Prognosis and Expanded Definition of Pregnancy-associated Breast Cancer: A Dose-Response Meta-Analysis

doi:10.21203/rs.2.17528/v1

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Research article

Prognosis and Expanded Definition of Pregnancy-associated Breast Cancer: A Dose-Response Meta-Analysis

https://doi.org/10.21203/rs.2.17528/v1

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published 10 Aug, 2020

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Background Pregnancy-associated breast cancer (PABC) is defined as breast cancer that is diagnosed during pregnancy and/or postpartum period. Deﬁnitions of the duration in the postpartum have controversial and this variability may led to diverse results on the prognosis. Moreover, evidence on the dose-response association between the time from last pregnancy to breast cancer diagnosis and overall mortality has not been synthesized.

Methods We systematically searched PubMed, Embase, and the Cochrane Database for observational studies about the prognosis of PABC published up to June 1, 2019. We estimated summary adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). Subgroup analyses based on diagnosed time, PABC definition, geographic region, year of publication and the way of HR estimate were performed. Additionally, the dose–response analysis was conducted by using the variance weighted least-squares regression (vwls) trend estimation.

Results A total of 54 articles (76 studies) were included in our study. PABC is associated with poor prognosis on overall survival (OS), disease-free survival (DFS) and cause-special survival (CSS), and the pooled HRs with 95% CIs were 1.45 (1.30-1.63), 1.39 (1.25-1.54) and 1.40 (1.17-1.68), respectively. According to subgroup analyses, the varied definition of PABC led to diverse results. The dose-response analysis indicated a non-linear association between the time from last pregnancy to breast cancer diagnosis and overall mortality ( P <0.001). Compared with nulliparous women, PABC had a HR for all cause death that peaked at 1.62 (95% CI, 1.46-1.80) at 28 months since last pregnancy, starting from 78 months since last pregnancy became insignificant 1.07(95%CI, 0.99-1.26). It suggested that the definition of PABC should be extended to include cases diagnosed up to about six-years postpartum (78 months since last pregnancy) in order to capture this ongoing increased risk.

Conclusion This meta-analysis suggests that PABC is associated with poor prognosis, and the definition of PABC should be extended to include cases diagnosed up to about six-years postpartum.

Oncology

Pregnancy-associated Breast Cancer

Prognosis

Survival

Dose-response

Meta-analysis

Breast cancer is the second most common cancer worldwide and the most commonly occurring malignancy in women [1]. Because of a trend of delayed childbearing, the number of women with breast cancer during a pregnancy or in the subsequent few years after a pregnancy is expected to increase [2].Breast cancer occurring during pregnancy presents a challenging clinical situation since the welfare of both the mother and the fetus must be taken into account in any treatment planning. Conventionally, pregnancy-associated breast cancer (PABC) is defined as breast cancer that is diagnosed during pregnancy or in the postpartum period. Deﬁnitions of how many years after delivery a breast cancer can be diagnosed under this deﬁnition have ranged from 0.5 to 5 years, and sometimes even longer [3, 4]. PABC is viewed as a clinically and biologically special type of breast cancer and only comprises 0.2–0.4% of all breast cancers [5, 6]. However, it is the most common cancer in pregnancy, and is diagnosed in approximately 15 to 35 per 100,000 deliveries, with fewer breast cancer cases diagnosed during pregnancy than during the postpartum period [7–10].

The literatures prove pregnancy itself may transiently increase the risk of developing breast cancer, despite its long-term protective effect on the development of breast cancer [11, 12]. But whether PABC has a worse prognosis is currently controversial. A meta-analysis published on 2016 has shown that risk of death increased in women with PABC compared with non-PABC (pooled hazard ratio (HR), 1.57; 95% confidence interval (CI), 1.35–1.82) [13]. However, other recent studies found there was no significant difference in prognosis of PABC and non-PABC [14–17]. Meanwhile, the specific definition of PABC has varied throughout the literatures and this variability may led to diverse results on the relationship among pregnancy, postpartum and breast cancer. So it is necessary to specify the definition of PABC through summarizing epidemiological evidence. Moreover, evidence on the dose-response association between the time from last pregnancy to breast cancer diagnosis and prognosis has not been synthesized. This study was initiated to understand prognosis of PABC and examine the dose-response relationship to provide quantitative evidence on defining PABC.

2.1 Search Strategy

This meta-analysis were performed in accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. We did our best to include studies published until date, regarding prognosis of PABC. Eligible studies were found by searching PubMed, Embase, and Cochrane library for relevant reports published before June 1, 2019. The keywords used for the search were (“pregnan*” OR “gestation*” OR “childbirth” OR “postpartum” OR “parity”) AND “breast” AND (“cancer” OR “neoplasia” OR “carcinoma”). The reference lists of all retrieved articles and previous systematic reviews were manually searched for additional relevant studies.

