Distant Disease-free Survival Research Articles

Abstract PO1-25-05: Adipose-enriched peri-tumoral stroma prognosticates poorer survival in breast cancers

Abstract Background: Adjuvant breast cancer therapy is informed by whether a tumour is positive or negative for the biomarkers ER, PgR, and HER2, often without regard to level of positivity. Quantitation has been proposed to improve therapeutic management. Adjunctive statistical standardization has been proposed to improve inter-laboratory comparability of biomarkers results. Methods: This primary report utilized adjunctive statistical standardization of machine-quantitated image analysis biomarker assessments. CCTG MA.27 (NCT00066573) is an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER, PgR, and HER2 were centrally assessed, with FISH (HER2;HER2/CEP17) determinations for equivocal IHC HER2. HSCOREs were statistically standardized to a mean of 0, standard deviation of 1 following Box-Cox variance stabilization transformations of square for ER and natural logarithm for PgR (0.1 was added to 0 HSCOREs). The primary endpoint was STEEP distant disease-free survival (DDFS) at the longest trial follow-up of median 4.1 years. Survival was described with Kaplan-Meier plots. The univariate Wilcoxon (Peto-Prentice) test statistic was used with usual designation of negative/positive (0; >0), and standardized cut-points at standard deviations about mean of 0(<-1; (-1,0]; (0,1]; >1). Cox multivariate regressions adjusted for age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics, utilized likelihood ratio tests. Nominal significance was p=0.05. Results: Of the 7576 women accrued, 3048 had machine-quantitated image analysis results: 2900 (95%) for ER; 2726 (89%) for PgR. Only 8 women were ASCO/CAP ER- (HSCORE 0); PgR HSCORE was 0 for 533. Statistically standardized units differentiated DDFS ER levels (p< 0.001) and PgR levels (p< 0.001). In adjusted multivariate analyses, higher ER HSCORE was associated with better DDFS (p=0.05) with weak evidence of an association (p=0.11) for standardized HSCORE, and no significant association (respectively, p=0.28, p=0.54) in models with PgR. Higher PgR was associated with better DDFS (p=0.001) in all multivariate assessments, including those with ER. Conclusions: DDFS was superior for patients with higher ER and PgR standardized units compared with those with HSCOREs <-1. Adjunctive statistical standardization, similar to that mandated for clinical practice by the World Health Organization for BMD, should improve inter-laboratory comparability of biomarker results for similar patient populations. Biomarker N DDFS DDFS 5-year (%) 95% CI ER total 2900 ER <-1 506 86 (82, 91) ER (-1, 0] 934 94 (92, 96) ER ( 0, 1] 919 94 (92, 96) ER 1 541 96 (93, 98) PgR total 2726 PgR <-1 734 89 (86, 92) PgR (-1, 0] 439 92 (89, 95) PgR ( 0, 1] 967 95 (93, 96) PgR 1.0 586 98 (97,100) Citation Format: Hannah Lau, Veronique Kiak Mien Tan, Benita Kiat Tee Tan, Yirong Sim, Jelmar Quist, Aye Aye Thike, Puay Hoon Tan, Shazib Pervaiz, Anita Grigoriadis, Kanaga Sabapathy. Adipose-enriched peri-tumoral stroma prognosticates poorer survival in breast cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-25-05.

Abstract PO1-27-10: Adjunctive statistical standardization of quantitated machine image analysis of Estrogen and Progesterone Receptors: CCTG MA.27 trial

Abstract Background: Adjuvant breast cancer therapy is informed by whether a tumour is positive or negative for the biomarkers ER, PgR, and HER2, often without regard to level of positivity. Quantitation has been proposed to improve therapeutic management. Adjunctive statistical standardization has been proposed to improve inter-laboratory comparability of biomarkers results. Methods: This primary report utilized adjunctive statistical standardization of machine-quantitated image analysis biomarker assessments. CCTG MA.27 (NCT00066573) is an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER, PgR, and HER2 were centrally assessed, with FISH (HER2;HER2/CEP17) determinations for equivocal IHC HER2. HSCOREs were statistically standardized to a mean of 0, standard deviation of 1 following Box-Cox variance stabilization transformations of square for ER and natural logarithm for PgR (0.1 was added to 0 HSCOREs). The primary endpoint was STEEP distant disease-free survival (DDFS) at the longest trial follow-up of median 4.1 years. Survival was described with Kaplan-Meier plots. The univariate Wilcoxon (Peto-Prentice) test statistic was used with usual designation of negative/positive (0; >0), and standardized cut-points at standard deviations about mean of 0(<-1; (-1,0]; (0,1]; >1). Cox multivariate regressions adjusted for age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics, utilized likelihood ratio tests. Nominal significance was p=0.05. Results: Of the 7576 women accrued, 3048 had machine-quantitated image analysis results: 2900 (95%) for ER; 2726 (89%) for PgR. Only 8 women were ASCO/CAP ER- (HSCORE 0); PgR HSCORE was 0 for 533. Statistically standardized units differentiated DDFS ER levels (p< 0.001) and PgR levels (p< 0.001). In adjusted multivariate analyses, higher ER HSCORE was associated with better DDFS (p=0.05) with weak evidence of an association (p=0.11) for standardized HSCORE, and no significant association (respectively, p=0.28, p=0.54) in models with PgR. Higher PgR was associated with better DDFS (p=0.001) in all multivariate assessments, including those with ER. Conclusions: DDFS was superior for patients with higher ER and PgR standardized units compared with those with HSCOREs <-1. Adjunctive statistical standardization, similar to that mandated for clinical practice by the World Health Organization for BMD, should improve inter-laboratory comparability of biomarker results for similar patient populations. Biomarker N DDFS DDFS 5-year (%) 95% CI ER total 2900 ER <-1 506 86 (82, 91) ER (-1, 0] 934 94 (92, 96) ER ( 0, 1] 919 94 (92, 96) ER >1 541 96 (93, 98) PgR total 2726 PgR <-1 734 89 (86, 92) PgR (-1, 0] 439 92 (89, 95) PgR ( 0, 1] 967 95 (93, 96) PgR >1.0 586 98 (97,100) Citation Format: Judy-Anne Chapman, Jane Bayani, Sandip SenGupta, John MS Bartlett, Tammy Piper, Mary Anne Quintayo, Shakeel Virk, Paul Goss, James Ingle, Matthew Ellis, George Sledge Jr, George Budd, Manuela Rabaglio, Rafat Ansari, Richard Tozer, David D'Souza, Haji Chalchal, Silvana Spadafora, Vered Stearns, Edith A. Perez, Karen Gelmon, Timothy Whelan, Catherine Elliott, Lois Shepherd, Bingshu Chen, Karen Taylor. Adjunctive statistical standardization of quantitated machine image analysis of Estrogen and Progesterone Receptors: CCTG MA.27 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-10.

Abstract PO2-17-06: Real world treatment patterns and clinical outcomes by germline BRCA (gBRCA) mutation status in patients with HER2-negative early breast cancer in the US community oncology setting: a retrospective observational chart-review study

