Abstract
Purpose
The 21-gene recurrence score (RS) can guide adjuvant chemotherapy decisions in the multidisciplinary treatment (MDT) of patients with early breast cancer. This study aimed to evaluate the influence of the 21-gene RS assay on patient’ compliance with MDT and its association with disease outcomes.
Methods
Patients diagnosed with pN0-1, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer between January 2013 and June 2019 were enrolled. A logistic regression model was used to identify parameters associated with treatment adherence. Prognostic indicators were evaluated using the Cox proportional hazard models.
Results
After the assay, patients were less likely to violate the treatment plan (14.9% vs. 23.1%, p < 0.001), and higher compliance rates were observed for chemotherapy (p = 0.042), radiotherapy (p = 0.012), and endocrine therapy (p < 0.001). Multivariable analysis demonstrated that the 21-gene RS assay (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.09–1.88; p = 0.009) was independently associated with MDT compliance. Moreover, compliance with MDT was independently associated with better disease-free survival (hazard ratio, 0.43; 95% CI, 0.29–0.64; p < 0.001), regardless of the 21-gene RS assay (interaction p = 0.842).
Conclusion
The 21-gene RS assay improved the MDT compliance rate in patients with early breast cancer. Adherence to MDT is associated with a better prognosis.
Keywords: Breast Neoplasms, Compliance, Genetic Testing, Patient Care Team, Prognosis
INTRODUCTION
Breast cancer is the most common malignant disease and ranks first among cancer-related deaths in women [1]. In 2020, there were more than 2,260,000 newly diagnosed cases and 680,000 deaths worldwide [2]. It is now considered a group of diseases with substantial heterogeneity [3]. Conventional clinicopathological factors alone are no longer sufficient to support treatment decision making and prognosis prediction. Under these circumstances, multigene assays facilitate the prescription of treatment strategies, as well as the prediction of prognosis and treatment benefit [4].
The 21-gene recurrence score (RS) assay is one of the most credible multigene assays for providing prognostic information for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer [5]. The predictive value of this assay for the benefits of chemotherapy has also been verified [6]. The prospective TAILORx study further validated the potential of the 21-gene RS assay for guiding treatment decisions [5], and this test has been included in several international guidelines to help treat patients with estrogen receptor-positive, N0 breast cancer [7,8]. Furthermore, the SWOG S8814, ECOG E2197, and WGS Plan B verified the 21-gene RS assay in N1 patients [4,9,10]. Only the results of the prospective trial SWOG S1007 in pN0-1 patients have just been reported. Overall, the 21-gene assay resulted in a 30% change in treatment decisions during multidisciplinary treatment (MDT) discussion [11].
With a deeper understanding of the disease, treatment strategies for breast cancer are becoming increasingly complex. Therefore, MDT have evolved [12]. The MDT strategy combines evidence-based management with individualized disease information, thus enabling patients with cancer to receive the most suitable therapy. Oncology professionals in the UK acknowledged that MDT could make treatment decisions that are more evidence-based, provide better medical care and nursing, and improve the quality of treatment. Currently, it is been widely used and regarded as the gold standard in cancer care [13]. However, non-concordance of actual treatment with the MDT recommendations accounted for up to 15% of all cases. Yang et al. [14] found that inpatients with breast cancer, noncompliance with MDT recommendations was correlated with worse prognosis, irrespective of the treatment modality [15]. Therefore, identifying the factors that influence treatment adherence is extremely important.
To date, several studies have focused on the factors affecting treatment adherence and the relation between MDT compliance and clinical outcomes. However, the effect of the 21-gene RS assay on patient’ adherence has rarely been investigated. The current study was designed to evaluate whether the 21-gene RS assay would influence patient’ adherence to MDT discussions and whether compliance would affect the disease outcomes.
METHODS
Study population
Patients with breast cancer who underwent surgical treatment between April 2013 and June 2019 and were treated at Shanghai Ruijin Hospital were reviewed. Patients who met the following eligibility criteria were included: 1) women, 2) those with hormone receptor-positive, HER2-negative invasive breast cancer, 3) having pathologically confirmed node-negative or having one to three lymph nodes involved. The exclusion criteria were as follows: 1) tumor < 0.5 cm; 2) those with bilateral breast cancer; 3) patients with de novo stage IV breast cancer or those who underwent neoadjuvant therapy; 4) unavailable 21-gene RS result due to technical reasons; and 5) missing data of MDT recommendations or actual treatment information. Data on clinicopathological features, MDT decisions, and follow-up were retrieved from Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) and an internet-based MDT platform (MDT4BC). Patients were classified into compliance and noncompliance groups according to whether they followed the MDT recommendations.
