Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case report
Under therapeutic pressure aggressive tumors evolve rapidly. Herein, a luminal B/HER2-low breast cancer was tracked for >3 years during a total of 6 largely unsuccessful therapy lines, from adjuvant to advanced settings. Targeted next generation sequencing (NGS) of the primary lesion, two met...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1050452/full |
| _version_ | 1797955994258505728 |
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| author | Matteo Allegretti Vittoria Barberi Cristiana Ercolani Antonello Vidiri Elena Giordani Gennaro Ciliberto Patrizio Giacomini Alessandra Fabi |
| author_facet | Matteo Allegretti Vittoria Barberi Cristiana Ercolani Antonello Vidiri Elena Giordani Gennaro Ciliberto Patrizio Giacomini Alessandra Fabi |
| author_sort | Matteo Allegretti |
| collection | DOAJ |
| description | Under therapeutic pressure aggressive tumors evolve rapidly. Herein, a luminal B/HER2-low breast cancer was tracked for >3 years during a total of 6 largely unsuccessful therapy lines, from adjuvant to advanced settings. Targeted next generation sequencing (NGS) of the primary lesion, two metastases and 14 blood drawings suggested a striking, unprecedented coexistence of three evolution modes: punctuated, branched and convergent. Punctuated evolution of the trunk was supported by en bloc inheritance of a large set (19 distinct genes) of copy number alterations. Branched evolution was supported by the distribution of site-specific SNVs. Convergent evolution was characterized by a unique asynchronous expansion of three actionable (OncoKB level 3A) mutations at two consecutive ESR1 codons. Low or undetectable in all the sampled tumor tissues, ESR1 mutations expanded rapidly in blood during HER2/hormone double-blockade, and predicted life-threatening local progression at lung and liver metastatic foci. Dramatic clinical response to Fulvestrant (assigned off-label exclusively based on liquid biopsy) was associated with clearance of all 3 subclones and was in stark contrast to the poor therapeutic efficacy reported in large liquid biopsy-informed interventional trials. Altogether, deconvolution of the tumor phylogenetic tree, as shown herein, may help to customize treatment in breast cancers that rapidly develop refractoriness to multiple drugs. |
| first_indexed | 2024-04-10T23:41:52Z |
| format | Article |
| id | doaj.art-c3518e7978bd404da058c8154119ab75 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T23:41:52Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-c3518e7978bd404da058c8154119ab752023-01-11T06:56:25ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-01-011210.3389/fonc.2022.10504521050452Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case reportMatteo Allegretti0Vittoria Barberi1Cristiana Ercolani2Antonello Vidiri3Elena Giordani4Gennaro Ciliberto5Patrizio Giacomini6Alessandra Fabi7Translational Oncology Research, IRCSS Regina Elena National Cancer Institute, Rome, ItalyMedical Oncology 1, IRCSS Regina Elena National Cancer Institute, Rome, ItalyPathology, IRCSS Regina Elena National Cancer Institute, Rome, ItalyRadiology and Diagnostic Imaging, IRCSS Regina Elena National Cancer Institute, Rome, ItalyTranslational Oncology Research, IRCSS Regina Elena National Cancer Institute, Rome, ItalyScientific Directorate, IRCSS Regina Elena National Cancer Institute, Rome, ItalyClinical Trial Center, IRCSS Regina Elena National Cancer Institute, Rome, ItalyPrecision Medicine in Senology, Scientific Directorate - Department of Women and Child Health, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, ItalyUnder therapeutic pressure aggressive tumors evolve rapidly. Herein, a luminal B/HER2-low breast cancer was tracked for >3 years during a total of 6 largely unsuccessful therapy lines, from adjuvant to advanced settings. Targeted next generation sequencing (NGS) of the primary lesion, two metastases and 14 blood drawings suggested a striking, unprecedented coexistence of three evolution modes: punctuated, branched and convergent. Punctuated evolution of the trunk was supported by en bloc inheritance of a large set (19 distinct genes) of copy number alterations. Branched evolution was supported by the distribution of site-specific SNVs. Convergent evolution was characterized by a unique asynchronous expansion of three actionable (OncoKB level 3A) mutations at two consecutive ESR1 codons. Low or undetectable in all the sampled tumor tissues, ESR1 mutations expanded rapidly in blood during HER2/hormone double-blockade, and predicted life-threatening local progression at lung and liver metastatic foci. Dramatic clinical response to Fulvestrant (assigned off-label exclusively based on liquid biopsy) was associated with clearance of all 3 subclones and was in stark contrast to the poor therapeutic efficacy reported in large liquid biopsy-informed interventional trials. Altogether, deconvolution of the tumor phylogenetic tree, as shown herein, may help to customize treatment in breast cancers that rapidly develop refractoriness to multiple drugs.https://www.frontiersin.org/articles/10.3389/fonc.2022.1050452/fullbreast cancercancer evolutionliquid biopsyESR1HER2molecular tumor board |
| spellingShingle | Matteo Allegretti Vittoria Barberi Cristiana Ercolani Antonello Vidiri Elena Giordani Gennaro Ciliberto Patrizio Giacomini Alessandra Fabi Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case report Frontiers in Oncology breast cancer cancer evolution liquid biopsy ESR1 HER2 molecular tumor board |
| title | Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case report |
| title_full | Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case report |
| title_fullStr | Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case report |
| title_full_unstemmed | Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case report |
| title_short | Unusual phylogenetic tree and circulating actionable ESR1 mutations in an aggressive luminal/HER2-low breast cancer: Case report |
| title_sort | unusual phylogenetic tree and circulating actionable esr1 mutations in an aggressive luminal her2 low breast cancer case report |
| topic | breast cancer cancer evolution liquid biopsy ESR1 HER2 molecular tumor board |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1050452/full |
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