Representation of CYP3A4, CYP3A5 and UGT1A4 Polymorphisms within Croatian Breast Cancer Patients’ Population

Single nucleotide polymorphism (SNP) in genes encoding drug-metabolizing enzymes (DME) could have a critical role in individual responses to anastrozole. Frequency of CYP3A4*1B, CYP3A5*3 and UGT1A4*2 SNPs in 126 Croatian breast cancer (BC) patients and possible association with anastrozole-induced undesirable side effects were analyzed. Eighty-two postmenopausal patients with estrogen receptor (ER)-positive BC treated with anastrozole and 44 postmenopausal ER-positive BC patients before hormonal adjuvant therapy were included in the study. Genomic DNA was genotyped by TaqMan Real-Time PCR. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The homozygotes for the variant G allele of CYP3A5*3 were predominant (88%), and the homozygotes for the reference A allele were not detected. While homozygotes for the variant G allele of CYP3A4*1B were not detected, predominantly wild type homozygotes for A allele (94%) were present. CYP3A4*1B and CYP3A5*3 SNPs were in 84.3% linkage disequilibrium (D’ = 0.843) and 95.1% (D’ = 0.951) in group treated with anastrozole and w/o treatment, respectively. Homozygotes for the A allele of UGT1A4*2 were not detected in our study groups. Although the variant CYP3A5*3 allele, which might result in poor metabolizer phenotype and more pronounced side effects, was predominant, significant association with BMD changes induced by anastrozole were not confirmed.

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Comparing the efficacy and side-effects of PDLASTA® (Pegfilgrastim) with PDGRASTIM® (Filgrastim) in breast cancer patients: a non-inferiority randomized clinical trial

BMC Cancer ◽

10.1186/s12885-021-08197-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Safa Najafi ◽

Maryam Ansari ◽

Vahid Kaveh ◽

Shahpar Haghighat

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Single Dose ◽

Side Effects ◽

Randomized Clinical Trial ◽

Cancer Patients ◽

Injection Site Reaction ◽

Study Groups ◽

Breast Cancer Patients ◽

Significant Difference

Abstract Background The objective of this study was to compare the efficacy and side effects of a single dose (Pegfilgrastim or PDL) or repeated six daily injections (Filgrastim or PDG) during chemotherapy courses in breast cancer patients in a non-inferiority clinical trial. Methods In this randomized clinical trial, 80 patients were recruited and allocated randomly to two equal arms. In one group, a single subcutaneous dose of PDL was injected the day after receiving the chemotherapy regimen in each cycle. The second arm received a subcutaneous injection of PDG for six consecutive days in each cycle of treatment. The side effects of GCF treatment and its effect on blood parameters were compared in each cycle and during eight cycles of chemotherapy. Results Hematologic parameters showed no significant differences in any of the treatment courses between the two study groups. The comparison of WBC (p = 0.527), Hgb (p = 0.075), Platelet (p = 0.819), Neutrophil (p = 0.575), Lymphocyte (p = 705) and ANC (p = 0.675) changes during the eight courses of treatment also revealed no statistically significant difference between the two study groups. Side effects including headache, injection site reaction and muscle pain had a lower frequency in patients receiving PDL drugs. Conclusion It seems that PDL is non-inferior in efficacy and also less toxic than PDG. Since PDL can be administered in a single dose and is also less costly, it can be regarded as a cost-effective drug for the treatment of chemotherapy-induced neutropenia. Trial registration IRCT20190504043465N1, May 2019.

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Effects of ‎tamoxifen on the reproductive system of female breast cancer patients: an ultrasound-based cohort study

F1000Research ◽

10.12688/f1000research.21481.1 ◽

2020 ◽

Vol 9 ◽

pp. 102

Author(s):

Ghasak Kais Abd-Alhussain‎ ◽

Mohammed Qasim Yahya Mal-Allah Alatrakji‎ ◽

Wieeam Abdulfattah Saleh‎ ◽

Hayder Adnan Fawzi ◽

Aqeel‎ Shaker Mahmood‎

Keyword(s):

