Gabriel N. Hortobágyi

Recurrence Score gene group components and outcomes in the RxPONDER trial (SWOG S1007)

BACKGROUND: The RxPONDER trial has guided adjuvant chemotherapy use in node-positive HR+/HER2- breast cancer; however, prior analyses showed poorer outcomes among non-Hispanic Black (NHB) women compared with non-Hispanic White (NHW) women despite similar 21-gene Recurrence Score® (RS) results. This suggests contributors to disparities may not be captured by the composite RS. We evaluated RS gene group components-proliferation, estrogen receptor (ER), HER2 (GRB7), and invasion-by ethnicity, body mass index, and menopausal status, and assessed associations with outcomes. METHODS: RxPONDER enrolled 5,083 women with HR+/HER2- breast cancer, 1-3 positive nodes, and RS ≤ 25, randomized to endocrine therapy ± chemotherapy. 3,102 participants with ethnicity and gene expression data were included. RS components were compared across subgroups, and associations with invasive disease-free survival (IDFS) and distant recurrence-free interval were evaluated using multivariable Cox models adjusted for clinicopathologic factors and treatment. RESULTS: Among 3,102 women (70.2% NHW, 15.5% Hispanic, 9.5% Asian, 4.7% NHB), RS distributions were similar across groups and prognostic overall. Tumors from NHB (p = 0.003) and Hispanic (p = 0.02) had higher proliferation scores versus NHW women, while Asian women had higher HER2 (p = 0.006) and ER scores (p = 0.028). IDFS differences were not statistically significant for NHB vs. NHW women (HR 1.41; 95% CI 0.98-2.03), whereas Asian women had improved IDFS (HR 0.63; 95% CI 0.43-0.91). CONCLUSIONS: Despite similar overall RS distributions, component pathways vary by ethnicity and may contribute to outcome differences. These findings support evaluating gene-specific biology beyond composite scores to better understand disparities and refine risk stratification. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01272037.

Cognitive Impairment and Chemoendocrine vs Endocrine Therapy in Pre- and Postmenopausal Women

Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/HER2-negative early breast cancer: 5-year follow-up of NATALEE efficacy outcomes and updated overall survival

At the primary efficacy analysis of the NATALEE phase III trial, ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) demonstrated a statistically significant improvement in invasive disease-free survival (iDFS) versus NSAI alone in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC). Continued follow-up of efficacy outcomes is important in assessing the durability of treatment benefit. We report 5-year estimates of efficacy outcomes, including an udpated analysis of overall survival (OS). Eligible patients included pre/postmenopausal women and men with HR-positive/HER2-negative EBC and anatomic stage IIA (N1 or N0 with high-risk factors), IIB, or III disease. Patients were randomized 1 : 1 to ribociclib 400 mg/day (3 weeks on/1 week off for 3 years) + NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 5 years) or NSAI alone. Premenopausal women and men received goserelin. The primary endpoint was iDFS, and secondary/exploratory endpoints included distant disease-free survival, recurrence-free survival, distant recurrence-free survival, and OS. With a median iDFS follow-up of 55.4 months, ribociclib + NSAI demonstrated persistent iDFS benefit versus NSAI alone [hazard ratio 0.716, 95% confidence interval (CI) 0.618-0.829, nominal one-sided log-rank P < 0.0001]. Absolute iDFS improvement between treatment arms increased from the 3- (Δ2.7%) to the 5-year (Δ4.5%) time points. Persistent benefit over time was also observed across subgroups [including N0 patients (hazard ratio 0.606, 95% CI 0.372-0.986)] and secondary/exploratory endpoints. As OS continues to mature, numerical improvement in favor of ribociclib was observed (hazard ratio 0.800, 95% CI 0.637-1.003, nominal one-sided log-rank P = 0.026). This prespecified 5-year follow-up of efficacy outcomes from NATALEE demonstrated that ribociclib + NSAI continued to reduce the risk of recurrence beyond the 3-year treatment window, supporting its use as adjuvant therapy in patients with HR-positive/HER2-negative EBC. An ongoing positive trend for improved OS in favor of ribociclib + NSAI was observed. • This prespecified analysis assessed 5-year efficacy outcomes of the NATALEE trial (median iDFS follow-up of 55.4 months). • Persistent iDFS benefit was observed with ribociclib + NSAI versus NSAI alone (hazard ratio 0.716, 95% CI 0.618-0.829). • iDFS benefit with ribociclib was observed across subgroups, including in node-0 disease (hazard ratio 0.606, 95% CI 0.372-0.986). • A positive trend for OS in favor of ribociclib continues to emerge (hazard ratio 0.800, 95% CI 0.637-1.003, nominal one-sided P = 0.026). • No new safety signals for causes of deaths or secondary primary malignancies were identified with this updated analysis.

