Desmedt, Christine

Abstract Background: Invasive lobular carcinoma (ILC) accounts for up to 15% of breast cancer (BC) cases and has distinct clinical and biological features compared to invasive carcinoma of no special type (IBC-NST). Prior studies, including PENELOPE-B, suggested greater benefit from adjuvant palbociclib (palbo) in ILC. We assessed the prognostic and predictive value of histology in patients (pts) treated with endocrine therapy (ET) ± palbo. Methods: PALLAS is a global, phase III trial in which pts with stage II-III, HR+/HER2− BC were randomized to 2 years (y) of adjuvant palbo + ET or ET alone. Pts with IBC-NST or pure ILC per local pathology assessment were included. Endpoints included invasive disease-free (IDFS; primary), distant recurrence-free (DRFS), locoregional recurrence-free (LRRFS), and overall survival (OS). Prognostic value was assessed using univariable and multivariate Cox models adjusted for age, T and N stage, grade, and progesterone receptor. Predictive value was assessed using histology-by-treatment interactions. Results: Among 5,748 pts in the ITT population, 4,982 (87%) were included (3,838 IBC-NST [67%], 1,144 ILC [20%]); median follow-up 6.9y. Compared with IBC-NST, ILC was associated with older age (median 54 vs 51 y), higher T stage (T3/T4: 41.7% vs 20.4%), fewer grade 3 tumors (12.7% vs 33.5%), higher mastectomy rates (74.5% vs 58.4%), less (neo)adjuvant chemotherapy (72.2% vs 86.2%), and less tamoxifen as initial ET (28.8% vs 34.5%) (all p<0.001). ILC prevalence varied by country: lower in Asia (Japan 10.5%, Korea 0%, Taiwan 2.8%) and higher in Europe (23.1%) and North America (24.0%). When evaluating the predictive value, palbo appeared to confer greater benefit in ILC for all endpoints (HRs ranging from 0.41 to 0.86) and not in IBC-NST (HRs ranging from 0.97 to 1.01), although the histology-by-treatment interaction was significant only for LRRFS (Table). In the overall population, 7-year IDFS was 79.3% for IBC-NST and 75.8% for ILC. While the difference was significant in univariable analysis (HR 1.17, 95% CI 1.01-1.35), it was not in multivariable analysis (HR 1.06, 0.91-1.24). Notably, the proportional hazards assumption was violated, and time-dependent modeling demonstrated that worse outcomes for ILC on IDFS, DRFS, and other endpoints emerged predominantly beyond 3 years. Conclusions: In this large, randomized dataset of pts with early HR+/HER2− breast cancer with long-term follow-up, ILC demonstrated distinct clinicopathologic features and geographic distribution. While ILC was not an independent prognostic factor over the entire follow-up, time-dependent modeling revealed worse long-term outcomes which only emerged after 3 years. Palbo appeared to be associated with more favorable outcomes in ILC than in IBC-NST across endpoints. These findings suggest a potential benefit of palbo in ILC that warrants further investigation in other adjuvant trials evaluating CDK4/6 inhibitors. Citation Format: G. Nader-Marta, C. Desmedt, D. Hlauschek, A. DeMichele, G. Zoppoli, E. Blondeaux, E. de Azambuja, M. Bellet-Ezquerra, O. Metzger-Filho, J. M. Suga, G. Pfeiler, M. P. Goetz, M. Ruiz-Borrego, S. Loibl, J. Meisel, A. Ring, K. Van Baelen, E. P. Mamounas, N. Zdenkowski, E. Agostinetto, M. Lambertini, E. Gauthier, L. Soelkner, A. C. Dueck, M. Gnant, E. L. Mayer. Long-term prognostic and predictive value of lobular histology in the PALLAS trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-06.

Importance Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug’s approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens’ related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.

