18F-FDG/PET May Help to Identify a Subgroup of Patients with T1-T2 Breast Cancer and 1-3 Positive Lymph Nodes Who Are at a High Risk of Recurrence after Mastectomy

Jee Suk Chang; Jeongshim Lee; Hyun Jung Kim; Kyung Hwan Kim; Mijin Yun; Seung Il Kim; Ki Chang Keum; Chang-Ok Suh; Yong Bae Kim

doi:10.4143/crt.2015.172

Articles

Page Path: HOME > Cancer Res Treat > Volume 48(2); 2016 > Article

Original Article ¹⁸F-FDG/PET May Help to Identify a Subgroup of Patients with T1-T2 Breast Cancer and 1-3 Positive Lymph Nodes Who Are at a High Risk of Recurrence after Mastectomy: Jee Suk Chang, MD¹, Jeongshim Lee, MD¹, Hyun Jung Kim, MD², Kyung Hwan Kim, MD¹, Mijin Yun, MD, PhD², Seung Il Kim, MD, PhD³, Ki Chang Keum, MD, PhD¹, Chang-Ok Suh, MD, PhD¹, Yong Bae Kim, MD, PhD^1,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2016;48(2):508-517.
DOI: https://doi.org/10.4143/crt.2015.172
Published online: September 9, 2015

¹Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Korea

²Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Korea

³Department of Surgery, Yonsei University College of Medicine, Seoul, Korea

Correspondence: Yong Bae Kim, MD, PhD Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
Tel: 82-2-2228-8095 Fax: 82-2-312-9033 E-mail: ybkim3@yuhs.ac

*Jee Suk Chang and Jeongshim Lee contributed equally to this work.

• Received: May 19, 2015 • Accepted: August 18, 2015

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

12,544 Views
102 Download
11 Web of Science
12 Crossref
11 Scopus

prev next

Full Article

Download PDF

Abstract

Purpose
The purpose of this study is to assess the utility of positron emission tomography (PET) for predicting recurrence among patients with T1-T2/N1 breast cancer who were treated with mastectomy.
Materials and Methods
Of 712 consecutive patients with T1-T2/N1 breast cancer treated during 2003-2012, 109 had undergone preoperative ¹⁸F-fluorodeoxyglucose/PET and were included. Metabolic (maximum standardized uptake value [SUV_max]), volumetric (metabolic tumor volume [MTV]), and combined (total lesion glycolysis [TLG]) indices were measured. The resulting values were analyzed and compared with clinical outcome.
Results
At the median follow-up of 46.7 months, the 3-year relapse-free survival (RFS) rate was 95.2%. SUV_max (area under curve, 0.824) was more useful than MTV or TLG as a means of identifying patients at high risk for any recurrence. In multivariate analysis, SUV_max remained an independent risk factor for RFS (p=0.006). Using the method of Contal and O’Quigley, a SUV_max threshold of 5.36 showed the best predictive performance. The PET-based high-risk group (≥ 5.36 in either breast or nodes) had more T1c-T2, high-grade, hormone-receptor negative, and invasive ductal carcinoma tumors than the low-risk group (< 5.36 in both breast and nodes). The prognosis was much worse when high SUV_max (≥ 5.36) was detected in nodes (p < 0.001). In the no-radiotherapy cohort, the PET-based high-risk group had increased risk of locoregional recurrence when compared to the low-risk group (p=0.037).
Conclusion
High SUV_max on preoperative PET showed association with elevated risk of locoregional recurrence and any recurrence. Pre-treatment PET may improve assessments of recurrence risk and clarify indications for post-mastectomy radiotherapy in this subset of patients.
Key words: Breast neoplasms, Positron-emission tomography, Recurrence, Prognosis, Mastectomy

Introduction

The results of meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed that postmastectomy radiotherapy (PMRT) reduced the risks of recurrence and cancer death [1]. Updated studies confirmed benefits of PMRT in patients with N1 disease, irrespective of the use of systemic therapy and axillary dissection [2,3]. When using modern treatment approaches, accurate identification of high-risk patients for PMRT while sparing the remaining patients from potentially unnecessary and costly therapy, and continuing to provide them with excellent local control rates is imperative [4,5]. However, the indications for PMRT are still determined on a case-by-case basis, and definitive indications have varied significantly across institutions and changed over time. Thus, the development of a practical prognostic indicator for recurrence is required to optimize the application of PMRT for this controversial situation.

¹⁸F-Fluorodeoxyglucose/positron emission tomography (¹⁸F-FDG/PET), which detects the enhanced glycolysis of tumors, has emerged as a useful imaging tool in staging, evaluation of treatment response, and predicting the prognosis of breast cancer [6]. In Korea, ¹⁸F-FDG/PET staging is reimbursed for patients who are newly diagnosed with breast cancer; as a result, its use has increased for both locally advanced and early-stage breast cancers. Here, we sought to evaluate the potential utility of ¹⁸F-FDG/PET for predicting prognosis in a group of T1-T2/N1 breast cancer patients who underwent mastectomy, and we assessed the question of whether this PET-based high-risk group was at increased risk of locoregional recurrence after treatment without PMRT, who might be potential candidates for adjuvant radiation therapy.

Materials and Methods

1. Patients

A total of 712 consecutive patients who underwent mastectomy and were diagnosed with pathologic T1-T2/N1 breast cancer at a single institution between 2003 and 2012 were identified. Of these 712 patients, the 109 who underwent preoperative ¹⁸F-FDG/PET scanning were included in the current study. At our institution, ¹⁸F-FDG/PET staging was first offered to patients with early breast cancer in November 2003. An increase in systemic staging with ¹⁸F-FDG/PET was observed in our study cohort during the study period (2003-2009: n=46/361, 14% vs. 2010-2012: n=63/114, 55%).

