Breast cancer is the most predominant malignancy in women worldwide. In 2020, 2.3 million women were diagnosed with breast cancer with 685,000 deaths globally (World Health Organization 2021; https://www.who.int). Factors that increase the risk for breast cancer include exogenous sex steroid exposure and increased endogenous sex steroid actions through early menarche and late menopause in combination with nulliparity. There is a significant increased risk of breast cancer in patients with a germ-line mutation in BRCA1 or BRCA2 which can be found in 3%–4% of all women with breast cancer. BRCA1 carriers present an increased risk of breast cancer peaking at 30–40 years of age, while BRCA2 peaks especially at 40–50 years. From that point on, the incidence rate is similar and constant at 20–30 per 1000 person-years until age 80. Most breast cancers are hormone-dependent (1ESHRE Capri Workshop Group
Hormones and breast cancer.). As fertility treatments can temporarily use and/or induce supraphysiologic levels of circulating sex steroid, they potentially could increase the risk of breast cancer. Thus, the possible association between ovulation-inducing drugs and increased risk of breast cancer has been the subject of several studies.In the article ‘‘Fertility treatments and breast cancer risk in Jewish Israeli BRCA mutation carriers,’’ Perri et al. (2

Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch G, et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril. In press.

) reported no association between fertility treatment and breast cancer risk regardless of the type of treatment. Although some studies found an association of fertility treatment with breast cancer, the increased risk was modest (2

Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch G, et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril. In press.

, 3Wang C. Bai F. Zhang L.H. Scott A. Li E. Pei X.H. Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression.) regardless of starting age of treatment, medication used, and comparison with a control population (4Luke B. Brown M.B. Spector L.G. Missmer S.A. Leach R.E. Williams M. et al.Cancer in women after assisted reproductive technology.). The study by Perri et al. (2

Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch G, et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril. In press.

) is in line with most other studies that have not shown an association between breast cancer and fertility treatment when comparing women undergoing in vitro fertilization (IVF) versus the general population and infertile controls. However, even though most studies have not shown an accordant relationship between breast cancer risk and fertility treatment, studies often are suffering from the same disadvantages of other cancer-related studies, particularly short-term follow-up, and other confounding variables. In particular, despite the large number of patients (n = 1824) included in the study by Perri et al. (2

Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch G, et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril. In press.

), this significant number does not result in an increased robustness of the study to validate the absence of risk. The take home message is that from a statistical viewpoint, a lack of evidence could mean an inability to prove the existence of something, not the complete absence of it. It might exist, but the study is not able to find it. That is a remarkable difference that sometimes is missed in cohort studies. Perri el al. (2

Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch G, et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril. In press.

) clearly identified several variables that are affecting the outcome. Even if the effect exists, the noise in the data, presence of biases, or other confounding variables can obscure the fact that IVF treatments do not increase breast cancer in BRCA patients.

The biggest confounding factor in their study is the use of patients who underwent bilateral salpingo-oophorectomy (RRBSO) and mastectomy. Clearly, they will never have breast cancer. This confounding factor is showed removing RRBSO and mastectomy patients, all protective effects disapear. However, the use of oral contraceptives (OC) does increase the risk of breast cancer, indicating a high penetrance of this variable and also the paternal origin of the mutation. Therefore, following the same logic, IVF patients and controls who used OC also should be removed from the study as well as patients whose mutation comes from a paternal origin.

The identification of all of these modifiers is a key finding that should be taken into account in future studies to demonstrate clearly that IVF treatments do not increase breast cancer in BRCA patients. Also, all these modifiers are even more important confounding factors from an anthropologic viewpoint. Infertile women generally are less prone to using long-term OC, patients who underwent RRBSO eventually will undergo mastectomy, and patients who underwent an IVF cycle are generally more likely to face an RRBSO and mastectomy. Therefore, all these confounding intricate variables make statistical analysis of the data difficult due to the potential unbalanced behavior between groups.

Thus, assuming all of these factors, it is quite complex to demonstrate a negative linkage between conditions in a cohort study full of multiple confounding variables and a clear example of this is the Perri el al. (2

Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch G, et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril. In press.