Ribociclib Plus Endocrine Therapy in Hormone Receptor–Positive/ERBB2-Negative Early Breast Cancer

FGFR3-induced Y158 PARP1 phosphorylation promotes PARP inhibitor resistance via BRG1/MRE11-mediated DNA repair in breast cancer models

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively correlated with PARPi resistance in TNBC patient-derived xenograft models, and in PARPi-resistant TNBC patient tumors. These findings reveal that PARP1 p-Y158 facilitates BRG1-mediated HR to resolve the PARP-DNA complex, and PARP1 p-Y158 may indicate PARPi resistance that can be relieved by combining FGFR inhibitors (FGFRis) with PARPis. In summary, we show that FGFRi restores PARP trapping and PARPi antitumor efficacy in PARPi-resistant breast cancer by decreasing HR through the PARP1 p-Y158/BRG1/MER11 axis, suggesting that PARP1 p-Y158 is a biomarker for PARPi resistance that can be overcome by combining FGFRis with PARPis.

ADAMs contribute to triple negative breast cancer via mTORC1 pathway: targeting ADAM-mTOR axis improves efficacy

Breast cancer is the most frequently diagnosed cancer globally and the second leading cause of cancer-related deaths in American women. Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Thus, fewer targeting therapies are available for this most aggressive subtype. The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this study, we demonstrate the upregulation of a panel of ADAM members in TNBC, and overexpression of all the individual ADAMs tested are correlated with poor patient survival, making it unlikely that targeting a single ADAM member would be effective. Reverse-phase protein array and multiplexed immunofluorescence revealed that ADAM10/15/17 expression was associated with activated mTOR signaling. Individual knockdown of ADAM10, ADAM15, or ADAM17 modestly reduced mTOR signaling, cellular proliferation and survival. However, the concurrent knockdown of the three ADAMs drastically decreased mTOR signaling and cellular aggressiveness. Consistently, combined targeting of ADAMs and mTOR increased inhibitory efficacy compared to monotherapy in ADAM-mTOR-activated tumor growth and invasion in vitro and in immunodeficient and immunocompetent mice. These results establish a functional link between ADAMs and activation of mTOR signaling, suggesting the ADAM-mTOR axis as a therapeutic target and biomarker for ADAM-enriched TNBC and, potentially, other tumor lineages with high ADAM activity.

Novel Postneoadjuvant Prognostic Breast Cancer Staging System

FaschingClinical Cancer Research

Health-Related Quality of Life in Patients with HR+/HER2− Early Breast Cancer Treated with Ribociclib Plus a Nonsteroidal Aromatase Inhibitor: Results from the NATALEE Trial

PURPOSE: The phase III NATALEE trial reported a statistically significant invasive disease-free survival benefit with ribociclib plus nonsteroidal aromatase inhibitor (NSAI) versus an NSAI alone in stage II/III hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer. In this study, we report health-related quality of life (HRQOL) data from NATALEE. PATIENTS AND METHODS: Patients were randomized to receive ribociclib plus NSAI or NSAI alone. Patient-reported outcome scores [European Organisation for Research and Treatment of Cancer core quality of life questionnaire global health status and physical, social, and emotional functioning domains; the supplementary European Organisation for Research and Treatment of Cancer breast cancer-specific QOL questionnaire breast symptoms scale; health on a visual analog scale of the generic EuroQOL 5-level instrument; and the Hospital Anxiety and Depression Scale] were assessed. The prespecified primary HRQOL endpoint was physical functioning. Mean scores and time-categorical and prespecified linear-time repeated-measure models were used to evaluate HRQOL changes during treatment. RESULTS: HRQOL was evaluated in all patients in the ribociclib plus NSAI (n = 2,549) and NSAI alone (n = 2,552) arms. Compliance was high in both arms (≈93%-97%). Mean scores did not differ meaningfully from baseline for any analyzed domain. Likewise, neither a meaningful change from baseline (in either treatment arm) nor a difference between arms was observed during treatment in the time-categorical, model-adjusted mean scores for any HRQOL domains-using published thresholds for interpreting longitudinal and between-group differences, with all values being within 0.5 SD of their baseline values. Linear-time regression analysis confirmed these findings. CONCLUSIONS: These analyses of NATALEE show that adding adjuvant ribociclib to an NSAI does not negatively affect HRQOL in patients with HR+/HER2- early breast cancer.

