The Effect of Clinical Trial Participation on Early Breast Cancer Outcomes
Malignancy is second only to heart disease and stroke as the leading cause of death, worldwide. Invasive breast cancer is the leading malignancy and the second most common cause of cancer-related death among North American women. Support and treatment costs for cancer-affected adults are significant. There has been a dramatic increase in 5-year survival from 75.2% in 1975 to 91.0% in 2007, much of which is because of advances in technology and treatment.
Most of these improvements were achieved through basic scientific efforts translated into clinical trials. While advances such as, prevention, treatment, and management, and possible cure, may be improved by findings from clinical trials, the personal participation of adult cancer patients is low, overall, especially for potential adjuvant therapies. Experts suggest poor patient understanding, limited access, mistrust, fear, low provider engagement, and poor communication may impair recruitment to cancer clinical trials. Increasing the non-monetary incentive for trial participation may enhance participation. Thus, determining the positive effects of trial participation may incentivize participation leading to faster development of supportive and curative therapies. Specifically, trial participation alone may improve early detection of recurrent disease, prevention or early detection of comorbidities, thereby improving survival. Participation alone may also minimize side-effects of standard therapies, and potentially improve access to effective primary and secondary prevention interventions for women diagnosed with early breast cancer.
The overall hypothesis of this study is clinical trial participation independently improves morbidity and mortality for women with early breast cancer. We will examine this through two specific aims. Specific Aim 1 will compare outcomes of women who received treatment in clinical trials (CT) and outside of a CT to one another. Specific Aim 2 will compare early breast cancer patients on randomized controlled trial (RCT), receiving standard adjuvant therapy to women reported to the U.S. population-based surveillance program: Surveillance Epidemiology and End Results (SEER) receiving similar therapy.
Specific Aim 1
In this secondary analysis, all patients treated with neoadjuvant chemotherapy between 2001 and 2015 were selected. A total 1038 patients with sufficient treatment, patient and tumor characteristics data were included. A total 260 of those patientts were treated in clinical trials. We examined whether CT participation status, in addition to commonly known predictors for pCR, improves prediction of pCR. We conducted similar analyses for the outcome of rate of mastectomy. Finally, survival analyses were evaluated as part of an exploratory analysis.
Study participation was an independent predictor of pCR in addition to commonly known predictors. The adjusted OR for trial participants versus non-participants was 1.53 (95% CI, 1.03 to 2.28). Also, study participation improved the prediction of mastectomy risk. The adjusted OR for trial participants versus non-participants was 0.62 (95% CI 0.42 to 0.90). Subgroup specific differences concerning the impact of study participation could not be shown for either pCR or mastectomy rate. Formal survival comparisons could not be conducted due to large differences in follow-up data in patients participating in clinical trials versus those who did not participate; however, pCR was a predictor of prognosis in both groups.
Patients taking part in neoadjuvant chemotherapy clinical trials have a higher pCR rate and a lower mastectomy risk than patients not participating in clinical trials for their cancer care. This finding is a supporting factor for trial participation in neoadjuvant chemotherapy trials.
Specific Aim 2:
This secondary analysis included patients from one of three (3) international, adjuvant breast cancer RCT (RCT-participants) and women with similar stage breast cancer from the general U.S. population, Surveillance Epidemiology and End Results Program (SEER-13), the controls. Kaplan-Meier curves were generated to display differences in survival patterns between the two groups. Propensity score analysis (PSA) was calculated and applied to a Cox proportional hazard models to determine hazard ratios (HR) of trial participation on survival. Similarly, PSA was also calculated and utilized in multivariable logistic regression models to calculate the odds ratios of surgical management, mastectomy or breast conserving surgery (BCS), for RCT participation compared to the SEER-13 controls.
Women diagnosed between 1997-2004 with invasive breast cancer, tumor (T) size 1-3, lymph node (LN) positive (LN1/2), hormone receptor positive or negative, HER2 positive or negative, treated with surgery and adjuvant chemotherapy were included in the analysis. The total sample size was 9255 patients, 1795 RCT-participants and 7460 SEER-13 controls. Multivariable analysis demonstrated reduction in risk of death by 17% [HR: 0.83 (95% CI: 0.72-0.95); p<0.001] for patients at 5-years and 21% reduction in risk for 10 years [HR:0.79 (95% CI: 0.71-0.87); p<0.001]. RCT-participants were significantly less likely to undergo mastectomy compared to SEER-13 controls [OR: 0.78 (95% CI: 0.66-0.92); p=0.03].
RCT participation significantly reduces the risk of death, all cause and breast cancer specific, up to 5 and 10 years compared to the general population. RCT is associated with less morbid surgical management (mastectomy) compared to the general breast cancer population. Additionally, RCT participants have unfavorable prognostic variables compared to the general population.
Clinical trial participation for women with early breast cancer leads to better outcomes, after controlling for other prognostic variables. The outcomes include higher probability of pCR, less risk of mastectomy and improved survival outcomes. Healthcare providers should consider this information carefully when determining their level of engagement and consideration for clinical trials and discussing participation with potential patients.