The 21-gene RS assay
The 21-gene RS assay was conducted on 10 μm thick, formalin-fixed, paraffin-embedded tissue slides. After ensuring that there were sufficient tissue samples without DNA contamination, RNA expression was measured in two unstained sections. Standardized quantitative reverse-transcription polymerase chain reaction was performed using an Applied Biosystems 7500 Real-Time PCR System (Applied Biosystems, Foster City, USA) after gene-specific reverse transcription using the Omniscript RT kit (Qiagen, Hilden, Germany). The RS was calculated from the expression levels of each cancer-related gene, which were measured in triplicate after normalization with reference genes.
MDT procedure, the definition of compliance, and clinical outcome
The MDT discussion was offered to every patient after surgery, to provide detailed treatment recommendations, including adjuvant chemotherapy (yes or no, specific regimens and number of cycles), endocrine therapy (recommended or not, drug type, and duration of medication), radiotherapy (recommended or not), and targeted therapy (recommended or not). The MDT panelists included breast surgeons, radiologists, medical oncologists, histopathologists, breast special care nurses, and coordinators. The MDT results were prospectively entered into the database.
Patient’ adherence was assessed during the follow-up. Detailed definitions of compliance and noncompliance with the MDT recommendations were described in our previous study [14]. Patients were considered compliant if they received the same drug, dose, and course of treatment recommended by the MDT. Noncompliance was defined as refusing treatment, receiving different drugs or dosages, taking drugs for insufficient duration, or refusing ovarian function suppression (only for endocrine therapy) if recommended. Overall compliance was calculated by summing the compliance with each treatment modality. The specific reasons given for treatment noncompliance include comorbidity, adverse events, patient’ will, flexible recommendations, economic reasons, withdrawal from clinical trials, treatment at a local hospital, and menstrual status change. Disease-free survival (DFS) and overall survival (OS) were defined using the STEEP standards.
Statistical analyses
The distribution of demographic and pathological characteristics between the compliance and noncompliance groups was compared using the χ2 test. Multivariable logistic regression models with odds ratios (ORs) and 95% confidence intervals (CIs) were used to identify factors influencing treatment compliance. Kaplan–Meier curves with the log-rank test were plotted to illustrate survival. Multivariate Cox regression analysis with hazard ratios (HR) and 95% CIs was used to evaluate the association between MDT compliance and prognosis. A two-sided p < 0.05 was considered statistically significant. Statistical analyses were performed using with SPSS version 23 (IBM Corp., Armonk, USA) and GraphPad Prism 8 (GraphPad Prism Inc., San Diego, USA).
Ethics approval
Institutional Review Board approval was not required because this was a retrospective study. The requirement for informed consent was waived due to the retrospective design of this study.
RESULTS
Baseline characteristics of the study population
A total of 2,466 patients were reviewed and 2,323 were enrolled in the current study (Figure 1). The baseline characteristics of the patients are summarized in Table 1. The mean age was 56.43 ± 12.79 years, and 822 (35.4%) patients were ≤ 50 years, 1,182 (50.9%) were 50–70 years, and 319 (13.7%) were > 70 years. Grade I/II tumors comprised 64.4% (1,496 patients) of all cases, and grade III tumors accounted for 20.3% (471 patients). Regarding the TNM stage, 1,224 (52.7%) patients were diagnosed with stage I disease, 1,087 (46.8%) had stage II tumors, and only 12 (0.5%) had stage III breast cancer. There were 1,514 (65.2%) tumors smaller than 2.0 cm, 785 (33.8%) tumors between 2.0–5.0 cm, and 24 (1.0%) tumors larger than 5.0 cm. A total of 1,731 (74.5%) patients had no lymph node metastasis, and 592 (25.5%) had 1–3 lymph nodes involved. Regarding the immunohistochemical results, 325 (14.0%) patients had estrogen–receptor expression < 50%, 506 (21.8%) patients had progesterone receptor (PR) expression of < 20%, and 1,441 (62.0%) patients had a Ki-67 index of > 14%. The luminal B subtype accounted for 58.5% (1,360/2,323) of all patients. A total of 1,760 (75.8%) patients underwent the 21-gene RS assay. Overall, 393 patients did not complete the recommended treatment; the noncompliance rate was 16.9%.
