Long- term survival of women with breast cancer in biomarker context

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.

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

LONG-TERM SURVIVAL OF WOMEN WITH BREAST CANCER IN BIOMARKER CONTEXT

Vu Hong Thang 1,2 , Tran Van Thuan 1,2 , Ta Thanh Van 2 , Lambert Skoog 3

¹National Cancer Hospital, Vietnam

²Hanoi Medical University, Vietnam 3

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 immunohisto-chemically 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 5 years and 62.3%, 68.1%, 78.9%, respectively, at 9 years Women with poor prog-nostic 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 Postmeno-pausal women had lower levels of survival than premenoPostmeno-pausal 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

Breast cancer is the most common cancer

in women and a major cause of cancer-related

deaths in many countries [1] There are,

how-ever, differences in incidence, prognostic

markers and survival among ethnic groups In

the USA, the breast cancer incidence among

Vietnamese women was 55.5/100.000, which

was found to be lower than those in other

eth-nic groups such as Chinese, Filipino,

Japa-nese and non-Hispanic white women [2] In Hanoi (Vietnam), the breast cancer incidence (per 100,000 people) was low, at 17.5 cases, which is considerably lower than that reported for Vietnamese women, 36.6 per 100.000, living in the US and Caucasian Americans, 98.7 per 100.000 [3]

In Vietnam, findings from cancer registries

in three regions showed that breast cancer is the most common form of cancer in women [4], but due to historical reasons, there are no 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

States showed that the mortality rates of

USA-born, Vietnamese patients were the lowest

among Asian populations and much lower

than that of non - Hispanic white women [2; 6]

Similarly, it was also found that

African-American women had lower survival rates

than white women, even after adjustment for

prognostic characteristics [7] Breast cancer

mortality has been declining in Europe over

time with marked decreases observed in

Northern countries attributable to early

detec-tion and treatment [8]

Very few data have been reported on

breast cancer survival among women living in

Vietnam Two studies showed that

premeno-pausal Vietnamese women benefited from

oophorectomy plus tamoxifen [9; 10]

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

amplifi-cation, 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

II METHODS

1 Study population and treatment

Two hundred and forty-eight patients with

primary breast cancer in clinical stage I-IIIb,

operated on between June 2002 and October

2003, were recruited randomly from the

National Cancer Hospital, Hanoi, Vietnam

Patients were treated with modified radical

mastectomy or conservative surgery and

axil-lary node sampling with a median of 10 lymph nodes excised (range 6-35) Classification of histological type was defined according WHO criteria Tumor grade was assessed by the Scarff-Bloom-Richardson (SBR) as well as the Elston-Ellis grading method [13] Informed consent was obtained from all patients before treatment Patients who received modified radical mastectomy were treated with adjuvant radiotherapy for tumors ≥ 3 cm at a dose of 50

Gy to the chest wall and 50 Gy to the axillary area if node positive Patients who received partial mastectomy were given 50 Gy to the entire breast and a boost to 60 - 65 Gy to the tumor bed Patients with lymph node metasta-sis received adjuvant chemotherapy with anthracycline or taxane regimens range over 4

- 6 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 meno-pausal after chemotherapy and 19 peri-menopausal women were treated with ta-moxifen 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 5 years In the first years, all patients were followed-up with physi-cal examination, chest x-rays, abdominal ultra-sound and a blood test for CA15-3 level Pa-tients with symptoms suggesting metastasis were examined by CT/ MRI scans or bone scan The majority of the patients were con-tinuously followed up by examination at Na-tional Cancer Hospital but some patients living outside of Hanoi could only be reached by telephone If a patient could not be contacted, the relatives were interviewed to clarify the reason for this failure The last day of

follow-up was July 31, 2011, with a 99-month median

follow-up (range 4 - 108 months) Patients

who were alive after the last day of follow-up

were censored

2 Tissue assessment

All tumors were analysed for hormone

receptor content by immunohistochemistry in

the Department of Pathology at the National

Cancer Hospital, Hanoi, Vietnam Receptor

positivity was defined as > 1% of stained

nuclei and patients with positive tumor(s)

