Premenopausal women had a higher survival rate than postmenopausal patients in groups treated by endocrine therapy or chemotherapy. Postmenopausal women had lower levels of survival than premenopausal women. This might be attributable to more poor prognostic factors in postmenopausal women. The cancer-specific survival in the present study was comparable to that for patients from other Asian and Western countries.
JOURNAL OF MEDICAL RESEARCH LONG-TERM SURVIVAL OF WOMEN WITH BREAST CANCER IN BIOMARKER CONTEXT Vu Hong Thang1,2, Tran Van Thuan1,2, Ta Thanh Van2, Lambert Skoog3 ¹National Cancer Hospital, Vietnam ²Hanoi Medical University, Vietnam Karolinska University Hospital, Solna, Stockholm, Sweden Little is known about breast cancer in Vietnamese women The aim of this study was to examine the correlation of prognostic factors with relative survival of Vietnamese women afflicted by breast cancer treated at the National Cancer Hospital in Hanoi, Vietnam We recruited 248 women with operable breast cancer treated with surgery and adjuvant therapy Tumor tissue samples were stained by a range of immunohistochemically approaches and analyzed for the hormone receptors, HER2 gene amplification status The Cox model was used to determine the relationship between survival and prognostic treatment factors The disease-free survival rate, overall survival rate and cancer-specific survival rate were 75.8%, 80.6%, and 86.4%, respectively, at years and 62.3%, 68.1%, 78.9%, respectively, at years Women with poor prognostic factors (e.g., advanced clinical stage, high tumor grade, progesterone receptor (PgR) negativity, HER2 amplification) had significantly lower survival rates Postmenopausal women had significantly lower survival rates as compared to premenopausal women when analyzed by univariate analysis (HR = 0.6, 95% CI: 0.38 - 0.95, p = 0.029) However, these comparisons were not statistically significant when subjected to a multivariable analysis (HR = 0.67, 95%CI: 0.41 - 1.08, p = 0.1) Premenopausal women had a higher survival rate than postmenopausal patients in groups treated by endocrine therapy or chemotherapy Postmenopausal women had lower levels of survival than premenopausal women This might be attributable to more poor prognostic factors in postmenopausal women The cancer-specific survival in the present study was comparable to that for patients from other Asian and Western countries Keywords: breast cancer; biomarkers; survival I INTRODUCTION nese and non-Hispanic white women [2] In Breast cancer is the most common cancer Hanoi (Vietnam), the breast cancer incidence in women and a major cause of cancer-related (per 100,000 people) was low, at 17.5 cases, deaths in many countries [1] There are, how- which is considerably lower than that reported ever, differences in incidence, prognostic for Vietnamese women, 36.6 per 100.000, markers and survival among ethnic groups In living in the US and Caucasian Americans, the USA, the breast cancer incidence among 98.7 per 100.000 [3] Vietnamese women was 55.5/100.000, which In Vietnam, findings from cancer registries was found to be lower than those in other eth- in three regions showed that breast cancer is nic groups such as Chinese, Filipino, Japa- the most common form of cancer in women [4], but due to historical reasons, there are no Corresponding author: Vu Hong Thang, Medical Oncology Department, National Cancer Hospital, Hanoi, Vietnam Email: vuhongthang@hmu.edu.vn Received: 6/11/2017 Accepted: 18/9/2018 34 nationwide data available on its incidence and prevalence Breast cancer death amounts to 5.69% of all cancer deaths in Vietnamese women [5] Recent reports from the United JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH States showed that the mortality rates of USA- lary node sampling with a median of 10 lymph born, Vietnamese patients were the lowest nodes excised (range 6-35) Classification of among Asian populations and much lower histological type was defined according WHO than that of non - Hispanic white women [2; 6] criteria Tumor grade was assessed by the Similarly, it was also found that African- Scarff-Bloom-Richardson (SBR) as well as the American women had lower survival rates Elston-Ellis grading method [13] Informed than white women, even after adjustment for consent was obtained from all patients before prognostic characteristics [7] Breast cancer treatment Patients who received modified mortality has been declining in Europe over radical mastectomy