Race and clinical outcomes in hormone receptor-positive, HER2-negative, node-positive breast cancer in the randomized RxPONDER trial

ClinicalTrials.gov: NCT01272037.

PusztaiJournal of Clinical Oncology

Development and Validation of the RSClinN+ Tool to Predict Prognosis and Chemotherapy Benefit for Hormone Receptor–Positive, Node-Positive Breast Cancer

RSClinN+ provides improved estimates of prognosis and absolute CET benefit for individual patients compared with RS or with clinical data alone and could be used in patient counseling.

HortobágyiAnnals of Oncology

A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial

With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.

Targeting the EGFR pathway in chemotherapy-resistant triple-negative breast cancer - a phase II study

Purpose: Epidermal growth factor receptor (EGFR) pathway activation causes chemotherapy resistance, and inhibition of the EGFR pathway sensitizes triple-negative breast cancer (TNBC) cells to chemotherapy in preclinical models. Given the high prevalence of EGFR overexpression in TNBC, we conducted a single-arm phase II study of panitumumab (anti-EGFR monoclonal antibody), carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with doxorubicin and cyclophosphamide (AC)–resistant TNBC (NCT02593175). Patients and Methods: Patients with early-stage, AC-resistant TNBC, defined as disease progression or ≤80% reduction in tumor volume after four cycles of AC, were eligible for this study and received panitumumab (2.5 mg/kg i.v., every week × 13), paclitaxel (80 mg/m2 i.v. every week × 12), and carboplatin (AUC = 4 i.v., every 3 weeks × 4) as the second phase of NAT. A two-stage Gehan-type design was used to detect an improvement in the pathological complete response (pCR)/residual cancer burden class I (RCB-I) rate from 5% to 20%. Whole-exome sequencing was performed on diagnostic tumor biospecimens, where available. Results: From November 3, 2016, through August 23, 2021, 43 patients with AC-resistant TNBC were enrolled. The combined pCR/RCB-I rate was 30.2%. The most common treatment-related adverse events were neutropenia (72%) and anemia (61%), with 7 (16%), 16 (37%), and 8 (19%) patients experiencing grade 4 neutropenia, grade 3 neutropenia, and grade 3 anemia, respectively. No new safety signals were observed. Conclusions: This study met its primary endpoint (pCR/RCB-I = 30.2% vs. 5% in historical controls), suggesting that panitumumab should be evaluated as a component of NAT in patients with chemotherapy-resistant TNBC in a larger, randomized clinical trial. Significance: The epidermal growth factor receptor (EGFR) pathway has been implicated as a driver of chemotherapy resistance in triple-negative breast cancer (TNBC). Here, we evaluate the combination of panitumumab, carboplatin, and paclitaxel as the second phase of neoadjuvant therapy (NAT) in patients with AC-resistant TNBC. This study met its primary efficacy endpoint, and molecular alterations in EGFR pathway genes did not seem to influence response to the study regimen.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor–Positive, Early-Stage Breast Cancer

Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy.

Correlation of serum anti-Müllerian hormone (AMH) levels on identification of premenopausal patients (pts) with hormone receptor positive (HR+), HER2-negative, node-positive breast cancer most likely to benefit from adjuvant chemotherapy in SWOG S1007 (RxPONDER).

