The UK Breast Cancer in Pregnancy (UKBCiP) Study. Incidence, diagnosis, management and short-term outcomes of breast cancer first diagnosed during pregnancy in the United Kingdom: A population-based descriptive study

Background The incidence of breast cancer first arising during pregnancy has been estimated in several countries to be 2.4–7.8/100,000 births, but has not been established in the United Kingdom (UK). We aimed to estimate the incidence of breast cancer diagnosed during pregnancy in the UK and to describe its management and short-term outcomes for mothers and babies. Methods This population-based descriptive study used the UK Obstetric Surveillance System (UKOSS). Cases were prospectively identified through monthly UKOSS mailings to all UK consultant-led maternity units. All cases of breast cancer diagnosed first during pregnancy, between October 1, 2015, and September 30, 2017, were eligible, with 84 confirmed cases analyzed. Women with breast cancer diagnosed before pregnancy or with a recurrence were excluded. The primary outcomes were the incidence of breast cancer first diagnosed during pregnancy, maternal mortality, severe maternal morbidity, perinatal mortality, and severe neonatal morbidity. Results The incidence was 5.4/100,000 maternities (95% CI 4.37, 6.70). Nine women (11%) had undergone in vitro fertilization (IVF), compared with an estimated 2.6% IVF pregnancies in the UK at that time. During pregnancy, 30 women (36%) underwent surgery and 37 women (44%) received chemotherapy. Three women had major maternal morbidity during pregnancy. Two women died and two perinatal deaths occurred. Conclusions The incidence of breast cancer arising in pregnancy in the UK is similar to that reported in other countries. The higher proportion of IVF pregnancies among women diagnosed with breast cancer during pregnancy needs further investigation, as it may not be entirely explained by relatively advanced maternal age. With caveats, the management followed that outside pregnancy, but there was considerable variation in practice. Although short-term outcomes were generally good for mothers and babies, a larger prospective study is required. It is often possible to avoid exposing the baby to iatrogenic prematurity.


Results
The incidence was 5.4/100,000 maternities (95% CI 4.37, 6.70).Nine women (11%) had undergone in vitro fertilization (IVF), compared with an estimated 2.6% IVF pregnancies in the UK at that time.During pregnancy, 30 women (36%) underwent surgery and 37 women (44%) received chemotherapy.Three women had major maternal morbidity during pregnancy.Two women died and two perinatal deaths occurred.

Conclusions
The incidence of breast cancer arising in pregnancy in the UK is similar to that reported in other countries.The higher proportion of IVF pregnancies among women diagnosed with breast cancer during pregnancy needs further investigation, as it may not be entirely explained by relatively advanced maternal age.With caveats, the management followed that outside pregnancy, but there was considerable variation in practice.Although short-term outcomes were generally good for mothers and babies, a larger prospective study is required.It is often possible to avoid exposing the baby to iatrogenic prematurity.

Plain Language Summary
Breast cancer is the most common cancer in the UK.We wanted to know how common it is for women in the UK to be diagnosed with breast cancer for the first time while pregnant, and what clinical treatment these women received.
Every month, all maternity units in the UK send anonymous information about pregnant women who have certain rare conditions diagnosed to a central database, the UK Obstetric Surveillance System (UKOSS).We looked at all the information that UKOSS collected during a two-year period about women who were newly diagnosed with breast cancer during pregnancy.
During the two years, 84 pregnant women were diagnosed with breast cancer for the first time.Based on this, we estimated that there were 5.4 new diagnoses of breast cancer per 100,000 women giving birth in the UK.This is similar to the numbers that researchers have estimated in other countries.The women received broadly similar clinical treatment to non-pregnant women with breast cancer.However, treatment varied a lot between individuals.
More diagnosed women than would be expected had undergone IVF.This finding might be partly related to the older age of the pregnant women diagnosed with breast cancer.However, this finding needs
The incidence of breast cancer rises with age.The fact that many women are delaying pregnancy until later in life may lead to an increasing incidence of breast cancer arising for the first time in pregnancy.Births to women aged 40 years or older increased by 9.5% between 2006-07 and 2017-18 in England 3 .Studies elsewhere have identified an increasing trend in the incidence of breast cancer during pregnancy; for example, in Sweden between 1963 and 2002 4 .
Breast Cancer Associated with Pregnancy (BCAP) is defined as breast cancer diagnosed during pregnancy or lactation up to 12 months postpartum, but some studies on this subject include cases diagnosed up to 5 years after delivery.Breast cancer arising during and after delivery appear to be two separate entities with different behaviors and outcomes [5][6][7][8][9] .Thus, the estimated incidence of BCAP ranges from 1/3,000 to 1/10,000 pregnancies, depending on the study population and definition used 4,[10][11][12] .It is estimated that 18%-33% of BACP cases are diagnosed specifically during pregnancy 4,[10][11][12] .Based on this observation, the incidence of breast cancer diagnosed for the first time during pregnancy can be estimated in other countries to range from 2.4 to 7.8 cases per 100,000 births 4,[10][11][12] , but the incidence has not been previously estimated in the UK.
The aim of this study was to identify cases of breast cancer diagnosed during pregnancy, a period when diagnosis, staging, and treatment can be challenging for women, their families, and clinicians.The objective was that these data could inform clinical discussions with women and their families in order to co-produce management decisions that must account for optimal maternal therapy as well as fetal well-being, in what is a rare situation for both clinicians and patients.

