Subclonal heterogeneity and evolution in breast cancer

Mavrommati, Ioanna; Johnson, Flora; Echeverria, Gloria V.; Natrajan, Rachael

doi:10.1038/s41523-021-00363-0

Cited by 26 publications

(22 citation statements)

References 133 publications

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“…These changes may have been induced by treatment or may reflect selection pressure of existing subclones following treatment. It is recognized that acquired treatment resistance is linked to intratumoral heterogeneity and clonal evolution [ 36 ]. Several studies have shown that breast tumors demonstrate intratumoral spatial heterogeneity and contain clonal tumor subpopulations [ 37 , 38 ], with others showing that a majority of mutations detected in primary breast cancers are subclonal [ 39 ] and unevenly distributed spatially among individual tumors [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors

Choo

Jan

et al. 2022

Targ Oncol

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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). Supplementary Information The online version contains supplementary material available at 10.1007/s11523-022-00886-x.

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Section: Discussionmentioning

confidence: 99%

Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors

Choo

Jan

et al. 2022

Targ Oncol

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“…Our results can be partly explained by tumor heterogeneity and selective pressure. When selective pressure, such as chemotherapy, is administered, the treatment-sensitive portion of a tumor is eliminated, while the resistant portion survives and expands [ 20 ]. Chemotherapy also induces new genomic, transcriptomic, and epigenetic aberrations at the subclonal level, which leads to resistance.…”

Section: Discussionmentioning

confidence: 99%

The Radiological Response Rate Pattern Is Associated With Recurrence Free Survival in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

et al. 2022

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Purpose The aim of this study was to evaluate the radiological response rate patterns during neoadjuvant chemotherapy (NAC) in patients with breast cancer. Methods Patients who underwent NAC with two specific chemotherapy regimens (doxorubicin with cyclophosphamide or doxorubicin with docetaxel) and who underwent a response evaluation every two cycles were included in the study. The initial response ratio was defined as the ratio of the largest tumor diameter at diagnosis to that after two cycles of NAC. The latter response ratio was defined as the ratio between the tumor size after two cycles and that after four cycles of NAC. The radiological response rate pattern was divided into three groups: the fast-to-slow response group (F–S group, initial response ratio > latter response ratio + 20%), slow-to-fast response group (S–F group, latter response ratio > initial response ratio + 20%), and constant response group (less than 20% difference between the initial and latter response ratios). Results In total, 177 patients were included in the analysis. Forty-two (23.9%) patients were categorized into the F–S group, 26 (14.8%) into the S–F group, and 108 (61.2%) into the constant group. Clinicopathologic factors did not differ according to radiologic response rate patterns. The median follow-up period was 50 months (range, 3–112) months. In the univariate analysis, the F–S group had a significantly worse recurrence-free survival than the S–F and constant groups (hazard ratio [HR], 3.63; 95% confidence interval [CI], 1.05–12.46; p = 0.041). The F–S group also presented with significantly worse survival than the S–F group in the multivariate analysis (HR, 3.45; 95% CI, 1.00–11.89; p = 0.049). Conclusion The F–S group had a poorer survival rate than the S–F group. Radiological response rate patterns may be useful for accurate prognostic assessments, especially when considering post-neoadjuvant therapy.

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“…It is also well-known and described that tissue heterogeneity contributes to these processes during progression. To model these processes in monolayer cultures is almost impossible, as only certain steps can be investigated using 2D cell cultures [24,25]. Three-dimensional bioprinting is a promising technology using ECM-compatible biomaterials and cells to create complex in vitro tissue-mimetic models, allowing longer culture.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

Dankó

Petővári

Raffay

et al. 2022

IJMS

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Monolayer cultures, the less standard three-dimensional (3D) culturing systems, and xenografts are the main tools used in current basic and drug development studies of cancer research. The aim of biofabrication is to design and construct a more representative in vivo 3D environment, replacing two-dimensional (2D) cell cultures. Here, we aim to provide a complex comparative analysis of 2D and 3D spheroid culturing, and 3D bioprinted and xenografted breast cancer models. We established a protocol to produce alginate-based hydrogel bioink for 3D bioprinting and the long-term culturing of tumour cells in vitro. Cell proliferation and tumourigenicity were assessed with various tests. Additionally, the results of rapamycin, doxycycline and doxorubicin monotreatments and combinations were also compared. The sensitivity and protein expression profile of 3D bioprinted tissue-mimetic scaffolds showed the highest similarity to the less drug-sensitive xenograft models. Several metabolic protein expressions were examined, and the in situ tissue heterogeneity representing the characteristics of human breast cancers was also verified in 3D bioprinted and cultured tissue-mimetic structures. Our results provide additional steps in the direction of representing in vivo 3D situations in in vitro studies. Future use of these models could help to reduce the number of animal experiments and increase the success rate of clinical phase trials.

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Subclonal heterogeneity and evolution in breast cancer

Cited by 26 publications

References 133 publications

Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors

Serial Tumor Molecular Profiling of Newly Diagnosed HER2-Negative Breast Cancers During Chemotherapy in Combination with Angiogenesis Inhibitors

The Radiological Response Rate Pattern Is Associated With Recurrence Free Survival in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

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