The science behind the case

An uncommon breast cancer that behaves like two diseases at once. Here, explained without jargon.

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Simple summary

The case, in plain language

No jargon: what's happening to Miriam, why her case is different, and what's needed now.

What exactly does she have?

A breast cancer that has spread to the bones. What's uncommon is that it behaves like two diseases at once: partly like a hormone-driven breast cancer, and largely like a different type (neuroendocrine). They're like two sides of the same tumor.

Why isn't standard treatment enough?

Protocols treat it as an ordinary breast cancer and target only one of its two sides. The other is left untreated, and the tumor finds a way to keep advancing.

Is there a way to target it?

Yes. Analysis of the tumor has found specific "weak points" that could be treated with targeted therapies. These are promising hypotheses, not a guaranteed cure: that's why they must be confirmed before acting.

What's needed now?

A new biopsy with an advanced molecular analysis to confirm those weak points and design a treatment tailored to her. That's what the campaign funds.

A medical or science professional and want the detail, with biomarkers and tables? Switch to "For professionals" above.

The anomaly

Why doesn't this tumor fit the protocols?

On paper this is a breast cancer (HR+/HER2−). Under the microscope, ~80% of the tumor shows neuroendocrine differentiation, with and amplification. Spanish protocols recommend treating it as standard luminal and ignoring the component; yet the WHO has recognized breast neuroendocrine neoplasms as a distinct entity since its 2019 classification, and clinical literature shows this hybrid subtype () has worse prognosis and usually needs different strategies.

Tap or hover the highlighted words and markers to see what they mean.

Goal: an N-of-1 trial that sets a precedent for precision oncology in ultra-rare subtypes.

The tumor, in schematic form

One tumor, two faces

It is not one tumor: it is two biologies in the same body, and both must be treated at once.

HR+hormone receptorsHER2−FGFR1CCND1ESR1BREAST · luminalwe know it80%Cg · Synneuroendocrinedifferentiationthe one we need to knowRB1 · the brakebeing lostSSTR2receptors → PRRT
Receptors: targets to attack (HR and SSTR2). HER2: a receptor she does not have (no target). Amplifications: extra copies that push the tumor. Mutations: resistances the tumor builds to keep growing. RB1: a brake that is being lost. Cg · Syn: neuroendocrine granules (80% of the tumor).

Tumor schematic. Luminal breast, the known part: HR+ receptors, HER2 negative, an 11q13 amplicon (FGFR1 ×13, CCND1 ×20, FGF3/4/19 ×18) and an ESR1 mutation in ctDNA. Neuroendocrine differentiation (Cg/Syn in ~80% of cells), barely known: loss of RB1 (a brake that is being lost) and SSTR2 receptors, the PRRT target. Block one side and it escapes through the other; it must be treated as a whole.

Molecular profile

The tumor’s genomic map

The profile combines primary tissue (NGS, 2024) with plasma ctDNA liquid biopsy (2026). Against a luminal HR+/HER2− background, the standouts are focal amplification of FGFR1 at 11q13, CCND1 and the FGF3/FGF4/FGF19 cluster; each row notes how it was measured.

Detailed molecular profile

TSO500 2024 + IHC + 2026 ctDNA + Ga-68 PET

Alterations, methods and clinical implication

Cross of every available molecular source, with no added interpretation. Each row shows the method by which the result was obtained.

