The shift toward human‑centred in‑vitro models is accelerating. A 2014–2019 review logged 935 advanced breast‑cancer test systems (including three‑dimensional cultures, microfluidic chips and other non‑animal methodologies) revealing rapid adoption across laboratories worldwide(9). In parallel, the FDA, EMA and other agencies now champion “new‑approach methodologies” (NAMs) to spare animals and generate data that mirror patient biology, thereby improving late‑stage trial success. Technically, these tools offer clear advantages: patient‑derived organoids (PDOs) can be grown in days to weeks, whereas patient‑derived xenografts (PDXs) need three to six months, delaying bedside feedback. The quick turnaround, lower cost and genomic fidelity of PDOs make them ideal for precision‑oncology workflows in which treatment decisions cannot wait(4).

To appreciate why regulators value these systems, it is worth defining them. Organoids are self‑organising, three‑dimensional micro‑tissues created from stem or tumour cells embedded in an extracellular‑matrix hydrogel and nurtured with lineage‑specific factors. A tiny biopsy or surgical fragment is minced or enzymatically dispersed; the cells then rebuild epithelium‑like spheres within 3–10 days in vitro. “Breast‑cancer organoid” media supplemented with EGF, Wnt agonists and R‑spondin preserves luminal, basal, HER2 and triple‑negative phenotypes for repeated passage or cryobanking(10).

Building on these biological foundations, PDOs now serve the entire oncology pipeline. High‑throughput drug panels rapidly flag subtype‑specific sensitivities and, in compassionate‑use settings, have already redirected adjuvant therapy while the patient is still in clinic(11). Beyond screening, genome editing or barcoding enables mechanistic studies of resistance, whereas co‑culture with autologous immune or stromal cells dissects micro‑environmental interactions(12). Recognising such breadth, regulators increasingly cite organoids as NAMs for pre‑clinical safety testing and have begun integrating them into guidance aimed at reducing animal use.

Across oncology, patient-derived organoids (PDOs) are proving their worth as functional read-outs for precision medicine. Brain-tumour PDOs from Peng et al. preserved native immune and stromal ecosystems and predicted individual treatment responses with high accuracy(13), while rectal-cancer PDO chemosensitivity profiles in Ye Yao et al. forecasted chemoradiation outcomes in > 80 % of patients, demonstrating the platform’s predictive power well before radiographic confirmation(14). Breast-cancer data now echo these successes. Mazzucchelli et al. generated matched pre- and post-neoadjuvant PDOs, revealing chemotherapy-driven clonal shifts toward Ki-67-high, stem-like sub-clones and offering a dynamic window on tumour evolution(15). Meanwhile, a living biobank of more than 100 breast-cancer lines compiled by Sachs et al. captured the full spectrum of receptor status, histology and driver mutations; drug screens in this collection paralleled patient responses, underscoring PDOs’ ability to reflect disease heterogeneity and guide precision therapy(16). Collectively, PDOs are high‑fidelity avatars that have the potential to capture evolution, anticipate treatment efficacy and encompass molecular diversity: an advantage PDX models hardly match due to long-term culture. Yet, while they may suffice for some applications, even these miniature tumours lack vascular‑like perfusion and dynamic gradients found in vivo.

Organ‑on‑chip (OoC), and Micro-Physiological System (MPS) technology closes that gap. By marrying microfluidics with 3D culture, OoCs supply continuous nutrients, shear forces and oxygen gradients while permitting real‑time imaging and automated analytics. Specifically breast cancer organoids as an alternative to animal models offer promising outcomes.  They therefore deliver animal‑free test beds that more faithfully reproduce tumour micro‑environments and metastatic processes(17,18).

Breast‑specific examples underline the promise. Yang et al’s system perfuses Matrigel domes so that breast‑cancer organoids reach diagnostic size in < 15 days, retain parental histology and generate therapy‑response curves weeks faster than static cultures(19). Complementing this, Testa et al. built a laser‑patterned tumour‑on‑chip whose electrospun scaffold houses cancer and stromal cells in communicating chambers; perfused chemotherapeutics reproduced in‑vivo responses while remaining inexpensive and scalable(20).

Together, these advances show how OoC platforms extend PDO realism with vascular‑like flow and compartmentalised co‑cultures, capturing invasion, immune interplay and therapy response in ways neither static organoids nor animal models can achieve.