Abstract Background: Women with early-stage breast cancer (eBC) who have inherited BRCA1 or BRCA2 mutations (gBRCAm) are typically diagnosed at a younger age and often require more intensive treatment. In the randomized, double-blind OlympiA trial of HER2-negative (HER2–) gBRCAm patients, olaparib, a targeted poly (ADP-ribose) polymerase inhibitor (PARPi), significantly improved invasive disease free survival (IDFS), distant disease free survival (DDFS) and overall survival (OS) and was subsequently approved for adjuvant treatment of gBRCAm HER2– high-risk eBC patients. This study examined the real-world patient characteristics, treatment patterns and clinical outcomes by gBRCA status among patients with HER2– eBC in a US community oncology setting prior to olaparib US approval for treatment of eBC. Methods: This retrospective observational study used chart review data from The US Oncology Network's iKnowMed database to examine adult patients diagnosed with HER2– eBC (stage I-III) initiating systemic neoadjuvant or adjuvant therapy with chemotherapy and/or endocrine therapy between January 1, 2012 and December 31, 2018. Patients with valid gBRCAm test results (all gBRCAm and randomly selected BRCAwt patients) were included and followed through December 31, 2021. Patients were excluded if they had HER2+ tumors and progressed to stage IV within 6 months after initiation of neoadjuvant therapy or were diagnosed with another primary cancer. Descriptive analyses assessed patient characteristics. Kaplan Meier methods and multivariate Cox proportional hazard models (CPHM) were used to evaluate IDFS, DDFS and OS by gBRCA status and by HR+/HER2– or TNBC eBC subsets. Results: Among 298 BC patients meeting initial criteria, 42% had gBRCAm (n=124, 43% hormone receptor positive [HR+], 56% triple-negative BC [TNBC], 1% unknown), and 58% had gBRCAwt (n=174, 74% HR+, 22% TNBC). Median (interquartile) age at surgery was numerically lower in gBRCAm (45 [36,55] years) than gBRCAwt (48 [41,55] years) patients. A numerically higher proportion of gBRCAm patients received neoadjuvant therapy compared with gBRCAwt (Neoadj: gBRCAm 37.1% vs gBRCAwt 12.6%) but the reverse was true for adjuvant (Adj: gBRCAm 42.7% vs gBRCAwt 65.5%) and neoadjuvant + adjuvant use was numerically similar (Neoadj+Adj: gBRCAm 20.1% vs gBRCAwt 21.8%). The majority of TNBC patients received neoadjuvant therapy while the majority of HR+ patients received adjuvant therapy (Neoadj: TNBC 51.4% vs HR+ 6.6%, Adj: TNBC 29.0% vs HR+ 71.4%, Neoadj+Adj: TNBC 19.6% vs HR+ 22.0%). Median IDFS, DDFS, and OS in both study cohorts were not reached. Median follow-up from surgery was < 5 years (overall 59.0 months; gBRCAm 50.6 months; gBRCAwt 61.3 months). At 60 months, in gBRCAm and gBRCAwt respectively, estimated IDFS were 85.5% and 90.9%, estimated DDFS 88.1% and 92.2%, and estimated survival 91.9% and 95.2%. At 60 months, in HR+/HER2– and TNBC respectively, estimated IDFS were 92.4% and 81.2%, estimated DDFS 93.9% and 85.7%, and estimated survival 96.3% and 90.9%. CPHM results showed that risks of invasive disease (HR 1.74; 95% CI 0.83-3.64; p=0.15), distant disease (HR 1.24; 95% CI 0.50-3.07; p=0.65) and death (HR 1.79; 95% CI 0.52-6.13; p=0.353) were similar between gBRCAm and gBRCAwt patients. Between HR+/HER2– and TNBC patients, risks of invasive disease (HR=0.63; 95% CI 0.21-1.89; p=0.41), distant disease (HR=0.42; 95% CI 0.11-1.67; p=0.22) and death (HR 0.48; 95% CI 0.09-2.70; p=0.41) were similar. Conclusions: This real-world chart review study of data through 2021 (before PARPi approval for eBC) with limited follow up of 5 years found that gBRCAm patients had a numerically shorter survival (IDFS, DDFS and OS) than gBRCAwt, but this difference was not statistically significantly different. Given that the follow-up period was too short to draw conclusions, further studies examining clinical outcomes over a longer follow-up period after approval of PARPi may be of interest. Citation Format: Jay Andersen, Jagadeswara Earla, Nicole Fulcher, Juliet Ndukum, Nicholas J Robert, Mark Robson, Weiyan Li, Jaime Mejia. Real world treatment patterns and clinical outcomes by germline BRCA (gBRCA) mutation status in patients with HER2-negative early breast cancer in the US community oncology setting: a retrospective observational chart-review study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-06.

Abstract PO4-02-04: Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort

Abstract Background: In the PENELOPEB trial, the addition of 1-year of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib to standard endocrine therapy (ET) for women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer at high risk of recurrence after neoadjuvant chemotherapy (NACT) did not improve invasive disease-free survival (iDFS) or overall survival (OS) in the main study analysis. Invasive lobular breast cancer (ILC) accounts for ~15% of all breast cancers (BC) and represents an underinvestigated subtype of BC with typically less sensitivity to (neo)adjuvant chemotherapy, and poor distant disease-free survival (DDFS) irrespective of response to NACT. Here, we report the post-hoc analysis results of iDFS, DDFS and OS in pre- and postmenopausal women enrolled on PENELOPEB and with ILC. Methods: Patients with HR+/HER2-negative BC without pathological complete response (pCR) after taxane-containing NACT and at high risk of relapse (CPS-EG score ≥3, or 2 and ypN+) were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 of a 28-day cycle in addition to standard ET with tamoxifen (TAM) +/- gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) +/- GnRH. Randomization was stratified by nodal status at surgery, age at first diagnosis (< 50 vs. ≥50 years), Ki-67, region, and CPS-EG score. ILC diagnosis was locally assessed and reported by the investigators on the pathology case report form. The primary objective of this post-hoc analysis was to evaluate iDFS, DDFS and OS by treatment arm in patients with high risk ILC. Results: A total of 1,250 patients were randomized, of whom 110 had ILC and were nearly uniformly distributed between both treatment arms (palbociclib n=58 vs. placebo n=52), with a higher proportion of postmenopausal women (58.6% in the palbociclib arm vs. 53.8% in the placebo arm) compared to premenopausal women (41.4% in the palbociclib arm vs. 46.2% in placebo arm). There was no difference in the distribution of AI/TAM use between the treatment arms. An estimated absolute 3-year-iDFS difference of 18.3% with palbociclib compared to placebo (iDFS 88.4% [95% CI 76.0-94.6] vs. 70.1% [95% CI 55.3-80.7]) with a HR of 0.66 [95% CI 0.27 – 1.61, log-rank p=0.354]) was observed. A comparable 3-year-DDFS difference of 16.3% was observed. An estimated 3-year-OS difference of 16.4% (98.0% [95% CI 86.6 – 99.7] vs. 81.6% [95% CI 67.5 – 90.0]) with a hazard ratio (HR) of 0.27 (95% CI 0.05 – 1.43, log-rank p=0.108) was observed. Out of 12 observed deaths (n=2 palbociclib vs. n=10 placebo), 11 (in placebo arm) were related to metastasic BC. Conclusions: In this post-hoc analysis, a trend towards improvement in OS and a trend in favor of iDFS and DDFS for the addition of palbociclib to ET was observed among women with HR+/HER2- ILC at high risk of recurrence after NACT, but these differences were not statistically significant. This could represent a valuable treatment option for patients with high risk ILC. Due to the small sample size of the ILC subgroup, further follow-up evaluation is necessary. Moreover, analyses in the ILC subgroup from other adjuvant CDK4/6 inhibitor trials could substantiate these findings. Table. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort Results of iDFS, DDFS and OS. Citation Format: Hervé Bonnefoi, Frederik Marmé, Miguel Martín, Michael Untch, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Karen Gelmon, José Ángel García-Sáenz, Catherine M. Kelly, Toralf Reimer, Zhe Zhang, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Nader Hirmas, Valentina Nekljudova, Johannes Holtschmidt, Sibylle Loibl. Overall survival and disease recurrence rates in patients with invasive lobular breast cancer of the PenelopeB cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-04.

Abstract PO5-19-10: First oncological outcomes of HypoG-01: a UNICANCER phase III trial comparing loco-regional hypo vs normo fractionated radiation therapy in early breast cancer patients

Abstract Objective Normofractionated (NF) radiation therapy (RT) is still standard for loco-regional early breast cancer (EBC) in many countries. HypoG-01, a UNICANCER, non-inferiority, open-label, multicenter, randomized phase III trial (NCT03127995), conducted in parallel with the DBCG Skagen trial 1 (NCT02384733), evaluated hypofractionated (HF) RT with 40 Gy/15 fr (2.67 Gy/fr) versus NF RT 50 Gy/25 fr (2.0 Gy/fr). This is the first report of oncological outcomes, secondary endpoints of the trial. Methods Patients (pts) ≥18 years old were operated for T1-3, N0-3, M0 breast cancer. All pts received nodal and thoracic wall or breast RT. Tumor-bed boost (sequential or simultaneous) and nodal levels treated were decided according to local guidelines. Target volumes were delineated according to the ESTRO consensus. RT technique was left at the investigator’s discretion. Stratification factors included treating center, type of surgery, number of positive nodes and body mass index. The primary endpoint, reported previously, was time to occurrence of arm lymphedema. Oncological outcomes included locoregional relapse free survival (LRFS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), breast cancer specific survival (BCSS) and overall survival (OS) as defined per DATECAN guidelines. All time to cancer related endpoints were defined as starting from the date of randomization until the event. The primary statistic test was stratified one-sided logrank test: 5% significance level in per-protocol population (PPP) with a pre-specified non-inferiority margin of 1.545. Stratified Cox model was used for calculating hazard ratios of oncological outcomes. Results In total, 1265 pts were randomized to HF versus NF RT from Sep 2016 to Mar 2020 with 1221 in the PPP (HF group 614 pts (50.3%); NF group 607 (49.7%)), 5 consent withdrawn and 39 major deviations. Median age was 58 years (range 23-91), surgery included mastectomy (501 pts; 45%) and axillary clearance (921 pts; 82.8%). Sequential (67.8%) or simultaneous integrated (32.2%) tumor-bed boost was used in 596 pts (48.8%). With a median follow-up for OS in PP analysis of 3.8 years (95% CI 3.3 to 3.9), HF was non-inferior to NF RT in terms of lymphedema (HR=1.07; 90% CI 0.86-1.34, non-inferiority p=0.003). Table 1 reports the hazard ratio and 3-year survival rates for the oncological endpoints LRFS, IDFS, DDFS, BCCS and OS. There was no sign of disadvantage for any of these endpoints comparing HF to NF. Additional analyses will be presented at the meeting. Conclusion Moderately HF loco-regional RT is non-inferior to NF RT in terms of lymphedema risk in EBC and does not show a disadvantage in terms of LRFS, IDFS, DDFS, BCCS and OS with a median follow-up of 3.8 years. Together with the Skagen 1 trial, this study provides level 1A evidence supporting the use of 40 Gy/15 fr for loco-regional radiation therapy in EBC with respect to arm lymphedema risk; Table 1: Oncological outcomes according to treatment arm in the per protocol analysis HF: Moderately hypofractionated radiation therapy; NF: Normofractionated radiation therapy; n:number of patients; N: number of events Citation Format: Sofia Rivera, Eleni Karamouza, Youlia Kirova, Séverine Racadot, Mohamed Benchalal, Jean-Baptiste Clavier, Claire Charra-Brunaud, Marie-Eve Chand-Fouche, Delphine Argo-Leignel, Karine Peignaux, Ahmed Benyoucef, David Pasquier, Philippe Guilbert, Julien Blanchecotte, Agnès Tallet, Adeline Petit, Guillemette Bernadou, Xavier Zasadny, Claire Lemanski, Jacques Fourquet, Emmanuelle Malaurie, Honorine Kouto, Carole Massabeau, Alexandre Henni, Pauline Regnault, Aurélie Belliere, Yazid Belkacemi, Magali Le Blanc-Onfroy, Julien Geffrelot, Jean-Briac Prevost, Marie Bergeaud, Assia Lamrani-Ghaouti, Amandine Ruffier, Naima Bonnet, Stephanie Wong, Christine Rossier, Thomas Brion, Pierre Maroun, Claire Petit, Guillaume Auzac, Stefan Michiels. First oncological outcomes of HypoG-01: a UNICANCER phase III trial comparing loco-regional hypo vs normo fractionated radiation therapy in early breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-10.

