Expanding the Horizon: Evolving Standards of Care and the Promise of MRD-Guided Therapy in Breast Cancer

Antibody-drug conjugates (ADCs) have reshaped the breast cancer treatment landscape over the past decade, and few clinician-researchers have been closer to that transformation than Paolo Tarantino, MD, PhD medical oncologist and clinical fellow at Dana-Farber Cancer Institute, whose career has tracked the rise of HER2-targeted ADCs from early-phase investigation to practice-changing approval. In a recent interview with Targeted Oncology, Dr Tarantino reflected on how the field has evolved, which developments have not received the attention they deserve, and why 2026 may be defined by a technology that forces clinicians to confront what they do not yet know.

From First-in-Human Data to a Field-Defining Drug Class

Dr Tarantino's interest in HER2-directed ADCs dates to his oncology training in Italy, where he had early exposure to trastuzumab deruxtecan (T-DXd; Enhertu). What struck him early on was the consistency of response.

"At the time, we didn't know that these new topoisomerase I ADCs would actually be a thing. And in truth, we saw that each and every patient with first HER2-positive breast cancer that were receiving these drugs would respond,” he said.

The scope of that benefit, it turned out, would extend well beyond HER2-positive disease. The pivotal observation that topoisomerase I ADCs could demonstrate activity in HER2-low tumors, a category that encompasses up to 70% of all breast cancers, fundamentally altered how clinicians and researchers conceived of HER2 as a therapeutic target.

"We discovered that these…ADCs could expand the activity beyond HER2-positive, which was a major thing, because HER2-positive breast cancer means around 15% of patients; HER2-low means up to 70% of all patients. And now we're starting to talk about ultra-low, up to 80 to 90%. So really, the idea here is to expand the benefit of these drugs to most patients with breast cancer, which is tremendous."

This conceptual shift from viewing HER2-low expression as a distinct biological entity to treating it as a targetable biomarker emerged from years of laboratory and translational work.

"We moved from thinking of HER2-low breast cancer as this distinct entity to thinking it's a target, like TROP2, like Nectin-4, like many other targets," Dr Tarantino explained. "Nowadays…we have so many targets. We have so many ways to deliver chemo toward these targets. And it is just starting; I really think it expands so much more."

ADCs Move Earlier—and the Headlines Reflect It

Among recent developments, Dr Tarantino emphasized the migration of ADCs into earlier lines of therapy as one of the most consequential trends in breast oncology.

"ADCs moving to early lines has been the headline of the past year," he noted, citing approvals and pivotal data supporting ADC use in first-line triple-negative metastatic breast cancer as well as neoadjuvant and adjuvant settings in HER2-positive disease. "All of this has been huge... it's practice changing.”

Yet Dr Tarantino believes at least two other developments of comparable significance have gone underappreciated. The first involves neoadjuvant immunotherapy in estrogen receptor (ER)-positive breast cancer, a disease subtype representing more than two-thirds of all breast cancer diagnoses. Results from the KEYNOTE-756 trial (NCT03725059) demonstrated that adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy improves pathologic complete response (pCR) rates at surgery. However, the absence of mature event-free survival data has tempered enthusiasm.

"The reason why there wasn't much attention is that it doesn't tell us yet that it reduces the rate of recurrence," Dr Tarantino acknowledged. "But I think it's coming soon, and when it comes it's going to be huge, because suddenly we're going to give immunotherapy to a very large proportion of patients."

The Quiet Dismantling of a Standard: Rethinking Neoadjuvant Therapy for HER2-Positive Disease

The second underappreciated story, Dr Tarantino noted, concerns the rapid evolution of neoadjuvant therapy for HER2-positive breast cancer, a setting where the 4-drug regimen TCHP (docetaxel, carboplatin, trastuzumab [Herceptin], pertuzumab [Perjeta]) has long been the US standard of care. That standard is now under pressure from multiple directions simultaneously.