Detailed molecular profile: alteration, result, method/source, category and clinical implication.
AlterationResultMethod / SourceCategoryClinical implication
FGFR1Amplified ×13TSO500 tissueLuminal driverCDK4/6i resistance; potential sensitivity to everolimus and to FGFR inhibitors (erdafitinib, futibatinib, ponatinib).
CCND1Amplified ×20TSO500 tissue + ctDNA11q13 clusterCo-amplified with FGFR1; reinforces CDK4/6i resistance.
FGF3 / FGF4 / FGF19Amplified ×18TSO500 tissue11q13 clusterCharacteristic 11q13 co-amplification; no direct target, marker of aggressive biology.
NE differentiation~80% (CgA, SYN)IHC primary tissueBC-NED subtypeDominant neuroendocrine behaviour. Justifies exploring NE-tumour therapies (PRRT, platinum regimens).
SSTR2 (somatostatin)PositiveGa-68 DOTATOC PETRadioligand targetOverexpression in bone metastases and focal uptake in the breast. Opens the door to PRRT (radioligand therapy).
Ki6760%IHC primary tissue (2024) · VHIO 2026: 40%GradeHigh proliferative index. Ki67 ≥20% would be compatible with high NE grade: a hypothesis, not the assigned grade (confirmed: Nottingham Grade II) ⁺⁺.
ESR1 p.D538GDetectedctDNA (Guardant360 + VHIO360, 2026)Endocrine resistanceAcquired resistance to aromatase inhibitors; entry criterion for the elacestrant trial (ADELA).
RB13 variantsctDNA Guardant360 (Apr 2026)Resistance / progressionp.V622Yfs*33 (1.58%), p.R661W (1.48%) and p.F226* (subclonal); absent in the primary tumour (TSO500, 2024). RB1 loss associated with CDK4/6i resistance and transformation to more aggressive / neuroendocrine phenotypes.
SMO p.V319DDetected (VUS)ctDNA (Guardant360 CDx, May 26, 2026)Uncertain significanceVariant of uncertain clinical significance, under watch.
TMB / MSILow / LowTSO500 tissueImmunotherapyNo profile for checkpoint inhibitors.
SNVs / INDELs / fusionsNone pathogenicTSO500 tissueRest of the panelNo other actionable targets in the original panel.
PIK3CANot detectedTSO500 tissuePI3K targetPending re-analysis on updated tissue.
HER2Negative (0)IHC primary tissueReceptorNegative staining.
ER / PRER 95% / PR 5%IHC primary tissueHormone receptorLuminal component of the tumour — basis of the current endocrine line.
Sources and methodological notes

The bone-lesion biopsy (right iliac, April 2026) contained no evaluable tumour —only mineralised bone trabeculae and muscle tissue—, so the molecular profile is read from ctDNA. It is also why the advanced rebiopsy targets the soft-tissue component, where NGS performs far better than in pure bone.

Sources: TSO500 on primary FFPE tissue (DIPCAN, MD Anderson Madrid, 2024) · IHC on primary tissue · Guardant360 / VHIO360 ctDNA (April–May 2026) · Ga-68 DOTATOC PET-CT (hospital centre, May 2026).

⁺⁺ In neuroendocrine oncology, Ki67 is the primary grading marker: G1 (<3%), G2 (3–20%), G3 (>20%). By that logic, a high Ki67 would be compatible with a high-grade neuroendocrine component (NEC G3): a hypothesis, not the assigned grade. The confirmed histological grade is Nottingham Grade II; reconciling it is pending tumour-board review.

Functional imaging

What the Gallium-68 PET shows

The tracer reveals an actionable target visible in vivo: the tumor expresses , the target of . Standard breast-cancer protocols do not consider this route.

Functional imaging — Gallium-68 PET

Gallium-68 DOTATOC PET-CT

Date:
May 26, 2026

PET with the 68Ga-DOTATOC radiotracer, which binds mainly the somatostatin receptor subtype 2 (SSTR2). Visualizes in vivo which lesions express SSTR2 and could therefore respond to radioligand therapy (PRRT).

«Study showing multiple blastic bone metastases with somatostatin receptor overexpression. Focal uptake in the right breast tail to be evaluated in a dedicated study.»

Clinical meaning: The tumor expresses somatostatin receptors — the target of radioligand therapy (PRRT). It confirms on imaging both tumor drivers (luminal FGFR1/CCND1 + neuroendocrine RB1 + SSTR) and opens a route that breast-cancer protocols do not contemplate as standard.