Patient and Public Involvement
No patients were involved in this study.The public was involved in the design of the study as part of the UKOSS Steering Committee.
All newly diagnosed cases of breast cancer during pregnancy in the UK were reported through the UK Obstetric Surveillance System (UKOSS) in women who delivered their babies or had a termination of pregnancy or miscarriage between October 1, 2015, and September 30, 2017.The total number of maternities in the UK over the 2 years of the study was used as the denominator to calculate the incidence.The incidence was calculated with 95% confidence intervals.
Women whose breast cancer had been diagnosed before pregnancy or who had recurrence of previously diagnosed disease were excluded.UKOSS collects information on specific rare events that occur during pregnancy, agreed on by a national steering committee, from all obstetric units in the UK.The reporters submit monthly returns for the current list of conditions, including zero values, notifying UKOSS when an event has occurred (in this case, the diagnosis of breast cancer in pregnancy).UKOSS staff sent the data collection form (https://www.npeu.ox.ac.uk/ assets/downloads/ukoss/forms/UKOSS-Breast-Cancer-V1.pdf) for completion when notified of a case.In addition, we notified oncologists around the UK of the study to gain their assistance with the completion of information on oncological diagnosis and management.The UKOSS methodology ensures that no patient identifiable data are included for analysis while excluding duplicate submissions 13 .Cases were allocated UKOSS identification numbers, and all data were anonymized.Once received, duplicate cases were excluded by comparison of key clinical information.Reminders were sent if forms were not returned or were incomplete.
Ethics committee approval was obtained (Wales Research Ethics Committee 5, January 15, 2015, EC 14/WA/1267, IRAS project ID 165517).Consent was not required for the collection of anonymous routine data.Betsi Cadwaladwr University Health Board sponsored and funded this study.
The information requested included maternal demographics, details of the current and past pregnancies, BRCA (BReast CAncer) gene mutation status, and details of the diagnosis and staging when known.Information about staging, surgical management, chemotherapy use, and pregnancy outcomes was also collected.Babies were categorized as small for gestational age (SGA) if the birth centile was less than the 10 th centile 14 .
Categorical data are summarized as percentages.Continuous data are presented as medians, IQR and ranges.Group comparisons were performed using Fisher's exact test.We used the STROBE cross sectional reporting guidelines 15 .

Results
A total of 132 cases were reported during the 24-month follow-up period.Of these, 29 cases were excluded as they did not meet the eligibility criteria, and 8 cases were duplicate notifications identified by UKOSS.The data collection form was not returned for 11 cases; therefore, 84 confirmed cases were available for analysis.
Data on presentation and diagnosis are presented in Table 2. Two women were asymptomatic; their tumors were identified at specific screening arising from known familial increased risk.The majority of symptomatic women (n=50, 61%) presented solely with a lump.Fourteen women (17%) presented with a lump associated with other breast symptoms, including pain, skin changes, discharge, or tenderness.The remaining 18 women (22%) presented with different combinations of symptoms but not a lump, including nipple inversion, pain and fullness, skin changes, breast enlargement, discharge from the nipple, and erythema.The median duration of symptoms before diagnosis was three weeks (IQR, 2-9 weeks; range, 0-56 weeks) (Table 2).

