Clinical Cancer Research最新文献

{"title":"DNA Methylation-based Risk Stratification and Classification of Pediatric Thyroid Carcinoma","authors":"Jenny Z. Li, Julio Ricarte Filho, Amber R. Isaza, Kyle Hinkle, Feng Xu, Marilyn M. Li, Andrew J. Bauer, Aime T. Franco, Wanding Zhou","doi":"10.1158/1078-0432.ccr-25-2109","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2109","url":null,"abstract":"Purpose: Accurate assessment of invasiveness in pediatric thyroid carcinomas is essential to prevent unnecessary surgery and avoid surgery-associated complications. DNA methylation, a proven molecular biomarker for cancer classification, holds promise for stratifying thyroid cancer risk. The objectives were to determine the epigenetic hallmarks of pediatric thyroid carcinomas and to investigate whether DNA methylome profiling is a feasible approach for pre-operative risk stratification of this pediatric disease. Experimental Design: We interrogated genome-wide DNA methylation profiles from two separately processed cohorts of pediatric thyroid carcinoma. The reference cohort included 100 samples, consisting of 87 well-differentiated primary tumors—77 papillary and 10 follicular thyroid carcinomas—and 13 matched lymph node metastases. To predict oncogenic drivers and tumor invasiveness, defined by the presence of nodal metastasis, we trained two classifiers on the reference cohort and then evaluated their performance on a second validation cohort of 84 samples, including 83 primary tumors and one lymph node metastasis. Results: We identified distinct methylation patterns associated with tumor invasiveness and key driver mutations, including BRAF p.V600E, RAS-like mutations, kinase fusions, and DICER1 mutations. The differentially methylated regions reflect inflammatory stress, disrupted thyroid development and function, implicating AR, Hippo, and AP-1 signaling. Leveraging these epigenetic signatures, we developed and validated two methylation-based classifiers that accurately predict tumor invasiveness and oncogenic mutation subgroups. Conclusions: In pediatric thyroid carcinoma patients, DNA methylation assays accurately predict tumor invasiveness and driver mutations. Our findings highlight the clinical value of DNA methylation profiling for risk stratification and classification of pediatric thyroid cancers.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"17 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146210231","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 PS4-10-24: Longitudinal trends in prognosis and post-treatment pregnancy in young woman with triple-negative breast cancer","authors":"M. Kasahara, A. Kataoka, A. Kanazawa, Y. Ito, Y. Kimura, N. Yoshida, U. Nakadaira, N. Uehiro, C. Takahata, Y. Ozaki, M. Nishimura, T. Takano, T. Kogawa, T. Sakai, T. Ueno","doi":"10.1158/1557-3265.sabcs25-ps4-10-24","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps4-10-24","url":null,"abstract":"Background: Triple-negative breast cancer (TNBC) in young women has traditionally been associated with poor prognosis. However, treatment outcomes are expected to improve with advances such as response-guided neoadjuvant chemotherapy, PARP inhibitors, and immune checkpoint inhibitors. For young women who have a desire for future pregnancies, whether pregnancy and childbirth are feasible after breast cancer treatment is a critical concern. Therefore, fertility preservation (FP) before cancer treatment and shared decision-making regarding post-treatment pregnancy are essential. Objective: To investigate treatment outcomes, temporal trends in FP, and pregnancy outcomes among young patients with TNBC. Methods: A retrospective analysis was conducted on 179 young patients under the age of 40 with stage I-III TNBC who underwent curative surgery at our institution between 2007 and 2022. We investigated treatment outcomes, FP rates, and subsequent pregnancy status. The primary endpoints were breast cancer recurrence, the development of secondary malignancies, and overall survival. Secondary endpoints were pregnancy and childbirth after breast cancer treatment. Results: The