Young women with breast cancer have many concerns about their future fertility. How confident are you in discussing their chances of a future pregnancy, the effect of breast cancer treatment and fertility interventions on these offspring, and their risk of a compromised oncologic outcome after fertility preservation interventions or pregnancy itself? These topics are important ones for clinicians to clarify for their patients, according to Ann H. Partridge, MD, MPH, an expert in this area, who discussed them at the 2023 Miami Breast Cancer Conference.1 Dr. Partridge is Founder and Director of the Program for Young Women with Breast Cancer, Director of the Adult Survivorship Program, and senior physician at Dana--Farber Cancer Institute, as well as Professor of Medicine at Harvard Medical School, Boston.
Premature menopause and fertility problems are “often induced with good intentions”—a result of effectively treating early-stage breast cancer, she noted. The concern of these young patients is clear. In a Web-based survey of 657 young women with breast cancer, Dr. Partridge and her colleagues found that 57% expressed substantial concerns about their subsequent fertility at diagnosis, and 29% reported these concerns influenced their treatment decisions.2
“Concern about fertility is prevalent at diagnosis in our younger-than-40 population, and it’s not something we should consider only at diagnosis.”— Ann H. Partridge, MD, MPH
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“This was a real eye-opener for us,” commented Dr. Partridge. “Not only was fertility causing concern and impacting quality of life, but these concerns were possibly getting in the way of women availing themselves of potentially life-saving therapies.”
In their more recent Dana-Farber cohort of 1,026 patients with early-stage breast cancer, 38% expressed interest in preserving fertility at diagnosis, and fertility remained a concern 3 years later for 24%.3
“Concern about fertility is prevalent at diagnosis in our younger-than-40 population, and it’s not something we should consider only at diagnosis. We need to reconsider it during follow-up, as emotionally, this issue may still be taking a toll. Women may feel like they are putting their lives on hold to take hormonal therapy. It’s important to look at what’s going on here and try to help these women,” Dr. Partridge emphasized.
Although clinicians may not be fully aware of a patient’s fertility potential or appropriateness for fertility preservation approaches, they should always ask adolescents and young adults diagnosed with cancer whether they might be interested in having biologic children in the future. These conversations can be difficult and time-consuming, but they help to avoid the potential “burning of bridges” with treatment and time, when efforts to preserve fertility may come too late. A diagnosis of metastatic disease does not make these conversations irrelevant, but it can be a different conversation. For these patients, there may be “losses to grieve” with the help of their providers, she said.
Fertility Preservation Approaches
“The good news is there are things women can do to preserve fertility while undergoing treatment,” stated Dr. Partridge. The standard approach since 2012 has been embryo cryopreservation, but recently oocyte preservation has also become easier and more feasible, and it results in more pregnancies now than in the past.
“Our reproductive endocrinologists tell us they will often freeze harvested oocytes half as eggs and half fertilized embryos, even in happily married couples, because, of course, they don’t always stay happily married. It can be logistically and legally less complicated [with both eggs and embryos available],” she added.
For patients who are pathogenic variant carriers, preimplantation genetic diagnosis should be part of the discussion. And for any patient hoping for a future pregnancy, clinicians need to “manage expectations” around the timing of a woman’s “natural clock” and her risk of disease recurrence.
Ovarian Function Suppression
Ovarian function suppression is often part of the treatment of patients with hormone receptor–positive disease. A 2018 meta-analysis by Lambertini et al showed that the use of gonadotropin-releasing hormone analogs during treatment may prevent premature ovarian insufficiency and positively impact future fertility, essentially halving the rates of premature ovarian insufficiency and doubling the live birth rate.4
“Clinicians can be fairly confident that, when pregnancy is desired, a temporary interruption of endocrine therapy will not do harm, at least in the short term.”— Ann H. Partridge, MD, MPH
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Of note, disease-free survival and overall survival rates were the same between the groups—a finding that was validated by results of the 2022 long-term follow-up of the PROMISE GIM-6 study.5 The important message from these and other studies is that there is no safety signal from the use of ovarian function suppression, shared Dr. Partridge.
“Ovarian function suppression is a reasonable thing to do, not necessarily as a fail-safe to assure fertility but as a ‘belt and suspenders’ approach for someone who might be going through in vitro fertilization and potentially to get them started on their endocrine therapy,” she added.
Is Pregnancy Safe After Breast Cancer?
“Patients will ask me, ‘Is it totally safe for me to get pregnant?’ and I say, ‘Pregnancy is not a spectator sport: There are lots of things that can happen when you are pregnant, and when someone’s been treated for cancer, there may be an increase in complications,” Dr. Partridge said.
For instance, it is unknown whether anthracycline exposure may result in a risk for peripartum cardiac complications; even less is known about peripartum risks after immunotherapy. On the other hand, the risks associated with multiple births—which often occur with in vitro fertilization—are well established. Especially with newer treatment regimens, clinicians “just need to be aware of our lack of knowledge,” Dr. Partridge said.
What about risks to the children born to women after treatment? There is no hard evidence, including from large registry data, that a history of cancer, cancer therapy, or fertility interventions increases the risk of genetic abnormalities, birth defects, or cancers, aside from hereditary syndromes, she said.
There may be a small increased risk for some fetal/antenatal risk, however, according to a 2021 meta-analysis that examined pregnancy complications and fetal outcomes after breast cancer treatment.6 Lambertini et al found no difference in spontaneous abortions, preeclampsia, postpartum bleeding, or congenital abnormalities, but they did observe increased risks for Caesarean section (odds ratio = 1.14), fetal low birth weight (odds ratio = 1.50), preterm birth (odds ratio = 1.45), and small-for-gestational-age infants (odds ratio = 1.16).
