Introduction
In the last decades, the number of fertility treatments is increasing due to postponing family planning to a later age. Improved techniques have led to enhanced success rates and social acceptance is high. A possible association between fertility treatments and ovarian cancer has been described. There are theories postulating an increasing risk promoted by polyfollicular ovulation or elevated gonadotropin levels, which are induced by fertility medication. However, the association between ovarian cancer risk and fertility treatments remains controversial [
1]. A recently updated Cochrane Review presents new data suggesting that substances used in fertility treatment may cause a slight increase in ovarian cancer risk in subfertile women as compared to the general population or to subfertile women without treatment. However, none of the studies provided high-certainty evidence [
2].
Large observational studies show a transient increase in breast cancer risk after the first full-term pregnancy and a long-term protective effect in uni- and biparous women as compared to nulliparous women. Higher transient breast cancer risk was observed especially in women who gave birth at an age of 30–35 years or older [
3,
4]. Pregnancies terminated by spontaneous or induced abortion and do not have an impact on breast cancer risk [
5]. Higher levels of estrogen and progesterone during pregnancy are discussed as underlying mechanisms that cause the transient increase in risk [
3].Therefore, it has to be considered that ovarian stimulation leads to high levels of estrogen and progesterone as well.
According to a recent review published in 2017, most studies do not show an elevated risk for breast cancer in women undergoing fertility treatment as compared to parous and nonporous women without fertility treatment. However, uncertainty remains particularly when the fertility treatment is started at a young age or contains a high number of clomiphene citrate cycles [
1].
Mutations in
BRCA1 and
BRCA2 genes represent a significant independent risk factor for ovarian and breast cancer. The cumulative risk to the age of 80 years for ovarian cancer is elevated up to 44% in
BRCA1 and up to 17% in
BRCA2 mutation carriers. Breast cancer risk is elevated up to 72% for
BRCA1 and up to 69% for
BRCA2 mutation carriers, respectively [
6]. There are theories indicating that deficient
BRCA function might lead to reduced fertility due to diminished ovarian reserve [
7]. Similarly, more recent studies suggest a negative impact of
BRCA mutations on fertility treatment response rates [
8]. This hypothesis and the possibly occurring psychological urge to fulfill family planning in a certain time in order to schedule risk-reducing surgery procedures contribute to the fact that fertility treatment and cancer risk is of particular interest for the subgroup of
BRCA1/2 mutation carriers. This applies especially for
BRCA1/2 mutation carriers with a previous history of malignant disease. For the general population, the recent data indicate that the long-term outcome of women with pregnancy after breast cancer is not inferior to the outcome of nonpregnant matched controls [
9]. This seems to be independent of hormone receptor status. The current data suggest safety for pregnancy after breast cancer also in
BRCA1/2 mutation carriers [
10]. However, the data are still inhomogeneous and scarce, a higher risk for recurrence cannot be excluded. Therefore, fertility protection and fertility treatment of healthy carriers of mutations in
BRCA1 and
BRCA2 as well as of carriers after breast cancer therapy are gaining importance. In this review, we analyze the published data on fertility treatments and their association with primary ovarian and breast cancer risk and risk for recurrence in
BRCA1/2 mutation carriers.
Materials and methods
A search for original articles was run from 1995 to 2018 on PubMed. The MeSH used for the search were: (“IVF” or “ovarian hyperstimulation”) and (“BRCA mutation”), and (“IVF” or “ovarian hyperstimulation”) and (“breast cancer” or “ovarian cancer”). The search created 12, 0, 99, 42, 75, and 28 hits, respectively. The hits were searched for relevance, clinical trials, reviews, and meta analyses. We also conducted a search within the Cochrane library. There were no Cochrane reviews available on fertility treatments and risk of cancer in BRCA1/2 mutation carriers.
We found four original publications, two of which regarding ovarian cancer risk, and two regarding breast cancer risk.
Discussion
Studies on the cancer risk of fertility treatment in women with mutations in the genes
BRCA1 and
BRCA2 are sparse. However, the clinical need for counseling on this subject is highly relevant. In women without evidence for hereditary breast or ovarian cancer, most of the existing studies do not show an elevated risk for breast cancer after clomiphene or gonadotropin treatment [
1]. Also, it is unlikely that these medications lead to increases of ovarian cancer risk.
For ovarian or breast cancer, the four available studies show no association between fertility treatments and risk of cancer in
BRCA1/2 mutation carriers. For breast cancer, one of the studies shows a possible non-significant adverse effect for gonadotropin-containing fertility medication, while another study does not confirm this effect [
13,
14]. Overall, the data on the safety of fertility treatments in
BRCA mutation carriers are limited. Most of the studies are retrospective and study populations were often small, especially regarding
BRCA2 mutation carriers. Study designs were different and only one of the studies included
BRCA1/2 mutation carriers already diagnosed with breast cancer [
14]. None of the published studies investigated a possible effect of dosage, number, and duration of the different treatments. Likewise, the causes of infertility and a possible impact on cancer risk were not examined. Only one of the included studies included information on different breast cancer subtypes [
14].
Prospective data from clinical registries are needed to further investigate the safety of fertility treatments in
BRCA1/2 mutation carriers and to be able to evaluate a possible impact of dosage, number, and duration of the different treatments. Longer follow-up periods are required. Counselling and treatment of families with hereditary breast and ovarian cancer under trial conditions is therefore strongly recommended. The German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) offers all families with known or suspected hereditary risk to be registered in the HerediCaRe study, which is supported by a grant of the German Ministry of Education and Research. The prospective follow up within this registry and the international cooperations on research about genetic and non-genetic risk factors will allow a more knowledge-based view on potential risks and clinical options of prevention in the future [
2,
6,
15,
16].
BRCA1/2-associated breast cancer differs from cancer that arises in non-carriers. In breast cancer, an onset about 20 years earlier (44 years in
BRCA1 vs 64 years for sporadic BC) and a higher number of hormone receptor negative cancers are the main differences [
6,
17,
18]. And even for
BRCA1/2-associated ovarian cancer, which is very close to sporadic ovarian cancer in terms of histopathology, the age of onset is at least 10 years earlier (59 years in
BRCA1 vs 69 years for sporadic OC) [
6,
17,
18]. Exposure of lifestyle factors at different ages might influence cancer risk in carriers in a different way than expected. Until association of lifestyle and cancer risk is not fully understood, it is difficult to exclude an elevated cancer risk. Intensified research in a small, well characterized group of women such as
BRCA1/2 mutation carriers will help elucidate tumorigenesis also for the general population. An example of how evidence in the field of hereditary breast and ovarian cancer changes understanding and therapy of other cancers is the targeted therapy with PARP inhibitors [
19].
Based on the existing studies, BRCA1/2 mutation carriers should be not be excluded from utilization of fertility treatments, but at the same time take part in a clinical registry to follow up cancer history. More data will be needed since possible increases in cancer risk cannot be excluded at this time. Therefore, women with BRCA1/2 mutations who consider fertility treatment have to be informed about the limited data. They have to be informed about possible increases in cancer risk associated with different treatments. Fertility treatments have to be used with care in this specific subgroup.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.