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Residual Tumor and Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, University Paris, Paris, France
Residual Tumor and Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, University Paris, Paris, France
Residual Tumor and Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, University Paris, Paris, France
Residual Tumor and Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, University Paris, Paris, France
Department of Surgical Oncology, Institut Curie, Paris, France, University Paris, Paris, FranceResidual Tumor and Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, University Paris, Paris, FranceClinical Research Department, Centre Georges-François Leclerc (Unicancer), Dijon, France
Department of Medical Oncology, Institut Curie, Paris, France, University Paris, Paris, FranceDepartment of Surgical Oncology, Institut Curie, Paris, France, University Paris, Paris, FranceResidual Tumor and Response to Treatment Laboratory, RT2Lab, Translational Research Department, INSERM, U932 Immunity and Cancer, University Paris, Paris, France
What are the real-life oncofertility practices in young women diagnosed with breast cancer?
Design
The FEERIC (FErtility, prEgnancy, contRaceptIon after breast Cancer in France) study is a web-based cohort study launched with the French collaborative research platform Seintinelles. The current work is based on the enrolment self-administered questionnaire of 517 patients with prior breast cancer diagnosis, free from relapse and aged 18 to 43 years at inclusion (from 12 March 2018 to 27 June 2019).
Results
Median age at breast cancer diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counselling, 181 patients underwent at least one fertility preservation procedure (FPP); 125 (24.2%) underwent one or more FPP with material preservation (oocytes n = 108, 20.9%; embryos n = 31, 6.0%; ovarian cryopreservation n = 6, 1.2%) and 78 patients received gonadotrophin-releasing hormone agonists (15.1%). With a median follow-up of 26.9 months after the end of treatments, 133 pregnancies had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were natural conceptions (n = 113, 87.6%), while 16 (12.4%) required medical interventions. For the planned pregnancies, median time to the occurrence of an ongoing pregnancy was 3 months. Patients who had an unplanned pregnancy reported lower rates of information on the consequences of the treatments on fertility (P = 0.036) at diagnosis.
Conclusions
Most of the patients were not offered proper specialized oncofertility counselling at the time of breast cancer diagnosis. Naturally conceived pregnancies after breast cancer were much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counselling seems as important as information about fertility and might prevent unplanned pregnancies.
Breast cancer is currently the most common cancer among young women according to the Global Cancer Observatory: Cancer Today website (http://gco.iarc.fr/today/home), with approximately 6000 women under the age of 45 years diagnosed in France every year, according to the Institut National du Cancer (https://www.e-cancer.fr/Professionnels-de-sante/Les-chiffres-du-cancer-en-France/Epidemiologie-des-cancers/Donnees-globales). Primary breast cancer treatments include surgery, chemotherapy, radiotherapy and targeted therapy as hormonal therapy and trastuzumab. Breast cancer treatments can have a direct (chemotherapy-induced ovarian damage) or indirect (fertility decline due to delayed pregnancy project) impact on fertility (
). In the general context of a trend towards women delaying their first pregnancies in the Western world, increasing numbers of women are being diagnosed with breast cancer before they have had their children (
Pregnancies during and after trastuzumab and/or lapatinib in patients with human epidermal growth factor receptor 2-positive early breast cancer: analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.
Fertility preservation procedures (FPP) have developed rapidly over the last decade and are now part of the supportive care offered to patients in routine practice. Available fertility preservation methods (
) include (i) the retrieval and storage of cryopreserved material sampled before the start of breast cancer treatment (mature oocyte or embryo cryopreservation, ovarian tissue cryopreservation and immature oocyte cryopreservation after in-vitro maturation [IVM]); and (ii) ovarian protection through treatment with gonadotrophin-releasing hormone agonists (GnRHa). In France, the Institut National du Cancer (National Institute of Cancer, InCA) considers improving access to oncofertility services a priority (The Cancer Plan 2014-2019, https://www.e-cancer.fr/Institut-national-du-cancer/Strategie-de-lutte-contre-les-cancers-en-France/Les-Plans-cancer/Le-Plan-cancer-2014-2019). Efforts have been made to guarantee universal access, and all fertility preservation costs in the context of cancer are covered by the national social security system, a feature rendering French oncofertility practices unique worldwide. Nevertheless, fertility preservation counselling and access remain heterogeneous in France, as many patients receive no fertility preservation information or are not referred at the optimal time (
International Society for Fertility Preservation–ESHRE–ASRM Expert Working Group Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives.
). In a recent meta-analysis, out of 711 breast cancer survivors who received systemic treatments, 14% had a pregnancy, which is on average 40% lower than in the general population (
). However, few – if any – data are available to determine whether these low pregnancy rates are due to an actual decrease in fertility, to a lower pregnancy attempt rate for medical reasons, or to the woman's reproductive choices. Natural fertility rates after cancer treatment remain difficult to assess. The pregnancy rates achieved through the use of reproductive techniques after cancer treatments have increased with the development of fertility preservation (
The FEERIC national study was launched in France in March 2018 and was designed to compare fertility, pregnancy and contraception outcomes in young breast cancer survivors and in matched cancer-free women. This online study was performed via the Seintinelles Research Network, a collaborative social network set up to provide a source of volunteers for participation in research studies. Data were collected on twice-yearly self-completed forms. The current paper aims to provide a situational analysis of the reproductive life of FEERIC breast cancer survivors at time of enrolment. Data presented involve (i) patient cancer history and treatments, (ii) fertility concerns and care at breast cancer diagnosis and (iii) reproductive history between breast cancer diagnosis and study inclusion.
