Treatment of women with BRCA mutation

Abstract

The cumulative risk for breast and ovarian cancer is high in BRCA1 or BRCA2 mutation carriers. The lifetime risk of breast cancer by the age of 80 years is respectively up to 72% and 69% in BRCA1 and BRCA2 mutation carriers. The risk of ovarian cancer is higher (44%) in BRCA1 than in BRCA2 (17%) mutation carriers. Breast and ovarian cancers tend to arise earlier in BRCA1 mutation carriers. Breast cancers in BRCA1 mutation carriers are more frequently (up to 70%) triple negative while the majority (up to 80%) of breast cancers in BRCA2 mutation carriers are hormone sensitive. Many issues remain to be resolved. In daily practice we are often confronted with patients having BRCA mutations classified as variants of unknown significance, who do have breast cancer personally or have a strong family history of breast cancer. On the other hand, 30–40% of mutation carriers will not develop breast cancer. Moreover, it is very difficult to predict the age at which cancer will arise. In a multidisciplinary setting we need to offer BRCA and other mutation carriers a wide range of information, advice and support.

摘要

在BRCA1和BRCA2突变携带者中, 80岁时患乳腺癌的终生风险分别高达72%和69%。BRCA1突变携带者患卵巢癌的风险(44%)高于BRCA2突变携带者(17%)。在BRCA1突变携带者中, 乳腺癌和卵巢癌往往出现得更早。BRCA1突变携带者的乳腺癌更常见(高达70%)是三重阴性, 而BRCA2突变携带者的大多数乳腺癌(高达80%)是激素敏感的。许多问题仍有待解决。在日常实践中, 我们经常遇到BRCA突变被归类为不明意义变异的患者, 他们确实患有乳腺癌或有很强的乳腺癌家族史。另一方面, 30%-40%的突变携带者不会患乳腺癌。此外, 很难预测癌症发生的年龄。在多学科环境中, 我们需要为BRCA和其他突变携带者提供广泛的信息、建议和支持

Keywords:

• BRCA
• hormone therapy
• prophylaxis
• surgery
• pregnancy hormone

This review was presented as a paper at the 18th IMS World Congress, Lisbon, Portugal in October 2022.

Introduction

Many important, individualized decisions must be made concerning the possibility to undergo pre-implantation diagnosis; how and when to start screening; contraception; type and timing of preventive ablative surgery; the opportunity, safety and duration of hormone therapy (HT) after adnexectomy; and the risk of Alzheimer’s disease, osteoporosis and cardiovascular disease after surgical-induced menopause [1–3]. Finally new scientific data are emerging that recombinant human chorionic gonadotropin (r-hCG) or pregnancy hormone injections (Ovidrel^®, 12 weeks, three times per week) in nulliparous BRCA carriers are inducing corrective, epigenetic changes in BRCA mutation carriers [4,5] mimicking a first full-term pregnancy (FFTP).

This article is conceived as a practical guide seen from a multidisciplinary, clinical perspective. Since the input of the geneticist, fertility specialist, gynecologist, reconstructive surgeon, psychologist and breast nurse is so different, it is mandatory that every clinical key player has a basic common knowledge of all treatment options.

Pre-implantation treatment

The ‘in vitro fertilization setting’ originally conceived to treat infertile couples is currently often used to perform pre-implantation diagnosis, more commonly known as pre-implantation genetic diagnosis (PGD). This procedure allows producing embryos devoid of the targeted mutations. Currently, pre-implantation diagnosis is a well-established and successful technique to remove the breast cancer mutation for the future generation [6].

Since the embryos will not be replaced during the stimulated cycle, a protocol with low risk of ovarian hyperstimulation syndrome (OHSS) can be used. To reduce the risk of OHSS, which can be life threatening, important adjustments to the stimulation protocol can be made [7,8]. Firstly, the gonadotropin dose, needed for the follicular stimulation, should be calculated using the age, body mass index, antral follicle count and anti-Mullerian hormone levels of the patient. Secondly, a gonadotropin/gonadotropin releasing hormone (GnRH) ‘antagonist’ protocol to stimulate follicle growth is to be preferred. As such, a GnRH ‘agonist’ can be used as an ovulatory trigger 36 h prior to the oocyte pick up, avoiding the need for r-hCG. Thirdly, no luteal support needs to be given after the pick-up. Fourthly, in instances where an unexpected high number of oocytes were obtained, further GnRH ‘antagonists’ can be given during the luteal phase. A detailed and extensive description to avoid and to treat OHSS is given in the ACCEPT Guidelines on OHSS prevention and management [8].

