Sequential Biopsies, Multi-Level Molecular Profiling Offer Important Insights into Tumor Evolution

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Gene copy number, methylation and metabolic changes during neoadjuvant chemotherapy predict treatment outcomes.
Gene copy number, methylation and metabolic changes during neoadjuvant chemotherapy predict treatment outcomes.

SAN ANTONIO—Gene copy number, methylation, RNA expression, protein, immune, and metabolic changes during neoadjuvant chemotherapy predict treatment outcomes in patients with breast cancer, and to a large degree, correspond with one another, Anne-Lise Børresen-Dale, MD, of Oslo University Hospital in Norway, reported at the 2015 San Antonio Breast Cancer Symposium.1

“All molecular levels change during treatment, with strong correspondence in the shifts at several molecular levels,” Dr Børresen-Dale reported. “The set of perturbations at each level is tumor subtype specific, unique for each subclone, and may evolve during treatment.”

For example, “tumors showed molecular subtype-specific changes in gene expression and gene pathway deregulation,” she reported. “The most significant changes were observed in Luminal B tumors treated with combination therapy.” DNA methylation variation might also predict therapeutic responses, she reported; DNA methylation patterns were distinct between FEC and taxane-treated tumors.

The preliminary, unpublished findings “highlight the importance of dissecting the tumor heterogeneity and molecular profile at all levels during tumor evolution under treatment,” she emphasized. “Even though sequential biopsies are invasive procedures, it could have major impact on patient prediction and prognosis.”

The findings were based on unpublished data from the NeoAva study, a randomized phase 2 trial of 132 patients with HER2-negative breast cancer who were treated with neoadjuvant fluorouracil/epirubicin/cyclophosphamide (FEC) and taxane chemotherapy with or without bevacizumab.

“We studied the different molecular levels separately and combined in order to capture the changes during treatment of the 2 regimes and correlate the findings to response,” explained Dr Børresen-Dale.

“Breast tumors are constituted of a number of subclonal populations. Some of these subclones will have stronger resistance to the applied treatment regime than others and will therefore constitute an increasing proportion of the tumor mass as treatment progresses, while sensitive populations will decline. Using the data from the different molecular levels, the subclonal architecture during treatment was evaluated.” 

Gene expression analysis showed that bevacizumab “enhanced the effect of chemotherapy,” Dr Børresen-Dale said. “Removal of proliferating cells with high cell-cycle activity was accelerated in the bevacizumab-treated group,” she said.

“Luminal A tumors showed a substantial change in gene expression. In Luminal B and Basal-like tumors, changes were mainly evident during the first treatment period. Bevacizumab enhanced and accelerated the efficacy of chemotherapy in patients with ER-positive tumors, and the effect was most evident in patients with Luminal B type.”

In the NeoAva study, a randomized phase 2 trial, 132 patients with HER2-negative breast cancer were treated with neoadjuvant FEC and taxane chemotherapy with or without bevacizumab. Serial biopsies were obtained at diagnosis, 12 weeks after treatment initiation, and at 25 weeks, at the time of surgical resection.

“Tumors that achieved pCR showed a significant higher expression of genes enriched for immune response related pathways, compared to the tumors that did not achieve pCR in the ER-negative group, particularly in tumors from patients treated with chemotherapy combined with bevacizumab,” she reported. “Analyses of selected proteins showed bevacizumab induced changes in expression for several proteins during the treatment period.”

Metabolic profiles were associated with responses to chemotherapy, with patients whose cancer responded to treatment experiencing reduced levels of choline-containing metabolites and higher levels of glucose, a sign of reduced glucose consumption by cells.

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“A reduction of the antioxidant glutathione was associated with the administration of bevacizumab,” Dr Børresen-Dale noted.

There were “substantial differences” in tumor DNA alterations over time, she reported: “In most cases, tumors that retained aberrations at all time points did not increase in size. Signs of subclonal reduction were observed, with some aberrations disappearing and others being retained during treatment.”


  1. Børresen-Dale, A-L. Molecular Evolution Under Neoadjuvant Chemotherapy. Oral presentation at: San Antonio Breast Cancer Symposium 2015; December 10, 2015; San Antonio, TX.

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