Neoadjuvant T-DXd Clouds Residual Disease Decisions in HER2+ Breast Cancer

Trastuzumab deruxtecan (T-DXd; Enhertu) is approved both before surgery, as part of a regimen with a taxane, trastuzumab (Herceptin), and pertuzumab (Perjeta), and after surgery for patients with residual invasive disease, in FDA decisions announced May 15, 2026.¹ Both indications are broader than the populations enrolled in the supporting trials, and neither trial tested what should follow when a patient who received T-DXd up front still has disease at surgery. Clinicians must decide who qualifies, which regimen to start with, and what comes next.

In a virtual Case-Based Roundtable event for oncologists, Neil M. Iyengar, MD, a breast medical oncologist at Winship Cancer Institute of Emory University in Atlanta, Georgia, reviewed neoadjuvant and adjuvant data for antibody-drug conjugates in HER2-positive breast cancer and moderated discussion of a case of residual disease after neoadjuvant therapy. Iyengar noted that the group's hardest question was how to treat residual disease after neoadjuvant T-DXd.

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CASE SUMMARY

Workup and Diagnosis

• A 46-year-old woman presents with a palpable breast mass identified on self-exam.
• Biopsy of the breast mass: poorly differentiated invasive ductal carcinoma (IDC)
• Estrogen receptor (ER)+ (5%), progesterone receptor (PR)− (0%), HER2 immunohistochemistry (IHC) 3+.
• Clinical staging: cT2, cN1.
• Labs: within normal limits.
• Germline testing: negative for BRCA1, BRCA2, and PALB2 pathogenic variants.

Pathology Report

• Following neoadjuvant therapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) and surgery, she is found to have residual disease.
• ypT1c (1.8 cm residual invasive tumor).
• ypN1 (2 of 3 sentinel nodes positive).

EVENT RECAP

Asked to choose a neoadjuvant regimen for the patient, participants split. TCHP was the most frequent choice, and the remaining votes were spread across dose-dense doxorubicin and cyclophosphamide (ddAC) followed by paclitaxel, trastuzumab, and pertuzumab (THP; ddAC-THP), T-DXd followed by THP (T-DXd-THP), THP alone, and other regimens.

One oncologist who chose THP said omitting carboplatin is reasonable given a trial supporting its omission. Another favored TCHP and reserved THP for smaller node-negative disease or substantial comorbidities, adding that low ER expression does not lessen the need for HER2 blockade. Iyengar called omission defensible but said larger tumors, poorly differentiated histology, and ER-low expression push him toward the platinum. "I do tend to still include the platinum as well," he said, and he would give additional taxane cycles if he left it out.

Because the patient's node-positive disease would have made her eligible for the phase 3 DESTINY-Breast11 trial (NCT05113251), Iyengar reviewed it next. The trial enrolled patients with high-risk disease, defined as cT3 or larger tumors or node-positive disease at any tumor stage, and randomized them to T-DXd alone, T-DXd followed by THP, or ddAC-THP. The T-DXd monotherapy arm closed early. The pathologic complete response (pCR) rate was 67.3% with T-DXd-THP vs 56.3% with ddAC-THP (absolute difference, 11.2%; 95% CI, 4.0%-18.3%; P = .003).² The difference appeared consistent across subgroups, at 9.1% (95% CI, 0.2%-17.9%) in hormone receptor–positive and 16.1% (95% CI, 3.0%-28.8%) in hormone receptor–negative disease. Event-free survival (EFS) data were immature (HR, 0.56; 95% CI, 0.26-1.17), which was not statistically significant at 4.5% maturity. Grade 3 or higher adverse events occurred in 37.5% of patients with T-DXd-THP and 55.8% with ddAC-THP, and all-grade interstitial lung disease (ILD) in 4.4% and 5.1% In an exploratory analysis, residual cancer burden (RCB) was lower with T-DXd-THP, including among patients without a pCR.³

Payers shaped uptake. One oncologist was waiting on insurance and expected a denial. Iyengar said his own early request was denied, but after NCCN listed T-DXd-THP for high-risk disease,⁴ "I have not encountered any insurance barriers." He said he and a participant keep to the trial population despite the broader FDA label.¹