2. Treatment

All patients underwent modified radical mastectomy. Sentinel lymph node (SLN) sampling was performed in all patients, except those (19%) who had biopsy-confirmed or suspicious axillary nodal metastasis on PET imaging. If the frozen section of the SLN was positive, the patient underwent completion of axillary dissection (median, 12 nodes; range, 4 to 34 nodes). Although PMRT was delivered at the physician’s discretion, it was generally performed for patients with high-risk features (mainly based on the number of positive lymph nodes). Adjuvant systemic therapy was selected after discussion with the patient’s medical oncologist.

3. ¹⁸F-FDG/PET

¹⁸F-FDG/PET scans were performed using a dedicated PET/computed tomography (CT) scanner (Discovery STE, GE Healthcare, Little Chalfont, UK, or Biograph TruePoint 40, Siemens Healthcare, Erlangen, Germany). The mean time interval from PET scan to mastectomy was 10±9 days. The detailed protocols for measurement of blood glucose concentration, determination of injected ¹⁸F-FDG quantity, low-dose and contrast enhanced CT and PET scans, and PET data reconstruction have all been described previously [7]. Semiquantitative and volumetric measurements of maximum standardized uptake value (SUV_max), mean SUV (SUV_mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of whole body tumors were performed with the PETedge tool that is available in MIMvista software (MIMvista Corp., Cleveland, OH), according to the protocol of Liao et al. [8]. After contouring the tumor using the PETedge tool, volumes of interest (VOIs) were automatically produced by spatial derivatives to locate the tumor surface. The estimated VOIs were manually adjusted using a 2-D “ball” contouring tool. In this study, SUV_max was the maximum SUV_max of all tumors either in breast tissue or in the axillary area. TLG was calculated as follows: TLG=SUV_mean×MTV. MTV and TLG were computed after summing the corresponding values of all tumors. ¹⁸F-FDG/PET was administered at the clinical discretion of the treating physician during the study period.

4. Statistical analysis

The primary end-point of our study was relapse-free survival (RFS), defined as the length of time from the date of mastectomy to any type of relapse. RFS was estimated using the Kaplan-Meier method. Comparisons of PET parameters according to clinical parameters or any recurrence (locoregional recurrence and distant metastasis as first site of failure) were performed using t tests. One-way analysis of variance (ANOVA) with a post-hoc Bonferroni’s correction was used for multiple comparisons. Receiver operating characteristics (ROC) analyses were performed to determine which parameter was most useful for predicting disease recurrence risk. Univariate and multivariate analyses of disease-free survival (DFS) were performed using Cox’s proportional hazards regression method to assess whether the PET parameter retained statistical significance after adjusting for known clinicopathologic variables. Clinically relevant variables were selected, and multivariate analysis was performed using backwards elimination. The method of Contal and O’Quigley was used to determine the cut-off point for the PET parameter, to allow objective dichotomization [9]. Using this method, the optimal cut-off point is determined by setting it to the point that maximizes the model likelihood. Because all possible cut-off points are assessed, an adjustment is applied to the p-value to control for type I error. Next, to identify the subgroup of patients who may benefit from PMRT, a secondary analysis was performed, excluding patients who underwent PMRT (no-PMRT cohort). The level of statistical significance was set at 0.05. All statistical analyses were performed using SPSS ver. 20.0 (IBM SPSS Statistics, IBM Co., Armonk, NY) or SAS (SAS Institute Inc., Cary, NC).

Results

1. Patient, tumor, and treatment characteristics

The median follow-up period was 46.7 months (range, 14 to 127 months). Data on patient, tumor, and treatment characteristics are summarized in Table 1. The median age of patients was 49 years (range, 27 to 92 years). The mean tumor size was 2.0±0.9 cm (range, 0.4 to 4.5 cm). SLN sampling was performed in 87 patients (81%), with a median of 3 (range, 1 to 7) identified. Axillary dissections were performed in all patients with a median of 12 (range, 4 to 34) total nodes dissected. Adjuvant systemic therapy was administered in most patients (105 of 109, 96%) as follows: chemotherapy (n=94, 86%) and endocrine therapy (n=58, 54%). PMRT was delivered to 34% of the patients.

2. Semiquantitative analysis of PET parameters

Most patients (97.2%) had ¹⁸F-FDG–avid tumors in the primary site, and 22 patients (20.2%) had ¹⁸F-FDG–avid tumors in axillary nodes. For whole body tumors (WT), the average SUV_max, MTV, and TLG was 4.79±3.07, 7.07±5.97 mL, and 20.22±26.0, respectively. For ¹⁸F-FDG–avid tumors in breast tissue (n=106), the average SUV_max, MTV, and TLG was 4.75±3.01, 5.92±5.02 mL, and 17.49±23.48, respectively. For ¹⁸F-FDG–avid tumors in axillary nodes (n=22), the average SUV_max, MTV, and TLG was 4.70±3.38, 4.09±4.14 mL, and 12.00±16.13, respectively.

Significant correlations were observed among three parameters (TLG_WT vs. MTV_WT, Spearman’s rho=0.882; TLG_WT vs. SUV_max _WT, rho=0.718; MTV_WT vs. SUV_max _WT, rho=0.574; all p < 0.001). Differences in SUV_max _WT, MTV_WT, and TLG_WT according to clinicopathologic parameters are shown in Table 2. A significantly higher mean SUV_max _WT was observed for invasive ductal carcinoma (IDC) tumors compared with non-IDC tumors (p < 0.001). Significantly higher mean values of SUV_max _WT, MTV_WT, and TLG_WTwere observed in T2, high-grade (G3), estrogen receptor (ER)–negative, or progesterone receptor (PR)–negative, tumors than in T1, non-high grade (G1/2), ER+, or PR+ tumors, respectively (all p < 0.05). In addition, as T stage increased, SUV_max of breast, axillary nodes, and WT were increased and more FDG-avid tumors were found in axillary nodes (T1a, 0%; T1b, 13.3%; T1c, 20.5%; T2, 22.9%) (Table 3).

