Association of Primary Tumor Volume with Survival in Patients with HER-2-positive Breast Cancer After Trastuzumab Treatment: A Retrospective Cohort Study

doi:10.21203/rs.3.rs-5280936/v1

Background:

The relationship between primary tumor volume (PTV) and overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER-2)-positive breast cancer following Ttrastuzumab therapy remains controversial in the medical research community. Currently, there is insufficient evidence to definitively establish the relationship between PTV and OS; understanding this relationship is critical for healthcare and public health because it has significant implications for patient outcomes. Consequently, the PTV and its effects on OS have become the focus of extensive research.

Objective:

The primary objective of this study was to improve our understanding of the influence of PTV on OS and elucidate the clinical implications of this correlation. The secondary objective was to determine the optimal cutoff value for assessing the effect of PTV on OS in patients with HER-2-positive breast cancer after trastuzumab treatment.

Methods:

In this retrospective cohort study, we analyzed the data of 666 participants retrieved from the Dryad database. Relevant variables, including PTV, OS, lymph node status, Nottingham Histology Grading, Ki-67 expression, and age, were collected for all participants. We employed Cox regression analysis to explore the potential interaction effects to support our research objectives.

Results:

In total, 666 patients were identified during the follow-up period. The mean (standard deviation, SD) age of participants was 60.7 years, and all were women. The mean (SD) tumor volume was 19.9 (11.1) mm. With a mean (SD) follow-up of 82.4 (30.2) months, increasing tumor volume (per 1-mm increase) was associated with significantly worse adjusted OS (hazard ratio, 1.03; 95% confidence interval, 1.02–1.05).

Conclusions:

To the best of our knowledge, this extensive retrospective cohort study of patients with HER-2 positive breast cancer after trastuzumab treatment is the first to demonstrate a significant association between the PTV and a 3% increase in the risk of OS.

primary tumor volume (PTV)

overall survival (OS)

breast cancer

progonosis

Breast cancer is one of the three most common types of cancers worldwide. Early stage breast cancer is considered curable [1]. Individualized treatment is a trend in future oncology treatment, and the search for necessary prognostic factors can provide the necessary basis for individualized treatment of patients with breast cancer. In recent years, treatment has made great progress by reducing the intensity of local and systemic therapy; avoiding over- and under-treatment has become the focus of treatment. The treatment approach is curative and requires multidisciplinary decision-making based on the molecular subtype and local tumor burden. Neoadjuvant targeted therapy has become a common option for human HER-2-positive early breast cancer, and the search for prognostic factors associated with OS may provide the necessary basis for individualized treatment of patients, thus avoiding over- and under-treatment and increasing the prospect of long-term disease control in patients with metastatic breast cancer.

Breast cancer consists of three major tumor subtypes categorized according to estrogen receptor (ER) or progesterone receptor (PR) expression and Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2) gene amplification. These three subtypes have distinct risk profiles and need different treatment strategies. The optimal therapy for each patient depends on the tumor subtype, anatomic cancer stage, and patient preferences [2]. Patient age, axillary lymph node status, tumor size, histological features (especially histologic grading and lymphovascular invasion), hormone receptor status, and HER-2 status have traditionally served as the primary factors utilized for the classification of patients with breast cancer, facilitating the assessment of prognosis and treatment determination. Typically, these factors are combined to stratify the patients into distinct risk categories. Although such risk categorizations offer utility in evaluating the prognosis and risk within breast cancer populations, their applicability to individual patient prognosis and risk assessment is limited. Consequently, there is a pressing need for enhanced methodologies to facilitate individualized prognostic assessment and treatment selection [3].

In the light of this, the current study was undertaken because of the lack of adequate evidence regarding OS and its associated risk factors. Our investigation aimed to explore the relationship between primary tumor volume (PTV), ER/PR status, patient age, lymph node status, Ki-67 expression, other pertinent factors, and OS in patients with HER-2-positive breast cancer treated with trastuzumab. Notably, our findings revealed a significant correlation between breast cancer tumor volume and OS. This discovery offers valuable insights for the development of future treatment strategies, particularly in the realm of individualized therapy for this patient cohort.