2.2 Inclusion and Exclusion Criteria

All eligible studies should meet the following criteria: (1) observational prognosis studies with follow-up period longer than 6 months; (2) participants were diagnosed with breast cancer on clinical diagnosis and/or histologically; (3) case group were diagnosed as PABC, control group were non-PABC or nulliparity; (4) the outcomes were in terms of overall survival (OS), disease-free survival (DFS) and cause special survival (CSS); (5) the risk point estimate was reported as an HR with 95% CI, or the data were presented such that an HR with 95% CI could be calculated. The exclusion criteria were as follows: (1) duplicated or irrelevant articles; (2) reviews, letters, case reports; (3) non-human studies; (4) study with inappropriate data for meta-analysis.

2.3 Data Extraction

Two reviews extracted data independently using a predefined data extraction form. Disagreements were resolved by discussion. Data extracted included the first author, publication year, country, PABC definition, control definition, sample size, cancer type, stage or grade, age, matching criteria, adjusted variables, adjusted HRs with 95% CIs.

2.4 Assessment of Study Quality

The methodological quality of studies was assessed by the Newcastle-Ottawa scale (NOS) for observational studies [18]. A score of 0–9 was allocated to each study, with higher scores indicating higher quality.

2.5 Meta and Statistical Analysis

We used adjusted HRs and 95%CIs which are most appropriate for time-to-data events. If HRs were not reported directly, we could estimate HRs from crude data or Kaplan-Meier curve[19]. Fixed or random effect model was used to summarize the study-specific estimates. I² was used to assess heterogeneity across studies. Visual inspection of the funnel plot, Egger’s and Begg’s tests were performed to assess publication bias. Subgroup analyses were performed according to diagnosed time, PABC definition, geographic region, year of publication and the way of HR estimate.

The dose–response association between the time from last pregnancy to breast cancer diagnosis and overall mortality was assessed using the variance weighted least-squares regression (VWLS) model [20]. Restricted cubic splines were used to examine the time from last pregnancy to breast cancer diagnosis as a continuous, nonlinear exposure, defining time with knots at the 5th, 35th, 65th, and 95th percentiles for the distribution [21]. The time from last pregnancy to breast cancer diagnosis reported in each study were converted to month. We used the average value of the lower and upper limits of each category. If the lowest category was open ended, the average value of the upper limit and 0 was used. If the highest category was open, the average value was defined as 1.5 times of the lower limit. All the statistical analyses were performed using STATA Version 13.0. P<0.05 was considered significant.

3.1. Search Results and Study Characteristics

We initially identified 12414 articles and screened their titles and abstracts, Figure 1. After duplicated and irrelevant articles were excluded, 54 articles with 76 studies met the inclusion criteria and were thus included in our meta-analysis. Quality of studies was assessed based on the 9-stars Newcastle-Ottawa Scale, ranged from 6 to 9 (mean of 7.2). The characteristics of the studies were summarized in Table 1.