Abstract PO2-15-07: HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial

Abstract HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial Background: Biomarkers for de-escalation and escalation of systemic therapy in early-stage TNBC are needed. HER2DX is a standardized prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay based on clinical and gene expression-based data. Here we aimed to test the value of HER2DX assay in early TNBC. Methods: Standardized HER2DX was evaluated centrally using RNA from baseline FFPE tumor biopsies from the WSG-ADAPT-TN study (NCT01815242), a multicenter phase II trial that randomized 336 patients with stage I–III early TNBC to 12-weeks of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 d1,8 every 3 weeks (arm A) versus nab-paclitaxel 125 mg/m2 plus carboplatin AUC2 day 1,8 every 3 weeks (arm B). The primary aim was to test the ability of HER2DX pCR and risk-score models to predict pCR (ypT0/isN0) and survival endpoints, respectively, such as invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Secondary objectives were to assess the association of the i) HER2DX immune signature score and ii) percentage (%) of stromal tumor infiltrating lymphocytes (sTILs) with efficacy endpoints. Uni- and multi-variable logistic regression and Cox models tested the association of each variable with each endpoint. Results: HER2DX was evaluated in 126 (37.5%) baseline pre-treatment tumors. Mean age was 52.1 (range 26-76). cT1 represented 40.5% of cases and 72.2% were cN0. Overall, pCR rate was 34.1% (95%CI 26.1 – 43.2) and median follow-up was 5.0 years. Median sTILs at baseline was 31.6% (range 0-90) and moderately correlated with the IGG signature (coefficient=0.57). The % of HER2DX high-, medium- and low-pCR groups was 41.3%, 47.6% and 11.1%, respectively. HER2DX pCR score (as a continuous variable) was significantly associated with pCR in univariate (odds ratio [OR per 10-unit increase]=1.31, 1.06-1.64, p=0.016) and after adjusting by treatment arm (OR=1.31, 1.06-1.65, p=0.015). Overall, the pCR rates in HER2DX pCR-high, -medium and -low groups were 46.2%, 26.7% and 21.4%, respectively (high vs medium/low OR=2.48, 1.17-5.34, p=0.018). In arm B (n=51), the pCR rates in HER2DX pCR-high, -medium and -low groups were 47.8%, 25.0% and 0.0% respectively (high vs medium/low OR=3.36, 1.02-12.0, p=0.051). In terms of the risk-score, the % of HER2DX low-risk and high-risk groups was 60.3% and 39.7%, respectively. HER2DX risk score as a continuous variable was significantly associated with iDFS, DDFS and OS (p< 0.001 in all univariate analysis), and after adjusting by variables such as arm and pCR status (all p< 0.05). sTILs were not associated with any survival endpoint (all p >0.35). The HER2DX immune signature was significantly associated with iDFS (p=0.012), DDFS (p=0.022) and OS (p=0.012). Conclusion: The HER2DX genomic test in TNBC provides valuable insights into the response and survival following neoadjuvant taxane-based chemotherapy in the absence of immunotherapy. The development of a tailored genomic assay for TNBC is currently in progress. Citation Format: Oleg Gluz, Fara Brasó-Maristany, Ulrike Nitz, Laia Paré, Matthias Christgen, Guillermo Villacampa, Benedetta Conte, Sherko Kuemmel, Ronald Kates, Cornelia Kolberg-Liedtke, Eva-Maria Grischke, Helmut Forstbauer, Michael Braun, Mathias Warm, John Hackmann, Christoph Uleer, Bahriye Aktas, Claudia Schumacher, Ana Vivancos, Rachel Wuerstlein, Joel S. Parker, Monika Graeser, Charles M. Perou, Christine zu Eulenburg, Patricia Villagrasa, Hans-Heinrich Kreipe, Aleix Prat, Nadia Harbeck. HER2DX genomic assay in triple-negative breast cancer (TNBC) patients treated with 12-weeks of neoadjuvant chemotherapy: a correlative analysis from WSG-ADAPT-TN phase II trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-07.

Abstract PO5-22-08: Comparison of long-term oncological outcomes in young women with breast cancer between BRCA-mutation carriers versus non-carriers: How genetic risk factors and tumor characteristics influence the prognosis

Abstract Objectives and rationale: Breast cancer (BC) arising at a young age is relatively uncommon; however, approximately 6 to 10% of women diagnosed with BC are younger than the age 40. This subgroup of young women presents different risk factors, tumor biology, and clinical outcomes. Moreover, the interpretation of the effects of inherited genetic factors on the prognosis of young patients with BC remains a subject of debate. The primary aim of this study was to evaluate the characteristics of young patients with BC and to compare the long-term oncological results between BRCA-mutation carriers and non-carriers. We retrospectively reviewed all the consecutive young (≤ 40 years old) BC patients treated at the Breast Unit of IRCCS Humanitas Research Hospital (Milan, Italy). All young patients underwent BRCA-mutation analysis. For further analysis young BC patients were divided into two groups: BRCA-mutation carriers versus non-carriers. Tumor, surgical treatment, and post-operative data were compared between the two groups. Primary end-points were: disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). The Kaplan-Meier method was used to generate the recurrence and survival curves. Multivariate analyses were performed using the Cox proportional hazards model to identify independent risk and protective factors for DFS, DDFS, and OS. Results: The characteristics of 63 young BC patients with BRCA-mutation were compared with 339 young BC patients without BRCA-mutation. BRCA-mutation carriers tend to be younger (60.3% versus 34.8% if age ≤ 35 years, odds ratio (OR) = 17.699, 95% confidence interval (95%CI) = 33.871-35.568, p = 0.001) and present more aggressive tumors (66.7% versus 40.7% if G3, OR = 17.119, 95%CI = 2.549-2.828, p = 0.001; 57.2% versus 12.4% if biological subtype triple negative, OR = 52.727, 95%CI = 2.042-2.417, p = 0.001; 73.0% versus 39.2% if Ki67 ≥ 25%, OR = 58.981, 95%CI = 47.135-58.505, p = 0.001). Young BC patients without BRCA-mutation presented significantly better long-term oncological results in terms of DFS, DDFS, and OS compared with young BRCA-mutation carriers (10-years DFS rate 91.1% versus 58.1%, p < 0.001; 10-year DDFS rate 91.2% versus 76.1%, p = 0.003; 10-year OS rate 98.0% versus 87.8%, p = 0.002, respectively). Neo-adjuvant chemotherapy was found to be an independent protective factor for OS in young BRCA-mutated BC patients (hazard radio = 14.885, 95%CI = 2.343-94.566, p = 0.004). Conclusions: Breast cancer is more likely to present at a younger age (≤ 35 years) and with more aggressive characteristics (G3, triple negative, Ki67 ≥ 25%) in patients with BRCA-mutation compared with their non-mutated counterpart. Young BRCA-mutation carriers show a poorer prognosis in terms of recurrence and survival compared with non-carriers. The implementation of neo-adjuvant chemotherapy may improve survival in young BC patients with BRCA-mutation. Citation Format: Damiano Gentile, Simone Di Maria Grimaldi, Andrea Sagona, Erika Barbieri, Alberto Bottini, Giuseppe Canavese, Giulia Caraceni, Shadya Darwish, Corrado Tinterri. Comparison of long-term oncological outcomes in young women with breast cancer between BRCA-mutation carriers versus non-carriers: How genetic risk factors and tumor characteristics influence the prognosis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-22-08.