Although the impact of PTV on tumor prognosis is well documented, its influence on OS remains relatively underexplored. Malik et al. reported a notable effect of PTV on survival in head and neck tumors [4]; however, such associations are largely absent in the literature on breast cancer. This study is the first to identify a significant correlation between PTV and OS in patients with HER-2-positive breast cancer treated with trastuzumab, offering valuable insights into personalized treatment strategies in this population.

The primary aim of this investigation was to elucidate the relationship between alterations in PTV and survival outcomes, particularly OS, in patients with breast cancer. A secondary objective was to establish the threshold level of PTV, which may impact OS. This retrospective study included 666 participants from the Dryad database.

Design and participants

Dryad is an open data publishing platform and a community committed to the open availability and routine re-use of all research data. The dataset used in this study comprised data from 682 consecutive patients diagnosed with HER-2-positive primary breast cancer. These patients did not receive neoadjuvant therapy and were treated with trastuzumab in conjunction with chemotherapy and/or adjuvant endocrine therapy between 2010 and 2018. Gene expression data and survival information were collected from tumor specimens obtained during surgery [5].

The exclusion criteria were as follows: (1) missing PTV data and (2) missing lymph node status data. A total of 666 patients were included in this study.

PTV as a predictor

The primary measure in this study was the PTV, and we used Cox regression to determine the optimal cutoff value (17 mm). We divided the patients into two groups according to the optimal cutoff value of PTV, averaged the values into four groups, and performed survival analysis (OS and recurrence-free survival [RFS]) separately.

OS as a primary outcome

The primary endpoint was survival of patients diagnosed with HER-2-positive breast cancer following treatment with trastuzumab. OS duration was calculated from the time of pathological diagnosis to the time of patient death. RFS was assessed from the time of pathological diagnosis to breast cancer recurrence.

Clinical variables

The clinical data pertaining to the study cohort included age, ER/PR status, HER-2 status, OS duration, RFS duration, Ki-67 expression, lymph node metastasis status, and PTV.

Statistical analyses

Analyses were conducted using Free Statistics version 2.0 .Continuous variables were presented as mean ± standard deviation. For categorical data, percentages were calculated and assessed using the chi-square test or Fisher's exact test. Estimation methods were not applied due to the minimal proportion of missing data across all variables in this study. Univariate and multivariate Cox proportional hazards regression analyses were employed to explore the impact of PTV on survival among patients with HER-2-positive breast cancer undergoing adjuvant trastuzumab therapy. The basic model included age, ER/PR status, lymph node metastasis status, Ki-67 expression, and other significant prognostic indicators for OS.

The hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated using two-sided p-values. Statistical significance was set at P <0.05.

To evaluate the robustness of the association between PTV and OS, various subgroups were analyzed based on age, Ki-67 expression, degree of pathological differentiation, and lymph node metastasis status. The study results are illustrated in a forest plot depicting the extended logistic regression models for each subgroup.（Figure6）

The primary objective of this study was to improve our understanding of the influence of PTV on OS and elucidate the clinical implications of this correlation. The secondary objective was to determine the optimal cutoff value for assessing the effect of PTV on OS in patients with HER-2-positive breast cancer after trastuzumab treatment.

We compared the baseline characteristics of the different patient variables in the two groups, with PTV ≤17 mm and >17 mm. This study included 666 eligible patients aged 30–90 years. The mean (standard deviation [SD]) age of participants was 60.7 years, and all were women. The mean (SD) tumor volume was 19.9 (11.1) mm and the mean (SD) follow-up was 82.4 (30.2) months. Compared with the group with PTV >17 mm, the group with PTV ≤17 mm included more patients with lymph node (-) status (P <0.05), had a higher Nottingham histological grade (NHG) (G3, P <0.05), and was more likely to included more patients with Ki-67 expression ≤60% (P <0.05). However, the two groups did not differ significantly in ER, PgR, HER2_IHC, and HER2_ISH (all P >0.05).