Table 1 Characteristics of studies included in meta-analysis

Study ID	Country	No. of PABC	No. of Control	PABC definition	Cancer Stage or Grade	Mean/Median Age of PABC	Follow-up years	Outcomes measured	HR estimate	HR	95% CI	NOS score	Matching criteria	Adjusting variable
Mausner,1969 [22]	USA	73	647	Pregnancy&<6 months postpartum	Stage Ⅰ Ⅱ Ⅲ, Grade Ⅰ Ⅱ Ⅲ	35	5	OS	indirect	1.36	1.07,1.73	7	-	-
Wallgren,1977[23]	Sweden	15	58	Pregnancy&<12 months postpartum	Grade Ⅰ Ⅱ Ⅲ	＜30	10	OS	indirect	1.35	0.71,2.58	7	-	-
Nugent,1985[24]	USA	19	155	Pregnancy	Stage Ⅰ Ⅱ Ⅲ	32	5	OS	indirect	0.96	0.55,1.67	6	-	-
Tretli,1988-Pregnancy[25]	Norway	20	40	Pregnancy	Stage Ⅰ Ⅱ Ⅲ	33	4	OS	indirect	2.41	1.32,4.37	6	Diagnosed year, diagnosed age	-
Tretli,1988-Postpartum[25]	Norway	15	40	Unspecified	Stage Ⅰ Ⅱ Ⅲ	36	4	OS	indirect	1.47	0.66,3.27	6	Diagnosed year, diagnosed age	-
Greene,1988[26]	USA	8	36	Pregnancy	NA	＜35	14	OS	indirect	1.50	0.18,12.62	6	-	-
Petrek,1991[27]	USA	56	166	Pregnancy&<12 months postpartum	NA	-	5	OS	paper	0.74	0.37,1.45	6	-	Node Status
Zemlickis,1992[28]	Canada	102	269	Pregnancy& postpartum(unspecified)	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ	33	25	CSS	indirect	1.25	0.93,1.69	8	Stage, ages diagnosis	-
Ishida,1992 [29]	Japan	192	191	Pregnancy&<24 months postpartum	Stage 0 Tis Ⅰ Ⅱ Ⅲ Ⅳ	32	10	OS	indirect	2.00	1.27,3.16	6	-
Guinee,1994-Pregnancy[30]	USA	26	139	Pregnancy	NA	28(20-29)	10	OS	paper	2.83	1.24,6.45	8	-	Tumor size and number of positive axillary nodes
Guinee,1994-Postpartum [30]	USA	40	139	<12 months postpartum	NA	28(20-29)	10	OS	paper	1.88	0.88,3.98	8	-	Tumor size and number of positive axillary nodes
Von Schoultz,1995 [31]	Sweden	173	1740	Pregnancy&<60 months postpartum	NA	＜50	7	DFS	paper	1.02	0.72,1.43	9	-	Age, nodal status, tumor size, and ER status
Ezzat,1996-OS[32]	Saudi Arabia	28	84	Pregnancy	Stage Ⅰ Ⅱ Ⅲ	20-45	7	OS	paper	0.90	0.6,1.3	6	Year of diagnosis, date of beginning	-
Ezzat,1996-DFS[32]	Saudi Arabia	28	84	Pregnancy	Stage Ⅰ Ⅱ Ⅲ	20-45	7	DFS	paper	1.10	0.8,1.5	6	Year of diagnosis, date of beginning	-
Anderson,1996-OS[33]	USA	22	205	Pregnancy&<12 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲa	＜30	10	OS	paper	2.40	1.28,4.50	8	-	Stage ,axillary LN involvement, adjuvant CT, tumor size
Anderson,1996-DFS[33]	USA	22	205	Pregnancy&<12 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲa	＜30	10	DFS	indirect	3.19	1.20,8.49	8	-	Stage ,axillary LN involvement, adjuvant CT, tumor size
Bonnier,1997-OS[34]	France	154	308	Pregnancy&<6 months postpartum	Grade Ⅰ Ⅱ Ⅲ	33.9(23.2-46.4)	5	OS	paper	1.46	0.72,2.96	6	-	Clinical tumor size, microscopic lymph-node involvement, inﬂammatory cancer, age
Bonnier,1997-DFS[34]	France	154	308	Pregnancy&<6 months postpartum	Grade Ⅰ Ⅱ Ⅲ	33.9(23.2-46.4)	5	DFS	paper	1.48	1.00,2.19	6	-
Olson,1998[35]	USA	146	-	-	NA	＜45	15	OS	paper	-	-	7	-	Age, tumor size, lymph nodes, ER status, histology
Reeves,2000[36]	UK	-	-	-	Stage Ⅰ Ⅱ Ⅲ Ⅳ	＜60	＞10	OS	paper	-	-	9	-	Age at diagnosis , year of diagnosis , hospital, and weight in kg
Ibrahim,2000[37]	Saudi Arabia	72	216	Pregnancy	Stage Ⅰ Ⅱ Ⅲ Ⅳ, Grade Ⅰ Ⅱ Ⅲ	34	10	OS	indirect	0.94	0.62,1.44	6	Age, stage, and year of diagnosis	-
Daling,2002[38]	USA	83	309	<24 months postpartum	Stage Ⅰ Ⅱ Ⅲ Ⅳ	＜45	5	OS	indirect	2.30	1.4,3.9	9	-	Age and diagnosis year.
Aziz,2003[39]	Pakistan	24	48	Pregnancy&<12 months postpartum	NA	32(20-45)	7	OS	indirect	1.67	0.82,3.41	6	Age, tumor grade, tumor size and axillary lymph node status	-
Siegelmann-Danieli,2003-OS[40]	Israel	22	192	Pregnancy&<12 months postpartum	NA	33(25-27)	5	OS	indirect	3.39	0.58,19.81	6	-	-
Siegelmann-Danieli,2003-DFS[40]	Israel	20	181	Pregnancy&<12 months postpartum	NA	33(25-28)	5	DFS	indirect	4.81	1.46,15.9	6	-	-
Bladstrom,2003[41]	Sweden	94	14599	pregnancy	NA	≤45	5	OS	paper	2.40	2.0,2.9	9	-	Age, time of diagnosis, time period interaction, number of children, age at first child’s birth
Bladstrom,2003(2)[41]	Sweden	94	14599	pregnancy	NA	≤45	10	OS	paper	1.20	0.9,1.7	9	-
