- Email: [email protected]
Oral Contraceptives and Breast Cancer
LETTERS TO THE EDITOR
4. Levy S, Harris SK, Sherritt L, Angulo M, Knight JR. Drug testing of adolescents in general medical clinics, in school and at home: physician attitudes and practices. J Adolesc Health. 2006;38(4):336-342. 5. Millgate AG, Pogson BJ, Wilson IW, et al. Analgesia: morphine-pathway block in top1 poppies. Nature. 2004;431(7007):413-414. 6. Swotinsky RB, Smith DR. The Medical Review Officer’s Manual. 3rd ed. Beverly Farms, MA: OEM Press; 2006. 7. Shults TF. Medical Review Officer Handbook. 8th ed. Durham, NC: Quadrangle Research; 2005. 8. 21 CFR 1308: clarification of listing of “tetrahydrocannabilols” in schedule I and exemption from control of certain industrial products and materials derived from the cannabis plant: final rules. Fed Regist. 2003;68(55):1411414126.
In reply: We thank Drs Reisfield and Bertholf for their insightful comments regarding our recent article. While we appreciate their concerns regarding possible inaccuracies in our review, we would like to clarify some of these comments for the benefit of readers. One of the first concerns they raise regarding opioids can be attributed to misinterpretation of connotation. We agree that fentanyl has metabolites, a concern when prescribing in clinical practices (eg, for elderly patients); however, our intended meaning was that fentanyl “lacks” the metabolites of morphine and codeine that are needed to elicit a positive response on a urine opioid screen. Along those same lines, we would like to clarify our passage regarding semisynthetic derivatives of morphine not being used therapeutically because of abuse potential. Actually, we were referring to illicit agents (eg, heroin), which are semisynthetic derivatives of morphine, not legal substances, such as hydrocodone or oxycodone. We agree that these latter agents are widely used and have substantial abuse potential. Last, we agree that exposure to heroin can be established only by demonstrating 6monoacetyl morphine metabolites, and a paragraph in our review provided this information. Drs Reisfield and Bertholf have also challenged our inclusion of an outdated reference regarding false-positive results from NSAIDS that can be observed using the Syva EMIT system. Indeed the Syva EMIT system was altered to fix the interference with NSAIDS in the urine cannabinoids test1; however, our reference by Rollins et al2 used the revised assay by Syva and still produced 2 false-positive results with exposure to NSAIDS. We thought that this was a significant finding that should be reported. In addition, some hospital laboratories, especially in rural or impoverished communitie s, may still use the old Syva EMIT systems, and clinicians should be aware of this potential interference. We, the authors, are well aware of the DEA’s stance that any amount of THC or cocaine in food and beverages is illegal. However, in view of the increased Internet sales of products and importation across borders (eg, from Mexico, Central America, and Canada) of herbal medicines, foods, and other products that could contain trace amounts of THC or cocaine, the use of these products cannot be ruled out in the United States. Our intended audience in this paper, practicing clinicians, should be aware of these potential interactions and inquire about herbal products with all of their patients. Mayo Clin Proc.
•
We agree with Drs Reisfield and Bertholf that amphetamine immunoassays are designed to detect both amphetamines and methamphetamines, as stated in the article. We would like to point out that the column headings for Table 3 should be “Potential agents causing positive results” instead of “false-positive results.” We recognize that this error could have contributed to misinterpretation of the table contents, and we apologize for this oversight. We hope that our clarifications have allayed some of the concerns raised by Drs Reisfield and Bertholf. We recognize that the area of urine drug screenings is complex and often challenging for clinicians when dealing with unexpected results. This complexity prompted us to publish this review for the sole purpose of providing additional resources for clinicians in everyday practice. While this review is not intended to be the sole authoritative article on urine drug screening, we hope we have increased basic understanding of commonly abused agents and their effect on urine drug screens to aid in clinical decision making. Karen E. Moeller, PharmD, BCPP University of Kansas School of Pharmacy Lawrence Kelly C. Lee, PharmD, BCPP UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences La Jolla, CA Julie C. Kissack, PharmD, BCPP Harding University College of Pharmacy Searcy, AR 1. Blanke RV. Accuracy in urinalysis. In: Hawks RL, Chiang CN, eds. Urine Testing for Drugs of Abuse. Rockville, MD: Department of Health and Human Services, National Institute on Drug Abuse;1986. NIDA Research Monograph 73. http://www.nida.nih.gov/pdf/monographs/73.pdf. Accessed May 21, 2008. 2. Rollins DE, Jennison TA, Jones G. Investigation of interference by nonsteroidal anti-inflammatory drugs in urine tests for abused drugs. Clin Chem. 1990;36(4):602-606.
