Lobular metastatic breast cancer sheds far more circulating tumor cells than ductal

Patients with metastatic breast cancer of lobular histology are dramatically more likely than those with ductal disease to have elevated levels of circulating tumor cells, the rare cancer cells that travel through the bloodstream and can be counted from a simple blood draw. That is the central finding of a new study from researchers at the University of Michigan, published in Breast Cancer Research and Treatment, which examined two independent patient cohorts and found that lobular metastatic tumors shed detectable cells at rates roughly double those seen in ductal tumors. Because elevated circulating tumor cell counts have long been associated with worse prognosis in metastatic breast cancer, the results add a measurable correlate to the increasingly recognized clinical differences between these two histologic subtypes, and they suggest that lobular metastatic disease may be more active in its dissemination behavior than its generally favorable hormone receptor profile would imply.

Infiltrating lobular carcinoma accounts for approximately ten percent of all invasive breast cancers, with ductal histology making up about eighty percent and mixed ductal-lobular tumors roughly five percent. Lobular cancers are almost always estrogen receptor positive and HER2 negative, a profile that has historically been considered favorable. For decades, most studies suggested that estrogen receptor positive lobular and ductal cancers carry the same prognosis, and the two subtypes have essentially been treated identically in the clinic. Recently, however, several studies have indicated that, despite its favorable hormone receptor status, early-stage lobular carcinoma is associated with less favorable long-term outcomes, stage for stage, than ductal carcinoma. Lobular cancer also appears less sensitive to chemotherapy, as reflected by lower pathologic complete response rates following neoadjuvant treatment, and emerging evidence suggests differential sensitivity to specific endocrine agents, with aromatase inhibitors providing greater benefit than tamoxifen in this subtype.

Lobular cancer clearly differs from ductal cancer in its metastatic patterns as well. It tends to spread to unusual locations, such as mesothelial and intra-luminal surfaces, hinting at a unique metastatic biology. Liquid biopsies such as circulating tumor cells overcome the challenges inherent in tissue biopsies for serial monitoring of cancer biomarkers. The CellSearch system, which captures circulating tumor cells using an antibody against EpCAM, a cell adhesion molecule abundant on epithelial cancers, is the most widely used assay to identify, enumerate, and characterize these cells. Circulating tumor cell levels measured with this platform are highly prognostic in metastatic breast cancer and other malignancies. Prior studies had already hinted that patients with lobular compared to ductal metastatic disease have a significantly higher incidence of circulating tumor cells as well as higher total counts, suggesting a more aggressive biology and worse clinical outcome, but the new work set out to establish real-world evidence for this difference.

To build their primary test set, the investigators conducted a retrospective electronic medical record chart review at Michigan Medicine, using the EMERSE search engine to identify patients with metastatic breast cancer who had undergone clinical circulating tumor cell assessment with CellSearch between August 2005 and June 2019. The search flagged 400 patients, of whom 294 met inclusion criteria, and 218 had circulating tumor cell results at what the team defined as informative timepoints: either a baseline draw before starting first-line treatment of metastatic disease, or a draw within a one-week window before or after progression on a later line of metastatic therapy. The one-week window was chosen because previous reports showed no major difference in circulating tumor cell incidence between baseline and 72 hours, but a decrease by day 15 or first follow-up. Tumor histology was determined by pathologic tissue review using standard histopathologic criteria, not molecular features such as E-cadherin loss, and archived tissue was re-reviewed whenever chart abstraction left a case ambiguous.

The clinical cohort ultimately included 38 patients with lobular, 29 with mixed ductal-lobular, and 151 with ductal metastatic breast cancer. As expected, lobular tumors were overwhelmingly hormone receptor positive: 92 percent of patients with informative results had estrogen receptor positive cancers, compared with 79 percent of mixed and 70 percent of ductal cases. Not a single patient with lobular metastatic disease had a HER2 positive tumor, whereas 17 percent of mixed and 19 percent of ductal cases did. Overall, 101 of the 218 patients, or 46 percent, had elevated circulating tumor cells, defined as five or more cells per 7.5 milliliters of whole blood. But the distribution across histologies was striking: 74 percent of lobular patients were elevated, compared with 48 percent of mixed and 39 percent of ductal patients, a difference that reached statistical significance at p equals 0.001.

The magnitude of elevation differed as well. Patients with lobular disease had a median of 24 circulating tumor cells per patient, versus a median of 4 in the mixed group and 2 in the ductal group. One-half of patients with lobular metastatic cancer had 26 or more circulating tumor cells per 7.5 milliliters, compared with 24 percent of mixed and 17 percent of ductal patients, a Pearson chi-square test difference of p less than 0.001. Among patients whose counts were elevated above the threshold, the median was 32 cells per patient in the lobular group, compared with 25 and 24 cells per patient in the mixed and ductal groups, respectively. In multivariate logistic regression adjusting for the number of disease sites, the presence of bone versus visceral metastases, and prior lines of therapy, patients with lobular histology had odds of elevated circulating tumor cells more than seven times larger than those with ductal disease. Sites of disease were also statistically associated with elevation, but not to the same degree as histologic subtype.

