How doctors personalize treatment across the course of hormone receptor-positive metastatic breast cancer

Hormone receptor-positive/HER2-negative disease accounts for roughly 60%-70% of metastatic breast cancers, so it is the form most women with metastatic disease face. Overall, five-year survival for metastatic breast cancer is only about 32%. About 30% of women diagnosed at an early stage eventually develop metastasis, and 5%-8% present with metastatic disease at diagnosis. More than 200,000 people in the United States are living with it at any time. This narrative review in CA: A Cancer Journal for Clinicians explains how treatment can be personalized across the disease course. A breast cancer researcher and survivor who is also a patient advocate helped shape it.

The authors begin with diagnosis. Staging uses CT, PET and bone scintigraphy, with MRI for suspected central nervous system disease. Biopsy of a suspicious lesion is essential, and a core needle (14-18 gauge) is preferred over fine-needle aspiration because it preserves tissue architecture and yields enough material for sequencing. Receptor status can shift: in pooled data on nearly 10,000 patients, ER, PR and HER2 discordance between primary and metastatic lesions was 20%, 33% and 8%. Comprehensive sequencing is most informative at progression, when ESR1 and other mutations emerge. It is helpful earlier for patients eligible for agents such as inavolisib.

History and biology follow. Beatson's 1896 oophorectomy report led to a series of 99 women, 24 of whom improved. Modern endocrine therapy grew from this work, including tamoxifen, aromatase inhibitors and fulvestrant. Endocrine therapy, usually with a CDK4/6 inhibitor, is the preferred first treatment. Trials show equivalent progression-free survival and better quality of life than chemotherapy, even in visceral crisis. Estrogen receptor signaling works through classical genomic routes (driving CCND1 and BCL2) and nonclassical kinase routes such as PI3K/AKT/MAPK. PIK3CA mutations are typically truncal. PTEN loss and AKT1 E17K also activate this pathway.

Resistance is defined as primary (relapse within 2 years of adjuvant therapy, or progression within 6 months of first-line therapy) or secondary. ESR1 ligand-binding-domain mutations such as Y537S and D538G appear after aromatase inhibitor or fulvestrant exposure and drive ligand-independent activity. These are targeted by elacestrant and imlunestrant. PIK3CA, AKT1 and PTEN alterations are matched to alpelisib, capivasertib or inavolisib with fulvestrant. BRCA1/2 mutations are matched to PARP inhibitors. NF1 loss and TP53 mutation also contribute to resistance or worse prognosis. Epigenetic changes and clonal evolution under treatment pressure remain poorly understood.

Transcriptomics adds prognostic detail. In a pooled MONALEESA analysis of 580 patients on first-line ribociclib plus endocrine therapy, median overall survival by PAM50 subtype was 68 months for luminal A, 59 for luminal B, 40 for HER2-enriched and 19 for basal-like (2.4% of patients). The 18-gene SETER/PR index predicted endocrine sensitivity in 140 patients but only works with wild-type ESR1. RB1 loss predicts CDK4/6 inhibitor failure: median progression-free survival was about 3.7 months with RB1-mutated tumors versus 9-12 months with wild-type tumors. Such patients may benefit sooner from chemotherapy, including antibody-drug conjugates.

The broader message is that sequencing should integrate genomics, tumor biology, side-effect profiles, patient-reported outcomes and preferences. The abstract also covers antibody-drug conjugates, tumor-agnostic therapies, the tumor microenvironment and invasive lobular carcinoma, but the supplied text cuts off before those sections. As a narrative review, it carries no pooled effect estimates, and many cited findings come from retrospective analyses of trial samples.