Comparative Survival Analysis of HER2-Positive Pregnancy-Associated Breast Cancer and Non-Pregnant Cohorts: A matched control study

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Comparative Survival Analysis of HER2-Positive Pregnancy-Associated Breast Cancer and Non-Pregnant Cohorts: A matched control study

https://doi.org/10.21203/rs.3.rs-4873580/v1

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Purpose: This retrospective matched cohort single-center study focused on comparing prognosis between HER2-positive PABC and non-pregnant individuals with HER2-positive breast cancer.

Methods: Clinical and histopathological data were collected from a prospectively maintained patient database at King Hussein Cancer Center, a tertiary cancer-care center in Jordan. The study analyzed overall survival (OS), recurrence-free survival (RFS), and event-free survival (EFS) in HER2-positive PABC matched 1:1 to non-pregnant patients with HER2-positive breast cancer (non-PABC).

Results: The analysis encompassed 128 patients, divided into two main groups: 64 patients diagnosed with PABC and 64 patients classified as non-PABC cases. Although there was not a statistically significant difference in OS between non-pregnant and pregnant individuals (p=0.12), it was notable that pregnant individuals experienced a significant delay in the initiation of anti-HER2 treatment (23.8± 19.3 weeks, p= 0.02). Additionally, there was a higher risk of recurrence or events in pregnant individuals, emphasizing the potential impact of pregnancy on these survival outcomes (HR=1.93, p=0.029 and HR=2.00, p=0.02, respectively). Furthermore, PABC individuals who completed the 12-months of anti-HER2 treatment were comparable to non-PABC individuals who completed the same treatment (p=0.3), while incomplete treatment significantly affected survival outcomes (HR=4.94, 95% CI: 1.41 to 17.3, p=0.012).

Conclusion: Despite a notable delay in the initiation of anti-HER2 treatment in PABC patients compared to non-PABC cases, both cohorts exhibited similar prognostic outcomes in terms of overall survival when anti-HER2 treatment has been completed. This discovery emphasizes the importance of promptly initiating and completing anti-HER2 treatment in pregnant individuals to optimize prognosis.

Breast cancer

HER2-Positive Breast Cancer

Pregnancy-Associated Breast Cancer

Survival Analysis

Pregnancy and Cancer

Oncological Outcomes

Breast cancer remains the most common cancer and the leading cause of cancer-related mortality in Jordan [1]. Pregnancy related cancer is uncommon, with breast cancer being the most frequently diagnosed with projections of increased incidence due to increased maternal ages worldwide [2, 3].

HER2-positive breast cancer is recognized for its aggressive nature, constituting a significant proportion of breast cancer cases and necessitates targeted therapies to improve patient outcomes [4–6]. PABC encompasses breast cancer diagnosed during pregnancy or in the first post-partum year, presenting a complex intersection of oncological and obstetric considerations [7, 8]. Understanding the epidemiological nuances of both HER2-positive breast cancer and pregnancy-associated breast cancer is vital for optimizing prevention, detection, and management strategies tailored to these specific patient populations.

Viuff et al showed that PABC patients exhibited decreased survival within the initial two years following diagnosis, yet no significant difference in survival was observed beyond this period [9]. Similarly, a Swedish study delved into the outcomes of 1,661 women with breast cancer, categorizing them into groups based on time since delivery, where after adjustment for confounding variables, PABC cases showed higher mortality rates in contrast to non-PABC cases, with a noticeable peak approximately two years after diagnosis [10].

Survival rates in HER2-positive breast cancer patients have significantly improved over the past few decades, primarily due to the advent of targeted therapies such as Trastuzumab (Herceptin), a cornerstone in HER2-positive breast cancer treatment, and other anti-HER2 agents [11–14]. However, concerns regarding its use during pregnancy and potential impact on fetal development have led to clinical hesitations and interruptions or discontinuation of therapy for pregnant patients. These interruptions or modifications in treatment pose critical questions regarding the optimal management and subsequent outcomes for this specific patient demographic [15].

Our study presents an investigation into the prognosis and treatment outcomes of HER2-positive PABC compared to non-PABC cohorts. We also aim to study the effect of delaying and interrupting anti-HER2 treatment in pregnant patients.