mean age at surgery was 34.4 years. Eighty-three patients (46.4%) had a history of childbirth. Among those tested, 41 patients (43.2%) carried pathogenic BRCA1/2 variants. The stage distribution was stage I in 42 patients (23.5%), stage II in 103 (57.5%), and stage III in 34 (18.0%). Chemotherapy was administered to 171 patients (95.5%), of whom 93 (52.0%) received neoadjuvant therapy. With a median follow-up of 5.8 years (range: 0.1-17.5), recurrence including contralateral breast cancer occurred in 14 patients (7.8%), secondary malignancies in 5 (2.8%)—of whom 3 had ovarian cancer—and 25 patients (14.0%) died. At the time of diagnosis, 61 patients (34.1%) had desire for future pregnancy. Among them, 26 (14.5%) underwent FP before chemotherapy, and 22 (12.3%) received LHRH analogs during chemotherapy for ovarian function protection. Comparing two time periods, 2007-2014 and 2015-2022, the 5-year overall survival significantly improved from 78.7% to 94.5% (p = 0.0088). FP implementation also increased over time, with the FP rate among those with desire for future pregnancies at the time of diagnosis rising from 12% to 58.3%. Seventeen patients conceived after treatment (6 spontaneously, 9 with assisted reproductive technology, 2 unknown), resulting in 23 pregnancies and 17 live births in 15 patients (8.4% of the total cohort, 24.6% of those who had desire for future pregnancies at the time of diagnosis). Among the patients who gave birth, one had been treated with immune checkpoint inhibitors. No serious perinatal complications were observed. All patients were disease-free at the time of attempting conception. No distant recurrence or breast cancer-related deaths occurred after childbirth. To date, none of the patients who treated with PARP inhibitor therapy became pregnant. Conclusion:","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204850","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 PS5-05-07: Real-world Patient Characteristics and Treatment Patterns with Pembrolizumab Among Patients with Early-Stage Triple-Negative Breast Cancer in the United States","authors":"A. Haiderali, Y. Sun, L. Ai, F. Beca","doi":"10.1158/1557-3265.sabcs25-ps5-05-07","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-05-07","url":null,"abstract":"Background: Pembrolizumab (pembro) was approved by the Food and Drug Administration in July 2021 to treat high-risk, early-stage triple-negative breast cancer (TNBC) based on the KEYNOTE-522 trial. To support post-launch assessments, this real-world study aimed to outline patient characteristics and treatment patterns in patients with Stage II-III TNBC in the US community setting. Methods: This retrospective study used electronic medical records accessed via the Syapse data platform to examine previously untreated adults diagnosed with Stage II-III TNBC from August 2021 to July 2023. We analyzed patient characteristics, surgery rates and types, treatment patterns and duration, and reasons for treatment discontinuation in the neoadjuvant and adjuvant settings. Results: 322 patients were identified with Stage II (61.3%) or Stage III (38.7%) TNBC and who had undergone definitive surgery. Mean age was 58 years (standard deviation [SD]: 15). 47% had an ECOG performance status of 0, 14% had an ECOG of 1, while 37% had unknown status. In the neoadjuvant setting, most patients (75%) received pembro + chemotherapy, 12% received chemotherapy alone and 12% received no neoadjuvant therapy. The most common therapy in patients receiving neoadjuvant pembro + chemotherapy was pembro + carboplatin + taxanes + anthracyclines (A) + cyclosphosphamide (C) (83%) while the most common therapy in patients receiving chemotherapy alone was taxanes + AC (50%). Patients receiving pembro + chemotherapy were more likely to undergo mastectomy (56% vs 38%) and less likely to undergo lumpectomy (44% vs. 63%). Among patients receiving adjuvant therapy in the cohort previously treated with neoadjuvant pembro + chemotherapy, the most frequently administered adjuvant regimens were pembro monotherapy (70%) and pembro + capecitabine (10%). On the other