|Year : 2013 | Volume
| Issue : 7 | Page : 169-172
Efficiency and prognosis of whole brain irradiation combined with precise radiotherapy on triple-negative breast cancer
Xinhong Wu1, Bo Luo2, Shaozhong Wei3, Yan Luo2, Yaojun Feng1, Juan Xu1, Wei Wei1
1 Department of Breast Cancer, Hubei Cancer Hospital, Wuhan, China
2 Department of Radiotherapy, Hubei Cancer Hospital, Wuhan, China
3 Department of Epidemiology, Hubei Cancer Research Institute, Wuhan, China
|Date of Web Publication||30-Nov-2013|
Department of Radiotherapy, Hubei Cancer Hospital, 116 Zhuodaoquan South Road, Hongshan District, Wuhan, China 430079
Source of Support: None, Conflict of Interest: None
Aim: To investigate the treatment efficiency of whole brain irradiation combined with precise radiotherapy on triple-negative (TN) phenotype breast cancer patients with brain metastases and their survival times.
Materials and Methods : A total of 112 metastatic breast cancer patients treated with whole brain irradiation and intensity modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3DCRT) were analyzed. Thirty-seven patients were of TN phenotype. Objective response rates were compared. Survival times were estimated by using the Kaplan-Meier method. Log-rank test was used to compare the survival time difference between the TN and non-TN groups. Potential prognostic factors were determined by using a Cox proportional hazard regression model.
Results : The efficiency of radiotherapy treatment on TN and non-TN phenotypes was 96.2% and 97%, respectively. TN phenotype was associated with worse survival times than non-TN phenotype after radiotherapy (6.9 months vs. 17 months) (P < 0.01). On multivariate analysis, good prognosis was associated with non-TN status, lower graded prognosis assessment class, and nonexistence of active extracranial metastases.
Conclusion: After whole brain irradiation followed by IMRT or 3DCRT treatment, TN phenotype breast cancer patients with intracranial metastasis had high objective response rates but shorter survival time. With respect to survival in breast cancer patients with intracranial metastasis, the TN phenotype represents a significant adverse prognostic factor.
Keywords: Breast cancer, brain metastases, precise radiotherapy, triple negative
|How to cite this article:|
Wu X, Luo B, Wei S, Luo Y, Feng Y, Xu J, Wei W. Efficiency and prognosis of whole brain irradiation combined with precise radiotherapy on triple-negative breast cancer. J Can Res Ther 2013;9, Suppl S2:169-72
|How to cite this URL:|
Wu X, Luo B, Wei S, Luo Y, Feng Y, Xu J, Wei W. Efficiency and prognosis of whole brain irradiation combined with precise radiotherapy on triple-negative breast cancer. J Can Res Ther [serial online] 2013 [cited 2021 May 19];9:169-72. Available from: https://www.cancerjournal.net/text.asp?2013/9/7/167/122518
| > Introduction|| |
Brain metastases from breast cancer are very common. Whole brain radiotherapy combined with tumor bed boost by means of precise radiotherapy, such as intensity modulated radiotherapy (IMRT) or 3D conformal radiotherapy (3DCRT), has become a common palliative treatment of metastatic breast cancer patient. Triple-negative (TN) breast cancer brain metastasis has overall poor prognosis and short survival time. Effect and prognosis of whole brain radiotherapy combined with precise radiation therapy on these cases has not been reported so far. In this study, we conducted a retrospective analysis of the clinical data of metastatic breast cancer patients who received precise radiotherapy with whole brain irradiation. Treatment efficiency, survival time, and prognosis of precise radiotherapy of brain cancer metastasis are discussed to help the oncologists choose the optimal treatment strategy.
| > Materials and Methods|| |
A retrospective analysis of 112 patients with brain metastases from breast cancer who were treated during April 2004-April 2009 was done. These patients met the following criteria: (1) Pathological diagnosis of breast cancer; (2) brain metastases were confirmed by magnetic resonance imaging (MRI) or computed tomography (CT), with brain metastases not more than five; (3) hormone receptor status and human epidermal growth factor receptor 2 (HER2) status was definite; (4) clear date of death; (5) the patients underwent whole brain radiotherapy and precise radiotherapy after diagnosis. Estrogen receptor (ER)-, progesterone receptor (PR)-negative and HER2 non-overexpressed is defined as a triple-negative breast cancer (TNBC), otherwise defined as non-TNBC. ER-, PR-, and HER2-positive diagnostic criteria are as follows. If less than 1% of the nucleus is shown to be positive by the ER or PR immunohistochemical staining, the tumor ER or PR is considered to be negative. If HER2 gene amplification is not displayed under fluorescence hybridization in situ or immunohistochemical staining specimen's score is less than 3+ (>10% of the cell membrane staining is strongly positive), the tumor is considered to be HER2-negative. There were 37 cases of TNBC and 75 cases of non-TNBC among the patients. The median age at diagnosis of breast cancer was 45 years and the mean age was 46 years (range 24-73 years). Patients received complementary treatment, including chemotherapy and radiotherapy.
