors (12 HR+, 9 HR-). PARPi was given +/- endocrine therapy in 236 pts (81.4%) and in combination with other therapies in 54 (18.6%). PARPi was given in 1L (14.1%), 2L (26.9%), 3L (19.3%), and ≥4L (39.7%). Tumors from 199 patients (59.2%) were HRDsig (+): 120 (60.3%) HR+ and 79 (39.7%) HR−. Overall, 237 pts (81.7%) harbored ≥1GA (mutation, homozygous copy loss, or rearrangement) in BRCA1 (n=90), BRCA2 (n=130), or PALB2 (n=19). Nineteen pts had BRCAloss (8 in BRCA1 and 11 in BRCA2). In pre-PARPi CGP samples, HR+ tumors most frequently harbored BRCA2 (52.7%), TP53 (32.8%), BRCA1 (21.0%), while HR- tumors showed higher rates of TP53 (85.6%), BRCA1 (49.0%), BRCA2 (30.8%), and PALB2 (4.8%). Among pts with HR+ disease, those with a BRCAloss vs other BRCA GA detected prior to PARPi exposure had more favorable TTNT (median 15.2 vs. 8.5 months HR:0.40; p=0.012). No differences in TTNT were observed by BRCA1/2 mutation origin (germline (g) vs somatic (s)), type (truncating vs missense), or location (Table 1). Conclusions: Response to PARPi varied across different GA. Among pts with HR+ MBC, those with BRCAloss appeared to derive the greatest benefit. These findings highlight the potential utility of CGP in guiding PARPi treatment decisions. Citation Format: A. Rodríguez-Hernández, J. Quintanilla, R. Graf, A. Schrock, A. Gasco, B. Bychkovsky, R. Kitadai, S. Morganti, D. Abravanel, S. Tolaney, J. Garber, R. Jeselsohn, N. Lin, F. Lyn","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"326 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205195","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 PS3-10-30: A clinical model to predict pathologic complete response using early peripheral absolute lymphocyte dynamics in HER2+ breast cancer","authors":"C. Bergstrom, I. Luo, E. Kotler, M. Satoyoshi, S. Philip, C. Curtis, A. Kurian, S. Han, J. Caswell-Jin","doi":"10.1158/1557-3265.sabcs25-ps3-10-30","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-10-30","url":null,"abstract":"Introduction: Immune activation and lymphocyte infiltration into the tumor microenvironment are known to predict treatment response in HER2-positive (HER2+) breast cancer. Our work has shown that dynamic changes in peripheral absolute lymphocyte count (ALC) following initial neoadjuvant therapy (NAT) are also associated with a higher likelihood of achieving pathologic complete response (pCR). In this study, we aimed to develop and validate a predictive model for pCR based on clinically obtained pre-treatment ALC and ALC following a single dose of NAT, with the goal of creating a tool for early response prediction in HER2+ breast cancer. Methods: We assembled a retrospective discovery cohort of patients with HER2+ breast cancer treated with trastuzumab-based NAT from the Oncoshare database, which integrates electronic medical records and California Cancer Registry data from patients diagnosed between 2000 and 2020 at Stanford University. Our non-overlapping validation cohort consisted of patients with HER2+ breast cancer who underwent NAT on clinical trials of HER2-targeted therapy and/or who were enrolled in prospective institutional tissue collection studies. In the discovery cohort, we constructed a multivariable logistic regression model to identify predictors of pCR, including baseline ALC, early ALC change, days between baseline and on-treatment ALC draws, age at diagnosis, estrogen receptor (ER) status, stage, grade, and self-reported race/ethnicity. Early ALC change was defined as 1 minus the ratio of cycle 1 ALC to baseline ALC. To develop an ALC-based risk grouping strategy, we used logistic regression to create a composite risk score from baseline ALC and early ALC change, followed by receiver operating characteristic curve analysis. We then applied grid search optimization to test combinations of cutoff points across the 10th to 90th percentiles of the risk score distribution and identified the pair of cutoffs that maximized area under the curve (AUC) when patients were stratified into three risk categories. Model performance was evaluated using AUC analysis in both the discovery and validation cohorts. Results: In the discovery cohort (n = 154), higher baseline ALC and greater early ALC decline were independently associated with increased odds of pCR. The composite ALC risk score, using baseline ALC and early ALC change, stratified patients into three groups: low (25% of patients, n = 39), intermediate (45%, n = 69), and high (30%, n = 46) probability of pCR. Observed pCR rates in these groups were 15%, 51%, and 76%, respectively. When this ALC-based risk grouping was integrated with the other covariates (including time interval between ALC draws, age, ER status, clinical stage, tumor grade, and race/ethnicity), the full multivariable model demonstrated strong predictive performance with an area under the curve (AUC) of 0.81 (95% CI 0.74-0.88). In the separate validation cohort (n = 83), the composite ALC risk score stratified patient","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"230 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205250","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 PS2-06-30: Real-world uptake of gBRCA testing as a companion diagnostic for olaparib in patients with HER2-negative recurrent high-risk early breast cancer in Japan: a cross-sectional multicenter study (BRCAwareness)","authors":"T. Taji, Y. Uemura, Y. Kimura, N. Maeda, A. Ito, H. Seki, D. Takabatake, M. Harao, S. Nakamoto, R. Matsunuma, C. Koganezawa, T. Iwamoto, H. Mukai, Y. Kikawa","doi":"10.1158/1557-3265.sabcs25-ps2-06-30","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-06-30","url":null,"abstract":"Background In patients (pts) with HER2-negative, high-risk early breast cancer (BC), adjuvant (adj) olaparib (OLA) significantly improves invasive disease-free survival and overall survival in those carrying germline BRCA1 or BRCA2 (gBRCA) pathogenic variants (PVs) 1). To optimize clinical outcomes, timely gBRCA testing as a companion diagnostic is essential. However, the real-world uptake of gBRCA testing in this population remains unclear. Methods We enrolled newly diagnosed pts with invasive HER2-negative BC who underwent curative surgery from January 1, 2023 to December 31, 2023 in Japan. Patient selection was based on the inclusion criteria from the OlympiA trial1). Specifically, ER-positive pts required either ≥ 4 positive lymph nodes after surgery or non-pathological complete response (pCR) with a CPS+EG score ≥ 3 following neoadjuvant chemotherapy (NAC). ER-negative pts required an invasive tumor >2 cm or ≥ 1 nodal metastasis after surgery, or non-pCR after NAC. Furthermore, we collected both patient-level and institutional data. The primary outcome was the proportion of pts who underwent gBRCA testing. Secondary outcomes included: (1) factors linked to no testing; (2) proportion of PVs among those tested; (3) proportion of pts with gBRCA PVs who started OLA; and (4) other treatments used in pts with gBRCA PVs not receiving OLA. Based on a previous U.S. report in which 87% of young women with BC underwent gBRCA testing2), we hypothesized that at least 88% of eligible pts should be tested. Assuming an expected testing rate of 88%, a sample size of 688 pts was required to maintain a 95% confidence interval (CI) width of 0.05. The target sample size was set at 700 to account for potential exclusions. Results Of 824 pts recruited from 46 facilities during the primary enrollment, 700 were randomly selected for secondary registration. After excluding 9 ineligible pts, a total of 691 were analyzed. The median age was 62 [20-96] years, 99% were female, 52 had bilateral BC, 157 had a family history of BC, and 18 had dementia. ER status was positive in 51%. NAC was administered to 362 pts (52%), including 148 (21%) with ER-positive BC, while 199 (29%) ER-positive BC pts had upfront surgery. Regarding facility characteristics, the median number of breast cancer specialists per facility was 3 [1-17], and genetic counselors were available in 27 facilities (59%). gBRCA testing was performed in 437 of 691 pts (63.2%; 95% CI, 59.5-66.9). Of 254 untested patients, 168 (66%) were not informed, mainly due to physician oversight (57%) or perceived ineligibility related to age, comorbidities, or