Study Population and Design:

The study involved a defined population comprising individuals younger than 45 years old who were diagnosed with HER2-positive PABC and then matched with HER2-positive non-PABC of similar age, histopathology, and clinical stage. Data for this study were collected retrospectively from the cancer registry at the King Hussein Cancer Center within the timeframe of April 2006 to January 2021.

None of the PABC patients received anti-HER2 therapy during pregnancy; instead, initiation of the anti-HER2 treatment was postponed until after delivery and the group was further divided into three subgroups based on the completion of anti-Her2 therapy; patients who received and completed the planned duration of therapy regimen of anti-HER2 (completion of anti-HER2), received and did not complete the regimen (partially completed) and those who did not receive any doses of the anti HER2 treatment regimen (No anti-HER2).

The primary endpoint for this study was the comparative survival analysis between HER2-positive PABC and HER2-positive non-PABC. Event free survival (EFS) was defined as time from diagnosis to disease recurrence, death or the date of the last follow-up. Recurrence free survival (RFS) is the time from diagnosis of breast cancer to disease recurrence and was amended to the last follow-up date or the date of death without recurrence. Recurrence events were defined as ipsilateral breast, ipsilateral or contralateral axillary recurrence, and other tissue/organ metastasis. Overall survival was the time from diagnosis till the date of last follow up date or the date of death whether related to the disease or not.

Statistical analysis:

The analysis was performed using R version 4.2.1. Descriptive analysis was presented in terms of frequency and percentages. Categorical data was illustrated using cross tabulations, and associations were assessed utilizing Chi-Square or Fisher's exact test. Variables that demonstrated significance in the univariate tests were integrated into a regression model for subsequent Cox regression analysis. The significance level was set at p < 0.05. The Kaplan-Meier method was employed to estimate overall survival (OS), Recurrence-free survival (RFS), and event-free survival (EFS) for the two cohorts. Comparisons between the cohorts were conducted using the log-rank test.

A total of 195 cases of PABC were identified from our hospital’s database. Among these cases, 64 (32.8%) patients were identified as HER2-positive PABC and 64 HER2-positive non-PABC were matched for age at diagnosis, treatment, clinical stage, and pathological response to reach an overall study population of 128.

Clinical and Pathological Characteristics

The mean age across the total study population was 34 years with no difference between the groups. There was no difference in tumor size (T) (p = 0.9), lymph node involvement (N) (p = 0.23), distant metastasis (M) (p = 0.23), type of breast cancer (p = 0.1), and histopathological treatment response (p = 0.908) between the two groups.

Moreover, distribution of hormonal-receptor status (ER and PR) between both groups did not show statistical differences where the hormonal status in the HER2-positive PABC group revealed 81.25% positivity, and 76.56% in the non-pregnant group (p = 0.52). (Table 1)

Pain was reported by 21.88% of non-pregnant and 23.44% of pregnant cases. A mass as a symptom was prevalent, noted by 84.38% of non-pregnant and 87.5% of pregnant individuals. Axillary lymph nodes were reported by 15.63% of non-pregnant and 23.44% of pregnant cases. Nipple retraction was experienced by 15.63% of non-pregnant and 12.5% of pregnant cases. There was no significant difference in symptom prevalence between the two groups (p = 0.908). (Table 1)

First Treatment Type

Among non-pregnant HER2-positive patients, 26.56% received surgery as their initial treatment, while 68.75% underwent neoadjuvant chemotherapy. A smaller proportion, 4.69%, received palliative chemotherapy. In comparison, among pregnant HER2-positive patients, 26.56% had surgery as the first treatment, 62.50% received neoadjuvant chemotherapy, and a slightly larger percentage, 10.94%, received palliative chemotherapy. The p-value of 0.2 suggests no statistically significant difference in the choice of initial treatment between the non-pregnant and pregnant HER2-positive groups. (Table 1)

Anti-HER2 (Herceptin) Therapy

Concerning the duration of Herceptin therapy, a significant distinction is observed. Among non-pregnant patients, 71.88% completed the recommended 12-month Herceptin regimen, 9.38% received Herceptin for less than a year, and 18.75% did not undertake the therapy. In contrast, pregnant patients exhibited a different pattern, with 45.3% completing the full 12-month regimen, 18.8% receiving Herceptin for a shorter duration, and 35.9% not initiating Herceptin. This disparity is statistically significant, underscored by a p-value of 0.01, indicating the influence of pregnancy on the duration of Herceptin therapy.