Materials and methods
Study design
The FEERIC study is a prospective study aiming at assessing the impact of breast cancer treatment on fertility, pregnancy and contraception. The data are collected through self-administered online questionnaires via the Seintinelles Research Network (Bauquier et al., 2017) (https://www.cairn.info/revue-sante-publique-2017-4-page-547.htm https://doi.org/10.3917/spub.174.0547), a collaborative social network created in 2012 to accelerate the recruitment of French volunteers for cancer research studies by connecting researchers with men and women of various ages, social and medical backgrounds, with or without a history of breast cancer, willing to participate in research studies. The Seintinelles scientific board approved the FEERIC project on 7 December 2015, and the ethics board of Sud Ouest Outre Mer II approved the project on 5 October 2017 (reference number: 2017:A02181-52). The primary objective of the FEERIC study is to compare naturally conceived pregnancies (odds ratio) between young breast cancer survivors and matched controls. Secondary outcomes are: time to pregnancy, use of assisted reproductive techniques, contraception prevalence and occurrence of unplanned pregnancies. The objective of the current work was to provide a situational analysis of these data in the breast cancer survivor population at enrolment, with a focus on patient cancer history and treatments, fertility concerns and care at breast cancer diagnosis, and reproductive history between breast cancer diagnosis and study inclusion.
Patients
Patients were recruited from 12 March 2018 to 27 June 2019. The inclusion criteria were: female patients with a previous diagnosis of localized, relapse-free breast cancer (invasive or in situ), aged 18 to 43 years at the time of diagnosis, and who had completed treatment (surgery and/or chemotherapy, and/or radiotherapy) at the time of enrolment, without any time criteria since the date of the end of treatment. Women on ongoing endocrine therapy or trastuzumab treatment were accepted. The exclusion criteria were previous hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy. The controls were women aged from 18 to 43 years, free from breast and other cancers, who had not undergone hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy.
Enrolment
Cases were recruited by both (i) the Seintinelles Research Network and (ii) eight breast care/oncofertility and gynaecology centres: Institut Curie (Paris and Saint Cloud), Hôpital Saint-Louis (Paris), Hôpital Cochin (Paris), Centre Léon Bérard (Lyon), Centre Oscar Lambret and Centre Hospitalier Régional Universitaire (Lille), and Institut Bergonié (Bordeaux). Patients were asked to participate in the study at follow-up consultations, or through the display of invitation flyers and posters in waiting rooms. In addition to the direct proposal to participate during follow-up consultations, six centres sent invitations to participate by mailing patients (electronic e-mail addresses when available, otherwise by postal mail) (Institut Curie, Paris and Saint Cloud; Léon Bérard, Lyon; Centre Georges-François Leclerc, Dijon; Hôpital Saint-Louis, Paris; Institut du Cancer de Montpellier, Montpellier).
Forms
The forms were designed by work groups including physicians involved in breast cancer, fertility or contraceptive care, and members of the Seintinelles staff. Key steps to form development were: scientific writing and review, beta-testing on a subset of 20 Seintinelles volunteers, feedback and improvement, submission to French authorities for approval (Advisory Committee on the Processing of Information in the Field of Health Research [CCTIRS] and the National Commission for Informatics and Freedoms [CNIL]). The database was hosted by a specialized health data provider (www.ids-assistance.com) in accordance with the EU General Data Protection Regulation, and was forwarded to the statistical team for analysis in a safe and anonymized manner.
Volunteers (cases and controls) matching the inclusion criteria (11 questions) were sent a link to the survey and were asked to complete a baseline form at inclusion and follow-up forms every 6 months (a total of six forms). This paper reports data from the baseline forms of the cases population. Data from the follow-up forms will be the subject matter of upcoming studies.
The baseline form contained 181 questions relating to demographic data, reproductive and contraceptive history, pregnancy plans, breast cancer history and treatments (if applicable), data on FPP if performed, and reproductive life since the end of treatment. The questions regarding patient satisfaction were rated from 0 (unsatisfied) to 10 (extremely satisfied).
Study end-points
FPP were defined as procedures intended to help a patient's ability to have children, and included: (i) FPP with material preservation (either oocyte, embryo or ovarian tissue cryopreservation); (ii) FPP without cryopreserved material, i.e. GnRHa during chemotherapy.
Oocyte retrieval was achieved either after ovarian stimulation or without ovarian stimulation (IVM). Ongoing pregnancies were defined as pregnancies continuing beyond the first trimester of pregnancy. Ectopic pregnancies, miscarriage, elective abortion or abortions for medical reasons were not considered ongoing pregnancies. Miscarriage in this study was defined as the spontaneous loss of a pregnancy before the 14th gestational week.
For each pregnancy declared, the specific question was asked: ‘Was this pregnancy desired?’. A pregnancy was considered desired when the patient answered ‘yes’ and was considered unplanned if the patient answered ‘no’.
Median time to pregnancy was defined as the time from first attempt to the occurrence of pregnancy, and median time to ongoing pregnancy was defined as the time from first attempt to the occurrence of an ongoing pregnancy.
The professions of participants were classified into three categories: low socio-professional category or unemployed (skilled or unskilled worker, farmer, students, unemployed, others), intermediate (teacher, technician, employee, military, police, craftsman, trader, entrepreneur, etc.) and superior (executive and higher intellectual profession, liberal profession, professors and engineers).
