ASCO 2026 Breast Cancer Highlights: Beyond the LBAs

The 2026 ASCO Annual Meeting breast cancer program offered a wealth of clinically meaningful data beyond its late-breaking abstracts. The following highlights capture key findings from across the meeting in triple-negative and hormone receptor-positive breast cancer, including emerging data on the potential role of GLP-1 receptor agonists in this setting.

GLP-1 Receptor Agonists Associated With Reduced HR+ Breast Cancer Incidence and Improved Survival

A real-world retrospective cohort analysis of more than 148,000 patients found that exposure to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) was associated with a modest but statistically significant reduction in the incidence of hormone receptor (HR)–positive, HER2-negative breast cancer and meaningfully improved overall survival (OS) among nondiabetic women with a body mass index (BMI) of 25 to 35 kg/m².¹

Investigators from Roswell Park Comprehensive Cancer Center leveraged the TriNetX US Collaborative Network to assemble a propensity score–matched cohort of 74,354 GLP-1 RA–exposed patients and 74,355 controls (total n = 148,709) with no prior breast cancer or laboratory-defined diabetes. At 36-month follow-up, incident HR-positive/HER2-negative breast cancer occurred in 0.29% of GLP-1 RA–exposed patients vs 0.33% of controls (RR, 0.88; 95% CI, 0.77-0.99; P =.046). Secondary subtypes—including HR-positive/HER2-positive (RR, 0.98; P =.78), HR-negative/HER2-positive (RR, 0.83; P =.35), and triple-negative breast cancer (RR, 0.68; P =.12)—did not reach statistical significance.

OS findings were notable across all strata. In the full matched cohort, GLP-1 RA exposure was associated with a 25% lower risk of death (HR, 0.75; 95% CI, 0.65-0.86; P <.0001). A 29% lower hazard of death was observed among premenopausal-proxy women younger than 50 years (n = 57,132; HR, 0.71; 95% CI, 0.58-0.86; P =.0004), and a statistically significant OS benefit also persisted in postmenopausal-proxy women aged 50 and older (n = 91,577; HR, 0.87; 95% CI, 0.81-0.94; P =.0003). The authors acknowledged limitations including age-based menopausal proxies and the 36-month observation window and called for prospective studies to validate these findings and clarify whether GLP-1 RA benefits are driven by direct antitumor effects or indirect cardiometabolic mechanisms.

Dato-DXd Demonstrates Sustained Benefit Across Secondary Efficacy End Points in First-Line Immunotherapy-Ineligible TNBC

Updated data from the phase 3 TROPION-Breast02 trial (NCT05104866) showed that datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) produced statistically significant improvements in time to first subsequent therapy or death (TFST), time to second progression or death (PFS2), and time to second subsequent therapy or death (TSST) compared with investigator's choice of chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) who were ineligible for immunotherapy.²

At a median follow-up of 27.5 months, the median TFST was 10.9 months with Dato-DXd (n = 323) vs 5.6 months with chemotherapy (n = 321; HR, 0.49; 95% CI, 0.41-0.59). The median PFS2 was 15.6 vs 11.8 months, respectively (HR, 0.61; 95% CI, 0.50-0.74), and the median TSST was 16.7 vs 12.6 months (HR, 0.67; 95% CI, 0.55-0.81). These data build on the primary analysis that supported the May 2026 FDA approval of Dato-DXd—the first TROP2–directed antibody-drug conjugate (ADC) approved for frontline TNBC in patients not eligible for PD-1/PD-L1 inhibitor therapy—which had demonstrated significant improvements in progression-free survival (PFS; HR, 0.57; 95% CI, 0.47-0.69; P <.0001) and OS (HR, 0.79; 95% CI, 0.64-0.98; P =.0290).

TROPION-Breast02 enrolled patients with no prior chemotherapy or targeted therapy in the metastatic setting and randomized them 1:1 to Dato-DXd 6 mg/kg every 3 weeks or investigator's choice of chemotherapy (paclitaxel, nab-paclitaxel, capecitabine, eribulin, or carboplatin). Most patients had PD-L1–low disease (89%-91%), visceral metastases (73%-78%), and received nab-paclitaxel as the preselected chemotherapy comparator. Subsequent ADC use was notably higher in the chemotherapy arm (41% vs 21%). The safety profile of Dato-DXd was described as manageable and consistent with its known profile.