In a PGD cycle, one blastomere is removed during early embryonic development to screen for the breast cancer mutation. After the biopsy, the embryos are frozen until the pre-implantation results are available. The healthy embryos are now available for transfer in a subsequent natural cycle. Once the unaffected embryos are frozen, they can be stored indefinitely. Prior to initiating the pre-implantation cycle, the genetic laboratory needs time to assess that the individualized probes, needed during the analysis of the blastomeres, are functional. This process usually takes a few months. It is advisable to do this preparing step early in the work-up process. This avoids waiting for a few months once the couple wants to start getting pregnant. Pre-implantation diagnosis is useful regardless of which partner is carrying the mutation.

It is important to discuss PGD in mutation carriers. Often, women already have children at the time a mutation is detected. Although it is too late to do a PGD procedure in these instances, it is still useful to discuss this option. As such, family members planning children are informed of the existence of this PGD option. This may motivate women who are reluctant to perform a mutation test. Informing that this may be of use for family members so that they can be offered PGD may help them take the mutation test.

Contraception

Contraception using oral combined pills reduces the risk of ovarian cancer in BRCA mutation carriers [9]. A meta-analysis with 14 included studies showed a 42% risk reduction for ovarian cancer associated with the use of combined hormonal contraceptives in women with BRCA1 or BRCA2 pathogenic variants, with no statistically significant increase in breast cancer risk [10]. The ideally planned scenario is to reduce the number of ovulations. The influence of taking oral contraceptive pills on the breast cancer risk has been studied in the general population. The consensus is that longer exposure to oral contraception and higher estrogen dose increases the risk of breast cancer [11]. The absolute number of observed breast cancers is very small. In a large, prospective study of almost 1.8 million women followed for a mean of 10.9 years, one additional breast cancer was diagnosed for every 7693 women using hormonal contraception for 1 year. Firm data on BRCA carriers and contraception are not available to draw firm conclusions. A meta-analysis found no significant effect of combined hormonal contraceptive use on breast cancer risk (odds ratio 1.21, 95% confidence interval 0.93–1.58) [9].

The influence of a levonorgestrel intrauterine system (LNG-IUS) on the breast is controversial [12]. Although a large observational study indicates an increased risk of breast cancer in the general population [11], the results do not really add up scientifically. With oral contraception there is an increase in breast cancer with long duration of use. In LNG-IUS users, there is an increase of risk of 20% virtually immediately. This is not logical taking tumor biology into account. Subsequently this increased risk does not change any more with longer duration of LNG-IUS use, which is again not logical from the tumor biology point of view. The only substantial information we have is the study where breast cancer histology and behavior were compared in a large set of breast cancers detected in copper intrauterine device and LNG-IUS users [13]. Histology, tumor size and extent of node involvement were the same in both groups. The results did not differ when intrauterine device use was initiated in relation with the tumor detection, nor did the duration of use matter. Both groups had a higher risk of breast cancer compared to controls, indicating that women opting for intrauterine devices are probably at higher risk, suggesting that this is the reason to choose contraception with the lowest possible hormonal burden.

In a study where women came to the esthetic surgeon for a breast reduction, women with a LNG-IUS were asked whether some of the removed breast tissue could be used for research purposes. Using highly sensitive mass spectrometer technology, the concentration of LNG in breast tissue was extremely low [14]. The levonorgestrel (LNG) concentration was lower than the lowest concentration used in in vitro culture experiments with breast cancer cells and different progestogens. Information on the LNG-IUS and breast cancer in mutation carriers is lacking. Considering that many BRCA1 tumors are receptor negative, hormones should have no influence on the breast cancer risk.

In a general population, the use of progestin-only contraception increased risk only with oral LNG (relative risk 1.93, 95% confidence interval 1.18–3.16: one additional breast cancer diagnosis for every 2127 women using oral LNG for 1 year). In the LNG group, 77.1% were nulliparous women compared to only 43% in the desogestrel group. Women taking LNG pills were 5.1 years older than women taking desogestrel pills. These two important issues may have been an important bias [11].

Preventive ablative breast surgery

All options of prophylactic breast removal eventually followed by breast reconstruction should be discussed in length. With the enormous progress in reconstructive surgery, many reconstructive options are now available. The skin and the areola, which is also skin tissue, can be saved. The option not to remove the nipple during breast ablation should be offered [15]. The removed breast tissue can be replaced by a breast implant. The advantage of this surgical option is that this operation is easy to perform, in virtually every clinical setting. A disadvantage is that this implant may need to be replaced when contractions of the capsule occur within the following years after the surgery. Newer techniques using injection of fat and fat stem cells may offer a solution. In this situation, the prosthesis is gradually deflated and replaced by autologous fat through fat injections. After several consecutive procedures the prosthesis may be completely replaced by this injected fat which has started to form viable fat tissue. Pictures of operations may help women to make the decision.