Abstract PO4-13-07: Association of clonal hematopoiesis (CH) with clinical outcomes among survivors of breast cancer (BC)

Abstract Background: Clonal hematopoiesis (CH) refers to the identification of clonal expansion of hematopoietic cells due to somatic mutations in leukemia-associated genes without evidence of hematologic anomalies. CH, particularly with variant allele frequency (VAF) ≥ 10%, has been associated with adverse outcomes, including reduced survival in advanced malignancies and higher risk of cardiovascular events. The aim of this study was to evaluate the biological and prognostic relevance of CH in survivors of breast cancer (BC). Methods: CANTO (NCT01993498) is a prospective, multicenter cohort enrolling patients diagnosed with stage I-III BC. CANTO collects clinical, tumor and treatment-related characteristics at diagnosis (dx). Follow-up visits are scheduled at 1, 2, 4 and 6 years after dx and data on disease status, type of recurrence, and survival status are collected. We assessed CH among pts ≥ 40 years, without previous solid or hematological cancer, with blood samples available at dx and year 4 or experiencing death or disease recurrence before year 4. CH was determined using Next-Generation Sequencing with unique molecular identifiers (HaloPlexHS, Agilent Technologies) for 17 genes (including DNMT3A, TET2, ASXL1, PPM1D, ATM, JAK2 and TP53) on blood samples obtained at dx. Outcomes of interest included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS) defined according to STEEP criteria. Kaplan-Meier estimator, log-rank test and multivariate Cox models assessed prognostic role of CH. Results: In the cohort with available CH data (N=1219) mean age (SD) was 57.5 (10.1) years, 62% of pts were postmenopausal, 40.9% were current or former smokers, 46.2% had stage I BC, 77.7% had HR+/HER2- BC, 53.5% received chemotherapy and 80.8% hormonal therapy. CH was detected with a VAF ≥ 1% in 306 pts (25.1%) including 207 pts (67.6%) with DNMT3A mutation, ≥ 2% in 186 (15.3%) and ≥ 10% in 45 (3.7%) pts. Pts with CH ≥ 10% were more frequently older (65.3 vs 57.2 years, p< .0001) and with a previous history of cardiovascular disease (53.3% vs 37.3%, p< 0.02). At a median (IQR) follow-up of 7.0 (6.2-7.8) years 246 iDFS, 161 DDFS and 118 OS events were observed. Only 8 cases of new hematological malignancies were observed. Pts harboring CH with a VAF ≥ 10% had worse OS (log-rank p=0.04) and CH with a VAF ≥ 10% was associated with higher risk of death (HR= 2.4, 95%CI 1.04-5.6); presence of CH with lower VAF was not associated with worse OS. Table displays complete results for all tested associations. Conclusions: CH at dx was identified in 25% of pts with stage I-III BC aged ≥ 40 years in the CANTO cohort, including 4% with a VAF ≥ 10%. In a large, prospective cohort of survivors of BC, we confirmed known associations of CH with older age and cardiovascular history. We observed few secondary hematological malignancies. CH with a VAF ≥ 10% was significantly associated with higher risk of death while adjusting for other relevant prognostic factors. Furthermore, a trend towards higher risk of DDFS events was observed among pts harboring CH with a VAF ≥ 10%. Table. Citation Format: Davide Soldato, Antonin Della Noce, Antonio Di Meglio, Christophe Marzac, Barbara Pistilli, Anne-Laure Martin, Sibille Everhard, Marie Breckler, Sandrine Boyault, Marina Rousseau, Olivier Trédan, Charles Coutant, Paul Cottu, Olivier Rigal, Christelle Levy, Christelle Jouannaud, Baptiste Sauterey, Nathalie Droin, Bastien Job, Aurélie Bertaut, Fabrice André, Ines Vaz Luis, Jean-Baptiste Micol. Association of clonal hematopoiesis (CH) with clinical outcomes among survivors of breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-07.

Abstract GS03-03: Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2− early breast cancer: final invasive disease–free survival (iDFS) analysis from the NATALEE trial

Abstract Background: Interim results from the phase 3 NATALEE trial demonstrated that adding RIB to standard-of-care adjuvant NSAI had a statistically significant iDFS benefit in patients with stage II and III HR+/HER2− early breast cancer at risk of recurrence, including those with node-negative disease (Slamon et al, ASCO 2023). We present the final protocol-specified analysis of the primary endpoint of iDFS. Methods: A total of 5101 pre-/postmenopausal women and men underwent 1:1 randomization to receive RIB (400 mg/day; 3 weeks on/1 week off for 36 months) + NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for ≥60 months) or NSAI alone. Men and premenopausal women received goserelin (3.6 mg once every 28 days). Patients were required to have anatomic stage IIA (either N0 with additional risk factors or N1), IIB, or III breast cancer per the AJCC (8th edition). Patients remained on trial as long as they were continuing on NSAI (≤5 years), regardless of RIB discontinuation. The primary endpoint was iDFS according to STEEP v1.0 criteria, and the secondary efficacy endpoints were recurrence-free survival (RFS), distant disease–free survival (DDFS), and overall survival (OS). This final analysis was planned after approximately 500 iDFS events. iDFS was evaluated by the Kaplan-Meier method, and statistical comparison was made by a stratified log-rank test. P values were not corrected for multiple comparisons. Results: At the data cutoff (July 21, 2023), among the 2549 patients in the RIB + NSAI arm, 1091 (42.8%) completed 3 years of RIB treatment, and 905 (35.5%) discontinued RIB or RIB + NSAI early and 528 patients (20.7%) remained on RIB. 1748 patients (68.5%) remain on treatment in the NSAI arm. Median follow-up for iDFS was 33.3 months, an additional 5.6 months from the previous interim analysis. A total of 509 iDFS events were observed, 226 (8.9%) in the RIB + NSAI arm and 283 (11.1%) in the NSAI alone arm. RIB + NSAI demonstrated a significant iDFS benefit over NSAI alone (HR, 0.749; 95% CI, 0.628-0.892; P=.0006). The 3-year iDFS rates were 90.7% (95% CI, 89.3%-91.8%) vs 87.6% (95% CI, 86.1%-88.9%). A consistent benefit was observed across patient subgroups, including those with node-negative, stage II, or stage III disease (Table). Secondary endpoints of DDFS and RFS favored RIB + NSAI over NSAI alone (Table). OS data were immature, with 84 (3.3%) and 88 (3.4%) total events in the RIB + NSAI and NSAI alone arms, respectively. No new safety signals were observed since the prior interim analysis. Discontinuation of RIB due to adverse events was observed in 19.5% of patients (a <1% increase from the prior interim analysis). Conclusions: With a substantial proportion of patients completing 3 years of RIB treatment, NATALEE continues to demonstrate a significant iDFS improvement with RIB + NSAI over NSAI alone. Efficacy results confirm continued improvement in benefit across subgroups, including stage II disease. Safety findings support the manageable toxicity profile of RIB at the 400-mg starting dose in early breast cancer. Table. Citation Format: Gabriel Hortobagyi, Daniil Stroyakovsky, Denise Yardley, Chiun-Shen Huang, Peter A. Fasching, John Crown, Aditya Bardia, Stephen Chia, Seock-Ah Im, Miguel Martín, Sherene Loi, Binghe Xu, Sara Hurvitz, Carlos Barrios, Michael Untch, Rebecca Moroose, Frances Visco, Federico Parnizari, Farhat Ghaznawi, Zheng Li, Sorcha Waters, Arunava Chakravartty, Dennis Slamon. Ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) as adjuvant treatment in patients with HR+/HER2− early breast cancer: final invasive disease–free survival (iDFS) analysis from the NATALEE trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-03.