were treated with adjuvant time with marked decreases observed in radiotherapy for tumors ≥ cm at a dose of 50 Northern countries attributable to early detec- Gy to the chest wall and 50 Gy to the axillary tion and treatment [8] area if node positive Patients who received Very few data have been reported on partial mastectomy were given 50 Gy to the breast cancer survival among women living in entire breast and a boost to 60 - 65 Gy to the Vietnam Two studies showed that premeno- tumor bed Patients with lymph node metasta- pausal Vietnamese women benefited from sis received adjuvant chemotherapy with oophorectomy plus tamoxifen [9; 10] anthracycline or taxane regimens range over In our previous studies, we have found that Vietnamese women had breast cancer tumors with a high frequency of the human epidermal growth factor receptor-2 (HER2) gene amplification, hormone receptor negativity and had more advanced stages of tumor compared to Swedish women [11; 12] The aim of this study was to examine the correlation of survival with prognostic factors and treatment of Vietnamese breast cancer women registered as patients at the National Cancer Hospital, Hanoi, Vietnam - cycles Of 123 premenopausal patients with hormone receptor-positive tumors, 104 (84.5%) received endocrine therapy including 74 patients with castration by radiotherapy at a dose of 15 Gy and 11 of those became menopausal after chemotherapy and 19 perimenopausal women were treated with tamoxifen alone Postmenopausal women with hormone receptor - positive tumors were treated with tamoxifen at a dose of 20 mg daily for at least two but often for years In the first years, all patients were followed-up with physical examination, chest x-rays, abdominal ultra- II METHODS Study population and treatment sound and a blood test for CA15-3 level Patients with symptoms suggesting metastasis were examined by CT/ MRI scans or bone Two hundred and forty-eight patients with scan The majority of the patients were con- primary breast cancer in clinical stage I-IIIb, tinuously followed up by examination at Na- operated on between June 2002 and October tional Cancer Hospital but some patients living 2003, were recruited randomly from the outside of Hanoi could only be reached by National Cancer Hospital, Hanoi, Vietnam telephone If a patient could not be contacted, Patients were treated with modified radical the relatives were interviewed to clarify the mastectomy or conservative surgery and axil- reason for this failure The last day of follow- JMR 116 E3 (7) - 2018 35 JOURNAL OF MEDICAL RESEARCH up was July 31, 2011, with a 99-month median gene In tumors with a ratio between 1.8 and follow-up (range - 108 months) Patients 2.2, a final decision was made after counting who were alive after the last day of follow-up an additional 20 nuclei The results have also were censored been presented previously and those indica- Tissue assessment tors were correlated to disease outcome in this study [11; 12] All tumors were analysed for hormone receptor content by immunohistochemistry in Statistical analysis the Department of Pathology at the National The data was stored using SPSS software, Cancer Hospital, Hanoi, Vietnam Receptor version 19.0 for Window (SPSS, Chicago, IL) positivity was defined as > 1% of stained Analyses were performed using SPSS and nuclei and patients with positive tumor(s) STATA version 10.1, StataCorp Texas, USA received endocrine treatment in the National Differences in clinicopathological characteris- Cancer Hospital These tumors were also tics, including tumor grade, tumor size, lymph analysed at Karolinska Hospital (Sweden) for node status and breast cancer subtypes hormone receptor content, HER2 expression between premenopausal and postmenopausal using an automated immunostaining platform patients, were examined using aχ2 test and and SISH procedure SISH scoring was odds ratio (OR) using 95% confident intervals carried out independently following the recom- (95% CIs) Disease-free survival (DFS) was mendation of the manufacturer The adequacy defined as the interval from the date of opera- of staining assessed by examining each slide tion to the date of first detection of metastasis for HER2 and chromosome 17 signals, identi- or contralateral breast cancer Breast cancer- fied as black and pink dots, respectively in the specific survival (CSS) was calculated from nuclei of normal cells, which can include fibro- the date of operation to the date of death of a