received endocrine treatment in the National

Cancer Hospital These tumors were also

analysed at Karolinska Hospital (Sweden) for

hormone receptor content, HER2 expression

using an automated immunostaining platform

and SISH procedure SISH scoring was

carried out independently following the

recom-mendation of the manufacturer The adequacy

of staining assessed by examining each slide

for HER2 and chromosome 17 signals,

identi-fied as black and pink dots, respectively in the

nuclei of normal cells, which can include

fibro-blasts, endothelial cells or normal epithelial

cells The entire stained section was scanned

and an area of the invasive tumor with the

most easily identifiable signal deposits was

chosen for counting Twenty cancer cells were

counted for dots representing both HER2 and

chromosome 17 A single dot was counted as

one, a small cluster as six and a large cluster

as twelve We did not count overlapping

nu-clei, or cells in which black dots were found in

the cytoplasm Finally, the ratio of HER2 gene⁄

chromosome 17 was calculated by dividing the

total score for HER2 by the total score for

chromosome 17 A ratio of < 1.8 indicated that

the HER2 gene was not amplified, whereas a

ratio of > 2.2 showed amplification of the

gene In tumors with a ratio between 1.8 and 2.2, a final decision was made after counting

an additional 20 nuclei The results have also been presented previously and those indica-tors were correlated to disease outcome in this study [11; 12]

3 Statistical analysis

The data was stored using SPSS software, version 19.0 for Window (SPSS, Chicago, IL) Analyses were performed using SPSS and STATA version 10.1, StataCorp Texas, USA Differences in clinicopathological characteris-tics, including tumor grade, tumor size, lymph node status and breast cancer subtypes between premenopausal and postmenopausal patients, were examined using aχ2 test and odds ratio (OR) using 95% confident intervals (95% CIs) Disease-free survival (DFS) was defined as the interval from the date of opera-tion to the date of first detecopera-tion of metastasis

or contralateral breast cancer Breast cancer-specific survival (CSS) was calculated from the date of operation to the date of death of a patient caused directly by cancer Overall survival (OS) was defined as the date of operation to date of death of any cause or the last day of follow up

The survival rates were estimated by using the Kaplan-Meier method Log-rank test was used to compare DFS and OS between groups Univariate and multivariate Cox re-gression models were used to determine the relationship between breast cancer deaths and the prognostic and treatment factors After the modeling process, the proportionality as-sumption was checked using Schoenfeld re-sidual plots and no violation was found All tests were two-sided and a p ≤ 0.05 value was used as the significance level

4 Research ethics

This work was approved by the ethical

committee of the Hanoi Medical University, No

38/HMUIRB, 95/HMUIRB-extension (Vietnam)

III RESULTS

Characteristics of the patients treated in

2002 - 2003

The median age of study participants was

46 years (range 26 - 72 years) From Table 1,

it can be seen that 159 patients (64.1%) were

premenopausal, 85 (34.3%) postmenopausal

and 4 (1.6%) had unknown menopausal status

at diagnosis Of all patients, 10.5%, 70.6%

and 18.9% were in clinical stages I, II and IIIa/

b, respectively 227 patients (91.5%) had

invasive ductal carcinoma, while 21 patients

(8.5%) had other subtypes The tumors were

classified according to SBR criteria as grades

I, II and III in 9.2%, 71.3% and 10.8% of

women, respectively At the time of surgery,

109 patients (44%) had metastatic axillary

node(s) and 76 of them (70%) were given

chemotherapy Hormone receptor-positive

tumors (ER + and/or PgR+) were found in 164

patients and 112 (68%) of these were given

tamoxifen 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%)

living patients, 13 had evidence of recurrence/ metastasis One patient dropped out after con-firmed metastasis In addition, during follow