Table 1 Study population clinical characteristics

Variables	Total (n = 666)	PTV≤17 (n = 301)	PTV>17 (n = 365)	p
age, n (%)				0.026
≤65	349 (52.4)	172 (57.1)	177 (48.5)
>65	317 (47.6)	129 (42.9)	188 (51.5)
lymphnode				< 0.001
Negative	411 (61.7)	223 (74.1)	188 (51.5)
Positive	255 (38.3)	78 (25.9)	177 (48.5)
NHG n (%)				< 0.001
G1,G2	198 (29.9)	116 (38.9)	82 (22.5)
G3	464 (70.1)	182 (61.1)	282 (77.5)
Ki67, n (%)				0.013
Ki≤60	593 (89.0)	278 (92.4)	315 (86.3)
Ki>60	73 (11.0)	23 (7.6)	50 (13.7)
HER2_IHC, n (%)				0.085
0-1+	1 ( 0.3)	0 (0)	1 (0.7)
2+	76 (24.1)	33 (20.2)	43 (28.1)
3+	239 (75.6)	130 (79.8)	109 (71.2)
HER2_ISH, n (%)				1
amplified	642 (99.7)	288 (99.7)	354 (99.7)
normal	2 ( 0.3)	1 (0.3)	1 (0.3)
ER, n (%)				0.37
neg	193 (29.0)	82 (27.2)	111 (30.4)
pos	473 (71.0)	219 (72.8)	254 (69.6)
PgR, n (%)				0.921
neg	351 (52.7)	158 (52.5)	193 (52.9)
pos	315 (47.3)	143 (47.5)	172 (47.1)
PTV, Median (IQR)	18.0 (13.0, 25.0)	13.0 (10.0, 15.0)	24.0 (20.0, 30.0)	< 0.001

ER estrogen receptor alpha,PgR progesterone receptor.

[Insert table 1 here]

Tumor volume

The mean (SD) tumor volume was 19.9 (11.1) mm, and the median value was 18 mm. The distribution of tumor volumes in the study cohort is shown in Figure 1.

OS and RFS

We analyzed the relationship between OS, RFS, and PTV (Tables 2 and 3). In the unadjusted model, patients with PTV ≤17 mm had a longer OS (HR: 1.03, 95% CI: 1.02–1.05, P=0.018) as well as RFS (HR: 1.99, 95% CI: 1.13–1.15, P=0.015), compared with those with PTV >17 mm. The significance of these associations persisted following multivariate analysis adjusted for age, ER/PR status, Ki-67 expression, lymph node involvement, and NHG. Among the patients enrolled in the follow-up observation, the OS was notably higher in those belonging to the group with PTV ≤17 mm and the group with PTV >17 mm, as depicted by the Kaplan–Meier curves (Log-rank test P=0.0015, Figure 2).In the OS analysis where the PTV was divided into four groups, the results similarly indicated that the PTV had a statistically significant impact on OS（P=0.0043,Figure3）. In the multivariate Cox proportional hazard model, after adjusting for potential confounders, there was also significant association between PTV expressed as a continuous variable (per 1-unit change) and the OS (HR: 1.03, 95% CI: 1.02–1.05, P=0.018). Similar results were also observed for the RFS in the two groups, as depicted by the Kaplan–Meier curves (log-rank test, P=0.0015; Figure 4).In the RFS analysis where the PTV was divided into four groups, the results also indicated that the PTV had a statistically significant impact on RFS（P=0.019,Figure5）. The results of the multivariate Cox proportional hazards model (Table 3) revealed an association between PTV and RFS. A higher PTV was significantly associated with a reduced RFS (per 1-unit increase: HR: 1.99, 95% CI: 1.22–3.24, P=0.006), even after adjusting for potential confounders (HR: 1.89, 95% CI: 1.13–3.15, P=0.006; Table 3).

