Endocrine Therapy Omission in Estrogen Receptor–Low (1%-10%) Early-Stage Breast Cancer

Author(s): Grace M. Choong, MD¹; Tanya L. Hoskin, MS²; Judy C. Boughey, MD³; James N. Ingle, MD¹; Matthew P. Goetz, MD¹;

Source: J Clin Oncol. 2025;43(16):1875-1885

Dr. Maen Hussein's Thoughts

DON’T omit, there is still a benefit, especially in 6-10% patients.

PURPOSE

Adjuvant endocrine therapy (ET) improves overall survival (OS) in estrogen receptor (ER)–positive early-stage breast cancer (BC). However, the benefit of ET for those with ER-low BC (ER 1%-10%) is unclear.

METHODS

Using the National Cancer Database, we studied patients with high-risk stage I to III, ER-low BC (defined as immunohistochemistry 1%-10%) who received (neo)adjuvant chemotherapy and did or did not initiate ET. OS was analyzed with ET initiation as a time-dependent covariate using Cox proportional hazards regression.

RESULTS

Of 10,362 patients with stage I to III ER-low BC, 7,018 received chemotherapy and met inclusion criteria. ET omission was 42% at 12 months and more common in patients with tumors that were progesterone receptor–negative, human epidermal growth factor receptor 2–negative, higher-grade (grade 2/3) and higher Ki-67 (≥20%; all P < .001) and those who received neoadjuvant chemotherapy (NAC; P < .001). With a median follow-up of 3 years, 586 deaths were observed. In a multivariable analysis, ET omission was associated with a higher risk of death (hazard ratio [HR], 1.23 [95% CI, 1.04 to 1.46]; P = .02), with a greater impact in those with higher ER levels: ER 1%-5% (HR, 1.15 [95% CI, 0.91 to 1.45]; P = .24) versus ER 6%-10% (HR, 1.42 [95% CI, 1.00 to 2.02]; P = .048). Among patients treated with NAC (n = 4,377, 62%), ET omission was associated with worse OS in those with residual disease (RD; HR, 1.26 [95% CI, 1.00 to 1.57]; P = .046) but not in those who achieved a pathologic complete response (HR, 1.06 [95% CI, 0.62 to 1.80]; P = .84).

CONCLUSION

In ER-low, early-stage BC, ET omission is associated with significantly worse OS, especially in patients with RD after NAC and those with higher (6%-10%) ER levels. Until prospective data are available, patients with ER-low BC should be counseled regarding the potential benefit of ET.

Author Affiliations

¹Department of Oncology, Mayo Clinic, Rochester, MN; ²Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN; ³Division of Breast and Melanoma Surgical Oncology, Mayo Clinic, Rochester, MN;

The Pathologic Response Evaluation and Detection in Circulating Tumor-DNA Study: Ultrasensitive Circulating Tumor-DNA Assessment of Breast Cancer Minimal Residual Disease

Primary objective not met, ctDNA clearance post- neoadjuvant therapy (NAT) cannot reliably predict pathologic complete response (pCR) and shouldn't be used to defer surgery. But the prognostic data are striking: post-NAT ctDNA positivity independently predicted recurrence in triple-negative breast cancer (TNBC) (HR 8.9), and the postsurgical landmark analysis is essentially binary, 100% of ctDNA-positive patients recurred while 94% of ctDNA-negative patients were disease-free at 5 years (HR 128). Not practice-changing yet pending prospective utility trials, but this strongly validates ultrasensitive ctDNA as a prognostic tool and a smart enrollment biomarker for future escalation/de-escalation trials.

VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor–Positive/HER2−/PIK3CA Wild-Type Advanced Breast Cancer

Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway. PFS was 9.3 m in the gedatolisib-triplet group vs 2.0 m in the fulvestrant group (hazard ratio) HR 0.24, and 7.4 m in the gedatolisib-doublet group HR 0.33 v fulvestrant.

Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer

This is impressive. However, there is no reported placebo trastuzumab deruxtecan arm, so this is not truly a “no chemotherapy” regimen. It is important to remember that deruxtecan is itself a chemotherapy agent. So, this is really comparing deruxtecan vs taxol or more accurately, a comparison of chemotherapy delivery systems.

Efficacy and Safety of Neoadjuvant TQB2102 in Locally Advanced or Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: A Randomized, Open-Label, Multicenter, Phase II Trial

The QUIWI study used quizartinib, a FLT3 drug added to standard chemo induction/consolidation in FLT-negative acute myeloid leukemia (AML) patients. There was a meaningful overall survival (OS) improvement across all age and risk groups including the NPM1+ population. They purposefully used a higher dose to achieve what is felt to be off-target TKI activity in familiar pathways of KIT, PDGRF…etc.

Sacituzumab Govitecan plus Pembrolizumab for Advanced Triple-Negative Breast Cancer

This really feels like a first-line practice changer in PD-L1+ MTNBC—the sacituzumab govitecan/pembrolizumab combination delivering a 3.4-month progression-free survival (PFS) improvement and pushing median PFS past 11 months is quite meaningful. Mature overall survival (OS) data will be interesting to see. Remember to watch closely and consider screening for drug-induced interstitial lung disease(ILD).