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Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination
Joan R E Choo1, Yi-Hua Jan2, Samuel G W Ow1
1Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS) National University Health System, 1E Lower Kent Ridge Road, Singapore, 119228, Singapore.
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).
Insights
Genomic profiling of HER2-negative breast cancer revealed early, sustained changes in variant allele frequency of SNVs, particularly in the PI3K/mTOR/AKT pathway. These molecular alterations correlate with treatment response and may guide future targeted therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Breast cancer exhibits significant heterogeneity, leading to variable clinical outcomes and treatment responses.
- HER2-negative breast cancers present unique challenges in treatment selection and response prediction.
Purpose of the Study:
- To investigate dynamic molecular alterations in HER2-negative breast tumors during chemotherapy combined with anti-angiogenic agents.
- To correlate observed genomic changes with treatment response using the Miller-Payne grading system.
Main Methods:
- Newly diagnosed HER2-negative breast cancer patients received sunitinib or bevacizumab followed by chemotherapy.
- Tumor biopsies were collected at baseline, 2 weeks, and 8 weeks for next-generation sequencing of 440 cancer-related genes.
- Single nucleotide variants (SNVs) and copy number alterations (CNAs) were analyzed, and genomic changes were correlated with histological response.
Main Results:
- Seventy-two percent of patients showed changes in variant allele frequency (VAF) of pathogenic SNVs, with most changes occurring early (2 weeks) and persisting.
- PI3K/mTOR/AKT pathway alterations were most commonly observed, with 13% developing mutations potentially sensitive to PIK3CA inhibitors.
- Tumors with a poor histological response were less likely to exhibit VAF changes in SNVs compared to those with a good response (p = 0.029).
Conclusions:
- Serial molecular profiling can detect early, therapy-induced genomic alterations in breast cancer.
- These early genomic changes may serve as predictive biomarkers for treatment response.
- Findings may inform the selection of targeted therapies for patients with advanced or progressing breast cancer.
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