Cancers with estrogen receptor (ER) expression of 50% or less, while technically HR+, often behave biologically like basal or triple-negative tumors. These cancers are not primarily endocrine-driven and show a significant benefit from the addition of immune checkpoint inhibitors, challenging traditional subtype classifications.

ctDNA testing (liquid biopsy) is more effective than tissue biopsy for identifying ESR1 mutations. It samples DNA from all metastatic sites, capturing the disease's genetic heterogeneity and reflecting the most active resistance mechanisms, unlike a single-site needle biopsy which can miss them.

There is a growing suspicion that conventional imaging understages many presumed early-stage lobular cancers. Using FES PET-CT upfront could detect small-volume metastatic disease missed by other methods. This would reclassify patients to a metastatic setting, sparing them the morbidity of major local surgeries that would not be curative.

FES PET-CT relies on a tracer binding to estrogen receptors. If a patient is on ER modulators or down-regulators (like tamoxifen or fulvestrant), these drugs will block the tracer, causing a false-negative scan. Clinicians must plan for a washout period of several weeks before imaging, which requires careful treatment coordination.

While powerful, FES PET-CT is a specialized tool with key limitations. It is not effective for evaluating disease in the liver, a common site of breast cancer metastasis. Furthermore, it cannot detect any disease that has become estrogen receptor-negative. Therefore, it must be used as part of a broader imaging program, not as a standalone surveillance tool.

The processing of bone biopsy samples can sometimes result in a false-negative finding for estrogen receptor (ER) status. If clinical suspicion remains high for ER-positive disease, an FES PET-CT can be used as a tiebreaker. A positive FES scan can confirm functional ER presence, overriding the biopsy and drastically altering patient care.

Fibrogen uses its PET imaging agent in Phase 2 not to pre-select patients, but to correlate target expression with treatment response. This data will allow them to enrich their Phase 3 trial with patients most likely to respond, significantly increasing the probability of success.

The Phase 3 Ladera study found gerodestrin not only reduced the risk of recurrence by 30% over standard endocrine therapy but also caused fewer treatment discontinuations due to side effects. This dual benefit of superior efficacy and improved tolerability represents a significant potential advancement for patients with ER-positive early breast cancer.

The introduction of highly sensitive PSMA PET scans means established endpoints like Metastasis-Free Survival (MFS) may no longer be valid. A metastasis detected by PET likely has a different, better prognosis than one found with older imaging, requiring new validation for this key endpoint.