LBA507 Background: In monarchE (NCT03155997), 2 years of adjuvant abemaciclib + ET resulted in sustained improvement in invasive disease-free survival (IDFS; HR=0.680, 7.6% absolute benefit at 5 years) in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Here, we investigate the prognostic value of ctDNA detection and dynamics in pts from monarchE. Methods: Samples were analyzed from a selected pt subset (n=1397; abemaciclib + ET arm, n=685; ET arm, n=712), enriched for overall IDFS events compared to the total monarchE study population (IDFS event rate: 31% [433/1397] vs 18% [992/5637]). Pts had blood collected pre-study treatment (baseline) and at 3, 6, or 24 months. ctDNA detection was performed using the personalized, tumor informed Signatera ctDNA assay (Natera, Inc) and whole exome sequencing (WES) of matched primary tumor and normal required for assay design was performed. Results: Among 1397 pts, 65% (n=910) had sufficient plasma samples and WES performed, and all 910 had successful ctDNA assay testing. Among these 910 pts, the IDFS event rate was 27% (abemaciclib + ET, 23% [101/438]; ET alone, 31% [146/472]). Rates of ctDNA positivity (at baseline and any change from baseline) and associated IDFS events are shown in Table. Among pts with ctDNA positivity, 87% had an IDFS event in comparison to 15% with persistent ctDNA negative (-) status during the study. Conclusions: In a pt subset from monarchE enriched for IDFS events, ctDNA detection was relatively infrequent (<20%); however, its detection at any time during the 24 months of study therapy was adversely prognostic. As compared to pts who had remaining ctDNA positive (+), pts who had clearance of ctDNA on therapy had lower risk of IDFS events, but the event risk still remained clinically meaningful in these pts. Clinical trial information: NCT03155997 . [Table: see text]

Abstract Background Two years of adjuvant abemaciclib + endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer (EBC) in the monarchE trial (NCT03155997). The benefit of abemaciclib was sustained beyond completion of treatment and deepened in magnitude at 4 years for IDFS and DRFS. This pilot study investigated the technical feasibility of ctDNA detection beginning prior to study treatment, as well as rates of persistence and clearance in a subset of EBC pts from monarchE using the clinically validated SignateraTM ctDNA assay. Methods Samples were analyzed from a selected subset of pts (n=178; 84 from abemaciclib+ET arm; 94 ET alone) who had blood collected both before initiating protocol directed therapy, Visit 1 (V1; randomization + ≤ 3 days) and near completion of the 2-year treatment period, Visit 27 (V27; 24 months +/- 5 days from V1). This cohort of pts was enriched for overall IDFS events compared to the total monarchE study population, however pts with relapses occurring prior to V27 were excluded. Primary tumors from selected pts were subjected to whole exome sequencing (WES). Selected samples included those from pts with a range of tumor mutation burden. Cell-free DNA was extracted from 356 plasma samples. A Signatera ctDNA assay was developed for each pt based on up to 16 variants detected by WES from each baseline tumor sample. Results The IDFS event rate for the selected subset (n=178) was 39.3% (abemaciclib+ET 34.5% [29/84] and ET alone 43.6% [41/94]). Ten pts (5.6%) were initially ctDNA+ and 42 pts (23.6%) were persistently (7 pts, 3.9%) or became (35 pts, 19.7%) ctDNA+ at V27. Notably, 70% of pts who were initially ctDNA+ and 100% of pts who were either persistently ctDNA+ or became ctDNA+ experienced recurrence (see Table 1). In contrast, none of the 3 pts that cleared ctDNA+ developed recurrence. In pts persistently ctDNA negative (neg), 28 (21.1%) experienced recurrence. Overall, 10% (7/70) of pts with IDFS events were initially ctDNA+ and 50% (35/70) had detectable ctDNA at V27. Conclusions Detection of ctDNA soon after completing neoadjuvant chemotherapy was infrequent, but also associated with a high-risk of recurrence. ctDNA positivity was common at the end of the 2-year treatment period and was highly prognostic with all pts subsequently developing disease recurrence. Importantly, ~30% of pts with early ctDNA detection ultimately dropped below detection limits during the 2-year treatment period and none developed recurrence. Although some pts remained persistently ctDNA neg during this study and experienced recurrence, the delay in recurrence may indicate longitudinal benefit from remaining ctDNA neg. Future planned analysis of an expanded cohort reflective of the intent to treat population including additional timepoints within the 2-year treatment period will further define how ctDNA dynamics may identify pts at high-risk of recurrence. Table 1. Summary of Subset Positivity Rates. + positive; - negative; NA, not applicable. Citation Format: Sherene Loi, Stephen Johnston, Carlos Arteaga, Stephanie Graff, Sarat Chandarlapaty, Matthew Goetz, Christine Desmedt, Jorge Reis-Filho, Hironobu Sasano, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Deli Liu, Lacey M. Litchfield, Nicholas Turner. Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, 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 PS06-01.

