Data indicate that it may be safe to pause endocrine therapy for patients to attempt to conceive, and experts in the space review how it has impacted treatment strategies.
Results from the POSITIVE trial (NCT02308085) have left the breast cancer community pondering an essential question: Can endocrine therapy be temporarily paused in patients with hormone receptor–positive disease long enough to allow for pregnancy and child birth? Data from the trial, which analyzed the risk of breast cancer events associated with pausing treatment in those with hormone receptor–positive, early breast cancer showed that it may be possible.1
Study results that were originally presented at the 2022 San Antonio Breast Cancer Symposium (SABCS) were met with some trepidation, specifically because this type of study had not been done before.2
CancerNetwork® sat down with lead investigator, Anna H. Partridge, MD, MPH, to discuss the impact these findings have had on the treatment landscape, and how she would like to see these results utilized in clinical practice. Additionally, Virginia Kaklamani, MD, also shared how results from the POSITIVE trial have impacted her practice and highlighted conversations she has with patients about fertility preservation.
One of the first conversations Partridge has with a patient who is pre-menopausal is if they may be interested in having future children.
“If [patients] are interested in future fertility, then I think about it from the standpoint of what is the likelihood that the treatments are best for this person’s cancer outcomes, and what is the likelihood that those treatments will impact their fertility; that can include both direct gonadal toxicity or toxicity to the ovaries [during] treatments,” Partridge, vice chair of Medical Oncology, founder and director of the Program for Young Adults with Breast Cancer, director of the Adult Survivorship Program, Eric P. Winer, MD, chair in Breast Cancer Research at Dana-Farber Cancer Institute, and professor of medicine at Harvard Medical School, explained.
Memorial Sloan Kettering Cancer Center published information on its Patient & Community Education page on fertility preservation options for female patients undergoing cancer treatment.3 The publication highlighted how chemotherapy may destroy eggs, pause menstrual periods, and result in early menopause. Other treatments like radiation to the whole pelvis or abdomen may disrupt reproductive organs or if radiation or surgery is performed on the brain, there may be disruption to the pituitary gland, which can also affect ovulation and menstruation.
There are several fertility preservation options available to female patients defined by the American Cancer Society (ACS).4 These include cryopreservation, ovarian transposition, fertility-sparing surgery, or progesterone therapy for those who have early-stage uterine cancer. For cryopreservation, patients may seek to freeze their eggs, embryos, or ovarian tissue. The ACS also provides options for women who are not fertile after treatment including using donor eggs or embryos, having a surrogate, or considering adoption.
Kaklamani, professor of medicine in the Division of Hematology/Oncology at UT Health San Antonio and the leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center noted how she approaches fertility preservation when treating her patients. Specifically, she discussed using Gonadotropin-releasing hormone [GnRH] analogues during chemotherapy. This includes beginning GnRH a week or 2 prior to chemotherapy and continuing during treatment. While utilizing GnRH analogues, Kaklamani has not seen a negative impact on breast cancer outcomes or patients' ability to have children.
Partridge uses a similar tactic in her practice by suppressing the ovaries with GnRH agonist leuprolide or goserelin (Zoladex) when aggressive cytotoxic chemotherapy may be used.
“This [treatment] prevents premature menopause in a proportion of patients and does appear to increase the number of babies born subsequently, although it’s controversial whether it truly impacts [patient’s] fertility in a measurable way,” she said. “The evidence is mixed in that regard, but I do it in patients because it’s something that might help, and they certainly don’t want to go through menopause if they don’t have to in some settings.”
Partridge also indicated that she utilizes the psychosocial oncology program at Dana-Farber because the inability to have children or the potential to not conceive can take a toll on patients’ and their partners’ mental health.
The concept of the POSITIVE trial was created to help young patients with breast cancer who needed to be on endocrine therapy for 5 to 10 years. Partridge and her colleagues posed the question “Can a patient take a break from endocrine therapy, resume treatment, and continue for a full 5 years, [and] do just as well?”
The study’s investigators sought out patients who wanted to start or expand their families and were willing to take a break from endocrine therapy. Patients who enrolled were treated with adjuvant endocrine therapy from 18 to 30 months and were able to come off treatment for no more than 2 years.
Although there weren’t previous data to support this strategy, Kaklamani has previously observed patients taking a break from treatment to pursue pregnancy.
“[Prior to the trial], we would tell women that after 2 to 3 years of being on endocrine therapy, if they wanted to have children, we would discontinue their endocrine therapy, and then allow them to have children and then have them go back on endocrine therapy,” she explained. “We didn’t have any data suggesting that this was safe. This was just a lifestyle decision that these women were making.”
Now with the results of the POSITIVE trial, Kaklamani said that the results show that this method can be safe for patients who want to attempt to have children while in the middle of treatment.
