Changing ADC Choices for HR+/HER2– Breast Cancer

Hormone receptor–positive, HER2-negative (HER2–) disease accounts for approximatley 75% of breast cancers,¹ and endocrine therapy plus a CDK4/6 inhibitor remains the standard frontline approach even though resistance is all but inevitable.² Historically, once endocrine options were exhausted, oncologists were left with sequential single-agent chemotherapy, modest response rates, and a steady erosion in quality of life as patients accumulated lines of therapy. The recent arrival of antibody-drug conjugates (ADCs) active in HER2-low and even HER2-ultralow disease has reshaped that landscape, but it has also put new pressure on a step that used to carry little weight: how a pathologist reads an immunohistochemistry (IHC) 0 result.

In a virtual Case-Based Roundtable event for oncologists in the Chicago, Illinois, area, Ruta Rao, MD, a breast medical oncologist at Rush University Medical Center, opened by reviewing how HER2 testing categories have evolved. The 2023 American Society of Clinical Oncology/College of American Pathologists (CAP) update recognized only HER2-positive, HER2-negative, and equivocal categories, and explicitly excluded IHC 0 tumors from predictive claims. The 2026 NCCN guidelines now separate HER2– disease further, into HER2 null (no membrane staining at all), HER2 ultralow (immunohistochemistry [IHC] 0 with faint, incomplete membrane staining in ≤ 10% of cells), and HER2 low (IHC 1+ or 2+/in situ hybridization negative). Rao noted that the CAP's updated biomarker-reporting template, in place since March 2025, now asks pathologists to explicitly record ultralow distinction rather than collapsing it into a generic IHC 0.

CASE SUMMARY

• A 61-year-old woman with ESR1-mutant, hormone receptor–positive/HER2– metastatic breast cancer progressed through anastrozole (Arimidex), letrozole (Femara) plus ribociclib (Kisqali), and elacestrant (Orserdu).
• She now presents with symptomatic liver progression.
• Her original liver biopsy read as HER2 IHC 0 with no comment on membrane staining.
• The pathologist rereviewed the slide; the report was changed to faint, incomplete membrane staining in 5% to 8% of cells, consistent with HER2 ultralow disease.

EVENT RECAP

Rao pointed out that interobserver agreement between IHC 0 and 1+ is modest, approximately 26% in some series, and that HER2 expression can vary between primary and metastatic sites, making pathology rereview or rebiopsy reasonable whenever the result would change treatment.

Several oncologists said this kind of additional manual request has become routine in their practices. One participant said that at his institution, pathologists had only begun reporting the ultralow category uniformly a little over a year earlier, and that community pathologists, in particular, need ongoing education and sometimes outside consultation to apply the distinction consistently. Another noted that sending slides out for central review can be slowed by insurance authorization, which complicates using rereview as a routine step rather than an exception.

Rao then walked through the trial data now underpinning that pathology-driven decision. In the phase 3 DESTINY-Breast04 trial (NCT03734029), trastuzumab deruxtecan (T-DXd; Enhertu) produced a median progression-free survival (PFS) of 10.1 months vs 5.4 months with chemotherapy in HER2-low patients who had already received chemotherapy for metastatic disease (HR, 0.51; 95% CI, 0.40-0.64), with a median overall survival (OS) benefit of 23.9 vs 17.5 months (HR, 0.64; 95% CI, 0.48-0.86).³

The phase 3 DESTINY-Breast06 trial (NCT04494425) moved T-DXd earlier into the first postendocrine line and extended eligibility to HER2-ultralow disease for the first time.⁴ Median PFS was 13.2 months with T-DXd vs 8.1 months with chemotherapy in the HER2-low group (HR, 0.62; 95% CI, 0.52-0.75) and a nearly identical 13.2 vs 8.3 months in the ultralow subset, though the ultralow subset's confidence interval crossed 1, reflecting its smaller size. Rao noted that in DESTINY-Breast06, 64% of samples read locally as HER2 null were reclassified on central testing, 40% as ultralow, and 24% as low, underscoring how much a local pathology read can undersell a patient's ADC eligibility.

With those data in front of them, the group's polling shifted. Before reviewing the trial results, 54.5% of participants chose T-DXd for the case patient once HER2 ultralow status was confirmed; after the discussion, that rose to 80%. Rao closed the segment by framing pathology communication, not trial availability, as the practical bottleneck: a drug can be FDA approved for ultralow disease, but a patient only becomes eligible for it once someone asks the right question of the pathology report.

Polling results from the live event reflected the discussion in real time.

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DISCLOSURES: Rao reported consulting/advisory relationships with AstraZeneca, Daiichi Sankyo, Lilly, Genentech, and Pfizer.

REFERENCES

1. Cancer stat facts: female breast cancer subtypes. National Cancer Institute. Accessed July 22, 2026. https://tinyurl.com/588u2dep

2. Jerzak KJ, Bouganim N, Brezden-Masley C, et al. HR+/HER2- advanced breast cancer treatment in the first-line setting: expert review. Curr Oncol. 2023;30(6):5425-5447. doi:10.3390/curroncol30060411

3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

4. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086