hand, capecitabine was the most commonly administered treatment (75%) among patients receiving adjuvant therapy in the cohort that received neoadjuvant chemotherapy without pembro. The median (95% CI) time on pembro in the neoadjuvant and adjuvant settings was 5.3 (5.1, 5.6) and 5.6 (5.6, 5.7) months, respectively. Comparatively, median time on chemotherapy was 4.2 (3.4, 4.9) and 5.2 (4.4, 5.7) months, respectively. The primary reasons for discontinuation among patients who had received neoadjuvant chemotherapy + pembro (n=236) were completion of planned therapy (72%) and intolerance/toxicity (24%). In the adjuvant pembro group (n=97), primary reasons for discontinuation were completion of therapy (78%) and intolerance/toxicity (8.2%). Conclusion: Findings show a high utilization of pembro in neoadjuvant and adjuvant early-stage TNBC, highlighting its role as standard of care. Treatment duration for pembro was consistent with that reported in clinical trials and previous real-world studies, supporting use in routine clinical practice. High treatment completion rates suggest that pembro is generally well tolerated, supporting its use as ","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204932","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 RF5-03: OlympiaN: a phase 2, multicenter, open-label study to assess the efficacy and safety of neoadjuvant olaparib monotherapy and olaparib plus durvalumab in patients with BRCA mutations and early-stage HER2-negative breast cancer","authors":"N. Tung, A. Stradella, A. Brufsky, P. A. Fasching, J. A. García-Sáenz, S. Paluch-Shimon, F. M. Henao Carrasco, A. Marquez Aragones, T.-W. Park-Simon, S. Antolin Novoa, N. Ditsch, R. Greil, M.-P. Graas, N. Harbeck, I. Pimentel, A. Schneeweiss, K.-A. Phillips, K. S. Saini, M. Dymond, X. Liu, G. Rychlik, J. Balmaña","doi":"10.1158/1557-3265.sabcs25-rf5-03","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-rf5-03","url":null,"abstract":"Background: PARP inhibitors (PARPi) are approved for the treatment of patients with early or advanced breast cancer harboring a germline pathogenic/likely pathogenic variant in BRCA1 and/or BRCA2 (gBRCAm). PARPi, including olaparib, have shown promising activity in the neoadjuvant setting, and the addition of the anti-PD-L1 antibody, durvalumab, may enhance the antitumor immune responses promoted by PARPi. The OlympiaN trial (NCT05498155) was designed to assess the efficacy and safety of neoadjuvant olaparib and olaparib plus durvalumab in stage I and stage II BRCAm HER2-negative breast cancer. Methods: Patients with early-stage BRCAm, estrogen receptor (ER)-negative or -low (≤10%) HER2-negative breast cancer received neoadjuvant olaparib 300 mg BID monotherapy (Cohort A: stage T1b-c/N0) or olaparib 300 mg BID plus durvalumab 1500 mg IV Q4W (Cohort B: stage T2/N0 or T1/N1) for 4-6 cycles, followed by surgery. The primary endpoint was pathological complete response (pCR), defined as ypT0/Tis ypN0, by independent central pathology review (ICPR). Secondary endpoints included residual cancer burden (RCB), tumor volume assessed by magnetic resonance imaging and local radiology review, safety, and tolerability. Patients with pCR by local assessment could continue olaparib post-surgery for a total of 12 cycles of treatment. Patients without pCR received radiation therapy and adjuvant treatment in accordance with local standard of care. Results: At the data cutoff of November 20, 2024, 25 patients had enrolled into Cohort A (5 T1b/N0, 20 T1c/N0; median age 46 years) and 25 had enrolled into Cohort B (all T2/N0; median age 44 years). One patient in Cohort A had a somatic BRCA1 mutation per local testing; all other patients in both cohorts had gBRCAm. In Cohort A, 23 (92%) patients completed 4-6 cycles of neoadjuvant olaparib, 1 (4%) discontinued treatment due to an adverse event (AE; grade 2 neutropenia), and 1 (4%) progressed on treatment; 24 (96%) patients underwent definitive surgery. pCR rate by ICPR was 68% (n=17/25; 95% CI, 47-85%) and 72% (n=18/25; 95% CI, 51-88%) had RCB class 0/I by ICPR. Grade ≥3 AEs occurred in 5 (20%) patients; olaparib-related grade ≥3 anemia occurred in 3 (12%) patients. No deaths occurred during the study period. In Cohort B, 21 (84%) patients completed 4-6 cycles of neoadjuvant olaparib plus durvalumab, 2 (8%) discontinued treatment due to an AE, and 2 (8%) progressed on treatment; 22 (88%) patients underwent definitive surgery with central pathological assessment. pCR rate by ICPR was 80% (n=20/25; 95% CI, 59-93%) and 84% (n=21/25; 95% CI, 64-95%) had RCB class 0/I by ICPR. Grade ≥3 AEs occurred in 6 (24%) patients; olaparib-related grade ≥3 AEs occurred in 3 (12%) patients (1 with anemia, 1 with diarrhea, and 1 with hypersensitivity leading to discontinuation in Cycle 1); 1 patient discontinued olaparib in Cycle 4 following grade 2 nausea and grade 2 dizziness; 1 (4%) had durvalumab-related grade ≥3 diabetes. No deaths o","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146204934","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 PS4-08-26: Weekly carboplatin and paclitaxel with trastuzumab and pertuzumab (HER2+) or bevacizumab (HER2-) in the neoadjuvant treatment of breast cancer: a phase II trial","authors":"F. Shah, S. Gibson, F. Luo, M. Thomas, N. N. Nafissi, E. Vosoughi, S. Lavasani, K. T. Lane, E. H. Lin, K. J. Kansal, H. M. Yong, R. S. Mehta, R. Parajuli","doi":"10.1158/1557-3265.sabcs25-ps4-08-26","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps4-08-26","url":null,"abstract":"Background: Neoadjuvant chemotherapy (NAC) enables breast conservation and early assessment of treatment response in breast cancer. Anthracycline-based regimens have shown efficacy, but their use is limited by associated long-term toxicities, including cardiotoxicity and secondary leukemia. Weekly taxane-based regimens offer improved tolerability, and dual HER2-targeted therapy with trastuzumab and pertuzumab has demonstrated high pathologic complete response (pCR) rates. For HER2-negative disease, antiangiogenic therapy with bevacizumab may help improve response rates in certain subsets of breast cancer. Objective: To evaluate the efficacy, safety, and tolerability of an anthracycline-free neoadjuvant regimen of weekly carboplatin and paclitaxel with trastuzumab/pertuzumab (HER2+) or bevacizumab (HER2-). Methods: In this single-institution, open-label, phase II trial, patients with histologically confirmed breast cancer (≥1 cm or node-positive) were enrolled. HER2+ patients (Cohort A) received weekly trastuzumab (2 mg/kg; loading 4 mg/kg) and pertuzumab every 3 weeks (420 mg; loading 840 mg). HER2- patients (Cohort B) received bevacizumab 10 mg/kg every 2 weeks. All received paclitaxel (80 mg/m2) and carboplatin (AUC 2) weekly for 12 weeks. Primary endpoint was 2-year progression-free survival (PFS), and secondary endpoints included pCR (RECIST) and toxicity (CTCAE v4.0). Results: 117 patients were randomized (47 to Cohort A, 70 to Cohort B). Baseline characteristics included a median age of 51 years and 80% hormone receptor positivity (HR+). The majority were White (47%) or Asian (24%). Estimated 10-year PFS was 90.3% (95% CI: 81.1-99.5) in Cohort A—89.3% in HR+ (n = 32) and 93.3% in HR- patients (n = 15). In Cohort B, PFS was 68.2% (95% CI: 51.7-84.7), including 59.2% in HR+ (n = 58) and 100% in triple-negative (TNBC) patients (n = 12) (p = 0.0176). Pathologic complete response rates were higher in Cohort A (58.3%) vs. Cohort B (42.6%), especially in HR-/TNBC subsets (88.2% vs. 66.7%). Grade ≥3 treatment-related adverse events (AE) occurred in 28% (Cohort A) and 40% (Cohort B) of patients. Neutropenia was the most common AE in both groups. Neuropathy was reported in 30% (Cohort A) and 51% (Cohort B) of patients, mostly grade 1-2. No cardiotoxicity occurred in Cohort A. Proteinuria was observed in 8.5% of Cohort B patients without treatment delays. Conclusions: This anthracycline-free neoadjuvant chemotherapy (NAC) regimen demonstrated robust efficacy and favorable tolerability in patients with HER2-positive breast cancer, achieving high long-term progression-free survival (PFS) and response rates, particularly among hormone receptor-negative (HR-) subgroups. In HER2-negative disease, clinical