Influence of pre-operative oral carbohydrate loading vs. standard fasting on tumor proliferation and clinical outcome in breast cancer patients ─ a randomized trial

Abstract Background Conflicting results have been reported on the influence of carbohydrates in breast cancer. Objective To determine the influence of pre-operative per-oral carbohydrate load on proliferation in breast tumors. Design Randomized controlled trial. Setting University hospital with primary and secondary care functions in South-West Norway. Patients Sixty-one patients with operable breast cancer from a population-based cohort. Intervention Per-oral carbohydrate load (preOp™) 18 and 2–4 h before surgery (n = 26) or standard pre-operative fasting with free consumption of tap water (n = 35). Measurements The primary outcome was post-operative tumor proliferation measured by the mitotic activity index (MAI). The secondary outcomes were changes in the levels of serum insulin, insulin-c-peptide, glucose, IGF-1, and IGFBP3; patients’ well-being, and clinical outcome over a median follow-up of 88 months (range 33–97 months). Results In the estrogen receptor (ER) positive subgroup (n = 50), high proliferation (MAI ≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p = 0.038). The CH group was more frequently progesterone receptor (PR) negative (p = 0.014). The CH group had a significant increase in insulin (+ 24.31 mIE/L, 95% CI 15.34 mIE/L to 33.27 mIE/L) and insulin c-peptide (+ 1.39 nM, 95% CI 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (− 0.26 nM; 95% CI − 0.46 nM to − 0.051 nM) compared to the fasting group. CH-intervention ER-positive patients had poorer relapse-free survival (73%) than the fasting group (100%; p = 0.012; HR = 9.3, 95% CI, 1.1 to 77.7). In the ER-positive patients, only tumor size (p = 0.021; HR = 6.07, 95% CI 1.31 to 28.03) and the CH/fasting subgrouping (p = 0.040; HR = 9.30, 95% CI 1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with relapse-free survival of 100% in the fasting group vs. 33% in the CH group (p = 0.015; HR = inf). The CH group reported less pain on days 5 and 6 than the control group (p < 0.001) but otherwise exhibited no factors related to well-being. Limitation Only applicable to T2 tumors in patients with ER-positive breast cancer. Conclusions Pre-operative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2 patients. Trial registration CliniTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.

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Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

10.21203/rs.2.11085/v1 ◽

2019 ◽

Author(s):

Tone Hoel Lende ◽

Marie Austdal ◽

Anne Elin Varhaugvik ◽

Ivar Skaland ◽

Einar Gudlaugsson ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Well Being ◽

Breast Cancer Patients ◽

Relapse Free Survival ◽

Free Survival ◽

C Peptide ◽

Er Positive ◽

Carbohydrate Load ◽

Per Oral

Abstract Background The influence of carbohydrates in breast cancer is conflicting. Objective To determine whether preoperative per-oral carbohydrate load influences proliferation in breast tumors. Design Randomized controlled trial. Setting University hospital with primary and secondary care functions in South-West Norway. Patients A population-based cohort of 61 patients with operable breast cancer. Intervention Per-oral carbohydrate load (preOp™) 18 and 2-4 hours before surgery (n=26) or standard pre-operative fasting procedure with free consume of tap water (n=35). Measurements Primary outcome was post-operative tumor proliferation measured as mitotic activity index (MAI). Secondary outcomes were changes in serum insulin, insulin-c-peptide, glucose, IGF-1 and IGFBP3. Other secondary outcomes were patients´ well-being and clinical outcome (median follow-up 88, range 33-97 months). Results In the estrogen receptor (ER) positive subgroup (n=50), high proliferation (MAI≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p=0.038). Progesterone receptor (PR) was more frequently negative in the CH-group (p=0.014). CH-patients had a significant between group rise in insulin (+ 24.31 mIE/L, 95% CI, 15.34 mIE/L to 33.27 mIE/L), insulin c-peptide (+ 1.39 nM, 95% CI, 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (– 0.26 nM; 95% CI, – 0.46 nM to – 0.051 nM). CH-Intervention ER-positive patients had poorer relapse free survival (73%) than the fasting group (100%) (p=0.012; HR= 9.3 (95%CI, 1.1 to 77.7)). In the ER-positive patients, only tumor size (p=0.021; HR=6.07, 95%CI=1.31 to 28.03) and CH-or-fasting grouping (p=0.040; HR=9.30, 95% CI=1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with Relapse Free Survival of 100% in the fasting group vs. 33% in the CH-group (p=0.015; HR= inf). The CH-group reported less pain on day 5 and 6 compared to the control group (p<0.001) but showed otherwise no factors related to well-being. Limitation Only applicable to ER-positive breast cancer patients with T2-tumors. Conclusions Preoperative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2-patients. Keywords: breast cancer, carbohydrate load, proliferation, insulin, insulin c-peptide, IGF-1, IGFBP3, tumor size, relapse free survival, breast cancer specific survival

