A breast cancer’s molecular subtype can help guide treatment, but it does not always predict how well a patient will respond. New research suggests that factors beyond tumor genetics, including interactions with surrounding nerves and immune cells, could provide additional clues for personalizing therapy.
In a study published in the Journal of Clinical Investigation, researchers at Fudan University Shanghai Cancer Center combined genomic, transcriptomic, digital pathology, and clinical data from 230 patients with hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer.
The analysis builds on the FASCINATE-N clinical trial, which investigated treatments tailored to four previously identified molecular subtypes. Although subtype-guided therapy improved pathological complete response rates compared with the trial’s chemotherapy control, many patients continued to respond poorly.
To understand these differences, the researchers examined patients with particularly favorable or unfavorable treatment responses, looking for molecular and tissue-level characteristics that conventional subtyping might overlook.
Tumor microenvironment offers new clues to drug resistance
One finding involved tumors belonging to the canonical luminal subtype, which is generally associated with sensitivity to endocrine therapy. Poor responders showed increased activity in nerve-related signaling pathways, particularly those involving gamma-aminobutyric acid (GABA).
The researchers also linked perineural invasion, in which cancer cells grow around nerves, to reduced treatment efficacy. Experiments in mice suggested that targeting nerve-associated signaling alongside endocrine therapy and CDK4/6 inhibition could improve tumor control.
Another finding emerged in tumors characterized by receptor tyrosine kinase signaling. Using spatial transcriptomics and digital pathology, the team found that the positioning of immune cells relative to cancer cells appeared to influence responses to apatinib-based treatment.
Immune cells that penetrated tumor tissue displayed stronger functional activity, whereas those restricted to surrounding stromal regions showed reduced activity.
As the authors wrote, “the spatial architecture of the tumor-stromal-immune interface influenced apatinib efficacy.”
This distinction highlights a potential limitation of conventional molecular profiling: identifying immune cells within a tumor does not necessarily reveal whether those cells can effectively interact with cancer cells.
Toward more refined precision treatment
The study also identified potential response markers in the remaining molecular subtypes.
In highly proliferative tumors, favorable responses to PARP inhibitor-based regimens were associated with deficiencies in DNA repair and increased cell-cycle activity. Meanwhile, in immunogenic tumors, markers of lymphatic vessels correlated with improved responses to immunotherapy.
Together, these findings suggest that treatment selection could benefit from combining molecular classification with additional information about tumor architecture, signaling pathways, and interactions with the surrounding microenvironment.
However, the findings are not yet ready to guide routine clinical decisions. The study was conducted at a single center, and several analyses relied on relatively small groups of exceptional responders. Longer follow-up and independent prospective validation will also be necessary to determine whether the identified biomarkers reliably predict clinical benefit.
It is important to note that pathological complete response does not necessarily translate into improved long-term outcomes for every patient with HR+/HER2− breast cancer.
Rather than replacing existing molecular subtyping, the research points toward a more layered approach to precision oncology, in which genomic characteristics and the broader tumor microenvironment are considered together to better understand treatment response and resistance.