Using a free fat flap to replace the removed breast tissue gives very natural results. Once the operation is successful, the flap provides a lifetime optimal result. The technique needs experienced reconstructive surgeons. It is associated with an important scar at the donor site. In a review of 1000 breast reconstructions with a free flap [16] an analysis was performed in order to increase the success rate of such operations. After skin, areola and nipple-sparing surgery, immediate reconstruction can be realized with a free flap from different donor sites. The deep inferior epigastric (artery) perforator flap from the infra umbilical region is commonly used [16]. Other donor sites can be used in lean women. The advantage of free flaps is the natural consistency of the donor fat which needs only one operation, since the flap will last for a lifetime. Indeed, within a short time after the surgery a large part of the vascularization of the flap is taken over by the subcutaneous blood vessels. The longer the time after the operation, the more natural the breast will feel.

Adnexectomy

Risk-reducing salpingo-oophorectomy is the current standard of care and reduces the lifetime risk of ovarian cancer by about 80% [17]. This procedure can only be performed after extensive consultation regarding the completion of the family. The adnexa can be removed during the ablation of the breast. In instances where a free fat and skin flap of the abdomen is taken, it is very easy to remove the ovaries and tubes since the skin and subcutaneous fat is already removed and the access to the abdomen is very easy. In instances where a prosthesis is used to replace the removed breast tissue or no breast removal is performed, the ovaries may be removed through a laparoscopic procedure. Due to the high triple negative rate, it seems logical that in BRCA1 mutation carriers, prospective studies could not confirm a risk reduction for breast cancer after bilateral salpingo-oophorectomy (RRBSO) [18]. Prior to the removal of the ovaries, the consequences of the hormone deprivation should be discussed if the procedure is performed in premenopausal women. The acute drop in hormone production after surgical menopause often induces more severe vasomotor symptoms. The long-term consequences such as increased risk of osteoporosis [19,20], cardiovascular disease [21], Alzheimer’s disease [22,23], cognitive disorders [24] and sexual problems [25] need to be discussed and put in their true perspective. Lean women can lose up to 30% of their bone mass in 6 months after menopause. Rocca et al. observed a significant increased risk with younger age at oophorectomy [22,23]. These consequences tend to be marginalized compared to the perceived risk of breast cancer.

Timing of the surgery

The screening for breast cancer can be well standardized with the use of mammography, ultrasound and magnetic resonance imaging for different mutation carriers. An earlier detection may reduce the required need for neo-adjuvant or adjuvant chemotherapy although chemotherapy can only be avoided in very small triple negative tumors. The indication for chemotherapy for triple negative breast tumors differs from center to center and many centers prescribe chemotherapy in instances where the tumor is as small as T1b [26]. This means that surgery is the only real solution to avoid chemotherapy in many BRCA1 mutation carriers. The risk to develop ovarian, fallopian or primary peritoneal cancer is 39–46% for BRCA1 and 10–27% for BRCA2 women. The only strategy shown to reduce ovarian cancer mortality in such women is a risk-reducing salpingo-oophorectomy. It is impossible to screen for primary peritoneal cancer. It is very disappointing to screen for ovarian cancer. Women should be screened until risk-reducing prophylactic bilateral salpingo-oophorectomy is performed between age 35 and 40 years or when childbearing is complete [18]. The optimal age to plan the oophorectomy should be 35–40 years in women with BRCA1 and 40–45 years in women with BRCA2 [17].

Use of hormone therapy

In industrialized countries, the lifespan of women has constantly increased from ∼50 years of age in the early twentieth century to the current 80–89 years of age (depending on the country). On the other hand, the average age of spontaneous menopause has only changed marginally. Therefore, women are expected to spend more than 30 years of their life after menopause (more than one-third of the entire lifespan). This menopausal hypo-estrogenic state accelerates many important diseases. One in three women will develop osteoporosis. Women have 1.6 times greater chance of developing dementia disorders than men [27], with an even higher incidence in women with premature menopause [23]. There is an increase in coronary and vessel disease. All of these long-term consequences will be more extreme in women with prophylactic oophorectomy.

In women with a high risk of developing cancer, many doctors feel very uncomfortable even discussing the option of HT after prophylactic surgery. Replacing hormones always raises the question of whether HT will increase the breast cancer risk. It is reassuring that most of the studies including BRCA1 mutation carriers with and without RRBSO [28] did not observe an increase in risk in breast cancer associated with HT. This is the case whether the woman had a surgical or a natural menopause

Although data are limited, HT does not seem to be associated with relevant increases in breast cancer risk according to the available studies. Given the risks of RRBSO in younger premenopausal women, HT can, therefore, be recommended after RRBSO prior to the age of 50 years [19]. In most of the studies, women with bilateral prophylactic mastectomy were excluded, which means that in these instances the use of HT would be even safer.