Statistical analysis
It was anticipated that 251 patients would be included in the FEERIC study. Thanks to the considerable involvement of the Seintinelles Research Network, a total of 517 breast cancer patients replied to the questionnaire.
The study population was described in terms of frequencies for qualitative variables, or medians and interquartile range (IQR) for quantitative variables. To compare continuous variables among different groups, the Wilcoxon–Mann–Whitney test was used for groups including fewer than 30 patients, and for variables displaying multimodal distributions, otherwise, Student's t-test was used. Association between categorical variables was assessed with the chi-squared test, or with the Fisher's exact test if at least one category included fewer than three patients. In box plots, lower and upper bars represent the first and third quartiles, respectively, the medium bar is the median, and whiskers extend to 1.5 times the IQR.
For analysis of the association between demographic and clinical variables (age, body mass index [BMI], profession, educational level, pregnancy plans, marital status and chemotherapy) and FPP rates, a univariate analysis was performed, with values of P ≤ 0.05 considered statistically significant. Analyses were performed with R version 3.1.2, 2015 for Windows (R Foundation for Statistical Computing, Vienna, Austria).
Results
Patient characteristics at breast cancer diagnosis
A total of 517 breast cancer patients were included in the study (Table 1, Supplementary Figure 1). Median age at breast cancer diagnosis was 33.6 years and median age at study inclusion was 38.0 years. Median time from breast cancer diagnosis to inclusion was 34.9 months. In total, 455 patients (88.0%) had been educated to university level. Most patients were living with a partner at the time of diagnosis (n = 431, 83.4% [cohabitation n = 245, 56.8%; married n = 186, 43.2%]). Sixty-seven patients (13.0%) were current smokers, and 368 patients (71.2%) declared no other comorbid conditions at the time of inclusion. Median BMI was 22.2 kg/m2 and 121 patients (23.4%) were overweight or obese. A history of infertility prior to breast cancer diagnosis was recorded for 77 patients (14.9%) and 210 (40.6%) patients had no children at breast cancer diagnosis; 271 patients (52.4%) had a family history of breast cancer (first degree: n = 115 [22.2%]; second or third degree: n = 156 [30.2%]).
Table 1Patient characteristics
Variable
Class
All(n = 517)
Age at breast cancer diagnosis (years)
33.6 [30.0, 37.1]
Age at study inclusion (years)
38.0 [34.0, 41.0]
Age (by class, years)
<30
38 (7.4)
30 to 34
132 (25.5)
35 to 39
215 (41.6)
≥40
132 (25.5)
Educational level
High school or lower
62 (12.0)
University
455 (88.0)
Profession (class)
Intermediate
221 (42.7)
Low socio-professional category or unemployed
48 (9.3)
Superior
248 (48.0)
Marital status (at breast cancer diagnosis)
Single
86 (16.6)
Couple
431 (83.4)
Relationship:
Cohabitation
245 (56.8)
Married
186 (43.2)
BMI, continuous (kg/m²)
22.2 [20.4, 24.6]
BMI, by class (kg/m²)
Underweight
30 (5.8)
Normal weight
366 (70.8)
Pre-obesity
84 (16.2)
Obesity
37 (7.2)
Smoking status
Current
67 (13.0)
Former
207 (40.0)
Never
243 (47.0)
Comorbidity
No
368 (71.2)
Yes
149 (28.8)
Co-medications
No
401 (77.6)
Yes
116 (22.4)
Infertility history
No
440 (85.1)
Yes
77 (14.9)
Previous pregnancy
No
150 (29.0)
Yes
367 (71.0)
Number of children
0
210 (40.6)
1
119 (23.0)
More than 1
188 (36.4)
Previous births
No
210 (40.6)
Yes
307 (59.4)
Breastfeeding history:
No
81 (26.4)
Yes
226 (73.6)
Breastfeeding duration (months)
4.0 [2.25, 9.00]
Familial history of breast cancer
No
246 (47.6)
At least one first-degree relative
115 (22.2)
At least one second-degree relative
156 (30.2)
Oncogenetic counselling
No
98 (19.0)
Yes
419 (81.0)
Genetic testing
No
107 (20.7)
Yes
410 (79.3)
Oncogenetic results:
No mutation
287 (70.0)
BRCA1
39 (9.5)
BRCA2
22 (5.4)
Others
4 (1.0)
Results awaited/not known
58 (14.1)
Time from breast cancer diagnosis to inclusion (months)
34.9 [18.7, 64.1]
Time from end of treatment to inclusion (months)
26.9 [10.0, 53.8]
Values are reported as median [interquartile range (IQR)] or n (%).
Missing data: age at breast cancer diagnosis, n = 3. Missing data: time from breast cancer diagnosis to inclusion, n = 3.
Most of the patients (n = 419, 81.0%) had received oncogenetic counselling and 410 (79.3%) had undergone genetic testing. No constitutional mutation was found in 287 (70.0%) (oncogenetic results available at the time of study inclusion, n = 352), whereas germline mutations were detected in 65 patients (BRCA1 n = 39 [9.5%]; BRCA2 mutation n = 22 [5.4%]; others n = 4 [1.0%]).