blasts, endothelial cells or normal epithelial patient caused directly by cancer Overall cells The entire stained section was scanned survival (OS) was defined as the date of and an area of the invasive tumor with the operation to date of death of any cause or the most easily identifiable signal deposits was last day of follow up chosen for counting Twenty cancer cells were The survival rates were estimated by using counted for dots representing both HER2 and the Kaplan-Meier method Log-rank test was chromosome 17 A single dot was counted as used to compare DFS and OS between one, a small cluster as six and a large cluster groups Univariate and multivariate Cox re- as twelve We did not count overlapping nu- gression models were used to determine the clei, or cells in which black dots were found in relationship between breast cancer deaths the cytoplasm Finally, the ratio of HER2 gene⁄ and the prognostic and treatment factors After chromosome 17 was calculated by dividing the the modeling process, the proportionality as- total score for HER2 by the total score for sumption was checked using Schoenfeld re- chromosome 17 A ratio of < 1.8 indicated that sidual plots and no violation was found All the HER2 gene was not amplified, whereas a tests were two-sided and a p ≤ 0.05 value was ratio of > 2.2 showed amplification of the used as the significance level 36 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH living patients, 13 had evidence of recurrence/ Research ethics This work was approved by the ethical committee of the Hanoi Medical University, No 38/HMUIRB, 95/HMUIRB-extension (Vietnam) metastasis One patient dropped out after confirmed metastasis In addition, during follow up, one patient developed leukaemia, another had Vaquez disease (Primary polycythemia) III RESULTS but both are still alive as of (insert date that this report was written) The DFS, OS and Characteristics of the patients treated in 2002 - 2003 CSS rates were 75.8%, 80.6% and 86.4% at years, respectively; and 62.3%, 68.1%, 78.9% The median age of study participants was 46 years (range 26 - 72 years) From Table 1, at years, respectively These trends of survival are shown in Fig it can be seen that 159 patients (64.1%) were A comparison of prognostic factors premenopausal, 85 (34.3%) postmenopausal between pre- and postmenopausal women and (1.6%) had unknown menopausal status can be seen in Table Postmenopausal at diagnosis Of all patients, 10.5%, 70.6% women more often had poor prognostic factors and 18.9% were in clinical stages I, II and IIIa/ such as hormone receptor-negative disease b, respectively 227 patients (91.5%) had and HER2 amplification In the univariate invasive ductal carcinoma, while 21 patients model, premenopausal women seemed to (8.5%) had other subtypes The tumors were have a better survival (HR = 0.61, 95%CI: classified according to SBR criteria as grades 0.38 - 0.95, p = 0.03), however, this relation I, II and III in 9.2%, 71.3% and 10.8% of was diminished when analysis was carried out women, respectively At the time of surgery, using the multivariate model (HR = 0.67, 95% 109 patients (44%) had metastatic axillary CI: 0.41 -1.08, p = 0.10) The improved node(s) and 76 of them (70%) were given survival rate for premenopausal patients is chemotherapy also seen in Fig We also confirmed, not Hormone receptor-positive tumors (ER + and/or PgR+) were found in 164 surprisingly, patients and 112 (68%) of these were given negative tumors also had lower survival than tamoxifen women with PgR-positive tumors (HR = 1.77, No patient was treated with Herceptin Survival and clinicopathologic factors During the median observation time of 99 months, 48 patients died from breast cancer and 28 patients died of unknown causes No autopsies were performed Of the 171 (68.9%) JMR 116 E3 (7) - 2018 that participants with PgR- 95%CI: 1.01 - 3.11, p = 0.045) (Table 1) ERpositive, PgR-positive, HER2-negative tumors had improved survival rate (Fig 3a-c) It can be seen from these Figures that premenopausal women had better survival than postmenopausal patients 37 JOURNAL OF MEDICAL RESEARCH Table Comparison of clinicopathological parameters according to menopause status Variable Pre n (%) Post n (%) OR (P-value) I, II 134 (85) 64 (75) 1.83 (0.069) III 24 (15) 21 (25) 148 (93) 76 (89) 11 (7) (11) 135 (86) 65 (78) III Unknown 17 (11) (3) 13 (15) (7) (-) 89 (56) 47 (55) (+) 70 (44) 38 (45) (-) 45 (29) 46 (54) (+) 112 (71) 39 (46) (-) 65 (41) 62 (73) (+) 92 (59) 