3. Recurrence

At the time of analysis, six patients (6%) had experienced any recurrences, three presented with locoregional recurrence and three presented with distant metastasis. Six patients (6%) died, either with (n=2) or without (n=4) disease progression. The 3-year RFS and overall survival (OS) rates were 95.2% (95% confidence interval [CI], 91.1% to 99.3%) and 91.8% (95% CI, 84.7% to 98.9%), respectively. The relationship between SUV results and tumor recurrence was examined; patients with any recurrence had higher levels of SUV_max _WT, MTV_WT, and TLG_WT at baseline than those without any recurrence (Fig. 1A). Similar levels of SUV_max _WT, MTV_WT, and TLG_WT were observed between patients who failed locoregionally or distally (all p=0.001; ANOVA with Bonferroni correction) (Fig. 1B).

4. Usefulness of PET for predicting recurrence

ROC curves were generated for SUV_max _WT, MTV_WT, and TLG_WT (Fig. 2). In the ROC analyses, the areas under the curves (AUCs) were 0.824 (95% CI, 0.715 to 0.932) for SUV_max, 0.733 (95% CI, 0.574 to 0.892) for MTV, and 0.778 (95% CI, 0.629 to 0.928) for TLG. These results indicated that SUV_max _WT was the most useful index for predicting patients at high risk of developing any recurrence. The relationship of SUV_max _WT with the time of any recurrence was also assessed after adjusting for all available clinicopathological variables. In univariate analysis, increased SUV_max _WT (considered as a continuous variable) showed significant association with poorer RFS (p=0.001). The significance of this relationship with RFS was retained in the stepwise multivariate regression analysis (p=0.004) (Table 4).

The method of Contal and O’Quigley was also used to objectively determine a cut-off point for SUV_max _WT [9]. According to this method, the best predicted clinical performance was a threshold of 5.36, which provided a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 71%, 17%, and 100%, respectively. The patients were then divided into two groups (high- vs. low-risk) according to this cut-off point, and the characteristics of patients with SUV_max _WT ≥ 5.36 were compared to those of patients with SUV_max < 5.36. PET-based high-risk patients (SUV_max _WT ≥ 5.36) had more T1c-T2 (vs. T1a-T1b), high-grade, ER/PR negative, and IDC (vs. non-IDC) tumors than lowrisk patients (SUV_max _WT < 5.36) (all p < 0.05). Three-year RFS was 85.4% in the PET-based high-risk group compared with 100% in the low-risk group (p < 0.001) (Fig. 3A). The prognosis was much worse when high SUV_max (≥ 5.36) was detected in axillary lymph nodes (p < 0.001) (Fig. 3B).

5. Locoregional recurrence in the no-PMRT cohort

In the no-PMRT cohort (n=72), an increased risk of locoregional recurrence was observed for the PET-based high-risk group, compared with the PET-based low-risk group (3-year locoregional recurrence-free survival, 92.9% vs. 100%; p=0.037) (Fig. 3C). However, age, T stage, number of positive lymph nodes, histologic grade, ER/PR/HER2 status, ¹⁸F-FDG–avidity in axillary nodes, and other factors did not show significant association with risk of locoregional recurrence.

Discussion

In this study, we have described the efficacy of PET for identifying patients with T1-T2/N1 breast cancer with a high risk of disease recurrence after mastectomy and standard systemic therapy. We found an association of higher SUV_max _WT with both poorer RFS in the entire cohort and a higher risk of locoregional recurrence in the no-PMRT cohort. The SUV_max cut-off value that best predicted prognosis was 5.36. Compared with tumors in the PET-defined low-risk group, tumors in the high-risk group were more likely to have the following characteristics: T1c-T2 (vs. T1a-T1b) stage, high grade, ER/PR negativity, and IDC (vs. non-IDC). In conjunction with conventional risk stratification that relies on multiple factors, preoperative ¹⁸F-FDG/PET information may enable identification of high-risk groups with enhanced accuracy. We hypothesize that once these select groups are identified, they may represent the population of T1-2/N1 breast cancer patients who might benefit from PMRT.

Previous retrospective studies have investigated the usefulness of PET in breast cancer, with findings similar to ours [10-14]. Osborne et al. [10] reported that ER– tumors had higher ¹⁸F-FDG-uptake than ER+ tumors (median SUV_max, 8.5 vs. 4.0). A study by Mavi et al. [11] reported that ER status alone (rather than PR or HER2 status) had an effect on FDG uptake (F=9.126, p < 0.01). Baba et al. [12] reported correlation of high SUV_maxwith larger tumor size, higher grade, and triple-negative tumors, as well as poor prognosis (5-year DFS: ≥ 4.16 [n=32], 80% vs. < 4.16 [n=28], 100%). Song et al. [13] reported that nodal SUV_max was the only determinant of DFS among well-known clinical variables in N1-3 patients (n=65), similar to our finding that high SUV_max in lymph nodes was associated with worse RFS than high SUV_max in the primary tumor. Nakajima et al. [14] reported association of MTV and TLG with tumor size, number of positive nodes, nodal ratio, nuclear grade, ER status, and triple negative status. Nakajima et al. [14] found that larger MTV was an independent risk factor for locoregional recurrence-free survival and DFS. In comparison with our cohort of patients, the cohort considered by Nakajima et al. [14] had different characteristics, including a higher proportion of T2 disease (63% vs. 44%), more biologically aggressive behavior (SUV_max, MTV, and TLG; median 7.2, 31.7, and 73.4 vs. mean 4.8, 7.1, 20.2), and lesser use of chemotherapy (62.4% vs. 86%). These differences may have increased the importance of MTV in the study by Nakajima et al. [14] as compared with our own. However, both studies found that the AUC of SUV_max was high (> 0.80), and the consistency of these findings should be highlighted.

