Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors
© 2022. The Author(s)..
BACKGROUND: Breast cancers are heterogeneous with variable clinical courses and treatment responses.
OBJECTIVE: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents.
PATIENTS AND METHODS: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco®). Observed genomic changes were correlated with the Miller-Payne histological response to treatment.
RESULTS: Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029).
CONCLUSIONS: Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Targeted oncology - 17(2022), 3 vom: 14. Mai, Seite 355-368 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Choo, Joan R E [VerfasserIn] |
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| Links: |
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| Themen: |
2S9ZZM9Q9V |
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| Anmerkungen: |
Date Completed 24.06.2022 Date Revised 18.07.2022 published: Print-Electronic ClinicalTrials.gov: NCT02790580 Citation Status MEDLINE |
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| doi: |
10.1007/s11523-022-00886-x |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Choo, Joan R E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 24.06.2022 | ||
| 500 | |a Date Revised 18.07.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02790580 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a BACKGROUND: Breast cancers are heterogeneous with variable clinical courses and treatment responses | ||
| 520 | |a OBJECTIVE: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents | ||
| 520 | |a PATIENTS AND METHODS: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco®). Observed genomic changes were correlated with the Miller-Payne histological response to treatment | ||
| 520 | |a RESULTS: Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029) | ||
| 520 | |a CONCLUSIONS: Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy | ||
| 520 | |a CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016) | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Ow, Samuel G W |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Matilda Xinwei |e verfasserin |4 aut | |
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| 700 | 1 | |a Yadav, Kritika |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Joline S J |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Siew Eng |e verfasserin |4 aut | |
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| 700 | 1 | |a Tang, Siau Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Goh, Boon Cher |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Hon Lyn |e verfasserin |4 aut | |
| 700 | 1 | |a Chong, Wan Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Yvonne, Ang Li En |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Gloria H J |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shu-Jen |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Kien Thiam |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Soo Chin |e verfasserin |4 aut | |
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