Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark
Purpose Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism),...
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| Veröffentlicht in: | Breast cancer research and treatment 2022-07, Vol.194 (2), p.353-363 |
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| creator | Hjorth, Cathrine F. Damkier, Per Stage, Tore B. Feddersen, Søren Hamilton-Dutoit, Stephen Rørth, Mikael Ejlertsen, Bent Lash, Timothy L. Ahern, Thomas P. Sørensen, Henrik T. Cronin-Fenton, Deirdre |
| description | Purpose
Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.
Methods
We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.
Results
Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of
GSTP1
rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and
CYP3A
rs10273424 (HR: 1.33, 95% CI 0.98–1.81).
SLCO1B1
rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98).
Conclusion
Docetaxel effectiveness was influenced by SNPs in
GSTP1, CYP3A,
and
SLCO1B1
in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy. |
| doi_str_mv | 10.1007/s10549-022-06596-2 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9239972</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A708580612</galeid><sourcerecordid>A708580612</sourcerecordid><originalsourceid>FETCH-LOGICAL-c572t-5ef0dfdddfbb61f1bed0b2d62b4f9f00978b45ff74a8bb506c6ea422c20b9c3</originalsourceid><addsrcrecordid>eNp9kttqFTEUhgdRbK2-gBcSEMSbqUnm7EWh1CMUvKj3IYeVPamZZEwyxf0wvquZ7p62iORiIPn-f81a6y-KlwQfE4y7d5Hgph5KTGmJ22ZoS_qoOCRNV5UdJd3j4hCTtivbHrcHxbMYLzHGQ4eHp8VB1TSY1JQeFr8vjNtYKN0iLfhkFKDZ2-3kwzyaOEXEnUJpBARag0zmChzEiLxGif_iDkrBIygkR5h8xgKft8g4NAeYwPmZL5FbJALwmJDkTkJ4j3guMS-WJ-Pdrd6PPiQU06Ku9R_ATTz8eF480dxGeHHzPSouPn38fvalPP_2-evZ6Xkpm46msgGNlVZKaSFaookAhQVVLRW1HvTadS_qRuuu5r0QDW5lCzy3LykWg6yOipOd67yICZQElwK3bA4m_8OWeW7Y_oszI9v4KzbQahg6mg3e3hgE_3OBmNhkogRr84D8EhnN26G07-o2o6__Qi_9ElxuLlM9aaumpdU9teEWmHHa57pyNWWnHe6bvFKylj3-B5WPgslI70CbfL8nePNAMAK3aYzeLusi4j5Id6AMPsYA-m4YBLM1e2yXPZazx66zx1bRq4djvJPchi0D1Q6I-cltINz3_h_bPyhw6F8</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2681635623</pqid></control><display><type>article</type><title>Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark</title><source>SpringerLink Journals</source><creator>Hjorth, Cathrine F. ; Damkier, Per ; Stage, Tore B. ; Feddersen, Søren ; Hamilton-Dutoit, Stephen ; Rørth, Mikael ; Ejlertsen, Bent ; Lash, Timothy L. ; Ahern, Thomas P. ; Sørensen, Henrik T. ; Cronin-Fenton, Deirdre</creator><creatorcontrib>Hjorth, Cathrine F. ; Damkier, Per ; Stage, Tore B. ; Feddersen, Søren ; Hamilton-Dutoit, Stephen ; Rørth, Mikael ; Ejlertsen, Bent ; Lash, Timothy L. ; Ahern, Thomas P. ; Sørensen, Henrik T. ; Cronin-Fenton, Deirdre</creatorcontrib><description>Purpose
Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.
Methods
We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.
Results
Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of
GSTP1
rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and
CYP3A
rs10273424 (HR: 1.33, 95% CI 0.98–1.81).
SLCO1B1
rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98).