Breast Cancer ◽

Cohort Study ◽

Side Effects ◽

Endometrial Thickness ◽

Menopausal Status ◽

Hormonal Treatment ◽

Female Breast Cancer ◽

Breast Cancer Patients ◽

Er Positive ◽

Adjuvant Hormonal Treatment

Background: Tamoxifen (TMX) is regarded as standard treatment for breast cancer (BC) patients‎. In recent years, several studies have reported gynecological side effects and due to TMX's estrogenic effects. Here, we evaluate the side effects of TMX on the ‎endometrium and ovaries of female BC patients. Methods: This was an ultrasound-based cohort study conducted in three oncology centers in Baghdad, Iraq. A total of ‎‎255 female patients were included, 140 premenopausal (PreM) and 115 postmenopausal (PostM), with estrogen receptor (ER)-positive BC using TMX adjuvant hormonal treatment for at least three months after surgery and adjuvant ‎chemo/radiotherapy.‎ Ultrasound (US) on the endometrium and ovaries of the women following ‎BC surgery/chemotherapy (baseline) and at 3, 6, 12, and 24 months following was performed‎. Data collected included age, menopausal status, co-morbid chronic illness and medications, including duration of TMX treatment. Results: Presence of ovarian cyst was significantly higher in the PreM ‎compared to PostM ‎women, while there were no significant differences for other gynecological findings.‎ At ‎baseline, endometrial thickness (ET) was significantly higher in the PreM compared to the PostM women. In both groups, women with increased ET became more frequent from baseline to 3 ‎months, from 3 to 6 ‎months, from 6 to 12 months, and from 12 ‎ to 24 months. At all time periods, ‎women with increased ET was ‎significantly higher in the PostM compared PreM women, resulting ‎in a risk of ET increase by 6 folds (ranging from 3 – ‎‎11 folds) ‎in PostM compared to PreM women. Conclusions: Longer duration of TMX is associated with increased ET. Duration of TMX did not appear to increase the risk of various gynecological outcomes, for example endometrial cancer rate was low. Finally, there was an increase in ET, which appeared to be six-folds higher in PostM compared to PreM women.‎

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Randomized trial to assess bone mineral density (BMD) effects of zoledronic acid (ZA) in postmenopausal women (PmW) with breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.19558 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 19558-19558 ◽

Cited By ~ 4

Author(s):

A. Tevaarwerk ◽

J. A. Stewart ◽

R. Love ◽

N. C. Binkley ◽

S. Black ◽

...

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Performance Status ◽

Study Endpoint ◽

Breast Cancer Patients ◽

Mineral Density ◽

Ecog Performance Status ◽

Cancer Relapse ◽

Femur Neck ◽

Clinically Significant

19558 Introduction: Osteoporotic fracture represents a major source of morbidity in PmW. Breast cancer patients can be at additional risk because of treatment related estrogen deprivation. The favorable effects of bisphosphonates in osteoporosis and potential reduction of metastases warrant evaluation of ZA in PmW at high risk for breast cancer relapse. We assessed whether ZA 4 mg IV every 12 weeks x 4 doses was associated with an increase in BMD. Secondary objectives included defining ZA’s toxicity profile in this setting, and assessing for differences in overall cancer relapse. Methods: PmW with node positive or stage III breast cancer diagnosed less than 5 years earlier were randomized to ZA or observation. BMD was assessed by dual energy xray absorptiometry (DXA) for all subjects at 0 and 12 months. A toxicity evaluation was performed pre- and post-treatment for patients receiving ZA. Study endpoint occurred when subjects completed the DXAs, had disease progression or declined further treatment. We calculated change in BMD between 0 and 12 months at the L1–4 spine and femur neck. Results: 66 women have enrolled since 2000; 49 women have completed DXAs at 0 and 12 months (observation 23, ZA 26). Median age was 52 (range 40–81 yr), median ECOG performance status was 0 (range 0–1), and most women received concurrent tamoxifen (observation 74%, ZA 61%). Over 12 months, L1–4 spine BMD decreased in the observation arm (-0.006 ± 0.034 g/cm2) and increased in the ZA arm (p<0.001; 0.050 ± 0.042 g/cm2). No significant BMD change occurred at the femur neck. Only three grade 3 events occurred (2 arthralgia, 1 myalgia). Side effects were mild and transient, but as frequent as 87% following dose 1. The most common side effects were fatigue, myalgia and arthralgia. No clinically significant changes in creatinine or calcium occurred. Osteonecrosis of the jaw was not observed. Of the 66 women enrolled, 7 have relapsed (observation 4, ZA 3) but time since diagnosis is less than 10 years for most patients. Conclusions: ZA administered every 12 weeks for 4 doses leads to a statistically and clinically significant change in BMD at the lumbar spine. Toxicity was mild but common. There are as yet no significant differences in cancer relapse. No significant financial relationships to disclose.

