Premenopausal Breast Cancer: Comparative analysis of clinical, pathological features and survival with postmenopausal breast cancer from an Indian cohort

doi:10.21203/rs.3.rs-2239930/v1

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Research Article

Premenopausal Breast Cancer: Comparative analysis of clinical, pathological features and survival with postmenopausal breast cancer from an Indian cohort

https://doi.org/10.21203/rs.3.rs-2239930/v1

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Purpose

Breast cancer (BC) among premenopausal women is an aggressive disease associated with poor outcome despite intensive treatment. Higher burden is observed in southeast Asian countries attributed to younger population structure.

Methods

We compared the reproductive and clinicopathological characteristics, distribution of subtypes and survival between pre and postmenopausal women from a retrospective cohort of BC patients with median follow up over 6 years to examine the differences.

Results

In our cohort of 446 BC patients,162/446 (36.3%) were premenopausal. Parity and age at last childbirth were significantly different between pre and postmenopausal women. Premenopausal BC had higher proportion of HER2 amplified and triple negative breast cancer (TNBC) tumors (p = 0.012). Stratified analysis by molecular subtypes showed TNBC had significantly better disease free (DFS) and overall survival (OS) among premenopausal group (mean survival, pre vs post, DFS = 79.2 vs 54.0 months, OS = 72.5 vs 49.5 months, p = 0.002 for both). Analysis on external datasets (SCAN-B, METABRIC) confirmed this finding for overall survival.

Conclusion

Our data confirmed the previously observed association of clinical and pathological features between pre and postmenopausal BC. Exploration of better survival among premenopausal TNBC tumors is warranted in larger cohorts with long term follow up.

Premenopausal breast cancer. Risk factors

survival

Triple negative breast cancer

India

Breast cancer (BC) is the most common cancer worldwide. Though incidence is higher in developed countries, mortality due to BC is significantly higher in less developed countries [1]. As per the national cancer registry program (2020), the incidence of BC is rising and it is now the most diagnosed cancer in women within India [2]. Women with BC in India are a decade younger in comparison to western counterparts, thus affecting younger women in premenopausal age group [3, 4]. Previous studies have reported young women have higher mortality even if diagnosed early and receive an intense treatment compared to the women in the elderly age group [5–7]. BC in the young women tend to be more aggressive and are often diagnosed in the advanced stage of the disease and have unfavorable tumor characteristics like larger tumor size, lymph node positivity [5, 7].

Premenopausal breast cancer is a distinct disease as the hormonal milieu is different from the postmenopausal women. Association of common risk factors such as obesity and waist circumference also differ from postmenopausal BC where some studies even suggest inverse relationship [8]. Young women also tend to have a higher proportion of aggressive subtypes such as HER2 amplified and triple negative breast cancer (TNBC) indicating difference in distribution of molecular subtypes [9, 10]. Early detection of the BC is challenging in the premenopausal women due to high density of the breast tissue. Current therapeutic regimens are based on the menopausal status and molecular subtype of BC [11] that contributes to differential prognosis and disease outcome between the pre and postmenopausal patients. Investigation into the trends of BC by menopausal status is important in countries with larger proportion of younger premenopausal women from the public and patient health perspectives to inform prevention and early detection policies.

It has been an issue of debate if BC in Asia with occurrence at early age is a different disease and examination of the population structure showed it could be due to strong cohort effect [12]. While the patterns of BC by menopausal status have been examined in broad geographical regions, information from sub regions such as individual countries and subregions is lacking. We evaluated the association of various reproductive and clinicopathological characteristics between pre and postmenopausal BC from a hospital based Indian cohort and examined the factors correlated with prognosis within them.

Patient Cohort

This is an observational retrospective hospital-based study conducted at St. John’s research Institute, Bangalore. In this study 446 BC patients were recruited from two tertiary cancer care hospitals in Bangalore, India between the year 2008 and 2013. Patients included in this study were women diagnosed with primary BC tumors which were confirmed histologically. These patients were followed-up to 9 years, with a total loss to follow-up of less than 4% and a median follow-up duration of 6 years. The study was approved by individual institutional ethical review board. Informed consent was obtained from all the patients. All the clinical and histopathological information was obtained from the patient’s clinical records. Age at menarche, age at first childbirth (FCB) and last childbirth (LCB) was collected from medical records of the patients or was documented based on patient’s memory recall. Information regarding treatment and progression of the disease or disease related events was obtained during follow-up.