The study was conducted between December 2014 to December 2019, during which 516 patients were included in the primary efficacy analysis. The median follow-up was 41 months, and the median time from diagnosis to enrollment was 29 months.
At enrollment, the median patient age was 37 years, and 34.3% of patients were younger than 35 years. Additional patient characteristics included 93.4% of patients having stage I or II disease, 29.3% having 1 to 3 positive nodes, 4.5% having 4 to 9 positive nodes, and 62.0% receiving neoadjuvant or adjuvant chemotherapy.
To be enrolled on the trial, patients needed to have discontinued endocrine therapy 1 month prior and have a 3-month washout period before attempting pregnancy. Patients took a 2-year break from treatment to attempt pregnancy. Additionally, patients were eligible if they were younger than 42 years, and had stage I, II, or III hormone receptor–positive breast cancer.
Forty-four patients who had their treatment interrupted experienced a breast cancer event, which was within the safety threshold of 46 events. In the treatment interruption group, the 3-year incidence of breast cancer was 8.9% (95% CI, 6.3%-11.6%) vs 9.2% (95% CI, 7.6%-10.8%) in the control cohort.
Regarding distant recurrence, the 3-year incidence rate in the treatment interruption group was 4.5% (95% CI, 2.7%-6.4%) vs 5.8% (95% CI, 4.5%-7.2%) in the control group.
Overall, 497 patients reported their pregnancy status, 74.0% of whom became pregnant at least once during the trial. Investigators used a multivariate Cox-model to determine an HR for breast cancer events associated with pregnancy of 0.53 (95% CI, 0.27-1.04).
Investigators reported successful pregnancies in 85.7% of patients who were younger than 35 years compared with 76.0% of patients who were between 35 to 39 years old. Additionally, 43.3% of patients noted that they used assisted reproductive technology during the trial.
Investigators outlined competing risks including the resumption of endocrine therapy, no longer attempting to become pregnant, and cancer events. At 6 months from enrollment, the incidence of a first pregnancy with competing risks occurred in 28.8% of patients, 53.6% at 12 months, and 70.5% at 24 months.
A total of 63.8% of women had a live birth at the time of the database lock, and 86.1% had at least 1 pregnancy. Of the women who reported at least 1 pregnancy, the most common complications included hypertension or preeclampsia (3.8%), diabetes mellitus (2.4%), and placental abnormalities (1.6%). Across the trial, of the 507 pregnancies that occurred, 69.0% were live births; investigators also indicated that 65.7% of live births were vaginal deliveries.
In total, 7.9% of babies born had low birth weights, and 2.9% had birth defects.
As the lead author of the study, Partridge was not surprised by the outcomes but has hope that the data will resonate in the breast cancer community.
“I think POSITIVE will open the door for more young women to say, ‘I can take a break and try to become pregnant’. At least in the short term, it appears safe. Hopefully, in the long term, we’ll have data that appear safe from a prospective standpoint.”
As more data are being collected and analyzed, Partridge and her colleagues hope to present updated results at the 2023 SABCS meeting. The updated trial results will include secondary outcomes including patients who became pregnant and the safety of using in-vitro fertilization (IVF) either at diagnosis or following diagnosis.
Follow-up studies will also focus on the children who were born while the POSITIVE trial was underway. Investigators also want to identify whether there were any complications, patients who were able to breastfeed, and any psychosocial effects. Additional studies will also include a circulating tumor DNA evaluation and an assessment of the relationship between pregnancy and the resumption of menses.
Looking toward the future, Kaklamani hopes to see this study continue to evolve to include other patient populations.
“In the future, I think we would need to focus more on the potential impact of IVF in women who are diagnosed with breast cancer and to look at GnRH analogues further and whether they can help in preserving ovarian function, and other methods,” Kaklamani explained. “They could potentially help in increasing that 63% [of live births] to 80% or even 90%.”
As endocrine therapy is typically given for a 10-year period, Partridge noted that she is investigating what years 5 to 10 during endocrine therapy receipt would look like if patients remained pre-menopausal. These patients who take a break from therapy remain at risk for recurrence. Currently, there aren’t any data on ovarian suppression for women receiving therapy between years 5 to 10.
Because of the results of this trial, Kaklamani is more comfortable pausing therapy to allow patients to try and get pregnant. When speaking with patients, she can now present data that shows it is safe to pause endocrine therapy and restart again within the 2-year time point.
Moving forward, Partridge hopes that these results and subsequent follow-up studies continue to make clinicians pause and consider new options for treatments.
“I think the more attention we can pay to this, the better to help these patients not just live through their cancers but thrive and have the fullest lives possible after their diagnosis and treatment,” Partridge concluded.