CYP1A2 – a novel genetic marker for early aromatase inhibitor response in the treatment of breast cancer patients

Simonsson, Maria; Veerla, Srinivas; Markkula, Andrea; Rose, Carsten; Ingvar, Christian; Jernström, Helena

doi:10.1186/s12885-016-2284-3

Cited by 12 publications

(11 citation statements)

References 53 publications

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“…Cigarette smoke may also interact with therapy through upregulation of cytochrome P 450 enzymes such as CYP1A2 that is involved in both metabolism of oestrogens and AIs ( Grimm and Dyroff, 1997 ; Schrenk et al , 1998 ; Tsuchiya et al , 2005 ; Kamdem et al , 2011 ). Moreover, CYP1A2 genotypes predicted short-term prognosis in AI-treated patients from a subset of this cohort ( Simonsson et al , 2016 ). If cigarette smoke interacts with AIs, smokers assigned to AIs should be encouraged to quit.…”

Section: Discussionmentioning

confidence: 99%

Impacts of smoking on endocrine treatment response in a prospective breast cancer cohort

et al. 2016

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Background:The association between smoking and breast cancer prognosis remains unclear. The purpose of this study was to investigate whether preoperative smoking was associated with prognosis in different treatment groups.Methods:This population-based cohort consisted of 1065 breast cancer patients without preoperative treatment included between 2002 and 2012 in Lund, Sweden. Smoking status was examined in relation to patient and tumour characteristics, and prognosis in different treatment groups.Results:At the preoperative visit, 21.0% smoked. Median follow-up time was 5.1 years. Overall, in the 1016 patients included in the survival analyses, there was no significant association between smoking and risk of breast cancer events (adjusted hazard ratio (adjHR): 1.45; 95% confidence interval (CI): 0.95–2.20). For the 309 aromatase inhibitor (AI)-treated patients ⩾50 years with oestrogen receptor-positive (ER+) tumours, smoking was associated with risk of breast cancer events (adjHR: 2.97; 95% CI: 1.44–6.13), distant metastasis (adjHR: 4.19; 95% CI: 1.81–9.72), and death (adjHR: 3.52; 95% CI: 1.59–7.81). Smoking was not associated with breast cancer events or distant metastasis in other treatment groups.Conclusions:Preoperative smoking was only associated with an increased risk for breast cancer events and distant metastasis in AI-treated patients. If confirmed, smoking status should be taken into consideration when selecting an endocrine therapy.

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Section: Discussionmentioning

confidence: 99%

Impacts of smoking on endocrine treatment response in a prospective breast cancer cohort

et al. 2016

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“…We selected 91 SNPs to include in the analyses based on our previous study [ 14 ] and other published studies that identified genes related to estrogen and inflammation pathways [ [12] , [13] , [14] , [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] ]. Participant DNA was extracted from buffy coat specimens using the Qiagen QiaAmp 96 DNA Blood Kit (Valencia, CA).…”

Section: Methodsmentioning

confidence: 99%

Clinical and genetic risk factors for aromatase inhibitor-associated arthralgia in breast cancer survivors

Romero

Satagopan

et al. 2020

The Breast

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Background Arthralgia is a common and debilitating toxicity of aromatase inhibitors (AI) that leads to premature drug discontinuation. We sought to evaluate the clinical and genetic risk factors associated with AI-associated arthralgia (AIAA). Methods We performed a cross-sectional study among postmenopausal women with stage 0-III breast cancer who were prescribed a third-generation AI for adjuvant therapy. The primary outcome was patient-reported AIAA occurrence. We extracted and assayed germline DNA for single nucleotide polymorphisms (SNPs) of genes implicated in estrogen and inflammation pathways. Multivariable logistic regression models examined the association between demographic, clinical, and genetic factors and AIAA. Analyses were restricted to White participants. Results Among 1049 White participants, 543 (52%) reported AIAA. In multivariable analyses, women who had a college education [Adjusted Odds Ratio (AOR) 1.49, 95% Confidence Interval (CI) 1.00–2.20], had a more recent transition into menopause (<10 years) (5–10 years AOR 1.55, 95% CI 1.09–2.22; <5 years AOR 1.78, 95% CI 1.18–2.67), were within one year of starting AIs (AOR 1.61, 95% CI 1.08–2.40), and those who received chemotherapy (AOR 1.38, 95% CI 1.02–1.88) were significantly more likely to report AIAA. Additionally, SNP rs11648233 ( HSD17B2 ) was significantly associated with higher odds of AIAA (AOR 2.21, 95% CI 1.55–3.16). Conclusions Time since menopause and start of AIs, prior chemotherapy, and SNP rs11648233 within the HSD17B2 gene in the estrogen pathway were significantly associated with patient-reported AIAA. These findings suggest that clinical and genetic factors involved in estrogen withdrawal increase the risk of AIAA in postmenopausal breast cancer survivors.

