PURPOSE:Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant. METHODS:This phase III randomized trial (VIKTORIA-1; ClinicalTrials.gov identifier: NCT05501886) evaluated the efficacy of gedatolisib-based therapy, comparing gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet) and gedatolisib plus fulvestrant (gedatolisib doublet) with fulvestrant monotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-), PIK3CA wild-type (WT) advanced breast cancer. Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Comparison of progression-free survival as assessed by blinded independent central review for gedatolisib triplet versus fulvestrant and gedatolisib doublet versus fulvestrant was the primary objective. RESULTS:A total of 392 patients were randomly assigned 1:1:1. The median study follow-up was 10.1 months. The median progression-free survival was 9.3 months in the gedatolisib-triplet group, 2.0 months in the fulvestrant group (hazard ratio [HR] for progression or death, 0.24 [95% CI, 0.17 to 0.35]; P < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; P < .001 v fulvestrant). Grade ≥3 treatment-related adverse events (TRAEs) reported in the gedatolisib-triplet and gedatolisib-doublet groups, respectively, included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Study treatment discontinuation because of TRAEs was reported in 2.3% (triplet) and 3.1% (doublet) of patients. CONCLUSION:The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor-positive/HER2-, PIK3CA WT advanced breast cancer.

Baseline characteristics comparison between our ctDNA analysis population and the overall plasmaMATCH population, (A) Cohorts A-D and (B) (Cohort E)

Prediction of treatment benefit from on treatment ctDNA dynamics optimal cutpoint in cohorts A-D

Boxplot graph showing distribution of CDR C2D1

Supplementary Figure 5: Boxplot graph showing distribution of CDR C2D1 values in patients in cohort E by BRCA status

C1D1 variants for BRCA1/2 wildtype patients with undetectable ctDNA at C2D1 (CDR = 0) (N=6)

PURPOSE:ctDNA dynamic levels may identify patients who will respond to therapy. We assessed ctDNA baseline levels and on-treatment dynamics in patients with advanced breast cancer on the plasmaMATCH trial with mutation-targeted therapies (cohorts A-D) and triple-negative breast cancer on olaparib and ceralasertib combination (cohort E). EXPERIMENTAL DESIGN:Blood samples were collected at baseline [cycle 1 day 1 (C1D1)] and before treatment on cycle 2 day 1 (C2D1). Samples were sequenced using error-corrected targeted panels (Guardant360/GuardantOMNI). Circulating DNA ratio was calculated as the ratio of C2D1/C1D1 circulating DNA ratio, and baseline ctDNA levels were associated with progression-free survival (PFS) and confirmed objective response rates (ORR). RESULTS:A total of 167 patients had assessable C1D1-C2D1 ctDNA results. There was a strong association between baseline ctDNA levels and response in cohort E; low baseline levels were associated with longer PFS (HR, 0.33; P = 0.001) and higher ORR (40% vs. 9.7%; P = 0.02). In cohorts A to D, there was a weaker association with PFS (HR, 0.60; P = 0.03) and ORR (15.2% vs. 5.7%; P = 0.17). Associations of baseline ctDNA level and ORR were validated in the independent PEARL study. For on-treatment dynamics, suppression of ctDNA below median was predictive in cohorts A to D (HR, 0.47; P = 0.001) but not in cohort E (HR, 1.02; P = 0.94). Undetectable ctDNA levels at C2D1 were associated with good outcomes in both cohorts: in cohort E with improved PFS (HR, 0.25; P = 0.01) and improved ORR (86% vs. 11%; P = 0.01). Six of seven patients with undetectable on-treatment ctDNA were BRCA1/BRCA2/PALB2 wild type. CONCLUSIONS:Baseline low ctDNA levels predict response to targeted therapy, potentially suggesting shared mechanisms between high ctDNA release and resistance to therapy. Both baseline ctDNA levels and on-treatment dynamics are a promising surrogate endpoint for drug development, with clearance of ctDNA being a robust cross-therapy surrogate for outcomes.