For your medical team

Interactive bone-metastasis map with dual tracers (Gallium-68 and FDG): every lesion, one by one, with its 3D location, SUVs and the spine-MRI reading.

Open the metastasis map

Share it with your doctor or tumor board: helpmiriam.com/caso · decision support, not medical advice.

Therapeutic axes

Where to aim

Several candidate targets follow from all of the above. These are the therapeutic axes the molecular profile points to, each with its own treatment rationale.

How to read these axes

Hypotheses derived from the molecular profile, not a prescribed treatment. The advanced rebiopsy will confirm or rule them out before defining the N-of-1 strategy.

The next step

Bone rebiopsy protocol

A single biopsy from which to obtain the most complete tumour characterisation that science currently allows —genomic, immunogenomic and epigenetic—, so it doesn’t have to be repeated. This is what the campaign funds.

Next step (June 2026): an extended, PET-guided bone rebiopsy. The first one (April 2026) did not yield viable tumour; this one aims to secure it, to complete the molecular profile and track how it evolves.

Proposed bone rebiopsy protocol: component, method and core/format, targets and clinical implication
ComponentMethodTargetsImplication
Germline reference (tumour-normal)One tube of blood or saliva · any day, spends no corePaired germline to separate inherited from tumour variantsThe highest-impact, near-zero-cost change: makes the WES/WGS somatic calls reliable
WES + WGS (genomics)≥500-gene panel from the FFPE block (Core 1) + quality WES/WGS from snap-frozen (Core 2), with paired germlineFGFR1-4, CCND1, CDK4, FGF3/4/19, ESR1, PIK3CA, PTEN, RB1, TP53, MET; CNV, SV, fusionsDominant drivers and co-alterations. PTEN and CDK4 reliable only in tissue; CDK4 co-amplified at 11q13 implies CDK4/6i resistance
Deep RNA-seq (expression + antigens)Snap-frozen (Core 2) · prioritise RNA qualityFGFR1/FGF3-4-19/MYC expression, NE signature, PAM50; non-SNV antigens (fusions, splicing) and cancer-testisWith low TMB, the main antigen source; better predictor of FGFRi response than amplification alone
Extended IHC + HLA typingIHC + RNAscope from the FFPE block (Core 1); HLA derived from sequencingER, PR, HER2, FGFR1, SSTR2, TROP-2, B7-H3, DLL3, CgA, SYN, INSM1, Rb, Cyclin E1; HLA I/IITROP-2→sacituzumab/Dato-DXd · SSTR2→PRRT · DLL3→anti-DLL3 · Cyclin E1 / Rb loss→CDK4/6i resistance
Immunopeptidomics (HLA peptidome)FRESH core to the lab as soon as possible, ischaemia ≤30 min (Core 3)Peptides actually presented on HLA (from ~15 mg → thousands of peptides)Confirms which antigens really reach the cell surface; basis for an N-of-1 strategy
Phosphoproteomics (RPPA / MS)Ultra-fast snap-freeze — the phosphoproteome changes in minutes (Core 4)p-FRS2α, p-AKT, p-ERK, p-Rb, p-S6, Cyclin E1, p-ERREAL pathway activation (FGFR, PI3K, MAPK, cell cycle); guides combinations
Epigenetics (methylation)EPIC + EM-seq from leftover DNA or the FFPE block · no extra coreMethylome and methylation classifier; NE vs luminalModulates antigen expression and immune evasion; helps classify the tumour
Single-cell + spatial transcriptomicsViable or snap-frozen tissue (Core 5); spatial from FFPE (Visium) or dedicated OCT (Xenium)NE vs luminal states, resistant clones, immune microenvironment; tumour–stroma–bone architectureDetermines whether to target only the NE phenotype or also the residual luminal component (cold vs hot tumour)
Organoids + drug screeningFresh or live-cryopreserved tissue (DMSO) to grow them later (Core 5)Ex vivo sensitivity: FGFRi, CDK4/6i, T-DXd, capivasertib, everolimus and combinationsPDOs predict response and improve PFS when guiding treatment
Serial liquid biopsy (ctDNA)Plasma (Guardant, HOPE/SOLTI) every 6–8 weeks · complement, no coreFGFR1 amp, ESR1 (Y537S/D538G), PIK3CA, FGFR kinase mutationsCloses the loop: detects resistance before imaging, without re-biopsying
Biopsy technical specifications