Oral Contraceptives and Breast Cancer To the Editor: In a Concise Review for Clinicians, Casey et al1 examine oral contraceptive (OC) use and the risk of breast cancer. It is noteworthy that the lead author is a consultant for Organon USA, maker of several OCs and other hormonal contraceptives; although Dr Casey disclosed this fact, a potential conflict of interest is nonetheless apparent. The authors conclude that “current evidence suggests that OCs do not play a clinically important role in the risk of breast cancer.” That overly broad and inaccurate statement does not reflect the existing literature on OCs and breast cancer. Specifically, the authors fail to discuss the known differences in the epidemiology and pathology between premenopausal and postmenopausal breast cancer, including the potential differences in risk of disease associated with OC use. Instead, they treat all breast cancers as the same. Casey et al further fail to discuss ad-
July 2008;83(7):848-851
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
849
LETTERS TO THE EDITOR
equately the timing of OC exposure as it relates to the risk of premenopausal and postmenopausal disease. Using data from 39 case-control studies conducted after 1980, we published in the October 2006 issue of Mayo Clinic Proceedings an analysis showing a link between OC use and premenopausal breast cancer (odds ratio, 1.19; 95% confidence interval, 1.09-1.29).2 This risk was greatest in women who used OCs for 4 or more years before a first full-term pregnancy (FFTP) (odds ratio, 1.52; 99% confidence interval, 1.19-1.93). Casey et al minimize our work by stating that it is based on “older data with higher-dose estrogen and older progestin OC formulations.” This is inaccurate: in 34 of the 39 studies in our meta-analysis, 100% of the cases developed breast cancer during or after 1980. In the remaining 5 studies, most cases developed breast cancer after 1980. Hence, nearly all women in our meta-analysis developed breast cancer after 1980, when newer low-dose, triphasic OCs were more common. Moreover, recent data, including those in the Oxford study,3 show that low-dose OCs are associated with a greater risk of breast cancer than are high-dose regimens,4,5 a point Casey et al overlooked by citing a single study from 2002 (which was included in our analysis) that showed no risk associated with OC use in general. The discussion section of our article reviews the potential links between newer OC formulations and breast cancer risk. To support their conclusion, Casey et al cite the Oxford study.6 However, the Oxford analysis has various weaknesses that were never mentioned: (1) it included several older studies in which data were obtained before 1980, when women tended to use OCs for shorter lengths of time before FFTP3; (2) two-thirds of the breast cancer cases were women older than 45 years and thus likely to be postmenopausal7; and (3) no data were published for the risks in parous premenopausal women (or women <50 years) who ook t OCs before their FFTP. Therefore, the Oxford data cannot be generalized to all women, especially not to parous premenopausal women. It is disappointing that an article aimed at providing clinicians with information to counsel their patients inaccurately and incompletely represents the established literature. Our work demonstrates that, contrary to the conclusion of the Casey et al article, current evidence does suggest that OCs increase the risk of breast cancer among premenopausal women. Notably, premenopausal women represent more than 20% of the newly diagnosed cases of breast cancer in the United States.8 Although the incidence rate of invasive breast cancer in postmenopausal women has sharply decreased since 2001, the rate among premenopausal women has remained steady.9 Moreover, premenopausal women often experience worse outcomes than postmenopausal women.9 While we agree with Casey et al that further research is needed to clarify the OC– breast cancer link, in the interim, we do not think it is fair to minimize or dismiss the potential risk of premenopausal breast cancer associated with OC use. Women deserve to be provided with the most accurate and up-to-date information on 850
Mayo Clin Proc.
