Are fertility treatments safe in young breast cancer survivors who have high-risk genes?

In young breast cancer survivors harbouring BRCA1/2 pathogenic variants, using assisted reproductive techniques (ART) to conceive did not appear to negatively affect maternal or pregnancy outcomes, findings from an international retrospective cohort study suggest.

“This global study reports the first analysis investigating the prognostic impact of ART in young BRCA carriers with breast cancer,” said Associate Professor Matteo Lambertini from the University of Genova in Italy, at ESMO Breast Cancer 2024.

In the media release, Lambertini noted that the study “provides the first evidence that use of fertility procedures is safe in young women with germline pathogenic/likely pathogenic variants in the BRCA1 or BRCA2 genes, which are known to increase the risks of developing breast and other cancers.” [https://www.esmo.org/newsroom/press-and-media-hub/esmo-media-releases/assisted-reproduction-treatments-are-safe-in-young-breast-cancer-survivors-with-high-risk-genes]

About 82 percent of women who used ART had no pregnancy complications, while for those who did not, the corresponding rate was 87 percent. When stratifying the complications, the rates were numerically similar: delivery complications (4 percent vs 5.5 percent), congenital abnormalities (0 percent vs 1 percent), foetal complications (1.3 percent vs 0.7 percent), and other complications (1.3 percent vs 0.3 percent).

At a median follow-up (from conception) of 5.2 years, ART had no detrimental effect on disease-free survival (DFS), with 13 and 118 DFS events in the respective ART and no-ART groups (p log-rank=0.147). [ESMO Breast Cancer, abstract 266O]

Looking at the types of DFS events, the ART group had a lower incidence of second primary breast cancer than the no-ART group (2 percent vs 15 percent). For other DFS event types, the rates were similar between arms: loco-regional recurrence (6 percent vs 5 percent), distant recurrence (4 percent vs 5 percent), second primary non-breast malignancy (1 percent vs 2 percent), and death without recurrence (0 percent vs 0.2 percent).

However, women who conceived with ART had more miscarriages (11.3 percent vs 8.8 percent) and fewer cases of induced abortion (0.9 percent vs 8.3 percent) than those who had spontaneous conception.

Discussant Dr Janice Tsang from The University of Hong Kong, Hong Kong SAR, China, cited possible reasons that could explain for these differences. Age at conception in the ART group was higher than the no-ART group (median 37 vs 34 years), she said. “Age is a powerful predictor of miscarriage rate.”

Moreover, spontaneous conception may have led to unintended pregnancies which, in turn, might have led to induced abortion, Tsang added.

At higher risk for recurrence, other cancers

In women with a history of breast cancer, ART before or after anticancer therapy has been shown to be safe. [Hum Reprod 2022;37:954-968] However, there is insufficient data backing its safety in breast cancer patients who are BRCA carriers, Lambertini said.

In the first report from the BRCA BCY Collaboration, only a descriptive evaluation was conducted owing to the limited sample size. [J Clin Oncol 2020;38:3012-3023; ESMO Open 2021;6:100300]

As such, the safety of ART in this specific cohort of breast cancer patients who have a higher risk of developing second breast cancer and other cancers remain a concern among physicians, Lambertini stressed.

The updated study included nearly 5,000 young women with stage I–III invasive breast cancer with known germline pathogenic variant in the BRCA1 and/or BRCA2 genes. Of the 659 women who had a pregnancy after breast cancer, 543 were included in the analysis. Eighty percent conceived spontaneously (n=436; no-ART group), while the rest conceived via ART (n=107).

In the ART group, nearly 50 percent received ART at diagnosis, a third after anticancer therapies, and 21 percent via oocyte donation.

Reassuring evidence supporting fertility preservation

In the press release, study co-author Professor Ann Partridge from Harvard Medical School, Boston, Massachusetts, US, noted that the study provides reassuring data to support fertility preservation prior to undergoing treatment or after surviving breast cancer, as well as the use of fertility preservation products (eggs or embryos). “[These] all appear to be safe from a cancer standpoint and in terms of the baby’s outcome.”

Apart from overcoming infertility, young women with BRCA1/2 breast cancer may want to resort to ART “for pre-implantation genetic diagnosis to select embryos that do not carry the same risky genes to avoid passing on a potential risk of hereditary breast cancer to the next generation,” she added.

Clinical implications

In light of patients’ hopes of building a family and avoiding transmission of BRCA pathogenic variants, Lambertini said the findings are crucial for improving onco-fertility counselling of young women with breast cancer and will have immediate implications in clinical practice.

“[Now,] when we counsel a young woman with breast cancer who has such variants, we can safely discuss the use of fertility preservation before starting treatment without major concern,” he said.

“The main take-home message … is that there is no increased risk of breast cancer recurrence with ART in young women with BRCA pathogenic variants having a pregnancy after breast cancer … The procedures are also safe for the baby,” said Lambertini.

Despite the relatively small sample size and retrospective trial design, Tsang referred to the study as “a big progress.”

While awaiting prospective studies for verification of the findings, Lambertini underlined that fertility preservation at diagnosis of early breast cancer should be offered to all women (including BRCA carriers) interested in future fertility.