Clinical target volume (CTV) was expanded to planning target volume (PTV) in 2-3 mm margin after outline gross tumor volume (GTV) and CTV. Also, 6 MV X-ray was used for whole brain radiotherapy. The patients were fixed by mask in supine position. They received whole brain radiation of 2 Gy/day, 5 times/week, total Dt 30-40 Gy in 3DCRT or IMRT local boost. 3DCRT or IMRT dose was 23.5 Gy, with a median dose of 24 Gy, Dt 2-4 Gy/day, 5 times/week. The dose to brain stem, eye, and other organs at risk was controlled within the safe range. One and 3 months after radiotherapy, MR was reviewed. The patients were followed up once in every 3 months. Term effect was evaluated on RECIST 1.1. Intracranial local control time was calculated from the first cranial irradiation day, and the survival time started from the day of brain metastases diagnosis.
Survival and local control rates were calculated through the Kaplan-Meier analysis. Cox regression model was used to determine the impact of independent prognostic factors on the survival of metastatic breast cancer by univariate and multivariate analyses. χ2 test or Fisher's exact test was applied to compare categorical variables between groups.
| > Results|| |
Clinical features of patients
One hundred and twelve cases of breast cancer with brain metastases were studied. There was no difference in age between the TN group and the non-TN group. TNM staging (Fisher's exact test), Karnofsky performance score (KPS) at diagnosis, and the number and location of brain metastases did not show significant difference as well [Table 1]. From the onset to diagnosis of brain metastasis, the median time was 35 months (range 0-377 months) (26 months in the TN group and 36 months in the non-TN group) (log-rank test, P = 0.442).
Patients were followed up until death or the end of the study. The median follow-up time was 19 months (range 3-48) months and three cases were lost to follow-up. After 1 month of administering radiotherapy, the remission rate was reviewed. Results are as follows: In TNBC group: complete response (CR) 10 cases, PR 16 cases, SD 10 cases, PD 1 case, the control rate 96.2% (36/37); non-TN group: CR 19 cases, PR 33 cases, SD 21 cases, PD 2 cases, the control rate 97.0% (73/75), which showed no significant difference (χ2 = 4.5, P > 0.05).
Tumor local control rates of TNBC group and non-TN group at 6, 12, and 24 months were 96.1%, 89.7%, and 79.3%, and 96.6%, 91.1%, and 87.3% respectively, which showed no difference between the two groups (log-rank test, P = 0.755).
At end of follow-up, there were 102 cases of deaths, including 34 TN patients (94.5%) and 67 non-TN patients (89.3%). TNBC group had eight cases of local recurrence brain metastases, 26 cases of distant metastasis, and 1 case lost to follow-up. Twenty-two cases of non-TN group of patients had local recurrence, 45 cases died of distant metastasis, and 2 were lost to follow-up. After radiotherapy, the TN group and non-TN group showed 3-year survival rates of 32.1%, 18.7%, and 6.3%, and 59.1%, 36.1%, and 15.3%, respectively. The median survival time was 6.9 months and 17 months, respectively (log-rank test, P = 0.015) [Figure 1].
Univariate analysis showed that control of extracranial metastasis, the KPS score, and graded prognostic assessment (GPA) grading are closely related to the survival of patients with brain metastases in TN phenotype. These factors were used for the next step of multivariate analysis. Cox multivariate analysis showed that GPA classification of brain metastases was an independent prognostic factor in TN phenotype [Table 2].
| > Discussion|| |
About 10-16% of patients with advanced breast cancer have brain metastases ultimately. Shorter survival period occurs with brain metastasis. Moreover, brain metastasis is a major cause of death in patients with breast cancer.  However, patients may still get a longer survival time if metastasis is controlled well.  Therefore, many researchers began to pursue long-time local control of brain metastases for metastatic breast cancer patients.
Although the treatment of brain metastases from breast cancer has made some progress due to trastuzumab, lapatinib, and other targeted drugs and the emergence of new chemotherapy drugs, the overall treatment effect is still not satisfactory, especially for HER2-negative patients with TN phenotype.  Currently, breast cancer brain metastasis is still treated mainly by the combined therapy of radiation and surgery.  The common treatment of radiation therapy is whole brain radiotherapy.
Whole brain radiotherapy for brain metastases can control localized disease and eliminate subclinical lesions to prevent recurrence. However, the whole brain irradiation may cause brain damage which results in neurocognitive disorder, even dementia lately. Due to normal tissue dose limitation, radiation dose of intracranial metastases cannot be increased with the conventional whole brain radiotherapy. Thus, precise radiotherapy can be used to boost the dose of tumor bed after whole brain radiotherapy, which increases the local dose of lesions while controlling the intracranial spread of metastases. This combination significantly prolongs the survival time in patients and makes effective protection of normal brain tissue. 
Precise radiotherapy includes IMRT and other conformal radiotherapy and Stereotactic Radiosurgery (SRS). Recent research shows local dose with precise radiotherapy boost will be higher than in the conventional whole brain radiotherapy alone. Higher dose of intracranial lesions will increase the local control rate and significantly prolong the survival time. This combination treatment modality has become the main treatment approach for patients with brain metastases in recent years and has achieved good results in clinical applications. 