Breast cancer treatments
Overall, 99.8% had surgery (n = 516); it was the first-line treatment in 66.5% of the patients (n = 343), whereas 33.5% underwent first-line systemic treatment (n = 173; chemotherapy n = 172 [33.3%]; trastuzumab n = 43 [8.3%]; endocrine therapy n = 2 [0.4%]) or radiotherapy (n = 1) (Figure 1a). All but one of the patients underwent surgery for breast cancer. Surgical procedures were mastectomy n = 239 (46.5%) / lumpectomy n = 275 (53.5%), axillary node dissection n = 252 (54.2%) / sentinel node biopsy n = 213 (45.8%). Chemotherapy was administered to 424 patients (82%), mostly with regimens involving anthracyclines followed by taxanes, 172 (40.6%) in a neoadjuvant setting (including nine with adjuvant treatment, 2.1%) and 252 (59.4%) in an adjuvant setting. In total, 443 (85.7%) patients received radiotherapy, 126 (24.4%) patients received trastuzumab treatment for HER2-positive cancers and 330 (63.8%) received endocrine therapy (Figure 1a) Figure 1b displays the different care pathways for the entire cohort.
Figure 1Breast cancer treatments and care pathway. (A) Distribution of breast cancer treatments. (B) Chart representing the sequential care pathways. Twelve patients were discarded from the sunburst because of discrepancies between the treatment dates mentioned in the study and the pathway, and one patient was discarded because she had no surgery. Values of 1 are not displayed for the sake of readability. CT = cancer treatment; NAC = neoadjuvant chemotherapy; Anthra-Taxanes refers to a chemotherapy regimen based on anthracyclines and taxanes.
Pregnancy plans and fertility counselling at breast cancer diagnosis and oncofertility preservation procedures
At the time of breast cancer diagnosis, 218 patients (42.2%) declared no wish for pregnancy, 206 stated they might consider a pregnancy in the future (39.8%) and 67 (13%) reported that they were trying to become pregnant (Figure 2a). Breast cancer was diagnosed during pregnancy in 26 patients (5%), and the outcome of the pregnancy was favourable in most cases (full-term pregnancy, n = 17 [65.4%]; elective abortion, n = 3 [11.5%]; abortion for medical reasons, n = 3 [11.5%]; miscarriage, n = 3 [11.5%]).
Figure 2Oncofertility counselling, FPP and decision-making. (A) Distribution of patient pregnancy plans at diagnosis. (B) Bar plot of medical inquiry about a patient's future pregnancy desire. (C) Bar plot representing the proportion of women who received information about the effects of cancer treatment on fertility. (D) Patient satisfaction with information on the effects of cancer treatment on fertility (0 to 10 numerical rating scale [NRS], where 0 is strongly dissatisfied and 10 is fully satisfied), out of 364 patients who received information. (E) Sankey diagram representing the association between oncofertility counselling proposal and completion of a FPP. Thirteen patients had a FPP with material preservation by their own initiative in the absence of counselling being offered by oncology team. (F) Distribution of FPP with or without material preservation. The figure accounts for crude counts of procedures (total of FPP n = 181), but procedures could be combined or not. The distribution (per patient, in combination or not) is as follows: oocyte cryopreservation n = 74, GnRHa n = 56, oocyte cryopreservation + GnRHa n = 15, oocyte cryopreservation + embryo cryopreservation n = 13, embryo cryopreservation n = 12, ovarian cryopreservation + oocyte cryopreservation n = 4, embryo cryopreservation + GnRHa n = 3, oocyte cryopreservation + embryo cryopreservation + GnRHa n = 2, ovarian cryopreservation + embryo cryopreservation + GnRHa n = 1, ovarian cryopreservation + GnRHa n = 1. (G) Bar plots representing ovarian stimulation performance according to chemotherapy setting. (H) Distribution of the reasons for not undergoing a FPP. Main reason was the absence of offer (n = 149). (I) Distribution of the personal reasons for not undergoing a FPP. CI = chemotherapy-induced; FP = fertility preservation; FPP = fertility preservation procedure; GnRH = gonadotrophin-releasing hormone; IVM = in-vitro maturation; MP = material preservation.
A healthcare practitioner enquired whether the patient would consider future pregnancy after treatment in 363 patients (70.2%) (Figure 2b) and 72.4% (n = 364) patients recalled being informed about the consequences of the treatments on fertility (Figure 2c). Of these, the degree of satisfaction with this information was high (median score 8/10) (Figure 2d). Specialized oncofertility counselling was offered to 236 patients (45.6%); it was performed in 205 patients (39.7%), and 124 women (24.0%) underwent at least one FPP with material preservation (Figure 2e). The distribution of procedures was as follows: oocyte cryopreservation (n = 108, 87.1%), embryo cryopreservation (n = 31, 25.0%), ovarian cryopreservation (n = 6, 4.8%) (Figure 2f). In addition, GnRHa were used during treatment in 78 patients (15.1%), representing a total of 181 patients with at least one FPP performed (35.0%) (Figure 2f). Eighty-eight patients (71.0%) had material preservation after ovarian stimulation, while 36 patients had an IVM procedure (29%). Ovarian stimulation was less frequent for FPP performed before surgery (n = 32, 52.5%) than for FPP after surgery (n = 56, 88.9%) (Figure 2g).
Age and year of breast cancer diagnosis (P < 0.001), educational level (P = 0.003), previous children (P < 0.001), plans for pregnancy at diagnosis (P < 0.001) and breast cancer treatment with chemotherapy (P = 0.001) were significantly associated with the likelihood of undergoing a FPP procedure with material preservation (Table 2). Of note, 22 out of the 218 patients who reported an absence of future pregnancy plans still chose to have a FPP. The reasons for which women did not undergo FPP procedures based on cryopreservation techniques was a lack of such procedures being offered (n = 149), personal choice of the patient (n = 110), insufficient time available (n = 50), oncological concerns (n = 32) and exclusion on the basis of fertility conditions (n = 9) (Figure 2h). The personal reasons for not undergoing FPP cited by patients included not wanting to have a baby (n = 79), followed by a desire to focus on breast cancer treatment (n = 27), and constraints (n = 10) or fears relating to treatment (n = 8) (Figure 2i).
