Hormone Receptor Levels Predict Who Benefits Most from Standard Advanced Breast Cancer Therapy

One of the most common forms of advanced breast cancer may finally have a way to sort its patients into very different futures, according to a sweeping real-world study from Italy. Researchers analysing more than 4,100 people with hormone receptor-positive, HER2-negative advanced breast cancer found that the precise percentage of tumour cells staining for the oestrogen receptor alpha and the progesterone receptor powerfully predicts how long patients remain progression-free on the modern standard of care: endocrine therapy combined with a cyclin-dependent kinase 4/6 inhibitor. The findings, published in eClinicalMedicine, come from PALMARES-2, a multicentre observational study spanning 26 Italian institutions and represent the largest real-world dataset yet assembled to answer a question that pivotal randomised trials never addressed.

The clinical backdrop is a striking gap in evidence. Drugs such as palbociclib, ribociclib and abemaciclib, when paired with endocrine therapy, have become the near-universal first-line treatment for this disease, regardless of how strongly a tumour expresses its hormone receptors. Current ASCO and College of American Pathologists guidelines classify a breast cancer as hormone receptor-positive if as little as 1 percent of tumour nuclei stain positive, creating a category so broad it spans tumours that behave like triple-negative disease and tumours that are exquisitely hormone-dependent. Yet the registration trials that established CDK4/6 inhibitors as standard therapy did not stratify their outcomes by oestrogen receptor or progesterone receptor expression levels, leaving clinicians with little guidance on whether a tumour with 5 percent receptor staining responds like one with 95 percent.

PALMARES-2 enrolled consecutive patients with unresectable locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer who began first-line endocrine therapy plus a CDK4/6 inhibitor after January 2016. At the second data cut-off in January 2025, the study had captured 4,187 patients, of whom 4,115 had quantitative oestrogen receptor data available from pathology reports. The median age was 62 years, most patients had good performance status, and roughly two-thirds had endocrine-sensitive disease. Ribociclib and palbociclib were each used in about 39 percent of patients, with abemaciclib in 22 percent. At a median follow-up of just over 40 months, median real-world progression-free survival for the whole cohort was 25.6 months, and median time to first chemotherapy was 37 months.

The researchers grouped patients by oestrogen receptor expression measured in the most recently available tumour specimen: very high at 90 percent or above, high at 50 to 89 percent, and low-to-intermediate at 1 to 49 percent. The differences in outcome were dramatic. Patients with very high receptor expression enjoyed a median progression-free survival of 28.5 months, those with high expression 20.5 months, and those with low-to-intermediate expression only 10.6 months. After adjusting for age, performance status, histology, progesterone receptor status, HER2 and Ki67 expression, endocrine sensitivity, and sites of metastasis, the hazard ratios confirmed a strong, graded relationship: compared with the low-to-intermediate group, high expression carried a 27 percent lower risk of progression, and very high expression a 46 percent lower risk. A trend test across the ordered categories was highly significant, and the association held in both endocrine-sensitive and endocrine-resistant subgroups.

Progesterone receptor expression added independent prognostic power. Using the well-established 20 percent cut-off that pathologists employ to separate luminal A-like from luminal B-like biology, patients with high progesterone receptor expression had a median progression-free survival of 30.7 months versus 19.2 months for those with low expression, a benefit that persisted in multivariable analysis. Statistically, adding progesterone receptor to models already containing oestrogen receptor significantly improved model fit and discrimination, with Harrell’s C-index rising and formal reclassification metrics confirming the gain. When the two markers were combined, the extremes separated sharply: patients with very high oestrogen receptor and high progesterone receptor tumours achieved a median progression-free survival of 32.4 months and a median time to chemotherapy of 46.4 months, while the 113 patients whose tumours expressed low-to-intermediate oestrogen receptor and low progesterone receptor fared dismally, with a median progression-free survival of just 8.3 months and a median time to chemotherapy of 13.1 months.

Perhaps the most biologically revealing finding concerned the timing of the biopsy. Among 1,408 patients with matched primary and metastatic tumour samples, nearly half — 49.8 percent — changed oestrogen receptor expression category between their original surgery and the diagnosis of advanced disease, reflecting the evolutionary pressure that years of endocrine therapy exert on tumour cells. When the researchers tested whether receptor levels measured in archival primary tumours predicted outcomes on first-line CDK4/6 inhibitor therapy, they found no association. Only receptor levels assessed in fresh biopsies taken at the time of advanced disease diagnosis carried prognostic weight, and a formal statistical interaction between biopsy timing and prognostic value was highly significant. The message is unambiguous: the hormone receptor status that matters is the one the tumour carries today, not the one it carried years ago.