Tumor cells showing ≥ 1% immunopositivity was considered as positive for estrogen receptor (ER) and progesterone receptors (PR) expression. Human epithelial growth factor receptor 2 (HER2) expression data was also obtained from the hospital records that was assessed by IHC and FISH for equivocal cases. Cases with 3 + IHC staining, or FISH amplified were categorized as HER2 positive. Based on expression of ER, PR and HER2 tumors were classified into three subtypes: hormone receptor positive (HR+), HER2 amplified and TNBC. Women were categorized into pre and postmenopausal groups based on age 50 as cut-off [13].

To validate our findings two publicly available external databases, The Sweden Cancerome Analysis Network-Breast (SCAN-B) and The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. SCAN-B is the large population-based cohort of primary breast tumors. Our analysis included a cohort of 3207 primary BC patients from the SCAN-B study (GSE202203; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE202203) [14] and data was downloaded from Gene expression Omnibus database (GEO) [15]. TNBC patient’s data (n = 320) (as per the clinical groups mentioned in the dataset) was used for analysis. METABRIC data (EGAS00000000098; https://cbioportal-datahub.s3.amazonaws.com/brca_metabric.tar.gz) was downloaded from cBioPortal [16–18]. TNBC patient’s data (n = 307) (as per the 3 gene classifier subtype mentioned in the dataset) from this database was considered for analysis.

Statistical analysis was performed using SPSS statistical software Version 25.0 (SPSS, Chicago, IL, USA). Descriptive statistics was used to examine the distribution of the study variables. Association of various reproductive and clinicopathological factors with pre and postmenopausal groups were assessed using Chi square test. Disease free survival (DFS) was calculated as duration from date of surgery till the first evidence of metastasis/recurrence. Overall survival (OS) was calculated as the duration from surgery to the death of the patient. Survival probability was calculated by Kaplan Meier survival analysis and was compared between groups using log rank test, in an entire cohort and stratified by menopausal status, the risk factor associated towards the progression of disease was calculated using univariate and multivariable Cox proportional hazard model. Results are represented as hazard ratio (HR) with 95% confidence interval (CI). In addition, stratified analysis was also carried out by subtype of tumour category to compare the disease-free survival and overall survival between pre and postmenopausal status. P value < 0.05 was considered as statistically significant.

Median age of the cohort was 55 years, ranging between 24–88 years. There were 162 premenopausal (36.3%) and 284 postmenopausal (63.7%) BC patients. Large proportion of the patients were from urban background (80–85%), 12% were illiterate and 76% belonged to home maker category. Around 13% patients had family history of BC and 15% patients had family history of any other cancer in the first-degree relatives. There was an overlap of 3% cases having family history of BC and any other cancer in the first-degree relatives.

Duration of the lump felt was ranging from a week to few years. In majority of the cases duration of the lump felt was between > 1 month to 12 months (55%). There were three cases that were detected at screening. Of the total patients 52% had tumor in the right breast, 45.5% had in the left breast and 2.5% had bilateral BC. Most common mode of detection was mammography (54%) followed by fine needle aspiration cytology (FNAC) (27%), ultrasound, biopsy/surgery, computed tomography (CT) scan and positron emission tomography (PET) CT. All patients received age and stage appropriate standard of care treatment. Majority of the patients (> 90%) received anthracycline or taxane based chemotherapy and all HR + patients received antihormonal therapy with tamoxifen or aromatase inhibitor. Most common site of metastasis was bone, liver, lung, followed by skeletal muscle, brain and others.

Association of reproductive features between pre and postmenopausal breast cancer

The association of reproductive features like, age at menarche, age at FCB and LCB and parity with the risk of the BC development/ progression were assessed between pre and postmenopausal BC groups. Based on median cut-off of age at menarche, FCB and LCB and parity, BC patients were divided into two categories. Results are represented in Table1.