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Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

10.21203/rs.2.11085/v2 ◽

2019 ◽

Author(s):

Tone Hoel Lende ◽

Marie Austdal ◽

Anne Elin Varhaugvik ◽

Ivar Skaland ◽

Einar Gudlaugsson ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Tumor Proliferation ◽

Breast Cancer Patients ◽

Relapse Free Survival ◽

Free Survival ◽

Er Positive ◽

Secondary Outcomes ◽

Carbohydrate Load ◽

Per Oral

Abstract Background The influence of carbohydrates in breast cancer is conflicting.Objective To determine whether preoperative per-oral carbohydrate load influences proliferation in breast tumors.Design Randomized controlled trial.Setting University hospital with primary and secondary care functions in South-West Norway.Patients A population-based cohort of 61 patients with operable breast cancer.Intervention Per-oral carbohydrate load (preOp™) 18 and 2-4 hours before surgery (n=26) or standard pre-operative fasting procedure with free consume of tap water (n=35).Measurements Primary outcome was post-operative tumor proliferation measured as mitotic activity index (MAI). Secondary outcomes were changes in serum insulin, insulin-c-peptide, glucose, IGF-1 and IGFBP3. Other secondary outcomes were patients´ well-being and clinical outcome (median follow-up 88, range 33-97 months).Results In the estrogen receptor (ER) positive subgroup (n=50), high proliferation (MAI≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p=0.038). Progesterone receptor (PR) was more frequently negative in the CH-group (p=0.014). CH-patients had a significant between group rise in insulin (+ 24.31 mIE/L, 95% CI, 15.34 mIE/L to 33.27 mIE/L), insulin c-peptide (+ 1.39 nM, 95% CI, 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (– 0.26 nM; 95% CI, – 0.46 nM to – 0.051 nM). CH-Intervention ER-positive patients had poorer relapse free survival (73%) than the fasting group (100%) (p=0.012; HR= 9.3 (95%CI, 1.1 to 77.7)). In the ER-positive patients, only tumor size (p=0.021; HR=6.07, 95%CI=1.31 to 28.03) and CH-or-fasting grouping (p=0.040; HR=9.30, 95% CI=1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with Relapse Free Survival of 100% in the fasting group vs. 33% in the CH-group (p=0.015; HR= inf). The CH-group reported less pain on day 5 and 6 compared to the control group (p<0.001) but showed otherwise no factors related to well-being.Limitation Only applicable to ER-positive breast cancer patients with T2-tumors.Conclusions Preoperative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2-patients.

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Influence of pre-operative oral carbohydrate loading vs. standard fasting procedure on tumor proliferation and clinical outcome in breast cancer patients — a randomized trial

10.21203/rs.2.11085/v3 ◽

2019 ◽

Author(s):

Tone Hoel Lende ◽

Marie Austdal ◽

Anne Elin Varhaugvik ◽

Ivar Skaland ◽

Einar Gudlaugsson ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Tumor Proliferation ◽

