Jennifer K. Litton, MD

Fertility is such an important concern for our young patients with breast cancer. In fact, I have had multiple patients tell me that one of their biggest treatment regrets was not discussing it upfront with me. We are still not doing what we should be doing discussing fertility concerns with our young patients. For those who with whom we do discuss it, we’re still leaving them with many questions. One of the first is: “When is the best time to get pregnant?” Data from older retrospective studies offer us some hints. Some of the earlier data suggest the farther away a patient is from diagnosis and treatment, the less chance they have of dying of breast cancer. Others suggest maybe 2 years out is better, whereas others suggest maybe 4 years out is better.
Regarding pregnancy planning according to subtype, for patients with hormone receptor-negative breast cancer, this isn’t as much of a problem when we’re suggesting patients to wait 18 months or 2 years, because at that time, no further systemic therapy is indicated. But what about our patients with hormone receptor-positive breast cancer? Endocrine therapy is now recommended for 10 years, which significantly delays a future pregnancy. In addition, tamoxifen is contraindicated during pregnancy due to the high risk for birth defects. These women often are left to decide whether to not take endocrine therapy or delay it to try to have a pregnancy, or as we saw in the current trial, start endocrine therapy for a period of time and then hold it, have a pregnancy, and then resume and complete it.
The 5 to 10 years of adjuvant endocrine therapy, especially for young women in their late 30s, can really take pregnancy as an option off the table for many patients. It is not just when they receive chemotherapy that they may go into premature menopause, but we also know that even if they don’t go into premature menopause, treatment can shift their natural age of menopause to an earlier time.
One of the biggest standouts of the current trial is that all women in this cohort wish to become pregnant. It is also very important to highlight who participated in the POSITIVE trial. The biggest portion of patients (43%) were aged 35 to 39 years, which is really important when thinking about adding 10 years of endocrine therapy. Three-quarters of these women had not had a prior birth, and 94% had stage I and stage II disease. As far as pregnancy status and therapy resumption, 74% of patients became pregnant, 86% had a live birth and 110 women had more than one pregnancy. The rate of birth defects is 2%, which is not above what we would expect in the general population. When looking at the curve of 76% of patients resuming endocrine therapy, 8% had died prior to the resumption of endocrine therapy, and 15% were still either in the process of trying to get pregnant, were postpartum or were breastfeeding.
There’s multiple strengths and limitations of this trial. This is the first study to tackle a really difficult question. It has been an incredible international collaboration and this gives us a first look into the safety of a practice that was already happening. Researchers have good follow-up of offspring, reproductive technologies and long-term survival. As for the weaknesses, it is a single-arm study compared with a historical control group, but this is a very important question that can never be studied in a randomized controlled trial. I congratulate the investigators for looking at different clinical trial designs and looking at different cohorts to go into questions that are important. They’ll need to continue to follow the long-term resumption, the length of endocrine therapy, and of course the longer follow up for hormone receptor-positive survival endpoints.
Going back to how we can better provide this information to our patients, during the last 15 years we have had multiple guidelines, multiple datasets and decision aids, but we’re still left with very wide risk estimates that often don’t individually account for ovarian reserve measures, comorbidities and personal fertility history. It is time for us to take the next steps to start to consider artificial intelligence to better identify and individualize who is at risk. In addition, with our electronic medical records, we have the datasets now not only to build and to train, but to truly validate such a tool. Also, it is very important to include our reproductive colleagues as part of our care team.
This was a challenging study to design and execute. It adds to the existing data of safety of subsequent pregnancies after a diagnosis of breast cancer. But I would still say that this is an exceptionally individual decision. I don’t think these results should be widely interpreted across all patients who are premenopausal with early breast cancer yet. We need to take into account the patient’s age and their personal risk for recurrence.
These early results are promising. However, given the nature of hormone receptor-positive disease, longer follow-up is necessary, and we need to continue to improve discussing fertility concerns with our patients who want future pregnancies. This is the time for better assessment tools and implementation tools.

Marleen I. Meyers, MD

This trial is very exciting. One of the most devastating results for young women with breast cancer is the potential loss of fertility and ability to have biological children. With maternal age increasing and many women not having children in their 20s comes the decrease in fertility and the opportunity to have children. We have come a long way with fertility preservation but the recommended treatment for hormone-blocking drugs in breast cancer is 5 to 10 years. Waiting to complete treatment makes the possibility of carrying a child less realistic. This study offers hope for some women with hormone receptor-positive breast cancer to be able to interrupt cancer treatment and still have good outcomes.
This study is the first real evidence we have about the safety in interrupting treatment for pregnancy. In addition, the babies appear to be healthy. I would be cautious as the follow-up is short and we know that hormone receptor-positive breast cancer can recur within 10 years of diagnosis and beyond. The next steps will be more long-term follow up and to parse out which subset of patients can do this safely.