Staging and tumor characteristics
Staging investigations performed during pregnancy were reported fully for 76 women and included various modalities and combinations.
Data are available on the histology type in 71 women.The histological type was invasive ductal carcinoma in 62 (74%) patients, poorly differentiated in 2 (2%), invasive lobular carcinoma in 3 (4%), and ductal carcinoma in situ (DCIS) in  2 (2%).Metaplastic, inflammatory, and invasive ductal and lobular carcinomas were reported in the remaining cases.
The TNM (tumor size, lymph nodes, metastasis) stage was known in 58 women (Table 3).The clinical tumor size at diagnosis was greater than 2 cm in 39 patients (68%).Just over one in six women (N=9) had a tumor greater than 5 cm.

Treatment
Data on the use of systemic chemotherapy were available for 79 women.This was administered during pregnancy in 37 cases (47%), was not recommended in 7 cases (9%), and was delayed until the end of pregnancy in 35 cases (44%).
The timing was unknown in 5 cases.Of the 37 women who received chemotherapy during pregnancy, 18 (49%) received neoadjuvant chemotherapy and 17 (46%) received adjuvant chemotherapy.One woman received palliative chemotherapy for metastatic disease.
Of the 18 women diagnosed during the first trimester, 11 received chemotherapy during pregnancy (all after 14 weeks), two received chemotherapy after miscarriage and in five cases chemotherapy was not indicated.Of these 18 women, 13 underwent surgery during pregnancy, all between 6 and 15 weeks.
Of the 23 women diagnosed during the second trimester, 20 had chemotherapy during pregnancy and 3 had the start of chemotherapy delayed until after delivery.In all three cases, delivery occurred after 37 completed weeks.In the same group of women, 11 had surgery during pregnancy and 8 had it delayed until the end of pregnancy (in two of these cases, the delivery was between 34 and 36 (39%) underwent surgery during pregnancy: breast conservation surgery, and 16 underwent mastectomy.One woman underwent both procedures during pregnancy.The median gestational age at breast conservation surgery was 17 weeks (range: 6-34 weeks).The median gestational age at mastectomy was 18 weeks (range: 9-35 weeks).Surgery was delayed until the end of pregnancy in 34 (44 %) women.Of the 34 women, 11 received neoadjuvant chemotherapy during pregnancy.The reasons for the delayed surgery were not collected.
Breast cancer was diagnosed in 37 women during their third trimester.Thirty-five of them had induction of labor or prelabor cesarean section, in 50% of the cases before 37 completed weeks (between 32 and 36 weeks).Of these women diagnosed during the third trimester, 6 underwent surgery during pregnancy and 25 had delayed surgery until the end of pregnancy.Five patients received chemotherapy during pregnancy, and 30 had it delayed until the end of the pregnancy.
The systemic regimen that most patients received was anthracycline-based chemotherapy (31 of 37).This was associated with cyclophosphamide use in 26 of the 37 women who received chemotherapy during pregnancy.Taxanes were used in 15 women.The most widely used combination was FEC (fluorouracil, epirubicin, and cyclophosphamide) in ten women.Chemotherapy regimens used during pregnancy and outcomes are given in Table 4.

Outcomes
There were 81 babies born to the 80 women who continued with pregnancy, with a median gestational age at delivery of 37 completed weeks (IQR: 35-38, range 28-41).In total, 41% of the babies were delivered preterm and 59% after 37 completed weeks.All 16 women who gave birth before 36 completed weeks received steroids for fetal lung maturation; two babies died, both prior to 30 weeks.Sixteen babies (20%) were to their prematurity.At of 78 (14%) neonates with known birth weight were classified as small for gestational age (SGA; weight below the 10 th centile) 14 .Eight of the babies who were SGA were born to the 35 mothers who had received chemotherapy, and three SGA babies were born to the 39 mothers who did not receive chemotherapy during pregnancy.This difference was not statistically significant (22.8% vs. 7.7%, P = 0.142; Fisher's exact test).
Thirty women were induced, 28 (93%) for reasons related to their cancer.The mode of delivery was known for 78 of the 80 women who continued pregnancy beyond the second trimester; 37 (47.4%) had pre-labor cesarean section, 21 (57%) after 37 weeks and 16 (43%) preterm.Of the 41 women who were planning a vaginal birth, 27 (66%) had a spontaneous vaginal birth, four (10%) had a ventouse birth, three (7%) had a forceps birth, one woman had a breech birth and six women (15%) had an emergency cesarean section after the onset of labor.Three women were diagnosed later in pregnancy with metastatic cancer in the liver, thoracic spine, and lung, respectively.Two maternal deaths were reported.Two additional women had major maternal morbidity during pregnancy or puerperium; the morbidity in one of these cases was thought to be directly related to chemotherapy.
Thirty-seven percent of women (27 out of 73 known) breastfed, and 19 had lactation suppression.

