Nomogram predicting survival as a selection criter...
Introduction
The role of postmastectomy radiotherapy (PMRT) in patients with pathologic T1 to T2 breast cancer with 1 to 3 positive lymph nodes (LNs) is controversial. What to the best of our knowledge is the only randomized trial focusing on this question, Selective Use of Postoperative Radiotherapy AftEr MastectOmy (SUPREMO), has not reported survival results1; conclusive evidence is awaited. A meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) demonstrated that PMRT reduced locoregional recurrence (LRR) and breast cancer mortality significantly in patients with pT1-T2N1 breast cancer.2 However, that particular meta-analysis was criticized for the outdated therapy the patients received. The observed 10-year LRR rate was >20% in those patients treated without PMRT.3-5 In some recent studies, lower rates of local failure have been observed because of modern surgical and contemporary systemic therapies, thereby suggesting reevaluation of the role of PMRT is needed.6-9
The St. Gallen International Expert Consensus suggested that omitting PMRT could be considered in patients with T1-T2N1 breast cancer with favorable biological profiles, yet to our knowledge those profiles were not defined.10 In which subset of patients could PMRT be omitted? Widely accepted criteria for patient selection for PMRT are lacking.
The Chinese Breast Cancer Adjuvant Radiotherapy Group was founded in 2015 to establish a “real-world” breast cancer database. One of the databases was built for patients with T1-T2N1 breast cancer who were treated with mastectomy, with data collected from 11 hospitals.
In the current study, we sought to establish a risk prediction model for OS using data from the Chinese Breast Cancer Adjuvant Radiotherapy Group database, and to identify those patients with T1-T2N1 disease who may benefit from PMRT.
Materials and Methods
Eligibility Criteria
The study protocol was approved (15-057/984) by the ethics review board of the leading cancer hospital within the Chinese Academy of Medical Sciences in Beijing, China. The inclusion criteria were: 1) presence of pathologically confirmed invasive breast cancer; 2) treatment with mastectomy and axillary lymph node dissection (ALND); 3) tumor size ≤5 cm and 1 to 3 positive LNs (pT1-T2N1 disease); 4) no supraclavicular or internal mammary lymph nodes or distant metastatic disease at the time of diagnosis; and 5) no neoadjuvant therapy received. The exclusion criteria were: 1) history of other cancers; 2) bilateral or occult breast cancer; 3) missing information regarding adjuvant treatment; and 4) follow-up <6 months.
Patient Selection and Data Collection
Women diagnosed between January 2000 and December 2014 at 11 Chinese hospitals who met the inclusion criteria stated above were included (Fig. 1). No patients in this cohort underwent breast reconstruction.
Patient information was extracted from the medical records of the 11 hospitals and coded to formatted electronic documents. The variables abstracted were age at the time of diagnosis; menopausal status; size, location, histology subtype, nuclear grade, hormone receptor expression, human epidermal growth factor receptor 2 (HER2) expression, and lymphovascular invasion of the tumor; and number of positive LNs. Treatment information (number of axillary LNs dissected, target volume and dose fractionation of radiotherapy, chemotherapy, anti–HER-2 targeted regimens) also was recorded.
Follow-Up and Outcome Definition
Patients were followed up in the hospital in which the first surgical procedure was performed. OS and time to disease recurrence were calculated from the date of mastectomy. Disease-free survival (DFS) was calculated at the time of disease recurrence, death, or last follow-up. LRR was defined as first tumor recurrence in the ipsilateral chest wall or regional LNs (including axillary, supraclavicular, or internal mammary lymph nodes) during follow-up. Distant metastasis (DM) was defined as first tumor recurrence beyond the locoregional area as defined above. Patients with simultaneous distant and locoregional recurrences were scored with both LRR and DM.
Statistical Analysis
The association between PMRT and patient characteristics was assessed using the Pearson chi-square test for categorical variables and the Student t test for continuous variables. OS and DFS were evaluated using the Kaplan-Meier method, and the differences were compared using the log-rank test. LRR and DM were assessed using competing risk analysis.