Table 2Association between clinical characteristics and the performance of FPP
Variable
Class
No FPP performed
FPP performed
P-value
n = 517
393
124
Age at breast cancer diagnosis (years)
34.5 [30.6, 37.6]
32.1 [29.1, 34.5]
<0.001
Age at breast cancer diagnosis (by class), years
<30
19 (4.8)
19 (15.3)
<0.001
30 to 34
80 (20.4)
52 (41.9)
35 to 39
170 (43.3)
45 (36.3)
≥40
124 (31.6)
8 (6.5)
Year of breast cancer diagnosis
<2010
50 (12.8)
1 (0.8)
<0.001
2010–2015
195 (50.0)
60 (48.4)
>2015
145 (37.2)
63 (50.8)
High school or lower
57 (14.5)
5 (4.0)
0.003
University
336 (85.5)
119 (96.0)
Profession (class)
Intermediate
178 (45.3)
43 (34.7)
0.105
Low socio-professional category or unemployed
36 (9.2)
12 (9.7)
Superior
179 (45.5)
69 (55.6)
BMI, by class (kg/m²)
Underweight
23 (5.9)
7 (5.6)
0.902
Normal weight
275 (70.0)
91 (73.4)
Pre-obesity
66 (16.8)
18 (14.5)
Obesity
29 (7.4)
8 (6.5)
Smoking status
No
341 (86.8)
109 (87.9)
0.861
Yes
52 (13.2)
15 (12.1)
BRCA mutation genes
43 (10.9)
22 (17.7)
BRCA1
24 (55.8)
15 (68.2)
0.358
BRCA2
17 (39.5)
5 (22.7)
Others
2 (4.7)
2 (9.1)
Infertility history
No
334 (85.0)
106 (85.5)
0.99
Yes
59 (15.0)
18 (14.5)
Previous children
No
120 (30.5)
90 (72.6)
<0.001
Yes
273 (69.5)
34 (27.4)
Marital status (at breast cancer diagnosis)
Single
60 (15.3)
26 (21.0)
0.178
Couple
333 (84.7)
98 (79.0)
Attitude towards pregnancy desire at breast cancer diagnosis
Attempting pregnancy
44 (11.2)
23 (18.5)
<0.001
Future pregnancy desire
128 (32.6)
78 (62.9)
No
196 (49.9)
22 (17.7)
Pregnant at diagnosis
25 (6.4)
1 (0.8)
Chemotherapy
No
84 (21.4)
9 (7.3)
0.001
Yes
309 (78.6)
115 (92.7)
Values are reported as median [interquartile range (IQR)] or n (%).
Gynaecological and reproductive history since breast cancer treatment
Amenorrhoea, endocrine therapy, marital status
Of the 424 patients who received cancer treatment, 406 (95.8%) reported amenorrhoea during treatment (median duration 11 months), and the duration of amenorrhoea increased with age, P < 0.001 (Figure 3a). Amenorrhoea was reversible in most patients (n = 317, 74.8%). Endocrine treatment was stopped prematurely (median 28 months) in 99 of 330 patients (30.0%), either temporarily (n = 77, 23.3%) or definitively (n = 22, 6.7%). The main reasons for stopping endocrine treatment were a desire to become pregnant (n = 51, 51.5%), adverse side effects (n = 35, 35.4%) or other reasons (n = 16, 16.2%). Median time of endocrine therapy intake was significantly shorter in patients who stopped due to side effects than in patients who stopped because of a pregnancy desire (19.8 months versus 36.4 months, respectively, P < 0.001).
Figure 3Occurrence and outcome of pregnancies after breast cancer treatment. (A) Association between age and duration of amenorrhoea. Median duration of amenorrhoea is as follows: <30 years old: 8 months; 30–34: 9 months; 35–39: 12 months; ≥40: 15 months. (B) Sankey diagram of the evolution of marital status between diagnosis and study inclusion. (C) Association between patient satisfaction with the information received on fertility and the occurrence of an unplanned pregnancy. (D) Association between patient satisfaction with the information received on contraception and the occurrence of an unplanned pregnancy. (E) Outcomes of the 133 pregnancies achieved after breast cancer in the FEERIC cohort. The ‘other’ category corresponded to a patient who experienced an abortion based on medical advice. (F) Bar plots of pregnancy outcomes depending on the status unplanned (n = 20) or desired (n = 109) and the pregnancy occurrence (natural conceptions n = 113 or use of assisted reproductive technology n = 16) out of the 129 pregnancies for which the unplanned/desired status was known. The outcome of the pregnancy was significantly different according to whether the pregnancy was unplanned or desired (P < 0.001). (G) Time from first attempt to pregnancy occurrence in months according to age classes and pregnancy achievement method out of the 102 patients for which the attempt duration was known. ART = assisted reproductive technology; BC = breast cancer.
Between the breast cancer diagnosis and inclusion in the study, 19.3% of patients (n = 100) changed marital status (Figure 3b). The proportion of patients who formed new couples (29/86; 33.7%) was higher than the proportion of patients who were initially in a couple but became single (29/431; 6.7%) (Figure 3b).