•
the potential risks associated with OCs so that they can make their own informed decisions. Their lives depend on it. Chris Kahlenborn, MD Holy Spirit Hospital Camp Hill, PA Francesmary Modugno, PhD, MPH Douglas M. Potter, PhD University of Pittsburgh Pittsburgh, PA Walter B. Severs, PhD Penn State University Hershey, PA 1. Casey PM, Cerhan JR, Pruthi S. Oral contraceptive use and the risk of breast cancer. Mayo Clin Proc. 2008;83(1):86-91. 2. Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006:81(10):1290-1302. 3. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception. 1996;54(3, suppl): 1S-106S. Appendix 62. 4. Breast cancer and combined oral contraceptives: results from a multinational study: WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Br J Cancer. 1990;61(1):110-119. 5. Rookus MA, van Leeuwen FE; Netherlands Oral Contraceptives and Breast Cancer Study Group. Oral contraceptives and risk of breast cancer in women aged 20-54 years. Lancet. 1994;344(8926):844-851. 6. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet. 1996:347(9017):1713-1727. 7. Althuis MD, Brogan DR, Coates RJ, et al. Hormonal content and potency of oral contraceptives and breast cancer risk among young women. Br J Cancer. 2003:88(1):50-57. 8. American Cancer Society. Breast Cancer Facts & Figures 2003-2004. Atlanta, GA: American Cancer Society; 2003. 9. American Cancer Society. Breast Cancer Facts & Figures 2007-2008. Atlanta, GA: American Cancer Society; 2007.
In reply: Dr Casey’s consultancy for Organon USA was fully disclosed and related to her training with the Implanon contraceptive implant. Kahlenborn et al claim our conclusion that “current evidence suggests that OCs do not play a clinically important role in the risk of breast cancer” was “overly broad and inaccurate.” We emphasize that this phrase from our conclusion was directly preceded by a statement noting that epidemiologic studies have documented a small increase in the risk of breast cancer with the use of older formulations and that no increased risk has been detected with newer formulations. Further, we directly addressed the issue of timing and age at onset of breast cancer, specifically noting the increased risks of breast cancer in women who began taking OCs when younger than 20 years and in women who used OCs before the birth of their first child, which was evident in both the Oxford pooled analysis and the Kahlenborn et al meta-analysis. Both analyses have considerable overlap and similar conclusions, and an in-depth discussion of the strengths and limitations of each study was beyond the scope of our review.
July 2008;83:(7):848-851 •
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
4. Levy S, Harris SK, Sherritt L, Angulo M, Knight JR. Drug testing of adolescents in general medical clinics, in school and at home: physician attitudes and practices. J Adolesc Health. 2006;38(4):336-342. 5. Millgate AG, Pogson BJ, Wilson IW, et al. Analgesia: morphine-pathway block in top1 poppies. Nature. 2004;431(7007):413-414. 6. Swotinsky RB, Smith DR. The Medical Review Officer’s Manual. 3rd ed. Beverly Farms, MA: OEM Press; 2006. 7. Shults TF. Medical Review Officer Handbook. 8th ed. Durham, NC: Quadrangle Research; 2005. 8. 21 CFR 1308: clarification of listing of “tetrahydrocannabilols” in schedule I and exemption from control of certain industrial products and materials derived from the cannabis plant: final rules. Fed Regist. 2003;68(55):1411414126.
In reply: We thank Drs Reisfield and Bertholf for their insightful comments regarding our recent article. While we appreciate their concerns regarding possible inaccuracies in our review, we would like to clarify some of these comments for the benefit of readers. One of the first concerns they raise regarding opioids can be attributed to misinterpretation of connotation. We agree that fentanyl has metabolites, a concern when prescribing in clinical practices (eg, for elderly patients); however, our intended meaning was that fentanyl “lacks” the metabolites of morphine and codeine that are needed to elicit a positive response on a urine opioid screen. Along those same lines, we would like to clarify our passage regarding semisynthetic derivatives of morphine not being used therapeutically because of abuse potential. Actually, we were referring to illicit agents (eg, heroin), which are semisynthetic derivatives of morphine, not legal substances, such as hydrocodone or oxycodone. We agree that these latter agents are widely used and have substantial abuse potential. Last, we agree that exposure to heroin can be established only by demonstrating 6monoacetyl morphine metabolites, and a paragraph in our review provided this information. Drs Reisfield and Bertholf have also challenged our inclusion of an outdated reference regarding false-positive results from NSAIDS that can be observed using the Syva EMIT system. Indeed the Syva EMIT system was altered to fix the interference with NSAIDS in the urine cannabinoids test1; however, our reference by Rollins et al2 used the revised assay by Syva and still produced 2 false-positive results with exposure to NSAIDS. We thought that this was a significant finding that should be reported. In addition, some hospital laboratories, especially in rural or impoverished communitie s, may still use the old Syva EMIT systems, and clinicians should be aware of this potential interference. We, the authors, are well aware of the DEA’s stance that any amount of THC or cocaine in food and beverages is illegal. However, in view of the increased Internet sales of products and importation across borders (eg, from Mexico, Central America, and Canada) of herbal medicines, foods, and other products that could contain trace amounts of THC or cocaine, the use of these products cannot be ruled out in the United States. Our intended audience in this paper, practicing clinicians, should be aware of these potential interactions and inquire about herbal products with all of their patients. Mayo Clin Proc.
