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The American Journal of Managed Care May 2016
Greater Potential Cost Savings With Biosimilar Use
Benjamin Yu, PharmD
Implementing a Hybrid Approach to Select Patients for Care Management: Variations Across Practices
Christine Vogeli, PhD; Jenna Spirt, MPH; Richard Brand, PhD; John Hsu, MD, MPH; Namita Mohta, MD; Clemens Hong, MD, MPH; Eric Weil, MD; and Timothy G. Ferris, MD, MPH
Medicaid Managed Care Penetration and Drug Utilization for Patients With Serious Mental Illness
Aaron L. Schwartz, PhD; Jacqueline Pesa, PhD, MPH; Dilesh Doshi, PharmD; John Fastenau, PhD, MPH; Seth A. Seabury, PhD; Eric T. Roberts, PhD; and David C. Grabowski, PhD
Clinical Interventions Addressing Nonmedical Health Determinants in Medicaid Managed Care
Laura M. Gottlieb, MD, MPH; Kim Garcia, MPH; Holly Wing, MA; and Rishi Manchanda, MD, MPH
Physician Perceptions of Choosing Wisely and Drivers of Overuse
Carrie H. Colla, PhD; Elizabeth A. Kinsella, BA; Nancy E. Morden, MD, MPH; David J. Meyers, MPH; Meredith B. Rosenthal, PhD; and Thomas D. Sequist, MD, MPH
Potential of Risk-Based Population Guidelines to Reduce Cardiovascular Risk in a Large Integrated Health System
Galina Inzhakova, MPH; Hui Zhou, PhD, MS; Macdonald Morris, PhD; Megan I. Early, MD, MPH; Anny H. Xiang, PhD; Steven J. Jacobsen, MD, PhD; and Stephen F. Derose, MD, MSHS
Enhanced Primary Care and Impact on Quality of Care in Massachusetts
Asaf Bitton, MD, MPH; Amy W. Baughman, MD, MPH; Sara Carlini, BA; Joel S. Weissman, PhD; and David W. Bates, MD, MSc
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Breast Cancer Multigene Testing Trends and Impact on Chemotherapy Use
G. Thomas Ray, MBA; Jeanne Mandelblatt, MD; Laurel A. Habel, PhD; Scott Ramsey, MD, PhD; Lawrence H. Kushi, ScD; Yan Li, MD; and Tracy A. Lieu, MD, MPH
Referring Wisely: Orthopedic Referral Guidelines at an Academic Institution
Maria E. Otto, MD; Carlin Senter, MD; Ralph Gonzales, MD, MSPH; and Nathaniel Gleason, MD

Breast Cancer Multigene Testing Trends and Impact on Chemotherapy Use

G. Thomas Ray, MBA; Jeanne Mandelblatt, MD; Laurel A. Habel, PhD; Scott Ramsey, MD, PhD; Lawrence H. Kushi, ScD; Yan Li, MD; and Tracy A. Lieu, MD, MPH
A multigene test for breast cancer recurrence risk was used in a minority of eligible patients, yet was associated with a decrease in chemotherapy use.
The first approach has been called an “individual-level analysis” and the second approach a “2-level analysis.”22 Each of these approaches has distinct advantages and disadvantages. The individual-level analysis has the advantage of directly measuring the relationship between the individual’s use of the test and their use of chemotherapy, but does not account for certain aspects associated with self-selection of testing. For example, women with a strong predilection for or against chemotherapy may choose not to be tested—a problem similar to “confounding by indication.” The 2-level “ecologic” analysis factors out some of the potential unmeasured confounders related to which women choose to be tested.22 However, that approach is prone to bias if there are other unmeasured factors that may have increased or decreased use of chemotherapy at the same time as the increase in the use of testing.