Variant Allele Fraction of CHIP genes at different timepoints

Alternative methodologies evaluated for the calculation of CDR and PFS predictions (cohorts A-D)

Using patient-reported outcomes (PROs) and more objective measures, we evaluated adherence to adjuvant palbociclib and ET in the PALLAS trial, and the impact of palbociclib on ET adherence. The open-label, global, phase 3 PALLAS trial randomized patients with hormone receptor-positive (HR+), HER2-negative stage II–III breast cancer (1:1) to either 26 cycles of palbociclib (125 mg/day for 21 days and then 7 days off) plus adjuvant ET, versus ET alone. After 23.7 months median follow-up, palbociclib was stopped due to futility of the intervention and patients were moved to follow-up. For each cycle, daily adherence to ET was measured with study diaries; for palbociclib, study diaries and pill counts. At cycles 2, 3, 6, 12, 18 and 24, patients completed the Morisky Medication Adherence Scale-4 plus an additional item and the McHorney Adherence Questionnaire. Mean persistence was defined in months from treatment initiation to cessation. Four thousand six hundred eighty-eight of 5796 total PALLAS participants were included. Across all cycles, mean daily ET adherence values measured by study diary were > 98.0

List of the 74 genes included in the Guardant360 panel used for sequencing

Background: Invasive Lobular Carcinoma (ILC) represents about 15% of all invasive breast cancers (BC). ILC seldom exhibits overexpression of human epidermal growth factor 2 (HER2+), and majority of research focuses on ER+ HER2-negative phenotypes. There is limited data on response of ER+HER2+ ILC to endocrine therapy (ET) and the therapeutic efficacy of combined chemotherapy and anti-HER2 treatments (C+T). This study aims to report the biological responsiveness of ER+HER2+ ILC to perioperative aromatase inhibitors (POAI) and their clinical outcome within POETIC trial, one of the most comprehensive studies of the ER+HER2+ BC. Methods: POETIC trial was a phase III study of post-menopausal patients with ER+ BC, randomized 2:1 to 2-weeks of POAI or control, followed by standard-of-care. This study focused on ER+HER2+ BC (n = 342), 27 of whom had ILC at baseline (B) (17 POAI and 10 control). Ki67 levels were assessed at B and on-treatment (2wk) (low ≤10%; high >10%). Biological response to AI were categorized to LowB -Low2wK (LL); HighB –Low2wk (HL) or HighB–High2wk (HH). Baseline and on-treatment samples were gene expression profiled (NanoString BC360TM) for BC intrinsic subtypes (IS) (Luminal A: LumA, Luminal B: LumB, HER2-enriched: HER2E, Basal) and 46 gene signatures. T-tests were used to compare gene expression profiles (GEP) between ILC and invasive ductal carcinoma (IDC). P-values were adjusted using false discovery rate (FDR). Time to recurrence (TTR) was estimated using Kaplan-Meier method. Results: Among the 27 ILC cases, the clinicopathological characteristics were similar to IDC. At the molecular level, the frequencies of IS in ILC were 22% (n = 6) LumA, 37% (n = 10) LumB and 41% (n =11) HER2E, compared to IDC being 17% (51/301) LumA, 37% (112/301) LumB, 44% (133/301) HER2E, and 2% (5/301) Basal. In terms of early response to POAI in ILC, 33% (5/15) were HH, 53% (8/15) were HL and 14% (2/15) were LL. In comparison in IDC, 53% (100/188) were HH, 36% (68/188) were HL and 9% (17/188) were LL. The 5 HH ILCs were mainly HER2E (1 LumB, 4 HER2E), while most HL were Luminals (1 LumA, 5 LumB, 2 HER2E), and all LL were Luminals, showing the poor anti-proliferative effect conferred by HER2E. There were no distinct GEP associated with ILC compared to IDC in the hierarchical clustering of gene signature scores. IS and immune signatures drove the distinct expression patterns across the population of ILC and IDC. ILC had lower expression of cell adhesion than IDC (T-test FDR < 0.001). The impact of POAI to molecular changes were comparable based on histological tumor types and were driven by their intrinsics subtypes. The 5-year TTR survival probabilities of ILC and IDC were 88% and 89.5% respectively. Fifty-two percent (14/27) of ILC received C+T and all remained recurrence free. Out of the 48% (13/27) ILC that did not receive adjuvant C+T and were only treated with ET, three (23%) had recurrence at 0.7, 2.1 and 4.1 years. Sixty-one percent (183/301) of IDC received C+T, of which 8% (14/183) had a recurrence event. Forty-nine percent (118/301) of IDC did not receive adjuvant C+T, from which 17% (20/118) recurred. Conclusions: This study reported comprehensive study on the molecular features and their clinical behavior of the understudied ER+HER2+ ILC. Our findings suggested there were no distinct molecular profiles between ILC and IDC phenotypes of ER+HER2+ at baseline; their response and molecular changes after POAI were driven by IS as expected. While there was an enrichment of early sensitive tumors to POAI, the combined C+T treatment and ET might represent a good option to preventing recurrence in clinical high risk ILC. However, the small sample size precludes definitive conclusions. Citation Format: Milana Bergamino Sirvén, Xixuan Zhu, Elena López-Knowles, Holly Tovey, Lucy Kilburn, Anthony Skene, Chris Holcombe, Alistair Ring, Ian Smith, John Robertson, Judith Bliss, Eugene F. Schuster, Mitch Dowsett, Maggie Chon U Cheang. Hormone receptor positive (ER+) HER2+ Lobular Breast Carcinoma: Molecular Response to Perioperative Endocrine Therapy and Clinical Outcomes in the POETIC Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-11-14.