The timing of pregnancy after breast cancer treatment could be relevant, according to Dr. Partridge. Infants conceived at least 1 year after completion of chemotherapy (with or without radiation) have been shown to have no higher health risks than infants of women without cancer. “In women with hormone receptor–negative disease, I generally counsel to wait at least a year—to get their chemotherapy out of their system and allow their ovaries to wake up again,” she said.
Breast Cancer Outcomes and Pregnancy
However, Dr. Partridge believes the idea of pregnancy around the time of breast cancer creates worry in and of itself. “Is pregnancy, especially in estrogen receptor–positive women, like throwing gasoline on the fire? We’ve all worried about this, despite fairly robust retrospective data, including a large meta-analysis suggesting safety,”6 she said.
In the meta-analysis, breast cancer survivors who became pregnant had no greater risk for recurrence than women who did not become pregnant. In fact, there was a trend toward better outcomes in that group, especially for women with estrogen receptor–negative disease who became pregnant. It is far from clear whether this is an effect of the pregnancy. It may, in fact, reflect “the healthy mother bias,” wherein women who became pregnant were more likely to be healthier and at lower risk to start with and more likely to be comfortable becoming pregnant, Dr. Partridge suggested.
A 2022 study from Europe made a similar observation: At 20 years, the breast cancer survival rate for women who gave birth within 5 years of treatment was 72%, vs 61% for women without a live birth (P = .0056).7 When the birth occurred beyond 5 years, the breast cancer survival rates were 80% vs 76% (P = .12), respectively.
Among the Dana-Farber cohort of 1,026 young breast cancer survivors, 368 (36%) expressed interest in becoming pregnant; of these patients, 126 (34%) attempted to become pregnant during follow-up, and 89 (71%) became pregnant in the first 5 years after diagnosis.3 A total of 32 patients underwent fertility treatment, and 75% of them resulted in a live birth. The majority who became pregnant had estrogen receptor–negative disease; most women with estrogen receptor–positive disease were still on endocrine therapy, which some may have viewed as a delay in getting on with their lives, she said.
Safety of Pausing Endocrine Therapy
For women who do not wish “to put their lives on hold” to complete endocrine therapy, the POSITIVE trial (IBCSG 48-14/BIG 8-13/Alliance A221405) addressed an important question: Is it safe to interrupt endocrine therapy to attempt a pregnancy and then return to treatment to complete the full course? Will breast cancer outcomes be compromised?
Primary results of this study, presented by Dr. Partridge at the 2022 San Antonio Breast Cancer Symposium, were reassuring.8 The study included 516 premenopausal women with stage I–III hormone receptor–positive breast cancer wishing to become pregnant. Patients had received 18 to 30 months of adjuvant
endocrine therapy, then paused treatment for up to 2 years to attempt pregnancy, conceive, deliver, and breastfeed. The women were strongly encouraged to resume endocrine therapy after pregnancy to complete 5 to 10 years of treatment.
After a median follow-up of 41 months, the prespecified safety threshold of 46 events was not met, indicating that interrupting endocrine therapy was safe. The occurrence of 44 events translated to a breast cancer–free rate of 8.9%. Half the events were distant recurrences, for a distant recurrence rate of 4.5%. Patients from the SOFT/TEXT trial served as controls,9 and their respective rates were 9.2% and 5.8%, Dr. Partridge reported.
“The curves are superimposed. There’s no delta for the breast cancer–free interval, and, if anything, the women in POSITIVE look to be doing a bit better,” she observed. Clinicians can be fairly confident that, when pregnancy is desired, a temporary interruption of endocrine therapy will not do harm, at least in the short term, she said.
Dr. Partridge emphasized that clinicians of course need to counsel patients about the risk of their disease—especially those at high risk of recurrence—in the context of their fertility issues and be careful not to push their own feelings and values on the patient. Lacking these careful discussions, patients may make treatment decisions without their physicians’ input. “Your patient may show you she’s not listening to you anyway and become nonadherent,” she cautioned. “Wouldn’t you rather support her and ultimately get her back on endocrine therapy than have her walk away from the table completely?”
DISCLOSURE: Dr. Partridge has received royalties from UpToDate.
REFERENCES
1. Partridge AH: Pregnancy in breast cancer survivors: Risk, timing, and counseling. Invited Lecture. 2023 Miami Breast Cancer Conference. Presented March 4, 2023.
2. Partridge AH, Gelber S, Peppercorn J, et al: Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 22:4174-4183, 2004.
3. Poorvu PD, Gelber SI, Zheng Y, et al: Pregnancy after breast cancer: Results from a prospective cohort of young women with breast cancer. Cancer 127:1021-1028, 2021.
4. Lambertini M, Moore HCF, Leonard RCF, et al: Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: A systematic review and meta-analysis of individual patient-level data. J Clin Oncol 36:1981-1990, 2018.
5. Lambertini M, Boni L, Michelotti A, et al: Long-term outcomes with pharmacological ovarian suppression during chemotherapy in premenopausal early breast cancer patients. J Natl Cancer Inst 114:400-408, 2022.
6. Lambertini M, Blondeaux E, Bruzzone M, et al: Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol 39:3293-3305, 2021.
7. Anderson RA, Lambertini M, Hall PS, et al: Survival after breast cancer in women with a subsequent live birth: Influence of age at diagnosis and interval to subsequent pregnancy. Eur J Cancer 173:113-122, 2022.
8. Partridge A, Niman SM, Ruggeri M, et al: Pregnancy outcome and safety of interrupting therapy for women with endocrine responsive breast cancer: Primary results from the POSITIVE trial. 2022 San Antonio Breast Cancer Symposium. Abstract GS4-09. Presented December 9, 2022.
9. Francis PA, Pagani O, Fleming GF, et al: Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med 379:122-137, 2018.