A nomogram predicting OS was constructed in patients who did not receive PMRT. All potentially extracted clinical factors listed above were included as covariables in Cox proportional hazards regression analysis. Variables with a P < .1 were included in the final model. Independent risk factors were used to formulate the nomogram. Internal validation of the nomogram was undertaken using 500 bootstrap resamples to estimate its predictive accuracy in terms of the concordance index (C-index). Calibration was conducted by comparing the predicted probabilities and actual probabilities. Based on the nomogram scores, we used X-tile11 to determine the optimal cutoff points.
Statistical tests were 2-sided, and P < .05 was considered statistically significant. Statistical analyses were performed using SPSS statistical software (v22.0), R statistical software (v3.5.2), and X-tile (v3.6.1).
Results
Baseline Characteristics
A total of 4869 women were included in the analysis (Fig. 1); 1571 patients (32.3%) underwent PMRT. The baseline characteristics of the entire cohort are shown in Table 1. The median age was 48 years (interquartile range [IQR], 42-55 years). The median number of axillary LNs dissected was 16 (IQR, 12-21 LNs); only 446 patients (9.2%) had <10 axillary LNs dissected. There were 4611 patients (94.7%) who were diagnosed with invasive breast cancer of nonspecific type.
| Characteristic | All No. (%) N = 4869 | No PMRT No. (%) N = 3298 | PMRT No. (%) N = 1571 | P |
|---|---|---|---|---|
| Age, y | ||||
| ≤40 | 864 (17.7) | 498 (15.1) | 366 (23.3) | <.001 |
| >40 | 4005 (82.3) | 2800 (84.9) | 1205 (76.7) | |
| Tumor location | ||||
| Inner/central | 1255 (25.8) | 876 (26.6) | 379 (24.1) | .48 |
| Other | 3418 (70.2) | 2349 (71.2) | 1069 (68.0) | |
| Unknown | 196 (4.0) | 73 (2.2) | 123 (7.8) | |
| Grade | ||||
| 1 | 121 (2.5) | 100 (3) | 21 (1.3) | <.001 |
| 2 | 2734 (56.2) | 1859 (56.4) | 875 (55.7) | |
| 3 | 1075 (22.1) | 738 (22.4) | 337 (21.5) | |
| Unknown | 939 (19.3) | 601 (18.2) | 338 (21.5) | |
| LVI | ||||
| Yes | 4070 (83.6) | 2772 (84.1) | 1298 (82.6) | <.001 |
| No | 577 (11.9) | 340 (10.3) | 237 (15.1) | |
| Unknown | 222 (4.6) | 186 (5.6) | 36 (2.3) | |
| Tumor size, cm | ||||
| Median (IQR) | 2.5 (1.9-3.0) | 2.3 (1.8-3.0) | 2.5 (2.0-3.0) | <.001 |
| T classification | ||||
| T1 | 2180 (44.8) | 1545 (46.8) | 635 (40.4) | <.001 |
| T2 | 2689 (55.2) | 1753 (53.2) | 936 (59.6) | |
| No. of positive LNs | ||||
| 1 | 2454 (50.4) | 1903 (57.7) | 551 (35.1) | <.001 |
| 2 | 1491 (30.6) | 950 (28.8) | 541 (34.4) | |
| 3 | 924 (19.0) | 445 (13.5) | 479 (30.5) | |
| LNR, %a a Positive lymph nodes/dissected lymph nodes. | ||||
| Median (IQR) | 9 (6-14) | 8 (6-13) | 12 (7-18) | <.001 |
| ER status | ||||
| Negative | 1408 (28.9) | 903 (27.4) | 505 (32.1) | <.001 |
| Positive | 3450 (70.9) | 2391 (72.5) | 1059 (67.4) | |
| Unknown | 11 (0.2) | 4 (0.1) | 7 (0.4) | |
| PR status | ||||
| Negative | 1527 (31.4) | 954 (28.9) | 573 (36.5) | <.001 |
| Positive | 3329 (68.4) | 2339 (70.9) | 990 (63.0) | |
| Unknown | 13 (0.3) | 5 (0.2) | 8 (0.5) | |
| HER2 status | ||||
| Negative | 3313 (68.0) | 2288 (69.4) | 1025 (65.2) | .02 |
| Positive | 972 (20.0) | 633 (19.2) | 339 (21.6) | |
| Unknown | 584 (12.0) | 377 (11.4) | 207 (13.2) | |
| Chemotherapy | ||||
| Yes | 4634 (95.2) | 3078 (93.3) | 1556 (99.0) | <.001 |
| No | 235 (4.8) | 220 (6.7) | 15 (1.0) | |
| Endocrine therapyb b Among ER- or PR-positive patients. | ||||
| Yes | 3312 (88.6) | 2292 (88.3) | 1020 (89.3) | .35 |
| No | 427 (11.4) | 305 (11.7) | 122 (10.7) | |
| Trastuzumabc c Among patients with HER2 overexpression. | ||||
| Yes | 257 (26.4) | 134 (21.2) | 123 (36.3) | <.001 |
| No | 715 (73.6) | 499 (78.8) | 216 (63.7) |
- Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IQR, interquartile range; LN, lymph node; LNR, positive lymph node ratio; LVI; lymphovascular invasion; PMRT, postmastectomy radiotherapy; PR, progesterone receptor.