TNBC patients have relatively unique clinical features, some of which are high rate of brain metastasis (up to 46%), short overall survival, and poorer prognosis. TNBC patients with brain metastases have a median survival of only 3 months, and the median survival of TNBC patients is 10 months. 
This study showed that symptoms of metastatic breast cancer patients could be alleviated in short term and local control could be achieved by precise radiation boost. However, TNBC has overall worse prognosis. Whether efficiency of this combined treatment equals that in non-TN type patients is still unknown. In this paper, efficiency and prognosis of TN and non-TN metastatic breast cancer patients after brain radiotherapy were analyzed in order to help oncologists choose the treatment strategies.
This study was based on a total of 112 breast cancer patient samples. On diagnosis of brain metastases, the patients underwent brain radiotherapy. Precise radiotherapy on the whole brain was able to improve the local dose, regardless of whether it was TN group or non-TN group. It also had a better local control rate and alleviated the symptoms. The results show whole brain radiotherapy combined with precise form of radiation therapy for brain metastases in TNBC is an effective palliative treatment. But the objective response rate did not differ much between the two groups. The result also reveals a worse overall prognosis of TNBC. However, the precise radiotherapy boost after conventional radiotherapy can push the volume, so that non-TN group can get the same short-term therapeutic effect.
Although the two groups of patients had acceptable objective response rate, survival analysis showed that the median survival time of TN group was 6.9 months, which was significantly lower than that of non-TN group (17 months). Even though dose boost of tumor bed with precise radiotherapy, the survival time of TNBC patients after treatment was still shorter than that of non-TN group patients. The main reason of death in TNBC is breast cancer brain metastases and extracranial metastasis. Proportion of patients in the TN group who died of extracranial distant metastases was 74%, higher than that (57.3%) of non-TN group, which complies with the characteristics of TNBC. More TN patients in this study developed intracranial and lung metastases, while fewer patients developed bone metastasis. The trend suggests metastases of TNBC may be organ specific.  TN group had shorter survival, which is also consistent with the overall poor prognosis of TNBC in clinical features. 
We also used multivariate Cox proportional hazards regression model to analyze the potential prognostic factors of breast cancer patients with brain metastases treated with precise radiotherapy. We tried to explore whether TN phenotype would affect its outcome. The present study shows that the major prognostic factors of brain metastases are the number of brain metastases, extracranial metastases, control of extracranial tumor, and the interval between metastasis to brain and formation of primary tumor. In univariate analysis, this study showed that only KPS and extracranial metastases activity, GPA grade, and TN phenotype are correlated with prognosis. The subsequent multivariate analysis showed that GPA grading, TN phenotype, and extracranial metastases activity are independent prognostic factors. GPA gives the established prognostic index evaluation criteria based on the Radiation therapy oncology group data in multiple randomized controlled studies in patients with brain metastases. Previous reports confirmed its good prognostic effect.  The results also showed that brain metastasis from GPA grading is an important prognostic factor.
| > Conclusion|| |
In summary, the TN phenotype of breast cancer patients who underwent whole brain radiotherapy combined with precise radiotherapy can obtain better objective response rate. But its survival time remains shorter compared to that of non-TN group. For the breast cancer patients with brain metastases, the TN phenotype may serve as an independent prognostic factor for survival.
| > Acknowledgment|| |
This study was supported by a grant from the National Nature Sciences Foundation of China (No. 81201795).
| > References|| |
|1.||Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010;28:3271-7. |
|2.||Melisko ME, Moore DH, Sneed PK, De Franco J, Rugo HS. Brain metastases in breast cancer: Clinical and pathologic characteristics associated with improvements in survival. J Neurooncol 2008;88:359-65. |
|3.||Niwinska A, Murawska M, Pogoda K. Breast cancer subtypes and response to systemic treatment after whole-brain radiotherapy in patients with brain metastases. Cancer 2010;116:4238-47. |
|4.||Kocher M, Soffietti R, Abacioglu U, Villà S, Fauchon F, Baumert BG. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 study. J Clin Oncol 2011;29:134-41. |
|5.||Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial. JAMA 2006;295:2483-91. |
|6.||Park HS, Chiang VL, Knisely JP, Raldow AC, Yu JB. Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases: An update. Expert Rev Anticancer Ther 2011;11:1731-8. |
|7.||Heitz F, Harter P, Lueck HJ, Fissler-Eckhoff A, Lorenz-Salehi F, Scheil-Bertram S, et al. Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and anearlier occurrence of cerebral metastases. Eur J Cancer 2009;45:2792-8. |
|8.||Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res 2008;68:3108-14. |
|9.||Jang G, Lee SS, Ahn JH, Jung KH, Lee H, Gong G, et al. Clinical features and course of brain metastases in triple-negative breast cancer: Comparison with human epidermal growth factor receptor 2-positive and other type at single institution in Korea. Breast Cancer Res Treat 2011;128:171-7. |
|10.||Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W. A new prognostic index and comparison to three other indices for patients with brain metastases: An analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008;70:510-4. |
[Table 1], [Table 2]