Abstract Background Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE trial (NCT03155997). Abemaciclib benefit was sustained beyond the completion of treatment (tx) with deepening magnitude of absolute benefit in IDFS and DRFS at 5 years. Here, we evaluate comprehensive molecular profiling of archived primary tumor tissue and association with clinical outcomes. Methods For biomarker analysis, a proportionally stratified random sampling case-cohort design was utilized to include all patients who experienced an IDFS event at a pre-specified interim analysis with a median follow up of 54 months. A cohort of 895 pts (189 with IDFS event) in the abemaciclib + ET arm was matched 1:1 with 903 pts (270 with IDFS event) in the ET arm. Baseline primary tumor samples underwent exome-capture RNA sequencing (RNAseq; n=1324, 23% intent-to-treat (ITT) population) and paired tumor-normal (germline blood samples) whole-exome sequencing (WES; n=1234, 22% ITT population). Expression-based intrinsic subtypes (i.e., luminal A (LumA), luminal B (LumB), HER2-enriched (HER2E), basal- and normal-like) were characterized using the Absolute Intrinsic Molecular Subtyping model. The 21-gene expression signature score (Oncotype DX test) was inferred from RNAseq; samples were categorized into lower (0-25) and high (26-100) risk groups. To investigate associations of biomarkers with abemaciclib benefit, WES genomic events including oncogenic and hotspot mutations by OncoKB, and copy number events, of incidence &gt;9% were pre-selected. Results The biomarker subset of monarchE was reflective of the ITT population. A total of 1190 tumors (abemaciclib+ET n= 605; ET alone n=585) yielded adequate RNAseq results. Intrinsic subtype distribution was consistent across tx arms (Table A). Low tumor purity limited assessment of the normal-like subtype. The 4-year IDFS benefit of abemaciclib was consistent across all subtypes. LumA cancers had the lowest risk of recurrence while HER2E and basal-like subtypes had the highest. Inferred 21-gene expression signature score showed similar benefits from abemaciclib in both lower and high-risk groups (Table B). A total of 1173 tumors yielded adequate WES results (abemaciclib+ET n=580; ET alone n=593). Consistent abemaciclib benefit was observed across the most frequently altered genes (Table C). In exploratory analysis, lower benefit from abemaciclib was seen in the subset of focal-high level MYC amplified tumors (n=176, HR 1.30, 95% CI, 0.77, 2.20) compared to MYC non-amplified tumors (n=997, HR 0.62, 95% CI, 0.47, 0.80, nominal interaction p=0.014). The treatment benefit of abemaciclib was observed across all subpopulations of altered genes based on gene expression data. Conclusions Adjuvant abemaciclib+ET maintained IDFS benefit compared to ET alone across all molecular subtypes as measured by RNAseq. Benefit was consistent across most altered genes assessed by WES, except for the subset of tumors with MYC amplification. Additional research is necessary to confirm these findings. Table. Citation Format: Nicholas Turner, Jorge Reis-Filho, Matthew Goetz, Christine Desmedt, Sarat Chandarlapaty, Hironobu Sasano, Carlos Arteaga, Sherene Loi, Stephanie Graff, Deli Liu, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Lacey M. Litchfield, Maria Munoz, Stephen Johnston. Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE 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 GS03-06.

Background: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. Methods: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, <18.5 kg/m2; normal weight, 18.5 to <25 kg/m2; overweight, ≥25 to <30 kg/m2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. Results: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04–1.50) and OS (aHR, 1.27; 95% CI, 1.01–1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97–1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05–1.71), DDFS (aHR, 1.46; 95% CI, 1.07–1.98), and OS (aHR, 1.83; 95% CI, 1.18–2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. Conclusions: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.