Estrogen receptor negative breast cancer and future fertility

Breast cancer is diagnosed in 240,000 reproductive age women each year worldwide and approximately 25,000 in the US. Breast cancer is usually classified into estrogen receptor positive or estrogen receptor negative depending whether the cells express the protein that renders the cell responsive to estrogen.  In 2010, The American society for Clinical Oncology and College of American Pathologist using a technique called IHC classified breast cancer according to the amount of estrogen receptor protein into estrogen receptor negative when <1% of cells express the protein, weekly positive (1-10% of cells) and estrogen receptor positive (>10% of cells). Approximately 45% of premenopausal breast cancers are estrogen receptor negative.

All women in this video are breast cancer survivors

Triple negative breast cancer (TNBC) indicates that the cells are negative for three markers – estrogen receptor, progesterone receptor and  do not over-express a third protein called HER2. Estrogen receptor negative and triple negative breast cancer is especially important because its commonly diagnosed in younger women while they are still in their reproductive years (24% of breast cancers diagnosed in women before menopause). Its more common in African American than Caucasian women and tend to be more aggressive and less responsive to treatment than estrogen receptor positive breast cancer. Also a large proportion of breast cancers diagnosed in women carrying BRCA1 mutations or shortly after delivery are estrogen receptor negative. It has also been recently linked to diabetes, insulin resistance and abdominal obesity. Since hormone treatment is not usually advocated, the mainstray of treatment is surgery and radiation followed by chemotherapy. In addition multiple additional agents are used or under trial as added treatment for TNBC.

Fertility preservation in women diagnosed with triple negative breast cancer is challenging. In my experience approximately 10% of women  diagnosed with cancer seeking counseling for future fertility are estrogen receptor negative.

Options for preservation of future fertility include, ovarian stimulation followed by embryo or egg freezing, In vitro maturation of oocytes or ovarian tissue freezing.

1. Ovarian stimulation and embryo freezing. This is the standard method . It is suitable for women with a stable partner and when treatment does not need to start immediately. Usually there is a 3-4 week gap between surgery and chemotherapy that can be used for preserving fertility. Minimizing estrogen exposure appears to be an important safety issue. A protocol that utilize a medicine that prevents the ovary from making estrogen during stimulation appears to be safe on intermediate term followup, thus far. In my opinion, even in estrogen receptor negative cancers, low estrogen stimulation may be safer. This is because estrogen can stimulate cancer cell growth through indirect ways e.g. increase formation of blood vessels in the tumor. Hundreds of thousands of babies were borne using this method worldwide.

2. Ovarian stimulation and egg freezing. This method should be considered in women with no partner. It requires ovarian stimulation and that treatment does not need to start immediately. This was discussed in details here. About a 1000 babies were borne using this method worldwide.

3. In vitro maturation of oocytes. The aim here is to retrieve immature oocytes after no ovarian stimulation or stimulation for 2-3 days. Eggs are matured in the lab for about 24 hours then fertilized and embryos are frozen or eggs are frozen unfertilized. Eggs are retrieved from 50% of follicles aspirated. Of those about 60-70% are successfully matured in the lab. Because of its low efficiency, its suitable for select women with high ovarian reserve where many small follicles (15 to 20) seen on initial evaluation and its not suitable for general use. It has the advantage of very short or no delay in cancer treatment. Few hundred babies were borne using this method worldwide.

4. Ovarian tissue freezing. This is the most experimental method of preservation of fertility. Its can be accomplished within few hours. The ovary is removed using minimal access surgery or at the time of other surgeries e.g. during cesarean delivery. Cancer treatment can start next day. It does not require stimulation of the ovary and does not require a partner. It usually reserved for women younger than 40 and when chemotherapy carries high risk for ovarian failure or if the ovaries have to be removed for another reason e.g. BRCA mutation. After the ovary is removed its cut into very thin strips and frozen. Part of the ovary is examined for contamination with malignant cells. The ovary can be transplanted back after treatment. about 10 babies were borne using this technique worldwide.

My approach is to

  • Make myself available for consultation as soon as possible and at a time suitable to the couple / woman’s schedule. Certainly women have to see many providers and its very difficult for her fit yet another consultation.
  • Careful review of all records related to biopsy and lab results, surgery, oncology notes and intended treatment plan.
  • With the patient permission I contact her oncologist to discuss his treatment plan, its timeline and the likelihood of cure.
  • During consultation I would discuss the state of science in relation to fertility preservation – what is known and what is uncertain about methods for preservation of fertility pertinent to her.
  • One important aspect of consultation is evaluation of ovarian reserve. This include ultrasound and ovarian reserve tests (blood work). These would indicate the potential for egg production and prospect of success for preservation of fertility irrespective of the method used
  • Careful evaluation of spread into the abdominal cavity especially the ovaries, since TNBC tend to spread to the abdomen early.
  • I provide the couple / woman with printed material to read and explain to her that this is the time for fact finding. I advice her not to make a decision for the coming few days and encourage her to seek advice from her oncologist, a second opinion from a colleague and support from other family members.
  • I would contact her few days later to inquire about any questions she may have and discuss lab results.
  • If she needs psychological support to cope with stresses of treatment and decision making with or without a partner, I usually refer them to a reproductive psychologist.
  • Whatever the final decision maybe, I discuss other elements of survivorship plan, including testing for ovarian reserve after chemotherapy, maintenance of bone, genital and sexual health.
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