BC-NED + FGFR1 × 13

The science behind the case

An ultra-rare molecular profile that challenges current clinical guidelines

Molecular profile (TSO500, primary tissue 2024)

Molecular profile: markers, results and clinical notes from TSO500 analysis
Marker	Result	Clinical note
FGFR1	Amplified ×13	Main driver; CDK4/6i resistance, everolimus sensitivity
CCND1	Amplified ×20	11q13 cluster
FGF3/4/19	Amplified ×18	11q13 cluster
NE Diff.	~80% (CgA, SYN)	BC-NED subtype: dominant neuroendocrine biology
Ki67	60%	High proliferative index in breast cancer. In neuroendocrine tumours, Ki67 ≥20% defines aggressiveness grade: 60% places this tumour at grade 3 (NEC) ⁺⁺
TMB / MSI	Low / Low	---
SNVs/INDELs	None pathogenic	No fusions detected
PIK3CA / ESR1	Not detected in tissue	Pending complementary analysis
HER2	Negative (0)	Negative staining
PR	Positive	Under evaluation

⁺ The HER2-ultralow category (membrane staining in <10% of cells) is present in this case according to data from the DIPCAN study / MD Anderson Madrid.

⁺⁺ In neuroendocrine oncology, Ki67 is the primary grading marker: G1 (<3%), G2 (3–20%), G3 (>20%). A Ki67 of 60% corresponds to a high-grade neuroendocrine carcinoma (NEC G3), with a biologically far more aggressive behaviour than conventional luminal breast cancer.

Why doesn't this tumor fit the guidelines?

Formally it is a luminal breast cancer (HR+), but with ~80% neuroendocrine differentiation and an FGFR1 ×13. Guidelines tend to recommend treating it as standard luminal, minimizing the neuroendocrine component. Literature and clinical reasoning suggest this hybrid subtype (BC-NED) has worse prognosis and may require completely different strategies.

The thesis: biology, not the organ of origin, should guide treatment.

Treatment history

Letrozole + Ribociclib + Zoladex (goserelin) + zoledronic acid

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

Fulvestrant + Abemaciclib + Zoladex (goserelin) + zoledronic acid

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

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Bone progression + abemaciclib discontinuation (March 2026)

PET-CT confirms new bone foci in pelvis and right femur. Abemaciclib is discontinued due to bone progression and hepatic toxicity (DILI G2-3). Zoladex and zoledronic acid continue. ECOG 0. No visceral crisis.

Key scientific evidence

Tarantino et al., 2020 — JCO

HER2-low: definition and clinical relevance in breast cancer

Seminal publication that formalised the HER2-low category and established that more than 55% of HER2-negative tumours are HER2-low.

Tarantino et al., 2023 — Ann. Oncol.

ESMO consensus: formal definition of HER2-ultralow (<10%)

International consensus defining HER2-ultralow as membrane staining in >0% to ≤10% of tumour cells.

Bardia et al., 2024 — NEJM

T-DXd in HER2-ultralow: first clinical evidence of benefit (DESTINY-Breast06)

First study with data in the HER2-ultralow cohort (n=153). Median PFS of 13.2 vs 8.3 months with T-DXd versus chemotherapy.

Ozaki et al., 2022 — Cancers

Neuroendocrine neoplasms of the breast: WHO classification and prognosis

Comprehensive review synthesising the WHO 2019 classification with survival data across the neuroendocrine spectrum of breast cancer.

Formisano et al., 2019 — Nat. Commun.

FGFR1 amplification: central mechanism of resistance to CDK4/6 inhibitors in ER+

Mechanistic study identifying FGFR1 as a resistance driver to ribociclib+fulvestrant in metastatic ER+ tumours.

Mao et al., 2020 — Clin. Cancer Res.

Acquired co-amplification FGF3/4/19 + CCND1 (11q13 cluster) and combined resistance

Using pre/post-resistance analysis in 60 patients, identified FGFR/FGF alterations in 37% of cases following CDK4/6i resistance.

André et al., 2022 — Nature (SAFIR02)

Genomics-guided precision oncology improves survival in metastatic breast cancer

Randomised trial in 1,462 HER2-negative patients. First demonstration that genomics-guided therapy improves progression-free survival in patients with actionable alterations.

Goal: N-of-1 Trial

A trial where Miriam is the sole unit of analysis, with therapeutic decisions guided by her specific molecular profile rather than "generic HR+". The path: re-biopsy with advanced panel → MTB at WIN Consortium international board for a molecularly-directed N-of-1 trial with AI.

WIN Consortium (Worldwide Innovative Network in Oncology) is an international network connecting centres of excellence in precision oncology to design personalised diagnostic and therapeutic strategies.

This would set a precedent: precision oncology adapted to each patient, without bureaucracy around the primary tumor.