Compared with other studies, our study had the following strengths: (1) the cohort consisted of a homogenous group of patients with pathologic T1-T2/N1 disease, who were treated with mastectomy and current standard adjuvant therapy. In addition, (2) we did not limit the investigation to metabolic (SUV_max) values, but also assessed volumetric (MTV) values and the combination of both indices (in the form of TLG). The relationships between these indices, RFS, and locoregional recurrence were then evaluated. Finally, (3) the analyses focused on an issue that is currently relevant in clinical practice.

From a cost-effectiveness perspective, it is not clear whether PET should be offered to all patients with T1-T2/N1 disease, in order to identify those at high risk of recurrence, and accordingly indicate PMRT. If our results are confirmed in other series, cost-effectiveness will present another clinical issue. Currently, National Comprehensive Cancer Network (NCCN) experts recommend against the routine use of PET in early breast cancer because of high false-negative rates in small or low grade breast tumors, low sensitivity for detection of nodal metastasis, low prior probability of distant metastasis, and (mainly) cost-ineffectiveness [15]. However, recent studies (including studies with prospective designs) have raised the possibility that PET may have a role in stage II breast cancer [15-19]. The following studies reported relevant results: Groves et al. [17] found that PET impacted cancer management in 16% of patients with stage II disease, Groheux et al. [15] reported that PET modified staging in 5.5% of patients with stage IA disease and 13% of patients with stage IB disease, and the Ontario Clinical Oncology Group Study reported that PET could influence surgical care by avoiding unnecessary SLN biopsies [16].

Our study has several limitations, including those that are inherent to retrospective analyses. Because of the small number of events (recurrences), it was not possible to perform a more complete statistical analysis. Longer follow-up is needed to clarify the relationship between ¹⁸F-FDG uptake and dormancy/late recurrence. Although the 5-year OS did not differ significantly according to the use of PET in our cohort (n=712; 5-year OS rate, 93.1% with PET vs. 91% without PET; p=0.412), it is possible that selection bias in our study sample resulted in a better prognosis in the PET group, affecting the results in terms of the cut-off value.

Conclusion

In conclusion, we found that a high SUV_max (≥ 5.36) was associated with an increased risk of locoregional recurrence, as well as any recurrence. Patients with high SUV_max in lymph node involvement appeared to have a much worse prognosis than those with high SUV_max in primary tumors. However, these findings are purely hypothesis generating; confirmatory studies with larger cohorts and longer follow-up periods are necessary before PET-defined risk assessment can be routinely adopted for early breast cancer. Efforts to define the optimal cut-off values of PET parameters are also necessary.

NOTES

Conflict of interest relevant to this article was not reported.

Acknowledgements

We thank Hye Sun Lee, MS, Department of Biostatistics, Severance Hospital, for statistical consultation and analysis of the data.

Fig. 1.

Box plots of maximum standardized uptake value (SUV_max _WT), metabolic tumor volume (MTV_WT), and total lesion glycolysis (TLG_WT), as shown for any recurrence (Rec) (A) and locoregional recurrence (LRR) and distant metastasis (DM) (B).

Fig. 2.

Receiver-operating characteristics curves for maximum standardized uptake value (SUV_max), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) of whole body tumors.

Fig. 3.

Relapse-free survival rates in the entire cohort (n=109) (A, B) and locoregional recurrence-free survival (C) in the no post-mastectomy radiotherapy cohort (n=72), according to high (≥ 5.36) and low (< 5.36) maximum standardized uptake value (SUV_max) of whole body tumors (WT) (SUV_max _WT), the primary tumor (Br) (SUV_max _Br), or the axillary lymph nodes (LN) (SUV_max _LN).

Table 1.

Patient, tumor, and treatment characteristics

Characteristic	No. (%) (n=109)
Age (yr)
< 45	29 (27)
≥ 45	80 (73)
Histology
IDC	100 (92)
Non-IDC	9 (8)
T stage
T1	61 (56)
T1a	2 (2)
T1b	15 (14)
T1c	44 (40)
T2	48 (44)
LVI
Negative	102 (94)
Positive	7 (6)
No. of positive lymph nodes
1	69 (63)
2	29 (27)
3	11 (10)
Percentage of positive lymph nodes
< 25	103 (94)
≥ 25	6 (6)
ECE
Negative	100 (92)
Positive	9 (8)
Histological grade
1	21 (20)
2	60 (57)
3	25 (24)
Estrogen receptor status
Negative	25 (23)
Positive	84 (77)
Progesterone receptor status
Negative	48 (44)
Positive	61 (56)
HER2 overexpression
Negative	73 (69)
Positive	33 (31)
Systemic chemotherapy and/or hormone therapy	105 (96)
Chemotherapy	94 (86)
AC±T	75 (69)
CMF	14 (13)
Unspecified	5 (5)
Hormone therapy	58 (53)
Post-mastectomy radiotherapy
No	72 (66)
Yes	37 (34)

IDC, invasive ductal carcinoma; LVI, lymphovascular invasion; ECE, extracapsular extension; AC, adriamycin cyclophosphamide; T, paclitaxel docetaxel; CMF, cyclophosphamide methotrexate 5-fluorouracil.

