Findings ‘of paramount importance’ should guide oncofertility counseling for BRCA carriers
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Key takeaways:
- One in five young BRCA carriers became pregnant within 5 years of diagnosis.
- Pregnancy did not compromise fetal outcomes or maternal prognosis.
SAN ANTONIO — One in five young BRCA carriers became pregnant within 10 years of breast cancer diagnosis, according to results of an international cohort study.
Pregnancy among these individuals did not appear to compromise fetal outcomes or maternal prognosis, findings presented at San Antonio Breast Cancer Symposium showed.
The findings should be incorporated into oncofertility counseling of young BRCA carriers with breast cancer, Matteo Lambertini, MD, PhD, associate professor at University of Genova — San Martino Hospital in Italy, and colleagues concluded.
“This global study provides solid evidence to advance our understanding of the reproductive needs of young BRCA carriers with prior history of breast cancer, as well as of maternal and fetal outcomes following conception,” Lambertini told Healio.
“Results of this study are of paramount importance during the oncofertility counseling for BRCA carriers interested in completing their family planning following diagnosis and treatment for breast cancer,” Lambertini added. “Based on these results, conceiving following proper treatment and follow-up for breast cancer should not be contraindicated [for] young BRCA carriers.”
Background
The potential negative effect of germline pathogenic or likely pathogenic variants on reproductive potential — as well as recommendations for risk-reducing bilateral salpingo-oophorectomy — make oncofertility counseling challenging for BRCA carriers, according to study background.
“Important knowledge gaps still exist among physicians caring for young women with breast cancer in their oncofertility counseling, and particularly about a potential detrimental prognostic effect of pregnancy following treatment completion,” Lambertini said. “[Although] several studies provided evidence on the feasibility and/or safety of conceiving following treatment completion for breast cancer, the evidence for BRCA carriers in particular is very limited. Therefore, considerations on family planning after breast cancer remain particularly overwhelming among BRCA carriers, and several physicians are still concerned about a potential detrimental prognostic effect of pregnancy after breast cancer [among] these patients.”
Lambertini and colleagues conducted an international, multicenter retrospective cohort study to investigate the likelihood of pregnancy after breast cancer among young BRCA carriers with a breast cancer history. Researchers also assessed reproductive and disease outcomes.
The analysis included 4,732 women treated at 78 centers worldwide. All women had germline pathogenic variants in BRCA1 and/or BRCA2, and they had been diagnosed with stage I to stage III invasive breast cancer at age 40 years or younger between January 2000 and December 2020.
Researchers excluded women with BRCA variants of unknown significance, those with noninvasive breast cancer, and those with history of ovarian cancer or other malignancies with no breast cancer history.
Pregnancy rate and DFS served as primary endpoints. Secondary endpoints included OS, breast cancer-specific survival, pregnancy, and fetal and obstetric outcomes.
Lambertini and colleagues performed two survival analyses to mitigate the effect of guaranteed time bias.
One analysis used an extended Cox model with occurrence of pregnancy as a time-varying covariate. Then, in a case-control analysis, researchers matched patients with or without pregnancy in a 1:3 ratio by type of BRCA pathogenic variant, nodal status, hormone receptor status and year of diagnosis. Each control had a disease-free interval longer than the time between breast cancer diagnosis and conception for each matched case.
Results
At 10 years, 22% (95% CI, 21-24) of women in the cohort had become pregnant. A higher percentage of those with hormone receptor-negative disease than hormone receptor-positive disease had become pregnant (26% vs. 18%).
“The cumulative incidence of pregnancy observed in this study is higher than previously reported [among] young breast cancer survivors,” Lambertini said. “There are some possible explanations: the younger patient age at time of diagnosis, an increased priority of pregnancy for the indication to undergo risk-reducing bilateral salpingo-oophorectomy during reproductive years and the large proportion of patients not requiring adjuvant endocrine therapy (66.7% had hormone receptor-negative disease).”
Median time from breast cancer diagnosis to conception was 3.5 years (interquartile range, 2.2-5.3), with significantly longer median time to conception among those with hormone receptor-positive than hormone receptor-negative disease (4.3 years vs. 3.2 years; P < .01).
Among women who became pregnant, 45 (6.8%) experienced induced abortion and 63 (9.6%) had miscarriages.
More than three-quarters (78.5%) of those who became pregnant had completed pregnancy; 406 (78.5%) delivered at term and 54 (10.4%) had twins.
Five (0.9%) of the 571 babies born had congenital anomalies.
After median follow-up of 7.8 years (interquartile range, 4.5-12.6), researchers observed no significant difference in DFS among women who became pregnant and those who did not (adjusted HR = 0.99; 95% CI, 0.81-1.2).
Women who became pregnant achieved significantly longer breast cancer-specific survival (adjusted HR = 0.59; 95% CI, 0.41-0.86) and OS (adjusted HR = 0.58; 95% CI, 0.4-0.85). The case-control analysis yielded similar findings, though researchers do not have a specific explanation for this finding, Lambertini said.
“The main message we want to convey is that pregnancy is safe after breast cancer, meaning that it does not increase the risk for recurrence,” he said. “We do not want to pass the message that pregnancy can be protective.”
Next steps
Additional research is needed in the field of oncofertility for patients with hereditary cancer syndromes, Lambertini said.
“[In particular], the potential increased risk of chemotherapy-induced premature ovarian insufficiency compared with age-matched noncarriers should be explored,” he said.
In addition, further treatments — including adjuvant olaparib (Lynparza; AstraZeneca, Merck) for 1 year following cytotoxic therapy for BRCA carriers at higher risk for disease recurrence, or carboplatin and pembrolizumab (Keytruda, Merck) as neoadjuvant therapy for triple-negative breast cancer — may pose added risk to fertility, as they have shown possible gonadotoxicity in mouse models, Lambertini said.
“Future studies are urgently needed to understand these risks,” he said.
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Lambertini M, et al. Abstract GS02-13. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2023; San Antonio.
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