Whiteman,2004[42]	USA	59	355	<12 months postpartum	NA	20-45	15	OS	paper	1.51	1.02,2.23	9	-	Surgery, radiation therapy, race, oral contraceptive use, education, BMI, stage and history of breast disease
Rodriguez,2008[43]	USA	797	4177	Pregnancy&<12 months postpartum	Stage Ⅰ Ⅱ Ⅲ Ⅳ	＜55	13	OS	paper	1.14	1.00,1.29	9	-	Race, tumor size, AJCC stage, surgery, hormone receptor
Stensheim,2009-Pregnancy[44]	Norway	59	13106	Pregnancy	NA	＜50	5	CSS	paper	1.23	0.82,1.81	7	-	Age, diagnostic period and initial extent of disease
Stensheim,2009-Postpartum[44]	Norway	46	13106	<6 months postpartum	NA	＜50	5	CSS	paper	1.95	1.36,2.78	7	-	Age, diagnostic period and initial extent of disease
Beadle,2009-OS[45]	USA	104	564	Pregnancy&<12 months postpartum	Stage Ⅰ Ⅱ Ⅲ	≤35	10	OS	indirect	1.24	0.87,1.79	6	-	-
Beadle,2009-DFS(distant metastasis) [45]	USA	104	564	Pregnancy&<12 months postpartum	Stage Ⅰ Ⅱ Ⅲ	≤35	10	DFS	indirect	1.35	0.98,1.85	6	-	-
Beadle,2009-DFS(locoregional recurrence) [45]	USA	104	564	Pregnancy&<12 months postpartum	Stage Ⅰ Ⅱ Ⅲ	≤35	10	DFS	indirect	1.44	0.78,2.66	6	-	-
Halaska,2009-OS[46]	Greece	32	32	Pregnancy&<12 months postpartum	Grade Ⅰ Ⅱ Ⅲ	＜45	10	OS	indirect	1.42	0.58,3.48	6	Age at diagnosis, tumor size, axillary lymph node status and presence or absence of metastatic deposits	-
Halaska,2009-DFS[46]	Greece	32	32	Pregnancy&<12 months postpartum	Grade Ⅰ Ⅱ Ⅲ	＜45	10	DFS	indirect	1.82	0.82,4.05	6		-
Largillier,2009-OS[47]	France	105	788	Pregnancy&<12 months postpartum	Grade Ⅰ Ⅱ Ⅲ	＜35	10	OS	paper	1.51	1.05,2.20	7	-	-
Largillier,2009-DFS[47]	France	105	788	Pregnancy&<12 months postpartum	Grade Ⅰ Ⅱ Ⅲ	＜35	10	DFS	paper	1.25	0.90,1.74	7	-	-
Phillips,2009[48]	Multicenter	676	-	-	NA	-	10	OS	paper	-	-	8	-	Study center, education, BMI, time since last full-term pregnancy and age at diagnosis
Moreira,2010[49]	Brazil	87	252	Pregnancy&<12 months postpartum	NA	≤ 45	10	OS	paper	1.52	1.10,2.10	7	Registration institution, age and registration year	-
Johansson,2011[50]	Sweden	1110	14611	Pregnancy&<24 months postpartum	NA	15-44	15	OS	paper	1.51	1.36,1.68	7	-	Age, calendar time, education
Murphy,2012[51]	USA	99	186	Pregnancy&<12 months postpartum	Grade 0 Ⅰ Ⅱ Ⅲ	35(24-48)	18	OS	paper	0.59	0.29, 1.17	7	Age, year of diagnosis	Tumor grade, ER status, LN involvement
Azim,2012-OS [52]	Italy	65	130	pregnancy	NA	＜50	6	OS	paper	1.70	0.80,3.90	7	Age, year of surgery , pathological tumor size , and pathological nodal status	Adjusted for pN, neoadjuvant chemotherapy, and ER
Azim,2012-DFS [52]	Italy	65	130	pregnancy	NA	＜50	6	DFS	paper	2.30	1.30,4.20	7		Age, pT, pN, neoadjuvant chemotherapy, ki-67, HER2 and perivascular invasion
Ali,2012-OS[53]	USA	40	40	Pregnancy&<12 months postpartum	Stage Ⅰ Ⅱ Ⅲ Ⅳ	33(24-42)	16	OS	indirect	2.15	1.13,4.09	7	-	Age and stage-matched
Ali,2012-DFS[53]	USA	40	40	Pregnancy&<12 months postpartum	Stage Ⅰ Ⅱ Ⅲ Ⅳ	33(24-42)	16	DFS	indirect	2.00	1.12,3.59	7	-	Age and stage-matched
Amant,2013-OS[54]	Belgium	311	865	pregnancy	Stage Ⅰ Ⅱ Ⅲ, Grade Ⅰ Ⅱ Ⅲ	33(31-36)	5	OS	paper	1.19	0.73,1.93	8	-	Age at diagnosis, stage, grading, histologic tumor type, ER/PR status, HER2, and chemotherapy
Amant,2013-DFS[54]	Belgium	311	865	pregnancy	Stage Ⅰ Ⅱ Ⅲ, Grade Ⅰ Ⅱ Ⅲ	33(31-36)	5	DFS	paper	1.34	0.93,1.91	8	-
Litton,2013-OS[55]	USA	75	150	pregnancy	Stage Ⅰ Ⅱ Ⅲ	24-45	5	OS	paper	1.87	1.04,3.36	7	Age at diagnosis, stage at diagnosis , and year of diagnosis	Age at diagnosis, year of diagnosis, clinical cancer stage and tumor nuclear grade
Litton,2013-DFS[55]	USA	75	150	pregnancy	Stage Ⅰ Ⅱ Ⅲ	24-45	5	DFS	paper	2.09	1.19,3.67	7
Valentini,2013[56]	USA	75	269	Pregnancy&<12 months postpartum	NA	32.5(20-45)	15	OS	paper	0.79	0.25,2.44	7	-	Age at diagnosis, tumor size , lymph node status, ER status, use of chemotherapy, and oophorectomy
Dimitrakakis,2013[57]	Greece	39	39	Pregnancy&<12 months postpartum	Stage Ⅰ Ⅱ Ⅲ Ⅳ, Grade Ⅰ Ⅱ Ⅲ	34.3 ± 5.0	5	OS	paper	9.28	2.94,29.27	6	Stage, age and year of diagnosis	Stage, ER status, grade, and age at diagnosis