Unplanned pregnancies
During a median follow-up of 26.9 months between the end of breast cancer treatment and inclusion in the study, 18 patients (3.5%) experienced an unplanned pregnancy. Patients who had an unplanned pregnancy were significantly younger at breast cancer diagnosis (P = 0.03), were more likely to have previous pregnancies (P = 0.01) or previous children at breast cancer diagnosis (P = 0.02), were less likely to have received fertility counselling (P = 0.04) and tended to have less contraceptive counselling (P = 0.08) (Table 3). The satisfaction regarding information on fertility and contraception was significantly lower in patients who had a subsequent unplanned pregnancy than in patients who did not (P = 0.021 and P < 0.001, respectively) (Figure 3c and 3d; Table 3).
Table 3Factors associated with the occurrence of an unplanned pregnancy
Variable
Class
No unplanned pregnancy
At least one unplanned pregnancy
P-value
n = 517
499
18
Age at breast cancer diagnosis, years
33.6 [30.1, 37.1]
30.8 [28.5, 34.2]
0.028
Educational level
High school or lower
58 (11.6)
4 (22.2)
0.322
University
441 (88.4)
14 (77.8)
Profession (class)
Intermediate
215 (43.1)
6 (33.3)
0.473
Low socio-professional category or unemployed
45 (9.0)
3 (16.7)
Superior
239 (47.9)
9 (50.0)
Marital status (at breast cancer diagnosis)
Cohabitation
238 (47.7)
7 (38.9)
0.153
Married
181 (36.3)
5 (27.8)
Single
80 (16.0)
6 (33.3)
Marital status (current)
Cohabitation
197 (39.5)
9 (50.0)
0.394
Married
217 (43.5)
8 (44.4)
Single
85 (17.0)
1 (5.6)
BMI (kg/m²)
22.3 [20.5, 24.6]
21.6 [20.2, 24.4]
0.489
Smoking status
Current
66 (13.2)
1 (5.6)
0.528
Former
198 (39.7)
9 (50.0)
Never
235 (47.1)
8 (44.4)
Infertility history
No
426 (85.4)
14 (77.8)
0.581
Yes
73 (14.6)
4 (22.2)
Previous pregnancy (at breast cancer diagnosis)
No
150 (30.1)
0 (0.0)
0.013
Yes
349 (69.9)
18 (100.0)
Previous children
No
208 (41.7)
2 (11.1)
0.019
Yes
291 (58.3)
16 (88.9)
Attitude towards pregnancy desire
Attempted pregnancy
66 (13.2)
1 (5.6)
0.722
Future pregnancy desire
197 (39.5)
9 (50.0)
No
211 (42.3)
7 (38.9)
Pregnant at diagnosis
25 (5.0)
1 (5.6)
Information on the effects of the treatments on fertility (out of 503)
No
130 (26.7)
9 (52.9)
0.036
Yes
356 (73.3)
8 (47.1)
Patient satisfaction with information on fertility:
8 [6–10]
5.50 [0–7]
0.021
Contraceptive counselling
No
164 (32.9)
10 (55.6)
0.081
Yes
335 (67.1)
8 (44.4)
Patient satisfaction with information on contraception:
9 [6–10]
5 [3.25–8]
<0.001
FPP
No
321 (64.3)
15 (83.3)
0.159
Yes
178 (35.7)
3 (16.7)
Values are reported as median [interquartile range (IQR)] or n (%).
14 patients had missing values for answer to the question regarding the delivery of counselling on the effects of treatment on fertility (no unplanned pregnancy, n = 13; at least one unplanned pregnancy n = 1).
BMI = body mass index; FPP = fertility preservation procedure; IQR = interquartile range.
Overall, a total of 133 pregnancies occurred in 85 patients (16.4%), with 20 of them (15.0%) being unplanned. Pregnancy onset was by natural conception in 113 cases (87.6%), and medical intervention was required for 16 pregnancies (12.4%; autologous IVF n = 10; oocyte donation n = 2; use of cryopreserved material obtained after ovarian stimulation n = 2; and ovulation induction n = 2) (Table 4). One of the two pregnancies achieved with cryopreserved material ended in a live birth; the other pregnancy was still under way at the time of inclusion in the study. The outcomes of pregnancies were as follows: pregnancy with live birth, n = 68 (51.1%); miscarriage, n = 31 (23.3%); ongoing pregnancy, n = 20 (15.0%); ectopic pregnancy, n = 6 (4.5%); elective abortion, n = 6 (4.5%); abortion for medical reasons, n = 1 (0.8%), or other (elective abortion following medical advice, n = 1 (0.8%)) (Figure 3e).
Table 4Occurrence of pregnancies after breast cancer treatment
Variable
Class
All
Pregnancies (in 85 patients)
133
Pregnancy planning
Unplanned (in 18 patients)
20 (15.5)
Desired
109 (84.5)
Pregnancy onset
Natural conception
113 (87.6)
Medical intervention
16 (12.4)
Autologous IVF
10 (62.5)
Oocyte donation
2 (12.5)
Cryopreserved material reuse
2 (12.5)
Ovulation induction
2 (12.5)
Delivery route
Caesarean section
13 (19.1)
Vaginal birth
55 (80.9)
Obstetrical and neonatal conditions
Twins
2 (1.6)
Pre-eclampsia
2 (1.6)
Gestational diabetes
3 (2.4)
Risk of preterm birth
1 (0.8)
Preterm births
2 (1.5)
Post-partum peritonitis
1 (0.8)
Cytomegalovirus seroconversion
1 (0.8)
Values are reported as n (%).
