[{"data":1,"prerenderedAt":243},["ShallowReactive",2],{"science-evidence-en":3},{"id":4,"boneBiopsy":5,"extension":10,"imaging":11,"liquidBiopsies":17,"liquidBiopsyPivot":34,"meta":101,"panelRows":102,"paperSections":143,"papers":215,"stem":220,"treatments":221,"__hash__":242},"science_en\u002Fen\u002Fscience.yml",{"title":6,"date":7,"site":8,"result":9},"Bone biopsy (right iliac lesion)","Received 2026-04-30 · report 2026-05-08","Right iliac lesion","No tumor present — “mineralized bone trabeculae and skeletal muscle fibers, no neoplasm observed”. Molecular information is obtained from plasma ctDNA instead.","yml",{"title":12,"date":13,"summary":14,"meaning":15,"quote":16},"Gallium-68 DOTATOC PET-CT","May 26, 2026","Multiple blastic bone metastases with somatostatin receptor overexpression (subtype 2, SSTR2). Focal uptake in the right breast tail pending a dedicated study.","The tumor expresses somatostatin receptors — the target of radioligand therapy (PRRT). It confirms on imaging both tumor drivers (luminal FGFR1\u002FCCND1 + neuroendocrine RB1 + SSTR) and opens a route that breast-cancer protocols do not contemplate as standard.","Study showing multiple blastic bone metastases with somatostatin receptor overexpression. Focal uptake in the right breast tail to be evaluated in a dedicated study.",[18,23,29],{"id":19,"date":20,"source":21,"findings":22},"ctdna-1","Apr 7, 2026","VHIO360 — HOPE-FOCUS SOLTI-2401 trial","Plasma ctDNA panel — baseline profile",{"id":24,"date":25,"source":26,"findings":27,"highlight":28},"ctdna-2","April 2026","Guardant360","ESR1 D538G · RB1 ×3 (p.V622Yfs*33 1.58% · p.R661W 1.48% · p.F226* subclonal) · FGFR1 amplified · CCND1 amplified",true,{"id":30,"date":31,"source":32,"findings":33,"highlight":28},"ctdna-3","Drawn 2026-05-13 · report 2026-05-26","Guardant360 CDx","ESR1 D538G (0.84%) · CCND1 amp (6.83) · FGFR1 amp (5.86) · RB1 V622Yfs*33 (0.19%) · SMO V319D (0.26%) — new",{"samples":35,"rows":47,"sources":100},[36,41,44],{"id":37,"label":38,"date":39,"matrix":40},"vhio360","VHIO360","2026-04-07","plasma",{"id":42,"label":26,"date":43,"matrix":40},"guardant1","2026-04-13",{"id":45,"label":32,"date":46,"matrix":40},"guardantcdx","2026-05-13",[48,58,67,77,84,93],{"alteration":49,"subscript":50,"values":51},"ESR1","p.D538G",{"vhio360":52,"guardant1":55,"guardantcdx":56},{"value":53,"tone":54},"detected","warn",{"value":53,"tone":54},{"value":57,"tone":54},"0.84%",{"alteration":59,"subscript":60,"values":61},"RB1","p.V622Yfs*33",{"vhio360":62,"guardant1":63,"guardantcdx":65},{"plain":28},{"value":64,"tone":54},"1.58%",{"value":66,"tone":54},"0.19%",{"alteration":68,"subscript":69,"values":70},"CCND1","amplification",{"vhio360":71,"guardant1":72,"guardantcdx":75},{"plain":28},{"value":73,"tone":74},"amplified","violet",{"value":76,"tone":74},"6.83",{"alteration":78,"subscript":69,"values":79},"FGFR1",{"vhio360":80,"guardant1":81,"guardantcdx":82},{"plain":28},{"value":73,"tone":74},{"value":83,"tone":74},"5.86",{"alteration":85,"subscript":86,"values":87},"SMO","p.V319D · VUS",{"vhio360":88,"guardant1":89,"guardantcdx":90},{"plain":28},{"plain":28},{"value":91,"tone":92},"0.26% — new","neutral",{"alteration":94,"values":95},"MSI Status",{"vhio360":96,"guardant1":98,"guardantcdx":99},{"value":97,"plain":28},"MSI-LOW",{"plain":28},{"plain":28},"Sources: 2026-04-07 VHIO360 (HOPE-FOCUS SOLTI-2401) · 2026-04-13 Guardant360 · 2026-05-13 Guardant360 CDx (report 2026-05-26)",{},[103,108,113,118,123,128,133,138],{"component":104,"method":105,"targets":106,"implication":107},"Broad NGS + WGS","≥500-gene panel + WGS · FFPE Core 5 \u002F frozen Core 6","FGFR1-4, CCND1, CDK4, FGF3\u002F4\u002F19, ESR1, PIK3CA, PTEN, RB1, TP53, MET; CNV, TMB, MSI, fusions, SV","Dominant drivers and co-alterations. PTEN and CDK4 reliable only in tissue; CDK4 co-amplified at 11q13 implies CDK4\u002F6i resistance",{"component":109,"method":110,"targets":111,"implication":112},"RNA-seq (expression)","Bulk RNA-seq · frozen Core 6","mRNA FGFR1, FGF3\u002F4\u002F19, MYC; NE signature; PAM50","Better predictor of FGFRi response than amplification alone; confirms the FGFR autocrine circuit",{"component":114,"method":115,"targets":116,"implication":117},"Extended IHC (30)","IHC + RNAscope · FFPE Core 3","ER, PR, HER2 (ultralow), FGFR1, SSTR2, TROP-2, B7-H3, DLL3, CgA, SYN, INSM1, Rb, Cyclin E1, GR","HER2-low→T-DXd · SSTR2→PRRT · DLL3→anti-DLL3 · Cyclin E1 \u002F Rb loss→CDK4\u002F6i resistance",{"component":119,"method":120,"targets":121,"implication":122},"Single-cell Multiome + CITE-seq","snRNA + ATAC, TCR\u002FBCR · frozen Core 7","Transcriptional states + chromatin; ER\u002FHER2\u002FSSTR2\u002FTROP-2\u002FB7-H3\u002FPD-L1; T\u002FB repertoire","NE vs luminal program, resistant clones and immune microenvironment (cold vs hot tumour)",{"component":124,"method":125,"targets":126,"implication":127},"RPPA \u002F phosphoproteomics","~95 proteins · lysate Core 9","p-FRS2α, p-AKT, p-ERK, p-Rb, p-S6, Cyclin E1, GR, p-ER","REAL pathway activation (FGFR, PI3K, MAPK, cell cycle); guides combinations",{"component":129,"method":130,"targets":131,"implication":132},"Spatial transcriptomics","Visium \u002F Xenium · OCT Cores 10–11","Tumour–stroma–bone architecture; is the NE differentiation homogeneous or are there residual HR+ islands?","Determines whether to target only the NE phenotype or also the residual luminal component",{"component":134,"method":135,"targets":136,"implication":137},"Organoids + drug screening","Ex vivo culture · fresh Core 12 \u002F live-cryo Core 13","Ex vivo sensitivity: FGFRi, CDK4\u002F6i, T-DXd, capivasertib, everolimus and combinations","PDOs predict response ~78% and improve PFS when guiding treatment (11.0 vs 5.0 months)",{"component":139,"method":140,"targets":141,"implication":142},"Serial ctDNA","Plasma every 6–8 weeks","FGFR1 amp, ESR1 (Y537S\u002FD538G), PIK3CA, FGFR kinase mutations; tumour fraction ≥1%","Closes the loop: detects resistance 4–8 weeks before imaging, without re-biopsying",[144,164,180,196,206],{"title":145,"tag":146,"tone":54,"subtitle":147,"papers":148},"Neuroendocrine Transformation and RB1 Loss","NE transformation","Most critical finding: 3 RB1 variants (p.V622Yfs*33, p.R661W, p.F226*) in Guardant360 ctDNA, April 2026",[149,154,159],{"ref":150,"finding":151,"relevance":152,"link":153},"Park et al., 2018 — Science (DOI: 10.1126\u002Fscience.aat5749)","RB1 + TP53 loss: reprogramming toward a neuroendocrine phenotype","Foundational experimental study showing that combined RB1 and TP53 loss reprograms hormone-dependent epithelial tissues toward an aggressive neuroendocrine phenotype. It is the direct biological basis of neuroendocrine transformation risk in this case, where 3 distinct RB1 mutations were detected in Guardant360 liquid biopsy (April 2026).","https:\u002F\u002Fdoi.org\u002F10.1126\u002Fscience.aat5749",{"ref":155,"finding":156,"relevance":157,"link":158},"Aggarwal et al., 2018 — Journal of Clinical Oncology (DOI: 10.1200\u002FJCO.2017.77.6880)","Neuroendocrine transformation under hormonal pressure: 17% of hormone-dependent tumors","Prospective multi-institutional study documenting that 17% of patients with hormone-dependent