outcomes were more heterogeneous, with particularly promising results observed in patients with TNBC. The 10-year follow-up provided critical insights, highlighting favorable outcomes across most subtypes, with the notable exception of HR+/HER2-negative p","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":"146204940","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 PS5-12-16: A Phase 2 Trial of (Z)-endoxifen + Goserelin as Neoadjuvant Treatment for Premenopausal Women with ER+, HER2-, Breast Cancer (EVANGELINE)","authors":"M. P. Goetz, V. J. Suman, C. Lopez, H. Erickson, L. Beaulieu, S. S. Hammer, L. Mina, R. Leon-Ferre, K. N. Hunt, M. Piltin, A. Degnim, J. N. Ingle, J. C. Boughey, B. A. Sarah, J. M. Reid, M. Schellenberg, J. R. Hawse, P. Advani, K. Giridhar, F. Batalini, D. Flora, J. M. Jones, N. A. Bagegni, J. Jakub, V. Abramson, V. Dabak, W. J. Irvin, E. Sima, K. Seema, S. C. Quay","doi":"10.1158/1557-3265.sabcs25-ps5-12-16","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-12-16","url":null,"abstract":"Background: Endocrine therapy (ET) with aromatase inhibitors (AIs) plus ovarian function suppression (OFS) is a standard endocrine strategy for premenopausal women with ER+/HER2- breast cancer. However, poor tolerability to AI+OFS limits its use, leaving tamoxifen as the only alternative. Prospective studies demonstrated that premenopausal women treated with neoadjuvant ET whose tumors exhibit Ki-67 ≤ 10% following 4 weeks of therapy achieve 5-year distant disease-free survival > 96%. Problematically, only 41% of patients reach this threshold with tamoxifen compared to 78% with AI+OFS (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent selective estrogen receptor modulator that dually targets ERα and PKCβ1. At plasma concentrations of 3-5 ng/mL, it inhibits ERα; at ≥ 500 ng/mL, it targets PKCβ1, leading to AKT suppression. The EVANGELINE trial aims to examine endocrine sensitivity in terms of Week 4 Ki-67 in premenopausal women whose baseline Ki-67 > 10%, and objective response rate after 24 weeks of ENDX + goserelin in premenopausal women with baseline Ki-67≤ 10%. Methods: EVANGELINE (NCT05607004) is a multicenter, open-label, Phase 2 study comprised of three parts. Eligible patients are premenopausal women with Stage IIA/IIB ER+/HER2- breast cancer. • Part 1 (PK Run-in): assessed 40mg vs 80mg ENDX (+/- OFS) in 22 patients. • Part 2: patients with baseline Ki-67 >10% were randomized to 40 mg ENDX + goserelin or exemestane + goserelin for 6 months with the primary objective being 4-week ESD rate. Patients with a baseline Ki-67 ≤10% were assigned to a single-arm cohort of 40 mg ENDX monotherapy (no OFS) to evaluate the 24-week endocrine sensitivity disease rate. • Part 3 (replaces Part 2): all patients are treated with ENDX 40mg daily + goserelin every 28 days. A two stage Phase II design was chosen to assess outcomes as follows: Part 3a: Up to 45 patients with baseline Ki-67> 10% to assess Week 4 Ki-67≤ 10% rate is at least 65%. If 9 or more of these patients have a Week 4 Ki-67>10%, enrollment will be stopped due to futility. Otherwise, enrollment will continue. Part 3b: Up to 20 patients enrolled with baseline Ki-67≤ 10% to assess Week 24 objective response rate. Ki-67 levels are determined by central laboratory and images are centrally reviewed. Secondary objectives include safety, tolerability, surgical outcomes, and biomarker analysis using paired biopsies (baseline, week 4) and surgical specimens. Results: The PK run-in (completed Fall 2024) enrolled 22 patients and assessed ENDX doses (40 mg daily vs 80 mg daily (+/-OFS)). The Week 4 Ki-67 ≤ 10% rate with ENDX was 86% and did not differ according to dose. Early safety, PK, efficacy and compliance data supported the selection of 40 mg ENDX daily as the optimal dose. Enrollment in Part 2 began in May 2025. Part 3 will replace Part 2 with simplification of the trial design. Conclusions: EVANGELINE is the first trial to evaluate (Z)-endoxifen + OFS as neoadjuva","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"84 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205166","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 