Abstract PS01-09: Early Results of a Phase I Pre-Operative Single Fraction Ablative Trial for Early Stage Breast Cancer

Abstract Objective(s): To explore the impact of pre-operative single fraction stereotactic ablative partial breast irradiation (SPBI) dose escalation (30, 34, or 38Gy) on toxicity and tumor response for early-stage hormone receptor (HR)+ breast cancer in an interim analysis of an expanded cohort phase I dose escalation study (NCT04040569). Methods: Eligible patients (pts) have < 3 cm, HR+, Her2 -, cN0 invasive breast carcinomas not requiring chemotherapy. Patients are treated on either MR LINAC, robotic radiosurgery, or cobalt stereotactic breast units. Endocrine therapy is started two weeks after SPBI. Surgery is completed 2-12 months after SPBI. The primary objective is to escalate single fraction SPBI to an ablative dose without exceeding maximum tolerable dose (MTD). Secondary endpoints include pathologic complete response (pCR), local control, toxicity, cosmesis, and distant disease-free survival. Near complete response (nCR) is defined as RCB 1 and Miller-Payne 4/5. Dose limiting toxicity (DLT) is defined as grade ≥3 toxicity or any grade 4/5 toxicity attributed to SPBI. Each dose cohort enrolls 7-15 pts. Dose escalation is permitted if 0/7, 2/9, ≤3/12, or ≤4/15 patients experienced a DLT within 90 days of SPBI. MTD is exceeded if more DLTs occur in any cohort. Results: From 12/2019 to 6/2023, 11 and 15 pts were treated with 30Gy and 34Gy, respectively. Rates of pCR/nCR are 37.5% for 30Gy versus 92.8% 34 Gy (p=0.01). At 30Gy, 8/11 pts (73%) underwent surgery with a median 4.3 (range 2.8-5.9) month interval from SPBI to surgery: 0/8 (0%) had a pCR and 3/8 (37.5%) had a nCR. At dose level 34Gy, 14/15 pts (93%) underwent surgery with a median 7.3 (range 5.9-12) month interval from SPBI to surgery: 6/14 (42.8%) had a pCR while 7/14 (50%) had a nCR. Of the 8 pts with a nCR, 50% had only 1-3mm of residual disease. The mean ki67 for the entire cohort was 12.0% +/- 6.9% at diagnosis and decreased to 1.4 +/-2.3% at surgery. 13/14 (92.8%) pts with residual disease had a ki67 < 3% after surgery and SPBI. There were 33 acute grade 1; 2 acute grade 2 (breast pain and dermatitis); and 10 late grade 1 [1 grade 2 (breast pain), and 1 grade 3 (slow healing wound) in an uncontrolled diabetic] toxicities. Conclusion: First study to show pre-operative SPBI up to 34Gy in a single fraction was safe and effective for early-stage HR+ breast cancer. Escalating the dose has achieved a dramatic improvement in pCR/nCR (92.8%) suggesting this is an exciting approach for potentially eliminating tumor with radiation/endocrine therapy alone in early stage breast cancer and potentially paving a path towards non-surgical management in highly selected patients. Citation Format: Asal Rahimi, A Marilyn Leitch, Baṣak Dogan, Prasanna Alluri, Deborah Farr, Mona Arbab, Stephen Seiler, Nathan Kim, Rachel Wooldridge, Nisha Unni, Chika Nwachukwu, Ina Patel, You Zhang, David Parsons, Anvy Nguyen, Howard E Morgan, Heather McArthur, Sunati Sahoo, Robert Timmerman. Early Results of a Phase I Pre-Operative Single Fraction Ablative Trial for Early Stage Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS01-09.

Abstract PO4-19-01: The SURVIVE-HERoes trial – a secondary adjuvant treatment intervention study with trastuzumab-deruxtecan in patients with HER2 positive/HER2 low early breast cancer and a molecular relapse, based on a positive ctDNA result

Abstract Background: Despite current adjuvant treatment strategies, ≥ 20% of patients with early breast cancer (EBC) experience a metastatic relapse. In the new era of highly effective antibody drug conjugates (ADCs), secondary adjuvant treatment options for EBC patients at a high risk of relapse arise. The ADC trastuzumab-deruxtecan (T-DXd) has so far shown promising efficacy in patients with HER2-positive and HER2-low metastatic breast cancer (DESTINY Breast 03 and -04 trial) and is currently tested in the post-neoadjuvant setting in patients with non-pCR (DESTINY Breast 05 (TRUDY) trial). However, to successfully apply ADCs as a secondary adjuvant treatment, identification of patients who would benefit the most is required. The detection of minimal residual disease (MRD) using liquid biopsy, e.g. ctDNA, may offer a promising approach for patient selection. The efficacy of such a secondary adjuvant treatment in terms of delaying or even preventing distant metastases has yet to be evaluated in a randomized clinical trial. Trial design: The SURVIVE-HERoes trial is a prospective, randomized, open label comparative Phase III superiority trial in patients with intermediate to high-risk HER2-positive or HER2-low EBC, who participate in the large breast cancer surveillance trial SURVIVE (NCT05658172) and experience a molecular relapse as determined by a positive ctDNA result, but show no evidence of relapse or metastatic disease based on imaging by CT-scan and SPECT. In total, 180 patients will be enrolled and randomized with 2:1 allocation to treatment with T-DXd + (only endocrine therapy, if HR positive) versus standard of care (including endocrine treatment +/- CDK4/6-inhibitors or Neratinib). The treatment period lasts 12 months during which ctDNA levels will be repeatedly measured every 3 months (additional ctDNA testing will be performed at month 24 and 36). Stratification factors are HER2-, hormonal- and nodal status. Recruitment start is planned for Q1 2024. Eligibility criteria: Eligible patients are adult females/males, with HER2-positive or HER2-low EBC, as defined in the ASCO-CAP guidelines, and a positive ctDNA result (obtained in the SURVIVE study) that has to be confirmed ≤ 8 weeks before randomization. Primary anti-tumor therapy (surgery, adjuvant chemo- or radiotherapy) has to be completed ≥14 months, (postneo)-adjuvant treatment with anti-HER2-antibodies, T-DM1, Capecitabine, Pembrolizumab and Olaparib ≥ 4 weeks before randomization. Adequate bone marrow and cardiac function and no signs of ILD are mandatory. Statistics: The primary objective of SURVIVE-HERoes is the comparison of ctDNA clearance rates 6 months after randomization between the two study arms, which will be analysed using the chi square test for two independent proportions. Secondary objectives include the comparison of overall survival (OS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), distant recurrence-free survival (DRFS), breast cancer specific survival (BCSS), invasive breast cancer free survival (IBCFS) and quality of life (QoL) between the study arms as well as the safety and tolerability of T-DXd. Secondary survival endpoints will be estimated by the Kaplan Meier method and compared between the randomization arms using log-rank tests and cox regression models. Special aims: This trial is a proof of principle study with the aim to establish the efficacy of secondary adjuvant treatment with the ADC T-DXd in patients with HER2-positive/HER2-low early breast cancer, who are at high risk of relapse, as evidenced by detection of ctDNA in the blood. Conclusion: If SURVIVE-HERoes is successful, it could lead to a treatment shift towards early intervention with secondary adjuvant targeted therapies following liquid-biopsy based MRD detection. Contact: University Hospital Ulm, Dpt. Obstetrics & Gynecology, Germany, mail: studienzentrale.ufk@uniklinik-ulm.de Citation Format: Sophia Huesmann, Franziska Mergel, Kerstin Pfister, Angelina Fink, Forca Mehmeti, Peter Möller, Tanja Fehm, Volkmar Müller, Klaus Pantel, Thomas Friedl, Andreas Hartkopf, Brigitte Rack, Wolfgang Janni. The SURVIVE-HERoes trial – a secondary adjuvant treatment intervention study with trastuzumab-deruxtecan in patients with HER2 positive/HER2 low early breast cancer and a molecular relapse, based on a positive ctDNA result [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-01.

Abstract PO1-19-05: COGNITION/-GUIDE – Implementation of Precision Oncology in Early High-Risk Breast Cancer