14G coaxial needle into peri-lesional soft tissue, without decalcification (acid degrades DNA ~10×; if bone must be decalcified, EDTA only, never acid). Touch-prep/ROSE to confirm ≥30% tumour cellularity before allocating anything. The germline reference (blood/saliva) goes separately, any day. WES+WGS+RNA-seq are not committed to a single core: 1–2 frozen cores are reserved for genomics and transcriptomics. Serial liquid biopsies close the loop with real-time decisions.

Consultation support material: it describes what a single biopsy could extract; it is not a treatment indication. The decisions —where to sample, how many cores are safe, which assays are feasible— are made by the treating medical team.

Clinical history

Treatment history

Each treatment line has held the disease for a while before the tumour escapes again: the pattern to expect when only the hormonal axis is targeted and the neuroendocrine component is left out.

  • dx

    Diagnosis and palliative radiotherapy (January–February 2024)

    Completed

    Diagnosed in January 2024 after presenting to the ER with low-back pain: vertebral metastases were found. Premenopausal. Palliative systemic treatment started in February 2024 with the goal of prolonging survival. Received radiotherapy to the spine with a good response: progressive improvement, spinal stability and no fractures.

  • 1L

    Letrozole + Ribociclib + Zoladex (goserelin) + zoledronic acid

    Completed

    Ribociclib discontinued after the 1st cycle due to toxicity. Zoladex continued.

  • 2L

    Fulvestrant + Abemaciclib + Zoladex (goserelin) + zoledronic acid

    Completed

    On confirmed progression, letrozole is replaced by fulvestrant and ribociclib by abemaciclib. Zoladex and zoledronic acid are maintained.

  • Bone progression (March 2026)

    Completed

    The PET-CT (24 Mar 2026) confirms bone progression (increased uptake in pelvis and right femur; new foci in D1 and left iliac). Abemaciclib (always at 100 mg) is stopped on 30 Mar 2026 due to progression and mild hepatotoxicity that normalized once it was withdrawn. Zoladex and zoledronic acid continue. No visceral crisis.

  • Current status (2026)

    Active

    As a standard 3rd line, elacestrant has been offered (ESR1 route, with public funding approved), pending start. In parallel, she is in screening for two phase 3 trials in HR+/HER2− breast cancer after CDK4/6i: ADELA (elacestrant + everolimus, for her ESR1 mutation) and KATSIS-1 (KAT6 inhibitor + fulvestrant). The first bone rebiopsy (April 2026) did not yield viable tumor, so an extended PET-guided bone rebiopsy is planned — the central test the campaign funds. Functional status: ECOG 1.

Goal

Goal: N-of-1 Trial

A clinical trial with one patient. Therapeutic decisions are designed on the tumor's actual molecular profile, not on a generic HR+ average. The path: rebiopsy with advanced panel → review at WIN Consortium international MTB → molecularly-directed N-of-1 treatment.

WIN Consortium (Worldwide Innovative Network in Oncology) connects precision-oncology centers of excellence to design individualized diagnostic and therapeutic strategies.

A precedent: precision oncology decided on the patient's molecular data, not on the tumor's label.

How to help

Every analysis depends on funding

You've just seen why this case is different. Every contribution funds the next analysis: the one that unlocks the next decision —rebiopsy, sequencing, international second opinions.

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Last updated: 14 June 2026