Missing data: pregnancy planning, n = 4, pregnancy onset, n = 4, obstetrical conditions, n = 8.
The outcome of the pregnancy was significantly different according to whether the pregnancy was unplanned or desired (P < 0.001), with notably a higher proportion of elective abortions in unplanned pregnancies than in desired pregnancies (30.0% versus 0%, respectively) (Figure 3f). There were few notable obstetrical complications (twins n = 2, gestational diabetes n = 3, pre-eclampsia n = 2, preterm birth n = 2, risk of preterm delivery n = 1, post-partum peritonitis n = 1, cytomegalovirus seroconversion n = 1) and no malformation was reported in the infants. The infants were delivered by the vaginal route (n = 55; 80.9%) or by Caesarean section (n = 13; 19.1%) (Table 4).
Pregnancy attempts after breast cancer and time to pregnancy
Overall, since the end of treatment, 127 patients (24.6%) had attempted to become pregnant; 78 of these patients (61.4%) had at least one pregnancy, 52 patients had at least one live birth (40.9%). Of the 78 patients who achieved pregnancy, 20 (25.6%) were pregnant at inclusion in the study (five patients were pregnant on inclusion and also had one prior live birth during the follow-up period). For the 109 desired pregnancies, both median time to pregnancy (TTP) and median time to ongoing pregnancy were 3 months, and 68.7% of the patients had conceived in the 6 months following first attempt. Median TTP was significantly higher in patients aged 40 and older (median TTP: 15 months) than in younger women (median TTP <30 years: 1 month; 30 to 34 years: 3.5 months; 35 to 39 years: 3 months, P = 0.02) (Figure 3g). At study inclusion, 66 breast cancer patients (12.8%) declared that they were still trying to become pregnant.
Discussion
This large study on young breast cancer survivors provides important insights into patient attitudes and expectations towards fertility and pregnancy, as well as oncofertility practices nationwide in France.
International Society for Fertility Preservation–ESHRE–ASRM Expert Working Group Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives.
) but little was known to date about the prevalence of counselling in French breast cancer survivors. American data have shown that 47–68% receive information about fertility preservation (
). In France, three previous studies were found reporting rates of fertility counselling before gonadotoxic treatment. In a survey on 282 female cancer patients under 45 years old diagnosed in 2002, the rate of information on fertility prior to treatment was available for women presenting with treatment-induced infertility (n = 104, 36.9%) and showed that 31 patients (30.0%) had not been informed about the risk of infertility before treatment (
). In the VICAN study, which included 427 women aged from 18 to 40 years treated in 2010, 291 women (68.1%) reported having received no fertility preservation counselling before cancer treatment (
). Finally, one single-centre study conducted on 230 breast cancer patients 37 years old or younger treated between 2000 and 2010 showed that fertility concerns were not mentioned in 88.7% of all participants (
). However, the data were collected on medical reports, which might cause underestimation of the rate of fertility preservation counselling.
In line with the lack of information on chemotherapy-induced ovarian damage, almost one-third of the patients in this study cohort reported not undergoing FPP because this option was not offered (n = 149, 28.8%), or because too little time was available (n = 50, 9.7%). Both these obstacles to FPP are avoidable and represent actionable ways of improving patient care. On the other hand, a significant subset of women (n = 110, 21.3%) decided not to go through with FPP despite receiving counselling. FPP are costly and the low rates of referral in other studies have been linked to the financial burden (
). However, this bias can be ruled out here, because all French citizens are covered by a universal social security system guaranteeing the full reimbursement of fertility preservation fees.
Second, the main material cryopreservation technique used was oocyte cryopreservation (87.1%), which was much more frequently used than embryo (25.0%) or cortex cryopreservation (4.8%). This distribution seems to be clinically relevant as, in addition to yielding similar results to embryo freezing for efficacy (
), nevertheless the preservation of the woman's fertility (oocyte), rather than that of the couple (embryo), is particularly advantageous for single women or women whose relationships are breaking down. Surprisingly, the current results showed that approximately half of patients who had FPP with material preservation in the neoadjuvant setting had ovarian stimulation. This result was unexpected, as ovarian stimulation was not recommended before breast tumour excision in France neither at the time of the study (
Fertility preservation before breast cancer treatment appears unlikely to affect disease-free survival at a median follow-up of 43 months after fertility-preservation consultation.
), approximately 30% of the patients who underwent ovarian stimulation had IVM. As this rate is expected to increase due to the widespread use of neoadjuvant chemotherapy in young women, results of such techniques should be monitored closely to assess the efficacy of this procedure with long-term follow-up. Of note, only 15.1% of patients received GnRHa treatment together with chemotherapy. This low rate may be accounted for by the study period during which most of the patients were treated, as only 117 patients from the cohort (22.6%) were treated in or after 2017. Indeed, the pre-2017 guidelines considered GnRHa to be an experimental technique (
), and GnRHa have been considered options in the National Comprehensive Cancer Network (NCCN) and ASCO guidelines only since 2017 and 2018, respectively (
) in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency. However, because many inconsistencies exist between trials, two randomized controlled trials (
Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.
) reported significantly lower rates of post-chemotherapy ovarian failure in patients receiving GnRHa during chemotherapy, while others did not report any benefit from adding GnRHa, either in terms of amenorrhoea (
GIM Study Group Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival: a randomized clinical trial.
GIM Study Group Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival: a randomized clinical trial.