Purpose: Despite recent improvements in the preoperative management of early breast cancer (eBC), many patients still do not achieve pathological complete response (pCR) and have inadequate treatment outcomes. Our analysis aims to investigate the role of human epidermal growth factor receptor 2 (HER2)-low status in predicting survival outcomes in patients not achieving a pCR. Methods: We retrospectively identified patients with stage I-III HER2-negative breast cancer receiving neoadjuvant treatment and who did not achieve pCR at The Royal Marsden NHS Foundation Trust, London, between 2013 and 2023. Disease characteristics including HER2-low status, defined as HER2 1+ on immunohistochemistry (IHC) or 2+ on IHC without in situ hybridization (ISH) gene amplification, were collected. We analysed relapse-free survival (RFS) and overall survival (OS) based on HER2 status in the overall population and in patients with oestrogen receptor (ER)-positive (ER+) and ER-negative (ER-) cancers. Results: Overall, 565 patients were included in the analysis. The mean age of the study population was 50.0 ± 11.1 years. Median follow-up time was 44.9 months (interquartile range 13.8-69.8). 370 patients (65.5%) had stage II disease, 390 (69.0%) had grade 3 disease, and 502 (88.8%) had ductal histopathology. 321 patients (56.8%) had ER+ BC, while 244 patients (43.2%) had ER- BC. Overall, 254 patients (45.0%) had HER2-low disease, while 174 (54.2%) ER+ BC patients and 80 (32.8%) ER- BC patients had HER2-low BC. HER2-low BC patients had significantly improved OS [HR 0.65 (95% CI, 0.45-0.95, p=0.026)] and a trend towards improved RFS compared to HER2-zero BC patients. Multivariable analysis did not confirm any impact of HER2, whereas ER status and BC stage impacted survival outcomes. In the ER- population, HER2-low status did not have any impact on RFS nor on OS. In the ER+ population, HER2-low BC patients had significantly improved RFS [HR 0.65 (95% CI, 0.43-1.00, p=0.047)] and OS [HR 0.50 (95% CI, 0.29-0.85, p=0.009)] compared with HER2-zero disease. In the same cohort, multivariable Cox-regression model confirmed the positive impact of HER2-low status on OS independently from stage, age, grade and ER-low/high positivity [HR 0.51 (95% CI, 0.30-0.88, p=0.015)]. Conclusions: The study highlights the potential relevance of HER2-low status as a predictive factor for survival outcomes in HER2-negative early BC patients, particularly in the context of ER+ disease. These findings underscore the importance of considering HER2 status (including HER2-low status) alongside traditional prognostic factors when assessing the prognosis and treatment strategies for this patient population. Citation Format: Matilde Corianò, Chiara Tommasi, Anh Thi Lan Dinh, Jazmine Needham, Hala Aziz, Nalinie Joharatnam-Hogan, Niamh Cunningham, Jasmin Waterhouse, Mingze Sun, Fiona Turkes, Benedetta Pellegrino, Sophie McGrath, Alicia Okines, Marina Parton, Nicholas Turner, Stephen Johnston, Antonino Musolino, Alistair Ring, Nicolò Matteo Luca Battisti. IMPACT OF HER2-LOW STATUS ON SURVIVORSHIP IN HER2-NEGATIVE EARLY BREAST CANCER PATIENTS UNDERGOING NEOADJUVANT TREATMENT WITHOUT PATHOLOGICAL COMPLETE RESPONSE [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-12-14.