up, one patient developed leukaemia, another had Vaquez disease (Primary polycythemia) but both are still alive as of (insert date that this report was written) The DFS, OS and CSS rates were 75.8%, 80.6% and 86.4% at 5 years, respectively; and 62.3%, 68.1%, 78.9%

at 9 years, respectively These trends of survival are shown in Fig 1

A comparison of prognostic factors between pre- and postmenopausal women can be seen in Table 1 Postmenopausal women more often had poor prognostic factors such as hormone receptor-negative disease and HER2 amplification In the univariate model, premenopausal women seemed to have a better survival (HR = 0.61, 95%CI: 0.38 - 0.95, p = 0.03), however, this relation was diminished when analysis was carried out using the multivariate model (HR = 0.67, 95% CI: 0.41 -1.08, p = 0.10) The improved survival rate for premenopausal patients is also seen in Fig 2 We also confirmed, not surprisingly, that participants with PgR-negative tumors also had lower survival than women with PgR-positive tumors (HR = 1.77, 95%CI: 1.01 - 3.11, p = 0.045) (Table 1) ER-positive, PgR-ER-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

Histological subtype

Tumor grade (SBR)

I,II

135 (86)

III Unknown

17 (11)

5 (3)

13 (15)

*ductal and ductal carcinoma component

** compared for hormone positive patients

Table 1 Comparison of clinicopathological parameters according to menopause status

Figure 1 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 2 Overall survival of operable breast cancers by menopause status

Figure 3a Comparison of overall survival by ER and menopausal status

Post 5 years 9 years Pre 5 years 9 years

Figure 3b Comparison of overall survival by PgR and menopausal status

Figure 3c Comparison of overall survival by HER2 and menopausal status

IV DISCUSSION

It is estimated that more than 16.000

women in Vietnam are diagnosed with breast

cancer every year Vietnamese patients are

younger than Western patients at the time of

diagnosis and it seems that there are

differ-ences in tumor prognostic markers between

Vietnamese and Swedish women with breast

cancer [11; 12]

The 5-year OS in the current study was 80.6% for all patients which was similar to sur-vival rates reported in France [14], but was lower than survival of foreign-born Vietnamese women living in the country which was re-ported to be 86% [6] The 5-year survival rate

of Vietnamese women less than 50 years treated in the National Cancer Hospital in Hanoi is similar to that reported in the Eastern

region of England (85.6% vs 85.0%) and

slightly lower after 9 years of treatment [15]

This might partly be explained by the fact that

all patients in these studies were most likely

treated in advanced hospitals with reliable

guidelines and techniques However, the

5-year DFS in our study population was lower as

compared to Chinese women in Hong Kong

with similar stages, 75.8% vs 81.2% [16]

To our knowledge, this is the first study

with active, long-term follow-up of pre- and

postmenopausal women with breast cancers

from Vietnam We usually recommend that

breast cancer patients have their check-up

after treatment at the Cancer Hospital in

Ha-noi This was, however, difficult for patients

living at a distance from Hanoi Therefore, 10

patients (4%) were lost to follow-up during the

course of the study One further difficulty is

that some patients decided to go to their local

hospital or to seek traditional medicine

treat-ment In fact, it appears that some patients did

not seek medical attention, although they had

various symptoms We therefore believe that

our data overestimates the DFS rate, and to

some extent also overestimates CSS, while

the OS data are likely to be more robust

Viet-nam introduced national mortality statistics in

1992 which was based on commune-level

re-ports However, the assessment of cause of

death is in many patients is not always

thor-ough[5] In the present study, 48 of 76 patients

that died (63%) had evidence of metastasis by

investigation at hospitals and cancer was

de-termined as the primary cause of death

More advanced treatment and early

diag-nosis has improved breast cancer survival

over the recent years [2; 7] In our study,

vari-ables including menopausal status, clinical

stage, tumor grade and various biomarkers

were associated with survival The lowest sur-vival was seen in women with advanced stages, high-grade tumors, high cell prolifera-tion, or triple negative tumors Stage of dis-ease was the strongest prognosticator regard-less of other factors A report on breast cancer survival among Asian patients living in Malay-sia and Singapore indicated a 5-year survival level was lower than that found in our study [17] The survival rate was associated with both tumor characteristics and hospital setting [15] Although ER and HER2 status in our study was found to not be statistically related