NCCN Guidelines, 2021. Adolescent and Young Adult (AYA) Oncology, NCCN Clinical Practice Guidelines in Oncology, Version 1.2022. doi.org/10.6004/jnccn.2017.0044
). All the patients in the current study were treated before 2019, and presumably, this treatment will be increasingly used in routine care as an ovary-protecting agent, in addition to other fertility preservation methods.
Third, with a rather short median time between the end of treatment and inclusion, 16.4% of the patients in the cohort had already experienced at least one pregnancy, most of which were natural conceptions, and only two pregnancies occurred after use of cryopreserved material. The occurrence of unplanned pregnancies (3.9%) was even more frequent than the use of ART (3.1%). These results highlight the statement that contraception is as important as fertility preservation in young breast cancer patients (
). In addition, the patient's satisfaction with fertility and contraceptive counselling was significantly associated with a lower likelihood of experiencing unplanned pregnancies. Properly addressing this topic could spare women the burden of undergoing elective abortions or abortions for medical reasons. Finally, for patients who became pregnant after breast cancer, the median time between pregnancy desire and its occurrence was short (3 months). Although the possibility that a subset of women currently attempting to become pregnant may remain genuinely infertile due to chemotherapy-induced ovarian damage cannot be formally excluded, the data provided here are reassuring concerning the likelihood of natural conception after breast cancer.
This study has several strengths. It reports one of the largest recent studies on fertility concerns and attitudes at breast cancer diagnosis based on patient-reported outcomes. It also provides unprecedented data on unplanned pregnancies, and time between pregnancy attempt and pregnancy occurrence, and provides a relative comparison in the number of pregnancies occurring after fertility preservation material reuse versus natural conceptions in a real-world cohort. It also has limitations. The data could have overestimated the information rate given in the entire young breast cancer population, as most of the FEERIC study women came from high-level socio-professional backgrounds. A similar bias has been reported in other studies recruiting patients via online networks (
). On the contrary, the underestimation of discussions related to fertility due to a recall bias cannot be excluded given the retrospective self-reported design of this study. Moreover, study inclusions performed by cancer centres or teaching hospitals might not exactly reflect the field reality. Finally, responders to the current study may represent a subset of breast cancer patients with a particular interest in fertility following breast cancer and contraceptive matters, and under-represent either patients who experienced relapse, patients in same-sex relationships or those who have already completed their parental project.
In conclusion, this work provides an overview of the fertility and pregnancy concerns in a selected cohort of young French breast cancer survivors. Considering the retrospective design of the study, results might be subject to recall bias; however, they point toward achievable care improvement. First, information about and access to FPP could be further improved. Healthcare professionals should be aware of the need to systematically offer fertility counselling to patients before breast cancer treatment. In addition, care pathways should be optimized to facilitate rapid access to FPP if desired by the patient and feasible. Finally, subject to the study's limitations, it is likely that contraception should also be considered a critical topic at breast cancer diagnosis and during the follow-up, as unplanned pregnancies represent a preventable burden for breast cancer survivors. Furthermore, the longitudinal follow-up of the FEERIC cohort for 3 years will make it possible to determine whether pregnancy rates differ between breast cancer survivors and matched controls.
Acknowledgements
The FEERIC study was funded by Institut National du Cancer (InCA), InCA-SHS, grant no. 2016-124, and is part of the Young Breast Cancer Project, funded by Monoprix. The funder was not involved in study design, or in the collection, analysis and interpretation of data, the writing of this article or the decision to submit it for publication. The authors thank all the study participants from the Seintinelles Research Network and Lili Sohn, who is the sponsor of the study.
Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.
Ovarian suppression with triptorelin during adjuvant breast cancer chemotherapy and long-term ovarian function, pregnancies, and disease-free survival: a randomized clinical trial.
Pregnancies during and after trastuzumab and/or lapatinib in patients with human epidermal growth factor receptor 2-positive early breast cancer: analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.
Fertility preservation before breast cancer treatment appears unlikely to affect disease-free survival at a median follow-up of 43 months after fertility-preservation consultation.
International Society for Fertility Preservation–ESHRE–ASRM Expert Working Group
Update on fertility preservation from the Barcelona International Society for Fertility Preservation-ESHRE-ASRM 2015 expert meeting: indications, results and future perspectives.
NCCN Guidelines, 2021. Adolescent and Young Adult (AYA) Oncology, NCCN Clinical Practice Guidelines in Oncology, Version 1.2022. doi.org/10.6004/jnccn.2017.0044
Anne-Sophie Hamy is a medical gynaecologist-oncologist, translational researcher and data analyst at Institut Curie in Paris. She co-directs the Residual Tumor and Response Rate Laboratory and specializes in fertility and pregnancy concerns of breast cancer survivors. She launched the FEERIC project (FErtility, prEgnancy, contRaceptIon after breast Cancer) through a web based collaborative research platform Seintinelles.
Key message
The FEERIC (FErtility, prEgnancy, contRaceptIon after breast Cancer in France) prospective study will provide real-life data on fertility and pregnancy issues of young women experiencing breast cancer. The enrolment questionnaire showed frequent natural conceptions after breast cancer and confirmed the importance of adequate oncofertility counselling, including information on contraception to avoid unplanned pregnancies.
Article info
Publication history
Published online: January 18, 2022
Accepted:
December 22,
2021
Received in revised form:
December 6,
2021
Received:
June 10,
2021
Declaration: The authors report no financial or commercial conflicts of interest.
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