Calliha,2013-OS[58]	USA	76	86	Pregnancy&<60 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ, Grade Ⅰ Ⅱ Ⅲ	≤45	5	OS	paper	2.65	1.09,6.42	6	-	Tumor biologic subtype, clinical stage, and year of diagnosis
Calliha,2013-DFS[58]	USA	74	84	Pregnancy&<60 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ, Grade Ⅰ Ⅱ Ⅲ	≤45	5	DFS	paper	2.80	1.12,6.57	6	-	Tumor biologic subtype, clinical stage, year of diagnosis and local recurrence
Bell,2013-OS[59]	Australia	13	377	Pregnancy&<12 months postpartum	NA	＜48	5	OS	paper	2.50	0.5,11.7	6	-	-
Bell,2013-DFS[59]	Australia	13	377	Pregnancy&<12 months postpartum	NA	＜48	5	DFS	paper	0.90	0.2,4.4	6	-	-
Moller,2013[60]	UK	-	-	-	Stage Ⅰ Ⅱ Ⅲ Ⅳ	10-54	10	OS	paper	-	-	7	-	Age, stage
Framarino-dei-Malatesta,2014[61]	Italy	22	45	pregnancy	NA	37.2±3.2	10	OS	indirect	0.96	0.29,3.21	6	Age	-
Madaras,2014[62]	Hungary	31	31	Pregnancy&<12 months postpartum	-	34	10	OS	indirect	5.76	2.09,15.98	7	Age and year of first breast cancer diagnosis	-
Nagatsuma,2014[63]	Japan	-	-	-	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ, Grade Ⅰ Ⅱ Ⅲ	26-44	10	OS	paper	-	-	7	-	Age at diagnosis, AJCC clinical stage , histological tumor grade , estrogen and progesterone receptor status and HER2 status
Strasser-Weippl,2014[64]	China	109	1274	Pregnancy&<60 months postpartum	Grade Ⅰ Ⅱ Ⅲ	＜45	5	DFS	paper	1.62	1.04,2.54	8	-	Age, estrogen receptor, progesterone receptor, HER2 status, disease stage
Genin,2015-OS[65]	France	87	174	Pregnancy&<12 months postpartum	Grade Ⅰ Ⅱ Ⅲ	35(27-40)	10	OS	indirect	1.09	0.79,1.52	7	Age and year of diagnosis	-
Genin,2015-DFS[65]	France	87	174	Pregnancy&<12 months postpartum	Grade Ⅰ Ⅱ Ⅲ	35(27-40)	10	DFS	paper	1.87	1.05,3.33	7	Age and year of diagnosis	Age, ER, HR status, tumor stage,HER2 status, Ki67 rate
Iqbal,2017[14]	Canada	501	5832	Pregnancy&<21 months postpartum	Stage Ⅰ Ⅱ Ⅲ Ⅳ	20-45	5	OS	paper	1.11	0.86,1.45	9	-	Year of diagnosis, age, tumor size, nodal status, estrogen receptor status, progesterone receptor status, chemotherapy, and radiotherapy, et al
Kim,2017[66]	Korea	344	668	Pregnancy&<12 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ, Grade Ⅰ Ⅱ Ⅲ	20-45	10	OS	indirect	1.85	1.28,2.67	8	Operation period, age, and initial stage	-
Bae,2018(1)[67]	Korea	40	2770	Pregnancy&<12 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲ	33.5 (27– 40)	5	CSS	paper	4.00	1.20,12.90	8	-	Age, stage, and chemotherapy
Bae,2018(2)[68]	Korea	411	83381	Pregnancy&<12 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ	20-49	15	OS	paper	1.03	0.74,1.42	9	-	Age at diagnosis, Stage, high versus low/intermediate, Luminal subtype, HER2 subtype, et al
Boudy,2018-DFS[16]	France	49	51	Pregnancy	Grade Ⅰ Ⅱ Ⅲ	＜46	5	DFS	indirect	1.19	0.75,1.91	8	Propensity score	-
Boudy,2018-CSS[16]	France	49	51	Pregnancy	Grade Ⅰ Ⅱ Ⅲ	＜46	5	CSS	indirect	1.06	0.65,1.72	8	Propensity score	-
Johansson,2018[2]	Sweden	778	1661	Pregnancy&<24 months postpartum	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ	15-44	10	OS	indirect	0.90	0.55,1.40	9	-	Age, period, education, region, tumor characteristics pathologic T stage, N stage and ER/PR
Chuang,2018[69]	China(Taiwan)	-	-	-	Stage Ⅰ Ⅱ Ⅲ	20-50	＞10	OS	paper	-	-	9	-	Age and year of diagnosis, stage, tumor size, positive lymph nodes, histological grading, and treatments
Ploquin,2018-OS[15]	France	111	253	Pregnancy	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ	22-46	5	OS	paper	1.10	0.67,1.79	8	Age, clinical T stage, hormone receptor	Clinical nodal status and age
Ploquin,2018-DFS[15]	France	111	253	Pregnancy	Stage 0 Ⅰ Ⅱ Ⅲ Ⅳ	22-46	5	DFS	paper	1.15	0.78,1.68	8	Age, clinical T stage, hormone receptor	Clinical nodal status and age
Suleman,2019-OS[70]	Saudi Arabia	110	114	Pregnancy	Stage Ⅰ Ⅱ Ⅲ Ⅳ	20-48	＞10	OS	indirect	2.58	1.26,5.26	7	Diagnosed year	-
Suleman,2019-DFS[70]	Saudi Arabia	110	114	Pregnancy	Stage Ⅰ Ⅱ Ⅲ Ⅳ	20-48	＞10	DFS	indirect	1.18	0.70,1.97	7	Diagnosed year	-
Choi,2019[17]	Korea	63	3804	Pregnancy&<12 months postpartum	NA	＜50	10	OS	paper	1.52	0.82,2.83	8	-	Histologic type, stage, ER, PR, age at diagnosis, Charlson comorbidity index