Abstract Background: The concept of precision oncology is nowadays increasingly implemented into clinical practice but is predominantly restricted to the metastatic setting limiting the benefits to prolongation of progression-free-survival (PFS). Implementation of precision oncology at an earlier disease stage with less tumor burden, heterogeneity and a higher capacity of tumor lesions to inform on the molecular tumor landscape holds the promise to impact cure rates. Methods: The prospective COGNITION/-GUIDE precision oncology platform encompasses the COGNITION diagnostic multi-omics biomarker screening platform (NCT05906407) linked to the multi-arm phase II COGNITION-GUIDE umbrella trial (NCT05332561). Based on a two-step consenting procedure, patients with early breast cancer (eBC) and poor response towards standard-of-care (SOC) neoadjuvant chemotherapy (NACT) are first enrolled into the COGNITION diagnostic platform. Residual bulk tumors are subjected to whole-genome- (WGS)/whole exome- (WES) and RNA-sequencing to enable streamlined detection of a rigorous biomarker-framework for subsequent genomics-guided arm allocation. Pilot analyses revealed that 78% (81/104) of high-risk tumors (TNBC or HER2+ BC with non-pCR or HR+/HER2- BC with non-pCR and CPS-EG score ≥ 3, or ypN+ and CPS-EG score ≥ 2) can be successfully sequenced and discussed within an interdisciplinary molecular tumor board. In 67% (70/104) eligible biomarker-profiles could be identified for potential biomarker-guided therapeutic intervention. In a second step, having completed all standard-of-care neoadjuvant and post-neoadjuvant treatments (except endocrine therapy, which can be administered simultaneously to the experimental therapy), patients can be enrolled into one of 6 biomarker-based arms in the COGNITION-GUIDE phase II trial (atezolizumab, inavolisib, ipatasertib, olaparib, sacituzumab govitecan or trastuzumab/pertuzumab). Primary end point is invasive disease-free survival (IDFS) at 4 years after surgery in the whole study population. Secondary endpoints are overall survival (OS), IDFS in each treatment arm, distant disease-free survival (DDFS) and patient-reported outcomes (PROs). Enrollment in COGNITION-GUIDE started in Q2/2023 and 240 patients will be enrolled in 5 German sites until Q2/2027. A comprehensive biomarker discovery program is integrated on longitudinal tumor tissue and liquid biopsies for exploratory analyses. Further clinical work and accrual will be reported at the meeting. Conclusion: The theranostic COGNITION/-GUIDE platform moves the concept of precision oncology to a potentially curative but still high-risk stage of eBC following SOC NACT. Hence, this novel application in the field of precision oncology harbours the prospect to increase cure rates. Citation Format: Verena Thewes, Luise Strassl, Marc Zapatka, Mario Hlevnjak, Constantin Pixberg, Christian Maurer, Katharina Smetanay, Carlo Fremd, Laura Michel, Sabine Heublein, Celina V. Wagner, Jan-Philip Suppelna, Lars Buschhorn, Albrecht Stenzinger, Renate Haidinger, Eva Schumacher-Wulf, Sibylle Loibl, Pauline Wimberger, Jens-Uwe Blohmer, Peter A. Fasching, Wolfgang Janni, Richard F. Schlenk, Peter Lichter, Andreas Schneeweiss. COGNITION/-GUIDE – Implementation of Precision Oncology in Early High-Risk Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-05.

Abstract PO5-19-07: A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer

Abstract Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with a high risk of early relapse. Patients not achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have a 3-year event free survival (EFS) of < 60%. Approximately 1/3 of patients receiving NAC with pembrolizumab-mediated immune therapy will not achieve a pCR and of those, approximately 1/3 will experience a recurrence within 3 years. Physical disruption of tumors with local strategies such as cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. The combination of cryo with immune checkpoint inhibition (ICI) has been shown to induce tumor regression and prevented tumor re-challenge in pre-clinical models. Clinical studies have also demonstrated that the combination of pre-operative cryo with ICI is safe in women with operable, early-stage breast cancer and generates intra-tumoral and systemic immune responses (NCT01502592, NCT02833233). This multi-center, single arm, phase 2 study is currently evaluating the impact of cryo with standard-of-care pembrolizumab (pembro) in women with residual TNBC after taxane-based NAC, a group at high risk of early relapse (NCT03546686). Methods: Eligible women are ≥18y, with ER < 10%, PR < 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and receive peri-operative pembro per standard-of-care. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients are stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Funding sources: Conquer Cancer Foundation, Breast Cancer Research Foundation, Boston Scientific Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen Solomon, Sangeetha Reddy, Isaac Chan, Baṣak Dogan, Dawn Klemow, Nisha Unni, Jorge Henrique Santos Leal, Cristal Martinez, Reva Basho, Dorothy Park, Philomena McAndrew, Brigid Larkin, David Page, William Mills, Staci Mellinger, Nicole Fredrich, Nicole Moxon, Lynette Currie, Meredith Carter, Melissa Ramos, Stephanie Rice, Sujata Patil, Margaret Gatti-Mays, Larry Norton. A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-07.

Abstract PO2-19-07: PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET

Abstract Background During the past years, clinical routine has shifted away from relying solely on clinicopathologic factors toward increasing use of multigene expression assays in guiding treatment decisions regarding adjuvant chemotherapy (CT) for hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (EBC) with 0 to 3 positive lymph nodes. In case of a low genomic risk, there is strong consensus in favor of endocrine treatment (ET) alone for postmenopausal patients, regardless of clinical risk (supported by data from planB, ADAPT, RxPonder, TailorX, MINDACT). However, there is still uncertainty regarding optimal therapy for pre- and perimenopausal patients with a similar clinical/genomic risk profile. Since the observed benefit of CT in this patient group may be partly attributable to CT-induced ovarian function suppression (OFS), some of these patients could be spared CT by adding OFS to endocrine therapy. The West German Study Group (WSG) initiated the PROOFS-registry to create a real-world database on how to optimally treat these patients. Eligibility Criteria PROOFS (NCT05792150) aims at the long-term follow up of pre- or perimenopausal patients with HR+/HER2- EBC with an intermediate to high clinical risk of recurrence and low genomic risk measured by MammaPrint(R). Additional endocrine response assessment (Ki67) after a short preoperative endocrine therapy is encouraged. Up to 25% of the study population may have node-positive disease. Participants undergo standard-of-care treatment at physician´s discretion and according to clinical routine, which may include CT neoadjuvant or adjuvant + ET, ET + OFS in premenopausal, or ET +/- OFS in perimenopausal women. Specific Aims PROOFS aims to give insights in the real-world use of OFS and to confirm an excellent outcome in pre-/perimenopausal women with HR+/HER2- early BC with an intermediate to high clinical risk of recurrence and low genomic risk treated by ET +/- OFS alone (without CT). In addition, quality of life is captured. Statistical Methods The primary objective is to demonstrate the 5-year distant recurrence-free interval (dRFI) in patients treated by ET +/- OFS alone. The null hypothesis H(0) is: 5-year dRFI < 92%. Secondary endpoints for all patients are 5- and 10-year dRFI, distant disease-free survival (dDFS), overall survival (OS), breast cancer-free interval (BCFI), quality of life (QLQ BR23 and QLQ-C30) and therapy adherence. Cox regression models, Kaplan-Meier method and log-rank tests will be applied for survival analysis. Linear mixed models will be utilized to quantitatively describe the course of quality of life-scores as well as therapy adherence, and to conduct group comparisons. Present and Target Accrual The study is open for recruitment of 1500 patients (approximately 20% receiving CT and 80% receiving ET +/- OFS) at up to 100 centers in Germany (June 2023: 24 open for recruitment). Funding AGENDIA N.V., Amsterdam Contact Information rachel.wuerstlein@med.uni-muenchen.de Citation Format: Rachel Wuerstlein, Lotta Ada Fischer, Nadia Harbeck, Monika Graeser, Ulrike Nitz, Matthias Christgen, Sherko Kuemmel, Christine zu Eulenburg, Matthias Warm, Oleg Gluz. PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-07.

Abstract PO1-20-13: TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– breast cancer

Abstract Background: The current standard of care for patients (pts) with treatment-naive Stage II–III triple-negative breast cancer (TNBC) is neoadjuvant pembrolizumab + anthracycline/taxane/platinum-based chemotherapy followed by surgery and adjuvant pembrolizumab monotherapy. However, among pts who received the combination of pembrolizumab and chemotherapy in the KEYNOTE-522 trial (NCT03036488), 28% ultimately discontinued therapy due to treatment-related adverse events, and 37% had residual disease at the time of surgery, which was associated with poor outcomes. Consequently, there remains an unmet need to develop a treatment approach that improves pathologic complete response (pCR) rates and long-term survival while reducing chemotherapy-associated toxicity in pts with early-stage TNBC. Dato-DXd is a TROP2-directed antibody-drug conjugate that consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I (Topo-I) inhibitor via a plasma stable tetrapeptide-based tumor-selective cleavable linker. Dato-DXd monotherapy has demonstrated a manageable safety profile and encouraging preliminary efficacy in pts with metastatic TNBC in the Phase 1 TROPION-PanTumor01 study (NCT03401385), with a confirmed objective response rate (ORR) of 32% in all pts and 44% in Topo-I inhibitor-naive pts with measurable disease at baseline. The combination of Dato-DXd with durvalumab has demonstrated durable responses in unresectable locally advanced or metastatic TNBC in the Phase 1b/2 BEGONIA study (NCT03742102), with an ORR of 79%, median duration of response of 15.5 months and median progression-free survival of 13.8 months. The ongoing Phase 3 TROPION-Breast03 trial (NCT05629585) is evaluating Dato-DXd ± durvalumab versus standard-of-care therapy as adjuvant treatment in pts with Stage I–III TNBC with residual invasive disease at the time of surgery after neoadjuvant treatment. The TROPION-Breast04 trial aims to determine if improved efficacy and safety can be achieved with neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab, compared with the pembrolizumab-based standard of care regimen in pts with previously untreated TNBC or hormone receptor-low (estrogen and/or progesterone receptor 1% to <10%; neither hormone receptor may be ≥10%)/HER2-negative (HR-low/HER2–) breast cancer. Trial design: TROPION-Breast04 (NCT06112379) is an ongoing Phase 3, 2-arm, parallel-group, randomized, open-label, multicenter, global trial. Approximately 1728 adults (aged ≥18 years) with previously untreated histologically confirmed Stage II–III unilateral or bilateral primary invasive TNBC or HR-low/HER2– breast cancer per AJCC edition 8 as assessed by the investigator, and an ECOG PS of 0 or 1, will be randomized 1:1 into one of two arms: neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab-based therapy, or neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab-based therapy (full treatment details are provided in the Table). Randomization will be stratified by lymph node status, tumor stage, HR status, and geographic region. Pts with distant disease and any prior surgery, radiotherapy, or systemic anticancer therapy will be excluded from the study. The primary endpoints are pCR and event-free survival. The key secondary endpoint is overall survival; others are distant disease-free survival, patient reported outcomes, pharmacokinetics, immunogenicity, and safety/tolerability. TROPION-Breast04 opened for enrolment in November 2023. Citation Format: Heather McArthur, Sara Tolaney, Sibylle Loibl, Rebecca Dent, Peter Schmid, Jamil Asselah, Erwei Song, Naoki Niikura. TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-13.