Additionally, the data addressed the timing of Herceptin initiation from diagnosis, measured in weeks. The mean time to initiate Herceptin was 16.9 weeks for non-pregnant individuals and 23.8 weeks for pregnant patients. The median time to commence Herceptin varied considerably, ranging from 0.57 to 35.05 weeks for non-pregnant individuals and from 3.28 to 125.66 weeks for pregnant individuals. This difference in the timing of Herceptin initiation holds statistical significance, corroborated by a p-value of 0.02. (Table 1)

Table (1): Comparison of clinical characteristics, histological, immunohistochemical characteristics, and Treatments received in HER2-positive PABC and HER2 non-PABC groups.

Variable		Total		Non-Pregnant HER2 Positive		Pregnant HER2 Positive		p Value
N (%)		128		64(50%)		64(50%)		p Value
Age(years)	Mean (Std.)	34.06 (4.190)		34.19 (3.995)		33.97 (4.398)		0.72
Age(years)	Median (Min-Max)	34 (25–25)		34(25–45)		33(26–45)		0.72
Clinical T	T0/Tis	7	5.47%	3	4.69%	4	6.25%	0.9
	T1	11	8.59%	6	9.38%	5	7.81%
	T2	49	38.28%	24	37.50%	25	39.06%
	T3	41	32.03%	20	31.25%	21	32.81%
	T4	20	15.63%	11	17.19%	9	14.06%
Clinical N	N0	39	30.47%	19	29.69%	20	31.25%	0.23
	N1	58	45.31%	30	46.88%	28	43.75%
	N2	20	15.63%	7	10.94%	13	20.31%
	N3	11	8.59%	8	12.50%	3	4.69%
Clinical M	M0	108	84.38%	56	87.50%	52	81.25%	0.24
Clinical M	M1	20	15.63%	8	12.50%	12	18.75%	0.24
Pathological Response	Complete	26	20.31%	17	26.56%	9	14.06%	0.31
	Partial	31	24.22%	15	23.44%	16	25.00%
	No Response	49	38.28%	21	32.81%	28	43.75%
	Progression	5	3.91%	2	3.13%	3	4.69%
	NA	17	13.28%	9	14.06%	8	12.50%
Histopathology	IDC	121	94.53%	58	90.63%	63	98.44%	0.1
	ILC	4	3.13%	4	6.25%	0	0.00%
	IMC	3	2.34%	2	3.13%	1	1.56%
Symptoms	Pain	29	22.66%	14	21.88%	15	23.44%	0.908
	Mass	110	85.94%	54	84.38%	56	87.50%
	Axillary LNs	25	19.53%	10	15.63%	15	23.44%
	Nipple Retraction	18	14.06%	10	15.63%	8	12.50%
	Other	28	21.88%	13	20.31%	15	23.44%
First Treatment Type	Surgery	34	26.56%	17	26.56%	17	26.56%	0.22
	Neoadjuvant CTX	84	65.63%	44	68.75%	40	62.50%
	Palliative CTX	10	7.81%	3	4.69%	7	10.94%
Hormonal Status	Positive	101	78.91%	49	76.56%	52	81.25%	0.52
Hormonal Status	Negative	27	21.09%	15	23.44%	12	18.75%	0.52
Anti-HER 2 (Herceptin)	Completed planned therapy duration	75	58.59%	46	71.88%	29	45.31%	0.007
	Did not complete planned therapy duration	18	14.06%	6	9.38%	12	18.75%
	Didn’t take	35	27.34%	12	18.75%	23	35.94%
Time to initiate Herceptin (week)	Mean(± Std.)	20 (± 14.1)		16.9 (± 6.5)		23.8 (± 19.3)		0.02
Time to initiate Herceptin (week)	Median(Min-Max)	18.2 (0.57-125.66)		16.81 (0.57–35.05)		19.52 (3.28-125.66)		0.02

Survival analysis:

The median follow-up duration for the study was 38.84 months (0.95 to 183.3 months). Among the 128 individuals, 32 events were recorded. The median survival was estimated at 122 months. The 10-year survival rate was 54% (95% CI 41% -72%) whereas for the 5-year survival, the rate was 76% (95% CI 67% − 85%).

