Is it safe to perform controlled ovarian stimulation (COS) for fertility preservation before starting anticancer therapies or ART after treatments in young breast cancer patients?
Performing COS ...before, or ART following anticancer treatment in young women with breast cancer does not seem to be associated with detrimental prognostic effect in terms of breast cancer recurrence, mortality or event-free survival (EFS).
COS for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors, even when associated with aromatase inhibitors. Moreover, limited evidence exists on the safety of ART in breast cancer survivors for achieving pregnancy after the completion of anticancer treatments.
The present systematic review and meta-analysis was carried out by three blinded investigators using the keywords 'breast cancer' and 'fertility preservation'; keywords were combined with Boolean operators. Eligible studies were identified by a systematic literature search of Medline, Web of Science, Embase and Cochrane library with no language or date restriction up to 30 June 2021.
To be included in this meta-analysis, eligible studies had to be case-control or cohort studies comparing survival outcomes of women who underwent COS or ART before or after breast cancer treatments compared to breast cancer patients not exposed to these strategies. Survival outcomes of interest were cancer recurrence rate, relapse rate, overall survival and number of deaths. Adjusted relative risk (RR) and hazard ratio (HR) with 95% CI were extracted. When the number of events for each group were available but the above measures were not reported, HRs were estimated using the Watkins and Bennett method. We excluded case reports or case series with <10 patients and studies without a control group of breast cancer patients who did not pursue COS or ART. Quality of data and risk of bias were assessed using the Newcastle-Ottawa Assessment Scale.
A total of 1835 records were retrieved. After excluding ineligible publications, 15 studies were finally included in the present meta-analysis (n = 4643). Among them, 11 reported the outcomes of breast cancer patients who underwent COS for fertility preservation before starting chemotherapy, and 4 the safety of ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n = 2386), those who underwent COS (n = 1594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor-positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65). A reduced risk of recurrence was also observed in patients undergoing COS before neoadjuvant chemotherapy (RR 0.22, 95% CI 0.06-0.80). Compared to women not exposed to ART following completion of anticancer treatments (n = 540), those exposed to ART (n = 123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11).
This meta-analysis is based on abstracted data and most of the studies included are retrospective cohort studies. Not all studies had matching criteria between the study population and the controls, and these criteria often differed between the studies. Moreover, rate of recurrence is reported as a punctual event and it is not possible to establish when recurrences occurred and whether follow-up, which was shorter than 5 years in some of the included studies, is adequate to capture late recurrences.
Our results demonstrate that performing COS at diagnosis or ART following treatment completion does not seem to be associated with detrimental prognostic effect in young women with breast cancer, including among patients with hormone receptor-positive disease and those receiving neoadjuvant chemotherapy.
Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health-5 × 1000 funds 2017 (no grant number). M.L. acted as consultant for Roche, Pfizer, Novartis, Lilly, AstraZeneca, MSD, Exact Sciences, Gilead, Seagen and received speaker honoraria from Roche, Pfizer, Novartis, Lilly, Ipsen, Takeda, Libbs, Knight, Sandoz outside the submitted work. F.S. acted as consultant for Novartis, MSD, Sun Pharma, Philogen and Pierre Fabre and received speaker honoraria from Roche, Novartis, BMS, MSD, Merck, Sun Pharma, Sanofi and Pierre Fabre outside the submitted work. I.D. has acted as a consultant for Roche, has received research grants from Roche and Ferring, has received reagents for academic clinical trial from Roche diagnostics, speaker's fees from Novartis, and support for congresses from Theramex and Ferring outside the submitted work. L.D.M. reported honoraria from Roche, Novartis, Eli Lilly, MSD, Pfizer, Ipsen, Novartis and had an advisory role for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, Seagen, AstraZeneca, Eisai outside the submitted work. The other authors declare no conflict of interest. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.
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Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its impact on prognosis of young patients harboring BRCA ...pathogenic variant (PV).
This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PV in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS) were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer.
Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and -negative disease, respectively. The hazard ratio of hormone receptor-positive versus -negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interactions of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype).
In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus -negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.
•In young BRCA carriers, hormone receptor status did not appear to be a strong positive prognostic factor.•Patients with luminal A-like disease seem to have the worst DFS compared to all the other subtypes.•Personalized treatment, surveillance, and prevention strategies based on disease biology are recommended in young BRCA carriers.
Prevalence of survivors of breast cancer has been steadily increasing in the last 20 years. Currently, more than 90% of women diagnosed with early-stage breast cancer are expected to be alive at ...5 years from diagnosis thanks to early detection and breakthrough innovations in multimodal treatment strategies. Alongside this advancement in clinical outcomes, survivors of breast cancer might experience several specific challenges and present with unique needs. Survivorship trajectories after diagnosis and treatment of breast cancer can be significantly impacted by long-lasting and severe treatment-related side effects, including physical problems, psychological distress, fertility issues in young women, and impaired social and work reintegration, which add up to patients’ individual risk of cancer recurrence and second primary malignancies. Alongside cancer-specific
sequelae
, survivors still present with general health needs, including management of chronic preexisting or ensuing conditions. Survivorship care should implement high-quality, evidence-based strategies to promptly screen, identify, and address survivors’ needs in a comprehensive way and minimize the impact of severe treatment
sequelae
, preexisting comorbidities, unhealthy lifestyles, and risk of recurrence on quality of life. This narrative review focuses on core areas of survivorship care and discuss the state of the art and future research perspectives in key domains including selected long-term side effects, surveillance for recurrences and second cancers, well-being promotion, and specific survivors’ needs.