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Comparing the Efficacy and Side Effects of PDLASTA® (Peg-Filgrastim) with PDGRASTIM® (Filgrastim) in Breast Cancer Patients; A Non-inferiority Randomized Clinical Trial

10.21203/rs.3.rs-78768/v1 ◽

2020 ◽

Author(s):

Safa Najafi ◽

Maryam Ansari ◽

Vahid Kaveh ◽

Shahpar Haghighat

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Single Dose ◽

Side Effects ◽

Randomized Clinical Trial ◽

Cancer Patients ◽

Injection Site Reaction ◽

Study Groups ◽

Breast Cancer Patients ◽

Significant Difference

Abstract Background: The objective of this study was to compare the efficacy and side effects of to evaluate the efficacy and safety of a single dose (Peg-Filgrastim or PDL) or repeated six daily injections (Filgrastim or PDG) during chemotherapy courses in breast cancer patients in a non-inferiority clinical trial.Methods: In this randomized clinical trial, 80 patients recruited and allocated randomly in two equal arms. In one group, a single subcutaneous dose of 6 mg of PDL was injected the day after receiving a chemotherapy regimen in each cycle. The second arm received a subcutaneous injection of 300 micrograms per day for six consecutive days in each course of treatment. Side effects of GCF treatment and its effect on blood parameters were compared in each cycle and during eight courses of chemotherapy.Results: hematologic parameters showed no significant difference in each course of treatment between two groups of study. The comparison of the WBC (p=0.527), Hgb (p=0.075), Platelet (p=0.819), Neutrophil (p=0.575), Lymphocyte (p=705) and ANC (p=0.675) changes during eight courses of treatment identified no statistically significant difference between two study groups. Side effects including headache, injection site reaction and muscle pain had a lower frequency in patients receiving PDL drugs.Conclusion: Regarding our results, PDL is completely non- inferior in efficacy and also less toxic compared to PDG. Prescribing in single-dose and lower expenses of PDL introduces it as a cost-effective drug in the treatment of chemotherapy-induced neutropenia. Trial registration number, date of registration: IRCT20190504043465N1, May 2019https://www.irct.ir/search/result?query=IRCT20190504043465N1

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A comparison of genomic assays in determining risk of late recurrence and benefit of extended endocrine therapy (EET).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e12045 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e12045-e12045

Author(s):

Kathleen Raque ◽

Lina Marie Rico ◽

Eddy Yu ◽

W. Bradford Carter ◽

Thomas G. Frazier

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Risk Model ◽

Uterine Cancer ◽

Recurrence Score ◽

Individual Risk ◽

Breast Cancer Patients ◽

Node Negative ◽

Gene Assay ◽

Er Positive

e12045 Background: Breast cancer patients who are ER positive, lymph node negative have the best overall prognosis. However 50% of recurrences occur after 5 years. The Breast Cancer Index (BCI) is a gene expression-based biomarker that provides an individual risk of distant recurrence and benefit of EET based on a continuous risk model. (1) The BCI may help with clinical decisions regarding EET since prolonged therapy may have an increase in side effects including uterine cancer, DVT, myalgias and bone loss. The OncotypeDX is a 21 gene assay that predicts recurrence with a recurrence score. A recent study by Wolmark et al. evaluated the use of quantitative Estrogen Receptor Index (ESRI) combined with RS and found that RS was prognostic in patients with higher quantitative ESRI, suggesting EET be used for patients with intermediate and high RS with ESR1 expression > 9.1. (2) Methods: 20 patients, ER positive, node negative who had the BCI and ONC-DX performed were evaluated in this retrospective IRB approved review. Results: Using ESRI alone 85% of patients would be recommended to continue an additional 5 years of EET. Using BCI this number was reduced to 35%. Conclusions: Comparing both the risk of recurrence and benefit of ETT, ESRI and BCI were concordant only 37.5% of the time. The cost of extended adjuvant therapy with Anastrazole ($190/mos x 60 mos = $11,400) or Tamoxifen ($50/mos x 60 mos = $ 3,000) would have resulted in a cost savings of $79,800 (Anastrazole) or $21,000 (Tamoxifen) for this small group of patients. Utilization of the BCI (cost $ 3416.00) may be a cost effective and accurate genomic approach in determining the use of EET and avoiding concomitant side effects.