Table 1

Association of reproductive features between pre and postmenopausal breast cancer
Variable	Subcategory (N = 446)	Premenopausal Group (N = 162) n (%)	Postmenopausal group (N = 284) n (%)	P value
Age at Menarche (years)	< 14 (n = 193)	66 (45.2)	127 (48.7)	0.503
Age at Menarche (years)	≥ 14 (n = 214)	80 (54.8)	134 (51.3)	0.503
Age at FCB (years)	< 23 (n = 169)	55 (42.6)	114 (48.1)	0.316
Age at FCB (years)	≥ 23 (n = 197)	74 (57.4)	123 (51.9)
Age at LCB (years)	< 30 (n = 138)	53 (56.4)	85(42.7)	0.029
Age at LCB (years)	≥ 30 (n = 155)	41 (43.6)	114 (57.3)
Parity	< 2 (n = 54)	29 (21.1)	25 (10)	0.003
Parity	≥ 2 (n = 330)	108 (78.9)	222 (90)
p < 0.05 - Statistically significant (represented in bold). FCB-First childbirth, LCB-Last childbirth

We observed significantly higher proportion of postmenopausal BC women with older age at LCB (≥ 30 years) which was further supported by increased parity in this group. Age at menarche and FCB did not differ with menopausal status. We also did not find any association of family history of BC or any other cancer with pre and postmenopausal groups.

Further, the association of these reproductive features towards the risk of progression of BC was assessed independently in the entire cohort, in pre and postmenopausal BC. None of these factors were associated with the risk of disease progression (data not shown).

Association of clinicopathological features between pre and postmenopausal breast cancer

Distribution of tumor characteristics such as tumor size, lymph node (LN) status, grade, tumor infiltrating lymphocytes (TILs), did not differ between pre and postmenopausal groups. Premenopausal group had significantly higher proportion of ER negative (p = 0.038), HER2 amplified and TNBC tumors (p = 0.012) compared to postmenopausal group. Association of various clinical characteristics of the tumor between pre and postmenopausal groups is represented in Table 2.

Table 2

Association of clinicopathological features between pre and postmenopausal breast cancer
Variable	Subcategory (N = 446)	Premenopausal (N = 162) n (%)	Postmenopausal (N = 284) n (%)	P value
T size (cm)	≤ 3 (n = 235)	77 (53)	158 (60)	0.163
T size (cm)	> 3 (n = 175)	69 (47)	106 (40)	0.163
LN status	Positive (n = 274)	105 (65)	169 (60)	0.268
LN status	Negative (n = 172)	57 (35)	115 (40)	0.268
Grade	I (n = 30)	9 (7)	21 (8)	0.525
	II (n = 186)	61(45)	125 (49)
	III (n = 175)	66 (48)	109 (43)
TILs	Present (n = 204)	81 (57)	123 (50)	0.136
TILs	Absent (n = 185)	60 (43)	125 (50)	0.136
ER	Positive (n = 284)	93 (57)	191 (67)	0.038
ER	Negative (162)	69 (43)	93 (33)	0.038
PGR	Positive (n = 265)	93 (57)	172 (61)	0.514
PGR	Negative (n = 181)	69 (43)	112 (39)	0.514
HER2	Positive (n = 86)	37 (23)	49 (17)	0.353
	Negative (n = 307)	107 (66)	200 (70)
	Equivocal (n = 53)	18 (11)	35 (13)
Subtype	HR+ (n = 253)	77 (47)	176 (62)	0.012
	HER2 (n = 86)	37 (23)	49 (17)
	TNBC (n = 107)	48 (30)	59 (21)
p < 0.05, statistically significant (represented in bold). LN status- lymph node status, TILs- tumour infiltrating lymphocytes, ER- estrogen receptor, PGR-progesterone receptor, HER2- human epithelial growth factor receptor, HR+- hormone receptor positive, TNBC- triple negative breast cancer

Association of clinicopathological features with disease progression within pre and postmenopausal tumors