505 Background: SWOG S1007 was a phase 3 randomized trial to evaluate the benefit of endocrine therapy alone (ET) or with chemotherapy (CET) in pts with HR+/HER2- invasive breast cancer with recurrence score (RS) ≤ 25. There was no invasive disease-free survival (IDFS) benefit for CET compared to ET in postmenopausal women However, in premenopausal women CET had an IDFS improvement compared to ET (HR=0.60; 95% 0.43-0.83). The objective was to further refine patient subgroups who benefit from CET, we measured baseline hormone levels in S1007 pts to quantify their menstrual status by serum hormone levels and associated clinical outcomes. Methods: Serum estradiol (E), progesterone (P), follicular stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), and inhibin B (IB) were assessed on baseline serum samples from 1,015 pts who self-reported being premenopausal and age < 55. Magnetic fluorescent bead-based immunoassays ( i.e., Luminex assays) or colorimetric ELISAs were performed at the Biomarker Discovery Laboratory at the University of Kansas Medical Center to measure hormone levels. Associations of the markers (both continuous and dichotomized) with IDFS and distant relapse-free survival (DRFS) were tested for prognosis and prediction of CET benefit using Cox regression. Results: Single baseline measurement of IB, P, E, LH, FSH, or combination of E/LH/FSH, was not prognostic for IDFS or predictive for chemotherapy benefit. However, AMH levels (≥10 pg/mL) showed significant interaction with chemotherapy benefit (p=0.019), and risk increased with continuous AMH with ET alone, but not CET (p=0.03). Compared to ET alone, CET was beneficial in the 79% of premenopausal patients with AMH levels ≥10 pg/mL, a standard cutoff to define normal ovarian reserve (HR=0.48; 95% 0.33-0.69, adjusting for RS). CET was not beneficial in the 21% with AMH < 10 (HR=1.21; 95% 0.60-2.43). Absolute 5-year IDFS benefit of CET for RS ≤ 25 was 7.8% (95.2%-87.4%) for AMH ≥ 10 vs. -1.7% (89.1%-90.8%) for AMH < 10. DRFS showed a similar pattern with CET benefit in AMH ≥10 pg/mL (5-year DRFS benefit: 4.4%; HR=0.41; 95% 0.25-0.68, adjusting for RS) and no benefit in AMH < 10 (5-year DRFS benefit: -0.9%, HR=1.50; 95% 0.62-3.63). Conclusions: Among self-reported premenopausal patients < age 55, pts with baseline serum AMH levels ≥10 pg/mL showed significant benefit from CET compared to patients with AMH levels <10 pg/mL. AMH levels were a better indicator of CET benefit than self-reported menopause status, age, or E/LH/FSH levels. Use of AMH-based selection of patients may inform who most benefits from the addition of adjuvant chemotherapy to ET. Clinical trial information: NCT01272037 .

Recurrence score gene axes scores and outcomes by race and ethnicity in the RxPONDER trial.