- a Positive lymph nodes/dissected lymph nodes.
- b Among ER- or PR-positive patients.
- c Among patients with HER2 overexpression.
Among the 4634 patients (95.2%) who underwent adjuvant chemotherapy, 4530 (97.8%) received anthracycline-based and/or taxane-based regimens. In the PMRT group, the chest wall was irradiated in 1484 patients (94.5%), and the supraclavicular and/or infraclavicular region was irradiated in 1414 patients (90.0%). Only 98 patients (6.2%) specifically received radiotherapy to the axilla, and 71 (4.5%) to the internal mammary drainage area. The radiation dose was 45 to 50 Gy in 25 fractions over 5 weeks in 1421 patients (90.5%). A total of 42 patients (2.7%) received hypofractionated radiotherapy of 40 to 43.5 Gy in 15 fractions administered over 3 weeks.
Comparison Between the PMRT and Non-PMRT Groups
Compared with patients in the non-PMRT group, those in the PMRT group had significantly more adverse factors: younger age, larger tumor size, more positive LNs, higher positive lymph node ratio (LNR), and fewer ER-positive and/or PR-positive tumors (Table 1). The percentage of patients in the PMRT group who received adjuvant chemotherapy and anti-HER2 targeted therapy was higher than that in the non-PMRT group.
With a median follow-up of 65.9 months (IQR, 46.4-90.3 months), the 5-year OS, DFS, LRR, and DM rates were 93.3%, 84.3%, 5.2%, and 8.3%, respectively, for the entire cohort. After adjustment for the other covariables, receipt of PMRT reduced LRR and improved OS significantly, but was found to have no effect on DM (Table 2).
| Group | PMRT | No. | 5-Year OS | 5-Year LRR | 5-Year DM | |||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |||
| All (N = 4869) | Yes | 1571 | 0.61 (0.48-0.78) | .002 | 0.27 (0.19-0.38) | <.001 | 0.92 (0.75-1.13) | .250 |
| No | 3298 | |||||||
| Low risk (N = 1374) | Yes | 1081 | 0.87 (0.39-1.93) | .728 | 0.38 (0.12-0.64) | .026 | 0.82 (0.44-1.52) | .153 |
| No | 293 | |||||||
| Intermediate risk (N = 2748) | Yes | 906 | 0.54 (0.39-0.74) | <.001 | 0.38 (0.25-0.56) | <.001 | 1.07 (0.85-1.36) | .216 |
| No | 1842 | |||||||
| High risk (N = 428) | Yes | 183 | 0.52 (0.33-0.82) | .004 | 0.19 (0.09-0.39) | <.001 | 0.76 (0.49-1.17) | .149 |
| No | 245 | |||||||
- Abbreviations: 95% CI, 95% confidence interval; DM, distant metastasis; HR, hazard ratio; LRR, locoregional recurrence; OS, overall survival; PMRT, postmastectomy radiotherapy.
- a Low-risk group indicates a risk score ≤110, intermediate-risk group indicates a risk score of 110 to 200, and high-risk group indicates a risk score ≥200.