23 (27) Negative 105 (66) 39 (46) Amplification 53 (34) 46 (54) No 97 (61) 58 (68) Yes 62 (39) 27 (32) No 19 (16) 11 (27) Yes 104 (84) 30 (73) Clinical stage Histological subtype Ductal carcinoma* Others Tumor grade (SBR) I,II 0.63 (0.319) 1.59 (0.242) Lymph node 1.03 (0.919) ER status 2.93 (0.0001) PgR status 3.81 (< 0.0001) HER2 gene 2.34 (0.002) Chemotherapy 1.37 (0.264) Hormone therapy** 0.5 (0.103) *ductal and ductal carcinoma component ** compared for hormone positive patients 38 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH Figure Disease-free survival, overall survival and cancer specific survival of operable breast cancers Univariate analysis Multivariate analysis (after adjusted stage, hormone receptors, HER2 status) Figure Overall survival of operable breast cancers by menopause status Post years years Pre years years ER(-) 69.6% 59.7% ER(-) 75% 72.7% ER(+) 75.8% 58.3% ER(+) 88.1% 73.3% Figure 3a Comparison of overall survival by ER and menopausal status JMR 116 E3 (7) - 2018 39 JOURNAL OF MEDICAL RESEARCH Post years years Pre years years PgR(-) 65.5% 50.3% PgR(-) 82.6% 71.3% PgR(+) 90.9% 81.8% PgR(+) 85.6% 74.5% Figure 3b Comparison of overall survival by PgR and menopausal status Post years years Pre years years HER2(-) 73.8% 62.2% HER2(-) 86.1% 74.9% HER2(+) 71% 56.0% HER2(+) 80.8% 69.2% Figure 3c Comparison of overall survival by HER2 and menopausal status IV DISCUSSION The 5-year OS in the current study was It is estimated that more than 16.000 80.6% for all patients which was similar to sur- women in Vietnam are diagnosed with breast vival rates reported in France [14], but was cancer every year Vietnamese patients are lower than survival of foreign-born Vietnamese younger than Western patients at the time of women living in the country which was re- diagnosis and it seems that there are differ- ported to be 86% [6] The 5-year survival rate ences in tumor prognostic markers between of Vietnamese women less than 50 years Vietnamese and Swedish women with breast treated in the National Cancer Hospital in cancer [11; 12] Hanoi is similar to that reported in the Eastern 40 JMR 116 E3 (7) - 2018 JOURNAL OF MEDICAL RESEARCH region of England (85.6% vs 85.0%) and were associated with survival The lowest sur- slightly lower after years of treatment [15] vival was seen in women with advanced This might partly be explained by the fact that stages, high-grade tumors, high cell prolifera- all patients in these studies were most likely tion, or triple negative tumors Stage of dis- treated in advanced hospitals with reliable ease was the strongest prognosticator regard- guidelines and techniques However, the 5- less of other factors A report on breast cancer year DFS in our study population was lower as survival among Asian patients living in Malay- compared to Chinese women in Hong Kong sia and Singapore indicated a 5-year survival with similar stages, 75.8% vs 81.2% [16] level was lower than that found in our study To our knowledge, this is the first study [17] The survival rate was associated with with active, long-term follow-up of pre- and both tumor characteristics and hospital setting postmenopausal women with breast cancers [15] Although ER and HER2 status in our from Vietnam We usually recommend that study was found to not be statistically related breast cancer patients have their check-up to survival, it seems that patients with ER (-) after treatment at the Cancer Hospital in Ha- and/or HER2 amplified tumors have poor sur- noi This was, however, difficult for patients vival These findings are consistent with previ- living at a distance from Hanoi Therefore, 10 ous reports based on random samples of patients (4%) were lost to follow-up during the either Asian or Western women [15, 18 - 21] It course of the study One further difficulty is should, however, be pointed out that the sur- that some patients decided to go to their local vival of patients suffering from breast cancer is hospital or to seek traditional medicine treat- not only dependent on clinicopathological fea- ment In fact, it appears that some patients did tures but also on hospital settings [15] A re- not seek medical attention, although they had cent report from Sweden found that CSS at various symptoms We therefore believe that ten years was lower in low socioeconomic our data overestimates the DFS rate, and to status women than in their high socioeco- some extent also overestimates CSS, while nomic status counterparts (78% vs 