BMI: body Mass Index

, ER: estrogen receptor, PR: progesterone receptor, HER-2:human epidermal growth factor receptor-2

3.2 Overall survival（OS）

45 studies comprising of 6602 PABC cases and a total of 157657 individuals were identiﬁed for the meta-analysis on OS. There was an overall increased risk of death for PABC compared to controls with a pooled hazard ratio of 1.45 (95 % CI 1.30-1.63). There was signiﬁcant heterogeneity (I² =64.9, P＜0.001). The subgroup analysis according to different follow-up duration (4 years, 5 years, 10 years and ＞10 years) had similar results with overall analysis, Figure 2. However, the 6 years and 7 years OS, with little numbers of studies, showed insigniﬁcant results.

3.3 Disease-free survival (DFS)

20 studies comprising of 1786 PABC cases and a total of 9762 individuals were identiﬁed for the meta-analysis on DFS. The overall HR was 1.39 (95 % CI, 1.25-1.54). There was no signiﬁcant heterogeneity (I² =24.5, P=0.146). The subgroup analysis according to different follow-up duration (5 years, 6 years, 10 years and＞10 years) had similar results with overall analysis, Figure 3. However, the 7 years DFS, with only 2 studies, showed insigniﬁcant results.

3.4 Cause-special survival (CSS)

Only 6 studies provided information on CSS with 296 PABC cases and a total of 29598 individuals. The overall HR was 1.40 (95 % CI, 1.17-1.68). There was no signiﬁcant heterogeneity (I² =53.1, P=0.074). The subgroup (5 years CSS) had similar results with overall analysis, Figure 4.

3.5 Subgroup analyses

Several factors that may have induced differences on outcomes were investigated with subgroup analyses, including diagnosed time, PABC definition, geographic region, year of publication and the way of HR estimate. They showed worse prognoses in women with PABC than those with non-PABC consistently except for the subgroup based on PABC definition and year of publication, Table 2. It was worth noted that the specific definition of PABC has varied throughout the literatures and this variability led to diverse results. Studies published during the year of 2000-2010 and 2011-2019 had clear trend of poor prognoses, which was less apparent in those published before 2000. The pooled HR of DFS based on studies published before 2000 was 1.27 (95% CI, 0.97-1.72).

Table 2 Subgroup analyses

Subgroups			No. of Articles (No. of Studies)	HR (95% CI)	Heterogeneity Test
Subgroups			No. of Articles (No. of Studies)	HR (95% CI)	*I²(%)*	P-Value
All studies Included			54 (76)	-	-	-
Diagnosed time	During pregnancy	OS	13 (14)	1.46(1.12,1.90)	73.6	＜0.001
		DFS	7 (7)	1.30(1.11,1.53)	26.3	0.228
	During postpartum period	OS	13(13)	1.97(1.67,2.33)	49.0	0.023
		DFS	2(2)	1.86(1.17,2.93)	0.0	0.740
PABC definition	Pregnancy& < 6 months postpartum	OS	2(2)	1.37(1.09,1.72)	0.0	0.852
	Pregnancy& < 12 months postpartum	OS	20(20)	1.44(1.20,1.72)	60.7	＜0.001
		DFS	8(9)	1.52(1.27,1.81)	17.4	0.288
	Pregnancy& < 24 months postpartum	OS	3(3)	1.42(1.01,2.01)	67.4	0.047
	Pregnancy& < 60 months postpartum	OS	3(3)	1.48(0.90,2.44)	65.2	0.057
Geographic region	Europe	OS	15(17)	1.53(1.26,1.86)	71.1	＜0.001
		DFS	9(9)	1.32(1.15,1.52)	8.7	0.363
	North America	OS	16(17)	1.38 (1.17,1.63)	53.2	0.005
		DFS	5(6)	1.68(1.35,2.08)	15.5	0.315
	Asia	OS	9(9)	1.42(1.09,1.85)	60.0	0.010
	Others	OS	2(2)	1.55(1.13,2.13)	0.0	0.544
Year of publication	Before 2000	OS	11(13)	1.46(1.18,1.82)	45.4	0.038
		DFS	3(3)	1.27(0.97,1.72)	50.7	0.107
	2000-2010	OS	11(12)	1.48(1.19,1.85)	79.0	＜0.001
		DFS	4(5)	1.40(1.14,1.71)	20.5	0.284
	2011-2019	OS	20(20)	1.43(1.20,1.72)	62.7	＜0.001
		DFS	11(11)	1.50(1.29,1.76)	11.5	0.334
HR estimate	Paper report	OS	24(25)	1.42(1.22,1.65)	73.1	＜0.001
		DFS	12(12)	1.35(1.19,1.53)	29.1	0.160
	Indirect	OS	19(20)	1.43(1.28,1.60)	47.4	0.010
		DFS	7(8)	1.48(1.22,1.79)	24.7	0.232