treatment refusal (40%). Among 69 pts who were informed but declined testing, the reasons for no testing were psychological distress (46%), cost of testing (35%), and concerns about genetic implications for family members (12%). Among 42 pts (9.6%) with gBRCA PVs (10 pts were ER-positive), 32 received OLA. Of the remaining 10, all but 3 had perioperative chemot","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204843","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 PS1-13-17: Rna-based immune features associated with benefit from distinct microtubule inhibitor therapy for metastatic her2-negative breast cancer: a post hoc analysis of the calgb 40502 (alliance) phase iii randomized clinical trial","authors":"E. K. Blige, K. V. Ballman, A. Michmerhuizen, M. Vater, L. A. Carey, A. H. Partridge, W. F. Symmans, M. A. Watson, C. M. Perou, D. G. Stover, H. S. Rugo","doi":"10.1158/1557-3265.sabcs25-ps1-13-17","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps1-13-17","url":null,"abstract":"Background: Microtubule inhibitors remain a standard chemotherapy in the management of HER2-negative metastatic breast cancer (MBC). CALGB (Alliance) 40502 was a phase 3 randomized study involving 799 patients with MBC receiving first-line chemotherapy, to determine the optimal chemotherapeutic agent among paclitaxel, nab-paclitaxel, or ixabepilone (with or without bevacizumab). Secondary analysis suggested inferior PFS with nab-paclitaxel specifically among patients with hormone receptor positive (HR+)/HER2-negative breast cancer. Correlative analysis demonstrated significant association of stromal tumor infiltrating lymphocytes (sTILs) with improved progression-free (PFS) and overall survival (OS) in CALGB40502. We hypothesized that immune activation would be associated with differential benefit among distinct microtubule agents. To address this, we evaluated the sTILs and RNA-based immune features association with clinical outcomes, including evaluation of nab-paclitaxel versus paclitaxel. Methods: To limit heterogeneity, analyses focused on pre-treatment primary tumor breast samples with central review/pathologist-enumerated sTILs in accordance with International TILs Working Group methods and RNAseq (n = 280). PAM50 molecular subtypes were assigned based on transcriptomic features. RNAseq data were used to generate immune deconvolution estimates from 5 distinct algorithms (CIBERSORT, xCell, ABIS, ConsensusTME, ImmuCellAI). 1,018 curated breast cancer gene expression signatures GES) were derived from previously published studies. Associations between sTILs and GES were evaluated with sTILs being a categorical variable with the thresholds <5% (low) and (≥5%) high. Results: In the evaluable population, basal-like PAM50 subtype was enriched for high sTILs category (p=1e-4), as anticipated. T-cell and B-cell immune signatures and immune deconvolution estimates were among most highly associated with sTILs. In addition to the expected prognostic association of high T-cell GES, high B-cell-related IgG signature score was also significantly associated with improved overall survival (OS) among triple-negative breast cancer (TNBC) in CALGB 40502 (HR = 0.50,95% CI:0.30-0.86, log-rank p=0.01) but not in HR+/HER2-. In an exploratory analysis of young patients (age at study entry <50 years), high sTILs were associated with improved OS among TNBC patients but worse OS among those with HR+/HER2- MBC (HR = 2.19, 95% CI:1.10-4.36, log-rank p=0.022). High (above median) RNA-based Xcell total immune score was significantly associated with worse OS in both CALGB 40502 and a validation dataset of primary breast cancers, METABRIC (OS HR = 2.12, 95% CI:1.01-4.45, log-rank p=0.042). To further investigate the clinical trial finding of inferior PFS for nab-paclitaxel compared with paclitaxel in patients with HR+/HER2- MBC, there was a significant enrichment of T-cell signatures associated with poor outcome in patients receiving nab-paclitaxel (Fisher exa","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"24 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204846","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 