Abstract PO1-19-02: A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007

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, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after 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 in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER &/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). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (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 &/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is in-breast recurrence (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% vs 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% per yr. Some of the 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. Current accrual (07-07-2023) is 555 screened and 488 randomized (~96% of predicted accrual). Support: U10CA180868, -180822, UG1CA189867, UG1CA189867; Susan G. Komen Foundation (JRW). NCT: 04852887. Citation Format: Julia White, Reena Cecchini, Eleanor Harris, Eleftherios Mamounas, Daniel Stover, Patricia Ganz, Reshma Jagsi, Stewart Anderson, Carmen Bergom, Valérie Théberge, Mahmoud El-Tamer, Richard Zellars, Dean Shumway, Guang-Pei Chen, Thomas Julian, Norman Wolmark. A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-02.

Abstract PO1-03-03: STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival

Abstract Background: Standardized definitions of efficacy endpoints are needed to improve clinical trial designs, data reporting and interpretation of results, and to allow cross-trial comparisons. STEEP (Standardized Definitions for Efficacy Endpoints) criteria were proposed in 2007 by an expert panel from the National Cancer Institute (NCI) to provide common definitions for clinical trials in early breast cancer (BC). Invasive disease-free survival (IDFS) was selected as a candidate surrogate endpoint for overall survival (OS) in adjuvant trials and has been widely used in the last 15 years. Advances in BC systemic treatment led to review these criteria (STEEP v2.0), with the definition of a new modified endpoint: invasive BC-free survival (IBCFS). IBCFS excludes second primary non-breast invasive cancers from IDFS which may better detect efficacy effects when the toxicity profile of the intervention is well-known and the risk of second primary cancer is small. Methods: We proposed a multi-trial analysis of 8 adjuvant chemotherapy (CT) trials from GEICAM and TRIO to evaluate the different surrogate endpoints defined in the STEEP v2.0. Trial-level surrogacy was assessed through correlation between the ln hazard ratio (HR) of OS and the ln HR of the different studied endpoints across trials. The correlation was estimated by the weighted, by trial size, least squares regression (WLS) line and evaluated comparing the R2 values between OS and the corresponding endpoint tested. Primary analyses evaluated the correlation of OS with IDFS/IBCFS. Secondary analyses evaluated the correlation of OS with other STEEP v2.0 endpoints (distant disease-free survival [DDFS], distant relapse-free survival [DRFS], recurrence-free survival [RFS], recurrence-free interval [RFI] and distant recurrence-free interval [DRFI]) and explored the surrogacy between OS and all endpoints in specific groups of patients (pts) according to their risk of relapse: hormone receptors positive (HR+)/HER2-negative (HER2-) pts with intermediate/high and high-risk and triple negative (TN) pts. Results: A total of 14,473 pts were included. Median age was 50 years (range, 20–82). All were female, and 51.8% were postmenopausal. With a median follow-up of 115 months (range, 0.0–188) we found 2,504 OS events, 4,146 IDFS events (60.9% being distant recurrences) and 3,810 IBCFS events (62.4% being distant recurrences). For each trial, HR of OS, IDFS and IBCFS indicated same conclusions. If HR< 1 for OS, it was also for IDFS and IBCFS and the same was true when HR >1. R2 results of the weighted linear correlations between the ln HR of OS versus (vs) IDFS and OS vs IBCFS were 0.86 and 0.89, respectively. Confidence intervals (CI) at 95% were both overlapping. All other efficacy endpoints showed strong correlation with OS in the overall analysis. R2 values for HR+/HER2- intermediate/high and high-risk pts were 0.89 (OS vs IDFS) and 0.84 (OS vs IBCFS). For TN pts the correlations were weaker, being 0.63 (OS vs IDFS) and 0.73 (OS vs IBCFS). All WLS R2 values are described in the table. Conclusions: All tested STEEP v2.0 endpoints were strongly correlated with OS (R2 close to 1), meaning that their use as surrogate endpoints for adjuvant CT trials is appropriate. Notably, no differences were found between them in this multi-trial analysis. Therefore, none of them is more appropriate than other to discriminate the value of a new intervention vs comparator in adjuvant CT studies with mature data and long-term follow-up. Table: Citation Format: Sara López-Tarruella, Marina Pollan, Ander Urriticoechea, Eva Carrasco, Gonzalo Spera, Miguel Martín, Begoña Bermejo, Linnea Chap, Manuel Ruíz - Borrego, John Crown, Jose Angel García-Sáenz, Arlene Chan, Angel Guerrero, Valerie Bee, Lourdes Calvo, Rodrigo Fresco, Andrea Blasco, Andrés Hernando, Dennis Slamon. STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-03.

Abstract PO3-20-06: TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer

Abstract Background: Despite being a rare presentation of breast cancer, inflammatory breast cancer (IBC) is responsible for up to 10% of all breast cancer-related deaths. Most IBCs express HER2, with up to 40% of all IBCs being HER2-positive and 40% being HER2-low. Additionally, IBC more often exhibits PD-L1 expression compared to non-IBC, suggesting a preeminent role for immune evasion in the development and progression of IBC. No systemic treatment approaches have been yet developed specifically for IBC, and standard treatments commonly lead to poor outcomes. Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate currently approved for patients with pretreated HER2-positive and HER2-low metastatic breast cancer. Early-phase data highlighted the safety and potential synergy of combining T-DXd with the immune checkpoint inhibitor durvalumab. The aim of TRUDI is to evaluate the clinical activity and safety of neoadjuvant T-DXd with durvalumab among patients with HER2-expressing IBC. Trial Design: TRUDI is an ongoing, open label, multicenter, two cohort investigator-initiated phase II neoadjuvant trial for patients with stage III HER2-expressing IBC. The trial was activated in May 2023, with enrollment ongoing. Eligible participants are women and men with previously untreated, stage III (T4d, any N) breast cancer, clinically determined to be IBC. Patients will be included in two cohorts, depending on the locally determined HER2 status (with any hormone receptor [HR] status): Cohort 1 (n=36) for patients with HER2-positive disease (HER2 IHC 3+ or 2+/ISH amplified); Cohort 2 (n=27) for patients with HER2-low disease (HER2 IHC 1+ or 2+/ISH not amplified). Patients will receive eight cycles of T-DXd (5.4 mg/kg IV every 21 days) combined with durvalumab (1125 mg IV every 21 days), followed by modified radical mastectomy and post-mastectomy radiation. Post-surgical systemic treatment will follow local standards. Tumor tissue will be collected at baseline, cycle 1 day 8, and at surgery; blood will be collected at baseline, cycle 4 day 1, cycle 7 day 1 and at surgery; stool will be collected at baseline, after 3-6 weeks of treatment and surgery. The primary endpoint is pathologic complete response (pCR; ypT0/Tis ypN0). Patients in each cohort will be enrolled based upon Simon two-stage designs: in Cohort 1, if ≥8/20 patients with HER2-positive IBC experience pCR then a total of 36 patients will be enrolled. In Cohort 2, if ≥1/18 patients with HER2-low IBC experience pCR then a total of 27 patients will be enrolled. Secondary endpoints include the residual cancer burden at surgery, event free survival, distant progression or distant disease-free survival, as well as safety of the regimen. Exploratory objectives will investigate biomarker analyses on tissue, blood, and microbiome to explore the association of HER2 expression, immune variables, and stool composition on the efficacy of T-DXd with durvalumab among patient with HER2-expressing IBC. To our knowledge, this is the first and only ongoing study testing the combination of an anti-HER2 antibody-drug conjugate with immunotherapy for the neoadjuvant treatment of patients with IBC. Clinical trial information: NCT05795101. Citation Format: Paolo Tarantino, Samuel Niman, Antonio Giordano, Faina Nakhlis, Jennifer Bellon, Wendy Woodward, Azadeh Nasrazadani, Sadia Saleem, Anthony Lucci, Michelle DeMeo, Naoto Ueno, Sara Tolaney, Vicente Valero, Meredith Regan, Rachel Layman, Filipa Lynce. TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-06.