Characteristics of Study Cohort

We identified 7004 women diagnosed with cancers meeting our inclusion criteria, who met guidelines for 21-gene testing (Table 1). The majority of women were under 65 years of age (57%) and 71% were non-Hispanic white. Three-fourths of cancers were stage I, and 70% of tumors were >1.0 cm in size. Overall, 21-gene testing was performed for 22% of women. In adjusted analyses, compared with women aged 50 to <65 years, women aged 40 to <50 years were more likely to be tested (OR, 1.22; 95% CI, 1.04-1.44), whereas women aged 65 to <75 years and ≥75 years were less likely to be tested (OR, 0.42; 95% CI, 0.36 to 0.49; and OR, 0.04; 95% CI, 0.02-0.06, respectively) (Table 2). Compared with women with tumors >2.0 cm, women with tumors 0.5 cm to ≤1.0 cm were less likely to be tested (OR, 0.51; 95% CI, 0.42-0.61), whereas women with tumors >1.0 to ≤2.0 cm were more likely to be tested (OR, 1.20; 95% CI, 1.03-1.40). Each $10,000 increase in block group median income was associated with increased odds of testing (OR, 1.05; 95% CI, 1.03-1.07).

Oncotype DX and Chemotherapy Use

Among women with 21-gene testing, 52%, 39%, and 9% had low-risk, intermediate-risk, and high-risk RS values, respectively (Table 3). Among women who had the test, a slightly higher percentage (26%) received chemotherapy compared with those who did not (22%; P <.01). Among women with low-, intermediate-, and high-risk RS, 8%, 40%, and 72%, respectively, received chemotherapy.

Between 2005 and 2012, the percent of eligible women receiving 21-gene testing rose from 8% to more than 25%, while the percent of women receiving chemotherapy decreased modestly from 26% to 22% (Figure 1). Younger women were much more likely to receive chemotherapy, and the 2 age groups with the most women receiving chemotherapy had the most pronounced downward trends in chemotherapy use from 2005 to 2012 (from 59% to 47% for those aged 40 to <50 years, and from 35% to 24% for those aged 50 to <65 years) (Figure 2).

In analyses with individual-level propensity score matching (n = 2924), receipt of the 21-gene testing was associated with decreased odds of chemotherapy (OR, 0.74; 95% CI, 0.63-0.87), corresponding to a reduction in the percent of women receiving chemotherapy from 32.7% to 26.5%, or an absolute reduction of 6.2% (95% CI, 2.9%-9.5%). When including only women with validated chemotherapy treatment status, 21-gene testing was associated with lower odds of chemotherapy (OR, 0.64; 95% CI, 0.53-0.78) than in the primary analysis, corresponding to an absolute reduction of 9.5% (95% CI, 5.3%-13.6%). Among this matched cohort, women who had received Oncotype DX testing and went on to receive chemotherapy were older, and were more likely to have stage I cancer and smaller tumors, than women who had not received Oncotype DX testing and went on to receive chemotherapy.

In the 2-level multivariable (ecological) analysis, each 10% increase in the absolute percent of women tested was associated with a 0.92 decreased odds of chemotherapy, but this result was not statistically significant (95% CI, 0.83-1.03; P = .14). The point estimates of this model imply that 26% of women in the study would have received chemotherapy in the absence of any testing, while 23% would receive chemotherapy if 30% of women were tested.

This is among the first large investigations of the use and impact of the 21-gene test for breast cancer recurrence risk in a managed care population. In this integrated system, we found that although rates of use increased over time, only 20% to 25% of patients meeting guidelines received testing. In adjusted analyses, use of testing was differential by age, tumor size, and neighborhood-level income. Patterns of chemotherapy use were generally consistent with test results, with those having a low RS far less likely to have chemotherapy than those with a high RS. When used, the test was associated with a modest reduction in overall chemotherapy use.

The rates of testing we observed were similar to other reports from US populations,2,4,5 including those of a large, for-profit oncology network.23 One difference from past studies is that we found no racial/ethnic differences in use of the test. For example, Guth et al found that women treated at municipal hospitals—who were more likely to be of low income and nonwhite—were less likely to have the 21-gene test than socioeconomically similar women seen in tertiary care settings (3% vs 30%).24 The fact that the test was fully covered by insurance in our setting removed patient-level financial barriers and may have mitigated racial/ethnic variation in test use. However, patients living in higher-income areas were more likely to have the test than those living in lower-income areas.