Breast Cancer Patients ◽

Relapse Free Survival ◽

Free Survival ◽

Er Positive ◽

Secondary Outcomes ◽

Carbohydrate Load ◽

Per Oral

Abstract Background The influence of carbohydrates in breast cancer is conflicting.Objective To determine whether preoperative per-oral carbohydrate load influences proliferation in breast tumors.Design Randomized controlled trial.Setting University hospital with primary and secondary care functions in South-West Norway.Patients A population-based cohort of 61 patients with operable breast cancer.Intervention Per-oral carbohydrate load (preOp™) 18 and 2-4 hours before surgery (n=26) or standard pre-operative fasting procedure with free consume of tap water (n=35).Measurements Primary outcome was post-operative tumor proliferation measured as mitotic activity index (MAI). Secondary outcomes were changes in serum insulin, insulin-c-peptide, glucose, IGF-1 and IGFBP3. Other secondary outcomes were patients´ well-being and clinical outcome (median follow-up 88, range 33-97 months).Results In the estrogen receptor (ER) positive subgroup (n=50), high proliferation (MAI≥ 10) occurred more often in the carbohydrate group (CH) than in the fasting group (p=0.038). Progesterone receptor (PR) was more frequently negative in the CH-group (p=0.014). CH-patients had a significant between group rise in insulin (+ 24.31 mIE/L, 95% CI, 15.34 mIE/L to 33.27 mIE/L), insulin c-peptide (+ 1.39 nM, 95% CI, 1.03 nM to 1.77 nM), but reduced IGFBP3 levels (– 0.26 nM; 95% CI, – 0.46 nM to – 0.051 nM). CH-Intervention ER-positive patients had poorer relapse free survival (73%) than the fasting group (100%) (p=0.012; HR= 9.3 (95%CI, 1.1 to 77.7)). In the ER-positive patients, only tumor size (p=0.021; HR=6.07, 95%CI=1.31 to 28.03) and CH-or-fasting grouping (p=0.040; HR=9.30, 95% CI=1.11 to 77.82) had independent prognostic value. The adverse clinical outcome of carbohydrate loading occurred only in T2 patients with Relapse Free Survival of 100% in the fasting group vs. 33% in the CH-group (p=0.015; HR= inf). The CH-group reported less pain on day 5 and 6 compared to the control group (p<0.001) but showed otherwise no factors related to well-being.Limitation Only applicable to ER-positive breast cancer patients with T2-tumors.Conclusions Preoperative carbohydrate load increases proliferation and PR-negativity in ER-positive patients and worsens clinical outcome in ER-positive T2-patients.

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Metabolic consequences of perioperative oral carbohydrates in breast cancer patients — an explorative study

BMC Cancer ◽

10.1186/s12885-019-6393-7 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Tone Hoel Lende ◽

Marie Austdal ◽

Tone Frost Bathen ◽

Anne Elin Varhaugvik ◽

Ivar Skaland ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Clinical Outcomes ◽

Breast Cancer Patients ◽

Positive Correlation ◽

Explorative Study ◽

Er Positive ◽

Lactate And Pyruvate ◽

Carbohydrate Load ◽

Per Oral

Abstract Background The metabolic consequences of preoperative carbohydrate load in breast cancer patients are not known. The present explorative study investigated the systemic and tumor metabolic changes after preoperative per-oral carbohydrate load and their influence on tumor characteristics and survival. Methods The study setting was on university hospital level with primary and secondary care functions in south-west Norway. Serum and tumor tissue were sampled from a population-based cohort of 60 patients with operable breast cancer who were randomized to either per-oral carbohydrate load (preOp™; n = 25) or standard pre-operative fasting (n = 35) before surgery. Magnetic resonance (MR) metabolomics was performed on serum samples from all patients and high-resolution magic angle spinning (HR-MAS) MR analysis on 13 tumor samples available from the fasting group and 16 tumor samples from the carbohydrate group. Results Fourteen of 28 metabolites were differently expressed between fasting and carbohydrate groups. Partial least squares discriminant analysis showed a significant difference in the metabolic profile between the fasting and carbohydrate groups, compatible with the endocrine effects of insulin (i.e., increased serum-lactate and pyruvate and decreased ketone bodies and amino acids in the carbohydrate group). Among ER-positive tumors (n = 18), glutathione was significantly elevated in the carbohydrate group compared to the fasting group (p = 0.002), with a positive correlation between preoperative S-insulin levels and the glutathione content in tumors (r = 0.680; p = 0.002). In all tumors (n = 29), glutamate was increased in tumors with high proliferation (t-test; p = 0.009), independent of intervention group. Moreover, there was a positive correlation between tumor size and proliferation markers in the carbohydrate group only. Patients with ER-positive / T2 tumors and high tumor glutathione (≥1.09), high S-lactate (≥56.9), and high S-pyruvate (≥12.5) had inferior clinical outcomes regarding relapse-free survival, breast cancer-specific survival, and overall survival. Moreover, Integrated Pathway Analysis (IPA) in serum revealed activation of five major anabolic metabolic networks contributing to proliferation and growth. Conclusions Preoperative carbohydrate load increases systemic levels of lactate and pyruvate and tumor levels of glutathione and glutamate in ER-positive patients. These biological changes may contribute to the inferior clinical outcomes observed in luminal T2 breast cancer patients. Trial of registration ClinicalTrials.gov; NCT03886389. Retrospectively registered March 22, 2019.