The risk associated with each tumor characteristics towards the progression of the disease was evaluated by univariate Cox proportional hazard model in the entire cohort. Grade II and III tumors were categorised into high grade with grade I as the reference (low grade) for examination of association with survival. High grade (HR = 4.3 95% (1.06–17.5), larger tumor size (> 3cm) (HR = 2.2, 95% CI = 1.45–3.2), LN positivity (HR = 2.9, 95% CI = 1.9–4.5), HER2 amplification (HR = 2.07 95% CI = 1.33–3.3) and TNBC subtype (HR = 1.62, 95% CI = 1.03–2.56) were significantly associated with increased hazard (p < 0.05), whereas presence of the TILs infiltration (HR = 0.62, 95% CI = 0.00-0.93), had significantly decreased hazard for the disease progression (p = 0.02). Pre and postmenopausal groups did not show any association with risk of the disease progression in our cohort. We further confirmed the association of these pivotal factors with progression of the disease by multivariate analysis. Tumor size, LN positivity, HER2 amplification and TNBC subtype were associated with significantly increased hazard whereas presence of TILs was associated with lower risk of disease progression as mentioned in Table 3.

Next, we evaluated the association of these factors independently in the pre and postmenopausal groups. Among the postmenopausal tumors, association of tumor size, LN positivity, HER2 amplification and TNBC subtype showed the similar trends of association as in the entire cohort. Presence of TILs was associated with decreased hazard and LN positivity was associated with increased hazard of disease progression in premenopausal BC.

Table 3

Multivariate analysis of clinicopathological tumor characteristics in entire cohort, pre and postmenopausal groups for disease free survival
			Entire Cohort (N = 314)		Premenopausal groups (N = 106)		Postmenopausal groups (N = 208)
	Reference	Variable	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
T size (cm)	> 3	≤ 3	1.7 (1.08–2.67)	0.020	1.06 (0.5–2.22)	0.89	2.2 (1.23–3.83)	0.008
LN status	Negative	Positive	3.2 (1.75–5.57)	0.0001	2.82 (1.1–7.5)	0.03	3.45 (1.67–7.3)	0.001
TILs	Absent	Present	0.55 (0.00-0.88)	0.011	0.42 (0.00–0.88)	0.02	0.7 (0.4–1.23)	0.218
Subtype	HR+	HER2 amplified	1.75 (1.05–2.96)	0.033	1.44 (0.64–3.25)	0.38	1.89 (0.97–3.7)	0.06
	HR+	TNBC	1.64 (0.93–2.89)	0.088	0.59 (0.2–1.7)	0.32	2.92 (1.47 − 5.78)	0.002
p < 0.05-statistically significant (represented in bold), HR- hazard ratio, CI- confidence interval, LN status- lymph node status, TILs- tumour infiltrating lymphocytes, HR+- Hormone Receptor positive, HER2- human epithelial growth factor receptor, TNBC- triple negative breast cancer

Though TNBC subtype was associated with higher hazard in the entire cohort and within postmenopausal subgroup, TNBC tumors within premenopausal group did not show any association with the hazard in multivariate analysis (Table 3). To verify these findings further, we evaluated the hazard associated with menopausal status within TNBC tumors alone. Both univariate (HR = 0.28 (0.0-0.67), p = 0.004) and multivariate analysis (HR = 0.20 (0-0-0.56), p = 0.002) showed within TNBC subtype, premenopausal BC patients had lower hazard of disease progression.

Kaplan Meier survival analysis confirmed the results of multivariate analysis and showed no difference in the DFS between women with pre and postmenopausal BC (mean survival time 77.1 vs 77.9 months) (p = 0.77). We next examined the influence of subtypes on DFS independently within pre and postmenopausal BC. In postmenopausal BC, patients with TNBC and HER2 amplified tumors were associated with poor outcome as expected and there was no difference in the survival between patients with HER2 amplified and TNBC tumors (mean survival, HR + vs TNBC, 83.8 vs 54 months, p < 0.0001, HR + vs HER2 amplified tumor 83.8 vs 63.3, p = 0.014, HER2 amplified vs TNBC 63.3 vs 54 months, p = 0.328).

However, comparison of DFS among different subtypes within premenopausal patients showed, no difference in the survival between HR + and TNBC breast cancer patients and both subtypes were associated with better outcome compared to patients with HER2 amplified tumors (Fig. 1A, mean survival between TNBC and HER2 amplified BC 79.2 vs 61 months, p = 0.006. Mean survival HR + vs HER2 amplified BC, 74.4 vs 61 months, p-0.058. Mean survival TNBC vs HR + tumors 79.2 vs 74.4 months, p = 0.228).