Table2.Multivariate analysis of association between PTV and OS

Variable	crude.HR (95%CI)	crude.P value	adj.HR (95%CI)	adj.P value
PTV	1.03 (1.02~1.05)	<0.001	1.03 (1~1.05)	0.018
age	1.03 (1.01~1.05)	0.015	1.03 (1~1.06)	0.09
ER_10	0.59 (0.35~0.98)	0.041	0.49 (0.18~1.37)	0.174
PgR_10	0.94 (0.57~1.56)	0.824	1.63 (0.62~4.3)	0.322
Ki67	1 (0.98~1.02)	0.767	1 (0.98~1.02)	0.869
lymphnode	1.83 (1.11~3.04)	0.018	1.55 (0.73~3.3)	0.253
NHG	0.99 (0.57~1.74)	0.979	0.71 (0.32~1.6)	0.409

Table3.Multivariate analysis of association between PTV and RFS

Variable	crude.HR (95%CI)	crude.P value	adj.HR (95%CI)	adj.P value
PTV	1.99 (1.22~3.24)	0.006	1.89 (1.13~3.15)	0.015
age	1.11 (0.71~1.74)	0.638	1.04 (0.66~1.64)	0.868
ER	0.65 (0.41~1.03)	0.065	0.55 (0.29~1.04)	0.065
PgR	0.96 (0.61~1.5)	0.852	1.29 (0.7~2.39)	0.42
Ki67	0.73 (0.32~1.68)	0.455	0.7 (0.3~1.63)	0.406
lymphnode	1.89 (1.21~2.96)	0.005	1.61 (1.01~2.56)	0.046
NHG	1.07 (0.65~1.77)	0.792	0.89 (0.53~1.49)	0.653

We also performed an exploratory analysis to assess the effect of the PTV on the OS in multiple subgroups (Fig. 6). The results of this stratified analysis indicated that the association between PTV and OS in the different subgroups was generally consistent with the results of the multivariate logistic regression analysis.

To the best of our knowledge, this extensive retrospective cohort study of patients with HER-2-positive breast cancer after trastuzumab treatment is the first to demonstrate a significant association between PTV and a 3% decrease in OS. Consistent patterns of association between PTV and OS were also observed in subsequent subgroup analyses.

Breast cancer comprises three primary tumor subtypes that are categorized based on ER or PR expression and ERBB2 gene amplification. These subtypes exhibit distinct risk profiles and require various therapeutic approaches. Tailoring the optimal treatment for individual patients involves consideration of the tumor subtype, cancer anatomical stage, and patient preferences [6]. Indeed, the prognostic landscape of breast cancer has transitioned into an era of molecular prediction, particularly notable in HER-2-positive breast cancer, where targeted therapy offers promising survival outcomes. However, the trajectory of tumor management is evolving towards personalized treatment, emphasizing the necessity of investigating pertinent risk factors within the respective populations. Particularly in the era of targeted therapy, emphasis should be placed on both pathological features and patients' baseline conditions, encompassing psychological well-being, nutritional status, social support, and intrinsic tumor characteristics, such as tumor volume, ER/PR status, degree of pathological differentiation, and Ki-67 expression. In the present study, we conducted a survival analysis of patients with HER-2-positive breast cancer following adjuvant trastuzumab therapy, which revealed a correlation between PTV and OS.