Background: Sacituzumab Govitecan (SG) is a new treatment option in the pre-treated advanced triple negative breast cancer (aTNBC) setting. Since the regulatory approval of SG in the UK in August 2022, there remains little real-world evidence on its safety for patients with aTNBC. Its registration study documented high rates of myelosuppression in this population. In this analysis, we investigated the incidence of neutropenia in patients with aTNBC treated with SG in a large tertiary centre in the UK and its impact on patient management. Methods: We retrospectively collected data on patients with aTNBC treated with at least one dose of SG between September 2022 and September 2023 at the Royal Marsden Hospital, London. We collected clinical data from the electronic patient records and analysed them with descriptive statistics. Results: Thirty-nine patients were included in the analysis. Of these, 28/39 (71.7%) experienced neutropenia of any grade. This was grade 1 in 15/28 (53.5%), grade 2 in 6/28 (21.4%), grade 3 in 7/28 (25.0%) and grade 4 in 1/28 (3.6%). Four patients (14.8%) experienced febrile neutropenia requiring antibiotics and hospitalisation. In 15/28 (53.6%), neutropenia occurred prior to Day 1 of treatment and in 13/28 (46.4%) neutropenia occurred prior to Day 8. Out of the 11 patients who did not experience neutropenia, 7 (63.6%) had upfront GCSF. Out of the 28 patients experience neutropenia, 13 (46.4%) required a dose delay, 5 (17.8%) had a Day 8 dose omitted and 8 (28.6%) had a dose reduction. All patients experiencing neutropenia were prescribed secondary GCSF prophylaxis: 11 (39.3%) following the first episode of neutropenia and 3 (10.7%) after the second episode. Conclusion: Our analysis documented a substantial rate of neutropenia in patients with aTNBC receiving SG. This is consistent with clinical trial data. Our findings support the use of primary GCSF prophylaxis to avoid preventable haematological toxicity and dose adjustments in this setting. Citation Format: Emma Crewe, Imun Gill, Juan Montes Gonzalez, Domingo Cano Gil, Sophie McGrath, Alistair Ring, Stephen Johnston, Alicia FC Okines, Nicolò Matteo Luca Battisti. Real-world safety of sacituzumab govitecan in patients with advanced triple receptor-negative breast cancer in a tertiary centre in the United Kingdom [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-11.