PS5-01-28: Us real-world clinical outcomes of tucatinib, trastuzumab, and capecitabine following trastuzumab deruxtecan for the treatment of her2+ metastatic breast cancer","authors":"J. Chien, E. Neuberger, S. Simon, K. Watkins, G. Curigliano, B. Li, S. Stergiopoulos, M. Czachorowski, H. Itakura","doi":"10.1158/1557-3265.sabcs25-ps5-01-28","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-01-28","url":null,"abstract":"Background: US and EU treatment guidelines currently recommend tucatinib in combination with trastuzumab and capecitabine (TTC) in third-line (3L) for patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC), and in second-line (2L) for those patients with brain metastases (BM). More recently, trastuzumab deruxtecan (T-DXd) has become the recommended 2L treatment option and may be considered as first-line treatment for patients with rapid progression after (neo)adjuvant therapy. Previous real-world studies in patients receiving TTC after T-DXd have reported median time to next treatment (TTNT) of 6 months and median overall survival (OS) of 13 months; however, these study populations included later line treatment, a small sample size, and did not solely include TTC immediately following T-DXd, limiting applicability to current clinical practice. This study aimed to describe real-world outcomes in patients with HER2+ MBC in the US who were treated with TTC in 2L, 3L and fourth-line (4L) immediately following T-DXd. Methods: We conducted a retrospective cohort analysis of patients with HER2+ MBC receiving TTC therapy using the Flatiron Health electronic health record (EHR)-derived deidentified longitudinal database. This US nationwide database, containing patient-level structured and unstructured data curated using natural language processing with machine learning and technology-enabled abstraction, includes >720,000 patients with breast cancer. Patients included were diagnosed with HER2+ MBC (January 2017 to July 2024), treated with TTC in 2L, 3L or 4L immediately following T-DXd, and were not enrolled in clinical trials. Patients were assessed from the start of TTC (index date) to death, last medical activity, or end of available study follow-up (January 2025), whichever came first. Primary outcomes included, but were not limited to, TTNT and OS in all patients. Exploratory analyses will assess TTNT and OS in patients stratified by BM status, duration of T-DXd treatment, and hormone receptor status. Descriptive statistics were used for patient characteristics, and outcomes were evaluated using Kaplan-Meier analyses. Results: In total, 92 patients with HER2+ MBC received TTC immediately following T-DXd. Overall, median (95% CI) TTNT was 8.6 (5.7-11.6) months and median (95% CI) OS was 19.5 (12.0-26.1) months (Table). Exploratory outcomes will be presented in future analyses. Conclusion: Patients with HER2+ MBC benefit from TTC immediately after treatment with T-DXd, demonstrating its clinically meaningful activity in a contemporaneous post-T-DXd setting. These results reinforce the effectiveness of tucatinib, with longer TTNT and OS than in previous real-world studies, in a population more applicable to current clinical practice. Citation Format: J. Chien, E. Neuberger, S. Simon, K. Watkins, G. Curigliano, B. Li, S. Stergiopoulos, M. Czachorowski, H. Itakura. Us real-world clinical outcomes of t","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"21 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204851","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 RF4-01: Central Nervous System Outcomes from the Phase III PATINA Trial (AFT-38)","authors":"O. Metzger, S. Mandrekar, T. Dockter, L. Gianni, E. Ciruelos, A. De Michele, J. Gligorov, E. Lim, S. Loibl, X. Gonzàlez Farré, F. Lynce, J. Lanzillotti, L. Carey, S. Goel, A. Partridge, E. Winer","doi":"10.1158/1557-3265.sabcs25-rf4-01","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-rf4-01","url":null,"abstract":"Background Central nervous system (CNS) metastases are a major clinical concern in patients with HER2-positive metastatic breast cancer (MBC). The PATINA phase III study showed