PS5-08-20: A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007","authors":"J. R. White, R. S. Cecchini, E. E. Harris, E. P. Mamounas, J. G. Bazan, D. G. Stover, P. A. Ganz, R. Jagsi, S. J. Anderson, C. Bergom, V. Théberge, M. B. El-Tamer, R. C. Zellars, D. A. Shumway, G. Chen, T. B. Julian, N. Wolmark","doi":"10.1158/1557-3265.sabcs25-ps5-08-20","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps5-08-20","url":null,"abstract":"Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy (ET), freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after breast-conserving surgery (BCS) and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for IBR and breast preservation in women intending ET for stage 1 invasive breast cancer (ER and/or PR-positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (≤11, >11-18/MammaPrint Low). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (moderate or ultra hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR-positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS ≤18 (diagnostic core biopsy or resected specimen). A “low risk” MammaPrint is permissible if completed as part of usual care prior to screening. Primary endpoint is IBR (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% v 91.6% for the omission-of-RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in Yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1%/yr. Some T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. As of July 9, 2025, 1,490 pts have been screened and 1,349 randomly assigned. NCT #: NCT04852887 Support: U10 CA180868, -180822, U24 CA196067, UG1 CA189867 Citation Format: J. R. White, R. S. Cecchini, E. E. Harris, E. P. Mamounas, J. G. Bazan, D. G. Stover, P. A. Ganz, R. Jagsi, S.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"17 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205170","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 PS3-05-15: Targeting Breast Cancer via Dual Antagonism of Estrogen Receptor α and GPER","authors":"S. SINGH, S. Vidaurri, M. Noorani, S. Goyal, A. Dhasmana, S. Dhasmana, M. Yallapu, S. Fofana, S. C. Chauhan, D. Nguyen, S. Khan","doi":"10.1158/1557-3265.sabcs25-ps3-05-15","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps3-05-15","url":null,"abstract":"Background Estrogen’s diverse biological effects are primarily driven by the classical receptors ERα and ERβ,which function as ligand-activated transcription factors. Among these, ERα plays a pivotal role inbreast cancer development, making it a key target for therapies such as tamoxifen. However,tamoxifen’s clinical success is often compromised due to both inherent and acquired resistance.Notably, tamoxifen inhibits ERα but paradoxically acts as an agonist for GPER/GPR30, estrogenreceptor that mediates non-classical estrogen signaling in normal and cancerous cells. Activationof GPER can promote gene expression and cell proliferation, contributing to tamoxifen resistancein hormone-sensitive tumors. Our study addresses this challenge by focusing on a dual-targetingstrategy that simultaneously inhibits both ERα and GPER, aiming to overcome resistance andimprove therapeutic outcomes in breast cancer treatment. Methods GPER expression was evaluated in breast cancer cell lines and tumor tissues using immunoblotting,qRT-PCR, and immunohistochemistry. Cell proliferation was assessed via MTT and colonyformation assays. Migration and invasion capabilities were measured using wound healing andtranswell invasion assays. Intracellular calcium signaling was monitored using fluorescence-basedcalcium imaging following GPER stimulation. Metagenomic analysis of Hispanic breast cancertissues were performed using 16S rRNA sequencing to identify microbial populations correlatedwith GPER expression and tumor subtypes. Statistical analyses included correlation tests andsubtype stratification. Results GPER expression was detected in both breast cancer cell lines and tumor tissues. Our resultsdemonstrate that GPER is significantly overexpressed in ERα-positive breast tumors, with aunique correlation