VOLUME
33
䡠
NUMBER
2
䡠
JANUARY
10
2015
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Tumor Markers in Older Patients With Early Breast Cancer: Why Are We Still Doing Useless Tests? Cynthia Owusu and Lyndsay Harris, Case Western Reserve University, Cleveland, OH See accompanying article on page 149
In the article that accompanies this editorial, Ramsey et al1 report the results of their study on tumor marker use among older women with early-stage breast cancer. The study is a Seer-Medicare database analysis that examined the use of tumor markers (CA-15.3, CA-27.29 and carcinoembryonic antigen [CEA]) among 39,650 women 65 years and older who had been diagnosed with breast cancer between the years 2001 to 2007. Findings from the study showed that a significant minority (42%) of women completed at least one tumor marker test during the period 2 years after diagnosis with an average of 5.7 tests per each woman, and an increase in the number of tests per person with increasing calendar year. In addition, the cost of medical care was 29% higher among women who completed tumor marker testing, compared with women who did not. These finding are consistent with findings from other studies,2,3 and suggest that use of tumor markers to predict recurrence after primary treatment of breast cancer is a common practice among oncologists despite the fact that current guidelines do not support their use for this indication. Ramsey et al1 identified factors that were independently associated with tumor marker use. Younger women, women diagnosed later rather than sooner, and women with more advanced stage at diagnosis, were more likely to undergo testing for tumor markers. Given the independent association of age with tumor marker testing, with younger women more likely to have undergone tumor marker testing, it is likely that these findings represent an underestimation of the scope of tumor marker testing within the oncology community as the study population was limited to women 65 years and older. Since 1996, the American Society of Clinical Oncology (ASCO) has periodically published guidelines for use of tumor markers in the management of breast cancer. The ASCO guidelines in 1996,4 1997,5 2000,6 and most recently in 2007,7 uniformly, do not recommend or support the use of CA-15.3, CA-27.29, and CEA for screening, diagnosis, staging of breast cancer, or as surveillance tests for detecting recurrence after primary treatment of breast cancer. The most current National Cancer Comprehensive Network (NCCN) guidelines on the management of breast cancer8 also does not recommend the use of tumor markers for surveillance after primary treatment for breast cancer. Furthermore, in an effort similar to the American Board of Internal medicine “Choosing Wisely Campaign,” ASCO’s Cost of Care Task Force in 20129 identified breast cancer tumor marker testing, after treatment with curative intent, as one of five key cost-cutting 136
© 2014 by American Society of Clinical Oncology
opportunities in oncology care which will improve care and reduce unnecessary expense for patients, their families, and society at large. Despite these recommendations, findings from Ramsey et al1 continue to show routine use of breast cancer tumor markers in nonmetastatic breast cancer by a significant proportion of oncologists. Even more concerning is the rising use of tumor markers over time, despite periodic updates. However, it is important to note that because the study population was diagnosed through to 2007 and followed prospectively for 2 years after diagnosis the impact of the 2007 ASCO update and ASCO’s Cost of Care Task Force recommendations on the pattern of tumor marker use may not be captured by the reported study. Regardless of the study caveats, tumor marker use after primary treatment of early-stage breast cancer appears to frequent. Reasons for continued use of these tumor markers remain unknown and may be multifactorial. While ASCO tumor marker guidelines do not recommend tumor markers due to lack of evidence of benefit to patients, observational studies have shown a prognostic association between CA 15.3 and CA 27.29, and recurrence after primary treatment of breast cancer.10-12 In addition, it has been shown that CA27.29 can predict breast cancer recurrence, 5.3 months before clinical symptoms or test results.13 However, these results do not translate into a survival benefit as the diagnosis of metastatic disease is not, as yet, a curable condition, therefore finding metastases with a few month lead time is not associated with benefit to the patient.14 Indeed, there is significant morbidity associated with unnecessary tumor marker testing in the early-stage setting including the distress and ongoing anxiety of the patient with a positive tumor marker in the setting of negative metastatic work-up, and excess testing resulting from this finding. This cost of excess testing in not only borne by society but is directly transferred to the patient in this era of