3.6 Dose-response association between the time from last pregnancy to breast cancer diagnosis and overall mortality

As the meta-analysis included studies reporting the HRs with their 95% CIs of overall mortality relating to three or more categories of time since last pregnancy, all the studies were eligible to be included in the dose-response analysis. A total of ten studies were included in dose-response meta-analysis, nulliparous were taken as comparison, Table 3. The analysis of departure from linearity indicated indeed a non-linear association between the time from last pregnancy to breast cancer diagnosis and PABC overall mortality (P<0.001). Compared with the reference group of nulliparous women, PABC had a hazard ratio for all cause death that peaked at 1.62 (95% CI, 1.46-1.80) at 28 months since last pregnancy, and starting from 78 months since last pregnancy became insignificant at 1.07(95% CI, 0.99-1.26). The hazard ratio reached its lowest observed point (0.99, 95% CI, 0.85-1.16) at 195 months since last pregnancy, Figure 5. It showed a higher risk for death compared to nulliparous cases, suggesting that the definition of PABC should be extended to include cases diagnosed up to about 6-years postpartum (78 months since last pregnancy) in order to capture this ongoing increased risk.

Table 3 Characteristics of studies included in dose-analysis meta-analysis

Study ID	Time point of breast cancer diagnosis	Time from last pregnancy to breast cancer diagnosis	No. of participant	Adjusted HR	95% CI
Guinee,1994[30]	Nulliparous	0	139	1	-
	Pregnant	1-10	26	2.83	1.24,6.45
	postpartum 1-12 m	11-22	40	1.88	0.88,3.98
	postpartum13-48 m	23-58	51	1.09	0.54,2.19
	postpartum≥49 m	≥59	35	0.54	0.19,1.55
Olson,1998[35]	Nulliparous	0	146	1	-
	postpartum＜24 m	12-34	42	3.1	1.8,5.4
	postpartum≥24 m	≥34	352	1.3	0.9,2.0
Reeves,2000[36]	Nulliparous	0	159	1	-
	postpartum＜60 m	10-69	67	1.56	1.01,2.42
	postpartum 60-108 m	70-118	80	0.88	0.58,1.32
	postpartum＞120 m	＞130	525	0.99	0.77,1.27
Daling,2002[38]	Nulliparous	0	309	1	-
	postpartum＜24 m	10-33	83	2.3	1.5,3.4
	postpartum24-60 m	34-70	120	1.5	1.0,2.1
	postpartum＞60 m	＞70	661	1.2	0.9,1.6
Whiteman,2004[42]	Nulliparous	0	355	1	-
	postpartum ≤12 m	10-22	59	1.51	1.02,2.23
	postpartum13-48 m	23-58	213	1.25	0.95,1.64
	postpartum＞48 m	＞58	1470	1.06	0.86,1.31
Phillips,2009[48]	Nulliparous	0	676	1	-
	postpartum＜24m	10-33	133	2.75	1.98,3.83
	postpartum 24-60 m	34-70	231	2.2	1.65,2.94
	postpartum ≥72 m	≥82	2067	0.98	0.79,1.22
Calliha,2013[58]	Nulliparous	0	76	1	-
	postpartum＜60 m	10-69	86	2.65	1.09,6.42
	postpartum≥ 60 m	≥70	172	1.52	0.71,3.28
Nagatsuma,2014[63]	Nulliparous	0	249	1	-
	postpartum≤24m	10-34	37	2.19	1.05,4.56
	postpartum 36-60 m	46-70	59	1.49	0.79,2.83
	postpartum＞60 m	＞70	181	0.81	0.46,1.43
Johansson,2018[2]	Nulliparous	0	770	1	-
	Pregnant	1-10	59	1.04	0.62,1.75
	postpartum 0–6 m	10-16	41	1.16	0.64,2.14
	postpartum 6–12 m	16-22	84	1.3	0.83,2.03
	postpartum 12–24 m	22-34	194	1.01	0.70,1.46
	postpartum 24–60 m	34-70	629	1.22	0.96,1.55
	postpartum 60–120 m	70-130	1106	1.08	0.87,1.53
	postpartum >120 m	＞130	1623	0.98	0.78,1.22
Chuang,2018[69]	Nulliparous	0	27800	1	-
	Pregnant	1-10	90	1.42	0.83,2.45
	postpartum 0-12 m	10-22	347	1.29	0.96,1.74
	postpartum 13-24 m	23-34	410	1.27	0.95,1.70
	postpartum 25-60 m	35-70	1583	1.06	0.88,1.27

3.7 Publication Bias

As shown in Figure 6, each point represents an independent study of the indicated association, visual inspection of the funnel plot did not suggest an evidence of publication bias among the articles (Egger’s test, P=0.451; Begg’s test, P=0.077).