Background: In the NATALEE trial, RIB + NSAI has demonstrated invasive disease-free survival and DDFS benefits in patients with stage II and III HR+/HER2− EBC. In an analysis with all patients off RIB, RIB + NSAI reduced the risk of distant disease recurrence vs NSAI alone. Understanding the impact of adjuvant treatments on distant disease recurrences across patient subgroups is critical for clinical decision-making. We present DDFS data from the 4-y landmark analysis of NATALEE across clinically relevant subgroups. Methods: In NATALEE, patients were randomized 1:1 to receive either RIB (400 mg/d, 3 wk on/1 wk off for 3 y) + NSAI (anastrozole 1 mg/d or letrozole 2.5 mg/d for 5 y) or NSAI alone, with men and premenopausal women also receiving goserelin. NATALEE included patients with anatomic stage IIA (either node-negative [N0] with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per AJCC (8th edition). DDFS was a secondary endpoint and was defined as the time from randomization to the first event of distant recurrence, second primary non-breast invasive cancer (except for basal and squamous cell skin carcinomas), or death from any cause. DDFS was assessed across patient subgroups, including anatomic stage and nodal status, using Kaplan–Meier analysis and a Cox proportional hazards model. Results: At the data cutoff of April 29, 2024, with a median duration of follow-up for DDFS of 44.2 months and all patients off RIB, RIB + NSAI demonstrated both a DDFS benefit (HR, 0.715 [95% CI, 0.604-0.847]; nominal P value <.0001) and a distant recurrence-free survival benefit (HR, 0.705 [95% CI, 0.589-0.844]; nominal P value <.0001) in the intent-to-treat population. The DDFS benefit was consistent regardless of anatomic stage (stage IIA [n=1001]: HR, 0.396 [95% CI, 0.218-0.720]; stage IIB [n=1045]: HR, 0.806 [95% CI, 0.524-1.238]; stage IIIA [n=1832]: HR, 0.697 [95% CI, 0.524-0.926]; stage IIIB [n=317]: HR, 0.569 [95% CI, 0.326-0.994]; stage IIIC [n=890]: HR, 0.878 [95% CI, 0.649-1.188]). The absolute DDFS benefit with RIB + NSAI vs NSAI alone increased from 3 y to 4 y for all stage subgroups (stage IIA, 2.3% to 5.1%; IIB, 0.8% to 2.6%; IIIA, 3.1% to 4.6%; IIIB, 6.8% to 11.4%; IIIC, 2.4% to 4.5%). Similarly, a consistent improvement in DDFS was observed regardless of nodal status (N0 [n=613]: HR, 0.696 [95% CI, 0.403-1.204]; node-positive [N+] [n=4480]: HR, 0.726 [95% CI, 0.608-0.867]), and the absolute DDFS benefit increased from 3 y to 4 y across nodal subgroups (N0, 2.7% to 4.2%; N+, 2.4% to 4.6%). The DDFS benefit with RIB + NSAI vs NSAI alone, with increasing benefit up to 4 y, was consistent across other clinically relevant subgroups, including those based on menopausal status and Ki-67 status. Conclusions: With all patients off RIB, RIB + NSAI consistently reduced the risk of distant recurrence across clinically relevant subgroups, including in patients with N0 disease. The DDFS benefit was sustained after the 3-y RIB treatment duration, with increasing absolute benefit up to 4 y. These findings further support adding RIB to adjuvant NSAI in a broad population of patients with HR+/HER2− EBC. Citation Format: Sara Hurvitz, Michal Jarzab, Montserrat Munoz Mateu, Erin Cobain, Jin Zhang, Arielle Medford, Alistair Ring, Priyanka Sharma, Christian Schem, Ionut Temciuc, Zheng Li, Murat Akdere, Juan Pablo Zarate, Denise A. Yardley. Distant disease-free survival (DDFS) across key subgroups from the phase 3 NATALEE trial of ribociclib (RIB) plus a nonsteroidal aromatase inhibitor (NSAI) in patients with HR+/HER2− early breast cancer (EBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-09-22.