To the best of our knowledge, few studies have reported an association between PTV and survival outcomes in patients with cancer, and only sporadic reports have shown that PTV is significantly associated with patient survival in certain head and neck tumor cohorts [7]. Flukes et al. noted that quantifying the tumor volume could help predict the risk of distant metastasis and mortality in sinonasal mucosal melanoma [8]. Lin et al. found that in patients treated with definitive radiotherapy for esophageal squamous cell carcinoma, a larger PTV was associated with poorer local control and OS [9]. Wald et al. observed that relative increases in tumor volume during treatment were associated with improved disease control and OS rates in patients with locally advanced non-small cell lung cancer [10]. Malik et al. reported that increased tumor size in cT3 acoustic neuroma was associated with poorer OS and disease-free survival [11]. However, the relationship between PTV and survival outcomes has not been extensively explored in studies on breast cancer.

These previous studies have consistently demonstrated an association between PTV and survival outcomes in selected tumor cohorts, suggesting that PTV may correlate with certain biological tumor characteristics, thereby contributing to differences in survival across specific patient populations. In the current study, we performed survival analysis investigating the relationship between PTV and OS as well as RFS. Our results, across both the dichotomized (two subgroups based on the optimal cutoff value of PTV, 17 mm) and quartile-based (four subgroups) PTV analyses, showed a significant inverse correlation - larger PTV was associated with poorer OS and RFS in patients with HER-2-positive breast cancer after treatment with trastuzumab. Olfatbakhsh et al. reported that tumor size and lymph node involvement, as indicators of delayed diagnosis, may affect the survival of patients with breast cancer; however, there is insufficient evidence for these being independent risk factors [12].

In addition, in the multifactorial analysis, corrected PTV and age had a significant effect on OS, whereas in the analysis of RFS, only PTV had an independent effect, which seems to be in line with the phenomenon observed in clinical practice and with the logic of its relevance, as age may affect OS but not RFS. The results of the subgroup analysis also supported these findings.

These findings suggest that PTV may serve as a risk factor for OS in patients with HER-2-positive breast cancer after trastuzumab treatment and could be a relevant biomarker. Further studies are warranted to elucidate the relationship between the PTV and OS in patients with HER-2-positive breast cancer after trastuzumab treatment.

The current study has some limitations. The database used in this study was not sufficiently variable, although it included several variables that have a greater impact on survival. Further, the specific treatment regimen was not detailed enough, and the personal history of the patients was not included as a variable. In addition, the missing data on covariates may have had an impact. Owing to the longer survival time associated with HER-2-positive breast cancer, fewer deaths occurred in the patient population. Although sufficient follow-up was conducted, longer observation is needed. Finally, future prospective studies are needed and more reliable variables should be evaluated to further substantiate the results of the current study.

The present study evaluated Dyrad data in Patients with Breast Cancer and indicates that PTV was associated with significantly worse OS in Patients with HER-2 Positive Breast Cancer After Trastuzumab

CI, confidence interval

ER, estrogen receptor

HER-2, human epidermal growth factor receptor 2

HR, hazard ratio

NHG, Nottingham histological grade

OS, overall survival

PR, progesterone receptor

PTV, primary tumor volume

RFS, Recurrence-free survival

SD, standard deviation

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

Publicly available datasets were analyzed in this study. These data are available at https://datadryad.org/stash

Competing interests

The authors declare no conflicts of interest.

Funding

This research received no specifc grant from any funding agency in the public, commercial or non-proft sectors.

Authors' contributions

SPC and YD are the lead authors who participated in data analysis and drafting of the manuscript. WLY and CXF generated the tables and figures. LJL、LXX and WLY revised the manuscript. MHX was responsible for the design and study supervision. All authors have read and approved the final manuscript.

Acknowledgements

We express our gratitude to all the participants, staff members, and fellow study investigators for their invaluable contributions to this research. Furthermore, we would like to extend our appreciation to the Free Statistics team based in Beijing, China, for their technical support and provision of data analysis and visualization tools.

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No competing interests reported.

Association of Primary Tumor Volume with Survival in Patients with HER-2-positive Breast Cancer After Trastuzumab Treatment: A Retrospective Cohort Study

Status:

Version 1

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Figures

Background

Methods

Results

Discussion

Conclusions

Abbreviations

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References

Additional Declarations

Status:

Version 1