"The totality of the data support Dato-DXd as a new first-line standard of care for patients with locally recurrent, inoperable, or metastatic TNBC for whom immunotherapy is not an option," said lead investigator David W. Cescon, MD, PhD.

Giredestrant Reduces Recurrence Risk in ER+/HER2- Early Breast Cancer Regardless of Menopausal Status

A prespecified subgroup analysis of the phase 3 lidERA Breast Cancer trial (NCT04961996) showed that adjuvant giredestrant, an investigational oral selective estrogen receptor degrader (SERD), improved invasive disease-free survival (iDFS) over standard-of-care (SOC) endocrine therapy in both premenopausal and postmenopausal patients with ER-positive, HER2-negative early breast cancer.³

Among 1687 premenopausal patients, giredestrant reduced the risk of invasive disease or death by 35% vs SOC endocrine therapy (HR, 0.65; 95% CI, 0.44-0.95), with 3-year iDFS rates of 94.0% vs 91.5%. Among 2456 postmenopausal patients, the hazard ratio was 0.74 (95% CI, 0.57-0.96), with 3-year iDFS rates of 91.3% vs 88.3%. The distant recurrence-free interval (DRFI) benefit was even more pronounced in premenopausal patients (HR, 0.58; 95% CI, 0.38-0.90; 3-year rates: 95.5% vs 92.6%). These results are consistent with the primary analysis from the 2025 San Antonio Breast Cancer Symposium, which reported an overall iDFS HR of 0.70 (95% CI, 0.57-0.87; P =.0014).

The 4170-patient lidERA trial enrolled patients with stage I to III ER+/HER2– early breast cancer who had completed surgery and indicated chemotherapy and were at elevated risk of recurrence. Patients were randomized 1:1 to giredestrant 30 mg orally once daily for 5 years or investigator's choice of SOC endocrine therapy; ovarian function suppression was required for premenopausal women in both arms. Tolerability favored giredestrant, with musculoskeletal-pain-driven treatment discontinuations occurring in 1.5% vs 3.7% of premenopausal patients (vs 5.0% in the aromatase inhibitor [AI]–treated subset) and 1.7% vs 4.1% of postmenopausal patients (vs 4.3% in the AI subset).

"Patients receiving giredestrant had fewer treatment discontinuations overall due to musculoskeletal pain, regardless of menopausal status," noted lead investigator Peter Schmid, MD, PhD, FACP.

Postsurgical ctDNA Status Outperforms Pathologic Complete Response as a Prognostic Tool in Early TNBC

A prospective sub-study of the phase 2/3 PARTNER trial (NCT03150576) demonstrated that circulating tumor DNA (ctDNA) status following surgery was strongly prognostic for distant recurrence in patients with early TNBC and outperformed pathologic complete response (pCR) status for risk stratification. The sub-study compared the prognostic performance of a whole-exome sequencing (WES)–based minimal residual disease (MRD) assay tracking up to 200 single-nucleotide variants (SNVs) against a whole-genome sequencing (WGS)–based assay tracking up to 5000 SNVs.⁴

Among 66 patients with post-surgical samples evaluable for WGS at a median follow-up of 5.0 years, the 3-year DRFI rate was 98.0% in ctDNA-negative patients (n = 52) vs 39.7% in ctDNA-positive patients (n = 14) by the WGS assay (HR, 52.1; 95% CI, 5.15-414.4; P =.0002). The WES assay was also significantly prognostic (HR, 15.2; 95% CI, 3.5-66.7; P =.0003), but the WGS assay showed approximately 3-fold higher prognostic strength. Notably, 7 ctDNA-negative WES results were reclassified as ctDNA positive by WGS, and the positive predictive concordance between the 2 assays was 100%. At the mid-neoadjuvant chemotherapy time point, WGS detected 11 ctDNA-positive samples vs only 1 by WES.

In a postsurgical multivariable analysis, ctDNA status by WGS remained an independent predictor of DRFI (HR, 35.4; 95% CI, 3.7-339.4; P =.0020), whereas pCR status did not (HR, 2.3; 95% CI, 0.2-21.6; P =.4797). Although pCR was significantly prognostic in univariable analysis (HR, 8.5; 95% CI, 1.9-38.4; P =.0055), it lost significance once ctDNA status was included. The authors concluded that the WGS assay's higher sensitivity supports its use for on-treatment molecular monitoring and that ctDNA status could inform decisions around adjuvant treatment intensification or de-escalation.

