Acute Side Effects of Radiotherapy in Breast Cancer Patients: Role of DNA-Repair and Cell Cycle Control Genes

Abstract Background DNA repair pathways, cell cycle arrest checkpoints, and cell death induction are present in cells to process DNA damage and prevent genomic instability caused by various extrinsic and intrinsic ionizing factors. Mutations in the genes involved in these pathways enhances the ionizing radiation sensitivity, reduces the individual’s capacity to repair DNA damages, and subsequently increases susceptibility to tumorigenesis. Body BRCA1 and BRCA2 are two highly penetrant genes involved in the inherited breast cancer and contribute to different DNA damage pathways and cell cycle and apoptosis cascades. Mutations in these genes have been associated with hypersensitivity and genetic instability as well as manifesting severe radiotherapy complications in breast cancer patients. The genomic instability and DNA repair capacity of breast cancer patients with BRCA1/2 mutations have been analyzed in different studies using a variety of assays, including micronucleus assay, comet assay, chromosomal assay, colony-forming assay, γ -H2AX and 53BP1 biomarkers, and fluorescence in situ hybridization. The majority of studies confirmed the enhanced spontaneous & radiation-induced radiosensitivity of breast cancer patients compared to healthy controls. Using G2 micronucleus assay and G2 chromosomal assay, most studies have reported the lymphocyte of healthy carriers with BRCA1 mutation are hypersensitive to invitro ionizing radiation compared to non-carriers without a history of breast cancer. However, it seems this approach is not likely to be useful to distinguish the BRCA carriers from non-carrier with familial history of breast cancer. Conclusion In overall, breast cancer patients are more radiosensitive compared to healthy control; however, inconsistent results exist about the ability of current radiosensitive techniques in screening BRCA1/2 carriers or those susceptible to radiotherapy complications. Therefore, developing further radiosensitivity assay is still warranted to evaluate the DNA repair capacity of individuals with BRCA1/2 mutations and serve as a predictive factor for increased risk of cancer mainly in the relatives of breast cancer patients. Moreover, it can provide more evidence about who is susceptible to manifest severe complication after radiotherapy.

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Intraoperative Radiotherapy (Iort) for Breast Cancer Using the Intrabeam™ System

Tumori Journal ◽

10.1177/030089160509100411 ◽

2005 ◽

Vol 91 (4) ◽

pp. 339-345 ◽

Cited By ~ 52

Author(s):

Uta Kraus-Tiefenbacher ◽

Antonella Scheda ◽

Volker Steil ◽

Brigitte Hermann ◽

Tanja Kehrer ◽

...

