Changing ADC Choices for HR+/HER2–Breast Cancer

Hormone receptor–positive, HER2-negative (HR+/HER2–) disease accounts for roughly three-quarters 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-ultra low 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 area, Ruta Rao, MD, a breast medical oncologist at Rush University Medical Center, opened by reviewing how HER2 testing categories have evolved. The 2023 ASCO/College of American Pathologists (CAP) update recognized only HER2-positive, -negative, and equivocal categories, and explicitly excluded IHC 0 tumors from predictive claims. The 2026 National Comprehensive Cancer Network (NCCN) guidelines now separate HER2– disease further, into HER2 null (no membrane staining at all), HER2 ultra-low (IHC 0 with faint, incomplete membrane staining in ≤10% of cells), and HER2 low (IHC 1+ or 2+/ISH-negative). Rao noted that the CAP's updated biomarker-reporting template, in place since March 2025, now asks pathologists to record that ultra-low distinction explicitly rather than collapsing it into a generic "IHC 0."

CASE SUMMARY

• A 61-year-old woman with ESR1-mutant, HR+/HER2– metastatic breast cancer progressed through anastrozole (Arimidex), letrozole (Femara) plus ribociclib (Kisqali), and elacestrant (Orserdu).
• Now presents with symptomatic liver progression
• Original liver biopsy read as HER2 IHC 0 with no comment on membrane staining
• Pathologist re-reviewed the slide; report changed to faint, incomplete membrane staining in 5% to 8% of cells, consistent with HER2 ultra-low

EVENT RECAP

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

Several oncologists said this kind of manual re-request has become routine in their own practices. One participant said that at his institution, pathologists had only begun uniformly reporting the ultralow category 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 re-review as a routine step rather than an exception.

Rao then walked through the trial data now underpinning that pathology-driven decision. In DESTINY-Breast04 (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 DESTINY-Breast06 (NCT04494425) moved T-DXd earlier into the first post-endocrine line and extended eligibility to HER2-ultra low 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 ultra-low subset, though the ultra-low 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 ultra-low 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 own polling shifted. Before reviewing the trial results, 54.5% of participants chose T-DXd for the case patient once HER2 ultra-low 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 ultra-low 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 Jun 2;30(6):5425-5447. doi: 10.3390/curroncol30060411.

3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;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 Dec 5;391(22):2110-2122. doi: 10.1056/NEJMoa2407086.