Figure 1. Schematic diagram of patient selection for matched study.
HR+ = hormone receptor-positive; HER2 = human epidermal growth factor receptor 2; RS = recurrence score; MDT = multidisciplinary treatment.
Table 1. Baseline clinicopathological characteristics of enrolled patients.
| Variables | Total (n = 2,323) | Non-compliance (n = 393) | Compliance (n = 1,930) | p-value | |
|---|---|---|---|---|---|
| Age (yr) | < 0.001 | ||||
| ≤ 50 | 822 (35.4) | 140 (35.6) | 682 (35.3) | ||
| 50–70 | 1,182 (50.9) | 176 (44.8) | 1,006 (52.1) | ||
| > 70 | 319 (13.7) | 77 (19.6) | 242 (12.6) | ||
| Menstrual status | 0.906 | ||||
| Pre/Peri-menopausal | 1,448 (62.3) | 246 (62.6) | 1,202 (62.3) | ||
| Post-menopausal | 875 (37.7) | 147 (37.4) | 728 (37.7) | ||
| Family history | 0.305 | ||||
| No | 2,159 (92.9) | 370 (94.1) | 1,789 (92.7) | ||
| Yes | 164 (7.1) | 23 (5.9) | 141 (7.3) | ||
| Comorbidity | 0.077 | ||||
| No | 1,325 (57.0) | 240 (61.0) | 1,085 (56.2) | ||
| Yes | 998 (43.0) | 153 (39.0) | 845 (43.8) | ||
| Benign breast disease | 0.612 | ||||
| No | 1,858 (80.0) | 318 (80.9) | 1,540 (79.8) | ||
| Yes | 465 (20.0) | 75 (19.1) | 390 (20.2) | ||
| Malignant tumor history | 0.616 | ||||
| No | 2,216 (95.4) | 373 (94.9) | 1,843 (95.5) | ||
| Yes | 107 (4.6) | 20 (5.1) | 87 (4.5) | ||
| Breast surgery | 0.406 | ||||
| BCS | 1,014 (43.7) | 179 (45.5) | 835 (43.2) | ||
| Mastectomy | 1,309 (56.3) | 214 (54.5) | 1,095 (56.8) | ||
| Pathological type | 0.497 | ||||
| Non-IDC | 110 (4.7) | 16 (4.0) | 94 (4.9) | ||
| IDC | 2,213 (95.3) | 377 (96.0) | 1,836 (95.1) | ||
| Histological grade | 0.032 | ||||
| I/II | 1,496 (64.4) | 246 (62.6) | 1,250 (64.8) | ||
| III | 471 (20.3) | 97 (24.7) | 374 (19.3) | ||
| Unknown | 356 (15.3) | 50 (12.7) | 306 (15.9) | ||
| TNM stage | < 0.001 | ||||
| I | 1,224 (52.7) | 176 (44.8) | 1,048 (54.3) | ||
| II | 1,087 (46.8) | 210 (53.4) | 877 (45.4) | ||
| III | 12 (0.5) | 7 (1.8) | 5 (0.3) | ||
| Tumor size (cm) | 0.243 | ||||
| < 2.0 | 1,514 (65.2) | 250 (63.6) | 1,264 (65.5) | ||
| 2.0–5.0 | 785 (33.8) | 136 (34.6) | 649 (33.6) | ||
| > 5.0 | 24 (1.0) | 7 (1.8) | 17 (0.9) | ||
| Lymph node status | < 0.001 | ||||
| N0 | 1,731 (74.5) | 257 (65.4) | 1,474 (76.4) | ||
| N1 | 592 (25.5) | 136 (34.6) | 456 (23.6) | ||
| LVI | 0.223 | ||||
| No | 189 (8.1) | 38 (9.7) | 151 (7.8) | ||
| Yes | 2,134 (91.9) | 355 (90.3) | 1,779 (92.2) | ||
| ER | 0.263 | ||||
| < 50% | 325 (14.0) | 62 (15.8) | 263 (13.6) | ||
| ≥ 50% | 1,998 (86.0) | 331 (84.2) | 1,667 (86.4) | ||
| PR | 0.097 | ||||
| < 20% | 506 (21.8) | 98 (24.9) | 408 (21.1) | ||
| ≥ 20% | 1,817 (78.2) | 295 (75.1) | 1,522 (78.9) | ||
| Ki-67 | 0.890 | ||||
| ≤ 14% | 882 (38.0) | 148 (37.7) | 734 (38.0) | ||
| > 14% | 1,441 (62.0) | 245 (62.3) | 1,196 (62.0) | ||
| Molecular Subtype | 0.993 | ||||
| Luminal A | 963 (41.5) | 163 (41.5) | 800 (41.5) | ||
| Luminal B | 1,360 (58.5) | 230 (58.5) | 1,130 (58.5) | ||
| With 21-gene RS testing | < 0.001 | ||||
| No | 563 (24.2) | 130 (33.1) | 433 (22.4) | ||
| Yes | 1,760 (75.8) | 263 (66.9) | 1,497 (77.6) | ||
Values are presented as number (%).