improved PFS with palbociclib added to maintenance anti-HER2/endocrine therapy (44.3 vs. 29.1 months; hazard ratio 0.75; 95% CI 0.59-0.96; 1-sided P=0.0109). Preclinical and early clinical data suggest palbociclib may have CNS activity. We conducted a pre-specified secondary analysis to evaluate the incidence and timing of CNS progression. Methods CNS progression was defined as the emergence of new intracranial lesions per investigator assessment. Baseline CNS imaging was not mandated but recommended if symptomatic. Competing risks analyses evaluated time from registration to first CNS progression or death (CNS PFS), treating non-CNS progression as a competing event. All randomized patients were included in the primary analysis, regardless of known baseline CNS involvement. Patients with baseline CNS metastases were not censored if progression involved the CNS. A secondary analysis excluded patients with CNS metastases present at baseline. Cumulative incidence functions were estimated and compared using 2-sided Gray’s test. Results Data cutoff for this analysis was on October 15, 2024. 518 participants were enrolled between June 2017 and July 2021, 261 to the palbociclib arm and 257 to the control arm. CNS metastases at baseline were present in 11 patients in the palbociclib arm and 9 patients in the control arm. Among all randomized patients, CNS progression occurred in 35 of 261 (13.4%; 95% CI: 9.5-18.2) in the palbociclib arm and 50 of 257 (19.5%; 95% CI: 14.8-24.8) in the control arm. When excluding patients with CNS metastases at baseline, CNS progression was observed in 32 of 250 (12.8%; 95% CI: 8.9-17.6) in the palbociclib arm and 47 of 248 (19.0%; 95% CI: 14.3-24.4) in the control arm. The median follow-up for patients who were alive and progression-free was 53.5 months. At 36 months, the cumulative incidence of CNS PFS was 13.4% vs. 19.9% for palbociclib versus control (Gray’s test p=0.0386). Importantly, when the analysis was restricted to pts without evidence of CNS disease at baseline (Table 1), —the CNS benefit with palbociclib was maintained (13.0% vs. 19.2% at 36 months, Gray’s test p = 0.0378). Conclusion The addition of palbociclib to anti-HER2 and endocrine therapy was associated with a lower incidence of CNS metastases. Among patients without known baseline CNS involvement, the absolute reduction in CNS progression at 36 months was 6.2% in favor of palbociclib. This benefit was observed at 12 months and sustained over 3 years (Table 1). These findings suggest that palbociclib may help delay or prevent CNS involvement in HR+/HER2+ MBC, warranting confirmation in future studies. Citation Format: O. Metzger, S. Mandrekar, T. Dockter, L. Gianni, E. Ciruelos, A. De Michele, J. Gligorov, E. Lim, S. Loibl, X. Gonzàlez Farré, F. Lynce, J. Lanzillotti, L. Carey, ","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"19 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204930","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 PS2-12-22: The Molecular Mechanism of PRAK Regulating DNA Damage Repair and Its Role in Breast Cancer","authors":"L. Jingjing","doi":"10.1158/1557-3265.sabcs25-ps2-12-22","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-12-22","url":null,"abstract":"Background: DNA damage plays a critical role in breast cancer, induced by both endogenous and exogenous factors. Abnormal repair mechanisms, such as homologous recombination repair (HRR) and non-homologous end joining (NHEJ), result in genomic instability and the accumulation of mutations, thereby driving cellular malignant transformation. DNA damage also promotes tumor progression by activating inflammatory pathways and modulating the immune microenvironment, serving as a key basis for breast cancer development and treatment resistance. Core Findings: PRAK (p38-regulated/activated protein kinase) is highly expressed in breast cancer and significantly correlates with poor patient prognosis and reduced survival rates. In vitro and in vivo experiments demonstrate that PRAK deficiency sensitizes tumor cells to PARP inhibitors and impairs DNA double-strand break (DSB) repair capacity, leading to