Nomogram Construction in the Non-PMRT Group
We developed an OS prognostic model in patients with T1-T2N1 breast cancer who were in the non-PMRT group (3298 patients). Age, tumor location, and tumor size as well as LNR, ER, PR, and HER2 status stratified by trastuzumab treatment were found to be independent prognostic factors for OS (Table 3). These 7 variables were factored into the prognostic nomogram for OS (Fig. 2). The C-index of the nomogram was 0.70 (95% confidence interval, 0.67-0.74). The calibration demonstrated favorable concordance between predicted and observed probabilities for OS at 5 years (see Supporting Fig. 1).
| Characteristic | Univariable Analysis | Multivariable Analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | aHR (95% CI)a a Only P values <.1 are listed. | P | |
| Age (>40 y vs ≤40 y） | 0.69 (0.53-0.90) | .007 | 0.64 (0.49-0.85) | .002 |
| Tumor location (other vs inner/central) | 0.79 (0.62-1.00) | .054 | 0.74 (0.58-0.95) | .019 |
| Grade | — | — | ||
| 1/2 | Referent | |||
| 3 | 1.43 (1.08-1.90) | .012 | ||
| Unknown | 1.54 (1.17-2.03) | .002 | ||
| LVI (yes vs no) | 1.17 (0.78-1.74) | .323 | — | — |
| Tumor size, continuous, cm | 1.44 (1.28-1.61) | <.001 | 1.37 (1.22-1.54) | <.001 |
| No. of positive LNs | — | — | ||
| 1 | Referent | |||
| 2 | 1.18 (0.91-1.52) | .214 | ||
| 3 | 1.37 (1.00-1.87) | .049 | ||
| LNRb b Positive lymph nodes/dissected lymph nodes. | ||||
| ≤10% | Referent | Referent | ||
| 10%-20% | 1.41 (1.11-1.80) | .006 | 1.41 (1.10-1.81) | .007 |
| >20% | 2.01 (1.38-2.93) | <.001 | 1.72 (1.16-2.56) | .007 |
| ER status ( vs −) | 0.45 (0.36-0.57) | <.001 | 0.68 (0.50-0.93) | .015 |
| PR status ( vs −) | 0.41 (0.33-0.51) | <.001 | 0.48 (0.35-0.65) | <.001 |
| HER2 status stratified by treatment | ||||
| Negative | Referent | Referent | ||
| Positive and received trastuzumab | 0.69 (0.30-1.16) | .370 | 0.47 (0.19-1.14) | .094 |
| Positive, did not receive trastuzumab | 1.48 (1.10-1.99) | .009 | 1.06 (0.85-1.31) | .079 |
| Unknown | 1.40 (1.00-1.95) | .048 | 1.32 (0.94-1.87) | .113 |
- Abbreviations: −, negative; , positive; 95% CI, 95% confidence interval; aHR, adjusted hazard ratio; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; LN, lymph node; LNR, positive lymph node ratio; LVI, lymphovascular invasion; OS, overall survival; PMRT, postmastectomy radiotherapy; PR, progesterone receptor.
- a Only P values <.1 are listed.
- b Positive lymph nodes/dissected lymph nodes.
Based on the cutoff values identified by X-tile, we divided patients into 3 risk groups with risk score cutoff values of 110 and 200. Patients with a risk score ≤110 were classified as “low risk” (1374 patients), those with a risk score ≥200 were classified as “high risk” (428 patients), and the remaining patients were classified as “intermediate risk” (2748 patients) (Fig. 2). The 5-year OS rate for patients in the 3 risk groups was significantly different: 97.4% in the low-risk group, 93.1% in the intermediate-risk group, and 81.4% in the high-risk group (P < .001). The DFS, LRR, and DM also were found to be significantly different between the 3 groups (Fig. 3).
Effect of PMRT in the Risk Groups
We stratified patients who received PMRT into risk groups based on their risk scores. In each risk group, we compared OS, LRR, and DM between patients who did and those who did not receive PMRT (Table 2).
PMRT improved the OS of patients in the intermediate-risk and high-risk groups significantly, but did not improve OS among those in the low-risk group (Fig. 4). In the latter group, the 5-year OS rate was 97.4% both in patients who were administered and those who were not given PMRT (P = .728). In the intermediate-risk group, the 5-year OS rate was 94.9% and 92.3%, respectively, in patients administered or not given PMRT (P < .001), whereas in the high-risk group, these values were 85.0% and 78.2%, respectively (P = .004). PMRT improved the DFS of patients in the intermediate-risk and high-risk groups, but not in the low-risk group (see Supporting Fig. 2). In each risk group, PMRT was found to reduce the risk of LRR significantly (see Supporting Fig. 3), but had no apparent effect on DM (see Supporting Fig. 4).