515 Background: Racial inequities in breast cancer outcomes remain a significant healthcare concern. In a previous analysis of the RxPONDER trial by race/ethnicity, we showed that non-Hispanic Black (NHB) women have worse outcomes compared to non-Hispanic Whites (NHW) despite similar 21-gene recurrence scores (RS). The RS is determined by an assay consisting of 16 cancer-related genes involved in invasion, ER and HER2 signaling, and proliferation. To provide a better understanding of the differences in underlying tumor biology amongst different racial/ethnic groups, we analyzed RS gene axes scores amongst each group and associations with outcomes. Methods: A total of 3,102 women were included: Hispanic (15.5%), NHB (4.7%), Asian (9.5%), and NHW (70.2%). The primary outcome was invasive disease-free survival (IDFS). This analysis extends median follow-up from 5 to 7 years and evaluates gene axes scores that are components of the RS by race/ethnicity. Impact of proliferation, ER, GRB7 (HER2), and invasion axes scores on IDFS was evaluated in Cox regression models. Results: There were no differences in RS distribution across racial/ethnic groups, and RS remained prognostic for each group with no significant variation in RS prognostic value. However, NHBs were noted to have significantly higher proliferation axis scores than NHWs (p<0.001); HER2 axis scores was higher for Asians than NHWs (p<0.001); and Hispanics had both higher HER2 (p=0.002) and proliferation (p=0.02) axes scores compared to NHWs. These results remained statistically significant after adjusting for age. Relative to NHWs, IDFS was worse for NHBs (HR 1.41; 95% CI 0.98-2.03) and better for Asians (HR 0.63; 95% CI 0.43-0.91) in unadjusted analysis. Adjusting for treatment arm, age, grade, menopausal status, proliferation, ER and HER2 axes scores attenuated the impact of race on IDFS for NHBs (HR 1.22; 95% CI 0.84-1.76), although the findings were unchanged for Asians (HR 0.64; 95% CI 0.44-0.93; Table). In a multivariable model, proliferation axis (HR 1.56; 95% CI 1.35-1.80) and ER axis (HR 0.81; 95% CI 0.71-0.93) were prognostic for IDFS. Conclusions: RS gene axes scores differ by race/ethnicity with higher proliferation axis scores noted in NHBs, which could partially explain their inferior outcomes noted in RxPONDER. These findings suggest that tumor biology is indeed important, however, we must dig deeper to uncover intricate factors that contribute to disparities, which is key to designing comprehensive strategies to address them. Clinical trial information: NCT01272037 . [Table: see text]

PusztaiJournal of Clinical Oncology

Development and validation of RSClin N+ tool for hormone receptor-positive (HR+), HER2-negative (HER2-), node-positive breast cancer.

508 Background: The RSClin tool was developed to provide estimates of recurrence risk and absolute chemotherapy benefit for patients with HR+/HER2- node-negative breast cancer using the 21-gene recurrence score (RS) and clinicopathologic factors. For patients with node-positive disease, we developed a new tool (RSClin N+) to increase the prognostic and predictive utility of risk estimates by combining RS with clinicopathologic factors and menopausal status. Methods: We used Cox regression to estimate 5-year risk of invasive disease or death (iDFS) and likelihood ratio (LR) tests to compare fit of RSClin N+ with RS alone and clinicopathologic factors (tumor grade, tumor size, positive lymph nodes [N1/N2], age) alone in 5283 node-positive patients treated with chemoendocrine therapy (CET) vs endocrine therapy alone (ET) in the S8814 (n=367: N1=227, N2=140, all postmenopausal) and RxPONDER (n/N1=4916) trials. Data from both studies were pooled and stratified by study for postmenopausal models; premenopausal models were fit only on RxPONDER data. Absolute CET benefit across combination of covariate values was estimated as the difference between ET and CET risk estimates. Validation of RSClin N+ was performed in 592 Nmic/N1 patients in the Clalit registry real-world dataset. Results: For pre- and postmenopausal patients, RSClin N+ provided significantly more prognostic information for iDFS than RS or clinicopathologic factors alone (LR Chi-square p<0.05). In postmenopausal patients, RS and clinicopathologic factors were independently prognostic, but only RS showed interaction with CET benefit (p=0.016). Absolute CET benefit for iDFS ranged from <0.1% to 21.5% as the RS increased from 0 to 50. Table shows examples of risk stratification and predicted benefit by RS within clinical low and high risk patients. In premenopausal patients, both RS and clinicopathologic factors remained prognostic but no interaction was observed between RS and CET.In external validation, RSClin N+ risk estimates were concordant with (Lin’s concordance=0.92) and prognostic for observed risk (HR 1.75; 95% CI 1.38 to 2.20). Conclusions: The RSClin N+ model provides improved estimates of prognostic risk and absolute CET benefit than clinical or genomic data alone in node-positive, HR+/HER2- breast cancer and could be used in patient counseling. [Table: see text]

Abstract PO4-18-01: International Validation of a Staging Model for de novo Metastatic Breast Cancer