Main findings
The incidence of breast cancer diagnosed during pregnancy in the UK (5.4 per 100,000 maternities) is similar to that found in other countries.
The median maternal age was 36 years, which is the same as that found in the Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH Breast Cancer Study) in the UK between 2000 and 2008, which included 2956 young women aged 18-40 years with breast cancer 18 , with a similar mean maternal age found in other studies during pregnancy: 35-37 [19][20][21][22] .In contrast, during the study period, the maternal age was less than 35 years in 78.5% of births in the UK 23 .This may partially explain the disproportionate number of women with IVF pregnancies who tend to be older.However, the percentage of IVF pregnancies in the UK in 2015 and 2016 was 2.57% and 2.6% 24 , respectively, compared to 11% in this study.This observation requires further investigation.While there is uncertainty, there is a need to discuss this potential additional risk, and special attention should be paid to breast symptoms and examinations during the antenatal period in women who conceive by IVF until the position is clarified.
Throughout the period of the study, pregnant women in the UK were overweight or obese in more than 47% of cases 25 .We found a median BMI of 25 in women presenting with breast cancer during pregnancy, with 42% of cases above the normal BMI.This finding is similar to the median found in the POSH study 18 .This tendency may reflect previously reported findings of lower BMI among premenopausal women with breast cancer 26 .
The high percentage of symptomatic women before diagnosis (97%) is similar to that found in the POSH study (98%) 18 , as might be expected outside a screening program population's demographic.In postmenopausal women, twothirds are asymptomatic at the time of diagnosis, with diagnosis at an earlier stage of screening.This may contribute to the worse prognosis in young women with breast cancer 27 .Three-quarters of the cases presented with a breast lump, two-thirds on its own and the remainder mostly with a lump and/or other symptoms.These other presentations, such as nipple inversion, pain and fullness, skin changes, breast enlargement, nipple discharge, and erythema, need to be highlighted to women and midwives because symptoms are easily dismissed as part of the normal pregnancy breast changes.This emphasizes the importance of increasing awareness of this diagnosis when discussing breast symptoms at any stage of pregnancy.
Pregnancy often masks symptoms and signs of breast cancer, leading to delayed diagnosis.The interval between the start of symptoms and diagnosis reported here (median 3 weeks; IQR: 2-9) is shorter than the median time of 4 weeks (range 1-104 weeks) found in the Australian study of Ives 10 , which included postpartum diagnosis, and the mean time of 3.9 months during pregnancy found by Langer et al. 28 .
The median gestational age at diagnosis, 25 weeks, had a wide range, similar to the findings of other, smaller studies 21 .A large number of women (44%) were diagnosed in the third trimester.Of these 37 women, 35 (95%) underwent induction of labor or pre-labor cesarean section.In most cases, treatment (surgery or chemotherapy) was delayed until the end of pregnancy with iatrogenic delivery between 32 and 36 weeks in nearly half (49%).This finding could reflect guidelines regarding safe delivery time for women receiving chemotherapy to allow both maternal and fetal bone marrow recovery 29,30 .The effects of granulocyte-colony stimulating factor on treating neutropenia in pregnancy may modify this decision, avoiding iatrogenic prematurity, and seems to be safe 31,32 .
The UK confidential inquiry into maternal mortality, Mothers and Babies: Reducing Risk through Audit and Confidential Enquiries (MBRRACE-UK), has recently reported on a subset of the cases identified through the UKOSS reporting system as part of this UK breast cancer in pregnancy (UKBCiP) study, with direct access to anonymized patient records for assessment.This suggests new guidance: in general, early delivery to avoid delays in chemotherapy should not be recommended 33 .For women diagnosed with breast cancer in the third trimester, the risk benefit is likely to favor both mother and baby if a .
Overall, we found that more likely to be induced (57% vs. 39%) or undergo elective cesarean section (47% vs. 15%) than the general population in England 31 .
The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH Breast Cancer Study) 18 , although not directly comparable, provides context outside pregnancy because the demographics overlap with this UKBCiP study.Breast cancer was found to present at a more advanced stage in pregnancy, with higher node involvement and tumor grade.
The finding that 59% of women with newly diagnosed breast cancer in pregnancy are estrogen receptor (ER) positive compares to 66% in the POSH study, with triple-negative tumors present in 29% and 20% of women, respectively.
Although in England, overall for the period 2016-17 7.9% of babies were preterm 35 and in Scotland 6.5% (https://www.opendata.nhs.scot/dataset/births-in-scottish-hospitals), the preterm delivery rate of 41% was lower than that reported by Amant et al. in an international collaborative study of 311 cases of breast cancer diagnosed during pregnancy (49.6%) 6 .A smaller case series reported higher rates of preterm delivery; Gomez-Hidalgo in 11 cases found that 54.6% of the neonates were preterm 19 and Framarino-dei-Malatesta in 54.5% of 22 women 21 .Outcome data suggest that the fetus does relatively well, even when exposed to several maternal chemotherapy regimens.Amant et al. (2015) concluded that prenatal exposure to maternal cancer, with or without treatment, did not impair the cognitive, cardiac, or general development of children in early childhood.Prematurity was correlated with worse cognitive outcomes; however, this effect was independent of cancer treatment 36 .
MBRRACE also noted that variations in staging practices may have led to unnecessarily extensive surgery 29 .
The safety of current chemotherapy regimens during pregnancy is well documented, and breast cancer treatment during pregnancy should adhere to that of non-pregnant women.Most patients (31 of 37) received anthracycline-based chemotherapy.This was associated with cyclophosphamide use in 26 of the 37 women who received chemotherapy during pregnancy.Taxanes were used in 15 women.The most widely used combination was FEC in ten women.
It seems that later delivery (for the fetus), providing appropriate chemotherapy in pregnancy, and aiming for vaginal delivery are all reasonably safe.In a situation that is psychologically distressing for a woman and her family, the creation of 'normality' in relation to the birthing experience can be hugely important to their well-being and future perception.

