Breast cancer

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Patients with breast cancer who require gonadotoxic chemotherapies or extended hormonal therapy (often for 5-10 years) will have diminished ovarian reserve at the end of their treatment either due to the negative impact of the chemotherapy on their egg supply or the effect of ageing and delaying attempts at pregnancy for up to 10 years. Patients with breast cancer who have not completed having their family usually have time to undergo treatments such as oocyte cryopreservation or embryo cryopreservation prior to initiating chemotherapy or hormonal treatments to provide them with the opportunity to have children in the future.

The focus for these patients should be on early referrals from the oncologists as soon as the diagnosis is made or suspected to provide patients with the time needed to undergo ovarian stimulation. Education of oncologists and breast surgeons is key as stimulation protocols and medications have changed over the years as well as data on success and long term outcomes on survival and breast cancer recurrence rates. Many of the reasons given in the past for oncologists not referring patients have been overcome with new approaches and understanding of ovarian physiology. One of the most common reasons was that there “was not enough time” to undergo fertility preservation or that conventional ovarian stimulation raises estrogen levels too high. Another reason often cited is that it is too expensive and that success rates are poor.

Let’s take a closer look at the time needed to undergo a cycle of egg or embryo freezing

Traditionally, with IVF for infertile patients, ovarian stimulation starts with the onset of a menstrual period. This approach can lead to significant delays of weeks before stimulation starts if the patient is in the late follicular/early luteal phase of her cycle and an additional 2 weeks of stimulation until oocyte retrieval can be performed.  Since ovarian folliculogenesis appears to be a continuous process starting with a primordial follicle developing for 3-4 months until the follicle becomes FSH-responsive, so called “random start” stimulation,  where initiation of gonadotropins occurs at any time during the menstrual cycle can be performed. This means that no matter where someone is in their menstrual cycle, initiation of gonadotropins can commence with similar outcomes in the late follicular phase and luteal phases of the cycle compared to the traditional early follicular initiation (1). This reduces the time that it takes to obtain mature oocytes before starting oncological treatments, with no significant difference in the number of retrieved oocytes compared to ovarian stiulation starting in early follicular phase.

The next barrier is success rates. Outcomes with oocyte cryopreservation have improved since initially described in. Slow freezing, the method of choice at the time required expensive freezers and skilled technicians who were only able to freeze limited quantities of oocytes at a time. Vitrification, or ultra-rapid freezing to a glass like state with high concentrations of cryoprotectants  reduces/eliminates ice crystal formation with improved outcomes for oocytes and embryos. Success rates with frozen oocytes under the age of 35 appear to be similar to success rates with fresh oocytes in IVF patients. Over the age of 35, fertilized oocytes appear to do slightly better than MII oocytes with regard to probability of success. So the more oocytes or embryos that are able to be frozen, the better the probability of having a child in the future with those frozen gametes/embryos. Additionally, since we are initiating stimulation within days of seeing these patients, they often have time to undergo more than 1 stimulation cycle- so called back-to-back stimulation. With this method, we use a GnRH antagonist during stimulation to prevent premature ovulation and only a GnRH agonist trigger to mature the oocytes. An ultrasound is performed 4 days after retrieval and stimulation can be initiated if the ovaries are relatively normal size similar to the luteal stimulation referred to above. Since the GnRH agonist trigger causes early luteolysis, other than a few small corpus luteum cysts on ultrasound, repeat stimulation usually results in similar #’s of oocytes from the second cycle compared to the first. Patients should be reminded that with all luteal start stimulations, menstruation will occur during stimulation.

Stimulation of patients with E2 responsive tumors can be tricky. Fertility patients are often concerned about the supraphysiologic estrogen levels seen with conventional stimulation. Breast cancer patients even more so. The initial approach to stimulating patients with estrogen responsive disease was to perform natural cycle or tamoxifen stimulation however success rates were poor with regard to number of oocytes retrieved. Subsequently, gonadotropins were added to the stimulation approach with better results of approximately 8 MII oocytes retrieved and estrogen levels still within the “physiologic range” with a peak E2 level with a fixed dose of letrozole and gonadotropins of ~405 pg/ml (2). We have modified this approach to stimulation so that we will titrate the dose of aromatase inhibitor during stimulation to patient individual requirements. In other words, if the E2 level is < 150 pg/ml, we do not use any letrozole. And we will give letrozole in increments of 2.5 mg up to 10 mg/day to maintain an E2 level < 350pg/ml if possible. After stop letrozole on the day of trigger and after retrieval, we re-initiate letrozole at 5mg/day until menses or until chemotherapy starts (personal data). Five-year recurrence rates for breast cancer appear to be similar between patients who elected to undergo ovarian stimulation to cryopreserve their oocytes and patients who did not (Azim A, et al J Clin Oncol 2008:26(16);2630-35).

 

BRCA mutations

There is little controversy over the concept that eliminating deleterious genetic mutations so that they are not passed on to future generations in affected families is considered not only ethical but desirable. Just a quick conversation with would-be parents who are themselves struggling with increased surveillance and testing for the cancer they know is going to come but not when or where makes you understand the relief surrounding the knowledge that they don’t have to pass this burden onto their children. While the technology to stimulate follicle development, create embryos and remove a few trophectoderm cells for testing is readily and widely available, it comes at a cost. Not just the financial cost of the In Vitro Fertilization (IVF) and pre-implantation genetic testing (PGT) procedure (which is not insignificant) but the emotional cost of “playing god” and selecting embryos for transfer or discard can be quite difficult for these patients.

