Meet the Expert: Prof. Rebecca Dent

Triple negative breast cancer (TNBC) remains one of the most challenging breast cancer subtypes to treat, with limited actionable biomarkers and poor durability of response to standard therapies. Most patients with TNBC still receive chemotherapy in the first-line setting, yet only a minority remain fit enough to proceed to subsequent lines of treatment. Patients with programmed death-ligand 1 (PD-L1)–negative disease, those who relapse early after modern neoadjuvant therapy, or those heavily pretreated with anthracyclines, platinums, taxanes, and immunotherapy face particularly stark therapeutic gaps.   



To address some of these unmet needs, the TROPION-Breast02 trial (NCT05374512) introduced an urgently needed alternative to conventional chemotherapy, offering a mechanistically distinct option that may reshape first-line decision-making and help address the substantial unmet need for more durable disease control in this rapidly progressive population [1]. Prof. Rebecca Dent (National Cancer Centre, Singapore) presented data from this trial at ESMO 2025 [2], demonstrating that both the dual primary end points, progression-free survival (PFS) by blinded independent central review (BICR) and overall survival, were met.

Briefly, in TROPION-Breast02, the investigational drug datopotamab deruxtecan (Dato-DXd) met its primary endpoints compared with chemotherapy in patients with locally recurrent inoperable or metastatic TNBC who were not eligible for first-line immunotherapy (n=644).  Notably, this is the first antibody–drug conjugate (ADC) trial in TNBC to demonstrate a significant improvement in both progression-free and overall survival. The median PFS was 10.8 months with Dato-DXd versus 5.6 months with chemotherapy, corresponding to a 43% reduction in the risk of PFS with the ADC (HR 0.57; 95% CI 0.47-0.69; P<0.0001). Overall survival also favoured the experimental arm (median 23.7 vs 18.7 months; HR 0.79; P=0.029). Medicom followed up with an interview with Prof. Dent to gain additional insight.

What unmet need is TROPION-Breast02 trying to address in first-line TNBC?

“Currently, 60–70% of patients in the first-line setting with TNBC are getting chemotherapy.” Yet despite years of research, “we really have only established 2 biomarkers,” PD-L1 and the germline BReast CAncer gene (BRCA) mutation. As a result, “PD-L1–negative TNBC is really an unmet need.” This included “around 20% of patients in TROPION-Breast02 who relapsed early after neoadjuvant therapy. These patients often are excluded from clinical trials and have very limited options.”

How urgent is it to get the first-line treatment decision right for these patients?

“This first-line therapy is actually far more important than in oestrogen receptor (ER)-positive or human epidermal growth factor (HER2)-positive breast cancer, because TNBC behaves more like an acute leukaemia: unless you get control of the disease, patients may not remain fit enough to receive second-line therapy.”

She cited recent US real-world data showing that “well over 1,000 patients out of a 4,000-patient cohort didn’t even receive first-line therapy. And among those treated in the first line, only 50% go on to reach the second line, and only 25% reach the third line.”

Many oncologists still consider post-neoadjuvant relapse as first-line disease. Do you agree?

“People often think of it as first-line therapy, but with modern-day regimens, patients will already have received anthracyclines, alkylating agents, platinums, taxanes, and immune checkpoint inhibition — that’s multiple lines of therapy. You don’t have time to wait, and you need something different from traditional chemotherapy. You need a weapon that is going to be a little bit more clever.”

Where do ADCs such as Dato-DXd fit into this picture?

“Where ADCs are effective, I think, is in their effect on the tumour microenvironment. They don’t just work while patients are on treatment; they change the milieu in which the cancer is functioning.” In TROPION-Breast02, “we see across the subgroups that it didn’t matter whether patients had early or late relapse. You really have to use something fundamentally different.”

What about CNS involvement? You mentioned activity in brain metastases.

She pointed to Rupert Bartsch’s (Medical University of Vienna, Austria) TUXEDO-2 trial (NCT05866432), which “clearly shows response in the brain,” [3] and noted parallels with “the trastuzumab deruxtecan (T-DXd) data, which also demonstrates CNS activity [4]. This compound, Dato-DXd, does seem active in the CNS, which is not the case for all ADCs.”

As for the mechanism, she posed several possibilities: “Is it the linker? Is it this clever molecule? Is it the payload that is different? Or are we simply achieving better systemic disease control and therefore better control of brain metastases? I don’t know.”

What are the next steps for the TROPION-Breast02 clinical programme?

“Whenever something works, we want to move it into earlier lines of therapy.” Early anecdotal reports from colleagues using Dato-DXd in the neoadjuvant setting have been encouraging. “They are seeing really good results, and it is well tolerated.”

“There may still be some work to do in optimising toxicity management, but overall it is quite tolerable. We don’t see the degree of myelosuppression or alopecia we associate with chemotherapy, but we do see mucositis and ocular events, so dose reduction probably helps.”

You highlighted the potential synergy with immunotherapy. Can you explain this further?

“Data from the phase 1b/2 BEGONIA study (NCT03742102) investigated Dato-DXd in combination with durvalumab (an anti-PD-L1 monoclonal antibody) as first-line treatment for unresectable locally advanced or metastatic TNBC” [5]. “The confirmed overall response rate was 79%, the median PFS was 13.8 months, and the duration of response was nearly 16 months.” Notably, “even the PD-L1–negative tumours appeared to benefit, possibly even more so, because you are converting a cold tumour into a hot one.”

She added that “ADCs may promote new antigen presentation and upregulate the stimulator of interferon genes (STING) pathway [6],” challenging the earlier assumption that chemotherapy is purely immunosuppressive. “We now understand that chemotherapy can, through cell death, actually trigger an immune response.”

This opens the door to combining ADCs “with immune checkpoint inhibition, bi-specifics, or anti-vascular endothelial growth factor (VEGF) therapies,” which she believes “is where we are going to see a transformational shift in disease control.”

What stood out most to you about the TROPION-Breast02 results?

“In TNBC, you can often get a response, but it is rarely sustained. I know that it is going to be short-lived. With Dato-DXd, seeing patients come back and still responding is really meaningful — it translates into improved quality of life.” She also highlighted the dosing schedule: “It’s an every 3-week regimen, which is important for patients, because they are not constantly back to the hospital.”

1. Dent RA, et al. Future Oncol. 2023;19(35):2349–2359.
2. Dent R, et al. First-line datopotamab deruxtecan (Data-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) for whom immunotherapy was not an option: primary results from the randomised phase 3 TROPION-Breast02 trial. European Society for Medical Oncology (ESMO) Congress 2025, 17-21 October, Berlin, Germany.
3. Bartsch R, et al. ESMO Open. 2025;10(1):104092.
4. Harbeck N, et al. Nat Med. 2024;30(12):3717–3727.
5. Schmid P, Wysocki PJ, Ma CX, et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase Ib/II study. 379MO, European Society for Medical Oncology (ESMO) Congress Ann Oncol 2023; 34: S337.
6. Vasiyani H, Wadhwa B. Cell Signal. 2025;128:111647.

Medical writing support was provided by Dr Rachel Giles

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Posted on 19 December 20257 January 2026