BCS = breast-conserving surgery; IDC = invasive ductal carcinoma; TNM = tumor-node-metastasis; LVI = lymph vascular invasion; ER = estrogen receptor; PR = progesterone receptor; RS = recurrence score.
Clinicopathological factors associated with noncompliance to MDT recommendations
In univariable analysis, patients aged > 70 or ≤ 50 years (≤ 50 years: 17.0%, 50–70 years: 14.9%, > 70 years: 24.1%, p < 0.001), had grade III tumors (20.6% vs. 16.4%, p = 0.032), had advanced disease (stage I: 14.3%, stage II: 19.4%, stage III: 58.3%, p < 0.001), had positive lymph nodes (23.0% vs. 14.8%, p < 0.001), and forwent the 21-gene test were significantly associated with noncompliance to MDT recommendations (Table 1). The non-adherence rate was 14.9% in patients receiving the 21-gene RS assay, and 23.1% in those not receiving the assay (p < 0.001).
Multivariable analysis showed that an age of > 70 years (OR, 0.56; 95% CI, 0.41–0.78; p < 0.001) was associated with a greater risk of non-compliance. Patients who underwent the 21-gene assay were also significantly more likely to be adherent (OR, 1.43; 95% CI, 1.09–1.88; p = 0.009; Table 2).
Table 2. Multivariable analysis of clinicopathological characteristics associated with multidisciplinary treatment compliance.
| Variables | OR (95% CI) | p-value | |
|---|---|---|---|
| Age (yr) | < 0.001 | ||
| 50–70 vs. ≤ 50 | 1.06 (0.83–1.37) | 0.627 | |
| > 70 vs. ≤ 50 | 0.56 (0.41–0.78) | < 0.001 | |
| Histological grade | 0.103 | ||
| III vs. I/II | 0.82 (0.63–1.08) | 0.160 | |
| Unknown vs. I/II | 1.25 (0.89–1.76) | 0.199 | |
| TNM stage | 0.056 | ||
| II vs. I | 0.95 (0.71–1.27) | 0.715 | |
| III vs. I | 0.23 (0.07–0.76) | 0.017 | |
| Lymph node status (N1 vs. N0) | 0.73 (0.53–1.01) | 0.059 | |
| With 21-gene RS testing (Yes vs. No) | 1.43 (1.09–1.88) | 0.009 | |
OR = odds ratio; CI = confidence interval; TNM = tumor-node-metastasis; RS = recurrence score.
The 21-gene test and compliance with MDT recommendations
Figure 2 illustrates the impact of the 21-gene test on patients’ compliance with MDT recommendations. A total of 1,760 patients (64.4%) underwent the 21-gene RS assay, of whom 263 (14.9%) violated the MDT recommendations. Among the 563 patients who did not underwent the 21-gene RS assay, the noncompliance rate was 23.1% (p < 0.001). Regarding chemotherapy compliance, 146 patients (6.3%) did not follow the prescription, and the noncompliance rate was 5.7% (101/1,760) in those receiving the assay and 8.0% (45/563) in those who did not (p = 0.042). For radiotherapy, the overall discordance rate was 4.9% (114 patients); 4.2% (74 patients) of the assay-received patients and 7.1% (40 patients) of the assay-forgoing ones did not complete the recommended treatment (p = 0.012). With regard to the endocrine therapy, 189 patients (8.1%) deviated from the treatment recommendation, and the non-adherence rates were 6.2% (109/1,760) and 14.2% (80/563) in the population who underwent the RS assay and those who did not (p < 0.001), respectively.
Figure 2. Impact of the 21-gene test on patients’ compliance with multidisciplinary team recommendations.