high deductible insurance plans and the Affordable Care Act. For these reasons ASCO guidelines do not recommend routine use of CEA and CA-15.3/CA-27.29 as surveillance tests after primary treatment with curative intent. Despite ASCO and NCCN recommendations, a significant minority of oncologists continue to use these tumor markers for surveillance in early-stage breast cancer. Factors that have been identified to be consistent with overuse of surveillance testing, including tumor markers, for breast cancer survivors include older age providers, lower provider self-efficacy, international medical graduates, and providers with greater perception that guideline recommendations regarding survivorship care may be conflicting or ambiguous.15 The 1999 Journal of Clinical Oncology, Vol 33, No 2 (January 10), 2015: pp 136-137
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 2, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
Editorial
United States Food and Drug Administration’s approval for clinical use of tumor markers in detecting recurrence, after primary treatment for early-stage breast cancer certainly is conflicting in the face of ASCO and NCCN recommendations.6 However, US Food and Drug Administration clearance of tests has thus far not required evidence of clinical utility, unlike the ASCO and NCCN guidelines. Other reasons are related to particular geographic locations (East and West coasts, rural practices) as was seen by Ramsey et al1 in their study. It is possible that providers feel pressure from patients to ‘do something’ and the time taken to explain the lack of clinical utility to a patient takes time in a busy practice. This may explain the East and West coast association of increased tumor marker usage, as populations in these areas are more likely to demand testing from providers. Alternatively, increased tumor marker usage by older providers and international graduates, along with rural areas suggest a possible lack of knowledge of ASCO guidelines. Regardless, these findings suggest a targeted educational campaign of ASCO and NCCN guidelines is necessary to emphasize not only the lack of benefit but significant harms (morbidity, cost to the medical system and patient) of use of serum tumor markers in early-stage disease. Furthermore, payers and CMS should ensure that these tests are not reimbursed to discourage their use. Finally, a direct-to-consumer educational approach may be helpful, as patients must bear now the burden of cost, particularly in older patients who can least afford it. The Institute of Medicine committee defines and states the purpose of Comparative Effectiveness Research (CER) as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels.”16 Given the widespread use of tumor markers in the nonmetastatic setting and associated increase in medical costs despite existing guidelines, generation and dissemination of CER, such as the excellent and eye-opening study by Ramsey et al,1 should be undertaken, particularly in the younger patients with early breast cancer. Most important, however, is the need for better methods of dissemination of these results and mechanisms to prevent inappropriate usage of serum tumor markers and the burden it places on the health care system and most importantly the patients we serve.
AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Ramsey SD, Henry NL, Gralow J, et al: Tumor marker usage and medical care costs among older early-stage breast cancer survivors. J Clin Oncol 33:149-155, 2015 2. Hensley ML, Dowell J, Herndon JE 2nd, et al: Economic outcomes of breast cancer survivorship: CALGB study 79804. Breast Cancer Res Treat 91:153-161, 2005 3. Keating NL, Landrum MB, Guadagnoli E, et al: Surveillance testing among survivors of early-stage breast cancer. J Clin Oncol 25:1074-1081, 2007 4. [No authors listed]: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer: Adopted on May 17, 1996, by the American Society of Clinical Oncology. J Clin Oncol 14:2843-2877, 1996 5. [No authors listed]: 1997 update of recommendations for the use of tumor markers in breast and colorectal cancer: Adopted on November 7, 1997, by the American Society of Clinical Oncology. J Clin Oncol 16:793-795, 1998 6. Bast RC Jr, Ravdin P, Hayes DF, et al: 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:18651878, 2001 7. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25:5287-5312, 2007 8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Breast Cancer, 2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site 9. Schnipper LE, Smith TJ, Raghavan D, et al: American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: The top five list for oncology. J Clin Oncol 30:1715-1724 10. Ebeling FG, Stieber P, Untch M, et al: Serum CEA and CA 15-3 as prognostic factors in primary breast cancer. Br J Cancer 86:1217-1222, 2002 11. Gion M, Boracchi P, Dittadi R, et al: Prognostic role of serum CA15.3 in 362 node-negative breast cancers. An old player for a new game. Eur J Cancer 38:1181-1188, 2002 12. Kumpulainen EJ, Keskikuru RJ, Johansson RT: Serum tumor marker CA 15.3 and stage are the two most powerful predictors of survival in primary breast cancer. Breast Cancer Res Treat 76:95-102, 2002 13. Chan DW, Beveridge RA, Muss H, et al: Use of Truquant BR radioimmunoassay for early detection of breast cancer recurrence in patients with stage II and stage III disease. J Clin Oncol 15:2322-2328, 1997 14. Kokko R, Hakama M, Holli K: Follow-up cost of breast cancer patients with localized disease after primary treatment: A randomized trial. Breast Cancer Res Treat 93:255-260, 2005 15. Han PK, Klabunde CN, Noone AM, et al: Physicians’ beliefs about breast cancer surveillance testing are consistent with test overuse. Med Care 51:315323 16. Institute of Medicine: Initial National Priorities for Comparative Effectiveness Research by the Committee on Comparative Effectiveness Research Prioritization. Washington, DC, The National Academies Press, 2009. http:// www.nap.edu
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org.
DOI: 10.1200/JCO.2014.58.1512; published online ahead of print at www.jco.org on December 1, 2014 ■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 2, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
137
Editorial
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Tumor Markers in Older Patients With Early Breast Cancer: Why Are We Still Doing Useless Tests? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Cynthia Owusu No relationship to disclose
© 2014 by American Society of Clinical Oncology
Lyndsay Harris No relationship to disclose
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 2, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
33
䡠
NUMBER
2
䡠
JANUARY
10
2015
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Tumor Markers in Older Patients With Early Breast Cancer: Why Are We Still Doing Useless Tests? Cynthia Owusu and Lyndsay Harris, Case Western Reserve University, Cleveland, OH See accompanying article on page 149
In the article that accompanies this editorial, Ramsey et al1 report the results of their study on tumor marker use among older women with early-stage breast cancer. The study is a Seer-Medicare database analysis that examined the use of tumor markers (CA-15.3, CA-27.29 and carcinoembryonic antigen [CEA]) among 39,650 women 65 years and older who had been diagnosed with breast cancer between the years 2001 to 2007. Findings from the study showed that a significant minority (42%) of women completed at least one tumor marker test during the period 2 years after diagnosis with an average of 5.7 tests per each woman, and an increase in the number of tests per person with increasing calendar year. In addition, the cost of medical care was 29% higher among women who completed tumor marker testing, compared with women who did not. These finding are consistent with findings from other studies,2,3 and suggest that use of tumor markers to predict recurrence after primary treatment of breast cancer is a common practice among oncologists despite the fact that current guidelines do not support their use for this indication. Ramsey et al1 identified factors that were independently associated with tumor marker use. Younger women, women diagnosed later rather than sooner, and women with more advanced stage at diagnosis, were more likely to undergo testing for tumor markers. Given the independent association of age with tumor marker testing, with younger women more likely to have undergone tumor marker testing, it is likely that these findings represent an underestimation of the scope of tumor marker testing within the oncology community as the study population was limited to women 65 years and older. Since 1996, the American Society of Clinical Oncology (ASCO) has periodically published guidelines for use of tumor markers in the management of breast cancer. The ASCO guidelines in 1996,4 1997,5 2000,6 and most recently in 2007,7 uniformly, do not recommend or support the use of CA-15.3, CA-27.29, and CEA for screening, diagnosis, staging of breast cancer, or as surveillance tests for detecting recurrence after primary treatment of breast cancer. The most current National Cancer Comprehensive Network (NCCN) guidelines on the management of breast cancer8 also does not recommend the use of tumor markers for surveillance after primary treatment for breast cancer. Furthermore, in an effort similar to the American Board of Internal medicine “Choosing Wisely Campaign,” ASCO’s Cost of Care Task Force in 20129 identified breast cancer tumor marker testing, after treatment with curative intent, as one of five key cost-cutting 136
© 2014 by American Society of Clinical Oncology