Next, we examined the DFS and OS independently in each of the molecular subtypes that is HR+, HER2 amplified and TNBC between pre and postmenopausal tumors. There was no difference in the survival between the two groups in the HR + tumors (mean survival pre vs post 74.4 vs 83.8 months, p = 0.374) and in HER2 amplified tumors (mean survival pre vs post 61 vs 63.3 months, p = 0.690). No difference was observed in OS either.

Interestingly in the TNBC subtype, premenopausal patients were associated with better outcome compared to postmenopausal BC patients (Fig. 1B, mean survival pre vs post 79.2 vs 54 months, p = 0.002) which was contrary to the notion that TNBC tumors are always associated with aggressive behaviour. Similar trends were noted with overall survival (mean survival pre vs post, 72.5 vs 49.5 months, p = 0.002). To rule out if these results could be due to the bias within our cohort, we validated our findings in two publicly available larger databases, SCAN-B and METABRIC with different population. OS analysis in these cohorts confirmed our findings on association of premenopausal BC patients with better prognosis within TNBC subtype (Fig. 1C and D, In SCAN-B database, mean survival pre vs post 94.2 vs 84.4 months, p = 0.008 and in METABRIC database, mean survival pre vs post 186.8 vs 157.2 months p = 0.033). We also performed the COX proportional hazard ratio model in these two cohorts to verify similar trends with pre and postmenopausal groups within TNBC subtype tumors. In both SCAN-B and METABRIC databases, TNBC tumors with premenopausal BC were associated with decreased hazard on univariate analysis [SCAN-B, HR = 0.42, 95% CI = 0.00-0.82), p = 0.010, METABRIC, HR = 0.68, 95% CI 0.00-0.98), p = 0.034] and multivariate analysis (SCAN-B HR = 0.45, 95% CI = 0.00-0.85), p = 0.014, METABRIC HR = 0.56 (0.00-0.82), p = 0.003) compared to postmenopausal tumors.

Epidemiological studies have often distinguished between pre and postmenopausal BC mainly based on difference in risk factors like age and reproductive factors. Risk factors such as abdominal obesity, parity and age at childbirth are shown to be different between pre and postmenopausal BC [19–21]. Average age of women with BC in developing countries is about 10 years lower than developed countries, leading to higher burden of younger patients. As early onset of disease could reflect more fundamental etiologic differences, we investigated the different reproductive and clinical features and compared them between pre and postmenopausal BC.

Previous studies have evaluated the association and prognostic significance of reproductive features such as age at menarche, FCB, LCB and parity with breast cancer outcomes [22, 23]. In our study cohort, women in postmenopausal age group had significantly higher age at LCB and higher parity. Early age at menarche, older age at menopause, older age at FCB and LCB are known to increase women’s risk of developing BC [24]. Zhang et al. evaluated the association of multiple reproductive factors with BC prognosis with respect to menopausal status and reported association of increased hazard with older age at FCB and LCB in premenopausal BC patients [10]. Significant inconsistencies are however found in association of the reproductive factors with prognosis in both pre and postmenopausal BC. A prospective cross-sectional study conducted in the Indian BC patient’s cohort reported that premenopausal BC patients had younger age at menarche, older age at FCB, lesser parity and lesser BMI and denser breast tissue compared to postmenopausal BC patients [25]. A study by Butt et al. reported that most of risk factors for premenopausal and postmenopausal BC are same except less parity, which increased the risk for postmenopausal BC [21].