RS = recurrence score.
Reasons for noncompliance with MDT recommendations
Among the 393 patients who violated the MDT recommendations, the common reasons for noncompliance were patient’ will (159 cases), comorbidities (95 cases), treatment at local hospitals (49 cases), menstrual status changes (49 cases), adverse events (45 cases), economic reasons (37 cases), flexible recommendations (12 cases), and withdrawal from clinical trials (three cases, Supplementary Table 1). There was no significant difference in the reasons for noncompliance before and after the 21-gene RS assay (p = 0.696, Supplementary Table 2).
Among the 146 patients noncompliant with chemotherapy decisions, 71 refused chemotherapy, 40 received different regimens, and 35 received an insufficient course of treatment. Endocrine therapy was recommended for all patients. Among the 209 non-compliant patients, 81 received different regimens and 108 refused endocrine therapy. Radiotherapy was recommended for 1,391 patients, and 54 refused therapies. Specific reasons for not receiving each treatment recommendation are shown in Supplementary Figure 1.
Factors associated with disease outcome
After a median follow-up time of 36.63 months, 115 DFS and 22 OS events were observed. The estimated 3-year DFS was 97.0%, and the 3-year OS was 99.6%.
In the univariate analysis, benign breast disease history (p = 0.003), histological grade (p = 0.001), TNM stage (p < 0.001), tumor size (p < 0.001), lymph node status (p = 0.013), and compliance with MDT recommendations (p < 0.001) were associated with DFS (Supplementary Table 3). Multivariable analysis demonstrated that benign breast disease history (HR, 1.91; 95% CI, 1.27–2.87; p = 0.002) and grade III tumor (HR, 1.92; 95% CI, 1.27–2.90; p = 0.002) were independently indicators of worse DFS. Patients compliant with MDT recommendations had a lower risk of disease relapse (HR, 0.43; 95% CI, 0.29–0.64; p < 0.001). Whereas, there was no significant difference between patients with or without the 21-gene assay (HR, 0.91; 95% CI, 0.59–1.40; p = 0.660; Table 3).
Table 3. Multivariate Cox proportional regression analysis of prognostic factors associated with disease-free survival.
| Variables | DFS | ||
|---|---|---|---|
| HR (95% CI) | p-value | ||
| Benign breast disease (yes vs. no) | 1.91 (1.27–2.87) | 0.002 | |
| Histological grade | 0.006 | ||
| III vs. I/II | 1.92 (1.27–2.90) | 0.002 | |
| Unknown vs. I/II | 1.61 (0.93–2.77) | 0.087 | |
| TNM stage | 0.278 | ||
| II vs. I | 1.80 (0.85–3.80) | 0.123 | |
| III vs. I | 1.36 (0.12–14.97) | 0.802 | |
| Tumor size (cm) | 0.776 | ||
| 2–5 vs. < 2.0 | 1.24 (0.68–2.27) | 0.479 | |
| > 5 vs. < 2.0 | 1.17 (0.22–6.15) | 0.855 | |
| Lymph node status (N1 vs. N0) | 1.06 (0.61–1.84) | 0.827 | |
| With 21-gene RS testing (yes vs. no) | 0.91 (0.59–1.40) | 0.660 | |
| Compliance with MDT (yes vs. no) | 0.43 (0.29–0.64) | < 0.001 | |
DFS = disease-free survival; HR = hazard ratio; CI = confidence interval; TNM = tumor-node-metastasis; RS = recurrence score; MDT = multidisciplinary treatment.
Regarding OS, histological grade (p = 0.005), TNM stage (p = 0.002), tumor size (p = 0.011), lymph node status (p = 0.004), lymph vascular invasion (p = 0.003), and use of the 21-gene RS assay (p = 0.005) were impact factors in the univariate analysis (Supplementary Table 3). There were no independent prognostic factors for OS in the multivariable analysis (Supplementary Table 4).
MDT compliance and disease outcome
There were 74 and 41 DFS events observed in the compliance and noncompliance groups, respectively. The estimated 3-year DFS was greater in the compliant group (96.3%) than in the non-compliant group (91.0%, p < 0.001; Figure 3A).
Figure 3. Multidisciplinary team compliance and disease outcome. (A) Disease-free survival of the compliance group and the non-compliance group. (B) Disease-free survival of compliance in chemotherapy subgroups. (C) Disease-free survival of compliance in endocrine therapy subgroups. (D) Disease-free survival of compliance in radiotherapy subgroups.