Conclusion
Docetaxel effectiveness was influenced by SNPs in
GSTP1, CYP3A,
and
SLCO1B1
in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.</description><identifier>ISSN: 0167-6806</identifier><identifier>EISSN: 1573-7217</identifier><identifier>DOI: 10.1007/s10549-022-06596-2</identifier><identifier>PMID: 35501422</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Analysis ; Anthracycline ; Anthracyclines ; Breast cancer ; Cancer ; Cancer research ; Care and treatment ; Chemotherapy ; Cohort analysis ; Cyclophosphamide ; Cytochrome P-450 ; DNA repair ; Drug metabolism ; Drug therapy, Combination ; Enzymes ; Epidemiology ; Formaldehyde ; Genetic aspects ; Glutathione transferase ; Health aspects ; Medicine ; Medicine & Public Health ; Menopause ; Metastases ; Metastasis ; Mortality ; Oncology ; Oncology, Experimental ; Paraffin ; Pharmacokinetics ; Physiological aspects ; Population studies ; Population-based studies ; Regression analysis ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Taxanes ; Tumors</subject><ispartof>Breast cancer research and treatment, 2022-07, Vol.194 (2), p.353-363</ispartof><rights>The Author(s) 2022. corrected publication 2022</rights><rights>2022. The Author(s).</rights><rights>COPYRIGHT 2022 Springer</rights><rights>The Author(s) 2022. corrected publication 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2022, corrected publication 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c572t-5ef0dfdddfbb61f1bed0b2d62b4f9f00978b45ff74a8bb506c6ea422c20b9c3</citedby><cites>FETCH-LOGICAL-c572t-5ef0dfdddfbb61f1bed0b2d62b4f9f00978b45ff74a8bb506c6ea422c20b9c3</cites><orcidid>0000-0003-4378-8531</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10549-022-06596-2$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10549-022-06596-2$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35501422$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hjorth, Cathrine F.</creatorcontrib><creatorcontrib>Damkier, Per</creatorcontrib><creatorcontrib>Stage, Tore B.</creatorcontrib><creatorcontrib>Feddersen, Søren</creatorcontrib><creatorcontrib>Hamilton-Dutoit, Stephen</creatorcontrib><creatorcontrib>Rørth, Mikael</creatorcontrib><creatorcontrib>Ejlertsen, Bent</creatorcontrib><creatorcontrib>Lash, Timothy L.</creatorcontrib><creatorcontrib>Ahern, Thomas P.</creatorcontrib><creatorcontrib>Sørensen, Henrik T.</creatorcontrib><creatorcontrib>Cronin-Fenton, Deirdre</creatorcontrib><title>Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark</title><title>Breast cancer research and treatment</title><addtitle>Breast Cancer Res Treat</addtitle><addtitle>Breast Cancer Res Treat</addtitle><description>Purpose
Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.
Methods
We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.
Results
Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of
GSTP1
rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and
CYP3A
rs10273424 (HR: 1.33, 95% CI 0.98–1.81).
SLCO1B1
rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98).
Conclusion
Docetaxel effectiveness was influenced by SNPs in
GSTP1, CYP3A,
and
SLCO1B1
in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.</description><subject>Analysis</subject><subject>Anthracycline</subject><subject>Anthracyclines</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer research</subject><subject>Care and treatment</subject><subject>Chemotherapy</subject><subject>Cohort analysis</subject><subject>Cyclophosphamide</subject><subject>Cytochrome P-450</subject><subject>DNA repair</subject><subject>Drug metabolism</subject><subject>Drug therapy, Combination</subject><subject>Enzymes</subject><subject>Epidemiology</subject><subject>Formaldehyde</subject><subject>Genetic aspects</subject><subject>Glutathione transferase</subject><subject>Health aspects</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Menopause</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mortality</subject><subject>Oncology</subject><subject>Oncology, Experimental</subject><subject>Paraffin</subject><subject>Pharmacokinetics</subject><subject>Physiological aspects</subject><subject>Population studies</subject><subject>Population-based studies</subject><subject>Regression analysis</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide polymorphism</subject><subject>Taxanes</subject><subject>Tumors</subject><issn>0167-6806</issn><issn>1573-7217</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kttqFTEUhgdRbK2-gBcSEMSbqUnm7EWh1CMUvKj3IYeVPamZZEwyxf0wvquZ7p62iORiIPn-f81a6y-KlwQfE4y7d5Hgph5KTGmJ22ZoS_qoOCRNV5UdJd3j4hCTtivbHrcHxbMYLzHGQ4eHp8VB1TSY1JQeFr8vjNtYKN0iLfhkFKDZ2-3kwzyaOEXEnUJpBARag0zmChzEiLxGif_iDkrBIygkR5h8xgKft8g4NAeYwPmZL5FbJALwmJDkTkJ4j3guMS-WJ-Pdrd6PPiQU06Ku9R_ATTz8eF480dxGeHHzPSouPn38fvalPP_2-evZ6Xkpm46msgGNlVZKaSFaookAhQVVLRW1HvTadS_qRuuu5r0QDW5lCzy3LykWg6yOipOd67yICZQElwK3bA4m_8OWeW7Y_oszI9v4KzbQahg6mg3e3hgE_3OBmNhkogRr84D8EhnN26G07-o2o6__Qi_9ElxuLlM9aaumpdU9teEWmHHa57pyNWWnHe6bvFKylj3-B5WPgslI70CbfL8nePNAMAK3aYzeLusi4j5Id6AMPsYA-m4YBLM1e2yXPZazx66zx1bRq4djvJPchi0D1Q6I-cltINz3_h_bPyhw6F8</recordid><startdate>20220701</startdate><enddate>20220701</enddate><creator>Hjorth, Cathrine F.