After a triple-negative breast cancer patient progresses on a first-line TROP2 antibody-drug conjugate (ADC), experts advise against immediately sequencing another ADC. Due to suspected cross-resistance, the recommended strategy is to return to traditional chemotherapy agents like taxanes or carboplatin, which remain effective options, before considering another ADC in later lines.

Advances like immunotherapy and Antibody-Drug Conjugates (ADCs) in early-stage Triple-Negative Breast Cancer (TNBC) are so effective that fewer patients are relapsing. This success paradoxically makes it harder to enroll patients in trials for metastatic disease, shifting the trial population toward those with de novo metastatic cancer.

Clinicians lack evidence to guide treatment for triple-negative breast cancer that relapses shortly after neoadjuvant chemo-immunotherapy. Pivotal trials for new ADCs like Dato-DXD included very few patients with prior immunotherapy, creating a significant and common evidence gap in clinical practice.

The KEYNOTE-756 and Checkmate 7FL trials found high pathological complete response (pCR) rates with neoadjuvant immunotherapy in ER-low (1-10%) breast cancers. This suggests this unique subgroup, often excluded from triple-negative trials but behaving similarly, may benefit significantly from immunotherapy, though it is not yet standard of care.

The Begonia trial showed an ~80% response rate by combining an ADC (Dato-DXD) with immunotherapy (Durvalumab) in first-line metastatic TNBC patients, 87% of whom were PD-L1 negative. This suggests ADCs, through immunogenic cell death, may create an immune-responsive environment, expanding IO benefit beyond the traditional biomarker.

This new combination therapy for triple-negative breast cancer showed no increased toxicity compared to its individual components. Surprisingly, immune-related side effects were numerically lower than in the standard chemotherapy-immunotherapy arm, highlighting a favorable safety profile that is crucial for patient management.

For frail, elderly, or low-tumor-burden patients with early-stage TNBC, single-agent ADCs in the neoadjuvant setting are being explored to de-escalate treatment, potentially sparing them the harsh toxicities of standard multi-agent chemotherapy regimens like KEYNOTE-522.

Antibody-drug conjugates can disrupt the tumor microenvironment, leading to an influx of immune cells. This may turn an immunologically "cold" tumor "hot," creating a rationale for re-challenging with an immune checkpoint inhibitor, even if the patient's tumor previously did not respond to one.

Clinical trial data suggests immunotherapy's timing is crucial in early-stage TNBC. Given with chemotherapy before surgery (neoadjuvant), it improves outcomes. However, when given alone after surgery (adjuvant), the IMPASSION 030 trial showed no benefit and was halted for futility, indicating pre-surgical tumor priming is essential.