A subgroup analysis of the effect of compliance with specific treatment recommendations (including chemotherapy, endocrine therapy, and radiotherapy) on disease outcomes was performed. For adjuvant chemotherapy, violating the recommendations from MDT was associated with greater risks of recurrence (HR, 5.54; 95% CI, 2.56–11.90; p < 0.001; Figure 3B). Regarding endocrine therapy recommendation, DFS was better in the compliance group than in that in the noncompliance group (HR, 0.21; 95% CI, 0.11–0.39; p < 0.001; Figure 3C). Similarly, compliance in terms of radiotherapy recommendation was also associated with more favorable DFS (HR, 0.25; 95% CI, 0.11–0.56; p = 0.001; Figure 3D).
Fifteen OS events observed in the compliance group and seven in the noncompliance group. The estimated 3-year OS was 99.4% in the compliance group and 98.2% in the noncompliance group (p = 0.155). Adherence to MDT recommendations did not significantly influence the OS (HR, 0.54; 95% CI, 0.19–1.53; p = 0.170). The subgroup analysis showed that compliance with specific treatment recommendations had no effect on OS.
Prognosis of patients according to compliance and clinicopathological features
When analyzing the factors affecting DFS, a significant interaction was observed between MDT compliance and PR expression (p = 0.030). Noncompliance was significantly correlated with poorer DFS in patients with PR < 20% (HR, 1.47; 95% CI, 1.31–1.65; p <0.001), but not in those with PR ≥ 20% (HR, 1.17; 95% CI, 0.96–1.43; p = 0.113; Supplementary Table 5).
When analyzed according to MDT compliance and usage of the 21-gene RS assay, the Kaplan–Meier curve illustrated significant survival differences among the four groups (p < 0.001; Supplementary Figure 2). Compliance with the MDT recommendation was related to better DFS in patients (HR, 0.42; 95% CI, 0.26–0.67; p < 0.001), regardless of the usage of the 21-gene RS assay (HR, 0.44; 95% CI, 0.24–0.81; p < 0.001) or not (HR, 0.41; 95% CI, 0.20–0.86; p = 0.005; interaction p = 0.842; Supplementary Figure 3).
DISCUSSION
In the current study, we enrolled 2,323 patients with hormone-receptor-positive, HER2-negative breast cancer, and found that application of the 21-gene assay had a positive effect on improving patients’ adherence to MDT recommendations, irrespective of the treatment modality. The most common cause of failure to complete the prescribed treatment were the patient’ will and comorbidities. Meanwhile, noncompliance with MDT recommendations was associated with worse DFS in patients, regardless of the use of the 21-gene RS assay.
MDT discussions have become the standard care process for patients with breast cancer. A previous study revealed that MDT care lowered the relative risk of recurrence and death in patients with breast cancer [16]. In another study, approximately 10% of respondents acknowledged that MDT was associated with better clinical outcomes [17]. A possible reason for this is that the patients may fail to precisely administer the treatment, even though physicians have made an appropriate treatment plan. Yang et al. [14] found that noncompliance with treatment decisions indicated worse disease outcomes, irrespective of the type of therapy. Thus, identifying factors associated with noncompliance and improving patient’ compliance are crucial during clinical practice.
The use of the 21-gene RS assay can offer additional information for MDT decision-making in addition to standard clinicopathologic features. Several studies have determined that the 21-gene RS assay changes adjuvant treatment recommendations by 18%–44% [18,19,20]. However, data on the clinical impact of the 21-gene test on patient’ compliance with MDT recommendations are limited. In this study, the noncompliance rate was 16.9% in the entire study population, which is similar to the rates reported in previous studies [21]. Notably, the discordance rates were 14.9% and 23.1% in patients receiving the multigene assay or not, respectively (p < 0.001). Multivariate analysis revealed that the 21-gene test was associated with higher noncompliance rates. Several studies have reported that the 21-gene RS assay can enhance not only physicians’ but also patients’ confidence in their treatment choices, which may promote treatment compliance [11,22]. Kuijer et al. [23] also reported a high compliance rate of 91% with the MDT recommendations using a 70-gene signature, another multi-gene assay. This may suggest the potential value of the 21-gene RS assay in addition to prognostic and predictive functions. Another independent factor of treatment compliance was patient’ age, which has been consistently noted in previous studies [24,25]. Older women have more comorbidities and lack tolerance for adverse events, which calls for stronger basic support and toxicity management during treatments.