To verify these findings, the team analyzed a second, separate group of 146 patients with metastatic breast cancer enrolled in the MI-CTC-ONCOSEQ research protocol, a companion study to the MI-ONCOSEQ comprehensive sequencing program at the UM Rogel Cancer Center. In this cohort, blood was collected into three CellSave tubes, pooled, re-aliquoted to 7.5 milliliters, and processed in an investigational laboratory using the CellSearch enrichment system with the CXC Kit. The results closely mirrored the clinical cohort: 79 percent of the 14 patients with lobular histology had five or more circulating tumor cells per 7.5 milliliters at their baseline draw, compared with 31 percent of 13 patients with mixed disease and 36 percent of 119 patients with ductal disease, differences that were statistically significant. The 35 to 40 percent elevation rate in ductal patients is consistent with many prior circulating tumor cell studies in breast cancer, most of which were dominated by ductal histology, lending further confidence to the representativeness of the findings.

The study also examined survival. With a median follow-up of 136 months, patients with estrogen receptor positive lobular metastatic disease had a median overall survival from the time of first metastasis of 36.9 months, numerically shorter than the 43.3 months observed among ductal patients, a nearly statistically significant difference with a hazard ratio of 1.52 and p equal to 0.054. This result is consistent with prior reports suggesting that lobular carcinoma carries a slightly worse prognosis when compared with equivalent cohorts of ductal cancer matched by stage and hormone receptor status. The authors speculate that this worse overall survival may be a biological function of higher rates of circulating tumor cells and therefore of tumor dissemination, an interpretation that remains to be tested, although elevated counts have consistently been associated with worse prognosis in both early and advanced breast cancer and other solid malignancies.

Circulating tumor cells are not the only liquid biopsy relevant here. Circulating cell free tumor DNA, the fragments of tumor genetic material that float in plasma, appears to be more commonly detected than circulating tumor cells in metastatic breast cancer, and elevated levels are likewise associated with worse prognosis. Genetic analyses of cell free tumor DNA have demonstrated similarity between lobular and ductal cancers, except for abnormalities in CDH1, the gene encoding E-cadherin, which is a hallmark of lobular cancer. Mutations in ESR1, the gene encoding the estrogen receptor, are related to resistance to estrogen depletion strategies such as aromatase inhibitors, and their emergence in cell free tumor DNA has been used to guide therapy. However, one research group reported that tissue ESR1 mutation frequency is approximately nine percent, with no differences in prevalence or distribution between lobular and ductal disease, and detected ESR1 mutations in cell free tumor DNA in 26.3 percent of estrogen receptor positive lobular versus 29.6 percent of ductal patients. By contrast, another group reported that single nucleotide variations were higher in lobular than ductal disease, as were mutations in ERBB2 and PTEN.

Although cell free tumor DNA may be elevated more frequently than circulating tumor cells, the cells offer the advantage of phenotypic analyses, allowing baseline and serial measurement of relevant tumor biomarkers including the estrogen receptor, HER2, Bcl2, Ki67, M30 as a marker of apoptosis, and PD-L1. Cell genomics may also complement cell free tumor DNA analyses. The authors caution that both cohorts suffer from patient selection: in the clinical cohort, the decisions of when and from whom circulating tumor cells were drawn were at clinicians’ discretion, and research cohort enrollment depended on clinical circumstances and physicians’ decisions. The team did not analyze progression-free or overall survival according to circulating tumor cell levels because of the confounding variability of draw timing, the heterogeneity of intrinsic subtypes, and the lack of prospective standardized follow-up. The retrospective design also prevented accurate determination of specific metastatic sites beyond bone and liver, so the widely recognized unusual metastatic pattern of lobular cancer could not be interrogated, nor could suggestions that estrogen receptor positive lobular disease may be less sensitive to endocrine therapy. The authors conclude that future studies should extend beyond enumeration toward comprehensive molecular characterization, including phenotypic biomarker assessment and genotyping for cancer-related abnormalities, to determine the clinical significance of distinct, therapeutically targetable clones that emerge during treatment.

Subject of Research: Circulating tumor cell levels in metastatic lobular versus ductal breast cancer

Article Title: Circulating tumor cells in lobular versus ductal metastatic breast cancer

Article References: Dolce, E. M., Darga, E. P., Henderson, N. C., Thomas, D. G., Hanauer, D. A., Chinnaiyan, A. M., Cobain, E. F., Henry, N. L., Paoletti, C., Cani, A. K., & Hayes, D. F. (2026). Circulating tumor cells in lobular versus ductal metastatic breast cancer. Breast Cancer Research and Treatment, 220(1), Article 15. https://doi.org/10.1007/s10549-026-08111-3

Image Credits: AI Generated

DOI: 10.1007/s10549-026-08111-3

Keywords: circulating tumor cells, metastatic breast cancer, invasive lobular carcinoma, invasive ductal carcinoma, CellSearch, liquid biopsy, breast cancer prognosis, tumor dissemination, cell-free tumor DNA, histologic subtype, EMERSE, MI-ONCOSEQ