In tune with the previous reports, our cohort of premenopausal BC had higher proportion of ER negative tumors, HER2 amplified and TNBC tumors compared to postmenopausal tumors which were predominantly hormone receptor positive (9,28,2). There was no difference in the relative distribution of other clinicopathological features between pre and postmenopausal groups. Among the molecular subtypes, previous studies such as the Carolina breast cancer study has reported premenopausal BC patients have higher prevalence of Basal-like breast tumors compared with postmenopausal patients [26]. The well-established clinical factors such as LN involvement, HER2 amplified status showed increased hazard of poor prognosis as expected. Better survival observed in the premenopausal TNBC tumors is unique finding of our study. Multiple studies have reported higher proportion of aggressive subtype TNBC within Asian countries [27, 28]. A very recent study by Nishimura et al. evaluated the clinical significance of menopausal status in TNBC. This study reported that higher proportion of TNBC tumors in postmenopausal patients and their association with favourable tumor characteristics and better DFS compared to premenopausal patients [29] which is contrary to our observations. Disparities in TNBC outcomes have been reported based on race and ethnicity in multiple studies earlier [30–32]. Younger median age of our cohort and ethnicity-based differences between Indian and Japanese women might have contributed to the observed difference. Recent study by Yunzi et al. [33] investigated tumor characteristics and mortality in south east Asian (SEA) women by regional distribution specific to countries in south east Asia and found the cancer specific survival was best for Japanese women among all SEA ethnic populations and suggests disaggregation by country or region of origin to identify subgroups that are at risk for worse outcomes.

Our study has limitations due to the retrospective cohort with non-availability of information on weight, BMI and obesity amongst the all the women enrolled for the study. Previous studies have correlated the importance of waist circumference and central obesity as both risk factor for BC occurrence and prognosis [34]. Excess weight gain with onset of menopause among women with BC is also associated with other morbidities. We were unable to derive association of prognosis with density of the breast tissue due to lack of radiological information on which is considered significant risk factor especially among young premenopausal women [35]. Lack of therapeutic interventions for ovarian suppression among the premenopausal women could have influenced the prognosis in this subgroup though majority of the women were treated with standard of care prevalent at the time of diagnosis. Findings from recent trails such as TEXT and SOFT [36] showing improvements with use aromatase inhibitors along with ovarian suppression over the traditionally used tamoxifen is likely to influence the prognosis among young patients with BC in future.

In conclusion, findings of our study confirm the higher proportion of aggressive subtypes such as ER negative, HER2 amplified and TNBC within premenopausal BC despite no difference in the associated risk factors between pre and postmenopausal women suggesting the effect of hormonal milieu on the biology of tumor development. We also noticed differential prognosis in TNBC based on menopausal status in our cohort, which needs verification based on ethnicity and age distribution across other cohorts. Categorising tumor subtypes especially, TNBC tumors based on the menopausal status will help in developing better treatment strategies and in predicting outcome.

Funding and acknowledgements

This work was supported by DBT/Wellcome Trust India Alliance Fellowship/Grant [IA/CPHI/18/1/503938] awarded to JSP. Patient recruitment and follow-up activities was supported by philanthropic funding received from Nadathur Estates Private Ltd., Bangalore, India and from Bagaria Education Trust, Bangalore, India. The authors declare that this study received funding from Nadathur Estates Private Ltd., Bangalore, India and Bagaria Education Trust, Bangalore, India for patient recruitment and follow-up activities. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Authors would like to acknowledge Ms Sumitra S for guidance in statistical analysis and Dr TS Sridhar for mentoring JSP and building the cohort with longitudinal follow up.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Authors contribution

VPN, SR and SVP collected the data and performed all the statistical analysis. RR and BSS provided all the patient information from their clinics. RK and AA collected data from medical records and patient interaction along with follow up and monitoring of the data. The first draft of the manuscript was written by VPN and JSP and all authors commented on previous versions of the manuscript. JSP was responsible for concept design, statistical analysis and interpretation. All authors read and approved the final manuscript.

Data Availability Statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics Statement

The studies involving human participants were reviewed and approved by the Institutional Ethical Committee, St John’s Medical College and Hospital, Bangalore. The patients/participants provided their written informed consent to participate in this study.

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of St John’s Medical College and Hospital, Bangalore (Date 31^st July 2019/No. IEC/1/655/2019).

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Premenopausal Breast Cancer: Comparative analysis of clinical, pathological features and survival with postmenopausal breast cancer from an Indian cohort

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Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Materials And Methodology

Patient Cohort

Results

Association of reproductive features between pre and postmenopausal breast cancer

Association of clinicopathological features between pre and postmenopausal breast cancer

Association of clinicopathological features with disease progression within pre and postmenopausal tumors

Discussion

Declarations

References

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