ASCO 2026 Breast Cancer Trials Affirm De-Escalation, Earlier Switching

Several trials presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting reinforced a multiyear push toward de-escalating and individualizing breast cancer treatment, according to Coral Omene, MD, PhD, program director of Breast Cancer Disparities Research and a medical oncologist at Rutgers Cancer Institute, and associate professor of medicine at Rutgers Robert Wood Johnson Medical School.

In the phase 3 OPTIMA trial (NCT03749421) investigators used the Prosigna (PAM50) gene expression test to identify patients with high clinical risk, hormone receptor (HR)–positive, HER2-negative early breast cancer who could safely forgo chemotherapy.¹ Even among premenopausal patients with substantial nodal involvement, "those patients were absolutely getting chemotherapy" under current practice, Omene said, but the test "could identify a genomic low-risk patient" who did just as well without it. "That, to me, is practice-changing," she said, noting the test was recently approved and "we can institute it right away."

The phase 3 lidERA trial (NCT04961996) compared the oral selective estrogen receptor degrader (SERD) giredestrant with standard adjuvant endocrine therapy in early-stage, HR-positive, HER2-negative breast cancer.² The drug improved invasive disease-free survival vs standard endocrine therapy in both pre- and postmenopausal patients. Because it was a head-to-head comparison, Omene said, "you can't beat that," predicting it will become "the go-to endocrine agent to use" once approved.

SERENA-6 (NCT04964934) introduced what Omene called a paradigm shift in monitoring metastatic, HR-positive, HER2-negative disease. Patients on first-line aromatase inhibitor plus CDK4/6 inhibitor therapy underwent serial ctDNA testing for emergent ESR1 mutations; once detected, before radiographic or clinical progression, patients switched to camizestrant while continuing the CDK4/6 inhibitor. The benefit "was there even after the first progression," Omene said, and patients also reported improvement in quality of life, leading her to conclude, "we cannot say that that's not clinically meaningful." She noted that the FDA's Oncologic Drugs Advisory Committee "didn't think that it was a meaningful way to assess for progression," partly because PFS2 outcomes could reflect heterogeneity in subsequent treatments; European regulators, by contrast, supported the approach. Omene called the strategy "very interesting and very compelling" but said she like others are awaiting overall survival data before it likely becomes standard of care.³

Two other trials reinforced existing strategies. The phase 3 ASCENT-03 (NCT05382299) and ASCENT-04 (NCT05382286) trials evaluated sacituzumab govitecan (Trodelvy) with or without immunotherapy by PD-L1 status in first-line metastatic triple-negative breast cancer.^4,5 Benefit held "across a variety of TROP2 expression," Omene said, and "regardless of the patient's BRCA genotype or HER2 low expression status, which firmly establishes it as first line treatment."

In the surgical space, the SENOMAC trial (NCT02240472) found that patients with 1 or 2 positive sentinel lymph nodes could safely omit completion axillary lymph node dissection (ALND) with appropriate adjuvant therapy, without compromising 5-year survival.⁶ Omitting the dissection "preserves the arm function" and "limits lymphedema" without sacrificing outcomes, Omene said. Unlike previous surgical de-escalation studies (like ACOSOG Z0011) which were largely limited to patients undergoing breast-conserving therapy, over one-third of the SENOMAC patients underwent mastectomies, proving omission of ALND is safe for this demographic as well.

Omene also highlighted the I-SPY 2.2 platform trial (NCT01042379), in which neoadjuvant rilvegostomig, a PD-1/TIGIT bispecific antibody, plus trastuzumab deruxtecan (T-DXd; Enhertu) produced an estimated pathologic complete response rate of 57% in HR-positive, immune-positive tumors and 52% in HR-negative, immune-positive tumors.⁷ The high response rate, she said, "may allow selected patients with immune-positive tumors to undergo surgery early" without standard chemotherapy, pending confirmation in larger phase 3 studies.

Finally, Omene pointed to izalontamab brengitecan (iza-bren), an investigational EGFR/HER3 bispecific antibody-drug conjugate evaluated in the phase 3 PANKU-Breast02 trial (NCT06382142) in pretreated, advanced triple-negative breast cancer.⁸ The agent met its primary end points of significant progression-free and overall survival improvement over chemotherapy, results Omene called "very exciting" given that EGFR and HER3 are expressed at high levels in triple-negative disease. She cautioned, however, that "payload resistance can happen" when patients receive antibody-drug conjugates with the same payload in sequence so we have to wait to see how and when would be best to use this promising agent.

REFERENCES

1. Stein RC, Makris A, Macpherson IR, et al. First results from the OPTIMA phase III randomized non-inferiority trial of test-directed chemotherapy in patients with high clinical risk ER-positive HER2-negative early breast cancer. J Clin Oncol. 44, 500-500(2026). doi:10.1200/JCO.2026.44.16_suppl.500

2. Schmid P, Geyer CE, Martin 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. 44, 502-502(2026). doi:10.1200/JCO.2026.44.16_suppl.502

3. Bidard FC, Meyer EL, Park YH, et al. First-line (1L) camizestrant (CAMI) for emergent ESR1 mutations (ESR1m) in advanced breast cancer (ABC): Final progression-free survival 2 (PFS2) from the phase III SERENA-6 trial. J Clin Oncol. 44, LBA1007-LBA1007(2026). doi:10.1200/JCO.2026.44.17_suppl.LBA1007

4. Barris CH, 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. 44, 1014-1014(2026). doi:10.1200/JCO.2026.44.16_suppl.1014

5. 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. 44, 1013-1013(2026). doi:10.1200/JCO.2026.44.16_suppl.1013

6. de Boniface J, Filtenborg Tvedskov T, Rydén L, et al. Omission of completion axillary dissection in patients with breast cancer and sentinel lymph node macrometastases: overall survival and patient-reported arm morbidity from the randomized SENOMAC trial. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29–June 2, 2026; Chicago, IL.

7. O’Sullivan CC, Kalinsky K, Yau C, et al. Neoadjuvant rilvegostomig (R) + trastuzumab deruxtecan (T-DXd) in high-risk HER2-negative breast cancer: Results from the I-SPY 2.2 trial. J Clin Oncol. 2026;44(suppl 17). doi: 10.1200/JCO.2026.44.17_suppl.LBA514

8. Wu J, Zhang J, Ouyang O, et al. Izalontamab brengitecan (iza-bren) versus physician’s choice of chemotherapy in patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC): a randomized phase III study. J Clin Oncol. 2026;44(suppl 17):LBA1003. doi:10.1200/JCO.2026.44.17_suppl.LBA1003