defects in the homologous recombination (HR) pathway. Molecular Mechanism: Through affinity chromatography, mass spectrometry, and co-immunoprecipitation, PRAK was confirmed to directly interact with FOXO3 in vitro and in vivo. DNA-damaging agents (PARP inhibitors) induce nuclear accumulation of FOXO3, promoting the interaction between PRAK and FOXO3 within the nucleus. RNA-seq analysis revealed that BRCA1 is a key target of PRAK. PRAK deficiency reduces FOXO3 nuclear localization and inhibits its binding to the BRCA1 promoter, thereby downregulating BRCA1 expression. In vivo validation demonstrated that PRAK deficiency enhances the sensitivity of mouse xenografts to DNA-damaging agents. Conclusions: PRAK is upregulated in multiple human tumor tissues. PRAK deficiency inhibits tumor cell proliferation and sensitizes cells to DNA-damaging agents. PRAK participates in HR-mediated DNA damage repair in an enzyme activity-independent manner. PRAK interacts with FOXO3, influences FOXO3 nuclear localization to regulate DNA damage responses, and affects FOXO3 binding to the BRCA1 promoter to modulate BRCA1 transcriptional activation. PRAK deficiency enhances tumor sensitivity to DNA-damaging drugs. Collectively, this study reveals that PRAK promotes DNA damage repair by transcriptionally regulating BRCA1 expression through FOXO3, representing a novel regulatory mechanism by which PRAK maintains genomic stability via DNA damage repair. Targeting the PRAK/FOXO3/BRCA1 axis may serve as a potential therapeutic strategy to enhance the efficacy of DNA-damaging agents in cancer treatment. Our findings uncover the functions and molecular mechanisms of PRAK in cell proliferation and DNA damage responses, with potential clinical implications for breast cancer therapy. Citation Format: L. Jingjing. The Molecular Mechanism of PRAK Regulating DNA Damage Repair and Its Role in Breast Cancer [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 PS2-12-22.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"177 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204931","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 PS5-08-16: Intratumoral Injections of INT230-6 Prior to Neoadjuvant Immuno-chemotherapy in Early-Stage Triple Negative Breast Cancer: Early observations from INVINCIBLE-4-SAKK 66/22 (NCT06358573), a Phase II Randomized Controlled Trial","authors":"U. Zürrer, A. Müller, O. Tredan, C. Micheloud, J. Musilova, R. Popescu, T. Schmid, L. Rossi, M. Schwitter, M. Vetter, M. Niemeyer, I. Witzel, A. Patsouris, S. Ladoire, J. Martin-Babau, A. Deleuze, M. Robert, L. H. Bender, M. Joerger","doi":"10.1158/1557-3265.sabcs25-ps5-08-16","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-08-16","url":null,"abstract":"Background: Triple Negative Breast Cancer (TNBC) poses significant challenges due to its aggressiveness, high relapse rate and mortality. Neoadjuvant immuno-chemotherapy (NAIC) is now a common treatment for early-stage TNBC before surgery. NAIC aims to eliminate viable cancer in the tumor, lymph nodes and possible occult distant metastases, shrink tumors to improve surgical outcomes and prevent disease recurrence. The Keynote-522 study revealed a 84.5% 3-year event-free survival in patients with early-stage TNBC using NAIC and improved pathological complete response (pCR) rates from 51.2% with neoadjuvant Chemotherapy to 64.8% with NAIC. A new potential method to improve clinical outcome and induce immune activation pre-surgery is through a novel local therapy in combination with NAIC that could cause increased apoptotic cell death and create personalized tumor antigens. Arnaout et al. conducted a randomized, phase 2 neoadjuvant window of opportunity trial using intratumoral (IT) INT230-6, a drug comprising vinblastine, cisplatin and a tumor dispersion and cell penetration enhancer molecule (SHAO), evaluating clinical and biological effects in women with early-stage operable BC (NCT04781725). Results in T2 to T4 tumors showed an average of over 30% necrosis in 74% of subjects at the time of surgery, with some patients having >95% tumor necrosis following a single dose. Adding immune-activating