Overall survival

There was no statistically significant difference in overall survival between non-pregnant and pregnant individuals. (Fig. 1a).

The 5-year survival rate for HER2-positive non-PABC was 83% (95% CI: 72–95%), indicating a favorable survival outcome during this period. In contrast, the 5-year survival rate for HER2-positive PABC was slightly lower at 68% (95% CI: 55–83%), suggesting a comparatively lower survival rate for this group within the same period. (p = 0.051) (Table 2)

HER2-positive non-PABC showed a 10-year survival rate of 49% (95% CI: 25–97%), suggesting that nearly half of the patients survived up to that point. On the other hand, HER2-positive PABC demonstrated a slightly higher 10-year survival rate of 53% (95% CI: 39–72%), indicating a somewhat improved long-term survival compared to the 5-year mark. (p = 0.2) (Table 2).

Overall, while HER2-positive PABC initially showed a lower 5-year survival rate compared to HER2-positive non-PABC, the 10-year survival rates are relatively comparable, exhibit potential improvements in survival for HER2-positive PABC over a longer period.

Recurrence free survival

The Kaplan-meier RFS curve illustrated higher likelihood of recurrences in the HER2-positive PABC group (HR 1.93 (1.07–3.49) (p = 0.029)). (Fig. 1b).

At the 5-year mark, RFS rates were 69% (95% CI: 57–83%) for non-PABC patients and 52% (95% CI: 40–68%) for PABC patients (p = 0.03). This trend persisted at the 10-year mark, with RFS rates of 46% (95% CI: 20–100%) for non-PABC and 40% (95% CI: 25–64%) for PABC (p-value: 0.03). These findings underscore that, in terms of RFS rates, non-PABC patients exhibited a relatively better outcome than those with a history of pregnancy-associated diagnosis. (Table-2)

Event free survival

The same was also reflected in the EFS Kaplan-meier curve, where pregnant individuals showed a higher chance of events compared to non-pregnant participants (HR 2.00 (1.11–3.60) (p = 0.02). (Fig. 1c).

The event-free survival (EFS) rates at the 5-year mark revealed significant differences, with rates of 69% (95% CI: 57–83%) for non-PABC and 51% (95% CI: 39–67%) for PABC (p = 0.02). Similarly, at the 10-year mark, the differences persisted, displaying EFS rates of 46% (95% CI: 20–100%) for non-PABC and 39% (95% CI: 24–100%) for PABC (p-value: 0.018). These results emphasize that, in terms of event-free survival rates, non-PABC patients demonstrated a comparatively better outcome than those with a history of pregnancy-associated diagnosis. (Table-2).

Table (2): OS, RFS and DFS (5 and 10-year survival) rate in HER2-positive PABC and non-PABC

		HER2-positive non-PABC	HER2-positive PABC	P value
OS	5-year rate (95% CI)	83% (72%, 95%)	68% (55%, 83%)	0.051
OS	10-year rate (95% CI)	49% (25%, 97%)	53% (39%, 72%)	0.2
RFS	5-year rate (95% CI)	69% (57–83%)	52% (40–68%)	0.03
RFS	10-year rate (95% CI)	46% (20–100%)	40% (25–64%)	0.03
EFS	5-year rate (95% CI)	69% (57–83%)	51% (39–67%)	0.02
EFS	10-year rate (95% CI)	46% (20–100%)	39% (24–100%)	0.018

Subgroup Survival analysis – completion of Anti-HER2 treatment

This sub-analysis focused on the completeness of the 12-month anti-HER2 (Herceptin) treatment. There was no significant difference between pregnant individuals who completed the 12-month anti-HER2 treatment and non-pregnant individuals who completed the 12-month anti-HER2 treatment, (HR = 1.89, 95%CI 0.57–6.28, p = 0.3).

However, pregnant individuals who did not complete the 12-month anti-HER2 treatment exhibited a worse prognosis compared to the non-pregnant group (HR = 4.94, 95% CI 1.41–17.3, p = 0.012). (Fig. 2a).