Strengths and limitations of this study
This is the first national prospective study of breast cancer diagnosed during pregnancy in the UK and its incidence, management, and short-term outcomes.The study raised awareness of the rare condition of breast cancer in pregnancy among UK obstetricians and oncologists during the 2 years of the UKOSS data collection.
UKOSS data rely on the reporting of monthly cases, and a certain amount of under-reporting may occur; hence, the use of a 95% confidence interval has been included with our estimate of incidence.
The incidence estimate reported here must be considered a minimum estimate for several reasons.UKOSS is a system that involves all consultant-led maternity units in the UK, but some women diagnosed with breast cancer during pregnancy could have chosen to undergo termination of pregnancy or had a miscarriage before reaching these maternity units; thus, this will not be a true reflection of what may be happening in early pregnancy.
Additionally, although we wrote to clinical oncology units and contacted patient support groups such as Mummy's Star to raise awareness of the study, the anonymized nature of UKOSS reporting precludes the study team from having women's details, for example, through self-reporting, to crosscheck with reporting units specifically to ensure their details had been included in the study.Currently, pregnancy data are not included in most cancer registries; therefore, these data cannot be used to enhance case ascertainment.

Conclusions
The incidence of breast cancer arising during pregnancy in the UK is 5.4 per 100,000 maternities.The relatively high number of IVF pregnancies requires further investigation as this may not be related to increased age alone.This study confirms relatively late presentation, with diagnosis at a more advanced stage, highlighting the need for education of women and those who care for them regarding breast symptoms in pregnancy.Breast symptoms should be discussed specifically, and women should be encouraged to report any concerns with a low threshold for seeking investigation or additional medical review.
With the exceptions that chemotherapy should not be administered in the first trimester and that the use of HER-2 targeted therapies should generally be avoided, the management of these women should be the same as chemotherapy can be safely delivered during pregnancy with good overall fetal outcomes.It is often possible to avoid exposing the baby to iatrogenic prematurity.
Co-ordinated multidisciplinary work among obstetricians, breast surgeons, and oncologists is essential to ensure optimal management.
A larger prospective study is required to allow longer-term follow-up, but this would require individual patient consent.Meanwhile, adding pregnancy status to the UK cancer registries would yield more information about treatment and outcomes.

Nimmi Kapoor
University of California Los Angeles, Los Angeles, California, USA This paper utilizes an incomplete set of data from 7-9 years ago to attempt to describe the incidence of breast cancer diagnosed during pregnancy in the UK.Understanding breast cancer in pregnancy is very important, with rising maternal age and increased incidence of breast cancer in young women, but this manuscript falls short in many areas.Major criticism #1: The primary objective set by the authors are not met accurately.The authors provide a calculation of incidence of 5.4 per 100,000 maternities.This number is flawed and not explained.The numerator includes women who terminated pregnancies, and they exclude 11 patients without information which is 11.6% of the data.The denominator is termed "maternities", yet it will miss the large number of women who were pregnant and did not carry the pregnancy to delivery.Some of these excluded women would have been included in the numerator.Major criticism #2: The authors are using a dataset from 2015-2017 for no clear reason, with missing stage information for over 30% of patients.This is not of great relevance.Minor critiques are below: Abstract This statement is unnecessary: "With caveats, the management followed that outside pregnancy, but there was considerable variation in practice."This is not clear or relevant: "It is often possible to avoid exposing the baby to iatrogenic prematurity."Methods See major comment #1 This is inaccurate: "No patients were involved in this study."Results See major comment #2 Organization of chemotherapy, surgery, and trimester timing of treatment is unclear.Consider a table sorted by trimester, tumor stage, receipt of chemotherapy, type of surgery, and then maternal and fetal outcomes.Combine Tables 1 and 2, consider removing clinical stage from the table since it is missing for so many women (could either delete or simply report in text).You don't need to report all the data in Table 2 in text format for gestational age.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above.

Hatem Azim
Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico A well written and needed report.Below are few points for the authors to consider -Provide if HER2 targeted therapy were received during pregnancy.
-provide difference in neonatal outcomes between those who were delivered at full term versus those before week 37.It is relevant to discuss impact of prematurity on the observed neonatal outcomes.

If applicable, is the statistical analysis and its interpretation appropriate? Yes
Are all the source data underlying the results available to ensure full reproducibility?Yes

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Breast cancer in the young and its relation to pregnancy and fertility I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.The authors' effort in producing this article is commendable.Data collection for breast cancer in pregnancy is frequently plagued with difficulties as obstetric data is not usually entered into breast cancer registries.The use of a nation-wide database, like UKOSS, helps to provide consistent and vital obstetric information.The paper is generally well-written, data is presented clearly and conclusions are reasonable.Below are some suggestions for improvement 1) Data was only collected for two years from 2015 to 2017.Collecting data across more years would add to the study population and allow more robust conclusions to be drawn from the results.
2) It would be easier to understand the different treatment plans within each trimester if patients were divided into groups eg.neoadjuvant chemotherapy and surgery, surgery and adjuvant chemotherapy, surgery only, palliative chemotherapy, no/declined treatment.
3) The paragraph describing treatment in the third trimester can go after the paragraph describing treatment in the second trimester to make for an easier read.4) The literature thus far does not show conclusive evidence of IVF causing an increase in breast cancer risk.Nonetheless, the observation regarding higher IVF rates in this group of pregnant patients deserves further investigations.In the current paper, it would be useful to know the tumour estrogen receptor status in these patients.
I support and approve the indexing of this paper with some minor suggestions for clarity.

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?I cannot comment.A qualified statistician is required.

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: I am a breast surgeon with research and clinical experience in breast cancer in young women and pregnancy associated breast cancer I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Reviewer Report 03
September 2024 https://doi.org/10.3310/nihropenres.14823.r32623© 2024 Azim H.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reviewer Report 06
August 2024 https://doi.org/10.3310/nihropenres.14823.r32364© 2024 Tan Q.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Qing Ting Tan KK Women's and Children's Hospital, Singapore, Singapore

Table 2 . Gestational age, symptoms and size of tumor at diagnosis.
*IQR = interquartile range.

Table 4 . Chemotherapy regimens used during pregnancy and outcomes.
*Gestational ages in the "other" category are presented as ranges because the patients received different treatment regimens.In nine cases, chemotherapy was continued postpartum, but the gestational age at which it was stopped antenatally is unknown.GA: gestational age.SGA: small for gestational age, includes cases with a birth weight below the 10 th centile.TOP: termination of pregnancy.NICU: neonatal intensive care unit.SROM: spontaneous rupture of membranes.FEC-T: fluorouracil, epirubicin, cyclophosphamide, and docetaxel.FEC: fluorouracil, epirubicin, and cyclophosphamide.EC: epirubicin and cyclophosphamide.EC-D: epirubicin, cyclophosphamide, and docetaxel.ECX: epirubicin, cisplatin, and capecitabine.AC-TH: doxorubicin (Adriamycin), cyclophosphamide, docetaxel, and trastuzumab.AC: doxorubicin and cyclophosphamide.