The iCanCare study¹⁶ selected 3,880 women aged 20-79 diagnosed with early-stage breast cancer and treated in 2013-14 as captured by rapid reporting systems from the Surveillance, Epidemiology, and End-Results (SEER) registries of Georgia and Los Angeles County (LA). African-American and Latinas were oversampled in LA to ensure diversity in the sample. We identified cases approximately two months after breast surgical treatment. Women with stage III or IV cancer, tumors >5 centimeters (cm) in size, or those with >3 positive lymph nodes were excluded. Non-Hispanic Whites and African Americans below the age of 50 in LA were not available for sampling due to an ongoing study in those populations. Modified Dillman techniques^17-18 were used to solicit high patient response rates. Women were invited to participate by mail with an upfront $20 cash incentive. Extensive follow-up was conducted for non-responders. Materials were sent in English, except for women with Spanish surnames who received materials in both English and Spanish.¹⁹ From 3,880 identified women, 249 were ineligible due to a prior breast cancer diagnosis or stages III-IV; residing outside the SEER registry area; or being deceased, too ill, or unable to complete a survey in Spanish or English. Another 1,053 women did not return surveys or refused participation. SEER registries collect RS as part of routine surveillance operations but there are concerns for completeness. Through an agreement between Genomic Health, Inc. and the National Cancer Institute SEER Program, records from the two datasets were linked using probabilistic methods including manual review and adjudication of potential linked pairs to assure the highest specificity while simultaneously maximizing sensitivity. Results showed that 97.2% of patients with a SEER-confirmed RS test linked to the Genomic Health, Inc. test dataset. The SEER registries then provided limited SEER data and RS results for iCanCare participants to the University of Michigan, which were merged to survey data under IRB approvals from partnering Universities and State Departments of Public Health of Georgia and California. RS results were linked to the sample of 2,578 women (71% of eligible patients). Our analytic sample consisted of 1,527 patients with Stage I-II, ER/PR-positive, HER2-negative disease.

We classified patients into three mutually exclusive clinical categories: lymph node-negative, more-favorable (age at diagnosis ≥50 years and/or tumor grade 1-2); node-negative, less-favorable (age at diagnosis <50 years, and/or grade 3 disease), and node-positive. Age and tumor grade were used to derive subgroups as these variables are prognostic for distance recurrence. ^{3, 20} We examined three outcomes: receipt of RS testing (obtained from Genomic Health, Inc.), medical oncologists’ recommendation for adjuvant systemic chemotherapy, and receipt of chemotherapy (both reported from the patient survey). RS results indicated whether the test was done or not and the numeric score (0-100 for tested subjects, with higher values reflecting increased likelihood of distant metastatic breast cancer recurrence and greater benefit from chemotherapy). Scores were categorized in accordance with current guidelines and laboratory reporting (low 0-17, intermediate 18-30, high 31-100). Surveyed patients reported their medical oncologists’ recommendations for adjuvant systemic chemotherapy across five responses: strongly against, against, left it up to the patient, for, or strongly for chemotherapy. We categorized these into three responses: against, left it up to patient, or for chemotherapy. Women indicated whether they had begun or were planning to begin chemotherapy, or whether they had refused/had no plans to begin chemotherapy.

Covariates were obtained from the patient survey and SEER registries. Tumor stage (I or II), grade (1, 2, or 3), and lymph node status (all nodes negative, 1-3 nodes positive for disease) were obtained from registries. Patients provided the following variables from surveys: age at diagnosis; education (high school or less, some college, college graduate or higher); family income (< $20,000/year, $20-60,000/year, >$60,000/year); race/ethnicity (white, black, Latina, Asian), and diagnosis of comorbidities, including chronic lung disease, heart disease, diabetes, or stroke (no diagnosis, one condition, two or more conditions).

We also examined patient experiences with testing and chemotherapy decisions. We first asked tested women how helpful RS was in making a chemotherapy decision, on a 5-point Likert scale (1 = not at all helpful, 5 = extremely helpful). Next, women indicated whether RS made them “much less”, “less”, ”no change in their mind”, “more”, or “much more” interested in chemotherapy. We asked women about their satisfaction with decisions surrounding RS and chemotherapy, on a 5-point Likert scale (1 = not at all satisfied, 5 = totally satisfied).

First, we described the association of patient characteristics and receipt of chemotherapy and RS tests. We then described medical oncologists’ recommendations for adjuvant systemic chemotherapy by clinical group and RS score. We then assessed chemotherapy use by clinical and RS groups. Next, we constructed a multivariable logistic model that examined receipt of RS testing as a function of clinical group, comorbidities, and various demographic characteristics including race, education, income, and geographical site. Further, we estimated the effect of RS on the likelihood of chemotherapy receipt, while controlling for clinical group and demographic characteristics listed above. Finally, we described patient recall of RS testing and their satisfaction with testing and treatment decision-making.

Survey design and non-response weights were created to compensate for differential probability of selection and to adjust for survey non-response to report results that resemble the target populations in LAC and Georgia.²¹ To reduce potential non-response bias due to missing data and changes in versions of the questionnaire we multiply imputed data using a sequential regression multiple imputation framework.²² We generated five independently-imputed data sets and then computed inferential statistics, combining estimates across the datasets.²³ Unless noted, results reported used multiply imputed weighted data.(SAS version 9.4).

Figure 1 shows the results of a logistic regression model that estimates factors associated with RS receipt. Compared with women with node-negative, more-favorable disease, women with node-negative, less-favorable disease were more likely to receive RS (OR 1.5, 95% CI 1.1-2.0), while women with node-positive disease were less likely to receive RS (OR 0.5, 95% CI 0.4-0.7). Women with two or more comorbidities were less likely to receive RS than women without a comorbidity (OR 0.5, 95% CI 0.3-0.7). There were no significant differences in RS use across education, income, and race/ethnicity.