and apoptotic induced necrosis caused by INT230-6 dosed prior to NAIC in TNBC patients has the potential to increase pCR. Methods: This is a randomized, open-label multicenter phase 2 clinical study to determine the clinical activity, safety, and tolerability of IT INT230-6 in patients with early-stage, operable TNBC in combination with NAIC (cohort A) or NAIC alone (cohort B). The INT230-6 dose is dependent on tumor size. The primary endpoint is pCR in the primary tumor (ypT0/Tis) and affected lymph nodes (ypN0). Key inclusion criteria include newly diagnosed, previously untreated, locally advanced non-metastatic TNBC stage cT1c N1-3 M0 or cT2-4c N0-3 M0. Multifocal and multicentric primary tumors are allowed. Patients must have measurable disease in the breast with at least one lesion with a diameter ≥1.5 cm visible in ultrasound and injectable. Patients are either male or female, age ≥ 18 years, ECOG performance status <2, adequate bone marrow, hepatic and renal function. STATS: The sample size calculation for both cohorts is determined based on a single-stage phase II single-arm clinical trial design (A’Hern). Null hypothesis (H0): pCR rate ≤ 0.6, Alternative hypothesis (H1): pCR rate ≥ 0.8. Type I error: 10% (one-sided), Power: 80%. The duration for accrual, patient therapy and follow-up is 12, 8 and 36 months respectively. The sample size per cohort is 27 patients. The study is recruiting in Switzerland and France in up to 16 sites. Results: By July 2025 15 of 54 patients could be enrolled, completion of accrual is expected in 2026. Prel","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"178 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205169","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 PS1-12-07: Impact of TP53 mutations on Treatment Duration with CDK 4/6 Inhibitors and Immune Checkpoint Inhibitors in ER-positive/HER2-negative Breast Cancer: Insights from Real-World Data","authors":"M. Oshi, M. Sugimori, K. Kawashima, A. Yamada, K. Narui, T. Ishikawa, K. Takabe","doi":"10.1158/1557-3265.sabcs25-ps1-12-07","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps1-12-07","url":null,"abstract":"Background: TP53 mutation is a key driver of breast cancer. However, its clinical impact remains unclear. This study investigates the relationship between TP53 mutations and response to CDK 4/6 inhibitors (CDK4/6i) and immune checkpoint inhibitors (ICI) in breast cancer using real-world data (RWD) from the C-CAT (Center for Cancer Genomics and Advanced Therapeutics) cohort, with particular focus on age-related differences. The duration of treatment was used as a surrogate of unresponsiveness to treatment and progression of disease during treatment. Material and Methods: We used METABRIC data for initial survival analysis and performed Gene Set Enrichment Analysis (GSEA) to identify pathway enriched in TP53-mutated ER-positive/HER2-negative breast cancers. We also investigated the relationship of TP53 mutations and durations of CDK4/6i and ICI treatments in the C-CAT cohort, a database that includes clinical and genomic data of metastatic breast cancer patients from Japan. To evaluate treatment resistance in metastatic breast cancer, we used treatment duration as a clinical endpoint. The CCAT cohort was stratified by age into four groups: Adolescent and Yong Adults (AYA: 15-39 y.o.), perimenopausal (40-54 y.o.), menopausal (55-64 y.o.), and old (over 65 y.o.). Results: TP53 mutations were significantly associated with poor prognosis in ER-positive/HER2-negative breast cancer in the METABRIC cohort. GESA revealed that TP53-mutated tumors were enriched with pro-cancerous gene sets, particularly those related with cell proliferation and immune response, while TP53-wild type tumors enriched estrogen response gene sets. These findings led to investigating the impact of TP53 mutations on durations of CDK4/6i and ICI treatments. In the CCAT cohort. TP53 mutation was not associated with the duration ICI treatment. On the other hand, TP53 mutation was significantly associated with shorter duration of CDK4/6i treatment in entire ER-positive/HER2-negative breast cancer, but