tumors under targeted therapy develop transition to small-cell neuroendocrine phenotype through RB1 loss. This molecular paradigm is transferable to HR+ breast cancer under prolonged endocrine pressure, as in this case after 25 months of endocrine therapy + CDK4\u002F6i.","https:\u002F\u002Fdoi.org\u002F10.1200\u002FJCO.2017.77.6880",{"ref":160,"finding":161,"relevance":162,"link":163},"Cancer Discovery, 2025 — Integrative review (DOI: 10.1158\u002F2159-8290.CD-24-0837)","Neuroendocrine transformation as an acquired resistance mechanism","Integrative review confirming combined RB1 + TP53 loss as the molecular hallmark of neuroendocrine transformation in hormone-dependent epithelial tumors (prostate, breast, lung). It synthesizes recent evidence and reinforces the biological rationale for exploring the neuroendocrine axis when RB1 alterations emerge under prolonged hormonal therapy.","https:\u002F\u002Fdoi.org\u002F10.1158\u002F2159-8290.CD-24-0837",{"title":165,"tag":166,"tone":167,"subtitle":168,"papers":169},"Biology of Breast Carcinoma with Neuroendocrine Differentiation","BC-NED biology","info","Subtype characterization, BC-NED with 80% Cg\u002FSyn",[170,175],{"ref":171,"finding":172,"relevance":173,"link":174},"Marchiò et al., 2017 — Journal of Pathology (DOI: 10.1002\u002Fpath.4837)","Genomic landscape of breast carcinoma with neuroendocrine differentiation","Genomic characterization of breast carcinomas with extensive neuroendocrine differentiation (>50% Cg\u002FSyn) identifying a molecular landscape distinct from classic NST, enriched for CCND1, FGFR1, and PI3K pathway alterations. The described profile matches this case (CCND1 ×20, FGFR1 ×13, amplified 11q13 cluster).","https:\u002F\u002Fdoi.org\u002F10.1002\u002Fpath.4837",{"ref":176,"finding":177,"relevance":178,"link":179},"Pareja et al., 2022 — Journal of Clinical Pathology (DOI: 10.1136\u002Fjclinpath-2020-207002)","Breast neuroendocrine tumors: WHO 5th edition classification and comparative biology","Application of WHO 5th edition (2019) diagnostic criteria to breast neuroendocrine tumors, with genomic comparison against gastroenteropancreatic NETs and mucinous breast carcinomas. It documents that some tumors acquire late neuroendocrine differentiation under therapeutic pressure, relevant to this clinical trajectory.","https:\u002F\u002Fdoi.org\u002F10.1136\u002Fjclinpath-2020-207002",{"title":181,"tag":182,"tone":183,"subtitle":184,"papers":185},"SSTR2 Pathway and Radioligand Therapy (PRRT)","SSTR2 · PRRT","positive","The 68Ga-DOTATOC PET (26 May 2026) confirmed SSTR2 overexpression in the bone metastases → opens the PRRT route (177Lu-DOTATATE); SSTR2 IHC on tissue pending the rebiopsy",[186,191],{"ref":187,"finding":188,"relevance":189,"link":190},"Terlević et al., 2019 — Annals of Diagnostic Pathology (DOI: 10.1016\u002Fj.anndiagpath.2018.11.002)","SSTR2 expression in neuroendocrine breast carcinoma: 71% positive (≈36% moderate-strong)","Immunohistochemical study: 71% of neuroendocrine breast carcinomas express SSTR2A (any intensity); ~36% with moderate-strong intensity, the range most relevant for PRRT with 177Lu-DOTATATE. Supports functional 68Ga-DOTATOC PET imaging and requesting SSTR2 IHC at the rebiopsy.","https:\u002F\u002Fdoi.org\u002F10.1016\u002Fj.anndiagpath.2018.11.002",{"ref":192,"finding":193,"relevance":194,"link":195},"Sharma et al., 2021 — European Journal of Nuclear Medicine and Molecular Imaging (DOI: 10.1007\u002Fs00259-020-05054-9)","177Lu-DOTATATE in metastatic neuroendocrine breast cancer: clinical evidence","Clinical series of metastatic