opportunities in oncology care which will improve care and reduce unnecessary expense for patients, their families, and society at large. Despite these recommendations, findings from Ramsey et al1 continue to show routine use of breast cancer tumor markers in nonmetastatic breast cancer by a significant proportion of oncologists. Even more concerning is the rising use of tumor markers over time, despite periodic updates. However, it is important to note that because the study population was diagnosed through to 2007 and followed prospectively for 2 years after diagnosis the impact of the 2007 ASCO update and ASCO’s Cost of Care Task Force recommendations on the pattern of tumor marker use may not be captured by the reported study. Regardless of the study caveats, tumor marker use after primary treatment of early-stage breast cancer appears to frequent. Reasons for continued use of these tumor markers remain unknown and may be multifactorial. While ASCO tumor marker guidelines do not recommend tumor markers due to lack of evidence of benefit to patients, observational studies have shown a prognostic association between CA 15.3 and CA 27.29, and recurrence after primary treatment of breast cancer.10-12 In addition, it has been shown that CA27.29 can predict breast cancer recurrence, 5.3 months before clinical symptoms or test results.13 However, these results do not translate into a survival benefit as the diagnosis of metastatic disease is not, as yet, a curable condition, therefore finding metastases with a few month lead time is not associated with benefit to the patient.14 Indeed, there is significant morbidity associated with unnecessary tumor marker testing in the early-stage setting including the distress and ongoing anxiety of the patient with a positive tumor marker in the setting of negative metastatic work-up, and excess testing resulting from this finding. This cost of excess testing in not only borne by society but is directly transferred to the patient in this era of high deductible insurance plans and the Affordable Care Act. For these reasons ASCO guidelines do not recommend routine use of CEA and CA-15.3/CA-27.29 as surveillance tests after primary treatment with curative intent. Despite ASCO and NCCN recommendations, a significant minority of oncologists continue to use these tumor markers for surveillance in early-stage breast cancer. Factors that have been identified to be consistent with overuse of surveillance testing, including tumor markers, for breast cancer survivors include older age providers, lower provider self-efficacy, international medical graduates, and providers with greater perception that guideline recommendations regarding survivorship care may be conflicting or ambiguous.15 The 1999 Journal of Clinical Oncology, Vol 33, No 2 (January 10), 2015: pp 136-137
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 2, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
Editorial
United States Food and Drug Administration’s approval for clinical use of tumor markers in detecting recurrence, after primary treatment for early-stage breast cancer certainly is conflicting in the face of ASCO and NCCN recommendations.6 However, US Food and Drug Administration clearance of tests has thus far not required evidence of clinical utility, unlike the ASCO and NCCN guidelines. Other reasons are related to particular geographic locations (East and West coasts, rural practices) as was seen by Ramsey et al1 in their study. It is possible that providers feel pressure from patients to ‘do something’ and the time taken to explain the lack of clinical utility to a patient takes time in a busy practice. This may explain the East and West coast association of increased tumor marker usage, as populations in these areas are more likely to demand testing from providers. Alternatively, increased tumor marker usage by older providers and international graduates, along with rural areas suggest a possible lack of knowledge of ASCO guidelines. Regardless, these findings suggest a targeted educational campaign of ASCO and NCCN guidelines is necessary to emphasize not only the lack of benefit but significant harms (morbidity, cost to the medical system and patient) of use of serum tumor markers in early-stage disease. Furthermore, payers and CMS should ensure that these tests are not reimbursed to discourage their use. Finally, a direct-to-consumer educational approach may be helpful, as patients must bear now the burden of cost, particularly in older patients who can least afford it. The Institute of Medicine committee defines and states the purpose of Comparative Effectiveness Research (CER) as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels.”16 Given the widespread use of tumor markers in the nonmetastatic setting and associated increase in medical costs despite existing guidelines, generation and dissemination of CER, such as the excellent and eye-opening study by Ramsey et al,1 should be undertaken, particularly in the younger patients with early breast cancer. Most important, however, is the need for better methods of dissemination of these results and mechanisms to prevent inappropriate usage of serum tumor markers and the burden it places on the health care system and most importantly the patients we serve.
AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Ramsey SD, Henry NL, Gralow J, et al: Tumor marker usage and medical care costs among older early-stage breast cancer survivors. J Clin Oncol 33:149-155, 2015 2. Hensley ML, Dowell J, Herndon JE 2nd, et al: Economic outcomes of breast cancer survivorship: CALGB study 79804. Breast Cancer Res Treat 91:153-161, 2005 3. Keating NL, Landrum MB, Guadagnoli E, et al: Surveillance testing among survivors of early-stage breast cancer. J Clin Oncol 25:1074-1081, 2007 4. [No authors listed]: Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer: Adopted on May 17, 1996, by the American Society of Clinical Oncology. J Clin Oncol 14:2843-2877, 1996 5. [No authors listed]: 1997 update of recommendations for the use of tumor markers in breast and colorectal cancer: Adopted on November 7, 1997, by the American Society of Clinical Oncology. J Clin Oncol 16:793-795, 1998 6. Bast RC Jr, Ravdin P, Hayes DF, et al: 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:18651878, 2001 7. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25:5287-5312, 2007 8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Breast Cancer, 2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site 9. Schnipper LE, Smith TJ, Raghavan D, et al: American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: The top five list for oncology. J Clin Oncol 30:1715-1724 10. Ebeling FG, Stieber P, Untch M, et al: Serum CEA and CA 15-3 as prognostic factors in primary breast cancer. Br J Cancer 86:1217-1222, 2002 11. Gion M, Boracchi P, Dittadi R, et al: Prognostic role of serum CA15.3 in 362 node-negative breast cancers. An old player for a new game. Eur J Cancer 38:1181-1188, 2002 12. Kumpulainen EJ, Keskikuru RJ, Johansson RT: Serum tumor marker CA 15.3 and stage are the two most powerful predictors of survival in primary breast cancer. Breast Cancer Res Treat 76:95-102, 2002 13. Chan DW, Beveridge RA, Muss H, et al: Use of Truquant BR radioimmunoassay for early detection of breast cancer recurrence in patients with stage II and stage III disease. J Clin Oncol 15:2322-2328, 1997 14. Kokko R, Hakama M, Holli K: Follow-up cost of breast cancer patients with localized disease after primary treatment: A randomized trial. Breast Cancer Res Treat 93:255-260, 2005 15. Han PK, Klabunde CN, Noone AM, et al: Physicians’ beliefs about breast cancer surveillance testing are consistent with test overuse. Med Care 51:315323 16. Institute of Medicine: Initial National Priorities for Comparative Effectiveness Research by the Committee on Comparative Effectiveness Research Prioritization. Washington, DC, The National Academies Press, 2009. http:// www.nap.edu
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org.
DOI: 10.1200/JCO.2014.58.1512; published online ahead of print at www.jco.org on December 1, 2014 ■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 2, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
137
Editorial
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Tumor Markers in Older Patients With Early Breast Cancer: Why Are We Still Doing Useless Tests? The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Cynthia Owusu No relationship to disclose
© 2014 by American Society of Clinical Oncology
Lyndsay Harris No relationship to disclose
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Buddhist Dalin Hospital on March 2, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 203.64.11.45