) study. We cannot be sure that IVF cycles do not increase breast cancer in patients carrying BRCA pathogenic variants.An increased risk of breast cancer in pathogenic BRCA carrier patients is supported clearly by a biological viewpoint. BRCA genes have a crucial role in homology-directed repair of DNA double-strand breaks (DSB). Breast and ovary tissues rely on estrogen for their proliferation. Estrogen induces cell proliferation through the activation of estrogen receptor α (ERα), which works as a transcription factor. Activated ERα recruits topoisomerase II (TOP2)α and TOP2β to some of the ERα target genes, and initiates transcription. TOP2 enzymes resolve DNA catenates by fixing the temporal formation of DSBs, followed by repair of the broken DNA strands. Transient DSB formation allows an intact DNA duplex to pass the DSB. During such temporal DSB formation, TOP2 is bound covalently to the 5′ DNA end of the break, forming TOP2–DNA cleavage-complex intermediates (TOP2ccs). BRCA promotes the removal of 5′ TOP2css adducts from pathologic stable TOP2css. Extended formation of pathologic TOP2ccs causes mutations in BRCA1-deficient tissues. In addition, estrogen has been found to activate epithelial-mesenchymal transition, stimulating cell proliferation, and promoting mammary tumor initiation and metastasis, promoting their stemness and invasiveness (3Wang C. Bai F. Zhang L.H. Scott A. Li E. Pei X.H. Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression.). It is also relevant that lesions associated with an increased risk of subsequent malignancy are found more commonly in prophylactic mastectomy specimens from women with BRCA mutations than in breast tissue obtained from unaffected women without a known predisposition (5Kauff N.D. Brogi E. Scheuer L. Pathak D.R. Borgen P.I. Hudis C.A. et al.Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations.). This finding indicates that hereditary breast carcinoma has a preinvasive state that may evolve to invasive cancer by the presence of supraphysiologic circulating sex steroid levels. Therefore, these patients are generally a high-risk population for breast cancer development, although not all lesions will develop into invasive carcinoma. Essentially, they are time-ticking bombs that in the presence of increased supraphysiologic estrogen treatment can activate subsequent invasive breast cancer.

In summary: How would you advise genetically susceptible patients carrying a dysfunctional BRCA variant? The most reasonable answer is to inform patients that there is no clear study that indicates that there is an increased risk, but also that the risk does not exist. The most conservative advice is to perform a mammography before the IVF cycle (preferably magnetic resonance imaging with contrast) to detect potential precancerous lesions, after the cycle during pregnancy between 4 and 6 months ultrasonography would be recommended.

From a clinical point perspective, the best treatment is a preventive and screening strategy. An example of the preventive approach would be the Gail Model Risk Assessment Tool used to estimate any woman’s 5-year and lifetime breast cancer risk. Testing for BRCA mutations is recommended for women whose family history suggests increased risk for mutations in the BRCA1 or BRCA2 gene (≥1 first-degree relatives on the same side <50 years with breast cancer or invasive ovarian cancer: ≥2 relatives at any age with breast, prostate, or pancreatic cancer). Expert opinion recommends women with BRCA 1/2 mutations should undergo breast cancer screening with magnetic resonance imaging beginning at age 25 years, then mammography starting at age 30 years, and ovarian cancer screening with pelvic examinations, ultrasonography, and CA-125 measurement.

Surgical prophylaxis options for carriers of BRCA1/2 mutations include prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy. The screening recommendations vary but the United States Preventive Services Task Force recommends biennial screening mammography for average risk women beginning at age 50 years and individualized screening decisions in women aged ≥75 years based on breast cancer risk.

ReferencesESHRE Capri Workshop Group

Hormones and breast cancer.

Hum Reprod Update. 10: 281-293

Perri T, Lifshitz D, Sadetzki S, Oberman B, Meirow D, Ben-Baruch G, et al. Fertility treatments and invasive epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation carriers. Fertil Steril. In press.

Wang C. Bai F. Zhang L.H. Scott A. Li E. Pei X.H.

Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression.

Breast Cancer Res. 20: 74Luke B. Brown M.B. Spector L.G. Missmer S.A. Leach R.E. Williams M. et al.

Cancer in women after assisted reproductive technology.

Fertil Steril. 104: 1218-1226Kauff N.D. Brogi E. Scheuer L. Pathak D.R. Borgen P.I. Hudis C.A. et al.

Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations.

Cancer. 97: 1601-1608Article InfoPublication History

Published online: July 08, 2021

Publication stageIn Press Corrected ProofFootnotes

You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33202

Identification

DOI: https://doi.org/10.1016/j.fertnstert.2021.06.011

Copyright

©2021 American Society for Reproductive Medicine, Published by Elsevier Inc.

ScienceDirectAccess this article on ScienceDirect Linked ArticleRelated Articles