Table 2.

Comparisons of PET indices in whole body tumors according to clinicopathologic parameters (n=109)

Variable	SUV_max	p-value	MTV (mL)	p-value	TLG	p-value
Age (yr)
< 45	3.99±2.44	0.099	5.15±3.81	0.042	13.84±13.92	0.038
≥ 45	5.09±3.24		7.77±6.46		22.54±28.90
Histology
IDC	5.04±3.07	< 0.001	7.22±5.75	0.409	21.19±26.52	0.196
Non-IDC	2.01±1.08		5.49±8.32		9.47±16.79
T stage
T1	4.12±2.29	0.014	5.40±5.14	0.001	12.17±13.29	< 0.001
T2	5.65±3.70		9.19±6.33		30.46±33.71
LVI
Negative	4.75±3.10	0.570	7.01±6.00	0.671	19.90±26.39	0.551
Positive	5.42±2.84		8.04±5.92		24.97±20.37
No. of positive LNs
1	4.43±2.59	0.101	6.22±5.23	0.051	15.84±17.40	0.020
2, 3	5.43±3.71		8.54±6.90		27.79±35.37
Positive LNs (%)
< 25	4.82±3.10	0.695	7.17±5.98	0.507	20.34±26.25	0.852
≥ 25	4.31±2.89		5.49±6.10		18.28±23.14
ECE
Negative	4.81±3.08	0.869	6.97±5.61	0.546	19.20±21.59	0.532
Positive	4.63±3.25		8.23±9.52		31.57±56.55
Histological grade
1, 2	3.97±2.59	< 0.001	6.04±5.02	0.004	14.05±16.20	0.002
3	7.73±2.85		10.93±7.40		42.04±38.88
Estrogen receptor status
Negative	6.66±4.03	0.008	9.50±6.19	0.020	33.72±31.19	0.014
Positive	4.24±2.50		6.35±5.75		16.21±22.96
Progesterone receptor status
Negative	5.52±3.53	0.028	9.22±7.00	0.001	29.37±32.93	0.002
Positive	4.22±2.55		5.39±4.38		13.03±15.74
HER2 overexpression
Negative	4.73±2.64	0.818	6.77±5.38	0.538	17.44±18.66	0.237
Positive	4.90±3.98		7.63±7.10		25.64±37.16

PET, positron emission tomography; SUV_max, maximum standardized uptake value; MTV, metabolic tumor volume; TLG, total lesion glycolysis; IDC, invasive ductal carcinoma; LVI, lymphovascular invasion; LN, lymph node; ECE, extracapsular extension.

Table 3.

Comparisons of PET indices in breast, lymph node, and WT according to T classification (n=109)

T stage	Breast		Lymph node		WT SUV_max
T stage	Non-avid	SUV_max	Non-avid	SUV_max	WT SUV_max
T1a	0/2 (0)	NA	2/2 (100)	NA	NA
T1b	1/15 (6.7)	1.84±0.39	13/15 (86.7)	3.00±2.80	3.55±2.03
T1c	0/44 (0)	4.80±1.97	35/44 (79.5)	3.64±2.15	5.59±2.00
T2	2/46 (4.2)	8.45±4.49	37/48 (77.1)	5.87±4.06	8.94±4.38

Values are presented as number (%) or mean±standard deviation. PET, positron emission tomography; WT, whole body tumors; SUV_max, maximum standardized uptake value; NA, not applicable.

Table 4.

Stepwise univariate and multivariate analyses using Cox’s regression method for disease-free survival in 109 patients

Variable	Univariate analysis			Multivariate analysis^a)
Variable	HR	95% CI	p-value	HR	95% CI	p-value
Age (≥ 45 yr vs. < 45 yr)	0.63	0.12-3.48	0.597	0.14	0.01-2.24	0.165
T stage (T1 vs. T2)	0.46	0.08-2.55	0.373	NI	-
No. of positive LNs (1 vs. 2, 3)	0.77	0.14-4.22	0.761	0.19	0.01-3.74	0.276
Histological grade (1, 2 vs. 3)	0.63	0.12-3.44	0.593	0.02	0.00-0.73	0.032
Estrogen receptor status (positive vs. negative)	0.16	0.03-0.86	0.033	0.04	0.00-0.60	0.02
Progesterone receptor status (positive vs. negative)	0.76	0.15-3.76	0.734	NI	-	-
HER2 overexpression (positive vs. negative)	1.19	0.22-6.51	0.844	NI	-	-
Post-mastectomy radiotherapy (yes vs. no)	0.39	0.05-3.41	0.396	0.06	0.00-2.58	0.141
¹⁸F-FDG-avidity in axillary nodes (avid vs. non-avid)	4.30	0.87-21.29	0.074	NI	-	-
SUV_max (as continuous)	1.43	1.15-1.78	0.001	1.77	1.19-2.62	0.004

HR, hazard ratio; CI, confidence interval; LN, lymph node; ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; SUV_max, maximum standardized uptake value.

^a) Variables were entered into the multivariate regression model in a stepwise method if p < 0.20 and were removed at any point if p-value was > 0.20.