The other clinical and demographic correlates of nonuse of 21-gene testing that we identified, such as smaller tumor size and older age, have also been observed in other settings.23 For these subgroups, clinicians and/or their patients may have decided that chemotherapy was not indicated, so that testing would not change treatment decisions. Clinicians may also feel that standard clinicopathologic prognostic factors, existing decision tools (eg, Adjuvant!),25 and/or a patient’s health status or preferences are more important in treatment decision making than 21-gene test results.26 However, it has been reported that, when obtained, the 21-gene results can change pre-testing treatment decisions in about 30% to 50% of cases.6,27-29 A survey of KPNC oncologists, completed in spring 2015, suggests that among those patients who have the 21-gene test, the results cause changes in chemotherapy decisions in approximately 40%—and that these changes are equally divided among changes away from having chemotherapy and changes toward having chemotherapy (Lieu et al [unpublished data from a survey of 85 KPNC oncologists via mail and e-mail, as part of the overall project that produced this paper]).

This 21-gene test and other multigene tests have been promoted as likely to be cost-effective since test costs are expected to be offset by decreases in chemotherapy use among women with low recurrence risk, and, hence, low predicted benefits of chemotherapy.3,6,30-32 In our matched analysis, we found that testing was associated with a 6% to 10% reduction in chemotherapy use. A recent meta-analysis estimated a somewhat higher percent reduction of 12%.6 Our “ecologic” analysis indicated that an increase in testing in the KPNC setting, from 0% to 30%, resulted in approximately a 3% absolute decrease in the percent of women getting chemotherapy. The 2-level analysis is a more indirect (and conservative) approach, with fewer observations due to the summarized nature of the analysis, and, therefore, has less power. Nevertheless, the direction of the result was the same as that of the propensity score-matched analysis. Regardless of approach, our estimated reductions in chemotherapy were far lower than the 31% reduction in chemotherapy observed in a smaller study of a younger cohort in Ireland.3 The lower reduction in chemotherapy we observed relative to other studies was most likely due to our patient population being older and having a lower baseline percent of women receiving chemotherapy, as well as a lower percentage of eligible women being tested, compared with the study from Ireland.

Limitations and Strengths

Our results should not be construed as suggesting that the 21-gene test is being underused, as the study only evaluated chemotherapy in relation to current levels of testing. Our results cannot be extrapolated to project whether, or by how much, chemotherapy use would decrease if the test were used for a higher percentage of patients. The current level of testing may reflect clinicians’ judgments that the nontested patients would not benefit from testing because the decision about chemotherapy is already clear in their cases.

Chemotherapy treatment decisions in our study were not always in accord with the RS. Among women with low RS, 8% received chemotherapy anyway, and 28% of those with high RS did not receive chemotherapy. Similar discordant use patterns were noted in a recent meta-analysis.28 Our data did not enable us to determine the reasons for these conflicting choices; however, based on other reports,23 it seems that discordant use patterns are not unexpected since multigene testing is only 1 factor in complex chemotherapy decisions, and test results are not an absolute mandate for or against chemotherapy. For instance, doctors may sometimes use the test to discourage a low-risk (based on tumor size, histology, grade) or unhealthy patient who wants chemotherapy from having it, or to encourage treatment in a high-risk, healthy patient who does not want it. In the latter situation, a patient may continue to refuse chemotherapy even after receiving a high-risk test result. Genomic testing may increase anxiety and impair decision making or results may be poorly understood.33-36

This study has many strengths, including its fully enumerated managed care population, inclusion of only those cases with clinical indications for 21-gene testing, and ability to relate test results to chemotherapy use. Although these findings from an integrated health plan population in California may not be representative of all practice settings, the testing and treatment patterns we found were remarkably similar to those reported from other settings.2,23 This suggests that clinical norms, randomized controlled trial evidence, and national recommendations may be more important to physicians’ ordering behavior than the costs of the test or who is covering those costs. That chemotherapy is sometimes discordant from therapy suggested by the RS indicates that patient factors may be as, or more important than the healthcare structure. These hypotheses will need to be tested explicitly in future research across diverse healthcare systems and populations.

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