Discussion
Based on a large, multicenter cohort of patients with T1-T2N1 breast cancer who underwent mastectomy in China, we constructed a nomogram for the prediction of OS to stratify patients into low-risk, intermediate-risk, or high-risk groups. We then evaluated the effect of PMRT on different risk groups. Patients in the low-risk group appeared to derive no survival benefit from PMRT.
All patients were diagnosed after the year 2000, after the development of modern standard chemotherapy and endocrine therapy. In the current study, the 5-year LRR rate was 5.2% for the entire cohort, which is nearly one-third the rate of 16.5% reported in the Early Breast Cancer Trialists' Collaborative Group meta-analysis.2 This result was comparable to those of recent similar studies, which have reported 5-year LRR rates ranging from 3.4% to 8.9%.6-8, 12
Patients with T1-T2N1 breast cancer are heterogenous, and thus a risk-adapted strategy is rational. Young age, histology grade 3, ER or PR negativity, lymphovascular invasion, large number of positive LNs, and large tumor size have been identified as adverse prognostic factors in patients with pT1-T2N1 breast cancer.8, 12-19 Recently, several scholars have developed different patient selection criteria by combining different risk factors.13-16 T classification and positive axillary LNs, which represent primary and metastatic tumor burden, respectively, have been the most common factors included in such criteria. The nomogram we built also included these 2 factors. Specifically, we used tumor size as a continuous variable to quantify individual risk, which may be more accurate than using the classification.
LNR, but not the number of positive LNs, was the independent prognostic factor in the model in the current study. Compared with the number of positive LNs, LNR reflected axillary tumor burden and the extent of surgery, which may provide more information than the number of positive LNs. Karlsson et al evaluated 8106 patients with breast cancer who were enrolled in 13 randomized trials. They found that among patients with 1 to 3 positive LNs, tumor recurrence to the chest wall was associated with the number of uninvolved LNs.20 Our nomogram was constructed among patients who underwent ALND and was not suited for those undergoing biopsy of axillary sentinel LNs only. However, compared with patients undergoing breast-conserving treatment, for those undergoing mastectomy, ALND is first-line treatment for individuals with macrometastases in the sentinel LNs.21, 22 Only approximately 18% of the study population in the Comparison of Complete Axillary Lymph Node Dissection With Axillary Radiation Therapy in Treating Women With Invasive Breast Cancer (AMAROS)23 trial and none in the Z001124 trial underwent mastectomy. Hence, whether sentinel LN biopsy could replace ALND safely in patients who have undergone mastectomy is inconclusive. A guideline published by the American Society for Radiation Oncology (ASTRO) strongly suggested that ALND should be performed unless the physician has decided to recommend PMRT based on the results of sentinel LN biopsy.22 Before the ongoing SENOMAC trial releases its results, the majority of patients with T1-T2N1 breast cancer who need to decide if they receive PMRT would undergo ALND, and LNR continues to be an important issue to consider.
Anti-HER2 targeted therapy was not used widely in the current study cohort, and therefore we stratified patients with HER2-positive disease by targeted therapy. In our nomogram, patients treated with targeted therapy were found to have the lowest score compared with those who did not receive targeted therapy or those who had HER2-negative disease. This finding is in accordance with observations from other studies, which demonstrated that anti-HER2 targeted therapy could improve survival and local control among patients with HER2–positive disease.25, 26 We believe that adding treatment factors into the nomogram model also made it useful in a population in which anti-HER2 targeted therapy was used widely.
Although the majority of studies in this field have selected LRR as the endpoint,12, 16, 17, 19 the nomogram in the current study focused on OS. First, OS was the most reliable endpoint compared with disease recurrence in the current retrospective study because OS is more objective. Furthermore, the decision to use PMRT is based on a balance between benefit and toxicity, and OS (which could be the result of both) may be a better endpoint with which to demonstrate the value of treatment compared with disease recurrence alone. More important, the recent NCIC Clinical Trials Group MA.20 and European Organization for Research and Treatment of Cancer (EORTC) 22922 trials demonstrated that regional radiotherapy reduced the risk of DM significantly,27, 28 suggesting that LRR may not be the only surrogate to guide decision making for PMRT.