Abstract PO1-20-05: SURVIVE study – a multicenter, randomized, controlled phase 3 superiority trial, evaluating liquid biopsy guided intensified follow-up surveillance in women with intermediate-to high-risk early breast cancer

Abstract Background: Current guidelines limit routine breast cancer follow-up to clinical examinations and breast imaging. This is based on the results of two large cohort studies conducted in the 1980s that showed no improvement in overall survival (OS) by an intensified screening for distant metastases. Thus, imaging for distant metastases should currently only be performed in patients with specific symptoms. To detect distant relapse in a pre-symptomatic stage, we suggest the evaluation of a liquid biopsy-guided intensified surveillance, analyzing tumor markers (CA 27.29, CA 125 and CEA), circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Trial design: Funded by the German Federal Ministry of Education and Research, the SURVIVE study is the first large, randomized breast cancer surveillance trial to investigate the potential survival benefit of a liquid biopsy guided follow-up care in intermediate- to high-risk early breast cancer patients. The trial is a German multicenter, controlled phase 3 superiority study, in which 3500 patients are randomized in a 1:1 ratio to standard vs. liquid biopsy guided intensified follow-up care. At the time of writing 150 patients have been enrolled since December 2022. The total study duration is 144 months. Stratification factors are study site as well as HR-, HER2- and nodal status at surgery. Both study arms receive standard follow-up according to national guidelines. Additional blood samples (year 1-3 every 3 months, year 4-5 every 6 months) and standardized Quality of Life (QoL) questionnaires (EORTC-QLQ-C30/PA-F12, every 6 months) will be collected. While the standard surveillance arm samples will only be stored in a biobank, samples collected in the intensive surveillance arm will be tested for standard tumor markers, CTCs and ctDNA. Pre-specified abnormal findings of any of the liquid biopsy markers indicative of minimal residual disease trigger complete staging. In the event of confirmed disease recurrence, guideline-based treatment follows, otherwise, liquid biopsy testing continues. If applicable, study participants may enter interventional trials. Eligibility criteria: Eligible patients are adult females or males with histologically confirmed primary invasive intermediate to high-risk early breast cancer, defined as an indication for (neo-)adjuvant chemotherapy, and/or large tumor size ( > 50 mm), and/or positive lymph nodes (≥ pN1mi), and/or high grade (≥ G3). Primary anti-tumor therapy (surgery, adjuvant chemo- or radiotherapy) must have been completed ≤ 24 months (≤ 60 months for luminal carcinoma) previously. Patient enrollment during adjuvant endocrine- or antibody-therapy, CDK4/6-/PARP- or PI3K-inhibitors and antibody-drug conjugates is allowed. Statistical methods: The two primary objectives are to determine whether intensified, liquid biopsy-guided surveillance leads to better OS or an overall lead-time effect, compared to standard surveillance. The primary endpoint OS will be analyzed in the ITT population using Kaplan Meier methods and cox regression models, the overall lead time effect is a purely descriptive composite measure. Secondary objectives include invasive disease-free survival (IDFS), distant disease-free survival (DDFS), distant recurrence free survival (DRFS), breast cancer-specific survival (BCSS) and quality of life (QoL). Specific aims: To improve OS and the QoL during breast cancer follow-up, we propose a liquid biopsy guided follow-up method, with high sensitivity and specificity for the earlier detection of distant (oligo-)metastases, to enable earlier initiation of therapy. Conclusion: The SURVIVE-study is a long-awaited trial in early breast cancer follow-up, based on promising liquid biopsy markers. If successful, the results will lead to a paradigm shift in current follow-up care of intermediate to high-risk early breast cancer survivors. Clinical trial information: NCT05658172 Citation Format: Franziska Mergel, Sophia Huesmann, Thomas Friedl, Kerstin Pfister, Tatjana Braun, Angelina Fink, Forca Mehmeti, Tanja Fehm, Volkmar Müller, Klaus Pantel, Andreas Hartkopf, Elisabeth Wiesmüller, Brigitte Rack, Wolfgang Janni. SURVIVE study – a multicenter, randomized, controlled phase 3 superiority trial, evaluating liquid biopsy guided intensified follow-up surveillance in women with intermediate-to high-risk early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-05.

Abstract PO5-19-02: I-PREPARE: International Prospective REgistry on Pre-pectorAl breast Reconstruction (EUBREAST 11R-NCT 05817175)

Abstract Background: Despite the progressive de-escalation of breast cancer (BC) surgery, mastectomy rates remain around 30-40%. Furthermore, up to 1/3 of BC patients undergo a contralateral risk-reducing mastectomy and around 40% of mutation carriers choose a bilateral intervention. To date, immediate breast reconstruction (IBR) with implants is the most commonly performed reconstructive procedure. After an initial experience with implants in subcutaneous positioning under the mastectomy flap in the seventies, this technique was abandoned due to a high rate of implant loss (28%), flap necrosis (13.5%) and capsular contracture (56%). For this reason, the positioning of the implant under the pectoralis major has become the standard of care. However, over time surgical techniques and implants have improved, resulting in decreasing implant loss, flap necrosis and capsular contracture rates. Moreover, biological/synthetic meshes have been used to cover the implant placed over the pectoralis major, thus avoiding to mobilize the muscle with some benefits in terms of reduced complications (no animation deformity, no chronic pain, no loss of muscular function), patients’ wellbeing, postoperative pain and recovery. Additionally, recent literature reported encouraging results with polyurethane breast implants in pre-pectoral positioning without any kind of implant coverage. Although these procedures are considered safe they were not evaluated in prospective randomized trials. In 2019 a joint consensus on pre-pectoral breast reconstruction (PBR) clearly recommended to properly audit the results in terms of surgical complications and patient-reported outcomes. Based on these premises the EUBREAST (European Breast Cancer Research Association of Surgical Trialists, www.eubreast.org) study group decided to launch a prospective international cohort study aimed at comparatively evaluating data on different surgical techniques of PBR with or without PMRT. Therefore, we will prospectively evaluate the utilization of PBR, including surgical, oncological, aesthetic and patients’ satisfaction and quality of life outcomes related to each type of surgical technique and the interaction with post-mastectomy radiation therapy (PMRT). Eligibility criteria: - Female patients age≥18 years - Signed informed consent - Patients undergoing mono/bilateral therapeutic mastectomy and immediate PBR Exclusion criteria - Patients not suitable for surgical treatment - Patients undergoing subpectoral reconstruction, reconstruction with tissue expander or autologous IBR Specific aims: The primary endpoint is implant-loss at 3 months defined as the unplanned removal or loss of the implant, as a result of infection or any other complication Secondary endpoints are infection, re-admission and re-operation rates, quality of life evaluated through BREASTQ Breast Reconstruction Module and EQ-5D-5L questionnaires on an App for patients before and after breast reconstruction at 6, 12, 24 months, early onset complication at 3 months, late-onset complications at 6, 12, 24 months, further surgery at 24 months, time to adjuvant therapy. Tertiary endpoints are further surgery, loco-regional recurrence, disease free survival, breast cancer specific survival, distant-disease free survival, overall survival, development of seroma/breast implant-associated anaplastic cell lymphoma. Statistics: We will use a single-arm design to assess the surgical safety of PBR through implant loss rate at 3 months which is expected to be ≤9% based on previous literature; 12% or greater will be regarded as unacceptably high. The assessment will be based on 1,112 patients. For this sample size calculation, power was set to 90%, and the two-sided alpha was set to 0.05. Allowing for a 10% loss to follow-up at 3 months, we aim at recruiting 1,236 patients. Accrual has not started yet. Funding: EUBREAST ETS Italy Contact: Oreste Davide Gentilini: gentilini@eubreast.org Citation Format: Rosa Di Micco, Maggie Banys-Paluchowski, Maria-Joao Cardoso, Jana de Boniface, Bahadir M. Gulluoglu, Orit Kaidar-Person, Thorsten Kühn, Maurizio Bruno Nava, Philip Poortmans, Shelley Potter, Nicole Rotmensz, Tanja Spanic, Marc Thill, Luzia Travado, Walter Weber, Oreste Davide Gentilini. I-PREPARE: International Prospective REgistry on Pre-pectorAl breast Reconstruction (EUBREAST 11R-NCT 05817175) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-02.