REFERENCES

1. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087–106. Article PubMed
2. EBCTCG (Early Breast Cancer Trialists' Collaborative Group); McGale P, Taylor C, Correa C, Cutter D, Duane F, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:2127–35. Article PubMed PMC
3. Poortmans P. Postmastectomy radiation in breast cancer with one to three involved lymph nodes: ending the debate. Lancet. 2014;383:2104–6. Article PubMed
4. Wallgren A, Bonetti M, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Holmberg SB, et al. Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII. J Clin Oncol. 2003;21:1205–13. Article PubMed
5. Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004;22:4247–54. Article PubMed
6. Langer A. A systematic review of PET and PET/CT in oncology: a way to personalize cancer treatment in a cost-effective manner? BMC Health Serv Res. 2010;10:283.Article PubMed PMC
7. Yun M, Lim JS, Noh SH, Hyung WJ, Cheong JH, Bong JK, et al. Lymph node staging of gastric cancer using (18)F-FDG PET: a comparison study with CT. J Nucl Med. 2005;46:1582–8. PubMed
8. Liao S, Penney BC, Wroblewski K, Zhang H, Simon CA, Kampalath R, et al. Prognostic value of metabolic tumor burden on 18F-FDG PET in nonsurgical patients with non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2012;39:27–38. Article PubMed
9. Contal C, O'Quigley J. An application of changepoint methods in studying the effect of age on survival in breast cancer. Comput Stat Data Anal. 1999;30:253–70. Article
10. Osborne JR, Port E, Gonen M, Doane A, Yeung H, Gerald W, et al. 18F-FDG PET of locally invasive breast cancer and association of estrogen receptor status with standardized uptake value: microarray and immunohistochemical analysis. J Nucl Med. 2010;51:543–50. Article PubMed PMC
11. Mavi A, Cermik TF, Urhan M, Puskulcu H, Basu S, Yu JQ, et al. The effects of estrogen, progesterone, and C-erbB-2 receptor states on 18F-FDG uptake of primary breast cancer lesions. J Nucl Med. 2007;48:1266–72. Article PubMed
12. Baba S, Isoda T, Maruoka Y, Kitamura Y, Sasaki M, Yoshida T, et al. Diagnostic and prognostic value of pretreatment SUV in 18F-FDG/PET in breast cancer: comparison with apparent diffusion coefficient from diffusion-weighted MR imaging. J Nucl Med. 2014;55:736–42. Article PubMed
13. Song BI, Lee SW, Jeong SY, Chae YS, Lee WK, Ahn BC, et al. 18F-FDG uptake by metastatic axillary lymph nodes on pretreatment PET/CT as a prognostic factor for recurrence in patients with invasive ductal breast cancer. J Nucl Med. 2012;53:1337–44. Article PubMed
14. Nakajima N, Kataoka M, Sugawara Y, Ochi T, Kiyoto S, Ohsumi S, et al. Volume-based parameters of 18F-fluorodeoxyglucose positron emission tomography/computed tomography improve disease recurrence prediction in postmastectomy breast cancer patients with 1 to 3 positive axillary lymph nodes. Int J Radiat Oncol Biol Phys. 2013;87:738–46. Article PubMed
15. Groheux D, Giacchetti S, Espie M, Vercellino L, Hamy AS, Delord M, et al. The yield of 18F-FDG PET/CT in patients with clinical stage IIA, IIB, or IIIA breast cancer: a prospective study. J Nucl Med. 2011;52:1526–34. Article PubMed
16. Pritchard KI, Julian JA, Holloway CM, McCready D, Gulenchyn KY, George R, et al. Prospective study of 2-[(1) (8)F]fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: an Ontario clinical oncology group study. J Clin Oncol. 2012;30:1274–9. Article PubMed
17. Groves AM, Shastry M, Ben-Haim S, Kayani I, Malhotra A, Davidson T, et al. Defining the role of PET-CT in staging early breast cancer. Oncologist. 2012;17:613–9. Article PubMed PMC
18. Riedl CC, Slobod E, Jochelson M, Morrow M, Goldman DA, Gonen M, et al. Retrospective analysis of 18F-FDG PET/CT for staging asymptomatic breast cancer patients younger than 40 years. J Nucl Med. 2014;55:1578–83. Article PubMed PMC
19. Groheux D, Moretti JL, Baillet G, Espie M, Giacchetti S, Hindie E, et al. Effect of (18)F-FDG PET/CT imaging in patients with clinical Stage II and III breast cancer. Int J Radiat Oncol Biol Phys. 2008;71:695–704. Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