•
We agree with Drs Reisfield and Bertholf that amphetamine immunoassays are designed to detect both amphetamines and methamphetamines, as stated in the article. We would like to point out that the column headings for Table 3 should be “Potential agents causing positive results” instead of “false-positive results.” We recognize that this error could have contributed to misinterpretation of the table contents, and we apologize for this oversight. We hope that our clarifications have allayed some of the concerns raised by Drs Reisfield and Bertholf. We recognize that the area of urine drug screenings is complex and often challenging for clinicians when dealing with unexpected results. This complexity prompted us to publish this review for the sole purpose of providing additional resources for clinicians in everyday practice. While this review is not intended to be the sole authoritative article on urine drug screening, we hope we have increased basic understanding of commonly abused agents and their effect on urine drug screens to aid in clinical decision making. Karen E. Moeller, PharmD, BCPP University of Kansas School of Pharmacy Lawrence Kelly C. Lee, PharmD, BCPP UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences La Jolla, CA Julie C. Kissack, PharmD, BCPP Harding University College of Pharmacy Searcy, AR 1. Blanke RV. Accuracy in urinalysis. In: Hawks RL, Chiang CN, eds. Urine Testing for Drugs of Abuse. Rockville, MD: Department of Health and Human Services, National Institute on Drug Abuse;1986. NIDA Research Monograph 73. http://www.nida.nih.gov/pdf/monographs/73.pdf. Accessed May 21, 2008. 2. Rollins DE, Jennison TA, Jones G. Investigation of interference by nonsteroidal anti-inflammatory drugs in urine tests for abused drugs. Clin Chem. 1990;36(4):602-606.
Oral Contraceptives and Breast Cancer To the Editor: In a Concise Review for Clinicians, Casey et al1 examine oral contraceptive (OC) use and the risk of breast cancer. It is noteworthy that the lead author is a consultant for Organon USA, maker of several OCs and other hormonal contraceptives; although Dr Casey disclosed this fact, a potential conflict of interest is nonetheless apparent. The authors conclude that “current evidence suggests that OCs do not play a clinically important role in the risk of breast cancer.” That overly broad and inaccurate statement does not reflect the existing literature on OCs and breast cancer. Specifically, the authors fail to discuss the known differences in the epidemiology and pathology between premenopausal and postmenopausal breast cancer, including the potential differences in risk of disease associated with OC use. Instead, they treat all breast cancers as the same. Casey et al further fail to discuss ad-
July 2008;83(7):848-851
•
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
849
LETTERS TO THE EDITOR
equately the timing of OC exposure as it relates to the risk of premenopausal and postmenopausal disease. Using data from 39 case-control studies conducted after 1980, we published in the October 2006 issue of Mayo Clinic Proceedings an analysis showing a link between OC use and premenopausal breast cancer (odds ratio, 1.19; 95% confidence interval, 1.09-1.29).2 This risk was greatest in women who used OCs for 4 or more years before a first full-term pregnancy (FFTP) (odds ratio, 1.52; 99% confidence interval, 1.19-1.93). Casey et al minimize our work by stating that it is based on “older data with higher-dose estrogen and older progestin OC formulations.” This is inaccurate: in 34 of the 39 studies in our meta-analysis, 100% of the cases developed breast cancer during or after 1980. In the remaining 5 studies, most cases developed breast cancer after 1980. Hence, nearly all women in our meta-analysis developed breast cancer after 1980, when newer low-dose, triphasic OCs were more common. Moreover, recent data, including those in the Oxford study,3 show that low-dose OCs are associated with a greater risk of breast cancer than are high-dose regimens,4,5 a point Casey et al overlooked by citing a single study from 2002 (which was included in our analysis) that showed no risk associated with OC use in general. The discussion section of our article reviews the potential links between newer OC formulations and breast cancer risk. To support their conclusion, Casey et al cite the Oxford study.6 However, the Oxford