The study also revisited a contentious question in routine oncology: whether the three approved CDK4/6 inhibitors perform equally. After extensive multivariable adjustment and inverse probability of treatment weighting, both ribociclib and abemaciclib outperformed palbociclib on progression-free survival and time to chemotherapy in the overall cohort, confirming and strengthening earlier results from a smaller PALMARES-2 dataset. In the very-high oestrogen receptor subgroup, both ribociclib and abemaciclib beat palbociclib, while in the high-expression subgroup only abemaciclib showed an advantage. In the small low-to-intermediate subgroup, no significant differences emerged, though the authors caution that covariate balance could not be adequately achieved there. These non-randomised comparisons carry residual confounding risks, and they contrast with the recently published P-VERIFY study, which found no differences among the three drugs; the Italian investigators attribute that discrepancy to P-VERIFY’s shorter follow-up and more limited covariate data.

The clinical implications are potentially practice-changing. For patients with strongly hormone-dependent tumours, the excellent outcomes support endocrine therapy plus a CDK4/6 inhibitor as the preferred first-line choice regardless of metastatic site or disease burden, and may even justify less intensive clinical and radiological monitoring. Patients with discordant receptor profiles — very high oestrogen receptor with low progesterone receptor, or low-to-intermediate oestrogen receptor with high progesterone receptor — still benefit but may warrant closer surveillance, particularly when other adverse features are present. For the small group with low-to-intermediate oestrogen receptor and low progesterone receptor tumours, the authors argue that alternative strategies deserve priority, including chemotherapy, antibody-drug conjugates such as trastuzumab deruxtecan, triple combinations adding the PI3K inhibitor inavolisib for PIK3CA-mutated tumours, or enrolment in clinical trials of novel approaches.

The study has limitations that temper, but do not erase, its conclusions. It is retrospective in design, the expression thresholds were chosen partly for convenience, pathology review was not centralised, and genomic data such as ESR1 or PIK3CA mutation status were unavailable. Overall survival analyses remain immature, particularly in the smaller subgroups, and race and ethnicity data were not systematically collected. Even so, the sheer scale of the cohort, the depth of clinical annotation, and the consistency of the signal across sensitivity analyses make a compelling case that quantitative hormone receptor expression — measured in a recent biopsy and read jointly — is one of the most actionable prognostic tools available for this population. If prospective studies confirm the results, routine re-biopsy at metastatic diagnosis and biomarker-guided tailoring of both treatment intensity and monitoring frequency could become standard practice, ending the era in which tumours differing by nearly a hundredfold in receptor expression were treated as a single, undifferentiated category.

Subject of Research: Prognostic value of quantitative oestrogen and progesterone receptor expression in hormone receptor-positive, HER2-negative advanced breast cancer treated with first-line endocrine therapy plus CDK4/6 inhibitors

Article Title: Prognostic value of hormone receptor expression in patients with HR+/HER2− advanced BC treated with first-line ET+CDK4/6i: results from the multicentre observational, real-world PALMARES-2 study

Article References: Ligorio, F., Provenzano, L., Caputo, R., Vigneri, P., Giuliano, M., Curigliano, G., Toss, A., Botticelli, A., Pedersini, R., Cinieri, S., Lambertini, M., Rizzo, G., Tagliaferri, B., Sirico, M., Giordano, M., Gerratana, L., Meattini, I., Piras, M., Fabi, A., … De Santis, C. (2026). Prognostic value of hormone receptor expression in patients with HR+/HER2− advanced BC treated with first-line ET+CDK4/6i: results from the multicentre observational, real-world PALMARES-2 study. eClinicalMedicine, 100, Article 104242. https://doi.org/10.1016/j.eclinm.2026.104242

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104242

Keywords: breast cancer, oestrogen receptor, progesterone receptor, CDK4/6 inhibitors, endocrine therapy, PALMARES-2, biomarkers, progression-free survival, real-world evidence, tumour re-biopsy, precision oncology, advanced breast cancer