"Suddenly, now there are 3 things converging which are demolishing this standard," Dr Tarantino said. First, the DESTINY-Breast11 trial (NCT04494425) demonstrated that sequencing T‑DXd followed by THP is extremely effective.¹ Second, 2 randomized trials from China indicated that carboplatin adds little benefit in this context—meaningful news for patients and providers alike, given that carboplatin is "a tough drug." Third, the large US-based CompassHER2-pCR trial (NCT04266249), enrolling approximately 2000 patients, suggested that an abbreviated THP regimen alone may be sufficient for at least half of patients.²

"Several forces are demolishing the old standard of care, building a new one, but right now we are in between," Dr Tarantino said. He recently published an editorial in the Journal of Clinical Oncology addressing this transition.³ "TCHP was such a straightforward standard, and now we're moving toward a more nuanced approach. But I do think it's an opportunity to treat patients in a more nuanced manner."

The Biggest Challenge of 2026: Minimal Residual Disease and the Limits of Current Evidence

Asked to identify the most pressing challenge facing breast cancer clinicians in 2026, Dr Tarantino pointed to the emerging use of circulating tumor DNA (ctDNA) assays for minimal residual disease (MRD) detection: a domain where the tools have outpaced the clinical evidence.

"I think 2026 will be the year of MRD," he said.

Commercially available ctDNA platforms, including those from Natera, Guardant, and Tempus, can detect tumor-derived DNA fragments in peripheral blood following surgical resection. Retrospective data consistently show that MRD positivity after breast surgery correlates with a substantially higher risk of disease recurrence. But knowing that a patient is MRD-positive and knowing what to do about it are different matters entirely.

"We have the tools... we also have abundant retrospective evidence telling us that if you do find ctDNA positivity after removing the breast tumor, that actually means a much higher risk of recurrence," Dr Tarantino explained. "Now, the last missing piece of this equation is what to do with that information. If I do a liquid biopsy and I find that there is MRD, there is some molecular disease in the blood, even if I cannot see it with scans, should I intensify my treatment to try to cure the patient? We have no trial that has proven this."

The clinical consequence is a difficult one: patients increasingly request MRD testing, and a positive result carries real psychological weight, yet no prospectively validated treatment algorithm exists to guide the response.

"If you have a positive test, it means a lot of anxiety, but very little data to decide what to do," he said.

Dr Tarantino expects this to change. Prospective trials are underway and being designed specifically to address treatment intensification in MRD-positive patients. He also pointed to the SERENA-6 trial (NCT04964934) in the metastatic setting, in which treatment escalation was triggered by molecular changes detected in ctDNA—a potential paradigm shift that may gain urgency if capivasertib (Truqap) or other agents are approved based on ctDNA-defined indications.⁴

"I think it will be very important to discuss this, but also very challenging, because the data is imperfect, and at a certain point, you have to decide if you're a believer or a nonbeliever in this approach," Dr Tarantino acknowledged. It is a tension that clinicians navigating this space will increasingly face: a technology rich in prognostic signal but still awaiting the interventional evidence to translate that signal into clinical action.

Hear more from Dr Tarantino on The Breast Friends Podcast.

REFERENCES

1. Harbeck N, Modi S, Pusztai L, et al. 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 Feb;37(2):166-179. doi: 10.1016/j.annonc.2025.10.019. Epub 2025 Oct 21. PMID: 41130363.

2. O'Sullivan CC, Ballman KV, McCall L, et al. Alliance A011801 (compassHER2 RD): postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer. Future Oncol. 2021 Dec;17(34):4665-4676. doi: 10.2217/fon-2021-0753. Epub 2021 Oct 12. PMID: 34636255; PMCID: PMC8600597.

3. Tarantino P. Rise and fall of neoadjuvant carboplatin for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2026 Jan 23:JCO2502855. doi: 10.1200/JCO-25-02855. Epub ahead of print. Erratum in: J Clin Oncol. 2026 Mar 10;44(8):723. doi: 10.1200/JCO-26-00219. PMID: 41576311.

4. Turner N, Huang-Bartlett C, Kalinsky K, et al. Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment. Future Oncol. 2023 Mar;19(8):559-573. doi: 10.2217/fon-2022-1196. Epub 2023 Apr 18. Erratum in: Future Oncol. 2024 Jan;20(3):159-161. doi: 10.2217/fon-2022-1196c1. PMID: 37070653.