In addition to those known prognostic factors, a better model may need to take the tumor gene profile into account. An observational cohort study by Goodman et al29 analyzed the interaction of the 21-gene recurrence score and PMRT with OS using data from the National Cancer Data Base and the Surveillance, Epidemiology, and End Results registries. They found that the improved survival associated with PMRT was limited to women with a low 21-gene recurrence score, suggesting a complicated competitive relationship between local recurrence and distant recurrence; this also suggests that prediction models that are created solely with clinical factors may be insufficient.29 The ongoing A Randomized Trial of Regional Radiotherapy In Biomarker Low Risk Node Positive Breast Cancer (MA.39/TAILOR RT trial) has selected low-risk patients with T1-T2N1 breast cancer. Patients were defined by ER positivity and an Oncotype DX score <18 and randomized to receive PMRT or not (ClinicalTrials.gov identifier NCT03488693). The results of that study still are pending.
The current study had limitations. First, its retrospective nature introduced a selection bias. Second, data were collected from each center without central validation, and therefore misrecording was possible. However, the use of multicenter data in the current study improved the generalizability of the results. Finally, the nomogram model herein has not been validated externally.
The current study had 2 main strengths. First, it comprised a large number of patients from different centers. Second, the LRR and OS rates were comparable to those noted in similar studies in other countries, suggesting the broad effectiveness of our model. Further validation in a completely independent data set is expected.
Conclusions
Patients with pT1-T2N1 breast cancer are a heterogenous group with myriad risk factors for disease recurrence. Based on our prognostic nomogram, we found a subgroup of patients with a good prognosis who may gain no survival benefit from PMRT. The omission of PMRT in this low-risk group is rational. Further validation and improvement of the nomogram are needed.
Funding Support
Supported by the National Key Projects of Research and Development of China (2016YFC0904600 to Ye-Xiong Li) and the Chinese Academy of Medical Science (CAMS) Innovation Fund for Medical Sciences (CIFMS 2016-I2M-1-001 to Ye-Xiong Li).
Conflict of Interest Disclosures
The authors made no disclosures.
Author Contributions
Yu Tang: Data collection, formal analysis, writing–original draft, and writing–review and editing. Yu-Jing Zhang: Conceptualization, data collection, formal analysis, and writing–review and editing. Na Zhang: Conceptualization, data collection, formal analysis, and writing–review and editing. Mei Shi: Conceptualization, data collection, and writing–review and editing. Ge Wen: Data collection and writing–review and editing. Jing Cheng: Conceptualization, data collection, and writing–review and editing. Hong-Mei Wang: Conceptualization, data collection, and writing–review and editing. Min Liu: Conceptualization, data collection, and writing–review and editing. Xiao-Hu Wang: Conceptualization, data collection, and writing–review and editing. Qi-Shuai Guo: Conceptualization, data collection, and writing–review and editing. Hong-Fen Wu: Conceptualization, data collection, and writing–review and editing. Chang-Ying Ma: Conceptualization, data collection, and writing–review and editing. Jing Jin: Data collection and writing–review and editing. Yue-Ping Liu: Data collection and writing–review and editing. Yong-Wen Song: Data collection and writing–review and editing. Hui Fang: Data collection and writing–review and editing. Hua Ren: Data collection and writing–review and editing. Shu-Lian Wang: Conceptualization, methodology, project administration, and writing–review and editing. Ye-Xiong Li: Conceptualization, funding acquisition, and writing–review and editing.
Supporting Information
| Filename | Description |
|---|---|
| cncr32963-sup-0001-FigS1.pdfPDF document, 13.1 KB | Fig S1 |
| cncr32963-sup-0002-FigS2.pdfPDF document, 399.9 KB | Fig S2 |
| cncr32963-sup-0003-FigS3.pdfPDF document, 389.7 KB | Fig S3 |
| cncr32963-sup-0004-FigS4.pdfPDF document, 391.2 KB | Fig S4 |
| cncr32963-sup-0005-Legends-F1-4.docxWord document, 12.5 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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