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CYP19A1 rs10046 Pharmacogenetics in Postmenopausal Breast Cancer Patients Treated with Aromatase Inhibitors: One-year Follow-up

Current Pharmaceutical Design ◽

10.2174/1381612826666200908141858 ◽

2020 ◽

Vol 26 (46) ◽

pp. 6007-6012

Author(s):

Karin Baatjes ◽

Armand Peeters ◽

Micheal McCaul ◽

Maria M. Conradie ◽

Justus Apffelstaedt ◽

...

Keyword(s):

Breast Cancer ◽

Lumbar Spine ◽

Bone Loss ◽

Cancer Patients ◽

Aromatase Inhibitors ◽

Postmenopausal Breast Cancer ◽

Breast Cancer Patients ◽

Mineral Density ◽

Er Positive ◽

Positive Breast Cancer

Background: Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer. Methods: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine. Results: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04). Conclusions: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.

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Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽

10.3390/cancers13040771 ◽

2021 ◽

Vol 13 (4) ◽

pp. 771

Author(s):

Tessa A. M. Mulder ◽

Mirjam de With ◽

Marzia del Re ◽

Romano Danesi ◽

Ron H. J. Mathijssen ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Cancer Patients ◽

Plasma Concentrations ◽

Tamoxifen Treatment ◽

Current Status ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Er Positive ◽

Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

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The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling

Nature Communications ◽

10.1038/s41467-021-24631-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Eui Jung Moon ◽

Stephano S. Mello ◽

Caiyun G. Li ◽

Jen-Tsan Chi ◽

Kaushik Thakkar ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Invasion ◽

Critical Role ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Invasion And Metastasis ◽

Stat3 Signaling ◽

Inducible Genes ◽

Transcriptional Target

AbstractHypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

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Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells

Molecules ◽

10.3390/molecules26113143 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3143

Author(s):

Sergey E. Parfenyev ◽

Sergey V. Shabelnikov ◽

Danila Y. Pozdnyakov ◽

Olga O. Gnedina ◽

Leonid S. Adonin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Malignant Neoplasm ◽

Malignant Neoplasms ◽

Breast Cancer Patients ◽

Survival Prognosis ◽

Mesenchymal Transition ◽

Wide Range

Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.

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The impact of hyperbaric oxygen therapy on late radiation toxicity and quality of life in breast cancer patients

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06332-2 ◽

2021 ◽

Author(s):

Marilot C. T. Batenburg ◽

Wies Maarse ◽

Femke van der Leij ◽

Inge O. Baas ◽

Onno Boonstra ◽

...

Keyword(s):

Breast Cancer ◽

Quality Of Life ◽

Side Effects ◽

Cancer Patients ◽

Oxygen Therapy ◽

Radiation Toxicity ◽

Breast Pain ◽

Breast Cancer Patients

Abstract Purpose To evaluate symptoms of late radiation toxicity, side effects, and quality of life in breast cancer patients treated with hyperbaric oxygen therapy (HBOT). Methods For this cohort study breast cancer patients treated with HBOT in 5 Dutch facilities were eligible for inclusion. Breast cancer patients with late radiation toxicity treated with ≥ 20 HBOT sessions from 2015 to 2019 were included. Breast and arm symptoms, pain, and quality of life were assessed by means of the EORTC QLQ-C30 and -BR23 before, immediately after, and 3 months after HBOT on a scale of 0–100. Determinants associated with persistent breast pain after HBOT were assessed. Results 1005/1280 patients were included for analysis. Pain scores decreased significantly from 43.4 before HBOT to 29.7 after 3 months (p < 0.001). Breast symptoms decreased significantly from 44.6 at baseline to 28.9 at 3 months follow-up (p < 0.001) and arm symptoms decreased significantly from 38.2 at baseline to 27.4 at 3 months follow-up (p < 0.001). All quality of life domains improved at the end of HBOT and after 3 months follow-up in comparison to baseline scores. Most prevalent side effects of HBOT were myopia (any grade, n = 576, 57.3%) and mild barotrauma (n = 179, 17.8%). Moderate/severe side effects were reported in 3.2% (n = 32) of the patients. Active smoking during HBOT and shorter time (i.e., median 17.5 vs. 22.0 months) since radiotherapy were associated with persistent breast pain after HBOT. Conclusion Breast cancer patients with late radiation toxicity reported reduced pain, breast and arm symptoms, and improved quality of life following treatment with HBOT.

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