Furthermore, considering the entire cohort, a notable distinction in survival curves was observed. Completing the 12-month anti-HER2 treatment resulted in a superior survival curve compared to patient who did not complete the regimen ((HR 4.67 95% CI: 1.93 to 11.3 p = < 0.001). A similar trend was observed for patients who did not initiate any anti-HER2 treatment in terms of prognosis, although it did not reach a significant statistical level ((HR 2.00 (95% CI: 0.86 to 4.66 p = 0.11)) (Fig. 2b). These findings underscore the importance of completing the full 12-month anti-HER2 treatment regimen in improving outcomes for HER2-positive breast cancer patients in the studied cohort.

Subgroup Survival analysis – Pregnancy trimester

There was no difference in OS when analyzing across pregnancy trimesters (first, second and third) and time after pregnancy, 5-years survival rates were 100%, 50%, 73%, & 55%, respectively. (p = 0.05) (Fig. 3)

Multivariate Analysis

In the Cox regression model assessing the relationship between specific factors and overall survival, we incorporated significant factors identified in the univariate analysis, namely time to initiate anti-HER2 treatment, and completeness of anti-HER2 treatment. This multivariate analysis provided crucial insights into the role of these factors concerning survival outcomes. First, the timing of initiating anti-HER2 treatment, whether before or after 18 weeks from diagnosis (sample Median), did not exhibit a statistically significant impact on survival (HR = 1.15, 95% CI: [0.40, 3.32], p = 0.8). However, the completeness of anti-HER2 treatment emerged as a significant factor. Patients who partially completed anti-HER2 treatment showed worse outcomes (HR = 3.78, 95% CI: [1.48, 9.64], p = 0.005) compared to those who completed the treatment. These findings emphasize the importance of completing the anti-HER2 treatment for optimal outcomes irrespective of delay in initiating therapy for different patient groups within the HER2 positive cohort. (Table 3)

Table (3): Cox_regression model

Characteristic	HR¹	95% CI¹	p-value
Time of anti-HER2 initiation
Less than 18weeks	—	—
More than 18weeks	1.15	0.40, 3.32	0.8
Completeness of Anti-HER2
Completed anti-HER2 treatment	—	—
Partially completed anti-HER2	3.78	1.48, 9.64	0.005
HER2 positive groups
Non-pregnant	—	—
pregnant	1.06	0.37, 3.00	> 0.9
¹ HR = Hazard Ratio, CI = Confidence Interval

Our study conducted a comprehensive comparative prognosis analysis, focusing on the distinct clinical outcomes of HER2-positive Pregnancy-Associated Breast Cancer (PABC) compared to HER2-positive non-PABC. This investigation, involving 128 patients (64 with PABC and 64 non-PABC), aimed to elucidate the influence of pregnancy on the prognosis of HER2-positive breast cancer, an area that remains underexplored. The analysis revealed that patients with HER2-positive PABC exhibited worse recurrence and event free survivals than their non-pregnant counterparts, although this was not reflected on overall survival, which was similar. Analysis from the French CALG (Cancer Associe a La Grossesse) network done by Boudy et al. also expressed similar findings of negative effects on recurrence free survival but not overall survival [16].

A novel aspect of our study is the examination of the timing of anti-HER2 therapy initiation on overall survival. We observed a significant delay in initiating Herceptin treatment among pregnant patients (23.8 weeks) compared to non-pregnant patients (16.9 weeks). Despite this delay, there was no significant difference in overall survival between the two groups. This suggests that the timing of Herceptin initiation, while delayed in pregnant patients, does not adversely impact overall survival outcomes if the regimen was completed.

Further analysis highlights the importance of completing the anti-HER2 treatment. Patients who partially completed their treatment showed significantly worse outcomes (HR = 3.78, 95% CI: 1.48–9.64, p = 0.005) compared to those who completed the treatment. This emphasizes the critical need for ensuring treatment adherence in pregnant patients to achieve optimal outcomes. Our findings, in line with Sardesai et al.'s study [17], emphasize the criticality of completing the anti-HER2 treatment without interruption for HER2-positive individuals. The study encompassed data from The Ohio State University collected between January 2005 and December 2015, defining treatment interruption as any delay of or exceeding 2 weeks during Trastuzumab therapy, encompassing permanent discontinuation of the therapy before the intended duration has completed. Notably, 11% of patients had permanent discontinuation of planned Trastuzumab therapy. Those with treatment interruption or discontinuation exhibited significantly worse overall survival outcomes (HR: 4.8, p < 0.001).

It is worth noting that delaying anti-HER2 therapy might have an effect on breast cancer prognosis in pregnant women as our cohort expressed decreased event and recurrence free survival, similar to the cohort from the French CALG, as several studies showed increased rates of pathological complete response when received neoadjuvant anti-HER2 therapy [5, 18].

Our study results in relation to the effect of the pregnancy term on prognosis also fall in line with the results published by Larouzee et al., which showed that pregnancy itself is prognostic indicator irrelevant of the term of pregnancy [19].

We acknowledge the limitations of our study, including the relatively modest sample size. A larger-scale investigation is warranted to validate and reinforce these findings and to discern any potential variations in survival outcomes with a more substantial dataset. Secondly, the relatively small sample size, particularly in subgroups, may have restricted the statistical power to detect subtle yet significant differences. Additionally, the study's focus on a specific geographic location may limit the generalizability of our findings to a broader, more diverse population.

In this study, we conducted an analysis of various factors pertinent to HER2-positive Pregnancy-Associated Breast Cancer (PABC) prognosis, aiming to identify potential determinants of overall survival. While pregnancy did not appear to affect overall survival, a notable outcome from our findings highlights the critical role of completing the anti-HER2 treatment regimen, where incomplete adherence was linked to a detrimental impact on overall survival. This insight is true for pregnant individuals and emphasizes the necessity for tailored treatment strategies for this specific cohort, highlighting the importance of completing anti-HER2 treatment. Interestingly, despite a notable delay in the initiation of anti-HER2 treatment in PABC compared to non-PABC cases, both cohorts exhibited similar prognostic outcomes in terms of overall survival. Further research and collaborative efforts are essential to validate and build upon these findings, advancing the field and optimizing treatment strategies for HER2-positive Pregnancy-Associated Breast Cancer.

Abbreviations	Description
CI	Confidence Interval
EFS	Event Free Survival
ER	Estrogen Receptor
HER2	Human Epidermal Growth Factor Receptor 2
HR	Hazards Ratio
OS	Overall Survival
PABC	Pregnancy-Associated Breast Cancer
PR	Progesterone Receptor
RFS	Recurrence Free Survival

Competing Interests

Financial interests: The authors declare they have no financial interests related to this work. Non-financial interests: The authors have no relevant non-financial interests to disclose.

Ethics Approval

This retrospective chart review study was performed in accordance with the principles of the Declaration of Helsinki. The study was approved by the Ethics Committee of King Hussein Cancer Center (Approval Date: 1/6/2016, No: 16 khcc 28).

Consent to Participate

Due to the retrospective nature of the study, informed consent from individual participants was not required. All patient data was anonymized to ensure confidentiality.

Consent to Publish

As this study involves retrospective data and does not include individual data or images that could identify participants, consent for publication was not required.

Funding

The authors declare that no funds, grants, or other supports were received during the preparation of this manuscript.

Author Contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Dr. Mahmoud Al-Masri, Dr. Basim Aljalabneh, Dr. Rama AlMasri, Dr. Osama Alayyan, Dr. Mohammad Almasri, and Yasmin Safi. The first draft of the manuscript was written by Yasmin Safi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgement

We would like to express our sincere appreciation to everyone who helped us to successfully complete this research project. We would like to express our profound thanks to the Institutional Examination Board (IRB) of the King Hussein Cancer Center for their meticulous review and perceptive remarks, which ensured the study's ethical conduct and safeguarded the participants' safety.

Data Availability

The datasets analyzed during the current study are available upon reasonable request from the corresponding author. Due to privacy concerns associated with patient data, the datasets are not publicly available.

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No competing interests reported.

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Comparative Survival Analysis of HER2-Positive Pregnancy-Associated Breast Cancer and Non-Pregnant Cohorts: A matched control study

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Abstract

Figures

Introduction

Methods

Study Population and Design:

Statistical analysis:

Results

Clinical and Pathological Characteristics

First Treatment Type

Anti-HER2 (Herceptin) Therapy

Survival analysis:

Overall survival

Recurrence free survival

Event free survival

Subgroup Survival analysis – completion of Anti-HER2 treatment

Subgroup Survival analysis – Pregnancy trimester

Multivariate Analysis

Discussion

Conclusion

Abbreviations

Declarations

Competing Interests

Ethics Approval

Funding

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Status:

Version 1