neuroendocrine breast cancer patients treated with PRRT (177Lu-DOTATATE), showing response rates and progression-free survival comparable to gastroenteropancreatic NETs. Provides the strongest available clinical evidence that PRRT can work in this breast tumor subtype.","https:\u002F\u002Fdoi.org\u002F10.1007\u002Fs00259-020-05054-9",{"title":197,"tag":198,"tone":74,"subtitle":199,"papers":200},"FGFR1\u002FCCND1 Axis and CDK4\u002F6i Resistance","FGFR1 \u002F CCND1","Molecular mechanism behind the observed clinical resistance in the first two lines",[201],{"ref":202,"finding":203,"relevance":204,"link":205},"Formisano et al., 2019 — Nature Communications (DOI: 10.1038\u002Fs41467-019-09068-2)","FGFR1 as a resistance driver to endocrine therapy and CDK4\u002F6i in HR+\u002FHER2- breast cancer","Molecular study showing that FGFR1 amplification functionally activates PI3K\u002FAKT\u002FmTOR signaling even without PIK3CA mutation and represents a known acquired resistance mechanism to endocrine therapy and CDK4\u002F6 inhibitors in HR+\u002FHER2- breast cancer. It explains the clinical resistance observed in the first two treatment lines.","https:\u002F\u002Fdoi.org\u002F10.1038\u002Fs41467-019-09068-2",{"title":207,"tag":208,"tone":92,"subtitle":209,"papers":210},"International Consensus Guidelines","Guidelines","Formal support for the clinical requests presented to the treating team",[211,216],{"ref":212,"finding":213,"relevance":214,"link":215},"NCCN Guidelines — Neuroendocrine and Adrenal Tumors, Version 1.2025","International algorithm for neuroendocrine tumors of breast origin","NCCN 2025 guidelines include a therapeutic algorithm for neuroendocrine tumors of breast origin with SSTR2 expression, where PRRT (177Lu-DOTATATE) is listed as an option after failure of standard hormonal therapy. Spanish SEOM guidelines do not yet include this algorithm for neuroendocrine breast disease, explaining the discrepancy between national and international recommendations.",null,{"ref":217,"finding":218,"relevance":219,"link":215},"ENETS Consensus Guidelines, 2023 — European Neuroendocrine Tumor Society","European recommendation: evaluate SSTR2 in advanced neuroendocrine breast carcinomas","ENETS 2023 consensus recommends assessing SSTR2 expression and considering functional DOTATATE imaging in advanced neuroendocrine carcinomas to stratify eligibility for somatostatin receptor-targeted therapies, including PRRT when appropriate.","en\u002Fscience",[222,227,231,235,239],{"line":223,"regimen":224,"outcome":225,"active":226},"dx","Diagnosis and palliative radiotherapy (January–February 2024)","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.",false,{"line":228,"regimen":229,"outcome":230,"active":226},"1L","Letrozole + Ribociclib + Zoladex (goserelin) + zoledronic acid","Ribociclib discontinued after the 1st cycle due to toxicity. Zoladex continued.",{"line":232,"regimen":233,"outcome":234,"active":226},"2L","Fulvestrant + Abemaciclib + Zoladex (goserelin) + zoledronic acid","On confirmed progression, letrozole is replaced by fulvestrant and ribociclib by abemaciclib. Zoladex and zoledronic acid are maintained.",{"line":236,"regimen":237,"outcome":238,"active":226},"→","Bone progression (March 2026)","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.",{"line":236,"regimen":240,"outcome":241,"active":28},"Current status (2026)","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+\u002FHER2− breast cancer after CDK4\u002F6i: 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.","skaHYsz5k6KWKuMd6491yHp9MaWdAST9MN2PIhUdB34",1781131813867]