observed in a Hispanic breast cancer patient population (P < 0.001). GPERexpression was also observed in Triple-Negative subtypes. The correlation of GPER expressionwas analyzed across different breast cancer subtypes, classified as Luminal A (HR+/HER2−),Luminal B (HR+/HER2+), HER2-Enriched (HR−/HER2+), and Triple-Negative (HR−/HER2−).In vitro studies confirmed the presence of GPER protein and RNA in breast cancer cells of varioussubtypes. Furthermore, this study identifies Ormeloxifene (ORM), a selective estrogen receptormodulator (SERM), as a dual antagonist of ERα and GPER. GPER expression was associated withincreased cancer aggressiveness, migration, and invasion, all of which were effectively inhibitedby Ormeloxifene. ORM acts as an antagonist ligand for both ERα and GPER by suppressing genetranscription and inhibiting growth signaling pathways in breast cancer cells. Mechanistically,Ormeloxifene suppresses GPER-induced calcium signaling and downstream activation of EGFR,ERK, YAP, and TAZ pathways, thereby inhibiting gene transcription and tumor growth. Additionally, metagenomic analysis of Hispanic breast cancer tissues revealed specific microbialpopulations ass","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205191","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 PS2-11-28: Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition","authors":"M. Hafner, S. Vartanian, G. Luca, N. Kosaisawe, M. Hwang, E. Lin, L. Wang, J. Oeh, J. Vijay, K. N. Islam, A. Zheng, K. Samy, U. Segal, J. Moffat, D. Zingg, A. Collier, I. Sanidas, J. Xie, S. A. Wander","doi":"10.1158/1557-3265.sabcs25-ps2-11-28","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps2-11-28","url":null,"abstract":"While CDK4/6 inhibitors (CDK4/6i) have changed the therapeutic landscape of hormone receptor-positive (HR+) breast cancer, resistance to these therapies is a major challenge limiting their clinical benefit. Recent studies have shown that CDK2 activity is a key mechanism of resistance to CDK4/6i. Adaptation to CDK4 inhibition can arise from the overexpression or amplification of cyclin E1 or E2, leading to increased CDK2 activity that phosphorylates Rb and bypasses CDK4/6i-induced G1 arrest. Additional alterations, such as p53 loss of function, can activate CDK2. It has been proposed that targeting CDK2, in addition to CDK4, can lead to more durable cell cycle arrest in HR+ cancer cells. In this study, we evaluated the preclinical activity of GDC-4198, a next-generation CDK4/2 inhibitor currently being tested in clinical trials, and its potential to address CDK2-driven resistance to CDK4 inhibition. In biochemical kinase activity assays, GDC-4198 has sub-nanomolar potency against CDK4 and is a more potent inhibitor of CDK2 than CDK6/CycD3, unlike approved CDK4/6i. Immunofluorescence data from HR+ breast cancer cells revealed that the shift in cell cycle distribution induced by GDC-4198 was differentiated from the effects of CDK4/6i and can most closely be reproduced by a combination of atirmociclib (a CDK4 inhibitor) and tagtociclib (a CDK2 inhibitor). This observation was most pronounced in cell line models that have developed resistance to CDK4/6i. RNA-seq data collected after 96 hours of treatment confirmed that the effects of GDC-4198 on gene expression are differentiated from CDK4 inhibition alone. In cell viability assays, GDC-4198 induced growth inhibition and sustained cell cycle arrest in a diverse panel of HR+ breast cancer cell lines. Notably, time-course assays demonstrated that parental T-47D cells can reenter the cell cycle within two days after initial arrest under treatment with CDK4/6i, whereas GDC-4198 led to sustained growth inhibition over five days. Across CDK4/6i resistant HR+ cells, engineered via either long-term exposure to palbociclib or CCNE1/2 overexpression, GDC-4198 was substantially more effective at inhibiting growth than approved CDK4/6i or atirmociclib. Notably, the activity of GDC-4198 was comparable to the combination of CDK4 and CDK2 inhibitors. Additional studies in patient-derived cell lines obtained in the setting of metastatic HR+ breast