Prognostic Value of Neutrophil-to-Lymphocyte Ratio and Early Standardized Uptake Value Reduction in Patients With Breast Cancer Receiving Neoadjuvant Chemotherapy
Soong June Bae, Sung Gwe Ahn, Jung Hwan Ji, Chih Hao Chu, Dooreh Kim, Janghee Lee, Soeun Park, Chihwan Cha, Joon Jeong
Journal of Breast Cancer.2022; 25(6): 485. CrossRef
Significance of Metabolic Tumor Volume at Baseline and Reduction of Mean Standardized Uptake Value in 18F-FDG-PET/CT Imaging for Predicting Pathological Complete Response in Breast Cancers Treated with Preoperative Chemotherapy
Tomoko Higuchi, Yukie Fujimoto, Hiromi Ozawa, Ayako Bun, Reiko Fukui, Yoshimasa Miyagawa, Michiko Imamura, Kazuhiro Kitajima, Koichiro Yamakado, Yasuo Miyoshi
Annals of Surgical Oncology.2019; 26(7): 2175. CrossRef
The ability of pre-treatment F-18 FDG PET/CT metabolic parameters for predicting axillary lymph node and distant metastasis and overall survival
Burcak Yilmaz, Sedef Dağ, Nurhan Ergul, Tevfik Fikret Çermik
Nuclear Medicine Communications.2019; 40(11): 1112. CrossRef
Postmastectomy radiotherapy in T1-2 patients with one to three positive lymph nodes – Past, present and future
Filip Kaššák, Christine Rossier, Cristina Picardi, Jacques Bernier
The Breast.2019; 48: 73. CrossRef
The prognostic value of SUVmax measuring on primary lesion and ALN by 18F-FDG PET or PET/CT in patients with breast cancer
Wei Diao, Fangfang Tian, Zhiyun Jia
European Journal of Radiology.2018; 105: 1. CrossRef
Differential Prognostic Impact of Strong PD-L1 Expression and 18F-FDG Uptake in Triple-negative Breast Cancer
Seo Hee Choi, Jee Suk Chang, Ja Seung Koo, Jong Won Park, Joo Hyuk Sohn, Ki Chang Keum, Chang-Ok Suh, Yong Bae Kim
American Journal of Clinical Oncology.2018; 41(11): 1049. CrossRef
Prediction of breast cancer recurrence using lymph node metabolic and volumetric parameters from 18F-FDG PET/CT in operable triple-negative breast cancer
Yong-il Kim, Yong Joong Kim, Jin Chul Paeng, Gi Jeong Cheon, Dong Soo Lee, June-Key Chung, Keon Wook Kang
European Journal of Nuclear Medicine and Molecular Imaging.2017; 44(11): 1787. CrossRef
Tumor size and proliferative marker geminin rather than Ki67 expression levels significantly associated with maximum uptake of 18F-deoxyglucose levels on positron emission tomography for breast cancers
Arisa Nishimukai, Natsuko Inoue, Ayako Kira, Masashi Takeda, Koji Morimoto, Kazuhiro Araki, Kazuhiro Kitajima, Takahiro Watanabe, Seiichi Hirota, Toyomasa Katagiri, Shoji Nakamori, Kouhei Akazawa, Yasuo Miyoshi, Renato Franco
PLOS ONE.2017; 12(9): e0184508. CrossRef
Prognostic Value of SUVmax of <sup>18</sup>F-FDG PET/CT in Early Stage Breast Cancer with No LN Metastasis
Ryusuke Murakami, Yoshimitsu Fukushima, Hitomi Tani, Kotomi Iwata, Shinichiro Kumita, Maki Nakai, Tomoko Kurita, Keiko Yanagihara, Hiroyuki Takei, Miyuki Matsubara
Open Journal of Medical Imaging.2017; 07(03): 112. CrossRef
Volume-based metabolic parameter of breast cancer on preoperative 18F-FDG PET/CT could predict axillary lymph node metastasis
Young-Sil An, Doo Kyoung Kang, Yongsik Jung, Tae Hee Kim
Medicine.2017; 96(45): e8557. CrossRef
Trends in the Application of Postmastectomy Radiotherapy for Breast Cancer With 1 to 3 Positive Axillary Nodes and Tumors ≤5 cm in the Modern Treatment Era
Jee Suk Chang, Jung Eun Choi, Min Ho Park, Sung Hoo Jung, Byung Ock Choi, Hyung Seok Park, Seho Park, Yong Bae Kim
Medicine.2016; 95(19): e3592. CrossRef
Prognostic significance of preoperative 18F-FDG PET/CT for breast cancer subtypes
Tomoko Higuchi, Arisa Nishimukai, Hiromi Ozawa, Yukie Fujimoto, Ayako Yanai, Yoshimasa Miyagawa, Keiko Murase, Michiko Imamura, Yuichi Takatsuka, Kazuhiro Kitajima, Kazuhito Fukushima, Yasuo Miyoshi
The Breast.2016; 30: 5. CrossRef

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

¹⁸F-FDG/PET May Help to Identify a Subgroup of Patients with T1-T2 Breast Cancer and 1-3 Positive Lymph Nodes Who Are at a High Risk of Recurrence after Mastectomy

Cancer Res Treat. 2016;48(2):508-517. Published online September 9, 2015

DOI: https://doi.org/10.4143/crt.2015.172

XML Download

Abstract
Introduction
Materials and Methods
Results
Discussion
Conclusion
NOTES
REFERENCES

¹⁸F-FDG/PET May Help to Identify a Subgroup of Patients with T1-T2 Breast Cancer and 1-3 Positive Lymph Nodes Who Are at a High Risk of Recurrence after Mastectomy

Fig. 1. Box plots of maximum standardized uptake value (SUVmax WT), metabolic tumor volume (MTVWT), and total lesion glycolysis (TLGWT), as shown for any recurrence (Rec) (A) and locoregional recurrence (LRR) and distant metastasis (DM) (B).

Fig. 2. Receiver-operating characteristics curves for maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) of whole body tumors.

Fig. 3. Relapse-free survival rates in the entire cohort (n=109) (A, B) and locoregional recurrence-free survival (C) in the no post-mastectomy radiotherapy cohort (n=72), according to high (≥ 5.36) and low (< 5.36) maximum standardized uptake value (SUVmax) of whole body tumors (WT) (SUVmax WT), the primary tumor (Br) (SUVmax Br), or the axillary lymph nodes (LN) (SUVmax LN).

Fig. 1.

Fig. 2.

Fig. 3.