For female BRCA mutation carriers, prophylactic surgeries like mastectomy, salpingectomy and oophorectomy can reduce the lifetime risk of developing breast and ovarian cancer but are associated with major surgery and, in the case of oophorectomy, iatrogenic menopause and sterility unless there are oocytes or embryos cryopreserved prior to the gonadectomy. In order to preserve gametes or create embryos for future use, ovarian stimulation is used to maximize numbers of eggs or embryos available each month. Conventional stimulation approaches, however, will result in elevated serum estradiol levels from ovarian stimulation (sometimes >10x peak values seen in the natural cycle) with the theoretical risk of tumor initiation or advancement from these supraphysiologic estradiol concentrations.

Estrogens promote cell proliferation and growth in breast tissue and their involvement in inducing breast cancers has long been suspected and evidence supporting this theory has been demonstrated in vitro (Russo 2006 J Steroid Biochem Mol Biol) proving their role in breast cancer initiation and propagation. This cell proliferation along with the ability of estrogen to induce direct genotypic alterations and mutations through a cytochrome P-450 mediated metabolic activity and induction of aneuploidy has been shown in vitro to induce neoplastic changes in breast epithelial cells similar to other potent carcinogens (Russo 2006 FASEB J).

The BRCA gene however, is a tumor suppressor gene such that inactivating mutations like BRCA1 and BRCA2 will allow the accumulation of mutations that are not repaired and lead to increased cancer risk.

Mutations in either of the breast cancer type 1 or 2 susceptibility genes are the most common mutations found in patients with a family history of hereditary breast and ovarian cancers, although increased fallopian tube, prostate and pancreatic cancer risk among others is also seen (Couch FJ 2014).  BRCA 1 mutation carriers have a 3% risk of breast cancer by age 30 which increases to 21% by age 40, 39% by age 50 and 69% by age 70 and a 20% risk of ovarian cancer by age 50. BRCA2 mutation carriers have a <1% risk of breast cancer by age 30 which increases to 17% by age 40, 34% by age 50 and 74% by age 70 with a 10% risk of ovarian cancer by age 50 (Finch 2006). Male carriers of BRCA mutations are not immune to the risks of cancer and the risk of male breast cancer is ~1% and ~8% for BRCA1 and 2 mutations respectively.

Patients often know of their BRCA status at a relatively early age based on family history and screening is recommended (by NCCN) for the following groups:

  • Personal history of ovarian, fallopian tube or peritoneal cancer
  • Personal history of breast cancer diagnosed prior to age 45
  • Breast cancer with at least 2 close relatives with breast/ovarian/fallopian tube/peritoneal cancer
  • 2 separate breast primaries
  • At least 2 close relatives with pancreatic or aggressive prostate cancer
  • Triple negative breast cancer under age 60
  • Any male breast cancer
  • Personal history of breast cancer and Ashkenazi jewish ancestry
  • Family history of any close relative meeting above criteria
  • Close family member on same side of family with known BRCA mutation

Management of female BRCA mutation carriers consists of risk reducing bilateral mastectomy as well as BSO between the ages of 35 and 40 depending on personal/family history as well as which mutated gene they carry. Since ovarian cancers tend to occur slightly later in BRCA2 carriers, BSO can be delayed until age 40 in patients with negative surveillance. Patients with BRCA mutations that conceive a pregnancy will have reduced rates of breast cancer and is somewhat protective (Freibel TM 2014). This same study found that while oral contraceptives may offer some protection against ovarian cancer risk, they were also associated with an increase in the risk of developing breast cancer.

Estrogen is mutagenic in breast tissue and has been shown in vitro to stimulate proliferation and mutations in breast tissue. Estrogens induce direct and indirect free radical mediated DNA damage, genetic instability and mutations. They also activate tumor suppressor genes like BRCA. BRCA allows for repair of these mutations in the cells but a non-functional BRCA gene due to inactivating mutations will prevent the cells from self-repair (ref). The issue of hormone replacement therapy in individuals with mutations in their BRCA gene who have undergone rrBSO is controversial. In patients who have not had bilateral prophylactic mastectomies, a theoretical increase in the risk of breast cancer is plausible (Sinno AK 2020). Studies have not confirmed a significantly increased risk of breast cancer formation in young BRCA carriers following rrBSO however after the age of 45 there may be some additional risk (Michaelson-Cohen R 2021). While the data is somewhat reassuring for HRT following rrBSO on breast cancer risk, the impact of a short course of ovarian stimulation with supra-physiologic levels of Estradiol for 2-3 weeks is not known since the risk of breast cancer detection may be remote from the sentinel event inducing the malignant mutation.

A study from 2008 appears to provide some evidence that infertility treatments are safe in BRCA carriers (Kotsopoulos 2008). In this study, 1380 women with either a BRCA 1 or 2 mutations were studied to see if a history of infertility, use of fertility medications or IVF were associated with an increased risk of breast cancer. Only 4% of this population ever used a fertility medication but those that had did not have a higher incidence of breast cancer. Another study looked specifically at IVF (Derks-Smeets 2018) and found that of the 2514 BRCA carriers studied, 3% (76 patients) had undergone IVF and did not have an increased risk of breast cancer. These studies provide some re-assurance, although the number of exposed patients is small, that undergoing ovarian stimulation to bank oocytes or create embryos for genetic testing prior to prophylactic oophorectomy should not come at the expense of increased risks of breast cancer.

 

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  11. Derks-Smeets I, Schrijver L, Die-Smulders C, et al. Ovarian stimulation for IVF and risk of primary breast cancer in BRCA1/2 mutation carriers. Br J Cancer 2018:119;357-363

 

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Genetic/familial high-risk assessment: Breast and ovarian. https:///www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

 

 

 

 

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