</creator><creator>Damkier, Per</creator><creator>Stage, Tore B.</creator><creator>Feddersen, Søren</creator><creator>Hamilton-Dutoit, Stephen</creator><creator>Rørth, Mikael</creator><creator>Ejlertsen, Bent</creator><creator>Lash, Timothy L.</creator><creator>Ahern, Thomas P.</creator><creator>Sørensen, Henrik T.</creator><creator>Cronin-Fenton, Deirdre</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>K9-</scope><scope>K9.</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4378-8531</orcidid></search><sort><creationdate>20220701</creationdate><title>Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark</title><author>Hjorth, Cathrine F. ; Damkier, Per ; Stage, Tore B. ; Feddersen, Søren ; Hamilton-Dutoit, Stephen ; Rørth, Mikael ; Ejlertsen, Bent ; Lash, Timothy L. ; Ahern, Thomas P. ; Sørensen, Henrik T. ; Cronin-Fenton, Deirdre</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c572t-5ef0dfdddfbb61f1bed0b2d62b4f9f00978b45ff74a8bb506c6ea422c20b9c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Analysis</topic><topic>Anthracycline</topic><topic>Anthracyclines</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer research</topic><topic>Care and treatment</topic><topic>Chemotherapy</topic><topic>Cohort analysis</topic><topic>Cyclophosphamide</topic><topic>Cytochrome P-450</topic><topic>DNA repair</topic><topic>Drug metabolism</topic><topic>Drug therapy, Combination</topic><topic>Enzymes</topic><topic>Epidemiology</topic><topic>Formaldehyde</topic><topic>Genetic aspects</topic><topic>Glutathione transferase</topic><topic>Health aspects</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Menopause</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mortality</topic><topic>Oncology</topic><topic>Oncology, Experimental</topic><topic>Paraffin</topic><topic>Pharmacokinetics</topic><topic>Physiological aspects</topic><topic>Population studies</topic><topic>Population-based studies</topic><topic>Regression analysis</topic><topic>Single nucleotide polymorphisms</topic><topic>Single-nucleotide polymorphism</topic><topic>Taxanes</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hjorth, Cathrine F.</creatorcontrib><creatorcontrib>Damkier, Per</creatorcontrib><creatorcontrib>Stage, Tore B.</creatorcontrib><creatorcontrib>Feddersen, Søren</creatorcontrib><creatorcontrib>Hamilton-Dutoit, Stephen</creatorcontrib><creatorcontrib>Rørth, Mikael</creatorcontrib><creatorcontrib>Ejlertsen, Bent</creatorcontrib><creatorcontrib>Lash, Timothy L.</creatorcontrib><creatorcontrib>Ahern, Thomas P.</creatorcontrib><creatorcontrib>Sørensen, Henrik T.</creatorcontrib><creatorcontrib>Cronin-Fenton, Deirdre</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Breast cancer research and treatment</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hjorth, Cathrine F.</au><au>Damkier, Per</au><au>Stage, Tore B.</au><au>Feddersen, Søren</au><au>Hamilton-Dutoit, Stephen</au><au>Rørth, Mikael</au><au>Ejlertsen, Bent</au><au>Lash, Timothy L.</au><au>Ahern, Thomas P.</au><au>Sørensen, Henrik T.</au><au>Cronin-Fenton, Deirdre</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark</atitle><jtitle>Breast cancer research and treatment</jtitle><stitle>Breast Cancer Res Treat</stitle><addtitle>Breast Cancer Res Treat</addtitle><date>2022-07-01</date><risdate>2022</risdate><volume>194</volume><issue>2</issue><spage>353</spage><epage>363</epage><pages>353-363</pages><issn>0167-6806</issn><eissn>1573-7217</eissn><abstract>Purpose
Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.
Methods
We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.
Results
Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of
GSTP1
rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and
CYP3A
rs10273424 (HR: 1.33, 95% CI 0.98–1.81).
SLCO1B1
rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98).
Conclusion
Docetaxel effectiveness was influenced by SNPs in
GSTP1, CYP3A,
and
SLCO1B1
in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>35501422</pmid><doi>10.1007/s10549-022-06596-2</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-4378-8531</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Breast cancer research and treatment, 2022-07, Vol.194 (2), p.353-363 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9239972 |
| source | SpringerLink Journals |
| subjects | Analysis Anthracycline Anthracyclines Breast cancer Cancer Cancer research Care and treatment Chemotherapy Cohort analysis Cyclophosphamide Cytochrome P-450 DNA repair Drug metabolism Drug therapy, Combination Enzymes Epidemiology Formaldehyde Genetic aspects Glutathione transferase Health aspects Medicine Medicine & Public Health Menopause Metastases Metastasis Mortality Oncology Oncology, Experimental Paraffin Pharmacokinetics Physiological aspects Population studies Population-based studies Regression analysis Single nucleotide polymorphisms Single-nucleotide polymorphism Taxanes Tumors |
| title | Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark |
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