analysis has various weaknesses that were never mentioned: (1) it included several older studies in which data were obtained before 1980, when women tended to use OCs for shorter lengths of time before FFTP3; (2) two-thirds of the breast cancer cases were women older than 45 years and thus likely to be postmenopausal7; and (3) no data were published for the risks in parous premenopausal women (or women <50 years) who ook t OCs before their FFTP. Therefore, the Oxford data cannot be generalized to all women, especially not to parous premenopausal women. It is disappointing that an article aimed at providing clinicians with information to counsel their patients inaccurately and incompletely represents the established literature. Our work demonstrates that, contrary to the conclusion of the Casey et al article, current evidence does suggest that OCs increase the risk of breast cancer among premenopausal women. Notably, premenopausal women represent more than 20% of the newly diagnosed cases of breast cancer in the United States.8 Although the incidence rate of invasive breast cancer in postmenopausal women has sharply decreased since 2001, the rate among premenopausal women has remained steady.9 Moreover, premenopausal women often experience worse outcomes than postmenopausal women.9 While we agree with Casey et al that further research is needed to clarify the OC– breast cancer link, in the interim, we do not think it is fair to minimize or dismiss the potential risk of premenopausal breast cancer associated with OC use. Women deserve to be provided with the most accurate and up-to-date information on 850
Mayo Clin Proc.
•
the potential risks associated with OCs so that they can make their own informed decisions. Their lives depend on it. Chris Kahlenborn, MD Holy Spirit Hospital Camp Hill, PA Francesmary Modugno, PhD, MPH Douglas M. Potter, PhD University of Pittsburgh Pittsburgh, PA Walter B. Severs, PhD Penn State University Hershey, PA 1. Casey PM, Cerhan JR, Pruthi S. Oral contraceptive use and the risk of breast cancer. Mayo Clin Proc. 2008;83(1):86-91. 2. Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006:81(10):1290-1302. 3. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: further results. Contraception. 1996;54(3, suppl): 1S-106S. Appendix 62. 4. Breast cancer and combined oral contraceptives: results from a multinational study: WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Br J Cancer. 1990;61(1):110-119. 5. Rookus MA, van Leeuwen FE; Netherlands Oral Contraceptives and Breast Cancer Study Group. Oral contraceptives and risk of breast cancer in women aged 20-54 years. Lancet. 1994;344(8926):844-851. 6. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet. 1996:347(9017):1713-1727. 7. Althuis MD, Brogan DR, Coates RJ, et al. Hormonal content and potency of oral contraceptives and breast cancer risk among young women. Br J Cancer. 2003:88(1):50-57. 8. American Cancer Society. Breast Cancer Facts & Figures 2003-2004. Atlanta, GA: American Cancer Society; 2003. 9. American Cancer Society. Breast Cancer Facts & Figures 2007-2008. Atlanta, GA: American Cancer Society; 2007.
In reply: Dr Casey’s consultancy for Organon USA was fully disclosed and related to her training with the Implanon contraceptive implant. Kahlenborn et al claim our conclusion that “current evidence suggests that OCs do not play a clinically important role in the risk of breast cancer” was “overly broad and inaccurate.” We emphasize that this phrase from our conclusion was directly preceded by a statement noting that epidemiologic studies have documented a small increase in the risk of breast cancer with the use of older formulations and that no increased risk has been detected with newer formulations. Further, we directly addressed the issue of timing and age at onset of breast cancer, specifically noting the increased risks of breast cancer in women who began taking OCs when younger than 20 years and in women who used OCs before the birth of their first child, which was evident in both the Oxford pooled analysis and the Kahlenborn et al meta-analysis. Both analyses have considerable overlap and similar conclusions, and an in-depth discussion of the strengths and limitations of each study was beyond the scope of our review.
July 2008;83:(7):848-851 •
www.mayoclinicproceedings.com
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.