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“…This study is based on 1,116 patients who were included in a prospective cohort of primary breast cancer patients (BC‐Blood Study) at the Skåne University Hospital in Lund, Sweden that has been previously described in depth . The patients in the present study were included between October 2002 and June 2012, were between 24 and 99 years of age, and did not have any history of cancer during the past 10 years.…”

Section: Methodsmentioning

confidence: 99%

The prognostic impact of COX‐2 expression in breast cancer depends on oral contraceptive history, preoperative NSAID use, and tumor size

Simonsson

Björner

Markkula

et al. 2016

Intl Journal of Cancer

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The association between tumor cyclooxygenase 2 (COX-2) expression and breast cancer prognosis has been inconsistent. The purpose of this study was to evaluate the prognostic significance of COX-2 tumor expression according to adjuvant treatment, and potential effect modifications of non-steroid anti-inflammatory drug (NSAID) use, and other tumor and lifestyle factors. A prospective cohort of 1,116 patients with primary breast cancer in Lund, Sweden, included 2002-2012 was followed until June 2014 (median 5 years). Tumor-specific COX-2 expression was evaluated on tissue microarrays using immunohistochemistry. Associations between COX-2 intensity (negative, weak-moderate, high) and patient and tumor characteristics as well as prognosis were analyzed. Tumor-specific COX-2 expression was available for 911 patients and was significantly associated with higher age at diagnosis and less aggressive tumor characteristics. Higher COX-2 expression was associated with lower risk for breast cancer events during the first five years of follow-up, adj HR 0.60 (95%CI: 0.37-0.97), per category. The association between COX-2 expression and prognosis was significantly modified by oral contraceptive (OC) use (P interaction 5 0.048), preoperative NSAID use (P interaction 5 0.009), and tumor size (P interaction 5 0.039). COX-2 negativity was associated with increased risk for events during the first five years in ever OC users, adj HR 1.94 (1.01-3.72) and during the 11-year follow-up in preoperative NSAID users, adj HR 4.51 (1.18-11.44) as well as in patients with large tumors, adj HR 2.57 (1.28-5.15). In conclusion, this study, one of the largest evaluating COX-2 expression in breast cancer, indicates that the prognostic impact of COX-2 expression depends on host factors and tumor characteristics.Breast cancer is a heterogeneous disease where most patients have a good prognosis. Improved tumor classification could identify subgroups of patients with a poorer prognosis who are in need of more personalized treatment. 1 In breast cancer, cyclooxygenase 2 (COX-2)-mediated prostaglandin aromatase gene activation increases both aromatase and estrogen levels that may lead to increased proliferation, primarily in patients with estrogen receptor positive (ER-positive) tumors and in postmenopausal patients. 2 COX-2 catalyzes the conversion of arachidonic acid to prostaglandins and have pro-inflammatory effects. 2 COX-2 expression in predominantly ER-negative tumors was shown to lead to Akt-pathway activation. 2,3 Regarding prognosis, most, 1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] but not all, 20-27 studies have found an association between high COX-2 expression and worse prognosis. Whether COX-2 expression was associated with prognosis in the different studies also depended on tumor characteristics, type of breast cancer treatment, body constitution, and concomitant medications. 1,6 Non-steroidal anti-inflammatory drugs (NSAIDs) including both selective COX-2 inhibitors and non-selective COX-1/2 inhibitors as well as ac...

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CYP1A2 – a novel genetic marker for early aromatase inhibitor response in the treatment of breast cancer patients

Cited by 12 publications

References 53 publications

Impacts of smoking on endocrine treatment response in a prospective breast cancer cohort

Impacts of smoking on endocrine treatment response in a prospective breast cancer cohort

Clinical and genetic risk factors for aromatase inhibitor-associated arthralgia in breast cancer survivors

The prognostic impact of COX‐2 expression in breast cancer depends on oral contraceptive history, preoperative NSAID use, and tumor size

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