¹⁸F-FDG/PET May Help to Identify a Subgroup of Patients with T1-T2 Breast Cancer and 1-3 Positive Lymph Nodes Who Are at a High Risk of Recurrence after Mastectomy

Characteristic	No. (%) (n=109)
Age (yr)
< 45	29 (27)
≥ 45	80 (73)
Histology
IDC	100 (92)
Non-IDC	9 (8)
T stage
T1	61 (56)
T1a	2 (2)
T1b	15 (14)
T1c	44 (40)
T2	48 (44)
LVI
Negative	102 (94)
Positive	7 (6)
No. of positive lymph nodes
1	69 (63)
2	29 (27)
3	11 (10)
Percentage of positive lymph nodes
< 25	103 (94)
≥ 25	6 (6)
ECE
Negative	100 (92)
Positive	9 (8)
Histological grade
1	21 (20)
2	60 (57)
3	25 (24)
Estrogen receptor status
Negative	25 (23)
Positive	84 (77)
Progesterone receptor status
Negative	48 (44)
Positive	61 (56)
HER2 overexpression
Negative	73 (69)
Positive	33 (31)
Systemic chemotherapy and/or hormone therapy	105 (96)
Chemotherapy	94 (86)
AC±T	75 (69)
CMF	14 (13)
Unspecified	5 (5)
Hormone therapy	58 (53)
Post-mastectomy radiotherapy
No	72 (66)
Yes	37 (34)

Variable	SUV_max	p-value	MTV (mL)	p-value	TLG	p-value
Age (yr)
< 45	3.99±2.44	0.099	5.15±3.81	0.042	13.84±13.92	0.038
≥ 45	5.09±3.24		7.77±6.46		22.54±28.90
Histology
IDC	5.04±3.07	< 0.001	7.22±5.75	0.409	21.19±26.52	0.196
Non-IDC	2.01±1.08		5.49±8.32		9.47±16.79
T stage
T1	4.12±2.29	0.014	5.40±5.14	0.001	12.17±13.29	< 0.001
T2	5.65±3.70		9.19±6.33		30.46±33.71
LVI
Negative	4.75±3.10	0.570	7.01±6.00	0.671	19.90±26.39	0.551
Positive	5.42±2.84		8.04±5.92		24.97±20.37
No. of positive LNs
1	4.43±2.59	0.101	6.22±5.23	0.051	15.84±17.40	0.020
2, 3	5.43±3.71		8.54±6.90		27.79±35.37
Positive LNs (%)
< 25	4.82±3.10	0.695	7.17±5.98	0.507	20.34±26.25	0.852
≥ 25	4.31±2.89		5.49±6.10		18.28±23.14
ECE
Negative	4.81±3.08	0.869	6.97±5.61	0.546	19.20±21.59	0.532
Positive	4.63±3.25		8.23±9.52		31.57±56.55
Histological grade
1, 2	3.97±2.59	< 0.001	6.04±5.02	0.004	14.05±16.20	0.002
3	7.73±2.85		10.93±7.40		42.04±38.88
Estrogen receptor status
Negative	6.66±4.03	0.008	9.50±6.19	0.020	33.72±31.19	0.014
Positive	4.24±2.50		6.35±5.75		16.21±22.96
Progesterone receptor status
Negative	5.52±3.53	0.028	9.22±7.00	0.001	29.37±32.93	0.002
Positive	4.22±2.55		5.39±4.38		13.03±15.74
HER2 overexpression
Negative	4.73±2.64	0.818	6.77±5.38	0.538	17.44±18.66	0.237
Positive	4.90±3.98		7.63±7.10		25.64±37.16

T stage	Breast		Lymph node		WT SUV_max
T stage	Non-avid	SUV_max	Non-avid	SUV_max	WT SUV_max
T1a	0/2 (0)	NA	2/2 (100)	NA	NA
T1b	1/15 (6.7)	1.84±0.39	13/15 (86.7)	3.00±2.80	3.55±2.03
T1c	0/44 (0)	4.80±1.97	35/44 (79.5)	3.64±2.15	5.59±2.00
T2	2/46 (4.2)	8.45±4.49	37/48 (77.1)	5.87±4.06	8.94±4.38

Variable	Univariate analysis			Multivariate analysis^a)
Variable	HR	95% CI	p-value	HR	95% CI	p-value
Age (≥ 45 yr vs. < 45 yr)	0.63	0.12-3.48	0.597	0.14	0.01-2.24	0.165
T stage (T1 vs. T2)	0.46	0.08-2.55	0.373	NI	-
No. of positive LNs (1 vs. 2, 3)	0.77	0.14-4.22	0.761	0.19	0.01-3.74	0.276
Histological grade (1, 2 vs. 3)	0.63	0.12-3.44	0.593	0.02	0.00-0.73	0.032
Estrogen receptor status (positive vs. negative)	0.16	0.03-0.86	0.033	0.04	0.00-0.60	0.02
Progesterone receptor status (positive vs. negative)	0.76	0.15-3.76	0.734	NI	-	-
HER2 overexpression (positive vs. negative)	1.19	0.22-6.51	0.844	NI	-	-
Post-mastectomy radiotherapy (yes vs. no)	0.39	0.05-3.41	0.396	0.06	0.00-2.58	0.141
¹⁸F-FDG-avidity in axillary nodes (avid vs. non-avid)	4.30	0.87-21.29	0.074	NI	-	-
SUV_max (as continuous)	1.43	1.15-1.78	0.001	1.77	1.19-2.62	0.004

Table 1. Patient, tumor, and treatment characteristics

Table 2. Comparisons of PET indices in whole body tumors according to clinicopathologic parameters (n=109)

Table 3. Comparisons of PET indices in breast, lymph node, and WT according to T classification (n=109)

Values are presented as number (%) or mean±standard deviation. PET, positron emission tomography; WT, whole body tumors; SUV_max, maximum standardized uptake value; NA, not applicable.

Table 4. Stepwise univariate and multivariate analyses using Cox’s regression method for disease-free survival in 109 patients

HR, hazard ratio; CI, confidence interval; LN, lymph node; ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; SUV_max, maximum standardized uptake value.

Variables were entered into the multivariate regression model in a stepwise method if p < 0.20 and were removed at any point if p-value was > 0.20.