to survival, it seems that patients with ER (-) and/or HER2 amplified tumors have poor sur-vival These findings are consistent with previ-ous reports based on random samples of either Asian or Western women [15, 18 - 21] It should, however, be pointed out that the sur-vival of patients suffering from breast cancer is not only dependent on clinicopathological fea-tures but also on hospital settings [15] A re-cent report from Sweden found that CSS at ten years was lower in low socioeconomic status women than in their high socioeco-nomic status counterparts (78% vs 82%, re-spectively) [22] We were not able to compare the socioeconomic status of our Vietnamese patients, but it can be assumed that such pa-rameters are highly likely to have influenced patient survival Therefore, further studies on Vietnamese patients should investigate the relationship between survival and socioeco-nomic factors, combined with the quality of breast cancer treatment available

As reported previously, we found different clinicopathological and tumor cell characteris-tics of breast cancers from Vietnamese and Swedish patients The difference was seen particularly with respect to patient age [11]

Dabakuyo et al stated that the survival rate

was lower in patients whose age was 60 years

or older and in postmenopausal women more

broadly [14] It has also been reported that the

cancer mortality rate has also increased with

rising age in Northern Vietnam [23] One

limi-tation in our study is that we were not able to

assess the exact cause of death in some

pa-tients; therefore, it is difficult to precisely

deter-mine breast cancer-specific survival

More-over, one important reason for the lack of the

precision is that for legal and cultural reasons,

autopsies are not performed in Vietnam The

modest sample size is also contributed to limit

in this study However, 48 (63%) of the dead

patients had been confirmed as having

metas-tatic disease and cancer death seems

plausi-ble among these patients We found that

post-menopausal women had a significantly lower

OS rate than premenopausal women But

postmenopausal women more often had

tu-mors with poor prognostic factors as

com-pared to premenopausal women in this study

When adjusted for disease stage, hormone

receptors and HER2 gene status, we found

that postmenopausal women still tended to

have a decreased survival rate although it was

not statistically significant

The National Cancer Hospital is the largest

cancer centre in Northern Vietnam with more

than 10,000 patients treated annually During

the past fifteen years, research on treatment

of breast cancer in cooperation with University

of Wisconsin showed that premenopausal

Vietnamese women benefited from

oophorec-tomy and tamoxifen regardless hormone

re-ceptor status [9] One limitation is that our

find-ings are based on breast cancer patients

treated in a single institution with access to

adequate therapies and thus do not reflect treatment in all hospitals in Vietnam Further studies are needed on similar groups of pa-tients in the other major cancer centres throughout Vietnam To improve survival rate,

it is additionally important for patients to be diagnosed at early stages as well

V CONCLUSION

Although many patients had tumors with unfavourable prognostic characteristics, their long-term survival prospects were favourable

In contrast to similar reports from western populations, postmenopausal women had shorter survival and poor prognostic factors as compared to premenopausal women Im-proved reports on disease recurrence and cause of death in combination with knowledge about socioeconomic status are needed to obtain a more precise picture of breast cancer survival Vietnamese patients

ACKNOWLEDGEMENTS

This work was supported by grants from Sida/SAREC, Stockholm, Sweden, for collabo-rative research between Hanoi Medical Uni-versity (Vietnam) and Karolinska Institute (Sweden) We would like to express our sin-cerest thanks to the nurses and doctors in the National Cancer Hospital for assistance in as-sessing the patient records, and Sinclair H Mantell for efficient suggestions and correcting

of the English text and Gaetano Marrone for guidance on statistical analysis

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