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Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.7.879 ◽

1989 ◽

Vol 7 (7) ◽

pp. 879-889 ◽

Cited By ~ 39

Author(s):

S G Taylor ◽

M W Knuiman ◽

L A Sleeper ◽

J E Olson ◽

D C Tormey ◽

...

Keyword(s):

Breast Cancer ◽

Eastern Cooperative Oncology Group ◽

Observation Group ◽

Oncology Group ◽

Relapse Free Survival ◽

Free Survival ◽

Node Positive ◽

Er Positive ◽

Free Status ◽

Positive Breast Cancer

The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.

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Genomic Grade Index Is Associated With Response to Chemotherapy in Patients With Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.5934 ◽

2009 ◽

Vol 27 (19) ◽

pp. 3185-3191 ◽

Cited By ~ 130

Author(s):

Cornelia Liedtke ◽

Christos Hatzis ◽

William Fraser Symmans ◽

Christine Desmedt ◽

Benjamin Haibe-Kains ◽

...

Keyword(s):

Breast Cancer ◽

Residual Disease ◽

Pathologic Complete Response ◽

Pathologic Response ◽

Relapse Free Survival ◽

Free Survival ◽

Genomic Grade Index ◽

Response To Chemotherapy ◽

Er Positive ◽

Grade Index

Purpose The genomic grade index (GGI) is a 97-gene measure of histological tumor grade. High GGI is associated with decreased relapse-free survival in patients receiving either endocrine or no systemic adjuvant therapy. Herein we examined whether GGI predicts pathologic response to neoadjuvant chemotherapy in patients with HER-2–normal breast cancer. Methods Gene expression data (gene chips) was generated from fine-needle aspiration biopsies (n = 229) prospectively collected before neoadjuvant paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Pathologic response was quantified using the residual cancer burden (RCB) method. The association between the GGI and pathologic response was assessed in univariate and multivariate analyses. The performance of a response predictor combining clinical variables and GGI was evaluated under cross-validation. Results Eighty-five percent of grade 1 tumors had low GGI, 89% of grade 3 tumors had high GGI, and 63% of grade 2 tumors had low GGI. Among both estrogen receptor (ER)-positive and -negative cancers, high GGI score was associated with pathologic complete response (RCB-0) or minimal residual disease (RCB-1). A multivariate model combining GGI and clinical parameters had an overall accuracy of 71%, compared with 58% for the GGI alone, for prediction of pathologic response. However, high GGI score was also associated with significantly worse distant relapse-free survival in patients with ER-positive cancer (P = .005), and was not associated with survival in patients with ER-negative cancer. Conclusion High GGI is associated with increased sensitivity to neoadjuvant paclitaxel plus fluorouracil, adriamycin, and cyclophosphamide chemotherapy in both ER-negative and ER-positive patients, but it remains a predictor of worse survival in ER-positive patients.

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Metabolic consequences of perioperative oral carbohydrates in breast cancer patients: An explorative study

10.21203/rs.2.14928/v1 ◽

2019 ◽

Author(s):

Tone Hoel Lende ◽

Marie Austdal ◽

Tone Frost Bathen ◽

Anne Elin Varhaugvik ◽

Ivar Skaland ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Clinical Outcomes ◽