We reviewed and meta-analyzed the existing scientific literatures on the prognosis of PABC to obtain the powerful conclusion that PABC is associated with a poor prognosis. This is the largest and latest meta-analysis in this field. It included a larger number of participants, thus reducing small-study effect to a great degree. And the studies included in our meta-analysis were with relatively high quality. The mean of Newcastle-Ottawa score of studies was 7.2.

There are two explanations that may account for the results. On one hand, mammary gland involution following pregnancy has been suggested to explain the poor prognosis [71]. Breast involution occurs as a tissue remodeling process to the state indistinguishable from the nulliparous gland through wound healing, inflammatory milieus and immune infiltrate [72, 73], which supposedly promotes tumor progression. On the other hand, pregnancy and breastfeeding lead less timely detection and clinical examination. The delayed diagnosis that allows the tumor more time to grow, increasing the metastatic potential of the disease [52, 74]. Pregnancy also makes treatment strategy more conservative to ensure the safety of the fetus [10, 75]. However, the exact reasons of the poor prognosis of PABC are needed to explore in future.

To the best of our knowledge, this is the first dose-response meta-analysis providing comprehensive insights into the association between the time from last pregnancy to breast cancer diagnosis and overall mortality of PABC. The scientific value of dose-response meta-analysis is higher than meta-analysis with exposure classified as two categories [20, 76]. Using this method, we were able to provide a detailed and more flexible description of the occurrence of outcomes throughout the observed range of exposure. Through the vwlr with random effects model, we found a non-linear direct association between the time from last pregnancy to breast cancer diagnosis and the overall mortality. Compared with nulliparous, PABC women had an elevated all-cause death risk that peaked at 28 months since last pregnancy and lasted to 78 months. We propose that the definition of PABC should include cases diagnosed up to at least 6-years postpartum to better delineate the increased risk imparted by a postpartum diagnosis. These findings also provide valuable insights into further research. Callihan’s cohort demonstrate that a breast cancer diagnosed within 5-years postpartum has a signiﬁcant higher risk for metastasis and mortality risk compared to nulliparous cases[58].Compared to his cohort, our dose-response meta-analysis provide a higher-level quality of evidence to expand the definition of PABC. Understanding the differences between breast cancers diagnosed during different time of postpartum would better permit the translation of informative data from basic science and epidemiologic studies into the clinical care and treatment of young women’s breast cancer.

The present meta-analysis has the following limitations that must be taken into account. Firstly, if HRs and 95% CI were not directly reported in included studies, we estimated HRs from crude data or Kaplan-Meier curve. It may cause bias without adjustment. However, we performed subgroup analysis based on the way of HR estimate. It showed the worse prognosis in women with PABC than those with non-PABC consistently. Secondly, the meta-analysis was based on data from observational studies, although most of the included studies adjusted for several relevant confounders (including age, year of diagnosis, tumor stage, axillary lymph node status, estrogen receptor, hormonal receptor status, HER2 status, family history, etc.), residual confounding by other potential factors cannot be ruled out. Thirdly, high between-study heterogeneity is another limitation of the current meta-analysis. It was likely due to significant differences in sample size, the definition of PABC and/or treatment interventions. Lastly, language of studies was limited to English, which may result in potential language bias.

In summary, this meta-analysis suggests that PABC is associated with a poor prognosis on overall OS, DFS and CSS compared to non-PABC cases. The definition of PABC should be extended to include cases diagnosed up to about six-years postpartum in order to capture this ongoing increased risk of death. Further long-term prospective cohorts with larger sample sizes should be conducted to validate this article’s findings.

Abbreviations

PABC:

Pregnancy-associated breast cancer

HR:

hazard ratio

CI:

confidence interval

VWLS:

variance weighted least-squares regression

OS:

overall survival

DFS:

disease-free survival

CSS:

cause-special survival

PRISMA:

preferred reporting items for systematic reviews and meta-analysis

NOS:

Newcastle-Ottawa scale

BMI:

body Mass Index

ER:

estrogen receptor

PR:

progesterone receptor

HER–2:

human epidermal growth factor receptor–2

Ethics approval and consent to participate：Not applicable

Consent for publication：Not applicable

Availability of data and material：Not applicable

Competing interests：The authors declare that they have no competing interests

Funding: This research was funded by Youth Talent Fund of the Second Hospital of Shandong University (2018YT26). The study funders had no role in the design, data acquisition, analyses, or data interpretation of this project.

Authors’ contributions: YZ and HJ designed the research, CS and JX performed the literatures search and statistical analysis, CS interpreted the data, and drafted the manuscript. Both YZ and HJ are Corresponding Authors. ZY, LL and FH made critical revision of the manuscript. All authors read and approved the final manuscript.

Acknowledgements: Not applicable

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Prognosis and Expanded Definition of Pregnancy-associated Breast Cancer: A Dose-Response Meta-Analysis

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Abstract

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1. Introduction

2. Materials and Methods

2.1 Search Strategy

2.2 Inclusion and Exclusion Criteria

2.3 Data Extraction

2.4 Assessment of Study Quality

2.5 Meta and Statistical Analysis

3. Results

4. Discussion

5. Conclusions

Declarations

Abbreviations

References

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