Overall, 47.2% of patients reported that their medical oncologist recommended against systemic chemotherapy, 12.3% reported their oncologist left the decision to them, and 40.5% reported their oncologist recommended for chemotherapy. Figure 2 shows the relationship between RS results and medical oncologist recommendations for the three clinical groups. RS results were highly associated with recommendations: virtually all patients with high scores (31-100) received a chemotherapy recommendation (86.9%-96.5% across subgroups). For women with node-negative disease, the majority with low-risk RS results (0-18) received a recommendation against chemotherapy (65.9%-78.2% across subgroups). Most women with favorable-risk, node-negative disease received a recommendation against chemotherapy (78.2%) and 11.7% received a recommendation for chemotherapy. Recommendations for chemotherapy varied in untested patients: 23.1% of those in the more-favorable group, 60.2% in the node-negative, less-favorable group and 83.2% in the node-positive group (p<.001). Women with less-favorable disease and intermediate RS results (19-30) reported the highest proportion (22.9% and 20.2% node-negative and node-positive disease, respectively) of a neutral oncologist’s recommendation.

Figure 3 shows the distribution of chemotherapy receipt by clinical and RS groups. The relationship between receipt of chemotherapy and RS was consistent across the 3 clinical subgroups. Most patients with high RS received chemotherapy (87.0%, 91.1%, 100% for node-negative more-favorable, node-negative less-favorable, and node-positive groups). Low scores were associated with low rates of chemotherapy in all clinical subgroups (2.9%, 9.5%, and 26.6%, respectively). Intermediate scores yielded rates between the low and high score groups. Absolute differences in chemotherapy receipt were particularly marked for patients with low RS versus no testing. In node-positive disease, 83.2% of untested women received chemotherapy, versus 27.2% with low RS. In node-negative favorable disease, 13.0% of untested women received chemotherapy versus 3% in women with low RS.

Figure 4 shows results of a multivariable logistic regression model to examine the association between chemotherapy receipt and selected covariates. Receipt of chemotherapy was associated with clinical subgroups and RS scores. Compared with women who did not have RS, women with low-risk RS results were less likely to receive chemotherapy (OR 0.1, 95% CI 0.1-0.2), while women with medium-risk and high-risk RS results were more likely to receive chemotherapy: ORs 1.4 (1.1-1.7) and 2.8 (2.0-4.0), respectively. Compared with women with more-favorable node-negative disease, women with node-negative disease but one unfavorable risk factor were more likely to receive chemotherapy (OR 4.3, 95% CI 3.0-6.1) while women with node-positive disease were considerably more likely to receive chemotherapy (OR 19.08, 95% CI 13.1-27.7). Higher-income patients were more likely to receive chemotherapy than lower-income patients (OR 1.6, 95% 1.0-2.5) but there were no differences in receipt by education or race/ethnicity. To investigate differences by race/ethnicity, we examined chemotherapy receipt by clinical subgroup, RS status, and race/ethnicity (full results not shown). The only subgroup where white women had notably higher rates of chemotherapy receipt than other racial/ethnic groups was for node-positive disease with intermediate RS (79% in whites, 50% in Asian women and Latinas, 20% in black women).

We compared observed self-reported RS results to RS test results from Genomic Health, Inc. About three quarters (76.5%) of patients accurately reported RS receipt, and among those who did receive RS, 61.7% correctly reported results by category of low, intermediate, or high risk. Among those who received RS, 63.9% of patients reported that it was “very” or “extremely” helpful. Among 420 women who reported low-risk RS results, 65.0% indicated that RS shifted their opinion against chemotherapy, whereas 73.1% of those who reported high scores reported that their RS result shifted their opinion toward receipt of chemotherapy. Satisfaction with decision-making about RS testing and receipt of chemotherapy was very high (4.4 out of 5.0 for both decisions) and these scores did not differ substantively by whether patients did or did not receive testing or chemotherapy.

Our results suggest that a major advance in oncology precision medicine, tumor genomic profiling, may improve treatment decision-making and communication. In the context of early-stage breast cancer, the combination of genomic test results and clinical data now offers more precise targeting of patients for chemotherapy, especially among those with node-negative disease. Additional clarity about the prediction of the marginal benefit of adjuvant chemotherapy in patients with intermediate score range in patients with node negative disease is forthcoming.²⁹

The majority of patients studied reported that their medical oncologist made a recommendation for or against chemotherapy, rather than leaving the decision up to the patient. Personalized recommendations appear to reduce potential overtreatment with chemotherapy and nearly eliminated socioeconomic disparities in treatment, after controlling for clinical factors. This is a notable benefit of incorporating RS into breast cancer treatment algorithms. Oncologists’ commitment to addressing overtreatment may be most evident by the substantial proportion of patients with node-positive disease who received RS, despite current guidelines that advise chemotherapy without RS testing. The impact of RS testing appeared greatest in node-positive patients because their baseline use of chemotherapy was high, such that RS results largely served to identify node-positive patients with low scores for whom chemotherapy might logically be omitted. However, definitive evidence for the benefit of RS testing among node-positive patients awaits the results of clinical trials.²⁴ Finally, our results suggest that many patients rely on their oncologist to incorporate RS results into chemotherapy recommendations, and that patient satisfaction with RS testing and treatment decisions is very high. This underscores another potential impact of precision medicine: to reduce lingering uncertainty and improve the patient experience of treatment decision-making and communication.