Magic Angle ◽

Breast Cancer Patients ◽

Explorative Study ◽

Er Positive ◽

Lactate And Pyruvate ◽

Carbohydrate Load ◽

Per Oral

Abstract Background: The metabolic consequences of preoperative carbohydrate load in breast cancer patients are not known. The present study investigated the systemic and tumor metabolic changes after preoperative per-oral carbohydrate load and their influence on tumor characteristics and survival. Design: Explorative study. Setting: University hospital with primary and secondary care functions in south-west Norway.Interventions and Outcome Measures: Serum and tumor tissue were sampled from a population-based cohort of 60 patients with operable breast cancer who were randomized to either per-oral carbohydrate load (preOp™; n=25) or standard pre-operative fasting (n=35) before surgery. Magnetic resonance (MR) metabolomics was performed on serum samples from all patients and high-resolution magic angle spinning (HR-MAS) MR analysis on 13 tumor samples available from the fasting group and 16 tumor samples from the carbohydrate group. Results: Fourteen of 28 metabolites were differently expressed between fasting and carbohydrate groups. Partial least squares discriminant analysis showed a significant difference in the metabolic profile between the fasting and carbohydrate groups, compatible with the endocrine effects of insulin (i.e., increased serum-lactate and pyruvate and decreased ketone bodies and amino acids in the carbohydrate group). Among ER-positive tumors (n=18), glutathione was significantly elevated in the carbohydrate group compared to the fasting group (p=0.002), with a positive correlation between preoperative S-insulin levels and the glutathione content in tumors (r=0.680; p=0.002). In all tumors (n=29), glutamate was increased in tumors with high proliferation (t-test; p=0.009), independent of intervention group. Patients with ER-positive / T2 tumors and high tumor glutathione (≥1.09), high S-lactate (≥56.9), and high S-pyruvate (≥12.5) had inferior clinical outcomes regarding relapse-free survival, breast cancer-specific survival, and overall survival. Moreover, Integrated Pathway Analysis (IPA) in serum revealed activation of five major anabolic metabolic networks contributing to proliferation and growth. Conclusions: Preoperative carbohydrate load increases systemic levels of lactate and pyruvate and tumor levels of glutathione and glutamate in ER-positive patients. These biological changes may contribute to the inferior clinical outcomes observed in luminal T2 breast cancer patients. Registration of trial: CliniTrials.gov; NCT03886389. Retrospectively registered March 22, 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT03886389?cond=Breast+cancer+diet&rank=1

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Effect of Wnt5a on aggressiveness of ER-positive breast cancer and cancer cell migration through JNK-ALCAM pathway.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11614 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11614-11614

Author(s):

Yoshie Kobayashi ◽

Takayuki Kadoya ◽

Ai Amioka ◽

Noriko Gohda ◽

Miho Kono ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Survival Rates ◽

Breast Cancer Patients ◽

Mcf7 Cells ◽

Relapse Free Survival ◽

Free Survival ◽

Wnt5a Expression ◽

Er Positive ◽

Positive Breast Cancer

11614 Background: Wnt5a is a representative ligand that activates β-catenin-independent pathways and involved in cell motility and cell polarity, and the like, being mediated by JNK. We elucidated the implication of Wnt5a expression in breast cancer. Methods: One hundred seventy eight breast cancer patients (mean age ± SD: 60.0 ± 13.2 years) with clinical Stage I-III between January 2011 and February 2014, were prospectively evaluated. We examined relationships between Wnt5a expression and clinicopathological factors by immunohistochemical analyses. 5-year relapse-free survival rates and sites of recurrence were analyzed. In addition, molecules induced by Wnt5a in cultured cells were identified by DNA microarray analysis. Results: Wnt5a expression was significantly more frequent when estrogen receptor (ER) was present, 68/153 (44%) than when ER was absent, 1/25 (4%) (P <0.001) (Table). In ER-positive breast cancer, a significant interaction between expression of Wnt5a with lymph node metastasis (P<0.001), high nuclear grade (P=0.004), and lymphatic invasion (P=0.001). 5-year relapse-free survival rates were 81.1% and 100% in Wnt5a-positive and Wnt5a-negative breast cancers, respectively (P = 0.024). All recurrent breast cancer patients in this study had bone metastasis. We established MCF7 stably expressing Wnt5a (Wnt5a/MCF7 cells) and microarray analyses identified several genes induced by Wnt5a (>3.0 fold), involving activated leukocyte cell adhesion molecule (ALCAM). ALCAM is known to be related with apoptosis, invasion and prognosis of breast cancer. We focused on ALCAM and investigated its protein expression by Western blotting, and found remarkable increase of ALCAM in Wnt5a/MCF7 cells. Conclusions: Wnt5a expresses in ER-positive breast cancer and is associated with high-grade malignancy and a poor prognosis through JNK-ALCAM pathway. Wnt5a could be a novel prognostic factor of ER-positive breast cancer. [Table: see text]

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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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