not in the patients who received CDK4/6i starting from late treatment phase. This trend was consistent across both Abemaciclib and Palbociclib, suggesting that TP53 mutations similarly affect treatment duration in both drugs. Further, AYA patients had the shortest treatment duration compared to the other age groups, with an earlier initiation of CDK4/6i treatment. The prevalence of TP53 mutation decreased with increasing age. When analyzing the impact of TP53 mutations by age group, TP53 mutation was significantly associated with shorter treatment duration in the perimenopausal, menopausal, and old groups, while no significant difference was found in the AYA group. Conclusion: This study demonstrated that TP53 mutation is associated with shorter duration of CDK4/6i treatment, particularly in the early stages, with similar trends observed for Abemaciclib and Palbociclib. These findings highlight the need for personalized treatment strategies based on TP53 mutation status. While the impact ","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"21 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205247","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 PS3-09-06: Comparative Predictive Utility of Oncotype DX and MammaPrint Using a Clinicopathologic Model in Matched HR+/HER2− Early Breast Cancer Cohorts: The BRAIN Study","authors":"J. Kim, S. Lee, S. Lee, I. Lee, J. Ahn, S. Park, S. Gwon, N. Son","doi":"10.1158/1557-3265.sabcs25-ps3-09-06","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-09-06","url":null,"abstract":"Oncotype DX (ODX) and MammaPrint (MMP) are two widely adopted multigene assays used to guide adjuvant chemotherapy decisions in patients with hormone receptor-positive (HR+), HER2-negative early breast cancer. Despite their similar clinical roles, ODX and MMP often produce discordant risk classifications. While head-to-head comparison in the same patient would be ideal, it is rarely feasible in practice due to cost, clinical utility, and reimbursement constraints. Therefore, we designed a pilot study to indirectly compare the predictive performance of ODX and MMP by applying a clinicopathologic model—the Tennessee nomogram—to matched cohorts of patients who received either test. A total of 2,542 patients who underwent ODX (n = 2,011) or MMP (n = 531) testing were retrospectively selected. Patients were matched 1:1 based on age and nodal status to control for key prognostic variables. Risk distribution was compared across both cohorts, followed by application of the Tennessee model to assess its predictive concordance with each assay’s reported risk classification. Model performance was evaluated using AUC, specificity, positive predictive value (PPV), and negative predictive value (NPV). The proportion of patients classified as high-risk differed between the two cohorts (ODX: 12.22% (8.21 - 17.28), MMP: 33.94% (27.72-40.59). The Tennessee model showed an AUC of 85.57 (77.49-93.65) for predicting high-risk ODX results and 70.70 (63.32-78.08) for MMP. Specificity and NPV were 90.21%, 94.59% in the ODX cohort, compared to 89.04% and 73.45% in the MMP cohort. Our findings indicate that the Tennessee model aligns more closely with ODX, suggesting that each assay may capture distinct biological dimensions of tumor behavior. This study highlights the importance of understanding the limitations of multigene tests when used interchangeably and supports the development of cost-effective, data-driven prediction tools that integrate clinicopathologic variables. These pilot results lay the groundwork for future AI-based models capable of refining treatment stratification in early HR+/HER2− breast cancer. Citation Format: J. Kim, S. Lee, S. Lee, I. Lee, J. Ahn, S. Park, S. Gwon, N. Son. Comparative Predictive Utility of Oncotype DX and MammaPrint Using a Clinicopathologic Model in Matched HR+/HER2− Early Breast Cancer Cohorts: The BRAIN Study [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 PS3-09-06.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"19 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205251","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}