Despite increasing evidence on the safety of pregnancy after anticancer treatments in breast cancer survivors, many physicians and patients remain concerned about a potential risk of pregnancy ...specifically in the case of hormone receptor-positive breast cancer.
A systematic literature search of Medline, Embase and Cochrane library with no language or date restriction up to 31 March 2023 was carried out. To be included, articles had to be retrospective and prospective case-control and cohort studies as well as clinical trials comparing survival outcomes of premenopausal women with or without a pregnancy after prior diagnosis of hormone receptor-positive breast cancer. Disease-free survival (DFS) and overall survival (OS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Study protocol is registered in PROSPERO (n. CRD42023394232).
Out of 7796 screened studies, 8 were eligible to be included in the final analysis. A total of 3805 patients with hormone receptor-positive invasive early breast cancer were included in these studies, of whom 1285 had a pregnancy after breast cancer diagnosis. Median follow-up time ranged from 3.8 to 15.8 years and was similar in the pregnancy and non-pregnancy cohorts. In three studies (n = 987 patients) reporting on DFS, no difference was observed between patients with and those without a subsequent pregnancy (HR 0.96, 95% CI 0.75-1.24, P = 0.781). In the six studies (n = 3504 patients) reporting on OS, patients with a pregnancy after breast cancer had a statistically significant better OS than those without a pregnancy (HR 0.46, 95% CI 0.27-0.77, P < 0.05).
This systematic review and meta-analysis of retrospective cohort studies provides updated evidence that having a pregnancy in patients with prior history of hormone receptor-positive invasive early breast cancer appears safe without detrimental effect on prognosis.
•Many young women with breast cancer wish to complete their families following completion of anticancer therapies.•Many physicians are concerned that pregnancy after hormone receptor-positive breast cancer may increase recurrences.•Our meta-analysis showed that pregnancy after hormone receptor-positive breast cancer did not impact prognosis.•Pregnancy after breast cancer did not impact DFS and was associated with improved OS.•Pregnancy following diagnosis and treatments of hormone receptor-positive breast cancer should not be discouraged.
Abstract
Study question
Is it safe to have a pregnancy in women with prior history of hormone receptor-positive early breast cancer?
Summary answer
Pregnancy following breast cancer treatments in ...young women with history of hormone receptor-positive disease is safe with no detrimental effect on patients’ prognosis.
What is known already
Breast cancer is the most common malignancy diagnosed in women of reproductive age. Both physicians and patients continue to have concerns about a potential detrimental effect of pregnancy after breast cancer, particularly in the setting of hormone receptor-positive disease. In recent years, several studies have demonstrated the safety of pregnancy after anticancer treatments in breast cancer survivors.
Study design, size, duration
A systematic literature search of Medline, Embase and Cochrane library with no language or date restriction up to January 1st, 2023, was performed following the PRISMA guidelines. We included retrospective or prospective case-control and cohort studies as well as prospective clinical trials comparing survival outcomes of premenopausal female patients with reported pregnancy or not after diagnosis and treatment for hormone receptor-positive breast cancer.
Participants/materials, setting, methods
Included patients were childbearing potential age women with a prior history of hormone receptor-positive early breast cancer. Outcomes of interest were disease-free survival and overall survival. Hazard ratios (HR) with 95% confidence intervals (CI) were extracted. Higgins I2 index was used to evaluate the degree of inconsistency in the results of the included studies. Pooled HRs were considered statistically significant with a P value of < 0.05 (two-sided).
Main results and the role of chance
Eight studies were eligible to be included in the final analysis. A total of 3,805 patients with hormone receptor-positive breast cancer were included in these studies, of whom 1,285 had a pregnancy after treatments. Median follow-up of the included studies ranged from 3.81 years to 15.8 years.
In three studies (n = 987 patients) reporting on disease-free survival outcomes, no difference was observed between patients with or without a subsequent pregnancy (HR 0.96, 95% CI 0.75 – 1.24, p = 0.781). Six studies (n = 3,504 patients) reported outcomes in terms of overall survival: patients with a pregnancy after breast cancer had better overall survival compared with those without a pregnancy (HR 0.46, 95% CI 0.27 – 0.77, p < 0.05).
At the subgroup analysis on timing of pregnancy, no detrimental effect of pregnancy after breast cancer in terms of disease-free survival was observed for patients achieving a late pregnancy (defined as 2 or 5 years after diagnosis) as compared to patients without a subsequent pregnancy (HR 1.08, 95% CI 0.80 – 1.46, p = 0.611). Increased disease-free survival was observed in patients with an early pregnancy (HR 0.63, 95% CI 0.47 – 0.85, p < 0.05).
Limitations, reasons for caution
This meta-analysis is based on abstracted data and most of the studies are retrospective cohort studies. Median follow-up in a large proportion of the studies was shorter than 10 years. Adjuvant hormone therapy before and after pregnancy was not available in many studies included.
Wider implications of the findings
Our results strengthen the evidence that having a pregnancy in women with prior history of hormone receptor-positive breast cancer is safe.
Trial registration number
not applicable
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