Sacituzumab Govitecan–Based Regimens Show Consistent PFS Benefit Across Biomarker Subgroups in First-Line Advanced TNBC

Prespecified exploratory biomarker analyses from the phase 3 ASCENT-03 (NCT05382299) and ASCENT-04 (NCT05382286) trials demonstrated consistent progression-free survival (PFS) benefit with sacituzumab govitecan-hziy (Trodelvy)–based regimens vs chemotherapy-based comparators across TROP2 expression quartiles, tumor BRCA genotype subgroups, and HER2 expression subgroups.

In ASCENT-03, which enrolled patients with previously untreated advanced TNBC not eligible for PD-(L)1 inhibitors, the median PFS in the intention-to-treat population was 9.7 months with sacituzumab govitecan (n = 279) vs 6.9 months with chemotherapy (n = 279; HR, 0.62; 95% CI, 0.50-0.77). PFS curves separated in favor of sacituzumab govitecan across all 4 TROP2 quartiles (HRs, 0.54, 0.62, 0.84, and 0.60 in quartiles 1-4), with no clear trend toward greater benefit at higher TROP2 levels. PFS benefit was also observed in BRCA–wild-type (HR, 0.70; 95% CI, 0.54-0.92) and BRCA-mutant (HR, 0.59; 95% CI, 0.32-1.09) subgroups, and in HER2 IHC 0 (HR, 0.63; 95% CI, 0.46-0.85) and HER2-low (HR, 0.74; 95% CI, 0.55-1.01) subgroups.⁵

In ASCENT-04, which enrolled patients with PD-L1–positive previously untreated metastatic TNBC, sacituzumab govitecan plus pembrolizumab (Keytruda) yielded a median PFS of 11.2 months (n = 221) vs 7.8 months with chemotherapy plus pembrolizumab (n = 222; HR, 0.65; 95% CI, 0.51-0.84). Unlike in ASCENT-03, ASCENT-04 showed a trend toward greater PFS benefit at higher TROP2 expression quartiles (HRs: 0.81, 0.73, 0.46, and 0.57 in quartiles 1 through 4). Benefit was consistent in BRCA–wild-type (HR, 0.67; 95% CI, 0.49-0.91) and HER2-low (HR, 0.67; 95% CI, 0.48-0.92) subgroups.Both analyses were exploratory in nature and not powered for subgroup comparisons; OS data were immature at the time of reporting.⁶

REFERENCES

1. Shah Z, Hundal J, Afridi SS, et al. GLP-1 therapy and hormone receptor–positive breast cancer risk and survival: A real-world analysis. J Clin Oncol. 2026;44(suppl 16):10548. doi:10.1200/JCO.2026.44.16_suppl.10548

2. Cescon DW, Traina TA, Schmid P, et al. First-line datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: additional efficacy endpoints from the TROPION-Breast02 study. J Clin Oncol. 2026;44(suppl 16):1002. doi:10.1200/JCO.2026.44.16_suppl.1002

3. Schmid P, Geyer CE Jr, Martín M, et al. Efficacy and safety of giredestrant (GIRE) in patients (pts) with estrogen receptor-positive, HER2-negative early breast cancer (ER+, HER2- eBC) in the phase III lidERA BC clinical trial: results by menopausal status. J Clin Oncol. 2026;44(suppl 16):502. doi:10.1200/JCO.2026.44.16_suppl.502

4. Dooley A, Fontenele RS, Grasse G, et al. Evaluation of whole-exome and whole-genome sequencing tumor-informed circulating tumor DNA MRD assays in patients with early triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy (NAC) with or without olaparib: a prospective sub-study of the PARTNER trial. J Clin Oncol. 2026;44(suppl 16):570. doi:10.1200/JCO.2026.44.16_suppl.570

5. Barrios C, Hurvitz SA, Tolaney SM, et al. ASCENT-03: Efficacy by biomarker subgroup with sacituzumab govitecan (SG) vs chemotherapy (chemo) in participants (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are not candidates for PD-(L)1 inhibitors (PD-[L]1i). J Clin Oncol. 2026;44(suppl 16):1014. doi:10.1200/JCO.2026.44.16_suppl.1014

6.Tolaney SM, Schmid P, de Azambuja E, et al. ASCENT-04: Analysis of efficacy by biomarker subgroups with sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in participants (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2026;44(suppl 16):1013. doi:10.1200/JCO.2026.44.16_suppl.1013