For patients with residual disease, ado-trastuzumab emtansine (T-DM1; Kadcyla) had been the standard after KATHERINE (NCT01772472), in which 7-year invasive disease-free survival (iDFS) was 80.8% with T-DM1 vs 67.1% with trastuzumab (HR, 0.54; 95% CI, 0.44-0.66) and overall survival favored T-DM1 (HR, 0.66; 95% CI, 0.51-0.87; P = .003).⁵ In the phase 3 DESTINY-Breast05 trial (NCT04622319), which enrolled patients at higher risk, T-DXd improved 3-year iDFS vs T-DM1 (92.4% vs 83.7%; HR, 0.47; 95% CI, 0.34-0.66; P < .001).⁶ Central nervous system recurrences were numerically fewer with T-DXd (2.1% vs 3.1%), but adjudicated drug-related ILD occurred in 9.6% vs 1.6%, including 2 grade 5 events with T-DXd. Rates did not differ materially with sequential (10.7%) vs concurrent (9.6%) radiation. The trials enrolled different populations, so the results cannot be compared directly. Two oncologists had started adjuvant T-DXd in patients with substantial residual disease without problems so far, and participants reached consensus on T-DXd for this patient. One had not been screening with CT until hearing it recommended at a panel; Iyengar said, "I definitely do CT scans for surveillance" in early-stage disease.

The harder question was a patient who has residual disease after neoadjuvant T-DXd. One oncologist said the concern keeps them from adopting it up front, since a sizable minority of patients will have residual disease and T-DM1 seemed a poor next step, and wanted mature EFS data first. Another would retest receptors, since disease can turn primarily hormone-driven, but otherwise keep a HER2-directed antibody-drug conjugate. Iyengar said he prefers sparing patients at high risk the adjuvant T-DXd, but that residual disease could reflect too little T-DXd or a resistant clone, and no data decide between them. Circulating tumor DNA, he added, is not yet ready to guide these decisions.

Participants treated residual disease after neoadjuvant T-DXd as the main unanswered question. Without data, the choice among more T-DXd, T-DM1, or another approach rests on how much disease remains, and at least one oncologist said discomfort with that gap would persist until EFS results mature.

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DISCLOSURES: Iyengar reports personal fees from Amneal Pharmaceuticals, Arvinas, AstraZeneca, Bayer, BD Life Sciences, Boehringer Oncology, Daiichi Sankyo, Genentech/Roche, Gilead Biosciences, Menarini Group/Stemline, Novartis, Pfizer, Seattle Genetics, SynDevRx, and TerSera Therapeutics.

REFERENCES

1. FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. FDA. May 15, 2026. Accessed October 15, 2026. https://tinyurl.com/3me3bz4k

2. Harbeck N, Modi S, Pusztai L, et al; DESTINY-Breast11 Trial Investigators. Neoadjuvant trastuzumab deruxtecan alone or followed by paclitaxel, trastuzumab, and pertuzumab for high-risk HER2-positive early breast cancer (DESTINY-Breast11): a randomised, open-label, multicentre, phase III trial. Ann Oncol. 2026;37(2):166-179. doi:10.1016/j.annonc.2025.10.019

3. Karamyan S. ESMO Breast Cancer Annual Congress 2026: DESTINY-Breast11 RCB Analysis Highlights Neoadjuvant T-DXd-THP in HER2-Positive Early Breast Cancer. OncoDaily. Accessed October 15, 2026. https://tinyurl.com/ykp8y7bz

4. NCCN. NCCN Guidelines for Breast Cancer, version 2.2026. Updated February 27, 2026. Accessed October 15, 2026. https://tinyurl.com/mr43a3hu

5. Geyer CE Jr, Untch M, Huang CS, et al. Survival with trastuzumab emtansine in residual HER2-positive breast cancer. N Engl J Med. 2025;392:249-257. doi:10.1056/NEJMoa2406070

6. Loibl S, Park YH, Shao Z, et al. Trastuzumab deruxtecan in residual HER2-positive early breast cancer. N Engl J Med. 2026;394(9):845-857. doi:10.1056/NEJMoa2514661