Background Given the heterogeneity in outcomes for de novo metastatic breast cancer (dnMBC), a staging system was recently developed that refines prognostic estimates for patients presenting with distant metastases (JCO 2023;10:2546). This staging model was developed using the National Cancer Database and stratified patients into 4 subgroups, termed IVA, IVB, IVC, and IVD based on 3-year overall survival (OS): IVA >70%, IVB 50-70%, IVC 25-< 50%, and IVD < 25%; the primary factors affecting higher stage grouping were negative for ER, PR, and HER2 expression and a higher number of involved organ sites. Here, we aim to validate this model using an international data set. Methods Data for dnMBC patients were obtained from the Netherlands Cancer Registry (NCR, hosted by IKNL), Epidemiological Strategy and Medical Economics (ESME) by Unicancer, British Columbia Cancer (BCCan), Instituto Nacional de Cancerología, México (INCan), and Grupo Español de Investigación en Cáncer de Mama (GEICAM); the diagnosis years included varied by organization (range 2002-2021). Stage groups were assigned based on previously published criteria, defined by T-category, grade, ER, PR, HER2, histology, organ system site of metastases (bone-only, brain-only, visceral), and number of organ systems involved. For each cohort, followup time and OS were estimated using the reverse Kapan-Meier and Kaplan-Meier method, respectively. Median rates were estimated across all cohorts by weighting on cohort sample size or number at risk. Cox proportional hazards models were used to estimate the association of stage with OS after adjustment for age at diagnosis (treatment data not available for all cohorts). For the ESME cohort, a subgroup multivariable analysis was used to estimate the association of stage with OS after adjustment for age, local (surgery or radiotherapy) and first line systemic treatments. Results The final validation cohort was comprised of N=11,199 patients from 5 international organizations: n=5063 (45.2%, IKNL), n=4139 (37.0%, ESME), n=774 (6.9%, BCCan), n=757 (6.8%, INCan), and n=466 (4.2% GEICAM). Median followup across all cohorts was 77.5 months (95% CI 74.3-80.2). Median followup (in months) for the IKNL, ESME, BCCan, INCan, and GEICAM cohorts was 45.3 (95% CI 43.6-47.1), 77.5 (95% CI 74.3-80.2), 105.0 (95% CI 95.9-106.5), 93.0 (95% CI 86.5-102.1), and 49.5 (95% CI 46.5-53.4), respectively. Patients were stratified into stage groups: IVA, n=603 (5.4%); IVB, n=5704 (50.9%); IVC, n=3356 (30.0%); IVD, n=1536 (13.7%). For all cohorts combined, the weighted average OS rates consistently decreased with increasing stage group; similar findings were noted for individual cohorts (all p< 0.001; Table). On multivariable subgroup analysis including age at diagnosis, stage group was significantly associated with OS, and the risk of death increased with increasing stage (all p< 0.001; Table). On multivariable subgroup analysis for n=4139 patients (ESME cohort), stage group remained significantly associated with OS [IVA: reference; IVB: HR 1.51 (95% CI 1.17-1.93); IVC: HR 2.11 (95% CI 1.64-2.72); IVD: HR 3.60 (95% CI 2.75-4.70)] after adjusting for age and treatment. Conclusions These findings provide external validation of the previously published staging guidelines for dnMBC. This may guide future revisions of the AJCC staging guidelines for patients with dnMBC and provide patients and providers valuable information in planning therapy and goals of care as they approach the end-of-life. Table. Citation Format: Jennifer Plichta, Samantha Thomas, Sabine Siesling, Linda de Munck, Amélie Lusque, Thomas Grinda, Lovedeep Gondara, Stephen Chia, Paula Cabrera-Galeana, Nancy Reynoso-Noverón, Sara López-Tarruella, Isabel Álvarez López, Stephen Edge, Gabriel Hortobagyi. International Validation of a Staging Model for de novo Metastatic 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 PO4-18-01.

113MO NATALEE update: Safety and treatment (tx) duration of ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+/HER2− early breast cancer (EBC)

SlamonNew England Journal of Medicine

Ribociclib plus Endocrine Therapy in Early Breast Cancer

Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. Download a PDF of the Research Summary. In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease–free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease–free survival was evaluated with the use of the Kaplan–Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease–free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease–free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P=0.003). Secondary end points — distant disease–free survival and recurrence-free survival — also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. Ribociclib plus an NSAI significantly improved invasive disease–free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.) QUICK TAKE VIDEO SUMMARYRibociclib in Early Breast Cancer 02:00

Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice.