No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Effect of pregnancy as a risk factor for breast cancer inBRCA1/BRCA2 mutation carriers
Abstract
Eligible women were selected from a registry of individuals assessed for genetic risk in 1 of 55 genetic counseling centers in North America, Europe, or Israel. Study subjects were women who attended a genetics clinic for the purpose of risk assessment and genetic counseling. All patients received their genetics test result (with the exception of those at the University of Utah, where patients were enrolled in a research study but did not receive their genetic test result). In most cases, the patient completed a questionnaire dealing with reproductive histories and cancer histories during one of the counseling sessions, but in some cases the questionnaire was mailed or was administered over the phone. Information was obtained on 6,133 carriers with deleterious mutations in BRCA1 (n = 4,612) or in BRCA2 (n = 1,521). The ethics committee or institutional review board at all participating centers approved this study and all women provided written informed consent. For the majority of cases, testing was initially offered to individuals with a diagnosis of breast or ovarian cancer. If a deleterious mutation was found, testing was offered to other at-risk family members. Mutations were initially identified using a variety of techniques, but all variant nucleotide sequences were confirmed with direct sequencing of DNA. The majority of women included in this study had nonsense mutations, deletions, insertions, or small frameshift mutations; these are known to confer an increased risk of breast cancer. Patients with variants of uncertain significance were not included in the study.
... Given the earlier age at which BC risk increases for women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation, it is important to know whether the BC risk for carriers is modified by the number and timing of their pregnancies and/or by breastfeeding. However, the few studies that assessed associations with pregnancies and breastfeeding for BRCA1/2 mutation carriers have reported inconsistent results [for reviews, see (11,12)], ranging from studies supporting a decreased risk from FTP (13,14) to studies supporting no association (15) to studies supporting an increased risk (16). Although more limited in numbers, studies that examined BRCA1 and BRCA2 mutation carriers separately have supported differences in associations by mutation type [eg, higher risk for late age at first FTP or parity in general for BRCA2 mutation carriers (13,16) and lower risk for multiparity for BRCA1 mutation carriers (16) and differences based on breastfeeding (17)(18)(19)]. ...
... However, the few studies that assessed associations with pregnancies and breastfeeding for BRCA1/2 mutation carriers have reported inconsistent results [for reviews, see (11,12)], ranging from studies supporting a decreased risk from FTP (13,14) to studies supporting no association (15) to studies supporting an increased risk (16). Although more limited in numbers, studies that examined BRCA1 and BRCA2 mutation carriers separately have supported differences in associations by mutation type [eg, higher risk for late age at first FTP or parity in general for BRCA2 mutation carriers (13,16) and lower risk for multiparity for BRCA1 mutation carriers (16) and differences based on breastfeeding (17)(18)(19)]. ...
... However, the few studies that assessed associations with pregnancies and breastfeeding for BRCA1/2 mutation carriers have reported inconsistent results [for reviews, see (11,12)], ranging from studies supporting a decreased risk from FTP (13,14) to studies supporting no association (15) to studies supporting an increased risk (16). Although more limited in numbers, studies that examined BRCA1 and BRCA2 mutation carriers separately have supported differences in associations by mutation type [eg, higher risk for late age at first FTP or parity in general for BRCA2 mutation carriers (13,16) and lower risk for multiparity for BRCA1 mutation carriers (16) and differences based on breastfeeding (17)(18)(19)]. ...
Background
Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.
Methods
Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.
Results
For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).
Conclusions
These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.
... Older age at first pregnancy is a strong predictor for increased risk of later onset breast cancer both in the general population [1] and in women with a family history of breast cancer [2]. However, published evidence for BRCA1 and BRCA2 pathogenic mutation carriers (with a very high lifetime risk of breast cancer) is conflicting [3][4][5][6][7][8]. Taking studies chronologically from 1999, an initial study showed no effect of age at first pregnancy but an increase in risk of breast cancer by age 40 in women who were parous compared to nulliparous [3]. ...
... Taking studies chronologically from 1999, an initial study showed no effect of age at first pregnancy but an increase in risk of breast cancer by age 40 in women who were parous compared to nulliparous [3]. Cullinane et al. showed some protective effect of multiple pregnancies in BRCA1 mutation carriers but an increase in breast cancer risk in BRCA2 carriers [4]. A further study showed an increased risk in BRCA1 carriers with early compared to late first pregnancy [5] (although, in BRCA2, early first pregnancy was protective), but no overall protective effect of pregnancy for either gene. ...
... There is, therefore, no consistent evidence for an effect of age at first pregnancy. Indeed, some studies demonstrate an increased risk of breast cancer with any pregnancy in mutation carriers in contrast to the general population [3][4][5]. In view of these inconsistencies, we have examined the effects of early age at first full-term pregnancy (FFTP) on breast cancer risk to age 50 years in the Manchester regional BRCA database. ...
Purpose:
Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.
Methods:
Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan-Meier analyses were performed.
Results:
2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30-39 years. Kaplan-Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002).
Conclusions:
The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.
... Should an invasive or occult carcinoma be found, patients should be referred to a gynaecologic oncologist (strong, high). 23 In this paper we summarize the risks of HBOC as they pertain to gynaecologic malignancy and address the full spectrum of care, from screening to contraceptive care and family planning to chemoprophylaxis and risk-reducing surgery. We then summarize the data on management of premature menopause in HBOC. ...
... One case-control study looking only at parity found an increased risk of breast cancer (OR 1.53; 95% CI 1.01−2.32) in BRCA2 mutation carriers with 2 or more children. 23 Because of lactational changes in the breast during pregnancy and postpartum, breast screening is not optimally performed during these times. 24 The risk-benefit analysis of suboptimal imaging versus prolonged breastfeeding seems to favour breastfeeding in BRCA1 carriers, while more data are required to make conclusions about the effects on BRCA2 carriers. ...
Objective:
This Committee Opinion outlines the gynaecologic management recommendations for women diagnosed with hereditary breast and ovarian cancer syndrome (HBOC) with respect to screening, contraception, chemoprophylaxis, fertility considerations, risk-reducing surgery, and post-oophorectomy care.
Intended users:
This Committee Opinion is designed for gynaecologic oncologists, general gynaecologists, family physicians, genetic counsellors, registered nurses, nurse practitioners, residents, and health care providers.
Target population:
Adult women (18 years and older) with a pathogenic germline variant in the BRCA1, BRCA2, and other ovarian cancer-associated genes.
Evidence:
While reviewing evidence, databases searched include Medline, Cochrane, and PubMed. Medical Subject Heading search terms used include BRCA AND gynaecology management, hormone replacement therapy, risk reduction, chemoprophylaxis, fertility from 01/2010 and 10/2017. Literature search was begun 07/2017 and finalized 10/2017. In total 183 studies were identified, and 101 were used.
Validation methods:
The content and recommendations were drafted and agreed upon by the principal authors. The Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework (Table 1). The interpretation of strong and conditional (weak) recommendations is described in Table 2. The Summary of Findings is available upon request.
Benefits, harms, and costs:
We may expect a risk reduction of up to 90% in women predisposed to HBOC who undergo risk-reducing bilateral salpingo-oophorectomy. The harms of iatrogenic premature menopause are offset by the benefits of risk reduction. By minimizing potential tubal/ovarian/peritoneal cancers, we can expect savings to the health care system.
Guideline update:
Evidence will be reviewed 5 years after publication to decide whether all or part of the opinion should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations.
Sponsors:
This guideline was developed with resources funded by the Society of Obstetricians and Gynaecologists of Canada.
Recommendations:
... 14 Em doentes com mutações BRCA1/2 portadoras de cancro da mama o risco de uma gravidez subsequente não está estabelecido, dada a escassez de resultados publicados. 17,30,55 No entanto, o conhecimento do status BRCA parece influenciar a decisão relativa a gravidez. Nas portadoras da mutação BRCA1 não existe consenso; um estudo multicêntrico, International BRCA1/2 Carrier Cohort Study (IBCCS), evidencia uma redução de 38% do risco de cancro da mama com a multiparidade, enquanto nas portadoras de mutações BRCA2 o risco de cancro da mama parece aumentar com a gravidez, sendo estatisticamente significativo nos primeiros dois anos após gravidez. ...
... Nas portadoras da mutação BRCA1 não existe consenso; um estudo multicêntrico, International BRCA1/2 Carrier Cohort Study (IBCCS), evidencia uma redução de 38% do risco de cancro da mama com a multiparidade, enquanto nas portadoras de mutações BRCA2 o risco de cancro da mama parece aumentar com a gravidez, sendo estatisticamente significativo nos primeiros dois anos após gravidez. 55 Na verdade, segundo um outro estudo retrospetivo, mulheres portadoras de mutação em BRCA1 que tenham o seu primeiro filho após os 30 anos apresentam um risco reduzido de cancro da mama, enquanto as portadoras da mutação em BRCA2 que engravidam após os 30 anos parecem ter um risco acrescido deste tumor. 56 ...
Breast cancer survivors have given rise to several issues of major relevance from a clinical and scientific point of view. In fact, breast cancer is the most prevalent malignancy in women of reproductive age. The effect of pregnancy on overall survival and in the recurrence after treatment of breast cancer, as well as the questions related to heredity continue to be matter of the highest timeliness and scientific interest. Most recent studies seem to agree in admitting that pregnancy after breast cancer appears to be potentially safe to both the women and her offspring, although this issue remains complex. Heredity and genetics seem to play an important role in this subject, but the conclusions lack absolute and unequivocal consistency. There is a need for meta-analysis, cohort and case-control studies, translational and prospective studies extended in time, in order to obtain greater safety in the establishment of strategies and guidelines for clinicians and adequate objective information for young breast cancer patients.
... Число родов > 4, по данным С.А. Cullinane (2005), снижает риск рака у носительниц BRCA1-мутации. При BRCA2мутации риск повышается при большем количестве родов, особенно на 2-й год после беременности [5]. ...
... Cullinane (2005), снижает риск рака у носительниц BRCA1-мутации. При BRCA2мутации риск повышается при большем количестве родов, особенно на 2-й год после беременности [5]. Лактация в течение > 1 года также снижает риск РМЖ у носительниц мутации BRCA1 [10]. ...
A group of reproductive age patients whose disease is associated with the carriage of BRCA1 gene mutation is of scientific interest. Differences in the molecular pathogenesis between BRCA-associated breast cancer and sporadic counterpart might presuppose anamnesis features of each group as well. We have ascertained that the mean age in young age patients with positive BRCA1 status is 31.8 ± 3.3 years, in 40 % of cases in the family history in the 1st and 2 nd order relatives a breast cancer was identified, in 40 % of cases breast cancer was diagnosed during pregnancy, breast feeding or 1 year post-pregnancy, the disease course in young BRCA1-positive patients is characterized by a 30 % risk of contralateral breast cancer during the first 5 years of observation.
... Nevertheless, the tendency for parity to increase the risk of ER-and TN breast cancers while reducing that of ER + breast cancer has been reported among African Americans [13]. Notably, the role of parity in breast cancer has been described as controversial (with tendency to both increase and reduce breast cancer risk [42]). Since the prevalence of ER-breast cancer, TN breast cancer, and total fertility rate is high in Nigeria compared to the experience in high income countries, it will be necessary to clarify the nature of their relationships. ...
Purpose of the study
The aim of the study was to investigate the association between reproductive factors and breast cancer risk in Nigeria. This has not been widely investigated in sub-Saharan Africa.
Methods
We conducted a hospital-based case–control study involving participants from five hospitals in Lagos and Abuja. Women were interviewed in-person between October 2016 and May 2017 using a semi-structured questionnaire. We collected data on parity, breastfeeding, age at first and last birth, age at menarche, oral contraceptive use and history of abortion. The data were analysed using multivariable logistic regression adjusting for relevant confounders.
Results
Every additional 6 months of breastfeeding over a lifetime reduced breast cancer odds by: 7% (95% CI: 1%, 12%) in all women, 15% (95% CI: 5%, 24%) in women < 50 years, and 8% (95% CI: 0%, 12%, p for trend = 0.043) in oestrogen receptor negative (ER-) cases. Each additional 1-year delay before the first full-term pregnancy increased oestrogen receptor positive breast cancer odds by 9% (95% CI: 2%, 17%). Each additional 1-year delay before the last full-term pregnancy increased breast cancer odds by: 7% (95% CI: 2%, 12%) in all women, 12% (95% CI: 4%, 21%) in ER- breast cancer patients, and 14% (95% CI: 4%, 25%) in triple negative breast cancer patients. Other reproductive factors did not significantly increased breast cancer odds.
Conclusion
While advanced age at first and last full-term pregnancies increased breast cancer odds, breastfeeding reduced it. These associations varied by age and oestrogen receptor status. Improved breastfeeding practices and timely births should be promoted in Nigeria.
... Though the issue is still controversial, one study suggested a differential association with parity between BRCA1 and BRCA2 mutation carriers. 60,61 Breastfeeding, on the other hand, can be protective. In a case-control study of more than 1500 pairs of women with BRCA1 or BRCA2 pathogenic mutations and matching patients with breast cancer and unaffected carriers of respective mutation as controls, investigators found significant reduction in breast cancer risk in BRCA1 carriers with reduction increased by increased duration of breast feeding: a 32% reduction in risk for one year of breastfeeding (OR=0.68; ...
Sarah Edaily, Hikmat Abdel-Razeq Department of Internal Medicine, King Hussein Cancer Center, Amman, JordanCorrespondence: Hikmat Abdel-Razeq, Department of Internal Medicine, King Hussein Cancer Center, Queen Rania Al Abdullah Street, P.O. Box: 1269, Amman, 11941, Jordan, Tel +962-6 5300460, Ext: 1000, Email habdelrazeq@khcc.joAbstract: Most of breast cancer cases are sporadic; however, 15– 20% are associated with family history, and some are inherited. Among those, deleterious mutations in BRCA1 and BRCA2 tumor suppressor genes are the most commonly encountered pathogenic germline variants (PGVs). Given the availability and affordability of multi-gene panel sequencing technologies, testing for PGVs is commonly practiced. With our enhanced understanding of cancer genetics and specific molecular alterations, the better acceptance of risk-directed screening and prevention, and the recent introduction of novel targeted therapies, management of BRCA-positive breast cancers is taking a new direction, focusing more on risk-reducing interventions, including mastectomy and salpingo-oophorectomy, and incorporating special treatment regimens, including platinum-based chemotherapy, and the recently-introduced PARP (poly (ADP)-ribose polymerase) inhibitors. Given the recent advances in reproductive technology and molecular medicine, younger women with PGVs may have the option of embryo selection through preimplantation genetic testing and diagnosis, thus preventing the potential transmission of the implicated genes to the next generations. In this review, we cover the clinical implications of identifying a pathogenic germline mutation in BRCA1 and BRCA2 genes in breast cancer patients, and their relatives, across the continuum of care – from cancer prevention and early detection, through active treatment and up to survivorship issues.Keywords: breast cancer, BRCA1, BRCA2, germline mutation, risk-reducing surgery
... A large prospective study showed that women with BRCA1 pathogenic variants who had two, three, four, or more full-term pregnancies were at 21%, 30%, and 50% decreased risk of BC compared to women with a single full-term pregnancy [9]. On the contrary, women with BRCA2 pathogenic variants with multiple pregnancies had a significantly increased risk of developing BC [10]. In the general population, healthy women have a transient increased risk of BC after a pregnancy and the increased risk is higher for women with a family history of BC and for women with a pregnancy at a later age [11,12]. ...
Background
Healthy individuals and patients with cancer who are carriers of germline pathogenic variants in the BRCA1/2 genes face multiple reproductive challenges that require appropriate counseling and specific expertise.
Main body
On December 5th–7th, 2019, patient advocates and physicians with expertise in the field of reproductive medicine, fertility preservation, and oncology were invited to “San Giuseppe Moscati” Hospital in Avellino (Italy) for a workshop on reproductive management of women with germline pathogenic variants in the BRCA1/2 genes. From the discussion regarding the current evidence and future prospective in the field, eight main research questions were formulated and eight recommendations were developed regarding fertility, fertility preservation, preimplantation genetic testing, and pregnancy in healthy carriers and patients with cancer.
Conclusion
Several misconceptions about the topic persist among health care providers and patients often resulting in a discontinuous and suboptimal management. With the aim to offer patient-tailored counseling about reproductive issues, both awareness of current evidences and research should be promoted.
... Pregnant women who inherit either the BRCA 1 or BRCA 2 mutation may also consist a significant percentage among the gestational BC cases. Moreover, although there are no sufficient scientific evidences, the inheritance of the BRCA 2 mutation may represent an important risk for GBG even in case of multiparity which is generally considered to protect against BC (4). Some studies have reported an advanced stage of the BC at the moment of diagnosis during pregnancy, namely between 65% and 90% stage II-III BCs compared to 45-66% stage II-III BCs in non-pregnant women (5,6). ...
Background. Gestational breast cancer (GBC) is also known as pregnancy-associated breast cancer and it comprises all the breast cancers (BCs) which are diagnosed either during pregnancy or in the first year after delivery or during the lactation period. At present it has been confirmed that the breast malignancies are the most common forms of cancer in pregnant women with a constant increase in its incidence because of the continuous postpone in childbearing especially in women older than 40 years. However, when diagnosed during the pregnancy, the treatment modalities of the BC are complex and difficult to establish as it must be considered the impact of the treatment both on the child and the course of pregnancy.
Purpose. Using an online search on Pubmed, our aim was to make a review of the treatment possibilities of a pregnant woman presenting a breast malignant tumor. We have concentrated our paper on the surgical treatment and the possibility of an oncoplastic reconstruction types, the facts of radiotherapy during pregnancy and the prognosis of the GBC particularly in women who opt to continue the pregnancy. A resume of the epidemiology of GBG is also presented.
Method. The following key words have been on Pubmed introduced: ,,breast cancer’’, ,,pregnancy’’, ,,staging”, ,,chemotherapy” and ,,radiotherapy”. As mentioned above, we have tried to select the BC cases diagnosed and treated during pregnancy for which the decision of the patient was to continue the pregnancy in
spite of the diagnosis. We further aimed to present the prognosis of the pregnancy-associated BC, namely the pregnancy and fetal outcome, and to investigate if the decision to terminate the pregnancy is associated with a survival benefit.
Conclusion. The surgical treatment of pregnancy-associated BC does not differ from that of non-pregnancy BC. Axillary LN-dissection is permitted while the data on the safety of sentinel-LN are still poor. Elective termination of the pregnancy has no impact on the overall survival of the patient.
... The lifetime risk for breast and ovarian cancer rises dramatically for BRCA mutation germline carriers compared to the general population ( Figure 1). The overall risk varies by family history, type and location of the mutation, age at diagnosis, parity (number of term pregnancies), environmental factors, and genetic modifiers [5][6][7][8][9][10]. The discovery of the hereditary breast and ovarian cancer (HBOC) BRCA genes in the early 1990s laid the framework for the future of precision medicine as patients became empowered with the ability to make life-changing decisions to manage and mitigate cancer risks [11,12]. ...
Pathological mutations in homology-directed repair (HDR) genes impact both future cancer risk and therapeutic options for patients. HDR is a high-fidelity DNA repair pathway for resolving DNA double-strand breaks throughout the genome. BRCA2 is an essential protein that mediates the loading of RAD51 onto resected DNA breaks, a key step in HDR. Germline mutations in BRCA2 are associated with an increased risk for breast, ovarian, prostate, and pancreatic cancer. Clinical findings of germline or somatic BRCA2 mutations in tumors suggest treatment with platinum agents or PARP inhibitors. However, when genetic analysis reveals a variant of uncertain significance (VUS) in the BRCA2 gene, precision medicine-based decisions become complex. VUS are genetic changes with unknown pathological impact. Current statistics indicate that between 10–20% of BRCA sequencing results are VUS, and of these, more than 50% are missense mutations. Functional assays to determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer risk and treatment options. In this review, we provide a brief overview of BRCA2 functions in HDR, describe how BRCA2 VUS are currently assessed in the clinic, and how genetic and biochemical functional assays could be integrated into the clinical decision process. We suggest a multi-step workflow composed of robust and accurate functional assays to correctly evaluate the potential pathogenic or benign nature of BRCA2 VUS. Success in this precision medicine endeavor will offer actionable information to patients and their physicians.
... At present, several other genes that increase the risk of breast cancer (PALB2, CHECK2, CDH1, etc.) are being identified in genetic screening panels. Genetic counseling is recommended for all patient with PABC [36]. Carriers of BRCA/2 not only have a higher risk of developing PABC but also have probably poorer outcomes with higher probability of developing distant metastases [37]. ...
The main goal of precision medicine in patients with breast cancer is to tailor the treatment according to the particular genetic makeup and the genetic changes in the cancer cells. Breast cancer occurring during pregnancy (BCP) is a complex and difficult clinical problem. Although it is not very common, both maternal and fetal outcome must be always considered when planning treatment. Pregnancy represents a significant barrier to the implementation of personalized treatment for breast cancer. Tailoring therapy mainly takes into account the stage of pregnancy, the subtype of cancer, the stage of cancer, and the patient’s preference. Results of the treatment of breast cancer in pregnancy are as yet not very satisfactory because of often delayed diagnosis, and it usually has an unfavorable outcome. Treatment of patients with pregnancy-associated breast cancer should be centralized. Centralization may result in increased experience in diagnosis and treatment and accumulated data may help us to optimize the treatment approaches, modify general treatment recommendations, and improve the survival and quality of life of the patients.
... Mutations in BRCA1/2 are considered as risk factors for the onset of breast cancer (131); Atchley et al. reported a significant association between mutations in breast cancer susceptibility gene 1 (BRCA1) and TNBC, with more than 2/3 of BRCA1 mutations cases being of TNBC phenotype (132). Earlier studies have indicated that BRCA1/2 mutation carriers can be at a higher risk for PABC (133,134). A study by Johannsson et al. analyzed the incidence of PABC in carriers of BRCA1 and BRCA2 mutations in comparison with premenopausal Swedish women aged ≤ 40 with sporadic PABC (133). ...
Breast and cervical cancers comprise 50% of all cancers during pregnancy. In particular, gestational breast cancer is considered one of the most aggressive types of cancers, which is a rare but fatal disease. However, the incidence of this type of cancer is increasing over the years and its prevalence is expected to rise further as more women delay childbearing. Breast cancer occurring after pregnancy is generally triple-negative with specific characterizations of a poorer prognosis and outcome. On the other hand, it has been pointed out that this cancer is associated with a specific group of genes that can be used as precise targets to manage this deadly disease. Indeed, combination therapies consisting of gene-based agents with other cancer therapeutics is presently under consideration. We herein review recent progress in understanding the development of breast cancer during pregnancy and their unique subtype of triple-negative which is the hallmark of this type of breast cancer.
... [9] показало, что у носителей BRCA2-мутаций c преждевременным менархе или отсутствием родов в анамнезе РМЖ чаще имел раннее начало, а вероятность развития РМЖ у рожавших женщин была выше, чем у нерожавших в группе с мутацией BRCA2. C. Cullinane [10], M. Alsaker и соавт. [11] сообщили о повышении риска развития рака РМЖ у носителей BRCA2-мутаций с большим числом родоразрешений (до 15% на каждое родоразрешение), в то время как N. Andrieu и соавт. ...
The literature review devoted to the evaluation of various methods of prevention, early diagnosis, and treatment of the hereditary breast cancer has been presented. Methods of surgical prevention, effectiveness of bilateral prophylactic mastectomy are considered.
... холи с метастазами повышена в 2,5 раза по сравнению с небеременными. Для женщин с генетической предрасположенностью к раку молочной железы -РМЖ (носительство мутаций гена BRCA2) не доказан протективный эффект от наличия и продолжительности грудного вскармливания в анамнезе [3]. ...
... This variation results in difficulties in risk calculation and genetic counseling. Several environmental factors such as birth cohort [10], age at menarche [11], number of pregnancies [12], therapeutic abortion [13], oral contraceptives [14], and prophylactic oophorectomy [15,16] are suspected to affect the risk of cancer in BRCA1/2 mutation carriers. Using data from the Generations Study, Brewer and colleagues showed that having a first-degree female relative with breast cancer increases the relative risk of breast cancer as compared to those without family history [17]. ...
Background:
Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon.
Methods:
We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways.
Results:
Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00-27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05.
Conclusions:
To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.
... Alternative mechanisms may include alteration in some specific molecular pathways in cancer. For example, pregnancy affords little protective effect for female carriers of BRCA1/BRCA2 mutations 36,37 . Moreover, a study of p53-null mice demonstrated the lack of a parity effect 38 . ...
Abstract Radiation exposure during the peri-pubertal period is a proven risk factor for breast cancer, whereas parity is an established protective factor. The present study investigated whether parity imposes differential protective effects against radiation-induced rat mammary carcinoma depending on the age at exposure. Pre- and post-pubertal female rats, irradiated or left unirradiated, were mated and allowed to nurse until weaning or left unmated. Appearance of mammary tumors was monitored, and serum concentrations of estradiol and progesterone were measured following weaning. Carcinomas were evaluated by immunohistochemistry for estrogen receptor, progesterone receptor, and the cell proliferation marker Ki-67. Parity reduced the risk of carcinoma in unirradiated and pre-pubertally irradiated rats but not post-pubertally irradiated rats. Although radiation exposure increased serum progesterone level, parity after pre-pubertal exposure significantly decreased the elevated progesterone to a normal level, reflecting a protective effect. Moreover, parity significantly decreased the proportion of hormone receptor–positive carcinomas after pre-pubertal exposure. Parity was also related to the observed positive association between progesterone receptor and Ki-67 indices in cancer tissue, implying progesterone receptor–dependent cell proliferation. Thus, parity protects against radiation-induced rat mammary carcinogenesis depending on the age at exposure; the mechanisms may involve changes in hormone levels and cancer tissue.
... In carriers of breast cancer susceptibility genes 1 and 2 (BRCA1/BRCA2) mutations, pregnancy also increases the risk of breast cancer. Cullinane et al. showed that in BRCA1 carriers, the risk of breast cancer decreases significantly after four or more births, whereas in BRCA2 carriers, parity after two or more births increases the risk of breast cancer (by 1.5-fold compared to nulliparous women) [49]. In BRCA2 mutation carriers, the breast cancer risk within two years after delivery is 70% higher than that in nulliparous women. ...
Breast cancer remains the most common cancer in women. A diagnosis of cancer during pregnancy is uncommon. In recent decades, obstetricians are seeing an increasing number of women who become pregnant or desire to become pregnant after breast cancer treatment because of a delay in childbearing for a variety of reasons, including cultural, educational, and professional. Consequently, breast cancer in young women often occurs before the completion of reproductive plans.
A discussion among the patient, the oncologist, and the obstetrician on the relative benefits of early delivery followed by treatment versus commencement of therapy while continuing the pregnancy is of utmost importance in order to reach a consensual decision. The best available evidence suggests that pregnancy after breast cancer increases the risk of recurrence. The birth outcome in women with a history of breast cancer is no different from that in the normal female population; however, increased risks of delivery complications have been reported in the literature.
As concurrent pregnancy and breast cancer are uncommon, there are no data from large randomized trials; hence, recommendations are mainly based on retrospective studies.
... In carriers of breast cancer susceptibility genes 1 and 2 (BRCA1/BRCA2) mutations, pregnancy also increases the risk of breast cancer. Cullinane et al. showed that in BRCA1 carriers, the risk of breast cancer decreases significantly after four or more births, whereas in BRCA2 carriers, parity after two or more births increases the risk of breast cancer (by 1.5-fold compared to nulliparous women) [49]. In BRCA2 mutation carriers, the breast cancer risk within two years after delivery is 70% higher than that in nulliparous women. ...
Breast cancer remains the most common cancer in women. A diagnosis of cancer during pregnancy is uncommon. In recent decades, obstetricians are seeing an increasing number of women who become pregnant or desire to become pregnant after breast cancer treatment because of a delay in childbearing for a variety of reasons, including cultural, educational, and professional. Consequently, breast cancer in young women often occurs before the completion of reproductive plans.
A discussion among the patient, the oncologist, and the obstetrician on the relative benefits of early delivery followed by treatment versus commencement of therapy while continuing the pregnancy is of utmost importance in order to reach a consensual decision. The best available evidence suggests that pregnancy after breast cancer increases the risk of recurrence. The birth outcome in women with a history of breast cancer is no different from that in the normal female population; however, increased risks of delivery complications have been reported in the literature.
As concurrent pregnancy and breast cancer are uncommon, there are no data from large randomized trials; hence, recommendations are mainly based on retrospective studies.
... We previously reported that breastfeeding was protective for BRCA1 mutation carriers [9], whereas parity (vs. nulliparity) may be a risk factor for BRCA2 mutation carriers [10]. In an attempt to disengage the effects of age at first full-term birth from other reproductive factors, we conducted a matched case-control study of 2295 pairs of women with a BRCA1 or BRCA2 mutation. ...
Purpose:
In the general population, an early age at first full-term birth confers protection against the risk of developing breast cancer. The relationship between age at first birth and breast cancer risk is not clear for women with a mutation in the BRCA1 or BRCA2 gene. Thus, we undertook a case-control study of women with a BRCA1 or BRCA2 mutation to study the effects of age at first full-term birth matched for other reproductive factors.
Methods:
Information about reproductive factors, including age at first birth as well as medical history, was collected from a routinely administered research questionnaire. There were 2,295 matched pairs of women with a BRCA1 or BRCA2 mutation included in the final analysis.
Results:
There was no significant difference in the mean age at first full-term birth among the BRCA1 (24.9 vs. 25.2; P = 0.10) or BRCA2 mutation carriers (26.5 vs. 26.6 years; P = 0.80). Findings were similar in the analysis limited to cases who were diagnosed with breast cancer prior to age 45.
Conclusion:
This matched analysis of a large number of BRCA mutation carriers suggests that age at first birth has little influence on BRCA1 or BRCA2 breast cancer risk.
... However, whether reproductive factors in the general population would act as risk factors for BC in BRCA1/2 mutation carriers remain questionable, because BRCA1/2 mutation can disrupt the estrogenic response in tissues by mutation itself [5] or an interaction with many other genes [6,7]. Previous studies of BC risk based on the reproductive factors in BRCA1/2 mutation carriers have produced inconsistent results; hence, the question remains [8][9][10][11][12][13][14][15][16][17]. Thus, the direction in the association of reproductive factors on BC risk in the general population has been hypothesized to be somewhat different from that in mutation carriers and genetically high-risk groups, such as familial BC or early-onset BC patients. ...
This study was conducted to identify the role of reproductive factors as environmental modifiers for breast cancer (BC) risk in clinic-based, East-Asian BRCA1 and BRCA2 mutation carriers and non-carriers with high-risk criteria of BRCA mutations (family history (FH) of BC, early-onset BC (aged ≤40 years)). A total of 581 women who were BRCA carriers (222 BRCA1 and 359 BRCA2), 1,083 non-carriers with FH, and 886 non-carriers with early-onset BC were enrolled and interviewed to examine the reproductive factors, from 2007 to 2014. The hazard ratio (HR) and its 95% confidence interval (CI) in the weighted Cox regression model were used to calculate the BC risk based on the reproductive factors. Earlier menarche increased BC risk by 3.49-fold in BRCA2 mutation carriers (95%CI=2.03–6.00) and 3.30-fold in non-carriers with FH (95%CI=1.73–6.34), but was insignificantly associated with BRCA1 carriers and non-carriers for early-onset BC (P-heterogeneity=0.047). Higher parity decreased BC risk in BRCA carriers and non-carriers with FH, especially in BRCA1 carriers (HR=0.27, 95% CI=0.09–0.83 for two parity; and HR=0.23, 95%CI=0.05–1.00 for ≥3 parity), but increased the early-onset BC risk (HR=4.63, 95%CI=2.56–8.51 for >3 parity, p-heterogeneity=0.045). Oral contraceptive (OC) use and longer estrogen exposure periods (≥30 years) were associated with an increased risk of early-onset BC (HR=3.99, 95%CI=1.65–9.67; HR=7.69, 95%CI=1.96–25.01), while OC use was not associated with BC risk in other groups and longer estrogen exposure had rather decreased risk for BC risk (both p-heterogeneity<0.001). Several reproductive factors as risk modifiers could heterogeneously be associated with BC among BRCA1/2 mutation carriers, non-carriers with FH, and early-onset BC non-carriers.
... Milne et al. [19] reported that parity was associated with protection from breast cancers in BRCA1 and BRCA2 mutation carriers, and each live-birth was associated with an estimated 13% risk reduction. On the other hand, a study based on 55 international collaborating centers [20] observed that increasing parity was associated with increased risk of breast cancer (15% per live-birth) in women who were BRCA2 carriers. In a recent meta-analysis, the risks of breast cancer in parous women who were BRCA1/2 mutation carriers were not statistically different from the risks in corresponding nulliparous women. ...
Purpose
Germline mutations in the BRCA1 and BRCA2 genes confer increased risks for breast cancers. However, the clinical presentation of breast cancer among women who are carriers of the BRCA1 or BRCA2 (BRCA1/2 carriers) mutations is heterogenous. We aimed to identify the effects of the reproductive histories of women with the BRCA1/2 mutations on the clinical presentation of breast cancer.
Methods
We retrospectively analyzed clinical data on women with proven BRCA1 and BRCA2 mutations who were recruited to the Korean Hereditary Breast Cancer study, from 2007 to 2014.
Results
Among the 736 women who were BRCA1/2 mutation carriers, a total of 483 women had breast cancers. Breast cancer diagnosis occurred at significantly younger ages in women who experienced menarche at ≤14 years of age, compared to those who experienced menarche at >14 years of age (37.38±7.60 and 43.30±10.11, respectively, p<0.001). Additionally, the number of full-term pregnancies was significantly associated with the age of diagnosis, especially in women with the BRCA2 mutation. The prevalence of advanced stages (stage II or III vs. stage I) of disease in parous women was higher than in nulliparous women (68.5% vs. 55.2%, p=0.043). This association was more pronounced in women with the BRCA2 mutation (hazard ratio, 2.67; p=0.014).
Conclusion
Our results suggest that reproductive factors, such as the age of onset of menarche and the presence of parity, are associated with the clinical presentation patterns of breast cancer in BRCA1/2 mutation carriers.
... These delays do not happen only because of the difficulty in the interpretation of clinical investigations, but sometimes also the unwillingness of the physician to do a biopsy during pregnancy plays a role [27]. Similar to the general population, genetic predisposition may increase the risk of breast cancer in pregnant women as well, it is postulated that in women with a mutation in BRCA2, the protective effect of multiparity on breast cancer has been lost [9,[28][29][30]. Family history as a strong risk factor may increase the possibility of breast cancer in young women by at least two-fold. ...
... However, many type of fruits for example orange and lemon have B and C vitamins and antioxidant elements that may decrease or prevente BC incidences (Blount, 2002;Azizi, 2003;Cullinane, 2005;Greene, 2006). Our incidences and use of fruits that is in agreement with some studies (Blount, 2002;Azizi, 2003). ...
... The largest study addressing this co-risk factor, which included 1260 pairs of BRCA carriers (BC cases and healthy controls) showed that the increase in the risk of BC with increasing parity was restricted to BRCA2 carriers. In these patients, in the 2-year period following a birth, the risk of BC was increased by 70% compared to nulliparous controls [16]. Conversely, a retrospective cohort study in 1601 carriers of BRCA1 or 2 mutations found no statistically significant difference in the risk of BC between parous and nulliparous women. ...
The interactions between pregnancy and breast cancer (BC) are complex. Overall, parity is associated with long-term protective effects against BC, however in a small group of susceptible patients, pregnancy can lead to the development of a form of BC with a particularly poor prognosis. Pregnancy-associated breast cancer (PABC) remains an under-studied but important and growing clinical problem worldwide. Several aspects of PABC, including risk factors and mechanisms involved in its occurrence and aggressiveness, are incompletely understood. This review aims to summarize the epidemiology, biology, patho-physiology and clinical characteristics of PABC. We emphasize that age at first pregnancy, absence of breastfeeding and family history stand out as possible risk factors for developing PABC that ought to be incorporated into clinical tools for assessing a woman's risk of developing PABC. Also, improved methods for identifying women at risk of developing PABC in the general population are needed.
... Multiple epidemiological studies have reported that the genetic factors, including breast cancer 1, early onset (BRCA1) or BRCA2 mutations, are involved in increasing the incidence of PABC (4)(5)(6). Overexpression of tumor protein p53 and Erb-B2 receptor tyrosine kinase 2 (ERBB2) in patients with PABC has been demonstrated to lead to high proliferation of the tumors (7). Furthermore, C-X-C motif chemokine ligand 13 (CXCL13) and C-C motif chemokine ligand 20 (CCL20) have also been demonstrated to be associated with the progression of PABC (8). ...
The present study aimed to screen the differentially expressed genes (DEGs) in tumor‑associated stroma of pregnancy‑associated breast cancer (PABC). By analyzing Affymetrix microarray data (GSE31192) from the Gene Expression Omnibus database, DEGs between tumor asso-ciated stromal cells and normal stromal cells in PABC were identified. Gene Ontology (GO) function and pathway enrichment analyses for the DEGs were then performed, followed by construction of a protein‑protein interaction (PPI) network. A total of 94 upregulated and 386 downregulated DEGs were identified between tumor associated stromal cells and normal stromal cells in patients with PABC. The upregulated DEGs were primarily enriched in the cytokine‑cytokine receptor interaction pathway and GO terms associated with the immune response, which included the DEGs of interleukin 18 (IL18) and cluster of differentiation 274 (CD274). The downregulated DEGs were primarily involved in GO terms associated with cell surface receptor linked signal transduction and pathways of focal adhesion and pathways in cancer. In the PPI network, nodes of jun proto‑oncogene (JUN), FBJ murine osteosarcoma viral oncogene homolog (FOS), V‑myc avian myelocytomatosis viral oncogene homolog (MYC), and alpha‑smooth muscle actin (ACTA2) had higher degrees. The hub genes of JUN, FOS, MYC and ACTA2, as well as the DEGs IL18 and CD274 that were associated with the immune response in GO terms may exert important functions in the molecular mechanisms of PABC. These genes may be used as new molecular targets in the treatment of this disease.
... Women with BRCA1 exhibited a reduced risk of breast cancer, whereas those with the BRCA2 mutation exhibited an increased risk. In addition, this study also observed that BRCA2 carriers exhibit an increased risk in the fi rst 2 years postpartum [ 19 ]. ...
Pregnancy-associated breast cancer (PABC) is defined as breast cancer that is diagnosed during gestation, lactation, or the first postpartum year. PABC is rare but extremely serious. The disease puts the lives of both mother and fetus at risk. In addition, PABC typically causes clinical, ethical, and psychological problems as well as doubts related to diagnosis and treatment. Clinical and ethical obstacles are frequently encountered during treatment. The gestational age is critical regarding therapeutic options, causing constant modifications and procedural delays. Surgical treatment can be undertaken during any phase of the pregnancy. Chemotherapy can potentially be administered during the second or third trimester. Radiotherapy is reserved for the postpartum period. Interruption of the gestation does not affect the treatment; however, it undoubtedly facilitates the therapeutic conduct. The indication of this course of action must be undertaken with great consideration and discussed openly with the patient and her family.
... Thus, excessive estrogen could be a non-genetic force to induce genomic instability and breast tumorigenesis. To support this notion, it has been shown that both pregnancy and estrogen supplement are associated with an increased breast cancer risk for BRCA1 mutation carrier (42)(43)(44). One function of estrogen is to induce ductal development in mammary gland. ...
There remains great interest in practical strategies to limit the elevated risks of familial breast and ovarian cancers driven by BRCA1 mutation. Here we report that limiting the production of reactive oxygen species (ROS) is sufficient to reduce DNA lesions and delay tumorigenesis in a murine model of BRCA1-deficient breast cancer. We documented a large amount of endogenous estrogen oxidative metabolites in the mammary gland of the model, which induced DNA adducts and apurinic/apyrimidinic sites associated with DNA double-strand breaks and genomic instability. Repressing estrogen oxidation via antioxidant treatments reduced oxidative DNA lesions and delayed the onset of mammary tumors. Overall our work suggests an answer to the long-standing question of why germline BRCA1 mutations cause tissue-specific tumors, in showing how tissue-specific, ROS-induced DNA lesions create a non-genetic force to promote mammary tumors in BRCA1-deficient mice. Our findings create a rationale for evaluating suitable antioxidant modalities as a chemopreventive strategy for familial breast cancer.
Relatamos e discutimos o caso de uma gestante portadora de Câncer de Mama. Objetiva-se compartilhar com a comunidade médica geral: o complexo desafio clínico de manusear adequadamente o caso relatado, além de apresentar informações científicas atuais referentes ao tema, pesquisadas em diferentes fontes de dados especializados, mediante uso de palavras-chave: câncer de mama; gestação; gravidez. Trata-se de uma pesquisa bibliográfica. Aprovada pelo Comitê de Ética em Pesquisas do Hospital Escola Álvaro Alvim, Campos dos Goytacazes, RJ. Não há conflitos de interesses (CFM, 1595/2000). Os dados foram analisados sistematicamente, tendo-se constantemente o foco no objetivo da pesquisa.
Introduction: Breast Cancer Associated with Pregnancy( "BCAP" ) is one of the rare entities of breast tumor pathologies in senology. According to the literature, it has a low frequency. But it is characterized by a clinical picture often very severe. The objective of this article is to illustrate the particularities of this type of cancer by the clinical cases diagnosed in 2022. In addition, to discuss and analyze the epidemio-clinical, histological, therapeutic aspects and short-term prognosis; consented genetic testing was initiated and justified by young age (less than 32 years). Patients and methods: This is a 12-month cross-sectional study, for analytical purposes with prospective collection, conducted at the Department of Gynaecology and Anatomopathology of Panzi/UEA Hospital in 2022. Two patients collected, after clinical examination, met the criteria for selecting BCAP definitions according to the "Journal of Gynaecological-Obstetrics" (36) [6]. Then, their biopsy and blood samples allowed histo-genetic diagnosis at the anatomopathology and molecular biology laboratories of the UEA with counter-expertise in Netherland-Amsterdam. Results: Over a period of twelve months and in a sample of 28 patients with breast cancer, there were 2 cases of BCAP, or 7% incidence. The patients were Bukavu residents from South Kivu, married, under 32 years of age and all with higher education. They consulted late; more than a year, after discovery of breast nodules by self-palpation. All have re-acknowledged having undergone exposure to potential ionizing irradiation. Risk factors were analyzed. For patient (A): menarche at 17 years, ages of marriage and 1st pregnancy at 31 years, primiparity, no breastfeeding, history of breast tumors and local treatment with indigenous products. For (B), obesity, shortened breastfeeding and taking hormonal con-traceptions were noted. The clinic noted in common, advanced cancer, large adherent mass; but, for the patient (A) were associated cachexia, infectious syndrome, anemia and fetal distress ended by fetal death in utero. Anatomical pathology has found a common type "advanced invasive ductal carcinoma"; grade SBR III for (A) and SBR I for (B). The extension assessment noted more peculiarities for (A) with hyperleukocytosis, low hemoglobin, radiopulmonary images in favor of metastases. Genetic testing, looking for BRCA 1&2 mutations, suspected the BRCA1 mutation for both patients, after PCR by presence of amplification of primers 185 and 187 at the UEA/HGRPanzi laboratory. However, sequencing done at the MACROGEN - Netherland laboratory, confirmed the presence of mutations at exon 2 of the objectified BRCA1 gene in the patient (B). Due to lack of resources, genetic analysis of other exons of the BRCA1 and BRCA2 genes has not been performed to exclude associated muta-tions. Conclusion: BCAP, being classically rare, had a very high frequency (7%) in our series. It has affected patients of young age (less than 32 years), diagnosed with late-stage invasive ductal carcinoma with at least 50 percent genetic factor positivity (BRCA 1 mutation). These elements suggest the prospect of undertaking a large-scale study to investigate the most common breast cancer risk factors in Bukavu.
This authoritative textbook provides a much-needed guide for postgraduate trainees preparing for the European Board and College of Obstetrics and Gynaecology (EBCOG) Fellowship examination. Published in association with EBCOG, it fully addresses the competencies defined by the EBCOG curriculum and builds the clinical practice related to these competencies upon the basic science foundations. Volume 1 covers the depth and breadth of obstetrics, and draws on the specialist knowledge of four highly experienced Editors and over 100 contributors from across Europe, reflecting the high-quality training needed to ensure the safety and quality of healthcare for women and their babies. It incorporates key international guidelines throughout, along with colour diagrams and photographs for easy understanding. This is an invaluable resource, not only for postgraduate trainees planning to sit the EFOG examination, but also for practising specialists looking to update their knowledge and skills to meet the ever-evolving complexity of clinical practice.
The diagnosis of breast cancer during pregnancy is uncommon. It varies among different studies between 1:10,000 and 1:3,000 of all pregnancies with a median age of 33 years. The pregnancy-associated breast cancer represents a challenge in terms of clinical management to guarantee both maternal and foetal security choosing the right treatment. This situation is complex and requires a multidisciplinary approach including the surgeon, anaesthesiologist, oncologist, radiotherapist, psychologist and maternal-foetal medicine specialist. In this review we examined the management of pregnancy-associated breast cancer, focusing on patho-physiological background, risk factors, diagnosis, staging procedures, anaesthesia, surgical management and systemic treatment.
Pregnancy-associated breast cancer (PABC) is defined as breast cancer that is diagnosed during gestation, lactation, or the first postpartum year. PABC is rare but extremely serious. The disease puts the lives of both mother and fetus at risk. In addition, PABC typically causes clinical, ethical, and psychological problems as well as doubts related to diagnosis and treatment. Clinical and ethical obstacles are frequently encountered during treatment. The gestational age is critical regarding therapeutic options, causing constant modifications and procedural delays. Surgical treatment can be undertaken during any phase of the pregnancy. Chemotherapy can potentially be administered during the second or third trimester. Radiotherapy is reserved for the postpartum period. Interruption of the gestation does not affect the treatment; however, it undoubtedly facilitates the therapeutic conduct. The indication of this course of action must be undertaken with great consideration and discussed openly with the patient and her family.
Contexte: La grande majorité des mutations délétères identifiées sur le gène BRCA1 sont des mutations « privées ». Cependant, certaines d’entre elles proviennent d’un ancêtre commun, à l’origine d’un effet fondateur. Ainsi, la mutation BRCA1-3600del11 (c.3481_3491del11, p.Glu1161Phefs*3) est localisée en France pour 82% des familles porteuses et 85% d’entre elles sont originaires du quart Nord-Est. En 2006, cette mutation représentait respectivement 51,5% et 42,0% de toutes les mutations du gène BRCA1 identifiées dans les familles lorraines et alsaciennes atteintes d’un cancer du sein et/ou de l’ovaire. En 2004, parmi les 27 cas-index ayant consulté en Alsace et présentant une mutation de BRCA1, 37% sont porteurs de cette mutation, tous issus de familles originaires des Vosges, suggérant l’existence d’un effet fondateur. L’identification d’un haplotype commun est venue confirmer l’existence de cette hypothèse. Une équipe alsacienne a mentionné dans deux publications en 2000 et 2004 sur la mise en évidence de la mutation 3600del11 que les caractéristiques des cancers associés à cette mutation, ne plaidaient pas en faveur d’une relation génotype-phénotype. Or, les caractéristiques anatomo-pathologiques des cancers associés à cette mutation n’ont pas été abordées par ces deux publications. Nous nous sommes alors posés la question de caractéristiques anatomo-pathologiques particulières des cancers du sein et des cancers de l’ovaire diagnostiqués chez les femmes porteuses de cette mutation dans notre région. Nous nous sommes également posés la question de l’existence d’un phénomène d’anticipation génétique dans ces familles. L’anticipation génétique est la survenue plus précoce d’une pathologie et/ou l’aggravation de ses signes cliniques lors de la transmission d’une mutation d’une génération à la suivante au sein d’une même famille. Très peu d’études ont cherché à mettre en évidence ce phénomène d’anticipation dans des cohortes issues de familles de syndrome sein-ovaire associées à une mutation de BRCA1 ou BRCA2. Les études publiées présentaient des biais de sélection du fait de l’inclusion de patients non testés dans leur analyse. Les études publiées sur des cohortes issues de familles présentant une mutation sur le gène BRCA1/2 suggéraient que le dépistage ciblé et l’excès de surveillance pourraient avoir une influence sur l’âge au diagnostic d’un cancer du sein chez les jeunes femmes incluses.Les améliorations majeures au niveau de la mammographie et du traitement du cancer du sein, de même que le programme de dépistage organisé pour les femmes de 50 ans et plus sont apparues en France, après 1980. A notre connaissance, à ce jour, aucune étude n’a été réalisée en France visant à identifier un phénomène d’anticipation génétique dans les familles associées à une mutation sur BRCA1ou BRCA2 et à analyser ce phénomène.Objectif: Notre premier objectif est de constituer une première cohorte lorraine de patientes porteuses de la mutation 3600del11 et d’analyser les caractéristiques anatomo-pathologiques des cancers du sein et de l’ovaire liés à cette mutation. Notre deuxième objectif rechercher l’existence d’une anticipation génétique dans des familles présentant la mutation fondatrice BRCA1-3600del11.Patientes: Quatre cent quatre patientes sont porteuses d’une mutation BRCA1 à l’Institut de Cancérologie de Lorraine (ICL) sur la période s’étendant de 1994 à 2012, parmi elles, nous avons identifié les patientes porteuses de la mutation BRCA1-3600del11. Nous avons identifié à l’Institut de Cancérologie de Lorraine, 38 paires mères-filles atteintes d’un cancer du sein ou de l’ovaire issues de 37 familles présentant le syndrome sein-ovaire associé à cette mutation dont 25 paires mères-filles atteintes d’un cancer du sein et 13 paires mères-filles atteintes d’un cancer de l’ovaire [...]
Résumé
Les grossesses après cancer du sein sont des observations encore relativement rares. Leur survenue, avec leurs conséquences hormonales, chez une femme traitée pour un cancer du sein ont longtemps été redoutés pour leur effet potentiel sur le risque de récidive. Cependant, l’amélioration, grâce aux progrès des connaissances, du pronostic du cancer du sein a permis à ces femmes d’envisager des grossesses après leur cancer ; les recommandations actuelles ne les contre-indiquent pas en cas de rémission complète. Cependant, ce contexte particulier suscite un certain nombre de questions telles que le délai entre le cancer et la grossesse, le déroulement de ces grossesses, le suivi oncologique et obstétrical, l’allaitement maternel et l’impact de la grossesse sur la maladie. Le but de ce travail était d’apporter des éléments de réponse à ces questions à travers une revue de la littérature.
Objectif:
La présente opinion de comité énumère les recommandations pour la prise en charge gynécologique des femmes ayant reçu un diagnostic de syndrome du cancer du sein et de l'ovaire héréditaire (CSOH) en ce qui a trait au dépistage, à la contraception, à la chimioprophylaxie, aux facteurs à considérer pour la fertilité, à la chirurgie de réduction du risque et aux soins post-ovariectomie.
Utilisateurs cibles:
La présente opinion de comité s'adresse aux gynécologues oncologues, aux gynécologues généralistes, aux médecins de famille, aux conseillers en génétique, aux infirmières autorisées, infirmières praticiennes, aux résidents et aux autres fournisseurs de soins.
Population cible:
Les femmes adultes (18 ans et plus) présentant une mutation des gènes BRCA1 ou BRCA2 ou d'autres gènes associés au cancer de l'ovaire. DONNéES: Pour la revue de la littérature, les bases de données Medline, Cochrane et PubMed ont entre autres été interrogées. Les termes de recherche des Medical Subject Headings utilisés ont été BRCA ET gynaecology management [prise en charge gynécologique], hormone replacement therapy [hormonothérapie substitutive], risk reduction [réduction des risques], chemoprophylaxis [chimioprophylaxie] et fertility [fertilité], et les recherches ont ciblé les articles publiés entre janvier 2010 et octobre 2017. La recherche de publications s'est déroulée de juillet à octobre 2017. Au total, 183 études ont été sélectionnées, et 101 ont été utilisées.
Valeurs:
Le contenu et les recommandations ont été rédigés et acceptés par les auteurs principaux. Le Conseil d'administration de la Société des obstétriciens et gynécologues du Canada a approuvé la version finale avant publication. La qualité des données probantes a été évaluée au moyen des critères de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) [tableau 1]. L'interprétation des recommandations fortes et conditionnelles (faibles) est décrite dans le tableau 2. Le résumé des conclusions peut être fourni sur demande. AVANTAGES DéSAVANTAGES, ET COûTS: Nous pouvons nous attendre à une diminution des risques allant jusqu'à 90 % chez les femmes prédisposées au CSOH qui subissent une salpingo-ovariectomie bilatérale de réduction du risque. Les méfaits associés à la ménopause précoce iatrogène sont compensés par les avantages découlant de la réduction du risque. En réduisant l'occurrence de cancers des trompes, de l'ovaire et du péritoine, nous pouvons nous attendre à des économies dans le système de santé. MIS à JOUR: Une revue des données probantes sera menée cinq ans après la publication de la présente opinion afin de déterminer si une mise à jour complète ou partielle s'impose. Cependant, si de nouvelles données probantes importantes sont publiées avant la fin du cycle de cinq ans, le processus pourrait être accéléré afin que certaines recommandations soient mises à jour rapidement.
Commanditaire:
Cette directive clinique a été élaborée à l'aide de ressources financées par la Société des obstétriciens et gynécologues du Canada.
Associated with pregnancy is breast cancer, which was first detected during pregnancy, during the first year after childbirth or at any time against lactation. Diagnosis of the disease in the first trimester is an indication for abortion. The detection of the disease after 20 weeks and the desire of the woman to maintain pregnancy is the basis for conducting a total mastectomy followed by polychemotherapy with doxorubicin with cyclophosphamide or with fluorouracil. Radiation therapy during pregnancy is not applied. The timing and method of delivery are determined individually and depend on the stage of the process and the period of pregnancy, when it was identified. A clinical case of a patient with edematous-infiltrative form of breast cancer of the IV stage, diagnosed for the first time in 22 weeks of pregnancy, is presented.
Genetic testing for BRCA1 and BRCA2 mutations has become an important part of the practice of medical oncology and clinical genetics over the past decade. Increasing numbers of women are requesting a genetic test so that they may better understand their personal risks of breast and ovarian cancer, and so that they may take appropriate measures to reduce the risk. Several of the risk factors can be modified, including breastfeeding and the use of oral contraceptives. A significant number of women opt for preventive mastectomy or oophorectomy, which will dramatically reduce the risks of breast and ovarian cancer. Chemoprevention with tamoxifen is still uncommon, largely due to women's fears of the side effects of the drug. A number of studies have shown that magnetic resonance imaging is superior to conventional mammography in terms of the early detection of breast cancer in the high-risk population. This article explores what is known about assessing genetic risk and the evidence supporting a range of preventive strategies.
Hereditary breast ovarian cancer (HBOC) syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in 90 percent of affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen–progestin formulations marketed for many years as combined oral contraceptives (COCs). Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification of prophylactic surgery and the use of COC to reduce the risk of gynecologic cancer in HBOC syndrome mutation carriers.
Summary: Hereditary breast ovarian cancer syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in most affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen-progestin formulations marketed for many years as combined oral contraceptives. Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification for those unfavorable effects.
Breast cancer diagnosed during pregnancy is a rare occurrence at present; however, in recent years a trend towards delayed childbirth is generating an increase in its incidence. This situation requires a multidisciplinary approach involving obstetricians, oncologists and surgeons.
In this review we analyse diagnostic methods, different possible treatments and long-term patient prognosis. We conducted a search for articles published in PubMed, or in abstract form from the San Antonio Breast Cancer Symposium (SABCS), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO) annual meeting, using the search terms:
“Breast cancer and pregnancy”.
Breast cancer occurring during pregnancy requires extra effort to offer patients the best multidisciplinary management. There is no difference in the pathology-based classification, but breast cancer during pregnancy seems to be associated with different patterns of gene expression. Chemotherapy and surgery are generally safe and well-tolerated by patients during the second and third trimesters of pregnancy. The poorer prognosis could be attributed mainly to a delay in diagnosis and because breast cancer in young patients is a more aggressive disease. Finally, balancing the health of mother and child must be paramount.
BRCA 1 and 2 genes play a critical role in the safeguarding of DNA integrity. It is now well established that BRCA1 and BRCA2-mutated women are at increased risk of breast and ovarian cancers. However, several lines of evidence indicate that this genetic status may also be associated with ovarian dysfunction, in particular a reduced ovarian reserve. Considering the gonadal toxicity of cancer treatments and the recommendation of prophylactic bilateral salpingo-oophorectomy around 40 years, young BRCA mutation carriers are confronted with difficult family planning decisions. Recent development in fertility preservation offers new possibilities for these women, not only before a potential cancer treatment, but also in healthy carriers. If the pregnancy seems to be safe in this population, oocyte vitrification following ovarian stimulation might help BRCA-mutated patients to conceive after cancer treatment or to undergo prenatal genetic diagnosis in order to avoid the risk of transmitting the genetic abnormality to their offspring. The present article aims to extensively discuss the fertility issues related to BRCA gene mutations and the questions raised by the possibility of fertility in this population.
Epidemiologic studies demonstrate that, overall, pregnancy is associated with a reduced lifetime risk of developing breast cancer. Yet this protective effect is not constant or immediate. Although uncommon, the development of breast cancer during the gestational or lactational period has traditionally been attributed a poor prognosis. With a tendency to delayed childbearing, an increase in the incidence of pregnancy-associated breast cancer is possible. This review outlines a tailored approach to the evaluation, diagnosis, and management of breast cancer during pregnancy. The majority of breast masses during pregnancy are benign, but the index of suspicion for cancer must be high for women who present with a breast mass during this period. Ultrasound and core biopsy are the fundamental diagnostic means. Many of the management strategies mirror those used in the treatment of breast cancer outside of pregnancy, with some important differences. Surgery and systemic chemotherapy, either in the neoadjuvant or adjuvant settings, are feasible options for most women during pregnancy. Chemotherapy is contraindicated in the first trimester of pregnancy, but after this, dose-dense regimens, including anthracyclines and taxanes, have been used with limited risk for both the mother and the fetus. Where patient and tumor factors allow, breast-conserving surgery followed by postpartum radiotherapy is appropriate. For axillary staging, the radiocolloids used for sentinel node mapping are safe to use given the locoregional administration. Recent advances have improved oncologic outcomes in patients with breast cancer, but not all of these have been adapted for pregnant patients. With serious adverse events on both the pregnancy and fetus, prolonged exposure to trastuzumab should be avoided. Further research, potentially through case registries with rigorous follow-up, is required to evaluate outcomes with pregnancy-associated breast cancer.
Genetic testing for individuals with familial or hereditary risk for breast cancer is essential to improving prevention and survival. Identifying unaffected BRCA1/2 mutation carriers before they develop breast cancer can reduce their risk and increase survival through increased intensity and frequency of screening, prophylactic surgery, and use of chemopreventive agents. Although the tools for genetic testing have been available for the past 20 years, nearly 95% of unaffected BRCA carriers remain unaware of their risk. The barriers to genetic screening are multiple. To identify patients for genetic testing, the clinician must first take the family history; analyze it using hereditary risk models, guidelines, or intuition; refer the patient for genetic testing; and most important, ensure that the patient follows through. With each of these steps, a certain proportion of patients is lost. Mary-Claire King, the human geneticist who discovered the BRCA mutation, once stated that “to identify a woman as a carrier only after she develops cancer is a failure of cancer prevention.” We can do better.
Breast cancer is very rare in young women below the age of 40 years. The estimated incidence is less than 0.2 per 100,000 women below the age of 20 years, increasing to 1.4 in women 20–24 years, 7.7 in women 25–29 years, and 25.5 in women 30–34 years old. Breast cancer in young women presents biological peculiarities compared with tumors in older women: a higher histological grade, no expression of estrogen receptors, and an aggressive growth pattern. The prognosis and survival of young women with breast cancer remains a controversial issue, with several studies showing discordant results. A worse prognosis was shown by some reports, whereas other studies have reported that age is not influencing disease-free or overall survival after adjustment for other prognostic factor. Special care is needed when facing breast cancer in young women. In particular, issues like fertility preservation and contraception, pregnancy after cancer or cancer during pregnancy, sexuality and body image, as well as familial, genetic, and career items are peculiar for young breast cancer patients. Younger women show greater psychological morbidity than older patients. This may be due to the fact that they face a severe disease and a burdensome treatment before they had the time and chance to achieve personal targets and purposes. A special challenging clinical situation is represented by breast cancer occurring during pregnancy because of the complex medical, ethical, and psychological problems arising in this situation.
The investigation included 39 female patients with different forms of trophoblastic disease whose immunity was studied by the cur- rently available procedures. The patients were divided into 2 groups. Group 1 comprised 29 patients with a history of hydatidiform mole, who received no chemotherapy (CT) since an analysis of the data did not show the presence of a trophoblastic tumor. Group 2 consisted of 10 patients with a verified trophoblastic tumor who received CT with various drugs. The patients with trophoblastic disease were found to have some abnormal immunological parameters; however, they differ little in patients with the malignant and benign course of the disease and cannot serve as a prognostic factor. Activated lymphocytes were substantially increased in both groups, suggesting an active immune response to antigen-foreign cells expressing along with parenteral antigens. The patients with hydatidiform mole have the sign to be further studied, that is a reduction in the count of СD25-positive Т lymphocytes, pos- sibly, suppressor cells.
Pathogenic mutations in BRCA1 and BRCA2 are associated with high risks of breast and ovarian cancer. However, penetrance estimates for mutation carriers have been found to vary substantially between studies and the observed differences in risk are consistent with the hypothesis that genetic and environmental factors modify cancer risks for women with these mutations. Direct evidence that this is the case has emerged in the past decade, through large-scale international collaborative efforts. Here, we describe the methodological challenges in the identification and characterisation of these risk-modifying factors, review the latest evidence on genetic and lifestyle/hormonal risk factors that modify breast and ovarian cancer risks for women with BRCA1 and BRCA2 mutations and outline the implications of these findings for cancer risk prediction. We also review the unresolved issues in this area of research and identify the strategies to clinical implementation so that women with BRCA1 and BRCA2 mutations are no longer counselled on the basis of "average" risk estimates.
Background
One in eight women will be diagnosed with breast cancer and 5 % of all breast cancer cases are attributable to a mutation in BRCA1 or BRCA2. Lifetime risk of the general population is about 1.5 %. The probability of an underlying mutation depends on family history, histologic subtype and age at diagnosis. For healthy BRCA1/2 mutation carriers, ovarian cancer risk varies between 15 and 60 % depending of the mutation and modifying factors.
Objectives
The safety of endocrine interventions in BRCA1/2 mutation carriers has been investigated in numerous trials. In this article an update on the current knowledge on safety of oral contraception, hormone therapy and fertility treatment in BRCA1/2 mutation carriers is provided. Furthermore, options for primary prevention are discussed.
Materials and methods
A systematic search in the Medline literature database through PubMed using the terms “BRCA”, “famil*”, “breast cancer”, “ovarian cancer”, “oral contraception”, “fertility”, “fertility treatment”, “infertility”, “tamoxifen”, “raloxifene”, “chemoprevention”, “prevention”, “hormone”, “hormone treatment”, “hormone therapy”, “salpingo-oophorectomy” and “endocrine” was performed. Articles published between 1995 and 2015 were included.
Conclusions
Oral contraceptives seem to slightly increase the breast cancer risk of BRCA1/2 mutation carriers, but they also have a tremendous protective effect against ovarian cancer. Parity, breastfeeding and fertility treatment do not seem to influence cancer risk in these women. Hormone therapy should be offered after risk-reducing salpingo-oophorectomy to limit osteoporosis and cardiac mortality. Tamoxifen and raloxifene are effective for primary prevention of breast cancer in BRCA1/2 mutation carriers; however possible adverse effects must be considered.
One of the most significant risk factors for developing early onset breast cancer is the presence of a BRCA1/2 mutation. The presence of a BRCA1/2 mutation confers a 40–90 % lifetime risk of developing breast cancer and up to a 60 % lifetime risk of developing ovarian cancer. BRCA1/2 plays an important role on the causal pathway for developing breast cancer and has a significant impact on the biological and clinical characteristics of BRCA1/2-associated breast cancer. The presence of a BRCA1/2 mutation has far-reaching impact on the full spectrum of reproductive issues, including the impact of risk-reducing salpingo-oophorectomy both on fertility and premature menopause. The presence of a BRCA1/2 mutation compounds the already complex and multifactorial challenges that exist when managing a young woman with breast cancer – the challenges range from medical (oncological, gynecological, surgical) to psychosocial and ethical; thus, a multidisciplinary approach is mandatory.
Oncofertility integrates the two previously distinct fields of cancer treatment and fertility research and aims to explore and expand the reproductive future of cancer survivors. In order to achieve the goal of fertility preservation, the Oncofertility community must focus on communication and the way data is provided and received. Concomitant with the rapidly changing technology of Oncofertility, there have been radical shifts and advances in the way health educators and clinicians can produce and share information. As success rates of reproductive techniques such as egg freezing and banking continue to rise, providing increasing opportunities for young cancer patients to preserve their fertility prior to the onset of cancer treatments, communication among professionals in oncology, reproductive medicine, and psychosocial work, among others, becomes crucial, and clinical demand for Oncofertility information is expected to rise considerably. Oncofertility Communication describes and addresses the myriad channels through which the multiple audiences involved in Oncofertility can be served with appropriate and accurate information about cancer-related fertility issues. The text answers frequently asked questions and provides invaluable insights to scientific and health care professionals about communication among the diverse Oncofertility audiences. It incorporates timely discussions about traditional and emerging electronic communication tools and discusses the impact of health care policy changes on the Oncofertility field.
The authors analyzed data from two multistate, population-based case-control studies to investigate the association between
age at any full-term pregnancy (FP) and breast cancer risk. Study subjects included breast cancer cases aged 20–79 years identified
from four statewide cancer registries and randomly selected controls interviewed from 1988 to 1996. Complete information on
a comprehensive set of risk factors for breast cancer was available for 9,891 cases and 12,271 controls. The large number
of subjects enabled simultaneous adjustment of the covariates and efficient application of various modeling approaches. Overall,
each 5-year increase in age at first FP was associated with an odds ratio of 1.07 (95% confidence interval (CI): 1.01, 1.13)
for breast cancer. The corresponding estimates were odds ratio = 1.02 (95% CI: 1.00, 1.05) for age at second through ninth
FPs. For age at last FP, the effect estimate (odds ratio = 1.01, 95% CI: 0.97, 1.06) was indistinguishable from that for other
FPs after the first. In this analysis, a modest and transient increase in breast cancer risk after childbirth was also observed.
The relatively greater effect of age at first FP is consistent with the existence of a long-term effect of early first FP
on the differentiation of mammary cells, causing them to become less susceptible to carcinogenesis. Am J Epidemiol 2000;151:715–22.
Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown.
We conducted a case-control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 280]), year of birth (+/-2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided.
Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P<.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; P(trend)<.001). Women with BRCA1 mutations who breast-fed for more than 1 year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P =.001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P =.83).
Women with deleterious BRCA1 mutations who breast-fed for a cumulative total of more than 1 year had a statistically significantly reduced risk of breast cancer.
The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers, Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes, The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due To BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes tvas found in families with four or five cases of female breast cancer only, These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated bg maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions, The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 pears. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years, The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.
Several large epidemiological studies in the Nordic countries have failed to confirm an association between age at first birth and breast cancer independent of parity. To assess whether lack of power or heterogeneity between the countries could explain this, a meta-analysis was performed of 8 population-based studies (3 cohort and 5 case-control) of breast cancer and reproductive variables in the Nordic countries, including a total of 5,568 cases. It confirmed that low parity and late age at first birth are significant and independent determinants of breast-cancer risk. Nulliparity was assoclated with a 30% increase in risk compared with parous women, and for every 2 births, the risk was reduced by about 16%. There was a significant trend of increasing risk with increasing age at first birth, women giving first birth after the age of 35 years having a 40% increased risk compared to those with a first birth before the age of 20 years. Tests for heterogeneity between studies were not significant for any of the examined variables. In the absence of bias, this suggests that several individual Nordic studies may have had too little power to detect the weak effect of age at first birth observed in the meta-analysis.
We set out to detect a transient increase in risk of breast cancer following childbirth, the existence of which has been postulated, but for which empirical evidence is contradictory. Breast cancers and births occurring among the cohort of Swedish women born after 1939 were linked, yielding 3,439 cases and 25,140 age-matched controls with at least two children. Within three years of their last childbirth, women had an estimated rate of breast cancer of 1.21 (95 percent confidence interval [CI]=1.02–1.44) times that of women whose last birth was 10 or more years earlier, after adjustment for parity and age at first birth. Further analyses suggested that this effect reflected, in part, a small transient increase in breast cancer risk that lasts for about three years following completed pregnancy. The effect of age at first birth on breast cancer risk appears to be confounded by time since last birth; the parity-adjusted rate ratio for having a first birth at age 35 years or more compared with under 20 years is reduced from 1.72 (CI=1.14–2.58) to 1.36 (CI=0.88–2.09) on additional adjustment for time since last birth. A transient increase in breast cancer risk after childbirth thus appears to account for part of the effect of age at first birth on breast cancer risk.
For most cancer sites there is a linear log-log relationship between incidence and age. This relationship does not hold for breast cancer, and certain 'key' breast cancer risk factors suggest that breast tissue does not 'age' in step with calendar time. A quantitative description of 'breast tissue age' is suggested which brings the age-incidence curve of breast cancer into line with the common log-log cancers and explains quantitatively the known key risk factors. The model also explains the 'anomalous' finding that although early first birth is protective, late first birth carries a higher risk than nulliparity. US breast cancer rates are some four to six times the rates in Japan--the model suggests that the key risk factors, when considered jointly with weight, can explain about 85% of the difference.
The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.
Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, whether pregnancy decreases the risk of early-onset hereditary breast cancer is unknown. There is concern that pregnancy may increase breast-cancer risk in carriers of BRCA1 and BRCA2 germline mutations. We aimed to establish whether pregnancy is a risk factor for hereditary breast cancer.
We did a matched case-control study of breast cancer in women who carry deleterious BRCA1 or BRCA2 mutations. Cases were carriers who developed breast cancer by age 40 years, and controls were carriers of the same age without breast cancer, or who were diagnosed with breast cancer after age 40 years. Women who had undergone preventive mastectomy, hysterectomy, or oophorectomy, or who were diagnosed with ovarian cancer before the age at which breast cancer was diagnosed in the matched case were excluded. Information about pregnancies and pregnancy outcome was derived from a questionnaire completed by women in the course of genetic counselling.
A higher proportion of cases than controls had had a full term pregnancy (173/236 vs 146/236; odds ratio 1.71 [95% CI 1.13-2.62], p=0.01). The mean number of births was also greater for cases than for controls (1.62 vs 1.38, p=0.04). The risk increased with the number of births and did not diminish with time since last pregnancy. There were no significant differences in age at first birth or age at last birth between cases and controls.
Carriers of the BRCA1 and BRCA2 mutations who have children are significantly more likely to develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy is associated with an increased cancer risk. An early first pregnancy does not confer protection for carriers of BRCA1 or BRCA2 mutations.
Identify time-points when the elevated postpartum maternal breast cancer risk peaks.
A case-control study nested within the Swedish Fertility Register included 34,018 breast cancer cases from the Swedish Cancer Register between 1961 and 1995. From the Fertility Register, 170,001 eligible subjects matched to the cases by age were selected as controls. Analysis contrasted risk between uniparous (7084 cases and 31,703 controls) and nulliparous (5411 cases and 22,580 controls) women and between biparous (13,239 cases and 65,858 controls) and uniparous women. Logistic regression analysis included indicator variables representing each year of age, ages at delivery, and time since delivery.
Comparing uniparous with nulliparous women the transient increase in maternal breast cancer risk peaked 5 years following delivery (odds ratio= 1.49, 95% confidence interval 1.01-2.20) and leveled off 15 years postpartum. Biparous women had a transient increase in risk that was lower at its peak than that of uniparous women, occurring about 3 years following second delivery.
A time window of 5 years postpartum when maternal breast cancer risk is highest was observed. Establishing timing of peak transient increase in postpartum breast cancer risk may define the latent period required for pregnancy hormones in promoting progression of breast cells that have undergone early stages of malignant transformation.
Hereditary breast and ovarian cancer is among the most commonly encountered adult genetic disease, and it is increasingly important that geneticists, oncologists, surgeons and gynaecologists are aware of the issues regarding risk assessment, prevention and management of women with inherited susceptibility to cancer. Genetic risk can be modified by external factors, but what are these factors, and how might our knowledge of them help us to better define the risks for individual women and to develop strategies for cancer prevention?
Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
Age at first birth, parity and risk of breast cancer: a meta-analysis of 8 studies from the Nordic countries
- M Ewertz
- S W Duffy
- H O Adami
- G Kvale
- E Lund
- O Meirik
- A Mel Lemgaard
- I Soini
- H Tulinius
Ewertz M, Duffy SW, Adami HO, Kvale G, Lund E, Meirik O, Mel
lemgaard A, Soini I, Tulinius H. Age at first birth, parity and risk of
breast cancer: a meta-analysis of 8 studies from the Nordic countries.
Int J Cancer 1990;46:597-603.