82%, re- the OS data are likely to be more robust Viet- spectively) [22] We were not able to compare nam introduced national mortality statistics in the socioeconomic status of our Vietnamese 1992 which was based on commune-level re- patients, but it can be assumed that such pa- ports However, the assessment of cause of rameters are highly likely to have influenced death is in many patients is not always thor- patient survival Therefore, further studies on ough[5] In the present study, 48 of 76 patients Vietnamese patients should investigate the that died (63%) had evidence of metastasis by relationship between survival and socioeco- investigation at hospitals and cancer was de- nomic factors, combined with the quality of termined as the primary cause of death breast cancer treatment available More advanced treatment and early diag- As reported previously, we found different nosis has improved breast cancer survival clinicopathological and tumor cell characteris- over the recent years [2; 7] In our study, vari- tics of breast cancers from Vietnamese and ables including menopausal status, clinical Swedish patients The difference was seen stage, tumor grade and various biomarkers particularly with respect to patient age [11] JMR 116 E3 (7) - 2018 41 JOURNAL OF MEDICAL RESEARCH Dabakuyo et al stated that the survival rate adequate therapies and thus not reflect was lower in patients whose age was 60 years treatment in all hospitals in Vietnam Further or older and in postmenopausal women more studies are needed on similar groups of pa- broadly [14] It has also been reported that the tients in the other major cancer centres cancer mortality rate has also increased with throughout Vietnam To improve survival rate, rising age in Northern Vietnam [23] One limi- it is additionally important for patients to be tation in our study is that we were not able to diagnosed at early stages as well assess the exact cause of death in some patients; therefore, it is difficult to precisely deter- V CONCLUSION mine breast cancer-specific survival More- Although many patients had tumors with over, one important reason for the lack of the unfavourable prognostic characteristics, their precision is that for legal and cultural reasons, long-term survival prospects were favourable autopsies are not performed in Vietnam The In contrast to similar reports from western modest sample size is also contributed to limit populations, in this study However, 48 (63%) of the dead shorter survival and poor prognostic factors as patients had been confirmed as having metas- compared to premenopausal women Im- tatic disease and cancer death seems plausi- proved reports on disease recurrence and ble among these patients We found that post- cause of death in combination with knowledge menopausal women had a significantly lower about socioeconomic status are needed to OS rate than premenopausal women But obtain a more precise picture of breast cancer postmenopausal women more often had tu- survival Vietnamese patients postmenopausal women had mors with poor prognostic factors as compared to premenopausal women in this study ACKNOWLEDGEMENTS When adjusted for disease stage, hormone This work was supported by grants from receptors and HER2 gene status, we found Sida/SAREC, Stockholm, Sweden, for collabo- that postmenopausal women still tended to rative research between Hanoi Medical Uni- have a decreased survival rate although it was versity (Vietnam) and Karolinska Institute not statistically significant (Sweden) We would like to express our sin- The National Cancer Hospital is the largest cerest thanks to the nurses and doctors in the cancer centre in Northern Vietnam with more National Cancer Hospital for assistance in as- than 10,000 patients treated annually During sessing the patient records, and Sinclair H the past fifteen years, research on treatment Mantell for efficient suggestions and correcting of breast cancer in cooperation with University of the English text and Gaetano Marrone for of Wisconsin showed that premenopausal guidance on statistical analysis Vietnamese women benefited from oophorectomy and tamoxifen regardless hormone re- REFERENCES ceptor status [9] One limitation is that our find- Parkin, D.M., L.M Fernandez (2006) ings are based on breast cancer patients Use of statistics to assess the global burden of treated in a single institution with access to breast cancer Breast J, 12(1), S70 - 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