When analyzing the reasons for noncompliance, we found that patients’ will and comorbidity ranked at the top of the decline in therapeutic motivation. However, the 21-gene RS assay did not influence the spectrum of noncompliance reasons. In previous studies, fear of toxicity and comorbidities were the major reasons for treatment-deviating behavior [26]. These findings indicate that patients’ attitudes toward treatment, as well as underlying diseases, should be considered and discussed during MDT decision making. In addition, allaying patients' concerns about treatment, choosing alternative but effective therapies, and using individualized interventions may improve the quality of MDT discussion [27].
Furthermore, our study confirmed that a higher compliance rate with MDT recommendations can confer better DFS in patients with breast cancer. The significance of MDT meetings for improving disease outcomes has been frequently reported. Wright et al. [28] reported that a multidisciplinary team could lower the mortality rates by 11%–18%. Chinese data showed that well-organized MDT resulted in a 15.6% higher survival rate at 5 years with breast cancer patients [29]. Tsai et al. [16] demonstrated that MDT for breast cancer could lower the risk of recurrence and an 11% risk of death. However, the effect of patient’ compliance on prognosis has rarely been studied. In the current study, the estimated 3-year DFS was 96.3% in the compliant group, compared with 91.0% in the non-compliant group (p < 0.001), which is congruent with our previously published articles. Unfortunately, we did not observe a direct influence of the 21-gene RS assay on disease outcomes. Zhang et al. [30] analyzed SEER registry data and concluded that use of the 21-gene RS test was associated with better breast cancer-specific survival and OS, especially during the first 36 months. The inconsistent results in our study may be due to the small sample size and the small numbers of events.
Our study has several potential limitations. First, a selection bias may exist due to the retrospective nature of this study, although multivariate analyses were used to minimize the role of confounding factors. Second, the follow-up time was too short, and only just a few events of interest were observed in the current study. Thus, the influence of the 21-gene RS assay and, MDT compliance on long-term survival, may be unconvincing, and results from continued follow-ups are worth waiting for. Third, we assessed noncompliance using patient-reported outcomes, which may have led to underestimation. Additionally, objective indicators are required in the future.
ACKNOWLEDGMENTS
We would like to thank the assistant from Yidong Du at Shanghai Ruijin Hospital for her significant contribution to the data input, management, and follow-up.
Footnotes
Funding: This work was supported by the National Natural Science Foundation of China (grant number: 81772797), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20172007), and Quanzhou City Science & Technology Program of China (grant number: 2020N019S).
Conflict of Interest: The authors declare that they have no competing interest, and there is any conflict of interest in funding.
Data Availability: The datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request. The URL of this database is http://bcdb.mdt.team:8080.
- Conceptualization: Li L.
- Data curation: Li L.
- Formal analysis: Li L.
- Funding acquisition: Li L.
- Methodology: Li L.
- Software: Yu J.
- Supervision: Shen K, Chen X.
- Validation: Yu J.
- Writing - original draft: Li L.
- Writing - review & editing: Yu J, Chen X.
SUPPLEMENTARY MATERIALS
Reasons for non-compliance with multidisciplinary treatment recommendations
Reasons for noncompliance with multidisciplinary treatment recommendations
Univariate analysis of prognostic factors associated with disease-free survival and overall survival
Multivariate Cox proportional regression analysis of prognostic factors associated with overall survival
Interaction analysis of factors associated with disease-free survival
Reasons for non-compliance in subgroups.
Disease-free survival of compliance or non-compliance with multidisciplinary treatment recommendations in patients with or without 21-gene recurrence score test.
Disease-free survival of compliance or non-compliance with multidisciplinary treatment recommendations in patients with or without 21-gene recurrence score test.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Reasons for non-compliance with multidisciplinary treatment recommendations
Reasons for noncompliance with multidisciplinary treatment recommendations
Univariate analysis of prognostic factors associated with disease-free survival and overall survival
Multivariate Cox proportional regression analysis of prognostic factors associated with overall survival
Interaction analysis of factors associated with disease-free survival
Reasons for non-compliance in subgroups.
Disease-free survival of compliance or non-compliance with multidisciplinary treatment recommendations in patients with or without 21-gene recurrence score test.
Disease-free survival of compliance or non-compliance with multidisciplinary treatment recommendations in patients with or without 21-gene recurrence score test.