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Local Recurrence ◽

Cancer Patients ◽

Tumor Resection ◽

Intraoperative Radiotherapy ◽

X Rays ◽

Breast Cancer Patients ◽

Tumor Bed ◽

Acute Side Effects

Introduction Intraoperative radiotherapy (IORT) with low-energy X-rays (30–50 KV) is an innovative technique that can be used both for accelerated partial breast irradiation (APBI) and intraoperative boosting in patients affected by breast cancer. Immediately after tumor resection the tumor bed can be treated with low-distance X-rays by a single high dose. Whereas often a geographic miss in covering the boost target occurs with external beam boost radiotherapy (EBRT), the purpose of IORT is to cover the tumor bed safely. This report will focus on the feasibility and technical aspects of the Intrabeam™ device and will summarize our experience with side effects and local control. Materials and methods Between February 2002 and June 2003 57 breast cancer patients, all eligible for breast conserving surgery (BCS), were treated at the Mannheim Medical Center with IORT using the mobile X-ray system Intrabeam™. The patient population in this feasibility study was not homogeneous consisting of 49 patients with primary stage I or II breast cancer, seven with local recurrence after previous EBRT and one with a second primary in a previously irradiated breast. The selection criteria for referral for IORT included tumor size, tumor cavity size, margin status and absence of an extensive intraductal component. The previously irradiated patients with local recurrences and 16 others received IORT as single modality. In all other cases IORT was followed by EBRT with a total dose of 46 Gy in 2-Gy fractions. The intraoperatively delivered dose after tumor resection was 20 Gy prescribed to the applicator surface. EBRT was delivered with a standard two-tangential-field technique using linear accelerators with 6- or 18-MV photons. Patients were assessed every three months by their radiation oncologist or surgeon during the first year after treatment and every six months thereafter. Breast ultrasound for follow-up was done every six months and mammographies once yearly. Acute side effects were scored according to the CTC/EORTC score and late side effects according to the Lent-Soma classification. Results Twenty-four patients received IORT only; eight patients because they had received previous radiotherapy, 16 because of a very favorable risk profile or their own preference. Thirty-three patients with tumor sizes between 1 and 30 mm and no risk factors were treated by IORT as a boost followed by EBRT. The Intrabeam™ system was used for IORT. The Intrabeam source produces 30–50 KV X-rays and the prescribed dose is delivered in an isotropic dose distribution around spherical applicators. Treatment time ranged between 20 and 48 minutes. No severe acute side effects or complications were observed during the first postoperative days or after 12 months. One local recurrence occurred 10 months after surgery plus IORT followed by EBRT. In two patients distant metastases were diagnosed shortly after BCS. Discussion IORT with the Intrabeam system is a feasible method to deliver a single high radiation dose to breast cancer patients. As a preliminary boost it has the advantage of reducing the EBRT course by 1.5 weeks, and as APBI it might be a promising tool for patients with a low risk of recurrence. The treatment is well tolerated and does not cause greater damage than the expected late reaction in normal tissue.

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Genetic Polymorphisms in the DNA Double-Strand Break Repair Genes XRCC3, XRCC2, and NBS1 Are Not Associated with Acute Side Effects of Radiotherapy in Breast Cancer Patients

Cancer Epidemiology Biomarkers & Prevention ◽

10.1158/1055-9965.epi-06-0046 ◽

2006 ◽

Vol 15 (5) ◽

pp. 1048-1050 ◽

Cited By ~ 33

Author(s):

O. Popanda

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Cancer Patients ◽

Genetic Polymorphisms ◽

Strand Break ◽

Double Strand Break Repair ◽

Breast Cancer Patients ◽

Dna Double Strand Break ◽

Acute Side Effects ◽

Repair Genes

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Association between TP53 and p21 genetic polymorphisms and acute side effects of radiotherapy in breast cancer patients

Breast Cancer Research and Treatment ◽

10.1007/s10549-005-9119-2 ◽

2005 ◽

Vol 97 (3) ◽

pp. 255-262 ◽

Cited By ~ 32

Author(s):

Xiang-Lin Tan ◽

Odilia Popanda ◽

Christine B. Ambrosone ◽

Silke Kropp ◽

Irmgard Helmbold ◽

...

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Cancer Patients ◽

Genetic Polymorphisms ◽

Breast Cancer Patients ◽

Acute Side Effects

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The role of chemotherapy in early breast cancer patients

Senologie - Zeitschrift für Mammadiagnostik und -therapie ◽

10.1055/s-2007-990338 ◽

2007 ◽

Vol 4 (03) ◽

Author(s):

T Čufer

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Early Breast Cancer ◽

Breast Cancer Patients

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Study of the prognostic role of immunohistochemical markers in a large series of breast cancer patients

10.26226/morressier.596dfd55d462b80292386f68 ◽

2017 ◽

Author(s):

David Guerrero Setas

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Large Series ◽

Breast Cancer Patients ◽

Prognostic Role ◽

Immunohistochemical Markers

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MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

npj Breast Cancer ◽

10.1038/s41523-020-00210-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Sanne Løkkegaard ◽

Daniel Elias ◽

Carla L. Alves ◽

Martin V. Bennetzen ◽

Anne-Vibeke Lænkholm ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Patients ◽

Endocrine Therapy ◽

Endocrine Resistance ◽

Predictive Marker ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Minichromosome Maintenance ◽

Primary Tumors

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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