cancer following progression on letrozole/ribociclib, as well as in patient-derived cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced antitumor activity of GDC-4198 compared to current CDK4/6i or atirmociclib. In xenograft studies of HR+ breast cancer, GDC-4198 demonstrated dose-dependent tumor growth inhibition. Pharmacokinetic and pharmacodynamic analyses indicated favorable drug exposure and pharmacodynamic modulation in tumor tissues consistent with the effects observed in in vitro experiments. Taken together, these preclinical findings","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":"146205196","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 PS1-05-29: Patient-reported reasons for discontinuing adjuvant endocrine therapy: a survey of early-stage breast cancer survivors","authors":"A. Dugonjic Okrosa, T. Silovski, N. Dedic Plavetic, D. Kifer, A. Budisavljevic, H. Silovski, A. Seselja Perisin, R. Kelemenic Drazin, M. Skelin, L. Jajac Brucic, J. Jovic Zlatovic, I. Mucalo","doi":"10.1158/1557-3265.sabcs25-ps1-05-29","DOIUrl":"https://doi.org/10.1158/1557-3265.sabcs25-ps1-05-29","url":null,"abstract":"Background: Adjuvant endocrine therapy (AET) for early-stage breast cancer (eBC) profoundlyreduces the risk of recurrence1, but the literature consistently reports high rates of discontinuation andnon-adherence2. This study aimed to identify the patient-reported reasons for discontinuing therapy. Methods: A self-administered, cross-sectional survey comprising open-ended questions wasconducted among female survivors of eBC who had been prescribed AET for a minimum of threemonths. Results: A total of 920 female survivors (median age 53 years) diagnosed with eBC were included inthe study. The median time since diagnosis was 2 years (IQR: 1.00-4.00), and 62% werepremenopausal at the time of their diagnosis. Among the 165 patients who discontinued or considered discontinuing AET without consulting theirphysician, the most frequently reported reasons were musculoskeletal pain (24.8%) and, as describedin responses to an open-ended question, unspecified severe adverse effects in general (18.8%). Thesewere followed by typical menopausal symptoms (15.5%), including hot flashes, night sweats, vaginaldryness, and osteoporosis and psychological effects (13.3%) such as depression, mood swings,memory problems, and irritability. In their open-ended responses, patients explained that despiteexperiencing significant adverse effects, they chose to continue AET, with fear of cancer recurrenceserving as the primary motivator. However, they also reported contemplating discontinuation due todiminished quality of life (QoL), emotional and cognitive challenges, and concerns about the long-term effects of the therapy. Discontinuations made in agreement with a physician (N=13) were primarily temporary and attributedto planned surgery (27.3%), switching AET (22.7%), gynaecological issues (20.4%), elevated liverenzymes (6.8%), or other adverse effects (22.7%). Conclusions: Although physicians rarely recommend discontinuing AET due to adverse effects, sucheffects remain the leading cause of patient-initiated treatment cessation. Effective side effectmanagement and personalised support are crucial for improving patients’ QoL and, in turn, promotingadherence to and persistence with AET. References: 1. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects ofcontinuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. The Lancet 2013;381:805-16. https://doi.org/10.1016/S0140-6736(12)61963-1. 2. Yussof I, Mohd Tahir NA, Hatah E, Mohamed Shah N. Factors influencing five-yearadherence to adjuvant endocrine therapy in breast cancer patients: A systematic review. Breast2022; 62:22-35. https://doi.org/10.1016/j.breast.2022.01.012 Citation Format: A. Dugonjic Okrosa, T. Silovski, N. Dedic Plavetic, D. Kifer, A. Budisavljevic, H. Silovski, A. Seselja Perisin, R. Kelemenic Drazin, M. Skelin, L. Jajac Brucic, J. Jovic Zlatovic, I. Mucalo. Patient-reported reasons for","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205245","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}