When a prophylactic skin/areola/nipple-sparing mastectomy with immediate breast reconstruction is performed, women may be even more reassured for the use of HT. The use of prophylactic surgery and subsequent HT offers both an esthetic and safe way of leading a normal life.

The risk of Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative disease and the most common cause of dementia, which affects around 43.8 million individuals and ranks as the fifth leading cause of death globally. The epidemic growth and the current lack of cures make Alzheimer’s disease one of the most significant unmet needs in medicine.

There is a huge unmet need to refine studies on the relation of menopause hormone treatment and Alzheimer’s disease. It took 27,347 women and 18 years of follow up in the Women’s Health Initiative study to prove that the risk of Alzheimer’s disease or dementia mortality was reduced (relative risk 0.85, 95% confidence interval 0.74–0.98) [29]. Using ultra-sensitive, well-documented core pathophysiological Alzheimer’s disease plasma biomarkers [30], one study observed a clear benefit of HT in APOE4 carriers [31]. In this study all women were healthy taking no other medication and were recently in menopause, and optimal bio-identical hormones were used. All women were karyotyped for APOE4 carriership. No confusion between Alzheimer’s disease and vascular dementia was present.

This study is the first clinical study proving that core pathophysiological Alzheimer’s disease plasma biomarkers are powerful markers that may be of paramount importance to develop new strategies to reduce the risk of Alzheimer’s disease and should be considered when prophylactic removal of the ovaries is performed.

Mimicking the effect of parity

Although prophylactic mastectomy decreases the incidence of breast cancer, the overall uptake is less than 30% [32]. A novel and non-surgical approach was recently described using the administration of pregnancy hormone (r-hCG or pregnancy hormone injections [Ovidrel^®, 12 weeks, three times per week]) in young nulliparous BRCA1 or BRCA2 carriers [4,5]. The rationale for the study was that in the ductal cells of the breast there is a high proliferation rate after puberty. As such, breast cells are very sensitive to chemical and physical genotoxic factors and several endogenous and exogenous hormone-disrupting molecules in that period. All of these factors seem to generate long-lasting changes in gene expression and epigenetic regulation [33,34]. A FFTP has an important impact to restore genomic and epigenetic alterations. Proliferation of breast cells is reduced after an early FFTP. This leaves more time to control and correct spontaneous mutations prior to cell division. An early FFTP reduces breast cancer risk substantially in the general population [35,36] and more specifically in BRCA1/2 mutation carriers [37].

The principal hormone responsible for this risk reduction is human chorionic gonadotropin (hCG). Ample in vitro, animal and clinical studies have shown that hCG could induce changes in gene expression and epigenetic markers, induce apoptosis, and protect breast epithelial cells from being transformed and inhibit breast tumorigenesis [38].

Data on 33 nulliparous women with BRCA1 and BRCA2 mutations undergoing three breast biopsies (before, immediately after and 6 months after 12 weeks of recombinant pregnancy hormone [r-hCG] injections) indicate that prolonged r-hCG administration is safe. All women finished the study. No serious complications occurred both at the end of r-hCG treatment and 6 months later. The administration of r-hCG had a remarkable effect on the gene expression profile of breast tissues from BRCA1 or BRCA2 carrier women. A clear description of the signaling pathways has been published [5]. There is a close overlap with the changes occurring during a FFTP.

Conclusions

• HT after RRBSO does not seem to be associated with relevant increases in breast cancer risk according to the available studies.

• Withholding HT in young women after RRBSO may, however, substantially increase the risk of osteoporosis, cardiovascular disease, Alzheimer’s disease (especially in APOE4 carriers), cognitive disorders and sexual problems.

• HT should be promoted more liberally after RRBSO in young women.

• PGD is a well-established treatment to have children without BRCA mutation.

• Optimal age to plan oophorectomy should be 35–40 years in women with BRCA1 and 40–45 years in women with BRCA2, after childbearing is complete.

• A prophylactic skin/areola/nipple-sparing mastectomy with immediate breast reconstruction should only be performed after extensive information of all different surgical options. The areola is skin and should be preserved as much as possible during reconstruction.

Potential conflict of interest

The author reports a claim according to patent number WO2022125417A1, ‘Treatment of females having brca1/2 mutations with human chorionic gonadotropin to reduce the risk of developing breast cancer’.

Source of funding

Nil.